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Drug Safety Impact of Regulatory Guidances and Drug Regulation on Risk Minimization Interventions in Drug Safety A Systematic Review Nkeng L, et al. Supplemental Digital Content This Supplemental Digital Content contains the appendices referred to in the full version of this article, which can be found at http://adisonline.com/drugsafety Adis © 2012 Springer International Publishing AG. All rights reserved. Appendix I – Literature Review Data Extraction Table Year 1 2000 Authors [Lit Review Source Ref #] Title Country of publication Region of implement as per article Product active ingredient Various requiring regular monitoring Therapeutic Area Intervention Type Patient Population Diverse EM – Communication All Women AE - SOC Corry et al [66] Hospitals do not inform GPs about medication that should be monitored. USA USA Various Diverse Diverse EM – Communication GBR EU Diverse 2 2000 Franic et al [77] Communicating the frequency of adverse drug reactions to female patients. 3 2000 Griffin et al [87] Prepulsid withdrawn from UK & US markets. GBR / USA INTL - 2UK / USA cisapride Alimentary tract and metabolism Cardiac Disorders Withdrawal All Morrison et al [121] Enhancing case managers' skills in the assessment and management of antipsychotic medication side-effects. AUS AUS Various Nervous System Diverse Education Program All USA USA Rotavirus Vaccine Various - vaccine GI Disorders Withdrawal Pediatric GBR EUSWE/NLD/ UK Biologicals Antineoplastic and immunomodulating agents Diverse Patient Registry All Alimentary tract and metabolism Cardiac Disorders EM – Communication All BBW All 4 5 6 7 8 9 10 2000 2000 2000 2000 2000 2000 2000 Silman et al [146] Withdrawal of rotavirus vaccine in the USA. Proposal to establish a register for the long term surveillance of adverse events in patients with rheumatic diseases exposed to biological agents: the EULAR Surveillance Register for Biological Compounds. Smalley et al [149] Contraindicated use of cisapride: impact of food and drug administration regulatory action. Offit et al [130] USA USA cisapride tolcapone/ entacapone Nervous System Hepatobiliary Disorders Watkins et al [161] COMT inhibitors and liver toxicity. USA INTL 3USA/EU/C AN FDA website [1] Food and Drug Administration. FDA talk paper: Janssen Pharmaceutica stops marketing cisapride in the US. USA USA cisapride Alimentary tract and metabolism Cardiac Disorders RD All Dahl et al [70] Pharmacogenetic methods as a complement to therapeutic monitoring of antidepressants and neuroleptics SWE Not indicated Various Nervous System Diverse Pharmacogenetics All Country of publication Lundmark et al [111] Title Therapeutic drug monitor of selective serotonin reuptake inhibitors influences clinical dosing strategies and reduces drug costs in depressed elderly patients. Region of implement as per article SWE EU SSRI's Nervous System 2000 Lundmark et al [110] Therapeutic drug monitoring of sertraline: variability factors as displayed in a clinical setting. SWE Not indicated sertraline 2000 Lotronex.com website [2] Prescribing program for Lotronex. Pharmacist information. USA USA 2000 Celgene.com website [3] Celgene. S.T.E.P.S. prevention and protection. Year Authors [Lit Review Source Ref #] 2000 12 13 11 14 15 2001 TDM Geriatric Nervous System Diverse TDM All alosetron Alimentary tract and metabolism Withdrawal Women thalidomide Antineoplastic and immunomodulating agents GI Disorders Congenital, familial and genetic disorders RD / Education Program Women Unk Not indicated [4] GBR Not indicated Various Diverse Diverse Black Triangle Symbol USA Not indicated Various Diverse Diverse BBW Unk DNK Not indicated Various Diverse Drug Interaction Other Unk All Not indicated [5] 17 2001 Bourke et al [55] Joint charts in drug handling. Toward increased drug safety. Brown et al [57] The incidence and reporting of adverse drug reactions in the Division of Psychiatry. 19 2001 Feltelius et al [74] New drugs require new follow-up surveillance. 20 2001 Kilborn et al [99] Registry for torsades de pointes with drug treatment exists. 2001 Diverse Failings in treatment advice, SPCs and black triangles. 2001 21 Patient Population AE - SOC USA 16 2001 Intervention Type Therapeutic Area USA Black-box' warning and letter are insufficient to protect patients, study finds. 18 Product active ingredient Singer et al [147] Cardiac toxicity of arsenic trioxide. Various Diverse Diverse Black Triangle Symbol SWE Not indicated TNF-blockers Antineoplastic and immunomodulating agents Diverse Other All USA Not indicated Various Diverse Diverse Patient Registry All arsenic trioxide Antineoplastic and immunomodulating agents Cardiac Disorders BBW All GBR EU USA USA Year 22 2001 Authors [Lit Review Source Ref #] Title Women CAN INTL Various Diverse Diverse bosentan CV system Hepatobiliary Disorders Pharmacogenetics RD/ patient registry / Medication Guide USA alosetron HCl Alimentary tract and metabolism GI Disorders EM Medication guide Women FRA EU methylphenid ate Nervous System Combinati on-Not specified RD / Restricted Prescription Pediatric USA USA droperidol Alimentary tract and metabolism Cardiac Disorders BBW All USA USA Various Nervous System Diverse IC All GBR EU Various Diverse Drug Interaction Other All Blood and blood forming organs Blood and Lymphatic system disorders EM – Communication All Pharmacogenetics- The therapeutic drug monitoring of the future? Thompson [154] Bosentan enters market with risk management program. Charatan [61] FDA advisory panels recommend Lotronex be put back on market. Methylphenidate (Ritalin) use in France. [French]. 27 2002 Frances et al [75] 28 2002 Horowitz et al [91] 29 2002 Masand et al [115] Droperidol--behind the black box warning. Prescribing conventional antipsychotics in the era of novel antipsychotics: informed consent issues. Magnus et al [112] GPs’ views on computerized drug interaction alerts: questionnaire survey. 2002 IC / EMMedication Guide Dermatologicals Ensom et al [72] 31 All isotretinoin 2001 2002 Patient Population USA 24 30 Intervention Type TDM / EMHCP Communication USA Schwetz [142] 2002 AE - SOC Graham et al [85] 2001 26 Therapeutic Area Hepatobiliary Disorders Congenital, familial and genetic disorders 23 2002 Product active ingredient Liver enzyme monitoring in patients treated with troglitazone. New measures to manage risks associated with accutane. 25 Country of publication Region of implement as per article Singapore H S A website [36] HSA product safety alert. Update on Eprex and pure red cell aplasia. USA USA USA SGP USA USA SGP trioglitazone HSA (ESA) Alimentary tract and metabolism All All 32 33 34 35 36 37 Year Authors [Lit Review Source Ref #] 2002 Australia TGA website [37] Title Country of publication Region of implement as per article 2002 France AFSSPS website [7] 2002 Health Canada website [11] Epoetin alfa and pure red cell aplasia. Australian adverse drug reactions bulletin. Agence Francaise de Securite Sanitaire des Produits de Sante, les lettre aux prescripteurs, Eprex®: information importante de pharmacovigilance. 17 December 2002 Important safety information— EPREXTM (epoetin alfa)—JanssenOrtho Inc. Health Canada. 26 November 2001 FDA website [13] Danco Laboratories. Open letter to health care providers (Apr. 19, 2002). (Dear doctor letter) USA Kivlahan et al [100] Developing a comprehensive electronic adverse event reporting system in an academic health center. Not indicated [16] Patients to have new role in improving methotrexate safety says NPSA. SWE EU USA USA 2002 2002 2003 AUS AUS Product active ingredient epoietin Therapeutic Area Blood and blood forming organs AE - SOC Blood and Lymphatic system disorders Intervention Type Patient Population EM – Communication All epoietin Blood and blood forming organs epoietin Blood and blood forming organs Blood and Lymphatic system disorders Blood and Lymphatic system disorders USA mifespristone Genitourinary system and sex hormones Pregnancy, puerperiu m etc. EM – Communication Women USA USA Various Diverse Diverse Other All GBR Not indicated methotrexate Alimentary tract and metabolism Unknown Black Triangle Symbol All nefazodone Nervous System Hepatobiliary Disorders Withdrawal All dofetilide CV system Cardiac Disorders RD / Education All venlafaxine Nervous System Psychiatric disorders EM – Communication Pediatric FRA CAN EU CAN EM – Communication All EM – Communication All 38 2003 Edwards [71] Withdrawing drugs: nefazodone the start of the latest saga. 39 2003 LaPointe et al [49] Evaluation of the dofetilide riskmanagement program. Not indicated [15] Suicide risk warning for children now extended by CSM to cover venlafaxine. GBR Not indicated DEU USA trycyclic antidepressants Nervous System Diverse TDM All USA USA alendronate sodium Alimentary tract and metabolism Diverse Education Program Women 40 2003 41 2003 Muller et al [122] Therapeutic drug monitioring of tricyclic antidepressants: how does it work under clinical conditions? 42 2003 Fosamax.com website [17] Merck. Paget’s patient support program. Year Authors [Lit Review Source Ref #] Title Country of publication Region of implement as per article GBR Not indicated paroxetine Product active ingredient AE - SOC Intervention Type Patient Population Nervous System Unknown EM – Communication Unk BBW Pediatric Withdrawal RD /Physician registry / Patient registry/ Education All All TDM All BBW All IC / TDM for at risk patients All IC All EM – Communication All EM – Communication All Therapeutic Area 43 2004 Not indicated [18] Paroxetine review makes safety warnings. 44 2004 Check [62] US panel recommends 'black box' warnings for antidepressants. USA USA Various Nervous System Psychiatric disorders 45 2004 Cockey [65] Ephedra banned. USA USA ephedrine Alimentary tract and metabolism Cardiac Disorders Congenital, familial and genetic disorders 46 2004 Crawford [68] Licensing thalidomide in Australia. AUS AUS thalidomide Antineoplastic and immunomodulating agents 47 2004 Fraunfelder [79] Twice-yearly exams unnecessary for patients taking quetiapine. USA USA quetiapine Nervous System 48 2004 Gebhart [82] Calls mount for black box warning on fluoroquinolones. USA USA Fluoroquinolones Antiinfective for systemic use Endocrine Disorders Metabolism and nutrition disorders 2004 Laugharne [104] Informing patients about tardive dyskinesia: A survey of clinicians' attitudes in three countries. Nervous System Nervous System disorder 2004 Schachter et al [140] Psychiatrists' attitudes about and informed consent practices for antipsychotics and tardive dyskinesia. FDA website [19] US Food and Drug Administration: 2004 Safety Alert: Zyprexa (olanzapine) Calhoun et al [59] Challenges to the FDA approval of mifepristone. 49 50 51 52 2004 2004 AUS CAN USA USA EU CAN USA USA Various Various Nervous System olanzapine Nervous System mifespristone Genitourinary system and sex hormones Nervous System disorder Metabolism and nutrition disorders Unknown 53 54 55 56 Year Authors [Lit Review Source Ref #] 2004 Baumann et al [51] 2004 2005 2005 Title Therapeutic monitoring of psychotropic drugs - An outline of the AGNP-TDM expert group consensus guideline. CHE EU Psychotropic drugs Nervous System USA USA sodium oxybate (GHB) The Xyrem risk management program. Not indicated [20] Calcineurin inhibitors: Black box warning for pimecrolimus and tacrolimus. [German]. DEU Not indicated Not indicated [21] FDA advisory committees recommend marketing of COX-2 inhibitors with 'black box' warning. USA USA USA USA USA USA 57 2005 Not indicated [22] 58 2005 Not indicated [23] Stronger warnings needed for asthma treatments. 2005 FDA website [26] 60 2005 Melnikow et al [119] 61 2005 Baumann et al [52] Food and Drug Administration, “2005 Safety Alert: Natrecor (nesiritide),” 13 July 2005. Preferences of Women Evaluating Risks of Tamoxifen (POWER) study of preferences for tamoxifen for breast cancer risk reduction. The AGNP-TDM Expert Group Consensus Guidelines: focus on therapeutic monitoring of antidepressants. 62 2005 Beltrani [53] The "black boxing" of protopic and elidel. 2005 Bensouda-Grimaldi et al [54] Isotretinoin: compliance with recommendations in childbearing women. 63 Product active ingredient Fuller et al [80] Impotence drugs receive blindness warning. 59 Country of publication Region of implement as per article USA USA Intervention Type Patient Population Diverse TDM All Nervous System Diverse RD All pimecrolimus / tacrolimus Antineoplastic and immunomodulating agents Neoplasms BBW All COX inhibitors Nervous System Cardiac Disorders BBW All CV system Eye Disorders EM – Communication Men Respiratory system GI Disorders BBW All nesiritide CV system Renal and urinary disorders EM – Communication All Diverse Education Program Women tadalafil/ vardenafil/ sidenafil fluticasone propionate/sa lmeterol/ formoterol / salmeterol Therapeutic Area AE - SOC USA USA tamoxifen Antineoplastic and immunomodulating agents CHE EU Various Nervous System Diverse TDM All USA USA tacrolimus / pimecrolimus Dermatologicals Neoplasms BBW Pediatric Dermatologicals Congenital, familial and IC / Medication Guide Women FRA EU isotretinon Year 64 65 66 67 68 69 70 71 72 2005 2005 2005 2005 2005 2005 2005 2005 2005 Authors [Lit Review Source Ref #] Title Hetland et al [90] "Therapeutic drug monitoring" a strategy for improving drug safety in child and adolescent psychiatry and psychotherapy. Routine database registration of biological therapy increases the reporting of adverse events twentyfold in clinical practice. First results from the Danish Database (DANBIO). Gerlach et al [83] Country of publication Region of implement as per article Product active ingredient DEU Not indicated Various Nervous System Biologicals Antineoplastic and immunomodulating agents Therapeutic Area Intervention Type Patient Population Diverse TDM Pediatric Diverse Patient Registry All AE - SOC genetic disorders DNK EU Hugman [92] From the Uppsala monitoring centre: a review of viewpoint part 1 and part 2. SWE INTL - ALL Who members Various Diverse Diverse Lederer et al [105] Reduction in anticoagulation-related adverse drug events using a triggerbased methodology. USA USA warfarin Blood and blood forming organs Shatin et al [144] Impact of mailed warning to prescribers on the co-prescription of tramadol and antidepressants. Cotter et al [67] FDA website [28] FDA website [33] FDA website [29] New restrictions on celecoxib (Celebrex) use and the withdrawal of valdecoxib (Bextra). Dear Health Care Provider letter. Important drug warning and new information for Clozaril (clozapine). Novartis Pharmaceuticals Corporation, December 2005. FDA, “FDA Public Health Advisory: Suicidality in Adults Being Treated with Antidepressant Medications” 30 June 2005. US Food and Drug Administration: FDA Public Health Advisory: Deaths with antipsychotics in elderly patients with behavioral disturbances, April 11, 2005, accessed January 30, 2006. USA USA CAN INTLCAN/US USA USA USA USA USA USA tramadol celecoxib clozapine Various Various Diverse EM – Communication Other Trigger based method All Nervous System Cardiac Disorders EM – Communication All Nervous System Cardiac Disorders EM – Communication All Nervous System Diverse EM – Communication All Nervous System Psychiatric disorders EM – Communication Adults Unknown EM – Communication Geriatric Nervous System All Year 73 74 75 2005 2005 2005 Authors [Lit Review Source Ref #] Title Country of publication Region of implement as per article Product active ingredient AE - SOC Intervention Type Patient Population Nervous System Cardiac Disorders EM – Communication All atomexitine Nervous System Psychiatric disorders EM – Communication Pediatric doxorubicin Antineoplastic and immunomodulating agents Diverse Education Program All All Therapeutic Area Grenieret al [86] European COX-2 review recommends new warnings. The Food and Drug Administration. Public Health Advisory: suicidal thinking in children and adolescents being treated with Strattera (atomoxetine). 29 September 2005. Nursing support program to decrease or prevent side effects of pegylated liposomal doxorubicin (PLD) in patients with recurrent epithelial ovarian cancer (REOC). USA USA Various Diverse Diverse EM – Communication Not indicated [24] Not indicated [31] GBR EU USA USA CAN Not indicated COX inhibitors 76 2005 Mazor et al [116] Communicating safety inforamtion to physicians: an examination of Dear Dr. Letters. 77 2006 Aaronson [48] The "black box" warning and allergy drugs. USA USA Various Alimentary tract and metabolism Diverse BBW All Feldstein et al [73] Improved therapeutic monitoring with several interventions: a randomized trial. USA USA Various Diverse Diverse TDM All Schussel et al [141] Prescribing of COX-2 inhibitors in Germany after safety warnings and market withdrawals. EU COX inhibitiors Nervous System Cardiac Disorders EM – Communication All Antineoplastic and immunomodulating agents Neoplasms Patient Registry All Nervous System Cardiac Disorders BBW All Diverse Diverse BBW All 78 79 80 81 82 2006 2006 2006 2006 2006 DEU Sheridan [145] Tysabri back on market. USA USA Wechsler [164] Advisory committee prompts FDA to consider black box warning for ADHD drugs. USA USA natalizumab Amphetamine -based drugs for ADHD, such as Adderall and Dexedrine Lasser et al [103] Adherence to black box warnings for prescription medications in outpatients USA USA Various Year 83 2006 Authors [Lit Review Source Ref #] FDA website [34] Title Medication Guide: Coumadin tablets (warfarin sodium tablets, USP) crystalline. 2006. Country of publication USA Region of implement as per article USA warfarin Therapeutic Area AE - SOC Blood and blood forming organs Diverse Dermatologicals Congenital, familial and genetic disorders Jones [96] Update on isotretinoin and the iPLEDGE system. Morrato et al [120] Effectiveness of risk management plans: a case study of pemoline using pharmacy claims data. USA USA pemoline Nervous System Hepatobiliary Disorders 2007 Muller et al [123] Therapeutic drug monitoring for optimizing amisulpride therapy in patients with schizophrenia. DEU EU amisulpride Nervous System Diverse 87 2007 Munzenberger et al [124] Safety of topical calcineurin inhibitors for the treatment of atopic dermatitis. Antineoplastic and immunomodulating agents 88 2007 Oppenheimer et al [131] 89 2007 Recupero et al [135] Impact of recent black box warnings in the allergy world. Managing risk when considering the use of atypical antipsychotics for elderly patients with dementia-related psychosis. 90 2007 Singh [148] Valente et al [157] 84 85 86 91 2007 2007 2007 USA Not indicated Product active ingredient isotretinoin Intervention Type EM Medication guide Patient registries / Pharmacist registries Physician registriesPregnancy BBW Patient Population Unk Women All Mainly Pediatric All Neoplasms TDM EM Medication Guide/ Black Box Warning Alimentary tract and metabolism Neoplasms BBW All USA USA USA USA topical calcineurin inhibitors long-acting agonists (LABAs) and calcineurin inhibitors USA USA Various Nervous System Cardiac Disorders BBW Geriatric The FDA black box for EPO: what should nephrologists do? USA USA epoietin Blood and blood forming organs Neoplasms BBW All Nurses improve medication safety with medication allergy and adverse drug reports. USA Not indicated Various Diverse Diverse Education Program All All Year Authors [Lit Review Source Ref #] 92 2007 Wysowski et al [168] 93 2007 Tanne [153] 94 2007 FDA website [35] FDA places “black box” warning on antidiabetes drugs. The Food and Drug Administration.FDA proposes new warnings about suicidal thinking, behavior in young adults who take antidepressant medications. 2 May 2007. FDA webite [47] FDA ALERT - Simvastatin Used With Amiodarone. Not indicated [39] Tegaserod: withdrawal from the world market. A treatment for constipation with cardiovascular adverse effects. Castaneda et al [60] RevAssist: A comprehensive risk minimization programme for preventing fetal exposure to lenalidomide. Mallal et al [114] HLA-B*5701 Screening for Hypersensitivity to Abacavir. 95 96 97 98 2008 2008 2008 2008 Title Bleeding complications with warfarin use: A prevalent adverse effect resulting in regulatory action. 99 2008 Jennings et al [94] 100 2008 Naso [126] Reducing anticoagulant medication adverse vents and avoidable patient harm. Optimizing patient safety by preventing combined use of intramuscular olanzapine and parenteral benzodiazepines. FDA website [43] Suicidality and antiepileptic drugs: FDA alert. 101 2008 Country of publication Region of implement as per article Product active ingredient USA USA warfarin USA USA USA Intervention Type Patient Population Blood and blood forming organs AE - SOC Blood and Lymphatic system disorders BBW All Various Alimentary tract and metabolism Cardiac Disorders BBW All USA Various Nervous System Psychiatric disorders BBW Pediatric USA USA simvtatin & amiodarone Alimentary tract and metabolism/ CV Musculosk eletal EM – Communication All FRA INTL tegaserod Alimentary tract and metabolism Withdrawal All lenalidomide Antineoplastic and immunomodulating agents Cardiac Disorders Congenital, familial and genetic disorders RD Women abacavir Antiinfective for systemic use Immune system disorders TDMPharmacogenomics All Diverse Education Program / TDM All USA AUS USA INTL Therapeutic Area USA USA Anticoagulant Blood and blood forming organs USA USA olanzapine Nervous System Drug Interaction Other All Nervous System Psychiatric disorders EM – Communication All USA USA Various Year Authors [Lit Review Source Ref #] 102 103 104 105 106 107 108 109 Country of publication Region of implement as per article 2008 von Moos et al [160] Title Pegylated liposomal doxorubicinassociated hand-foot syndrome: recommendations of an international panel of experts. CHE INTL 2008 Wright [167] Tell patients about yellow card reporting. GBR EU 2008 UK MHRA website [42] 2008 2008 2008 2008 2009 Product active ingredient Intervention Type Patient Population doxorubicin Antineoplastic and immunomodulating agents AE - SOC Metabolism and nutrition disorders Education Program All Various Diverse Diverse Patient alert card Unk exenatide Alimentary tract and metabolism Hepatobiliary Disorders EM – Communication All Various Antineoplastic and immunomodulating agents Neoplasms EM – Communication All moxifloxacin Antiinfective for systemic use Hepatobiliary Disorders EM – Communication All Hepatobiliary Disorders Diverse EM – Communication EM – Communication / Medication Guides All Pediatric Therapeutic Area FDA website [6] MHRA Drug Safety Update on Exenatide . Tumor necrosis factor-alpha blockers (TNF blockers), Cimzia (certolizumab pegol), Enbrel (etanercept), Humira (adalimumab), and Remicade (infliximab) Sept 2008. Prinset al [132] Novel side effects of moxifloxacin: making a balanced decision again. FDA website [46] Information on exenatide (marketed as Byetta®). USA USA exenatide Alimentary tract and metabolism Lee et al [106] Drug-risk communication to pharmacists: Assessing the impact of risk-minimization strategies on the practice of pharmacy. USA USA Various Diverse Franke et al [78] 110 2009 McCann et al [117] 111 2009 Murray et al [125] High-alert medications in the pediatric intensive care unit. Patients' perceptions and experiences of using a mobile phone-based advanced symptom management system (ASyMS) to monitor and manage chemotherapy related toxicity. Effect of a pharmacist on adverse drug events and medication errors in outpatients with cardiovascular disease. GBR EU USA USA NLD Not indicated USA USA All Various Diverse Diverse EM – Communication Metabolism and nutrition disorders Other All Diverse Education Program All GBR EU Various Antineoplastic and immunomodulating agents USA USA Various Diverse Country of publication Region of implement as per article Product active ingredient Year Authors [Lit Review Source Ref #] 112 2009 Prinz [133] The EMEA suspends approval of Raptiva for psoriasis. Commentary. DEU EU efalizumab 113 2009 Pugashetti et al [134] Efalizumab discontinuation: a practical strategy. USA INTL 114 2009 Richins [137] Regulation of smoking cessation drugs by the Food and Drug Administration. USA Effectiveness of safety warnings in atypical antipsychotic drugs: an interrupted time-series analysis in Spain. Title 115 2009 Sanfelix-Gimeno et al [139] 116 2009 Traynor [155] 117 2009 Van Geffen et al [158] Close vote by FDA advisers favors propoxyphene withdrawal. Patients' perceptions of information received at the start of selective serotonin-reuptake inhibitor treatment: Implications for community pharmacy. 118 2009 Yetzer et al [169] Medication safety series: take charge! Hitt, E [46] Botulinum Toxin Safety Warnings Updated and Name Changes Issued 119 2009 AE - SOC Intervention Type Patient Population Dermatologicals Neoplasms Withdrawal All efalizumab Dermatologicals Neoplasms Withdrawal All USA varenicline, buproprion Nervous System Diverse All ESP EU olanzapine and risperidone Nervous System Diverse BBW EM Communicat ion / Prior authorisation policy All USA USA propoxyphene Nervous System Cardiac Disorders BBW All NLD EU SSRI inhibitors Nervous System Diverse IC All USA Not indicated Various Diverse Diverse Education Program All USA botulinum toxin Musculoskeletal system Diverse EM – Communication All USA Therapeutic Area LITERATURE REVIEW SOURCE REFERENCES 1. Food and Drug Administration. 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Fatal hypersensitivity reactions are a described risk associated with the use of abacavir. Recent reports indicate that severe or fatal hypersensitivity reactions can occur within hours after Ziagen reintroduction in patients who have no identified history or unrecognized symptoms of hypersensitivity to abacavir therapy. 2000 Regulatory Authority/Reg ion Product active ingredient abacavir sulfate Fatal hypersensitivity reactions alosetron HCl Constipation, that in a few cases have resulted in serious sequelae and infrequent reports of ischemic colitis FDA-USA autologous cultured chondrocytes Narrowed indications for Carticel to second line therapy for the repair of cartilage defects of the femoral condyle Withdra wal RDrestrictio n to 2nd line therapy/ DHCPL FDA-USA basilixima Severe acute hypersensitivity reactions EM capecitabine Renal Insufficiencycontraindicated in patients with renal impairment FDA-USA cisapride Serious cardiac arrhythmias including ventricular tachycardia, ventricular fibrillation, torsades de pointes, and QT prolongation FDA-USA divalproex sodium FDA-USA etanercept FDA-USA Lotronex (alosetron HCl) Tablets [UPDATE November 29, 2000] Glaxo Wellcome withdraws Lotronex tablets from the market. New safety information and labeling changes for Lotronex. This new information pertains to reports of constipation, that in a few cases have resulted in serious sequelae and infrequent reports of ischemic colitis occurring in association with the use of Lotronex. 2 2000 FDA-USA Carticel (autologous cultured chondrocytes) Genzyme notifies health professionals of changes in the product labeling for Carticel. The change narrows the indication for Carticel to second line therapy for the repair of cartilage defects of the femoral condyle. 3 2000 Simulect (basiliximab) Postmarketing reports of seventeen cases of severe acute hypersensitivity reactions, including anaphylaxis, occurring in patients following the administration of Simulect. Other reactions may include hypotension, tachycardia, cardiac failure, dyspnea, wheezing, bronchospasm, pulmonary edema, respiratory failure, urticaria, rash, pruritus, and/or sneezing. The onset of these reactions occurred within 24 hours following initial exposure and/or following re-exposure to Simulect. 4 2000 Xeloda (capecitabine) (11/28/2000) Important safety-related changes to the prescribing information concerning the use of Xeloda in patients with renal impairment at baseline. 5 2000 FDA-USA Propulsid (cisapride) Health professionals are notified that Janssen Pharmaceutica Inc., has announced it will stop marketing Propulsid in the United States as of July 14, 2000. The effective date of the voluntary action is intended to provide adequate time for patients and their health care providers to make alternative treatment decisions. 6 7 2000 2000 Depakote (divalproex sodium delayed-release tablets) / valproate acid and Depakote (divalproex sodium coated particles in capsules) Update to the WARNINGS section in the labeling. Cases of life-threatening pancreatitis have been reported in both children and adults receiving valproate. Some of the cases have been described as hemorrhagic with a rapid progression from initial symptoms to death. Enbrel (etanercept) May 2000 Post-marketing reports of adverse events of rare cases of nervous system disorders including demyelinating disorders such as multiple sclerosis, myelitis, and optic neuritis have been reported in patients with rheumatoid arthritis who have received Enbrel therapy. 8 2000 Safety Issue (AE) Intervention Type Life-threatening pancreatitis Rare cases of nervous system disorders including demyelinating disorders such as multiple sclerosis, myelitis, and optic neuritis EM TDM / EM Voluntar y withdraw al/ BBW/TD M/ EMDHCPL EM EM Year 9 2000 10 2000 11 2000 Title Fluothane (halothane, U.S.P.) Wyeth-Ayerst Laboratories notifies health professionals of changes to the prescribing information for Fluothane. The changes are intended to highlight and expand upon information already presented in the labeling for Fluothane. Important new information has been included to reflect current scientific opinion, accepted standards of care, and safety information in an effort to ensure the anesthesia care provider remains informed in making treatment decisions regarding the administration of Fluothane. Antiviral drugs Orlaam (Levomethadyl Acetate HCl) Apr 2001 Audience: Addiction treatment specialists Healthcare professionals are notified about serious cardiac adverse events, including QT prolongation and severe cardiac arrhythmia, associated with Orlaam (levomethadyl acetate HCl), a drug for opiate addiction treatment. Roxane Laboratories, Inc. has made important changes to the Orlaam label, adding a black box warning, and changes to the precautions, contraindications, and drug interactions sections. Regulatory Authority/Reg ion 2000 halothane FDA-USA Influenza Q-T Interval Prolongation and Arrythmias Important clinical decisions that need to be made when considering use of anti-viral drugs for signs and symptoms of influenza. FDA-USA Levomethadyl Acetate HCl Serious cardiac adverse events, including QT prolongation and severe cardiac arrhythmia EM FDA-USA mesoridazine besylate Prolong the QTc interval BBW FDA-USA nevirapine Continued reports of severe, life-threatening and in some cases, fatal hepatotoxicity that have been reported from clinical trials and postmarketing use EM FDA-USA Phenylpropanola mine HCl Risk of hemorrhagic stroke EM FDA-USA Pooled Plasma, [Human] Solvent Detergent Treated FDA-USA Rho(D) Immune Globulin Intravenous (Human Death due to thrombotic events or excessive bleeding during the transplant procedure Rho(D) positive patients treated with WinRho SDF should be monitored for signs and/or symptoms of intravascular hemolysis (IVH trastuzumab Hypersensitivity reactions, infusion reactions, and pulmonary reactions. Viramune (nevirapine) (11/9/2000) The existing labeled warnings for the risk of hepatotoxicity with Viramune treatment have been strengthened in response to continued reports of severe, life-threatening and in some cases, fatal hepatotoxicity that have been reported from clinical trials and postmarketing use with Viramune. 13 14 2000 2000 Phenylpropanolamine HCl (PPA) FDA is taking steps to remove phenylpropanolamine HCl from all drug products due to the risk of hemorrhagic stroke. FDA has significant concerns because of the seriousness of stroke and the inability to predict who is at risk. PLAS+SD (Pooled Plasma, [Human] Solvent Detergent Treated) A cluster of serious adverse events, in six (6) patients, occurring at a single institution during orthotopic liver transplantation. All six patients died due to thrombotic events or excessive bleeding during the transplant procedure. All patients received intra-operative PLAS+SD along with multiple other blood components. Letter reviews storage and handling of PLAS+SD. 15 16 17 2000 2000 2000 WinRho SDF (Rho(D) Immune Globulin Intravenous (Human)) Health professionals are notified of updated prescribing and treatment information regarding use of WinRho SDF™ (Rho(D) Immune Globulin Intravenous (Human)). Based on a recent assessment of adverse events following administration of WinRho to immune thrombocytopenic purpura (ITP) patients positive for Rho(D) antigen (D-positive), we have revised the package insert to state that "Rho(D) positive patients treated with WinRho SDF should be monitored for signs and/or symptoms of intravascular hemolysis (IVH), clinically compromising anemia, and renal insufficiency." Herceptin (trastuzumab) May 2000 Follow-up to May letter. Changes to BOXED WARNINGS, WARNINGS, and ADVERSE REACTIONS sections. MAY LETTER: Health professionals are notified of 62 postmarketing reports of serious adverse events related to the use of Herceptin. The serious adverse events are characterized by one or more of the following categories: hypersensitivity reactions, infusion reactions, and pulmonary reactions. Fifteen (15) patients died and nine (9) of these patients had onset of symptoms within 24 hours of infusion. Safety Issue (AE) Intervention Type FDA-USA Serentil (mesoridazine besylate) Important labeling changes for all dosage forms of Serentil including a boxed WARNING to advise clinicians that Serentil has been shown to prolong the QTc interval in a dose related manner and drugs with this potential have been associated with torsade de pointes-type arrhythmias and sudden death. 12 Product active ingredient FDA-USA EM EM EM EM BBW modificat ion Year 18 Title triCitrasol Cytosol Labs and Medcomp are voluntarily recalling triCitrasol, an unapproved product that has been used to keep bloodlines open and may cause death when infused into patients. FDA has learned that a patient died of cardiac arrest shortly after triCitrasol, a 46.7% concentration of sodium citrate anticoagulant, was injected full strength into a hemodialysis permanent blood access catheter that had just been implanted. Rapid or excessive infusion of citrate solutions can cause fatal heart arrhythmias, seizures or bleeding due to loss of blood calcium. 2000 Regulatory Authority/Reg ion Product active ingredient Safety Issue (AE) FDA-USA triCitrasol Death due to cardiac arrest Voluntar y withdraw al FDA-USA troglitazone Liver toxicity Withdra wal FDA-USA zafirlukast Hepatic dysfunction; arthralgia and myalgia EM zanamivir Additional updated safety information/ more clearly reflect that serious respiratory adverse events. EM amiodarone HCl Potentially fatal or developmental side effects associated with use of this product in neonatal and infant pediatric patients EM FDA-USA arsenic trioxide QTc prolongation with torsade de pointes arrhythmia and sudden death EMDHCPL FDA-USA Blood products, plasmacontaining products Transfusion Related Acute Lung Injury (TRALI) EM capecitabine Drug interaction increased prothrombin time with warfarin use EM Rezulin (troglitazone) Parke-Davis/Warner Lambert agree to FDA's request to withdraw Rezulin from the market. FDA asked Parke-Davis/Warner Lambert to withdraw Rezulin after a review of recent safety data on Rezulin and two similar drugs, Avandia (rosiglitazone) and Actos (pioglitazone), showed that Rezulin is more toxic to the liver than the other two drugs. Data to date show that Avandia and Actos, both approved in the past year, offer the same benefits as Rezulin without the same risk. 19 2000 20 2000 21 Accolate (zafirlukast) Revisions to the Precautions and Adverse Events sections of the labeling for Accolate. Relenza (zanamivir for inhalation) Health professionals are notified of important revisions to the safety labeling for Relenza. The labeling has been revised to more clearly reflect that serious respiratory adverse events have been reported in patients with or without known underlying respiratory disease, and to incorporate additional updated safety information. 2000 FDA-USA Cordarone I.V. (amiodarone HCl) Audience: Neonatologists, Pediatricians, Cardiologists, and other healthcare professionals Wyeth-Ayerst Pharmaceuticals notified health care professionals of two safety-related changes to the Cordarone IV (amiodarone HCl) prescribing information, describing potentially fatal or developmental side effects associated with use of this product in neonatal and infant pediatric patients. Wyeth-Ayerst Pharmaceuticals is aware that Cordarone IV is used off-label to treat arrhythmias in pediatric patients. The safety and efficacy of amiodarone IV in the pediatric population have not been established; therefore, its use in pediatric patients is not recommended. 22 2001 FDA-USA Arsenic trioxide Healthcare providers reminded to closely monitor patients on arsenic trioxide CTI has issued a "Dear Health Care Provider" letter reminding clinicians that QTc prolongation with torsade de pointes arrhythmia and sudden death have been associated with the use of arsenic trioxide. An article published recently in Blood (Unnikrishnan, et al, 1 March 2001;97:1514–1516) describes prolonged QT interval and torsade de pointes in 3 patients being treated with arsenic trioxide for acute myeloid leukemia (AML). The arsenic trioxide used in the reported study was not Cell Therapeutics’ Trisenox™ (arsenic trioxide) injection. The current Trisenox label emphasizes the importance of ECG and electrolyte monitoring prior to and during therapy in patients given arsenic trioxide. 23 2001 Transfusion Related Acute Lung Injury (TRALI) Audience: Health Professionals, particularly Respiratory Specialists FDA alerts health professionals to the risk of Transfusion Related Acute Lung Injury (TRALI) in patients who receive blood products, particularly plasma-containing products. TRALI is a serious pulmonary syndrome that can lead to death if not recognized and treated appropriately. Recognition of symptoms and immediate treatment are imperative. 24 2001 Xeloda (capecitabine) Audience: Oncologists, Pharmacists, and other healthcare professionals FDA and Roche have added a BLACK BOX WARNING and strengthened the PRECAUTIONS section in the label for Xeloda, indicated for the treatment of colorectal and breast cancer. A clinically important XELODA-Warfarin drug interaction was demonstrated in a clinical pharmacology trial. Postmarketing reports have shown clinically significant increases in prothrombin time and INR in patients who were stabilized on anticoagulants at the time XELODA was introduced. Patients receiving concomitant capecitabine and oral coumarin-derivative anticoagulant therapy should have their anticoagulant response (INR or prothrombin time) monitored frequently in order to adjust the anticoagulant dose accordingly. The Patient Package Insert was also revised to reflect this new safety information. 25 2001 Intervention Type FDA-USA Year 26 Title Baycol (cerivastatin sodium tablets) Audience: Primary Care Physicians and other health professionals Bayer Corporation has notified healthcare professionals of changes in the prescribing information for Baycol, providing more specific guidance on initiating therapy and dose adjustment in order to reduce the risk of myopathy and rhabdomyolysis. 2001 Regulatory Authority/Reg ion Product active ingredient Safety Issue (AE) Intervention Type FDA-USA cerivastatin sodium Risk of myopathy and rhabdomyolysis. Withdra wal/EM FDA-USA droperidol QT prolongation and/or torsades de pointes BBW FDA-USA infliximab Tuberculosis and other serious opportunistic infections, including histoplasmosis, listeriosis, and pneumocystosis BBW FDA-USA isotretinoin Teratogenicity IC/ EM(MG) linezolid Myelosuppression (including anemia, leukopenia, pancytopenia and thrombocytopenia) EM FDA-USA miconazole Drug interaction increased prothrombin time with warfarin use EM FDA-USA oprelvekin Papilledem in the pediatric population EM Inapsine (droperidol) Audience: Anesthesiologists and other healthcare professionals FDA and Akorn Pharmaceuticals added a "black box" warning and strengthened the WARNINGS and PRECAUTIONS sections in the labeling for Inapsine, a tranquilizer used as a premedication for anesthesia, as treatment for nausea after anesthesia, and for sedation of agitated patients. Cases of QT prolongation and/or torsades de pointes have been reported at doses at or below recommended doses. Some cases have occurred in patients with no known risk factors for QT prolongation and some cases have been fatal. 27 2001 Remicade (infliximab) - Black Box Warning Audience: Rheumatologists, Gastroenterologists and other healthcare professionals FDA notifies health professionals that tuberculosis and other serious opportunistic infections, including histoplasmosis, listeriosis, and pneumocystosis, have been reported in both the clinical research and post-marking surveillance settings. Some of these infections have been fatal. Centocor has added a BOXED WARNING to the labeling for the product, and the WARNINGS and ADVERSE REACTIONS sections of the product labeling were revised. 28 2001 Accutane (isotretinoin) Feb 2001 Manufacturer releasing two new communication tools for this acne treatment: a EM-MG and an Informed Consent for all Accutane patients. MAY 2000 Supplements consent form in Accutane Label, May 2000: Background info on pregnancy, psychiatric events risk management issues. 29 2001 Zyvox (linezolid) Mar 2001 Myelosuppression (including anemia, leukopenia, pancytopenia and thrombocytopenia) has been reported in patients receiving linezolid. Complete blood counts should be monitored weekly in patients who receive linezolid, particularly in those who receive linezolid for longer than two weeks, those with pre-existing myelosuppression, those receiving concomitant drugs that produce bone marrow suppression, or those with chronic infection who have received previous or concomitant antibiotic therapy. 30 2001 FDA-USA Miconazole Women who take a warfarin anticoagulant and use miconazole intravaginal cream or suppository may be at risk for developing an increased prothrombin time. 31 2001 Neumega (oprelvekin) Audience: Oncologists, particularly Pediatric Oncologists Wyeth-Ayerst notifies health professionals of safety information for NEUMEGA use in the pediatric population. Preliminary data from a safety and pharmacokinetic study in 47 children has identified papilledema as a dose-limiting adverse reaction in the pediatric population. There are no controlled clinical studies that have established a safe and effective dose of NEUMEGA in children. Therefore, the administration of NEUMEGA in children, particularly those under 12 years of age, should be restricted to controlled clinical trial settings with closely monitored safety assessments. See the full letter below for further details. 32 2001 Year Title Regulatory Authority/Reg ion Product active ingredient Safety Issue (AE) Intervention Type OxyContin (oxycodone HCl) Audience: Health Professionals and Consumers FDA and Purdue Pharmaceuticals have strengthened the warnings and precautions sections in the labeling of OxyContin, a narcotic drug approved for the treatment of moderate to severe pain, because of continuing reports of abuse and diversion. The changes are intended to reinforce proper prescription practices and increase physician focus on the potential for abuse, misuse, and diversion. 33 2001 FDA-USA oxycodone HCl Abuse and diversion EM FDA-USA pioglitazone HCl/ rosiglitazone Cardiovascular risks EMwarnings strengthe ned FDA-USA propofol Increased number of deaths EMDHCPL FDA-USA rapacuronium bromide Serious adverse events, including bronchospasm and unexplained fatalities Voluntar y withdraw al FDA-USA rivastigmine tartrate Severe vomiting EM FDA-USA rosiglitazone Warnings revised / strengthened EM Thiazolidinediones [Actos (pioglitazone HCl), Avandia (rosiglitazone)] Audience: Primary care providers, endocrinologists, cardiologists and other healthcare professionals treating patients with type 2 diabetes mellitus FDA approved changes to strengthen the labeling for Actos and Avandia. The WARNINGS, PRECAUTIONS, and ADVERSE REACTIONS sections have been modified to more clearly describe the cardiovascular risks associated with the use of thiazolidinediones as monotherapy and in combination with other antidiabetic agents, particularly insulin. 34 2001 Diprivan Audience: Pediatricians and Pediatric ICU healthcare professionals The FDA has determined that there may be important safety concerns when propofol, marketed by AstraZeneca as DIPRIVAN (propofol) Injectable Emulsion, is used for sedation in the Intensive Care Unit (ICU) in pediatric patients. Healthcare professionals are reminded that propofol is not approved in the U.S. for sedation in pediatric ICU patients. 35 2001 Raplon (rapacuronium bromide) Audience: Hospital pharmacists, anesthesia professionals, wholesalers Organon Inc. initiated a voluntary recall of Raplon (rapacuronium bromide) for injection. Several serious adverse events, including bronchospasm and unexplained fatalities, were reported during postmarketing surveillance (in each of these cases the cause was unknown, as there were multiple drugs administered and other conditions present). The posted letter is part of a package distributed by the manufacturer. 36 2001 Exelon (rivastigmine tartrate) Changes to Prescribing Information for Exelon. The changes provide guidelines for reinitiating therapy in patients who have interrupted treatment with Exelon, to reduce the risk of severe vomiting. 37 2001 Avandia (rosiglitazone) April 2002 Audience: Primary care providers, endocrinologists, cardiologists and other healthcare professionals treating patients with type 2 diabetes mellitus FDA approved changes to strengthen the labeling for Actos and Avandia. The WARNINGS, PRECAUTIONS, and ADVERSE REACTIONS sections have been modified to more clearly describe the cardiovascular risks associated with the use of thiazolidinediones as monotherapy and in combination with other antidiabetic agents, particularly insulin. 38 2001 Year 39 Title Sodium Phosphates oral solution Audience: Healthcare professionals and patients FDA issues a Science Background paper to provide additional safety information to health care practitioners and patients concerning dosage recommendations and the risks of sodium phosphate products. 2001 Regulatory Authority/Reg ion Product active ingredient Safety Issue (AE) Intervention Type FDA-USA Sodium Phosphates oral solution General safety info EM FDA-USA stavudine / didanosine Fatal lactic acidosis EM FDA-USA terbinafine HCl/ itraconazole Serious cardiac adverse events EM FDA-USA topiramate Secondary angle closure glaucoma characterized by ocular pain, accute myopia, and increased intraocular pressure were reported in pediatric and adult populations EM FDA-USA Alpha Interferons, Intron A, Rebetron Combination Therapy, Roferon-A (Interferon alfa2a, recombinant) Neuropsychiatric, autoimmune, ischemic, and infectious disorders in patients taking alpha interferons BBW baclofen injection Rare cases of intrathecal baclofen withdrawal that can lead to life threatening sequelae and/or death in patients who abruptly discontinue therapy. BBW Videx (didanosine) and Zerit (stavudine) Jan 2001 Fatal lactic acidosis has recently been reported in pregnant women treated throughout gestation with the combination of stavudine and didanosine. Based on these cases, the combination of Zerit (stavudine) and Videx (didanosine) should be used with caution during pregnancy and is recommended only if the potential benefit clearly outweighs the potential risk, such as when there are few remaining treatment options. 40 2001 Lamisil (terbinafine HCl) Sporanox (itraconazole) Audience: Dermatologists and other healthcare professionals FDA is issuing a public health advisory concerning Sporanox and Lamisil, systemic drug therapies to treat onychomycosis (fungal nail infections). Healthcare professionals are notified of the possible association of serious cardiac adverse events with the administration of Sporanox and hepatic adverse events with the administration of both Sporanox and Lamisil. New labeling for both Sporanox and Lamisil recommends that healthcare providers obtain nail specimens for laboratory testing prior to prescribing the medications for onychomycosis to confirm the diagnosis. FDA's concerns do NOT apply to the over-the-counter versions of Lamisil, which are topical creams. 41 2001 Topamax (topiramate) Sep 2001 Audience: Neurologists, Ophthalmologists, and other Healthcare professionals FDA and Ortho-McNeil have strengthened the WARNINGS and PRECAUTIONS sections in the label of Topamax Tablets and Sprinkle Capsules, indicated as adjunctive therapy for adults and pediatric patients ages 2-16 years with seizure disorders. Cases of secondary angle closure glaucoma characterized by ocular pain, accute myopia, and increased intraocular pressure were reported in pediatric and adult populations. The primary treatment is discontinuation of Topamax. If left untreated, serious sequelae, including permanent vision loss, may occur. Patients taking Topamax should be told to seek immediate medical attention if they experience blurred vision or periorbital pain. 42 2001 Alpha Interferons (Roferon-A, Intron A, Rebetron Combination Therapy) Intron A (Interferon alfa 2b, recombinant) Rebetron Combination Therapy (Rebetrol (Ribavirin, USP) Capsules and Intron A) Roferon-A (Interferon alfa-2a, recombinant) Audience: Oncologists and other Healthcare professionals Healthcare professionals are advised of important safety information for all alpha interferons. A BOXED WARNING has been added regarding the occurrence of neuropsychiatric, autoimmune, ischemic, and infectious disorders in patients taking alpha interferons; additional safety information and direction for patient monitoring is also provided in the WARNINGS section of the prescribing information. 43 2002 Lioresal Intrathecal (baclofen injection) Audience: Neurologists, Neurosurgeons, and other healthcare professionals Medtronic and FDA added a BOXED WARNING and strengthened the WARNINGS sections of the prescribing information of Lioresal Intrathecal, indicated for use in the management of severe spasticity of cerebral and spinal origin. The warnings inform healthcare professionals about rare cases of intrathecal baclofen withdrawal that can lead to life threatening sequelae and/or death in patients who abruptly discontinue therapy. 44 2002 FDA-USA Year 45 Title Clozaril (clozapine) February 2002 Audience: Psychiatrists, Pharmacists FDA and Novartis have strengthened the BOXED WARNING and WARNINGS sections of the prescribing information (PI) for Clozaril (clozapine) as follows: (1) The previously existing BOXED WARNING has been relocated to the beginning of the PI and revised to advise health care providers of the association of myocarditis with clozapine therapy; (2) A subsection has been added to the WARNINGS section entitled "Myocarditis" to provide data and clozapine treatment guidelines related to this issue. 2002 Regulatory Authority/Reg ion Product active ingredient Safety Issue (AE) Intervention Type FDA-USA clozapine Myocarditis BBW revised FDA-USA conjugated estrogens/medro xyprogesterone acetate tablets Increased risks of cardiovascular events, breast cancer and venous thromboembolic events EM FDA-USA divalproex sodium / valproic acid / valproate sodium Hyperammonemic encephalopathy, sometimes fatal EM enoxaparin sodium Contraindication for thromboprophylaxis in patients with prosthetic heart valves EM FDA-USA ergotamine tartrate and caffeine Drug interaction - Serious and/or life-threatening peripheral ischemia has been associated with the coadministration of Cafergot with potent CYP 3A4 inhibitors including protease inhibitors and macrolide antibiotics. BBW strengthe ned warnings FDA-USA gammahexachlorocycloh exane Potential risks, especially in children and adults weighing less than 110 pounds, BBW Prempro/Premphase (conjugated estrogens/medroxyprogesterone acetate tablets) August 2002 Audience: Reproductive healthcare professionals FDA and Wyeth notified healthcare professionals about safety related labeling changes to the INDICATIONS and USAGE, CONTRAINDICATIONS, WARNINGS, PRECAUTIONS, and DOSAGE and ADMINISTRATION sections of the labels. The new safety information reflects new data, primarily from the Women's Health Initiative (WHI). 46 2002 Depakote / Depakene / Depacon (divalproex sodium / valproic acid / valproate sodium) Audience: Neuropsychiatric healthcare professionals FDA and Abbott strengthened the CONTRAINDICATIONS, WARNINGS and PRECAUTIONS sections of the label for Depakote Tablets, Depakote ER Tablets, Depakote Sprinkle Capsules, Depakene Capsules and Syrup and Depacon for Injection. Healthcare professionals were informed that hyperammonemic encephalopathy, sometimes fatal, has been reported following initiation of valproate therapy in patients with urea cycle disorders [UCD], a group of uncommon genetic abnormalities. Patient criteria to consider in evaluation for UCD prior to initiation of valproate therapy are offered. 47 2002 Lovenox (enoxaparin sodium) Audience: Healthcare Professionals FDA and Aventis strengthened the WARNINGS and PRECAUTIONS sections of the Lovenox prescribing information to inform healthcare professionals that the use of Lovenox Injection is not recommended for thromboprophylaxis in patients with prosthetic heart valves. New postmarketing safety information concerning congenital anomalies and non-teratogenic effects on pregnant women and fetuses are described. 48 2002 FDA-USA Cafergot (ergotamine tartrate and caffeine) Audience: Neurologists and other healthcare professionals FDA and Novartis strengthened the labeling, including a new BOXED WARNING and updates to the CONTRAINDICATIONS, WARNINGS, PRECAUTIONS, and CLINICAL PHARMACOLOGY sections of the prescribing information. Serious and/or life-threatening peripheral ischemia has been associated with the coadministration of Cafergot with potent CYP 3A4 inhibitors including protease inhibitors and macrolide antibiotics. Because CYP 3A4 inhibition elevates the serum levels of Cafergot, the risk for vasospasm leading to cerebral ischemia and/or ischemia of the extremities is increased. Because of the increased risk of serious vasospastic adverse events, concomitant use of these medications is contraindicated. 49 50 2002 2002 Lindane (gamma-hexachlorocyclohexane) Audience: Primary Care providers, Pharmacists, and consumers FDA issued a Public Health Advisory concerning the use of topical formulations of Lindane Lotion and Lindane Shampoo for the treatment of scabies and lice. A boxed warning emphasizes that it is a second-line treatment, updates information about its potential risks, especially in children and adults weighing less than 110 pounds, and reminds practitioners that reapplication of Lindane Lotion or Lindane Shampoo is not the appropriate treatment, if itching continues after the single Year 51 52 2002 Title treatment. A EM-MG, designed to inform patients of the risks of Lindane products and provide instructions for appropriate use of the drugs, must now be dispensed by the pharmacist with each new prescription. Rebif* (interferon beta-1a) [2002 version] Camptosar (irinotecan HCl) The prescribing information in the BOXED WARNING, WARNINGS, and PRECAUTIONS sections were revised to identify patients at higher risk of severe toxicity, to clarify dose modification guidelines, and to augment information about management of treatment-related toxicities, including severe and occasionally life-threatening diarrhea. 2002 Regulatory Authority/Reg ion FDA-USA Product active ingredient interferon beta1a Safety Issue (AE) Intervention Type Not specified EM-MG FDA-USA irinotecan HCl General safety info BBW warning revised FDA-USA isotretinoin Warnings revised BBW mefloquine HCl Contraindicated for prophylaxis in patients with active depression, a recent history of depression, generalized anxiety disorder, psychosis, schizophrenia or other major psychiatric disorders, or with a history of convulsions EM mifepristone Ectopic pregnancy, (including one fatal case) severe systemic infection (sepsis), and one heart attack case. EM Rare cases of liver failure leading to transplant and/or death BBW /EMwarnings strengthe ned Accutane (isotretinoin) November 2002 Audience: Dermatologists and other healthcare professionals FDA and Roche revised the WARNINGS: Psychiatric Disorders, Boxed CONTRAINDICATIONS AND WARNINGS, DOSAGE AND ADMINISTRATION, and PRECAUTIONS: Drug Interactions sections of the prescribing information. Changes in pediatric labeling were made to the CLINICAL PHARMACOLOGY: Special Patient Populations: Pediatric Patients, WARNINGS: Skeletal: Bone Mineral Density, and PRECAUTIONS: Pediatric Use:sections. Aggressive and/or violent behaviors have been added to the list of events that Accutane may cause, based on post-marketing safety reports. A new table has been added to clarify those circumstances where pregnancy tests and Accutane Qualification Stickers are applicable 53 2002 Lariam (mefloquine HCl) October 2002 Audience: Infectious disease and other healthcare professionals FDA and Roche strengthened the CONTRAINDICATIONS, WARNINGS, PRECAUTIONS, and ADVERSE REACTIONS sections of the label. Healthcare professionals were notified that Lariam is contraindicated for prophylaxis in patients with active depression, a recent history of depression, generalized anxiety disorder, psychosis, schizophrenia or other major psychiatric disorders, or with a history of convulsions. During prophylactic use, if psychiatric symptoms such as acute anxiety, depression, restlessness or confusion occur, these may be considered prodromal to a more serious event. In these cases, the drug must be discontinued and an alternative medication should be substituted. 54 2002 FDA-USA Mifeprex (mifepristone) April 2002 Audience: Obstetricians/Gynecologists and other healthcare professionals The following is new safety information about Mifeprex (mifepristone): 55 2002 FDA-USA Serzone (nefazodone HCL) Audience: Psychiatrists, Pharmacists FDA and BMS added a Black Box Warning and strengthened the WARNINGS, CONTRAINDICATIONS, and PRECAUTIONS sections of the label for Serzone, an antidepressant drug. Rare cases of liver failure leading to transplant and/or death in patients have been reported. A new Patient Package Insert is provided in the product packaging. 56 2002 FDA-USA nefazodone HCL Year 57 Title Actos (pioglitazone HCl) Audience: Primary care providers, endocrinologists, cardiologists and other healthcare professionals treating patients with type 2 diabetes mellitus FDA approved changes to strengthen the labeling for Actos and Avandia. The WARNINGS, PRECAUTIONS, and ADVERSE REACTIONS sections have been modified to more clearly describe the cardiovascular risks associated with the use of thiazolidinediones as monotherapy and in combination with other antidiabetic agents, particularly insulin. 2002 Regulatory Authority/Reg ion 2002 Safety Issue (AE) Intervention Type pioglitazone HCl Warnings revised / strengthened EM FDA-USA Pooled Plasma, (Human) Solvent Detergent Treated Contraindicates the use of PLAS+SD in patients undergoing liver transplant, patients with severe liver disease and known coagulopathies. BBW revision FDA-USA sertraline HCl Drug interaction with pimozide EM sirolimus Risk of hepatic artery thrombosis, graft loss, and death EMDHCPL tamoxifen citrate Serious, life-threatening or fatal events in the risk reduction setting [women at high risk for cancer and women with DCIS] include endometrial cancer, uterine sarcoma, stroke, and pulmonary embolism. BBW /EM warnings strengthe ned FDA-USA PLAS+SD (Pooled Plasma, (Human) Solvent Detergent Treated) Audience: Transplantation Health Care Professionals Healthcare professionals were advised of the addition of a Boxed Warning and a strengthened Warning section in the labeling for PLAS+SD (Pooled Plasma,(Human) Solvent Detergent Treated). The new Boxed Warning contraindicates the use of PLAS+SD in patients undergoing liver transplant, patients with severe liver disease and known coagulopathies. In addition, the Warnings have been strengthened to advise that patients receiving large volumes of PLAS+SD be monitored for evidence of thrombosis, excessive bleeding, or exacerbation of DIC. PLAS+SD is manufactured by V.I. Technologies, Inc. and distributed by American National Red Cross, Blood Services. 58 Product active ingredient Zoloft (sertraline HCl) Audience: Psychiatrists and other healthcare professionals At the request of the FDA, Pfizer issued an important drug warning letter announcing that they have added new information to the CONTRAINDICATIONS and PRECAUTIONS sections of the Zoloft labeling, contraindicating the concomitant use of pimozide with sertraline. 59 2002 Rapamune (sirolimus) April 2002 Audience: Transplantation Surgeons and other healthcare professionals FDA notified healthcare professionals of a "Dear Health Care Provider" letter issued April 24, 2002 by Wyeth, sent to members of the American Society of Transplantation and The American Society of Transplant Surgeons. The letter informs clinicians of the risk of hepatic artery thrombosis, graft loss, and death associated with the use of Rapamune (sirolimus) in de novo liver transplantation. 60 2002 FDA-USA Nolvadex (tamoxifen citrate) Audience: Oncologists and other healthcare professionals caring for women with breast cancer FDA and AstraZeneca added a boxed warning and strengthened the WARNINGS section of the label to inform healthcare professionals about new risk information of particular relevance to women with ductal carcinoma in situ [DCIS] and women at high risk for developing breast cancer and are receiving or considering Nolvadex therapy to reduce their risk of developing invasive breast cancer. Serious, life-threatening or fatal events associated with Nolvadex in the risk reduction setting [women at high risk for cancer and women with DCIS] include endometrial cancer, uterine sarcoma, stroke, and pulmonary embolism. Healthcare providers should discuss the potential benefits versus the potential risks of these serious events with women considering Nolvadex to reduce their risk of developing breast cancer. 61 2002 FDA-USA Abbokinase (urokinase) Audience: Cardiologists, Intensivists, and other healthcare professionals FDA and Abbott announced the reintroduction of Abbokinase (urokinase) for use in the lysis of massive pulmonary emboli and pulmonary emboli accompanied by unstable hemodynamics. The WARNINGS section of the labeling has been strengthened to include post-marketing reports of anaphylaxis, other infusion reactions, and class information regarding the potential for cholesterol embolization. The ADVERSE REACTIONS section of the product labeling reflects the analysis of postmarketing safety data. 62 2002 FDA-USA urokinase FDA-USA valdecoxib Bextra (valdecoxib) Audience: Rheumatologists and other healthcare professionals FDA and Pharmacia/Pfizer strengthened the CONTRAINDICATIONS, WARNINGS, and ADVERSE REACTIONS sections of the prescribing information. In postmarketing experience, rare reports of hypersensitivity reactions (i.e, anaphylatic reactions and angioedema) and skin reactions, including cases of Stevens-Johnson syndrome, toxic epidermal necrolysis, exfoliative dermatitis, and erythema multiforme, have been received. These cases, some of which were serious/life threatening, have occurred in patients with and without a history of allergic type reactions to sulfonamides. 63 2002 Anaphylaxis, other infusion reactions, and class information Rare reports of hypersensitivity reactions (i.e, anaphylatic reactions and angioedema) and skin reactions, including cases of Stevens-Johnson syndrome, toxic epidermal necrolysis, exfoliative dermatitis, and erythema multiforme EM EM Year 64 Title Geodon (ziprasidone HCl) Audience: Healthcare Professionals caring for persons with schizophrenia FDA and Pfizer strengthened the WARNINGS and CONTRAINDICATIONS sections of the Geodon prescribing information to inform healthcare professionals of the particular drugs or types of drugs that are contraindicated with Geodon. 2002 Regulatory Authority/Reg ion FDA-USA Product active ingredient ziprasidone HCl Drug interactions EM FDA-USA zonisamide Increased risk for zonisamide-associated oligohidrosis and hyperthermia in paediatric patients EM FDA-USA abacavir Early virologic non-response EM FDA-USA Antidepressants for Major Depressive Disorder Suicidality EM FDA-USA atazanavir sulfate and tenofovir disoproxil fumarate Drug interaction- reduced effectiveness EM FDA-USA conjugated estrogens tablets, USP Should not be used for the prevention of cardiovascular disease. BBW Zonegran (zonisamide) Audience: Neurologists, Pediatricians, and other healthcare professionals FDA and Elan Pharmaceuticals added a bolded WARNING to inform healthcare professionals that pediatric patients appear to be at an increased risk for zonisamide-associated oligohidrosis and hyperthermia. Patients, especially pediatric patients, treated with Zonegran should be monitored closely for evidence of decreased sweating and increased body temperature, especially in warm or hot weather. The safety and effectiveness of zonisamide in pediatric patients have not been established. Zonisamide is not approved for use in pediatric patients. 65 2002 Safety Issue (AE) Intervention Type Ziagen (abacavir) Jul 2003 Audience: Infectious Disease and other healthcare professionals GlaxoSmithKline (GSK) notified healthcare professionals of a high rate of early virologic non-response observed in a GSK-sponsored clinical study of therapy-naive adults with HIV infection receiving once-daily three-drug combination therapy with lamivudine (Epivir, GSK), abacavir (Ziagen, GSK) and tenofovir (Viread, TDF, Gilead Sciences). Based on these results: Abacavir and lamivudine in combination with tenofovir should not be used as a triple antiretroviral therapy when considering a new treatment regimen for naive or pre-treated patients. 66 67 2003 2003 Public Health Advisory - Suicidality in Pediatric Patients Treated with Antidepressants for Major Depressive Disorder Audience: Mental health professionals, pediatricians, and other healthcare professionals The FDA notified healthcare professionals of reports of the occurrence of suicidality (both suicidal ideation and suicide attempts) in clinical trials for various antidepressant drugs in pediatric patients with major depressive disorder (MDD). FDA has completed a preliminary review of such reports for 8 antidepressant drugs (citalopram, fluoxetine, fluvoxamine, mirtazapine, nefazodone, paroxetine, sertraline, and venlafaxine) studied under the pediatric exclusivity provision, and has determined that additional data and analysis, and also a public discussion of available data, are needed. FDA plans to hold an advisory committee meeting before the Psychopharmacologic Drugs Advisory Committee and the Pediatric Subcommittee of the Anti-Infective Drugs Advisory Committee on February 2, 2004. Reyataz (atazanavir sulfate) Audience: Infectious Disease and other healthcare professionals BMS and FDA notified clinicians caring for HIV-infected patients of important new safety data concerning the coadministration of Reyataz (atazanavir sulfate) and Viread (tenofovir disoproxil fumarate.) Clinicians should use caution when administering unboosted Reyataz with tenofovir DF. Unboosted Reyataz may be less effective due to decreased atazanavir concentrations in patients taking Reyataz and tenofovir DF. As a result the coadministration of unboosted Reyataz with tenofovir DF may lead to loss or lack of virologic response and possible resistance to Reyataz. 68 69 2003 2003 Premarin (conjugated estrogens tablets, USP) Audience: Reproductive healthcare professionals FDA and Wyeth revised the prescribing information to include a boxed warning, which states that estrogens and estrogens plus progestin therapies should not be used for the prevention of cardiovascular disease. The boxed warning includes risk information from the Women's Health Initiative (WHI) study. The study reported increased risks of myocardial infarction, stroke, invasive breast cancer, pulmonary emboli, and deep vein thrombosis in postmenopausal women during 5 years of treatment with conjugated equine estrogens (0.625 mg) combined with medroxyprogesterone acetate (2.5 mg) relative to placebo. Because of these risks, estrogens with or without progestins should be prescribed at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman. Year 70 Title Zenapax (daclizumab) Audience: Transplantation healthcare professionals FDA and Roche revised the WARNINGS, PRECAUTIONS, ADVERSE REACTIONS, and CLINICAL STUDIES sections of the prescribing information to include important new safety information describing the increased mortality seen in a cardiac transplant study and other updated information regarding hypersensitivity reactions. Other sections of the ZENAPAX labeling impacted by the addition of the information from the cardiac transplant study have also been revised. 2003 Regulatory Authority/Reg ion 2003 Safety Issue (AE) Intervention Type FDA-USA daclizumab Increased mortality EM FDA-USA fluticasone propionate and salmeterol inhalation powder Significant, increased risk of life-threatening asthma episodes or asthma-related deaths BBW Interferon beta1a Post-marketing reports of depression, suicidal ideation and/or development of new or worsening of pre-existing psychiatric disorders, including psychosis, and reports of anaphylaxis, pancytopenia, thrombocytopenia, autoimmune disorders of multiple target organs, and hepatic injury and hepatitis EM-MG leflunomide Rare, serious hepatic injury, including cases with fatal outcome, EM Advair Diskus (fluticasone propionate and salmeterol inhalation powder) Audience: Pulmonary specialists and other healthcare professionals The FDA announced the addition of new safety information and warnings to the labeling for drug products that contain salmeterol, a long-acting bronchodilator used to treat asthma and chronic obstructive pulmonary disease (COPD). The new labeling includes a boxed warning about a small, but significant, increased risk of lifethreatening asthma episodes or asthma-related deaths observed in patients taking salmeterol in a recently completed large U.S. safety study. 71 Product active ingredient Avonex (Interferon beta-1a) Revisions Audience: Neurologists and other healthcare professionals Biogen and FDA revised the WARNINGS, PRECAUTIONS, ADVERSE REACTIONS, PATIENT INFORMATION, and CLINICAL STUDIES sections of the prescribing information to include important new safety information and a patient EM-MG. Updated safety information includes a cautionary note regarding use in patients with depression and other severe psychiatric symptoms. Post-marketing reports of depression, suicidal ideation and/or development of new or worsening of pre-existing psychiatric disorders, including psychosis, and reports of anaphylaxis, pancytopenia, thrombocytopenia, autoimmune disorders of multiple target organs, and hepatic injury manifesting itself as elevated serum enzyme levels and hepatitis were added to the labeling. An FDA-approved Patient EM-MG, providing important patient safety information and comprehensive instructions for patient self-administration of Avonex, was added. 72 73 2003 2003 FDA-USA Arava (leflunomide) Audience: Rheumatoid specialists and other healthcare professionals Aventis Pharmaceuticals and FDA updated the prescribing information for Arava (leflunomide), indicated for the treatment of active rheumatoid arthritis. In postmarketing experience worldwide, rare, serious hepatic injury, including cases with fatal outcome, have been reported during treatment with Arava. Most cases occurred within 6 months of therapy and in a setting of multiple risk factors for hepatotoxicity. Rare postmarketing reports of severe infections, including sepsis, which may be fatal, were also received. Most of the reports were confounded by concomitant immunosuppressant therapy and/or comorbid illness, which, in addition to rheumatoid disease, may predispose patients to infection. FDA-USA Year 74 Title Orlaam (levomethadyl acetate HCl) Audience: Pharmacists and drug dependency healthcare professionals Roxane Laboratories, Inc. is discontinuing the sale and distribution of ORLAAM, a synthetic opioid agonist solution indicated for the management of opiate dependence, reserved as second-line therapy for the treatment of opiate-addicted patients who fail to show acceptable response to other adequate treatments for opiate addiction. ORLAAM was removed from the European market in March 2001 following reports of severe cardiac-related adverse events, including QT interval prolongation, Torsades de Pointes and cardiac arrest. Other first-line treatment options are available for the management of opiate dependence, including methadone and buprenorphine. 2003 Regulatory Authority/Reg ion Product active ingredient Safety Issue (AE) Intervention Type Withdra wal FDA-USA levomethadyl acetate HCl Severe cardiac-related adverse events, including QT interval prolongation, Torsades de Pointes and cardiac arrest FDA-USA mefloquine HCl Potentially serious psychiatric adverse events EM-MG FDA-USA morphine sulfate Serious adverse events and deaths resulting from accidental overdose EMDHCPL FDA-USA pergolide mesylate Possibility of patients falling asleep while performing daily activities EM FDA-USA Pyrazinamide plus Rifampin for Treatment of Latent Tuberculosis Infection (LTBI) High rates of hospitalization and death from liver injury EM Lariam (mefloquine HCl) Audience: Pharmacists, infectious disease specialists and consumers FDA and Roche Laboratories notified healthcare professionals of the introduction of the Lariam EM-MG (MedGuide). The Lariam MedGuide was developed in collaboration with the FDA to help travelers better understand the risks of malaria, the risks and benefits associated with taking Lariam to prevent malaria, and the rare but potentially serious psychiatric adverse events associated with use of the drug. As required by law, a Lariam EM-MG is supplied to patients each time Lariam is dispensed. Patients should be instructed to read the MedGuide when Lariam is received. 75 2003 Roxanol (morphine sulfate) Concentrated Oral Solution Audience: Pharmacists and other healthcare professionals NOTE: A corrected "Dear Healthcare Professional" letter was issued October 22, 2003. Elan Pharmaceuticals issued a "Dear Healthcare Professional" October 6, 2003 reporting serious adverse events and deaths resulting from accidental overdose of high concentration morphine sulfate oral solutions. In most of these cases, morphine oral solutions ordered in milligrams (mg) were mistakenly interchanged for milliliters (mL) of the product, resulting in 20-fold overdoses. Procedures for proper ordering and dispensing were included in the "Dear Healthcare Professional" letter. 76 2003 Permax (pergolide mesylate) Dec 2003 Audience: Neurological and other healthcare professionals FDA and Lilly modified the WARNINGS and PRECAUTIONS sections to inform healthcare professionals of the possibility of patients falling asleep while performing daily activities, including operation of motor vehicles, while receiving treatment with Permax, a dopamine agonist, indicated as adjunctive treatment to levodopa/carbidopa in the management of the signs and symptoms of Parkinson's disease. Many patients who have fallen asleep have perceived no warning of somnolence. Healthcare professionals should be alerted to the potentially serious risks associated with these events and should carefully evaluate their patients for the presence of somnolence 77 2003 Pyrazinamide plus Rifampin for Treatment of Latent Tuberculosis Infection (LTBI) Audience: Infectious Disease and other healthcare professionals The Centers for Disease Control and Prevention (CDC) notified healthcare professionals of revised recommendations against the use of rifampin plus pyrazinamide for treatment of latent tuberculosis infection, due to high rates of hospitalization and death from liver injury associated with the combined use of these drugs. 78 2003 Year 79 Title Prandin (repaglinide) Audience: Endocrinologists, pharmacists and other healthcare providers Novo Nordisk and FDA revised the PRECAUTIONS/Drug Interaction section of the prescribing information to inform healthcare professionals of a drug-drug interaction between repaglinide (PRANDIN), a short-acting insulin secretagogue, and gemfibrozil (Lopid) a lipid-lowering agent used to treat dyslipidemia. A study that evaluated the co-administration of gemfibrozil with PRANDIN in healthy subjects found a significant increase in repaglinide blood levels. Concomitant use may result in enhanced and prolonged blood glucose-lowering effects of repaglinide. For patients already on PRANDIN and gemfibrozil, blood glucose levels should be monitored and PRANDIN dose adjustment may be needed. 2003 Regulatory Authority/Reg ion 2003 FDA-USA repaglinide FDA-USA Rifampin plus Pyrazinamide for Treatment of Latent Tuberculosis Infection (LTBI) High rates of hospitalization and death from liver injury associated with the combined use of rifampin plus pyrazinamide EMDHCPL FDA-USA risperidone Cerebrovascular adverse events (e.g., stroke, transient ischemic attack), EM FDA-USA salmeterol xinafoate Life-threatening asthma episodes or asthma-related deaths BBW FDA-USA sirolimus Bronchial anastomotic dehiscence EM Risperdal (risperidone) Apr 2003 Audience: Neuropsychiatric healthcare professionals Janssen Pharmaceutica and FDA revised the WARNINGS section of the prescribing information for Risperdal (risperidone), indicated for the treatment of schizophrenia. Cerebrovascular adverse events (e.g., stroke, transient ischemic attack), including fatalities, were reported in patients in trials of risperidone in elderly patients with dementia-related psychosis. In placebo-controlled trials, there was a significantly higher incidence of cerebrovascular adverse events in patients treated with risperidone compared to patients treated with placebo. RISPERDAL has not been shown to be safe or effective in the treatment of patients with dementia-related psychosis. 81 2003 Safety Issue (AE) Intervention Type Drug interaction with gemfibrozil - increase in repaglinide blood levels. Rifampin plus Pyrazinamide for Treatment of Latent Tuberculosis Infection (LTBI) Audience: Infectious Disease and other healthcare professionals The Centers for Disease Control and Prevention (CDC) notified healthcare professionals of revised recommendations against the use of rifampin plus pyrazinamide for treatment of latent tuberculosis infection, due to high rates of hospitalization and death from liver injury associated with the combined use of these drugs. 80 Product active ingredient EM Serevent Inhalation Aerosol and Diskus (salmeterol xinafoate) Audience: Pulmonary specialists and other healthcare professionals The FDA announced the addition of new safety information and warnings to the labeling for drug products that contain salmeterol, a long-acting bronchodilator used to treat asthma and chronic obstructive pulmonary disease (COPD). The new labeling includes a boxed warning about a small, but significant, increased risk of life-threatening asthma episodes or asthma-related deaths observed in patients taking salmeterol in a recently completed large U.S. safety study. 82 2003 Rapamune (sirolimus) Audience: Transplantation surgeons and other healthcare professionals Wyeth, in cooperation with FDA, notified healthcare professionals of post-marketing reports of bronchial anastomotic dehiscence, including fatal cases, in lung transplant patients treated with Rapamune in combination with tacrolimus and corticosteroids. The safety and efficacy of Rapamune as immunosuppressive therapy has not been established in lung transplant patients. 83 2003 Year 84 Title Genotropin (somatropin [rDNA origin] for injection) Audience: Pediatricians, endocrinologists and other healthcare professionals Pharmacia and FDA revised the CONTRAINDICATIONS and WARNINGS sections of the prescribing information for Genotropin, indicated for the long-term treatment of pediatric patients who have growth failure. Fatalities have been reported with the use of growth hormone in pediatric patients with Prader-Willi syndrome with one or more of the following risk factors: severe obesity, history of respiratory impairment or sleep apnea, or unidentified respiratory infection. Male patients with these factors may be at increased risk. 2003 Regulatory Authority/Reg ion somatropin [rDNA origin] for injection EM FDA-USA tenofovir disoproxil fumarate Tenofovir DF in combination with didanosine and lamivudine is not recommended when considering a new treatment regimen for therapy-naïve or experienced patients with HIV infection EM FDA-USA topiramate Hyperchloremic, non-anion gap metabolic acidosis EM FDA-USA topiramate Oligohidrosis (decreased sweating) and hyperthermia EM FDA-USA valganciclovir HCl Not indicated for use in liver transplant patients EM FDA-USA 2003 Safety Issue (AE) Intervention Type Fatalities in pediatric patients with Prader-Willi syndrome with one or more of the following risk factors: severe obesity, history of respiratory impairment or sleep apnea, or unidentified respiratory infection Viread (tenofovir disoproxil fumarate) Oct 2003 Audience: Infectious Disease and other healthcare professionals Gilead Sciences, Inc. notified healthcare professionals of a high rate of early virologic failure and emergence of nucleoside reverse transcriptase inhibitor (NRTI) resistance associated mutations observed in a clinical study of HIV-infected treatmentnaïve patients receiving a once-daily triple NRTI regimen containing didanosine enteric coated beadlets (Videx EC, Bristol-Myers Squibb), lamivudine (Epivir, GlaxoSmithKline), and tenofovir disoproxil fumarate (Viread, Gilead). Based on these results, Tenofovir DF in combination with didanosine and lamivudine is not recommended when considering a new treatment regimen for therapy-naïve or experienced patients with HIV infection. Patients currently on this regimen should be considered for treatment modification. 85 Product active ingredient Topamax (topiramate) Tablets, Sprinkle Capsules Dec 2003 Audience: Neurologists and other Healthcare professionals Ortho-McNeil and FDA revised the WARNINGS and PRECAUTIONS sections of the prescribing information, notifying healthcare professionals that Topamax causes hyperchloremic, non-anion gap metabolic acidosis (decreased serum bicarbonate). Measurement of baseline and periodic serum bicarbonate during topiramate treatment is recommended. 86 2003 Topamax (topiramate) Tablets, Sprinkle Capsules July 2003 Audience: Neurologists, Pediatricians, and other Healthcare professionals Ortho-McNeil and FDA revised the WARNINGS and PRECAUTIONS sections of the prescribing information to provide updated information about oligohidrosis (decreased sweating) and hyperthermia, which have been reported in topiramate-treated patients. Oligohidrosis and hyperthermia may have potentially serious sequelae, which may be preventable by prompt recognition of symptoms and appropriate treatment. 87 2003 Valcyte (valganciclovir HCl tablets) Oct 2003 Audience: Transplantation and other healthcare professionals FDA and Roche notified healthcare professionals of the findings of an active comparator study of Valcyte and ganciclovir in heart, liver, kidney, and kidney-pancreas transplant patients at high risk for CMV disease. Based on those findings: (1) Valcyte is indicated for the prevention of CMV disease in kidney, heart, and kidney-pancreas transplant patients at high risk, (2) Valcyte is not indicated for use in liver transplant patients, and (3) The safety and efficacy of Valcyte for the prevention of CMV disease in other solid organ transplant patients, such as lung transplant patients, have not been established. 88 2003 Year 89 Title OTC pain and fever reducers (acetaminophen / NSAIDs) Audience: Pharmacists, other healthcare professionals, and consumers The FDA notified healthcare professionals of a national education campaign to provide advice on the safe use of over-the-counter (OTC) pain and fever reducers that contain acetaminophen and non-steroidal anti-inflammatory drugs (NSAIDs). The campaign is intended to raise consumer awareness of these safety issues and to inform healthcare providers about the role that they can play in preventing acetaminophen induced hepatotoxicity and NSAID-related gastrointestinal bleeding and renal toxicity in patients using these medicines. 2004 Regulatory Authority/Reg ion FDA-USA Product active ingredient acetaminophen / NSAIDs Gastrointestinal bleeding and renal toxicity EM adalimumab Serious infections with the combined use of Humira (adalimumab) and anakinra, hypersensitivity reactions, including anaphylaxis, and hematologic events, including pancytopenia and aplastic anemia. EM amiodarone HCl Pulmonary toxicity (hypersensitivity pneumonitis or interstitial/alveolar pneumonitis) EM-MG anagrelide HCl Contraindication to the use of Agrylin in patients with severe hepatic impairment EM antidepressants Increased risk of suicidality (suicidal thinking and behavior) in children and adolescents EM Humira (adalimumab) Nov 2004 Audience: Rheumatologists and other healthcare professionals FDA and Abbott Pharmaceuticals notified healthcare professionals of revisions to the WARNINGS section of the prescribing information, indicated for the treatment of rheumatoid arthritis. These warnings include serious infections with the combined use of Humira (adalimumab) and anakinra, hypersensitivity reactions, including anaphylaxis, and hematologic events, including pancytopenia and aplastic anemia. 90 2004 FDA-USA Cordarone (amiodarone HCl) Audience: Cardiologists, pharmacists and other healthcare professionals FDA and Wyeth notified pharmacists and physicians of a new EM-MG for Cordarone (amiodarone HCl tablets). The FDA regulation 21CFR 208 requires a EM-MG to be provided with each prescription that is dispensed for products that FDA determines pose a serious and significant public health concern. The EM-MG and current Prescribing Information for Cordarone and its generic equivalents are also provided below. 91 92 93 2004 2004 2004 FDA-USA Agrylin (anagrelide HCl) Audience: Hematology/Oncology and other healthcare professionals Shire and FDA notified healthcare professionals about changes to the CONTRAINDICATIONS and WARNINGS sections of the prescribing information for Agrylin (anagrelide HCl), a medication approved for the treatment of thrombocythemia secondary to myeloproliferative disorders to reduce platelet count and the risk of thrombosis and to ameliorate associated symptoms including thrombohemorrhagic events. Pharmacokinetic studies have revealed an 8-fold increase in total exposure (AUC) to anagrelide HCl in patients with moderate hepatic impairment. Use of anagrelide HCl has not been studied in patients with severe hepatic impairment. Labeling changes include the contraindication to the use of Agrylin in patients with severe hepatic impairment. The WARNINGS section describes the need for dosage reduction in patients with moderate hepatic impairment and the necessity of monitoring these patients carefully for cardiovascular effects. Public Health Advisory: Suicidality in Children and Adolescents Being Treated with Anti-depressant Medications Audience: Neuropsychiatric healthcare professionals and consumers The Food and Drug Administration issued a Public Health Advisory, asking manufacturers of all antidepressant drugs to revise the labeling for their products to include a boxed warning and expanded warning statements that alert health care providers to an increased risk of suicidality (suicidal thinking and behavior) in children and adolescents being treated with these agents, and additional information about the results of pediatric studies. FDA also informed these manufacturers that it has determined that a Patient EMMG (MedGuide), which will be given to patients receiving the drugs to advise them of the risk and precautions that can be taken, is appropriate for these drug products. FDA-USA FDA-USA Safety Issue (AE) Intervention Type Year 94 Title Abilify (aripiprazole) Audience: Neuropsychiatric healthcare professionals FDA and Bristol-Myers Squibb notified healthcare professionals of revision to the WARNINGS section of labeling, describing the risk of hyperglycemia and diabetes in patients taking Abilify. FDA asked all manufacturers of atypical antipsychotic medications, including BristolMyers Squibb, to add this Warning statement to labeling. 2004 Regulatory Authority/Reg ion Product active ingredient Safety Issue (AE) Intervention Type FDA-USA aripiprazole Hyperglycemia and diabetes EM FDA-USA atomoxetine Potential for severe liver injury EM FDA-USA bevacizumab Increased risk of serious arterial thromboembolic events, including cerebrovascular accident, myocardial infarctions, transient ischemic attacks, & angina EM FDA-USA clozapine Increased risk of hyperglycemia and diabetes EM FDA-USA COX-2 selective agents (Vioxx, Celebrex, and Bextra) Increased risk of serious cardiovascular events (heart attack and stroke) EM FDA-USA darbepoetin alfa Increased mortality and thrombotic vascular events EM Strattera (atomoxetine) Dec 2004 Audience: Neuropsychiatric and other healthcare professionals FDA notified health care professionals about a new warning for Strattera, a drug approved for attention deficit hyperactivity disorder (ADHD) in adults and children. The labeling is being updated with a bolded warning about the potential for severe liver injury following two reports (a teenager and an adult) in patients who had been treated with Strattera for several months, both of whom recovered. Health care professionals are encouraged to report any unexpected adverse events associated with Strattera to Eli Lilly or to the FDA MedWatch program. 95 2004 Avastin (bevacizumab) Aug 2004 Audience: Oncologists and other healthcare providers FDA and Genentech, Inc. issued an important drug warning to healthcare providers that there is evidence of an increased risk of serious arterial thromboembolic events, including cerebrovascular accident, myocardial infarctions, transient ischemic attacks, and angina related to Avastin. The risk of fatal arterial thrombotic events is also increased. In randomized, active-controlled studies conducted in patients with metastatic colorectal cancer, the risks of a serious arterial thrombotic event was approximately two-fold higher in patients receiving infusional 5-FU based chemotherapy plus Avastin, with an estimated overall rate of up to 5%. A revised Avastin package insert containing more information on arterial thromboembolic events is in development. 96 2004 Clozaril (clozapine tablets) Audience: Neuropsychiatric healthcare professionals FDA and Novartis notified healthcare professionals of revision to the WARNINGS section of labeling, describing the increased risk of hyperglycemia and diabetes in patients taking Clozaril. FDA has asked all manufacturers of atypical antipsychotic medications, including Novartis, to add this Warning statement to labeling. 97 98 99 2004 2004 2004 Public Health Advisory: FDA Recommendations Concerning the Use of NSAIDs Audience: All healthcare professionals and consumers The FDA issued a Public Health Advisory summarizing the agency's recent recommendations concerning the use of non-steroidal anti-inflammatory drug products (NSAIDs), including those known as COX-2 selective agents. This advisory was issued because of recently released data from controlled clinical trials showing that the COX-2 selective agents (Vioxx, Celebrex, and Bextra) may be associated with an increased risk of serious cardiovascular events (heart attack and stroke) and after release of preliminary results from a long-term clinical trial which suggested that long-term use of a non-selective NSAID, naproxen (sold as Aleve, Naprosyn and other trade name and generic products), may be associated with an increased cardiovascular risk compared to placebo. The public health advisory is an interim measure, pending further review by FDA of data that continue to be collected. Aranesp (darbepoetin alfa) Jan 2005 Audience: Oncologists, hematologists and other healthcare professionals FDA and Amgen notified healthcare professionals of revisions to the WARNINGS and PRECAUTIONS sections of the prescribing information for Aranesp, indicated for the treatment of chemotherapy-induced anemia in patients with nonmyeloid malignancies. This safety information alerts physicians to the adverse effects observed with other products in this class in association with off-label dosing strategies. Two recent investigational studies with other erythropoietic products permitted or required dosing to achieve hemoglobin levels of greater than 12 grams per deciliter. An increased frequency of adverse patient outcomes, including increased mortality and thrombotic vascular events were reported in these studies. As indicated in the Aranesp prescribing information, the target hemoglobin level should not exceed 12 grams per deciliter in men or women. Year 100 2004 Title Xigris [drotrecogin alfa (activated)] Mar 2005 Audience: Infectious Disease healthcare professionals, Intensivists, and other healthcare professionals Eli Lilly and FDA notified healthcare professionals about revisions to the WARNINGS section of labeling for Xigris [drotrecogin alfa (activated)], a biological therapeutic product indicated for the treatment of adult patients with severe sepsis who are at high risk of death. This warning is based upon analyses of two clinical trial databases. Among patients with single organ dysfunction and recent surgery, all-cause mortality was numerically higher in the Xigris group compared to the placebo group. Patients with single organ dysfunction and recent surgery may not be at high risk of death and therefore may not be among the indicated population. Xigris should be used in these patients only after careful consideration of the risks and benefits. Regulatory Authority/Reg ion Product active ingredient drotrecogin alfa (activated) High risk of death EM FDA-USA enoxaparin sodium injection Dosage adjustment for patients with severe renal impairment (creatinine clearance <30mL/min) who have increased exposure to enoxaparin. TDM/ EM FDA-USA epoetin alfa Changes to hemoglobin rate of rise and target hemoglobin EM FDA-USA hydromorphone HCl Life threatening AEs EM-MG FDA-USA infliximab May be at a higher risk (up to several fold) than the general population for the development of lymphoma. EM FDA-USA infliximab Lymphoma EM FDA-USA Lovenox (enoxaparin sodium injection) Audience: Physicians, pharmacists, and other healthcare providers FDA and Aventis Pharmaceuticals revised the CLINICAL PHARMACOLOGY, PRECAUTIONS, and DOSAGE AND ADMINISTRATION sections of labeling, describing the need for a dosage adjustment for patients with severe renal impairment (creatinine clearance <30mL/min) who have increased exposure to enoxaparin. No specific dosage adjustment is required in patients with mild or moderate renal impairment and in low-weight patients. However, low-weight patients should be observed carefully for signs and symptoms of bleeding. 101 2004 Safety Issue (AE) Intervention Type Procrit (epoetin alfa) Dec 2004 Audience: Oncologists, hematologists and other healthcare professionals Ortho Biotech Products notified healthcare professionals of important changes to the safety information and dosing sections of the product labeling for Procrit. To ensure consistency with labeling for other products in this class, changes to hemoglobin rate of rise and target were made. The new prescribing information recommends that the target hemoglobin in patients with cancer should not exceed 12 grams per deciliter in men and women. 102 2004 103 2004 104 2004 105 2004 Palladone (hydromorphone HCl) [2004 version] Remicade (infliximab) Audience: Rheumatologists, gastroenterologists and other healthcare professionals FDA and Centocor notified healthcare professionals of revisions to the WARNINGS and ADVERSE REACTIONS sections of the prescribing information for Remicade, indicated for the treatment of rheumatoid arthritis and Crohn's disease. In controlled studies of all TNFα-blocking agents, including Remicade, more cases of lymphoma have been observed among patients receiving the agents than among control group patients. Malignancies have also been observed in open-label, uncontrolled clinical studies at a rate several-fold higher than expected in the general population. Patients with Crohn's disease or rheumatoid arthritis, particularly patients with highly active disease and/or chronic exposure to immunosuppressant therapies, may be at a higher risk (up to several fold) than the general population for the development of lymphoma. FDA has recommended a warning concerning malignancy be added to the labeling for all therapeutic agents that block TNF. Remicade (infliximab) Aug 2004 Audience: Rheumatologists, gastroenterologists and other healthcare professionals FDA and Centocor notified healthcare professionals of revisions to the WARNINGS and ADVERSE REACTIONS sections of the prescribing information for Remicade, indicated for the treatment of rheumatoid arthritis and Crohn's disease. In controlled studies of all TNFα-blocking agents, including Remicade, more cases of lymphoma have been observed among patients receiving the agents than among control group patients. Malignancies have also been observed in open-label, uncontrolled clinical studies at a rate several-fold higher than expected in the general population. Patients with Crohn's disease or rheumatoid arthritis, particularly patients with highly active disease and/or chronic exposure to immunosuppressant therapies, may be at a higher risk (up to several fold) than the general population for the development of lymphoma. FDA has recommended a warning concerning malignancy be added to the labeling for all therapeutic agents that block TNF. Year 106 Title Remicade (infliximab) Dec 2004 Audience: Rheumatologists, gastroenterologists and other healthcare professionals FDA and Centocor notified healthcare professionals of revisions to the WARNINGS, ADVERSE REACTIONS sections and PATIENT PACKAGE INSERT of the prescribing information for Remicade, indicated for the treatment of rheumatoid arthritis, Crohn's disease and ankylosing spondylitis. Severe hepatic reactions, including acute liver failure, jaundice, hepatitis and cholestasis, have been reported in postmarketing data in patients receiving Remicade. Autoimmune hepatitis has been diagnosed in some of these cases. Severe hepatic reactions occurred between two weeks to more than a year after initiation of Remicade. Some of these cases were fatal or necessitated liver transplantation. 2004 Regulatory Authority/Reg ion Product active ingredient Safety Issue (AE) Intervention Type infliximab Severe hepatic reactions, including acute liver failure, jaundice, hepatitis and cholestasis, EM FDA-USA levothyroxine sodium Choking, gagging, tablets stuck in throat and dysphagia while taking Levoxyl EM FDA-USA medroxyprogeste rone acetate injectable suspension Loss of significant bone mineral density BBW FDA-USA Levoxyl (levothyroxine sodium) Audience: Endocrinologists and other healthcare professionals FDA and King Pharmaceuticals notified healthcare professionals of revisions to the PRECAUTIONS, ADVERSE REACTIONS and DOSAGE AND ADMINISTRATION sections of labeling, describing reports of choking, gagging, tablets stuck in throat and dysphagia while taking Levoxyl. These reports have predominately occurred when Levoxyl tablets were not taken with water. It is recommended that Levoxyl tablets be taken with a full glass of water. 107 2004 Depo-Provera (medroxyprogesterone acetate injectable suspension) Audience: Reproductive and other healthcare professionals FDA and Pfizer notified healthcare professionals of the addition of a BOXED WARNING along with revisions to the WARNINGS, INDICATIONS AND USAGE, PRECAUTIONS and POSTMARKETING EXPERIENCE sections of the prescribing information to include information on the loss of significant bone mineral density. DepoProvera Contraceptive Injection is indicated only for the prevention of pregnancy in women of child-bearing potential. Bone loss is greater with increasing duration of use and may not be completely reversible. Depo-Provera Contraceptive should be used as a long-term birth control method (eg, longer than 2 years) only if other birth control methods are inadequate. 108 2004 Mifeprex (mifepristone) Nov 2004 Audience: Reproductive healthcare professionals and consumers Danco Laboratories and FDA notified healthcare professionals of revisions to the BOXED WARNING and WARNINGS sections, the EM-MG and PATIENT AGREEMENT of the Prescribing Information to describe serious and sometimes fatal infections and bleeding that may occur following the use of Mifeprex. 109 110 111 2004 2004 2004 Naproxen Audience: Rheumatologists and other healthcare professionals FDA announced that it was reviewing the available scientific information on naproxen following the decision of the National Institute on Aging to halt a clinical trial studying non-steroidal anti-inflammatory drugs in patients at risk of developing Alzheimer's disease. Preliminary information from the study showed some evidence of increased risk of cardiovascular events, when compared to placebo, to patients taking naproxen. FDA advises patients who are currently taking over-the-counter naproxen products to carefully follow the instructions on the label. Patients should not exceed the recommended doses for naproxen (220 milligrams twice daily) and should not take naproxen for longer than ten days unless a physician directs otherwise. Serzone (nefazodone HCl) Audience: Neuropsychiatric healthcare professionals FDA and Bristol-Myers Squibb notified healthcare professionals of revisions to the INDICATIONS AND USAGE, DOSAGE AND ADMINISTRATION, and WARNINGS sections to encourage healthcare providers to engage in a thorough risk-benefit analysis, including consideration of the risk of hepatic failure associated with Serzone treatment, when deciding among alternative treatments available for depression. In addition, healthcare providers and consumers are cautioned about the need for close observation of patients being treated with antidepressants for clinical worsening of the symptoms of depression, for the emergence of suicidality, and for the emergence of a variety of other symptoms that may represent a worsening of the patient's condition. FDA-USA mifepristone Serious and sometimes fatal infections and bleeding EM-MG/ Pt. Agreeme nt FDA-USA naproxen Increased risk of cardiovascular events EM nefazodone HCL Risk of hepatic failure associated with Serzone treatment EM FDA-USA Year 112 Title Viramune (nevirapine) Feb 2004 Audience: Infectious disease and other healthcare professionals Boehringer Ingelheim and FDA notified healthcare professionals of new safety information added to the WARNINGS and Boxed Warning for VIRAMUNE. Severe, life-threatening, and in some cases fatal hepatotoxicity, including fulminant and cholestatic hepatitis, hepatic necrosis and hepatic failure, has been reported in patients treated with VIRAMUNE. These events are often associated with rash. Women, and patients with higher CD4 counts, are at increased risk of these hepatic events. Women with CD4 counts >250 cells/mm3, including pregnant women receiving chronic treatment for HIV infection, are at considerably higher risk of these events. Prodromal signs and symptoms, risk information and monitoring recommendations have been added to the labeling. 2004 Regulatory Authority/Reg ion Product active ingredient Safety Issue (AE) Intervention Type FDA-USA nevirapine Severe, life-threatening, and in some cases fatal hepatotoxicity, including fulminant and cholestatic hepatitis, hepatic necrosis and hepatic failure FDA-USA olanzapine Increased risk of hyperglycemia and diabetes EM FDA-USA oxandrolone Drug interaction with warfarin EM FDA-USA paroxetine HCl Patients with major depressive disorder, both adult and pediatric, may experience worsening of their depressionand/or the emergence of suicidal ideation and behavior (suicidality), EM FDA-USA promethazine HCl Fatal respiratory depression in pts under 2 yo contraindication EM BBW Zyprexa (olanzapine) Mar 2004 Audience: Neuropsychiatric healthcare professionals FDA and Lilly notified healthcare professionals of revision to the WARNINGS section of labeling, describing the increased risk of hyperglycemia and diabetes in patients taking Zyprexa. FDA has asked all manufacturers of atypical antipsychotic medications, including Lilly, to add this Warning statement to labeling. 113 2004 Oxandrin (oxandrolone, USP) Audience: Physicians, pharmacists, and other healthcare professionals Savient Pharmaceuticals, Inc. notified healthcare professionals of an important drug interaction between Oxandrin, a synthetic derivative of testosterone, and the oral anticoagulant warfarin for systemic anticoagulation. Oxandrin is indicated as adjunctive therapy to promote weight gain and for the relief of the bone pain frequently accompanying osteoporosis. Concurrent dosing of Oxandrin and warfarin may result in unexpectedly large increases in the International Normalized Ratio (INR) or prothrombin time (PT). When Oxandrin is prescribed to patients being treated with warfarin, doses of warfarin may need to be decreased significantly to maintain a desirable INR level and diminish the risk of potentially serious bleeding. 114 2004 Paxil (paroxetine HCl) Audience: Neuropsychiatric healthcare professionals FDA and GlaxoSmithKline notified healthcare professionals of revisions to the WARNINGS and PRECAUTIONS sections of labeling to alert healthcare professionals that patients with major depressive disorder, both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality), whether or not they are taking antidepressant medications. The warning recommends patients being treated with antidepressants be observed closely for clinical worsening and suicidality, especially at the beginning of a course of drug therapy, or at the time of dose changes, either increases or decreases. 115 2004 Phenergan (promethazine HCl) Audience: Pediatricians and other healthcare professionals FDA and Wyeth notified healthcare professionals of revisions to the CONTRAINDICATIONS, WARNINGS/Use in Pediatric Patients, and DOSAGE AND ADMINISTRATION sections of the prescribing information for Phenergan. Phenergan is contraindicated for use in pediatric patients less than two years of age because of the potential for fatal respiratory depression. Postmarketing cases of respiratory depression including fatalities, have been reported with use of Phenergan in pediatric patients less than two years of age. Caution should also be exercised when administering Phenergan to pediatric patients two years of age and older. 116 2004 Year 117 Title Seroquel (quetiapine fumarate) Audience: Neuropsychiatric healthcare professionals FDA and AstraZeneca notified healthcare professionals of revision to the WARNINGS section of labeling, describing the increased risk of hyperglycemia and diabetes in patients taking Seroquel. FDA has asked all manufacturers of atypical antipsychotic medications, including AstraZeneca, to add this Warning statement to labeling. 2004 Regulatory Authority/Reg ion Product active ingredient Safety Issue (AE) quetiapine fumarate Increased risk of hyperglycemia and diabetes EM risperidone Increased risk of hyperglycemia and diabetes EMDHCPrevised rituximab Hepatitis B virus (HBV) reactivation with fulminant hepatitis, hepatic failure, and death EM FDA-USA rosuvastatin Increased risk for serious muscle toxicity (myopathy) in certain populations EM FDA-USA Technetium [99m Tc] fanolesomab Serious safety concerns/ serious and life-threatening cardiopulmonary events Voluntar y withdraw al tegaserod maleate Serious consequences of diarrhea and a Precaution for rare reports of ischemic colitis EM FDA-USA Risperdal (risperidone) Aug 2004 Audience: Neuropsychiatric healthcare professionals FDA and Janssen revised the WARNINGS section of labeling, describing the increased risk of hyperglycemia and diabetes in patients taking Risperdal. MedWatch is posting a revised version of a letter originally distributed to health care professionals November 2003. FDA asked all manufacturers of atypical antipsychotic medications, including Janssen, to add this Warning statement to labeling. 118 2004 FDA-USA Rituxan (rituximab) Oct 2004 Audience: Oncologists, hematologists and other healthcare professionals Biogen Idec and Genentech notified healthcare professionals of revisions to the WARNINGS section of the prescribing information due to reports of Hepatitis B virus (HBV) reactivation with fulminant hepatitis, hepatic failure, and death in some patients with hematologic malignancies. Persons at high risk of HBV infection should be screened before initiation of Rituxan. Carriers of hepatitis B should be closely monitored for clinical and laboratory signs of active HBV infection and for signs of hepatitis during and for up to several months following Rituxan therapy. 119 2004 FDA-USA Crestor (rosuvastatin) Jun 2004 Audience: Physicians, pharmacists, and other healthcare professionals FDA issued a Public Health Advisory notifying healthcare professionals of a revised package insert for use in the 22 member states of the European Union (EU). The changes to the European labeling are in response to adverse event reports in patients receiving Crestor and highlight certain patient populations who may be at an increased risk for serious muscle toxicity (myopathy) associated with Crestor use, especially at the highest approved dose of 40 mg. These risk factors and many of the recommendations for how to minimize the risk of myopathy are already captured in the FDA approved labeling for Crestor in the U.S. FDA alerted physicians to carefully read the Crestor product label and follow the recommendations for starting doses, dose adjustments, and maximum daily doses to minimize the risk of myopathy in individual patients. 120 121 2004 2004 NeutroSpec (Technetium [99m Tc] fanolesomab) Audience: Medical imaging specialists, hospital administrators and risk managers.] FDA issued a Public Health Advisory to alert patients and health care providers that Palatin Technologies Inc. and Mallinckrodt have agreed to implement an immediate voluntary market suspension due to serious safety concerns, making NeutroSpec unavailable for approved or investigational uses. Postmarketing reports of serious and life-threatening cardiopulmonary events following the administration of NeutroSpec [Technetium (99m Tc) fanolesomab], a radiodiagnostic agent consisting of a murine IgM monoclonal antibody formulated to be labeled with technetium, indicated for scintigraphic imaging of patients with equivocal signs and symptoms of appendicitis who are five years of age or older. Additional cases of serious cardiopulmonary events including cardiac arrest, hypoxia, dyspnea and hypotension required resuscitation with fluids, vasopressors, and oxygen. Intervention Type Zelnorm (tegaserod maleate) Apr 2004 Audience: Gastroenterologists and other healthcare professionals The FDA and Novartis notified healthcare professionals of an important drug warning and prescribing information for Zelnorm, a serotonin 5-HT4 receptor partial agonist indicated for the short-term treatment of women with irritable bowel syndrome (IBS) whose primary bowel symptom is constipation. This new information relates to a Warning for serious consequences of diarrhea and a Precaution for rare reports of ischemic colitis in post marketing use of Zelnorm. 122 2004 FDA-USA Year 123 Title Desyrel (trazodone HCl) Audience: Neuropsychiatric healthcare professionals FDA and Bristol-Myers Squibb notified healthcare professionals of revisions to the CLINICAL PHARMACOLOGY and PRECAUTIONS sections of the Desyrel labeling. Desyrel is indicated for the treatment of depression. In vitro drug metabolism studies suggest that there is a potential for drug interactions when trazodone is given with the CYP3A4 inhibitors ketoconazole, ritonavir, and indinavir. It is likely that CYP3A4 inhibitors may lead to substantial increases in trazodone plasma concentrations with the potential for adverse effects. If trazodone is used with a potent CYP3A4 inhibitor, a lower dose of trazodone should be considered. Conversely, carbamazepine reduced plasma concentrations of trazodone when coadministered. Patients should be closely monitored to see if there is a need for an increased dose of trazodone when taken with carbamazepine. 2004 Regulatory Authority/Reg ion Product active ingredient Safety Issue (AE) Intervention Type FDA-USA trazodone HCl Potential for drug interactions when trazodone is given with the CYP3A4 inhibitors ketoconazole, ritonavir, and indinavir FDA-USA valdecoxib Life-threatening skin reactions BBW FDA-USA venlafaxine HCl Exposure during pregnancy leading to complications requiring prolonged hospitalization, respiratory support, and tube feeding EM FDA-USA ziprasidone Increased risk of hyperglycemia and diabetes EM FDA-USA zoledronic acid Osteonecrosis of the jaw mainly in cancer patients, EM EM Bextra (valdecoxib) Audience: Healthcare professionals and consumers The FDA announced important new information on side effects associated with the use of Bextra, a COX-2 selective non-steroidal anti-inflammatory drug (NSAID) indicated for the treatment of osteoarthritis, rheumatoid arthritis and dysmenorrhea (menstrual pain). A "boxed" warning, strengthening previous warnings about the risk of life-threatening skin reactions, and a new bolded warning contraindicating the use of Bextra in patients undergoing coronary artery bypass graft (CABG) surgery were added to the label. 124 2004 125 2004 126 2004 Effexor and Effexor XR (venlafaxine HCl) Audience: Neuropsychiatric, obstetric and neonatology healthcare professionals FDA and Wyeth Pharmaceuticals notified healthcare professionals of revisions to the WARNINGS, PRECAUTIONS, and DOSAGE AND ADMINISTRATION sections of labeling to alert healthcare providers of two important safety issues. Neonates exposed to Effexor, other SNRIs (Serotonin and Norepinephrine Reuptake Inhibitors), or SSRIs (Selective Serotonin Reuptake Inhibitors), late in the third trimester of pregnancy have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. Such complications can arise immediately upon delivery. Patients with major depressive disorder, both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality), whether or not they are taking antidepressant medications. The warning recommends patients being treated with antidepressants be observed closely for clinical worsening and suicidality, especially at the beginning of a course of drug therapy, or at the time of dose changes, either increases or decreases. Geodon (ziprasidone) Audience: Neuropsychiatric healthcare professionals FDA and Pfizer notified healthcare professionals of revision to the WARNINGS section of labeling, describing the increased risk of hyperglycemia and diabetes in patients taking Geodon. FDA has asked all manufacturers of atypical antipsychotic medications, including Pfizer, to add this Warning statement to labeling. Zometa (zoledronic acid) Injection Audience: Oncologists, dentists, and other healthcare professionals FDA and Novartis notified healthcare professionals of revisions the PRECAUTIONS and ADVERSE REACTIONS sections of labeling, describing spontaneous reports of osteonecrosis of the jaw mainly in cancer patients, who have received bisphosphonates as a component of their therapy. A dental examination with appropriate preventive dentistry should be considered prior to treatment with bisphosphonates in patients with concomitant risk factors (e.g. cancer, chemotherapy, corticosteroids, poor oral hygiene). 127 2004 Year 128 Title Amevive (alefacept) Audience: Dermatologists and other healthcare professionals [Posted 11/10/2005] Biogen Idec and FDA notified healthcare professionals of revisions to CONTRAINDICATIONS section of the prescribing information for Amevive, indicated for the treatment of adult patients with moderate to severe chronic plaque psoriasis who are candidates for systemic therapy or phototherapy. Amevive should not be administered to patients infected with HIV. Amevive reduces CD4+ T lymphocyte counts, which might accelerate disease progression or increase complications of disease in these patients. In addition, other sections of the product labeling were revised to reflect additional safety information. 2005 Regulatory Authority/Reg ion Product active ingredient FDA-USA alefacept Contraindication with patients infected with HI EM FDA-USA amphetamine Sudden deaths in pediatric patients. Withdra wal antidepressants Risk of suicidality (suicidal thinking or behavior) in adults being treated with antidepressant medications. EM FDA-USA atomoxetine Suicidal thinking in children and adolescents being treated with this medication. BBW FDA-USA Atypical Antipsychotic Drugs Increased mortality in elderly EM Adderall XR (amphetamine) Audience: Neuropsychiatric and other healthcare professionals FDA issued a Public Health Advisory to notify healthcare professionals that Health Canada, the Canadian drug regulatory agency, has suspended the sale of Adderall XR in the Canadian market. Adderall XR is a controlled release amphetamine used to treat patients with Attention Deficit Hyperactivity Disorder (ADHD). The Canadian action was based on U.S. post-marketing reports of sudden deaths in pediatric patients. FDA is continuing to evaluate these and other post-marketing reports of serious adverse events in children, adolescents, and adults being treated with Adderall and related products. Adderall XR is approved in the United States for the treatment of adults and pediatric patients 6-12 years old with ADHD, and Adderall, the immediate release formulation of the drug, is approved for pediatric patients with ADHD. 129 130 131 132 2005 2005 2005 2005 Antidepressant Medications in Adults: Public Health Advisory Audience: Neuropsychiatric healthcare professionals and consumers [UPDATE 07/08/2005] FDA notified healthcare professionals about the availability of updated Healthcare Professional and Patient Information Sheets for antidepressant medications that were the subject of a June 30, 2005 Public Health Advisory issued about the risk of suicidality (suicidal thinking or behavior) in adults being treated with antidepressant medications. [Posted 07/01/2005] In response to recent scientific publications that report the possibility of increased risk of suicidal behavior in adults treated with antidepressants, the FDA has issued a Public Health Advisory to update patients and healthcare providers with the latest information on this subject. Even before the publication of these recent reports, FDA had already begun the process of reviewing available data to determine whether there is an increased risk of suicidal behavior in adults taking antidepressants. The Agency has asked manufacturers to provide information from their trials using an approach similar to that used in the evaluation of the risk of suicidal behavior in the pediatric population taking antidepressants. Strattera (atomoxetine) Sep 2005 Audience: Neuropsychiatric and other healthcare professionals, consumers [Posted 09/29/2005] The FDA directed Eli Lilly and Company (Lilly), the manufacturer of Strattera (atomoxetine), to revise the prescribing information to include a boxed warning and additional warning statements that alert health care providers of an increased risk of suicidal thinking in children and adolescents being treated with this medication. FDA also informed Lilly that a Patient EM-MG (MedGuide) should be provided to patients when Strattera is dispensed. The MedGuide advises patients of the risks associated with and precautions that can be taken when Strattera is dispensed. Further, pediatric patients being treated with Strattera should be closely observed for clinical worsening, as well as agitation, irritability, suicidal thinking or behaviors, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases. Atypical Antipsychotic Drugs Audience: Neuropsychiatric healthcare professionals, patients and caregivers The Food and Drug Administration has issued a public health advisory to alert health care providers, patients, and patient caregivers to new safety information concerning an unapproved, “off-label” use of certain antipsychotic drugs approved for the treatment of schizophrenia and mania. FDA has determined that the treatment of behavioral disorders in elderly patients with dementia with atypical (second generation) antipsychotic medications is associated with increased mortality. Clinical studies of these drugs in this population have shown a higher death rate associated with their use compared to patients receiving a placebo. Safety Issue (AE) Intervention Type FDA-USA Year 133 Title Avastin (bevacizumab) Jan 2005 Audience: Oncologists and other healthcare professionals FDA and Genentech notified healthcare professionals of revisions to the WARNINGS, PRECAUTIONS, ADVERSE EVENTS, and DOSAGE AND ADMINISTRATION sections of the Avastin labeling. Avastin, used in combination with intravenous 5-fluorouracil–based chemotherapy, is indicated for first-line treatment of patients with metastatic carcinoma of the colon or rectum. Arterial thromboembolic events, including cerebral infarction, transient ischemic attacks (TIAs), myocardial infarction (MI), and angina, occurred at a higher incidence in patients receiving Avastin in combination with chemotherapy as compared to those receiving chemotherapy alone. These events were fatal in some instances. 2005 Regulatory Authority/Reg ion FDA-USA Product active ingredient bevacizumab Arterial thromboembolic events, including cerebral infarction, transient ischemic attacks (TIAs), myocardial infarction (MI), and angina in those taking chemotherapy EM bupropion Risk of suicidality (suicidal thinking or behavior) in adults being treated with antidepressant medications. EM celecoxib CV risks, serious, potential life-threatening gastrointestinal (GI) bleeding EM-MG celecoxib CV risks, reports of serious and potentially lifethreatening skin reactions, including deaths BBW cetuximab Hypomagnesemia and recommendations for electrolyte monitoring. EM Wellbutrin (bupropion) Audience: Neuropsychiatric healthcare professionals and consumers [UPDATE 07/08/2005] FDA notified healthcare professionals about the availability of updated Healthcare Professional and Patient Information Sheets for antidepressant medications that were the subject of a June 30, 2005 Public Health Advisory issued about the risk of suicidality (suicidal thinking or behavior) in adults being treated with antidepressant medications. [Posted 07/01/2005] possibility of increased risk of suicidal behavior in adults treated with antidepressants, the FDA has issued a Public Health Advisory to update patients and healthcare providers with the latest information on this subject. 134 2005 FDA-USA Celebrex (celecoxib) June 2005 Audience: Healthcare professionals and consumers FDA has requested that sponsors of all non-steroidal anti-inflammatory drugs (NSAID) make labeling changes to their products. FDA recommended proposed labeling for both the prescription and over-the-counter (OTC) NSAIDs and a EM-MG for the entire class of prescription products. All sponsors of marketed prescription NSAIDs, including Celebrex (celecoxib), a COX-2 selective NSAID, have been asked to revise the labeling (package insert) for their products to include a boxed warning, highlighting the potential for increased risk of cardiovascular (CV) events and the well described, serious, potential life-threatening gastrointestinal (GI) bleeding associated with their use. FDA regulation 21CFR 208 requires a EM-MG to be provided with each prescription that is dispensed for products that FDA determines pose a serious and significant concern. 135 136 137 2005 2005 2005 FDA-USA Celebrex (celecoxib) Apr 2005 Audience: Healthcare professionals and consumers After concluding that the overall risk versus benefit profile is unfavorable, FDA has requested Pfizer, Inc. to voluntarily withdraw Bextra (valdecoxib) from the market. This request is based on: The lack of adequate data on the cardiovascular safety of long-term use of Bextra, along with the increased risk of adverse cardiovascular (CV) events in short-term coronary artery bypass surgery (CABG) trials that FDA believes may be relevant to chronic use. Reports of serious and potentially life-threatening skin reactions, including deaths, in patients using Bextra. The risk of these reactions in individual patients is unpredictable, occurring in patients with and without a prior history of sulfa allergy, and after both short- and long-term use. Lack of any demonstrated advantages for Bextra compared with other NSAIDs. Patients currently taking Bextra should contact their physicians to consider alternative treatments. FDA is also asking manufacturers of all marketed prescription NSAIDs, including Celebrex (celecoxib), a COX-2 selective NSAID, to revise the labeling (package insert) for their products to include a boxed warning and a EM-MG. The boxed warning will highlight the potential for increased risk of CV events with these drugs and the well-described, serious, and potentially life-threatening gastrointestinal (GI) bleeding associated with their use. The EM-MG will accompany every prescription NSAID at the time it is dispensed to better inform patients about the CV and GI risks. Finally, FDA is asking manufacturers of non-prescription (OTC) NSAIDs to revise their labeling to include more specific information about the potential GI and CV risks, and information to assist consumers in the safe use of the drug. This announcement does not apply to aspirin as it has clearly been shown to reduce the risk of serious adverse CV events in certain patient populations. Erbitux (cetuximab) Audience: Oncologists and other healthcare professionals [Posted 09/14/2005] ImClone Systems Incorporated, Bristol-Myers Squibb Company and the FDA notified healthcare professionals of changes to the WARNINGS, PRECAUTIONS, ADVERSE REACTIONS, and DOSAGE AND ADMINISTRATION sections of the prescribing information for Erbitux, indicated for the treatment of epidermal growth factor receptor (EGFR) expressing metastatic colorectal carcinoma. The WARNINGS and DOSAGE AND ADMINISTRATION sections have been revised to notify healthcare providers about specific recommendations on observation periods following Erbitux infusion. In addition, the PRECAUTIONS and ADVERSE REACTIONS sections have been revised to discuss results seen in Erbitux clinical trials regarding an increased incidence of hypomagnesemia and recommendations for electrolyte monitoring. FDA-USA FDA-USA Safety Issue (AE) Intervention Type Year 138 139 140 2005 Title Celexa (citalopram) Public Health Advisory: Suicidality in Adults Being Treated with Antidepressant Medications Audience: Neuropsychiatric healthcare professionals and consumers [UPDATE 07/08/2005] FDA notified healthcare professionals about the availability of updated Healthcare Professional and Patient Information Sheets for antidepressant medications that were the subject of a June 30, 2005 Public Health Advisory issued about the risk of suicidality (suicidal thinking or behavior) in adults being treated with antidepressant medications. [Posted 07/01/2005] In response to recent scientific publications that report the possibility of increased risk of suicidal behavior in adults treated with antidepressants, the FDA has issued a Public Health Advisory to update patients and healthcare providers with the latest information on this subject. Even before the publication of these recent reports, FDA had already begun the process of reviewing available data to determine whether there is an increased risk of suicidal behavior in adults taking antidepressants. The Agency has asked manufacturers to provide information from their trials using an approach similar to that used in the evaluation of the risk of suicidal behavior in the pediatric population taking antidepressants. This effort will involve hundreds of clinical trials and may take more than a year to complete. Clozaril (clozapine) Audience: Neuropsychiatric healthcare professionals and patients [Posted 01/13/2006] Novartis and FDA notified healthcare professionals of revisions to the BOXED WARNING, WARNINGS, CONTRAINDICATIONS, PRECAUTIONS (Information for Patients and Pharmacokinetic-Related Interactions subsections), and ADVERSE REACTIONS (Postmarketing Clinical Experience subsection) sections of the prescribing information for Clozaril (clozapine) tablets. Recommendations from the FDA's Psychopharmacological Drugs Advisory Committee regarding the white blood cell monitoring schedule, required for all clozapine users, has resulted in modification in the monitoring schedule. Additional labeling changes address safety issues related to dementia-related psychosis, parlytic ileus, hypercholesterolemia and pharmacokinetic interaction with citalopram. 2005 2005 COX-2 Selective (includes Bextra, Celebrex, and Vioxx) and Non-Selective Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) Audience: Healthcare professionals and consumers FDA has requested that sponsors of all non-steroidal antiinflammatory drugs (NSAID) make labeling changes to their products. FDA recommended proposed labeling for both the prescription and over-the-counter (OTC) NSAIDs and a EM-MG for the entire class of prescription products. All sponsors of marketed prescription NSAIDs, including Celebrex (celecoxib), a COX-2 selective NSAID, have been asked to revise the labeling (package insert) for their products to include a boxed warning, highlighting the potential for increased risk of cardiovascular (CV) events and the well described, serious, potential life-threatening gastrointestinal (GI) bleeding associated with their use. FDA regulation 21CFR 208 requires a EM-MG to be provided with each prescription that is dispensed for products that FDA determines pose a serious and significant public health concern. Regulatory Authority/Reg ion Product active ingredient Safety Issue (AE) Intervention Type citalopram Suicidality in Adults Being Treated with Antidepressant Medications EM FDA-USA clozapine Dementia-related psychosis, parlytic ileus, hypercholesterolemia and pharmacokinetic interaction with citalopram BBWrevisions FDA-USA COX-2 Selective (includes Bextra, Celebrex, and Vioxx) and NonSelective NonSteroidal AntiInflammatory Drugs (NSAIDs) Increased risk of cardiovascular (CV) events and the well described, serious, potential lifethreatening gastrointestinal (GI) bleeding BBW FDA-USA darbepoetin alfa Pure red cell aplasia and severe anemia EM duloxetine Risk of suicidality (suicidal thinking or behavior) in adults EM FDA-USA Aranesp (darbepoetin alfa) Audience: Hematology/Oncology, Nephrology and other healthcare professionals [Posted 12/01/2005] Amgen and FDA notified healthcare professionals of revision to the WARNINGS, ADVERSE REACTIONS, and DOSAGE AND ADMINISTRATION sections of the prescribing information for Aranesp. The revised labeling provides updated safety information on reports of pure red cell aplasia and severe anemia, with or without other cytopenias, associated with neutralizing antibodies to erythropoietin in patients treated with Aranesp. This has been reported predominantly in patients with CRF receiving Aranesp by subcutaneous administration. Recommendations for evaluation and treatment are provided in the new prescribing information. 141 142 2005 2005 Cymbalta (duloxetine) Public Health Advisory: Suicidality in Adults Being Treated with Antidepressant Medications Audience: Neuropsychiatric healthcare professionals and consumers [UPDATE 07/08/2005] FDA notified healthcare professionals about the availability of updated Healthcare Professional and Patient Information Sheets for antidepressant medications that were the subject of a June 30, 2005 Public Health Advisory issued about the risk of suicidality (suicidal thinking or behavior) in adults being treated with antidepressant medications. [Posted 07/01/2005] In response to recent scientific publications that report the possibility of increased risk of suicidal behavior in adults treated with antidepressants, the FDA has issued a Public Health Advisory to update patients and healthcare providers with the latest information on this subject. Even before the publication of these recent reports, FDA had already begun the process of reviewing available data to determine whether there is an increased risk of suicidal behavior in adults taking antidepressants. FDA-USA Year 143 Title Cymbalta (duloxetine HCl) Oct 2005 Audience: Neuropsychiatric and other healthcare professionals [Posted 10/17/2005] Eli Lilly and FDA notified healthcare professionals of revision to the PRECAUTIONS/Hepatotoxicity section of the prescribing information for Cymbalta (duloxetine HCl), indicated for treatment of major depressive disorder and diabetic peripheral neuropathic pain. Postmarketing reports of hepatic injury (including hepatitis and cholestatic jaundice) suggest that patients with preexisting liver disease who take duloxetine may have an increased risk for further liver damage. The new labeling extends the Precaution against using Cymbalta in patients with substantial alcohol use to include those patients with chronic liver disease. It is recommended that Cymbalta not be administered to patients with any hepatic insufficiency. 2005 Regulatory Authority/Reg ion Product active ingredient duloxetine HCl Hepatic injury (including hepatitis and cholestatic jaundice) EM efalizumab Postmarketing reports of thrombocytopenia and serious infections including necrotizing fasciitis, tuberculous pneumonia, bacterial sepsis with seeding of distant sites, severe pneumonia with neutropenia, and worsening of infection (e.g. cellulitis, pneumonia) EM FDA-USA efavirenz Neural tube defects in infants born to women with first trimester exposure to SustivaAn antiretroviral pregnancy registry has been established to monitor fetal outcomes of pregnant women exposed to Sustiva. Registry Pregnanc y FDA-USA epoetin alfa Pure red cell aplasia and severe anemia EM FDA-USA escitalopram Risk of suicidality (suicidal thinking or behavior) EM FDA-USA Raptiva (efalizumab) Revised Warnings Audience: Dermatological and other healthcare professionals [Posted 07/20/2005] Genentech and FDA revised the WARNINGS, ADVERSE REACTIONS sections and Patient Information Sheet for RAPTIVA (efalizumab), indicated for the treatment of adult patients (18 years or older) with chronic moderate to severe plaque psoriasis who are candidates for systemic therapy or phototherapy. Healthcare professionals and patients were informed about reports of immune-mediated hemolytic anemia and warnings regarding postmarketing reports of thrombocytopenia and serious infections including necrotizing fasciitis, tuberculous pneumonia, bacterial sepsis with seeding of distant sites, severe pneumonia with neutropenia, and worsening of infection (e.g. cellulitis, pneumonia) despite antimicrobial treatment. [Posted 07/20/2005] Genentech and FDA revised the WARNINGS, ADVERSE REACTIONS sections and Patient Information Sheet for RAPTIVA (efalizumab), indicated for the treatment of adult patients (18 years or older) with chronic moderate to severe plaque psoriasis who are candidates for systemic therapy or phototherapy. Healthcare professionals and patients were informed about reports of immune-mediated hemolytic anemia and warnings regarding postmarketing reports of thrombocytopenia and serious infections including necrotizing fasciitis, tuberculous pneumonia, bacterial sepsis with seeding of distant sites, severe pneumonia with neutropenia, and worsening of infection (e.g. cellulitis, pneumonia) despite antimicrobial treatment. 144 2005 FDA-USA Sustiva (efavirenz) Capsules and Tablets Audience: Infectious disease and other healthcare professionals, consumers Bristol-Myers Squibb and FDA notified healthcare professionals of revisions to the WARNINGS, PRECAUTIONS/Pregnancy and Information for Patients, and PATIENT INFORMATION sections of the prescribing information for Sustiva (efavirenz), indicated in the treatment of HIV-1 infection. The revisions are a result of four retrospective reports of neural tube defects in infants born to women with first trimester exposure to Sustiva, including three cases of meningomyelocele and one Dandy Walker Syndrome. As Sustiva may cause fetal harm when administered during the first trimester to a pregnant woman, pregnancy should be avoided in women receiving Sustiva. An antiretroviral pregnancy registry has been established to monitor fetal outcomes of pregnant women exposed to Sustiva. 145 2005 Epogen (epoetin alfa) Dec 2005 Audience: Hematology/Oncology, Nephrology and other healthcare professionals [Posted 12/01/2005] Amgen, Ortho Biotech and FDA notified healthcare professionals of revision to the WARNINGS, PRECAUTIONS, ADVERSE REACTIONS, and DOSAGE AND ADMINISTRATION sections of the prescribing information for Epogen and Procrit. The revised labeling provides updated safety information on reports of pure red cell aplasia and severe anemia, with or without other cytopenias, associated with neutralizing antibodies to erythropoietin in patients treated with these products. This has been reported predominantly in patients with CRF receiving these products by subcutaneous administration. Recommendations for evaluation and treatment are provided in the new prescribing information. 146 147 2005 2005 Lexapro (escitalopram) Audience: Neuropsychiatric healthcare professionals and consumers [UPDATE 07/08/2005] FDA notified healthcare professionals about the availability of updated Healthcare Professional and Patient Information Sheets for antidepressant medications that were the subject of a June 30, 2005 Public Health Advisory issued about the risk of suicidality (suicidal thinking or behavior) in adults being treated with antidepressant medications. [Posted 07/01/2005] In response to recent scientific publications that report the possibility of increased risk of suicidal behavior in adults treated with antidepressants, the FDA has issued a Public Health Advisory to update patients and healthcare providers with the latest information on this subject. Even before the publication of these recent reports, FDA had already begun the process of reviewing available data to determine whether there is an increased risk of suicidal behavior in adults taking antidepressants. Safety Issue (AE) Intervention Type Year 148 2005 149 2005 150 151 152 Title Fentanyl Transdermal (Skin) Patch Audience: Healthcare professionals, patients and their caregivers [Posted 07/15/2005] FDA issued a public health advisory to alert health care professionals, patients and their caregivers of reports of death and other serious side effects from overdoses of fentanyl in patients using fentanyl transdermal (skin) patches for pain control. Deaths and overdoses have occurred in patients using both the brand name product Duragesic and the generic product. Some patients and health care providers may not be fully aware of the dangers of this very strong narcotic painkiller. The directions for using the fentanyl skin patch must be followed exactly to prevent death or other serious side effects from overdosing with fentanyl Duragesic (fentanyl) [2005 version] Duragesic (fentanyl transdermal system) Audience: Pharmacists, other healthcare professionals, and consumers [Posted 07/08/2005] Janssen and FDA notified healthcare professionals of changes to the BOXED WARNING/WARNINGS, CONTRAINDICATIONS, PRECAUTIONS, and DOSAGE AND ADMINISTRATION sections of the prescribing information for Duragesic. These changes include important safety information in the following areas of the labeling: Use Only in Opioid-Tolerant Patients, Misuse, Abuse and Diversion, Hypoventilation (Respiratory Depression), Interactions with CYP3A4 Inhibitors, Damaged or Cut Patches, Accidental Exposure to Fentanyl, Chronic Pulmonary Disease, Head Injuries and Intracranial Pressure, Interactions with Other CNS Depressants, and Interactions with Alcohol and Drugs of Abuse 2005 2005 Prozac (fluoxetine) Audience: Neuropsychiatric healthcare professionals and consumers [UPDATE 07/08/2005] FDA notified healthcare professionals about the availability of updated Healthcare Professional and Patient Information Sheets for antidepressant medications that were the subject of a June 30, 2005 Public Health Advisory issued about the risk of suicidality (suicidal thinking or behavior) in adults being treated with antidepressant medications. [Posted 07/01/2005] In response to recent scientific publications that report the possibility of increased risk of suicidal behavior in adults treated with antidepressants, the FDA has issued a Public Health Advisory to update patients and healthcare providers with the latest information on this subject. Even before the publication of these recent reports, FDA had already begun the process of reviewing available data to determine whether there is an increased risk of suicidal behavior in adults taking antidepressants. 2005 Advair Diskus (fluticasone propionate & salmeterol inhalation powder) Audience: Pulmonologists, other healthcare professionals and consumers [Posted 11/18/2005] FDA notified manufacturers of Advair Diskus, Foradil Aerolizer, and Serevent Diskus to update their existing product labels with new warnings and a EM-MG for patients to alert health care professionals and patients that these medicines may increase the chance of severe asthma episodes, and death when those episodes occur. All of these products contain long-acting beta2-adrenergic agonists (LABA). Even though LABAs decrease the frequency of asthma episodes, these medicines may make asthma episodes more severe when they occur. A EM-MG with information about these risks will be given to patients when a prescription for a LABA is filled or refilled. Regulatory Authority/Reg ion Product active ingredient Safety Issue (AE) Intervention Type FDA-USA fentanyl Overdoses leading to death and other serious side effects EM FDA-USA fentanyl Deaths and life threatening AEs EM-MG FDA-USA fentanyl transdermal system Use Only in Opioid-Tolerant Patients, Misuse, Abuse and Diversion, Hypoventilation (Respiratory Depression), Interactions with CYP3A4 Inhibitors, Accidental Exposure to Fentanyl, Chronic Pulmonary Disease, Head Injuries and Intracranial Pressure, Interactions with Other CNS Depressants, and Interactions with Alcohol and Drugs of Abuse BBW revised FDA-USA fluoxetine Risk of suicidality (suicidal thinking or behavior) EM FDA-USA fluticasone propionate & salmeterol inhalation powder May increase the chance of severe asthma episodes, and death EM-EMMG Year 153 2005 Title Fluvoxamine Audience: Neuropsychiatric healthcare professionals and consumers [UPDATE 07/08/2005] FDA notified healthcare professionals about the availability of updated Healthcare Professional and Patient Information Sheets for antidepressant medications that were the subject of a June 30, 2005 Public Health Advisory issued about the risk of suicidality (suicidal thinking or behavior) in adults being treated with antidepressant medications. [Posted 07/01/2005] In response to recent scientific publications that report the possibility of increased risk of suicidal behavior in adults treated with antidepressants, the FDA has issued a Public Health Advisory to update patients and healthcare providers with the latest information on this subject. Even before the publication of these recent reports, FDA had already begun the process of reviewing available data to determine whether there is an increased risk of suicidal behavior in adults taking antidepressants. Regulatory Authority/Reg ion 2005 Safety Issue (AE) Intervention Type FDA-USA fluvoxamine Increased risk of suicidal behavior in adults treated with antidepressants, FDA-USA formoterol fumarate inhalation powder May increase the chance of severe asthma episodes, and death when those episodes occur EM FDA-USA galantamine hydrobromide Increased mortality in the elderly EM FDA-USA hydromorphone HCl Potential for severe side effects if Palladone is taken with alcohol Withdra wal FDA-USA ibritumomab tiuxetan Severe cutaneous or mucocutaneous reactions, some with fatal outcome BBW revised Foradil Aerolizer (formoterol fumarate inhalation powder) Audience: Pulmonologists, other healthcare professionals and consumers [Posted 11/18/2005] FDA notified manufacturers of Advair Diskus, Foradil Aerolizer, and Serevent Diskus to update their existing product labels with new warnings and a EM-MG for patients to alert health care professionals and patients that these medicines may increase the chance of severe asthma episodes, and death when those episodes occur. All of these products contain long-acting beta2-adrenergic agonists (LABA). Even though LABAs decrease the frequency of asthma episodes, these medicines may make asthma episodes more severe when they occur. A EM-MG with information about these risks will be given to patients when a prescription for a LABA is filled or refilled. 154 Product active ingredient EM Reminyl (galantamine hydrobromide) Audience: Neuropsychiatric healthcare professionals Ortho-McNeil Neurologics modified the PRECAUTIONS section of the Prescribing Information for Reminyl, approved only for the treatment of mild to moderate Alzheimer’s Disease. The changes provide new safety information regarding the results of two randomized, placebo-controlled trials of 2 years duration in subjects with mild cognitive impairment (MCI). A total of 13 subjects on REMINYL (n=1026) and 1 subject on placebo (n=1022) died. The deaths were due to various causes which could be expected in an elderly population. About half of the REMINYL deaths appeared to result from various vascular causes (myocardial infarction, stroke), and sudden death. 155 2005 Palladone (hydromorphone HCl) Audience: Pain Specialists and other healthcare professionals [Posted 07/14/2005] FDA issued a public health advisory to notify health care professionals and consumers that the sponsor of Palladone, Purdue Pharma, has agreed to suspend sales and marketing of Palladone (hydromorphone HCl, extended release capsules), a potent narcotic painkiller, because of the potential for severe side effects if Palladone is taken with alcohol. Drinking alcohol while taking Palladone may cause rapid release of hydromorphone, leading to high drug levels in the body, with potentially fatal effects. High drug levels of hydromorphone may depress or stop breathing, cause coma, and even cause death. 156 2005 Zevalin (ibritumomab tiuxetan). Audience: Hemato-oncologists and other healthcare professionals. [Posted 10/28/2005] Biogen Idec and FDA notified healthcare professionals of revision to BOXED WARNINGS, WARNINGS, and ADVERSE REACTIONS sections of the Prescribing Information to describe severe cutaneous or mucocutaneous reactions, some with fatal outcome, that have been reported in association with the Zevalin therapeutic regimen in the post-marketing experience. Patients experiencing a severe cutaneous or mucocutaneous reaction should not receive any further components of the Zevalin therapeutic regimen and should seek prompt medical evaluation. 157 2005 Year 158 Title Avonex (interferon beta-1a) Audience: Neurologists and other healthcare professionals FDA and Biogen notified healthcare professionals of revisions to the WARNINGS, PRECAUTIONS/Drug Interactions and ADVERSE REACTIONS/Post-Marketing Experience sections and EM-MG. Severe hepatic injury, including cases of hepatic failure, has been reported in patients taking Avonex. Asymptomatic elevation of hepatic transaminases has also been reported, and in some patients has recurred upon rechallenge. In some cases, these events have occurred in the presence of other drugs that have been associated with hepatic injury. The potential risk of Avonex used in combination with known hepatotoxic drugs or other products (e.g. alcohol) should be considered prior to Avonex administration, or when adding new agents to the regimen of patients already on Avonex. 2005 Regulatory Authority/Reg ion FDA-USA Product active ingredient interferon beta1a Safety Issue (AE) Severe hepatic injury, including cases of hepatic failure EM Accutane and Isotretinoin Audience: Dermatological, other healthcare professionals and patients [Posted 08/12/2005] FDA notified healthcare professionals and patients of the approval of a strengthened risk management program, called iPLEDGE, for Accutane and generic isotretinoin. The strengthened program requires registration of wholesalers, prescribers, pharmacies and patients who agree to accept specific responsibilities designed to minimize pregnancy exposures in order to distribute, prescribe, dispense and use Accutane. In addition to approving the iPLEDGE program, FDA has approved changes to the existing warnings, patient information and informed consent document so that patients and prescribers can better identify and manage the risks of psychiatric symptoms and depression before and after prescribing isotretinoin. 159 2005 FDA-USA Isotretinoin Teratogenicity Registry wholesale rs, prescribe rs, pharmaci es and patients FDA-USA Long-acting Beta2Adrenergic Agonists May increase the chance of severe asthma episodes, and death when those episodes occur. EM-MG mifepristone Died from sepsis (severe illness caused by infection of the bloodstream) after medical abortion with mifepristone and misoprostol EMDHCPL mifepristone Septic deaths; Heavy Bleeding; Abdominal Pain or “Feeling Sick”; Fever EM-MG Long-acting Beta2-Adrenergic Agonists Audience: Pulmonologists, other healthcare professionals and consumers [Posted 11/18/2005] FDA notified manufacturers of Advair Diskus, Foradil Aerolizer, and Serevent Diskus to update their existing product labels with new warnings and a EM-MG for patients to alert health care professionals and patients that these medicines may increase the chance of severe asthma episodes, and death when those episodes occur. All of these products contain long-acting beta2-adrenergic agonists (LABA). Even though LABAs decrease the frequency of asthma episodes, these medicines may make asthma episodes more severe when they occur. A EM-MG with information about these risks will be given to patients when a prescription for a LABA is filled or refilled. 160 161 162 2005 2005 2005 Mifeprex (mifepristone) July 2005 Audience: Reproductive healthcare professionals Mifeprex (mifepristone) [2005 version] Intervention Type FDA-USA FDA-USA Year 163 Title Remeron (mirtazapine) Audience: Neuropsychiatric healthcare professionals and consumers [UPDATE 07/08/2005] FDA notified healthcare professionals about the availability of updated Healthcare Professional and Patient Information Sheets for antidepressant medications that were the subject of a June 30, 2005 Public Health Advisory issued about the risk of suicidality (suicidal thinking or behavior) in adults being treated with antidepressant medications. [Posted 07/01/2005] In response to recent scientific publications that report the possibility of increased risk of suicidal behavior in adults treated with antidepressants, the FDA has issued a Public Health Advisory to update patients and healthcare providers with the latest information on this subject. Even before the publication of these recent reports, FDA had already begun the process of reviewing available data to determine whether there is an increased risk of suicidal behavior in adults taking antidepressants. The Agency has asked manufacturers to provide information from their trials using an approach similar to that used in the evaluation of the risk of suicidal behavior in the pediatric population taking antidepressants. This effort will involve hundreds of clinical trials and may take more than a year to complete. 2005 Regulatory Authority/Reg ion Product active ingredient Safety Issue (AE) Intervention Type FDA-USA mirtazapine Immune-mediated hemolytic anemia Postmarketing reports of thrombocytopenia and serious infections including necrotizing fasciitis, tuberculous pneumonia, bacterial sepsis with seeding of distant sites, severe pneumonia with neutropenia, and worsening of infection (e.g. cellulitis, pneumonia) despite antimicrobial treatment FDA-USA mitoxantrone for injection concentrate Adverse effects on survival and kidney function EMDHCPL FDA-USA mitoxantrone for injection concentrate Risks of cardiotoxicity EMDHCPL Patients should not consume alcohol while taking Avinza BBW strengthe ned /EM warning strengthe ned EM Natrecor (nesiritide) May 2005 Audience: Cardiologists/cardiovascular healthcare professionals Scios and FDA notified healthcare professionals of revisions to the ADVERSE REACTIONS/Effect on Mortality section of the prescribing information for Natrecor [nesiritide], indicated for patients with acutely decompensated congestive heart failure. The Dear Healthcare Professional letter also provided information from Scios on several published reports that raise the question of whether the product may have adverse effects on survival and kidney function compared to control agents (generally nitroglycerin and diuretics). 164 2005 Novantrone (mitoxantrone for injection concentrate) Audience: Neurologists, oncologists, cardiologists, and consumers Serono and FDA notified healthcare professionals of revisions to the BOXED WARNING, WARNINGS, and DOSAGE AND ADMINISTRATION sections of the prescribing information for Novantrone [mitoxantrone], indicated for treatment of multiple sclerosis (MS). The Dear Healthcare Professional letter provides additional information concerning the risks of cardiotoxicity associated with Novantrone and also provides supplemental information regarding secondary acute myelogenous leukemia (AML) reported in MS patients treated with Novantrone. 165 2005 Avinza (morphine sulfate extended-release capsules) Audience: Pain specialists, other healthcare professionals and consumers [Posted 11/03/2005] Ligand Pharmaceuticals Inc. and FDA notified healthcare professionals of revisions to BOXED WARNING, WARNINGS, PRECAUTIONS, CLINICAL PHARMACOLOGY, and DOSAGE AND ADMINISTRATION sections of the prescribing information to highlight and strengthen the warning that patients should not consume alcohol while taking Avinza. Additionally, patients must not use prescription or non-prescription medications containing alcohol while on Avinza therapy. 166 2005 FDA-USA morphine sulfate Year 167 168 2005 2005 Title Tysabri (natalizumab) Public Health Advisory Audience: Neurological and other healthcare professionals [02/28/2005] FDA issued a public health advisory to inform patients and health care providers about the suspended marketing of Tysabri (natalizumab) due to two serious adverse events reported with its use. FDA received reports of one confirmed, fatal case and one possible case of progressive multifocal leukoencephalopathy (PML) in patients receiving Tysabri for multiple sclerosis. Although the relationship between Tysabri and PML is not known at this time, because of the rare, serious and often fatal nature of PML, FDA announced the following, effective immediately: Biogen Idec is voluntarily suspending marketing of Tysabri. Biogen Idec is suspending dosing of Tysabri in clinical trials and is notifying patients and investigators of the possible association between Tysabri and PML Patients being treated with Tysabri should contact their physician to discuss appropriate alternative treatments. At this time, there are no specific diagnostic or therapeutic interventions recommended for patients who have been taking Tysabri, other than to discontinue its use. Physicians should evaluate all patients who have received Tysabri and who have signs or symptoms suggestive of PML. Serzone (nefazodone) Audience: Neuropsychiatric healthcare professionals and consumers [UPDATE 07/08/2005] FDA notified healthcare professionals about the availability of updated Healthcare Professional and Patient Information Sheets for antidepressant medications that were the subject of a June 30, 2005 Public Health Advisory issued about the risk of suicidality (suicidal thinking or behavior) in adults being treated with antidepressant medications. [Posted 07/01/2005] In response to recent scientific publications that report the possibility of increased risk of suicidal behavior in adults treated with antidepressants, the FDA has issued a Public Health Advisory to update patients and healthcare providers with the latest information on this subject. Even before the publication of these recent reports, FDA had already begun the process of reviewing available data to determine whether there is an increased risk of suicidal behavior in adults taking antidepressants. Regulatory Authority/Reg ion FDA-USA FDA-USA Safety Issue (AE) Intervention Type natalizumab Progressive multifocal leukoencephalopathy (PML) Voluntar y withdraw al nefazodone HCL Risk of suicidality (suicidal thinking or behavior) in antidepressant medications EM nesiritide Worsened renal function and mortality, EP recomme nded nevirapine Higher observed risk of serious liver toxicity in patients with higher CD4 cell counts prior to initiation of therapy TDM Product active ingredient Natrecor (nesiritide) July 2005 Audience: Cardiologists/cardiovascular healthcare professionals [Posted 07/18/2005] Scios and FDA notified healthcare professionals about the recommendations of an expert panel of cardiology and heart failure clinicians with regard to NATRECOR (nesiritide). With respect to recent questions raised about worsened renal function and mortality, the panel provided a consensus statement on each issue, provided advice on the ongoing and planned clinical development program, made recommendations about the appropriate use of the drug and recommended an educational campaign to ensure that clinicians understand when the use of NATRECOR is appropriate and when it is not appropriate. 169 170 2005 2005 FDA-USA Viramune (nevirapine) Jan 2005 Audience: Infectious disease and other healthcare professionals FDA issued a public health advisory to inform health care providers and patients about recent safety-related changes to the nevirapine (Viramune®) label and about appropriate use of HIV triple combination therapy containing nevirapine, a treatment option in the United States which is increasingly being used globally. The Indications and Usage section now recommends against starting nevirapine treatment in women with CD4+cell counts greater than 250 cells/mm3 unless benefits clearly outweigh risks. This recommendation is based on a higher observed risk of serious liver toxicity in patients with higher CD4 cell counts prior to initiation of therapy. In addition, the revised label now includes a EM-MG to inform patients about risks associated with nevirapine when used for the treatment of HIV. FDA-USA Trileptal (oxcarbazepine) Tablets and Oral Solution Audience: Neuropsychiatric healthcare professionals and consumers Novartis Pharmaceuticals and FDA notified healthcare professionals about revisions to the WARNINGS and PRECAUTIONS sections of the prescribing information for TRILEPTAL (oxcarbazepine) tablets and oral suspension, indicated for use as monotherapy or adjunctive therapy in the treatment of partial seizures in adults and children ages 416 years with epilepsy. The updated WARNINGS section describes serious dermatological reactions, including StevensJohnson syndrome (SJS) and toxic epidermal necrolysis (TEN) that have been reported in both children and adults in association with Trileptal use. The PRECAUTIONS section has been updated to include language regarding multi-organ hypersensitivity reactions that have been reported in association with Trileptal use. 171 172 2005 2005 Aredia (pamidronate disodium), Zometa (zoledronic acid) Audience: Dental and oncologic healthcare professionals Novartis and FDA notified dental healthcare professionals of revisions to the prescribing information to describe the occurence of osteonecrosis of the jaw (ONJ) observed in cancer patients receiving treatment with intravenous bisphosphonates, Aredia (pamidronate disodium) and Zometa (zoledronic acid). The prescribing information recommends that cancer patients receive a dental examination prior to initiating therapy with intravenous bisphosphonates (Aredia and Zometa), and avoid invasive dental procedures while receiving bisphosphonate treatment. For patients who develop ONJ FDA-USA oxcarbazepine FDA-USA pamidronate disodium and zoledronic acid serious dermatological reactions, including StevensJohnson syndrome (SJS) and toxic epidermal necrolysis (TEN) Recommendation that cancer patients receive a dental examination prior to initiating therapy with intravenous bisphosphonates (Aredia and Zometa), and EM TDM Year 173 174 175 Title while on bisphosphonate therapy, dental surgery may exacerbate the condition. Aredia is used in the treatment of hypercalcemia of malignancy, Paget’s disease, osteolytic bone metastases of breast cancer and osteolytic lesions of multiple myeloma. Zometa is used in the treatment of hypercalcemia of malignancy, the treatment of patients with multiple myeloma and patients with documented bone metastases from solid tumors, in conjunction with standard antineoplastic therapy. Paroxetine HCl - Paxil and generic paroxetine Audience: Neuropsychiatric and other healthcare professionals [Posted 12/08/2005] The FDA has determined that exposure to paroxetine in the first trimester of pregnancy may increase the risk for congenital malformations, particularly cardiac malformations. At the FDA’s request, the manufacturer has changed paroxetine’s pregnancy category from C to D and added new data and recommendations to the WARNINGS section of paroxetine’s prescribing information. FDA is awaiting the final results of the recent studies and accruing additional data related to the use of paroxetine in pregnancy in order to better characterize the risk for congenital malformations associated with paroxetine. Physicians who are caring for women receiving paroxetine should alert them to the potential risk to the fetus if they plan to become pregnant or are currently in their first trimester of pregnancy. Discontinuing paroxetine therapy should be considered for these patients. Women who are pregnant, or planning a pregnancy, and currently taking paroxetine should consult with their physician about whether to continue taking it. Women should not stop the drug without discussing the best way to do that with their physician. 2005 2005 Paxil (paroxetine) Audience: Neuropsychiatric healthcare professionals and consumers [UPDATE 07/08/2005] FDA notified healthcare professionals about the availability of updated Healthcare Professional and Patient Information Sheets for antidepressant medications that were the subject of a June 30, 2005 Public Health Advisory issued about the risk of suicidality (suicidal thinking or behavior) in adults being treated with antidepressant medications. [Posted 07/01/2005] In response to recent scientific publications that report the possibility of increased risk of suicidal behavior in adults treated with antidepressants, the FDA has issued a Public Health Advisory to update patients and healthcare providers with the latest information on this subject. Even before the publication of these recent reports, FDA had already begun the process of reviewing available data to determine whether there is an increased risk of suicidal behavior in adults taking antidepressants. The Agency has asked manufacturers to provide information from their trials using an approach similar to that used in the evaluation of the risk of suicidal behavior in the pediatric population taking antidepressants. This effort will involve hundreds of clinical trials and may take more than a year to complete. Paxil (paroxetine HCL), Paxil CR Controlled-Release Tablets Audience: Neuropsychiatric and other healthcare professionals [Posted 09/27/2005] GlaxoSmithKline (GSK) and FDA notified healthcare professionals of changes to the Pregnancy/PRECAUTIONS section of the Prescribing Information for Paxil and Paxil CR Controlled-Release Tablets to describe the results of a GSK retrospective epidemiologic study of major congenital malformations in infants born to women taking antidepressants during the first trimester of pregnancy. This study suggested an increase in the risk of overall major congenital malformations for paroxetine as compared to other antidepressants 2005 Regulatory Authority/Reg ion Product active ingredient Safety Issue (AE) avoid invasive dental procedures while receiving bisphosphonate treatment FDA-USA paroxetine HCl Cardiac malformations due to exposure to paroxetine in the first trimester of pregnancy FDA-USA paroxetine HCl Risk of suicidality (suicidal thinking or behavior) EM paroxetine HCl Congenital malformations in infants born to women taking antidepressants during the first trimester of pregnancy EM Liver toxicity Voluntar y withdraw al FDA-USA Cylert and generic pemoline products Audience: Neuropsychiatric healthcare professionals, Pediatricians, Pharmacists and consumers [Posted 10/24/2005] FDA has concluded that the overall risk of liver toxicity from Cylert and generic pemoline products outweighs the benefits of this drug. In May 2005, Abbott chose to stop sales and marketing of Cylert in the U.S. All generic companies have also agreed to stop sales and marketing of this product. Cylert, a central nervous system stimulant indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD), is considered second line therapy for ADHD because of its association with life threatening hepatic failure. Health care professionals who prescribe Cylert, or any of its generics, should transition their patients to an alternative therapy. Cylert will remain available through pharmacies and wholesalers until supplies are exhausted. No additional product will be available. 176 2005 Intervention Type FDA-USA pemoline EM Year 177 Title Vioxx (rofecoxib) June 2005. Audience: Healthcare professionals and consumers FDA has requested that sponsors of all non-steroidal anti-inflammatory drugs (NSAID) make labeling changes to their products. FDA recommended proposed labeling for both the prescription and over-the-counter (OTC) NSAIDs and a EMMG for the entire class of prescription products. All sponsors of marketed prescription NSAIDs, including Celebrex (celecoxib), a COX-2 selective NSAID, have been asked to revise the labeling (package insert) for their products to include a boxed warning, highlighting the potential for increased risk of cardiovascular (CV) events and the well described, serious, potential life-threatening gastrointestinal (GI) bleeding associated with their use. FDA regulation 21CFR 208 requires a EM-MG to be provided with each prescription that is dispensed for products that FDA determines pose a serious and significant public health concern. 2005 Regulatory Authority/Reg ion Product active ingredient Safety Issue (AE) Intervention Type FDA-USA rofecoxib CV risks and stroke BBW FDA-USA rosiglitazone maleate Diabetic macular edema EM FDA-USA rosuvastatin calicum Serious muscle toxicity (myopathy/rhabdomyolysis) EM FDA-USA salmeterol xinafoate inhalation powder Increase chance of severe asthma episodes, and death when those episodes occur EM-MG saquinavir soft gelatin capsules Drug-induced hepatitis with transaminase elevations observed in healthy volunteers receiving rifampin 600 mg once daily in combination with ritonavir 100 mg/saquinavir 1000 mg twice daily EM Avandamet, Avandia (rosiglitazone maleate); Avandamet (rosiglitazone maleate/metformin HCl) Audience: Endocrinologists, other healthcare professionals and patients [Posted 01/05/2006] GlaxoSmithKline and FDA notified healthcare professionals about post-marketing reports of new onset and worsening diabetic macular edema for patients receiving rosiglitazone. In the majority of these cases, the patients also reported concurrent peripheral edema. In some cases, the macular edema resolved or improved following discontinuation of therapy and in one case, macular edema resolved after dose reduction. 178 2005 Crestor (rosuvastatin calicum) Audience: Physicians, pharmacists, and other healthcare professionals FDA issued a public health advisory describing revisions to the WARNINGS, DOSAGE AND ADMINISTRATION, CLINICAL PHARMACOLOGY, and PRECAUTIONS sections of the labeling. The revisions include results from a Phase 4 pharmacokinetic study in Asian-Americans and highlight important information on the safe use of Crestor to reduce the risk for serious muscle toxicity (myopathy/rhabdomyolysis), especially at the highest approved dose of 40 mg. At this time, the FDA is also making statements about the muscle and kidney safety of Crestor based on extensive review of available information. 179 2005 Serevent Diskus (salmeterol xinafoate inhalation powder) Audience: Pulmonologists, other healthcare professionals and consumers [Posted 11/18/2005] FDA notified manufacturers of Advair Diskus, Foradil Aerolizer, and Serevent Diskus to update their existing product labels with new warnings and a EM-MG for patients to alert health care professionals and patients that these medicines may increase the chance of severe asthma episodes, and death when those episodes occur. All of these products contain long-acting beta2-adrenergic agonists (LABA). Even though LABAs decrease the frequency of asthma episodes, these medicines may make asthma episodes more severe when they occur. A EM-MG with information about these risks will be given to patients when a prescription for a LABA is filled or refilled. 180 2005 Fortovase (saquinavir soft gelatin capsules), Invirase (saquinavir mesylate capsules and tablets) Audience: Infectious disease and other healthcare professionals Roche and FDA notified healthcare professionals about an Important drug interaction warning. Drug-induced hepatitis with marked transaminase elevations has been observed in healthy volunteers receiving rifampin 600 mg once daily in combination with ritonavir 100 mg/saquinavir 1000 mg twice daily (ritonavir boosted saquinavir). Roche now advises prescribers that Rifampin should not be administered to patients also receiving saquinavir/ritonavir (ritonavir boosted saquinavir) as part of combination antiretroviral therapy (ART) for HIV infection. 181 2005 FDA-USA Year 182 183 184 2005 2005 2005 185 2005 186 2005 187 Title Zoloft (sertraline). Audience: Neuropsychiatric healthcare professionals and consumers [UPDATE 07/08/2005] FDA notified healthcare professionals about the availability of updated Healthcare Professional and Patient Information Sheets for antidepressant medications that were the subject of a June 30, 2005 Public Health Advisory issued about the risk of suicidality (suicidal thinking or behavior) in adults being treated with antidepressant medications. [Posted 07/01/2005] In response to recent scientific publications that report the possibility of increased risk of suicidal behavior in adults treated with antidepressants, the FDA has issued a Public Health Advisory to update patients and healthcare providers with the latest information on this subject. Even before the publication of these recent reports, FDA had already begun the process of reviewing available data to determine whether there is an increased risk of suicidal behavior in adults taking antidepressants. The Agency has asked manufacturers to provide information from their trials using an approach similar to that used in the evaluation of the risk of suicidal behavior in the pediatric population taking antidepressants. This effort will involve hundreds of clinical trials and may take more than a year to complete. Viagra (Sildenafil citrate). Audience: Urologists, Ophthalmologists and other healthcare professionals[Posted 07/08/2005] FDA notified healthcare professionals of updated labeling for Cialis, Levitra and Viagra to reflect a small number of postmarketing reports of sudden vision loss, attributed to NAION (non arteritic ischemic optic neuropathy), a condition where blood flow is blocked to the optic nerve. FDA advises patients to stop taking these medicines, and call a doctor or healthcare provider right away if they experience sudden or decreased vision loss in one or both eyes. Patients taking or considering taking these products should inform their health care professionals if they have ever had severe loss of vision, which might reflect a prior episode of NAION. Such patients are at an increased risk of developing NAION again. At this time, it is not possible to determine whether these oral medicines for erectile dysfunction were the cause of the loss of eyesight or whether the problem is related to other factors such as high blood pressure or diabetes, or to a combination of these problems. 2005 Regulatory Authority/Reg ion FDA-USA FDA-USA Product active ingredient Safety Issue (AE) Intervention Type sertraline Risk of suicidality (suicidal thinking or behavior) EM sildenafil citrate Sudden vision loss, attributed to NAION (non arteritic ischemic optic neuropathy) EM sodium oxybate Risk for depression, confusion, and other neuropsychiatric adverse events EM-MG EM Xyrem (sodium oxybate) [2005 version] Cialis (Tadalafil) Audience: Urologists, Ophthalmologists and other healthcare professionals [Posted 07/08/2005] FDA notified healthcare professionals of updated labeling for Cialis, Levitra and Viagra to reflect a small number of postmarketing reports of sudden vision loss, attributed to NAION (non arteritic ischemic optic neuropathy), a condition where blood flow is blocked to the optic nerve. FDA advises patients to stop taking these medicines, and call a doctor or healthcare provider right away if they experience sudden or decreased vision loss in one or both eyes. Patients taking or considering taking these products should inform their health care professionals if they have ever had severe loss of vision, which might reflect a prior episode of NAION. Such patients are at an increased risk of developing NAION again. At this time, it is not possible to determine whether these oral medicines for erectile dysfunction were the cause of the loss of eyesight or whether the problem is related to other factors such as high blood pressure or diabetes, or to a combination of these problems. FDA-USA FDA-USA tadalafil Sudden vision loss, attributed to NAION (non arteritic ischemic optic neuropathy) Soltamox (tamoxifen citrate) [2005 version] Flomax (tamsulosin HCl) Audience: Ophthalmologists, Urologists, and other healthcare professionals [Posted 11/22/2005] Boehringer Ingelheim and FDA notified healthcare professionals of revisions to PRECAUTIONS and ADVERSE REACTIONS sections of the prescribing information for Flomax, indicated for the treatment of the signs and symptoms of benign prostatic hyperplasia (BPH). A surgical condition termed Intraoperative Floppy Iris Syndrome (IFIS) has been observed during phacoemulsification cataract surgery in some patients treated with alpha-1 blockers including Flomax. Most of these reports were in patients taking the alpha-1 blocker when IFIS occurred, but in some cases alpha-1 blocker had been stopped prior to surgery. It is recommended that male patients being considered for cataract surgery, as part of their medical history, be specifically questioned to ascertain whether they have taken Flomax or other alpha-1 blockers. If so, the patient's ophthalmologist should be prepared for possible modifications to their surgical technique that may be warranted should IFIS be observed during the procedure. FDA-USA tamoxifen citrate Not specified EM-MG tamsulosin HCl Surgical condition termed Intraoperative Floppy Iris Syndrome (IFIS) EM FDA-USA Year 188 2005 189 2005 Title Gabitril (tiagabine) Audience: Neuropsychiatric and other healthcare professionals FDA and Cephalon, Inc. notified healthcare professionals and the public that a Bolded Warning has been added to the labeling for Gabitril (tiagabine) to warn prescribers of the risk of seizures in patients without epilepsy being treated with Gabitril. FDA has received reports of the occurrence of seizures in more than 30 patients prescribed Gabitril for conditions other than epilepsy. Most of these uses were in patients with psychiatric illnesses. Such off label prescribing is a common practice among physicians. Because of the risk of seizures, however, in addition to adding the Bolded Warning to product labeling, the sponsor has agreed to undertake an educational campaign, targeted to healthcare professionals and patients, in which such off-label use will be discouraged. Herceptin (trastuzumab) Audience: Oncologists, cardiologists, and other healthcare professionals [Posted 08/31/2005] Genentech and FDA notified healthcare professionals of updated cardiotoxicity information related to the use of Herceptin (trastuzumab), obtained from the National Surgical Adjuvant Breast and Bowel Project (NSABP) study (B-31), a randomized, Phase III trial that was conducted in 2043 women with operable, HER2 overexpressing breast cancer (IHC 3+ or FISH+). This study demonstrated a significant increase in cardiotoxicity in patients who were randomized to the Herceptin-containing arm as compared to patients who received chemotherapy alone. Regulatory Authority/Reg ion Product active ingredient Safety Issue (AE) FDA-USA tiagabine Risk of seizures in patients without epilepsy EM FDA-USA trastuzumab Cardiotoxicity information EM FDA-USA valdecoxib CV risks Withdra wal FDA-USA vardenafil HCl Sudden or decreases vision loss EM FDA-USA venlafaxine Risk of suicidality (suicidal thinking or behavior) in adults FDA-USA zoledronic acid Renal deterioration Bextra (valdecoxib) Apr 2005 Audience: Healthcare professionals and consumers After concluding that the overall risk versus benefit profile is unfavorable, FDA has requested Pfizer, Inc. to voluntarily withdraw Bextra (valdecoxib) from the market. This request is based on: The lack of adequate data on the cardiovascular safety of long-term use of Bextra, along with the increased risk of adverse cardiovascular (CV) events in short-term coronary artery bypass surgery (CABG) trials that FDA believes may be relevant to chronic use. Reports of serious and potentially life-threatening skin reactions, including deaths, in patients using Bextra. The risk of these reactions in individual patients is unpredictable, occurring in patients with and without a prior history of sulfa allergy, and after both short- and long-term use. Lack of any demonstrated advantages for Bextra compared with other NSAIDs. 190 2005 Levitra (Vardenafil HCl) Audience: Urologists, Ophthalmologists and other healthcare professionals [Posted 07/08/2005] FDA notified healthcare professionals of updated labeling for Cialis, Levitra and Viagra to reflect a small number of postmarketing reports of sudden vision loss, attributed to NAION (non arteritic ischemic optic neuropathy), a condition where blood flow is blocked to the optic nerve. FDA advises patients to stop taking these medicines, and call a doctor or healthcare provider right away if they experience sudden or decreased vision loss in one or both eyes. 191 192 2005 2005 Effexor (venlafaxine) Audience: Neuropsychiatric healthcare professionals and consumers [UPDATE 07/08/2005] FDA notified healthcare professionals about the availability of updated Healthcare Professional and Patient Information Sheets for antidepressant medications that were the subject of a June 30, 2005 Public Health Advisory issued about the risk of suicidality (suicidal thinking or behavior) in adults being treated with antidepressant medications. [Posted 07/01/2005] In response to recent scientific publications that report the possibility of increased risk of suicidal behavior in adults treated with antidepressants, the FDA has issued a Public Health Advisory to update patients and healthcare providers with the latest information on this subject. Zometa (zoledronic acid) Audience: Oncologists, Endocrinologists, Pharmacists and other healthcare professionals Novartis and FDA notified healthcare professionals of revisions to the DOSAGE AND ADMINISTRATION and WARNINGS sections of the prescribing information to reflect new safety information on management of patients with advanced cancer and renal impairment, whose baseline creatinine clearance is 60 ml/min or lower. The recommended Zometa doses for patients with reduced renal function (mild and moderate renal impairment) are provided in a table. It is recommended that, during treatment, serum creatinine be measured before each dose and treatment should be withheld for renal deterioration. 193 2005 Intervention Type EM TDM serum creatinin e measured before each dose; treatmen t withheld for renal deteriora tion. Year 194 195 Title Zometa (zoledronic acid), Aredia (pamidronate disodium). Audience: Dental and oncologic healthcare professionals Novartis and FDA notified dental healthcare professionals of revisions to the prescribing information to describe the occurence of osteonecrosis of the jaw (ONJ) observed in cancer patients receiving treatment with intravenous bisphosphonates, Aredia (pamidronate disodium) and Zometa (zoledronic acid). The prescribing information recommends that cancer patients receive a dental examination prior to initiating therapy with intravenous bisphosphonates (Aredia and Zometa), and avoid invasive dental procedures while receiving bisphosphonate treatment. For patients who develop ONJ while on bisphosphonate therapy, dental surgery may exacerbate the condition. 2005 2006 196 2006 197 2006 198 2006 Angiotensin-converting enzyme inhibitor (ACE inhibitors) drug class Audience: Reproductive and other healthcare professionals, patients [Posted 06/07/2006] The New England Journal of Medicine published an article reporting that infants whose mothers had taken an angiotensin-converting enzyme inhibitor (ACE inhibitors) drug during the first trimester of pregnancy had an increased risk of major congenital malformations, compared with infants who had not undergone first trimester exposure to ACE inhibitor drugs. The FDA-approved labels recommends discontinuing the ACEI as soon as possible if a patient becomes pregnant. ACE inhibitor drugs are labeled pregnancy category C for the first trimester of pregnancy, and are labeled pregnancy category D during the second and third trimesters. Healthcare professionals should take these findings into consideration with other information about a patient’s medical situation when prescribing ACE inhibitors. Trasylol (aprotinin). Audience: Cardiovascular and other healthcare professionals [UPDATED 12/15/2006] FDA and Bayer Pharmaceuticals notified healthcare professionals of revisions to the prescribing information for Trasylol. The new labeling has a more focused indication, a new Warning that Trasylol administration increases the risk of renal dysfunction and may increase the need for dialysis in the perioperative period, and stronger warnings about anaphylactic reactions. In addition, due to the higher risk for anaphylactic reactions, re-administration of Trasylol to patients with a known or suspected exposure during the past 12 months is contraindicated. [Posted 02/08/2006] FDA issued a public health advisory and other advisory information to notify both healthcare professionals and consumers of recently published studies of serious renal and cardiovascular toxicity following Trasylol administration to patients undergoing coronary artery bypass grafting surgery (CABG). An observational study published in The New England Journal of Medicine reported that Trasylol may be associated with increased risk of myocardial infarction, stroke and renal dysfunction. Another publication (Transfusion, on-line edition, January 20, 2006) has reported that Trasylol administration may increase the risk for renal toxicity. Benzocaine sprays; Audience: Healthcare professionals and patients [Posted 02/13/2006] FDA issued a Public Health Advisory to notify healthcare professionals and patients about adverse events, including methemoglobinemia, associated with the use of benzocaine sprays used in the mouth and throat. Benzocaine sprays are used in medical practice for locally numbing mucous membranes of the mouth and throat for minor surgical procedures or when a tube must be inserted into the stomach or airways. On February 8, 2006, the Veterans Health Administration (VA) announced the decision to stop using benzocaine sprays for these purposes. The FDA is aware of the reported adverse events and is reviewing all available safety data, but at this time is not planning action to remove the drugs from the market. The FDA is highlighting safety information previously addressed by the Agency (see below), has provided other information for the consideration of clinicians in the PHA and will make further announcements or take action as warranted by the ongoing review. Avastin (bevacizumab) Sept 2006; Audience: Oncological and neurological healthcare professionals. [Posted 09/25/2006] Genentech and FDA notified healthcare professionals about revisions to the WARNINGS and ADVERSE REACTIONS sections of the prescribing information to inform healthcare professionals of 1] cases of a rare brain-capillary leak syndrome [reversible posterior leukoencephalopathy syndrome (RPLS)] and 2] postmarketing reports of nasal septum perforation. The onset of symptoms has been reported to occur from 16 hours to 1 year after initiation of Avastin. Magnetic Resonance Imaging (MRI) is necessary to confirm the diagnosis of RPLS. Regulatory Authority/Reg ion Product active ingredient Safety Issue (AE) Intervention Type FDA-USA zoledronic acid; pamidronate disodium Osteonecrosis of the jaw (ONJ) TDM dental exam for cancer pts prior to therapy FDA-USA Angiotensinconverting enzyme inhibitor (ACE inhibitors) Increased risk of major congenital malformations in first trimester EM FDA-USA aprotinin Risk of renal dysfunction and may increase the need for dialysis in the perioperative period, and stronger warnings about anaphylactic reactions EM FDA-USA Benzocaine sprays Adverse events, including methemoglobinemia EM FDA-USA bevacizumab Rare brain-capillary leak syndrome EM Year 199 2006 200 2006 201 2006 Title Tracleer (bosentan); Audience: Cardiopulmonary healthcare professionals [Posted 03/02/2006] Actelion and FDA notified healthcare professionals of changes to the prescribing information based on cases of hepatotoxity reported. The notification underscored the need to continue monthly liver function monitoring for the duration of Tracleer treatment and the need to adhere to the recommended dosage adjustment and monitoring guidelines described in the product labeling. Propulsid (cisapride) [2006 version] Ontak (denileukin diftitox); Audience: Hemato-oncological healthcare professionals [Posted 03/15/2006] Ligand Pharmaceuticals and FDA notified healthcare professionals of changes to the WARNINGS section of the prescribing information for Ontak, indicated for the treatment of patients with persistent or recurrent cutaneous T-cell lymphoma. Loss of visual acuity, usually with loss of color vision, has been reported following administration of Ontak. While recovery was reported in some of the affected patients, most patients reported persistent visual impairment. Regulatory Authority/Reg ion FDA-USA bosentan Hepatotoxity Intervention Type TDMmonthly liver function monitori ng for treatmen t duration FDA-USA cisapride Not specified EM-MG FDA-USA denileukin diftitox Loss of visual acuity, usually with loss of color vision, has been reported following administration of Ontak EM FDA-USA dextroamphetam ine sulfate Reports of sudden death EM FDA-USA Fleet PhosphoSoda and Fleet Accu-Prep Acute phosphate nephropathy, a type of acute renal failure EM gatifloxacin Hypoglycemia (low blood sugar) and hyperglycemia (high blood sugar), and a CONTRAINDICATION for use in diabetic patients. EM Heparin Sodium Injection Delayed onset of heparininduced thrombocytopenia (HIT), a serious antibodymediated reaction resulting from irreversible aggregation of platelets EM Dexedrine (dextroamphetamine sulfate); Audience: Psychiatrists, pediatricians, mental healthcare professionals, pharmacists and consumers [Posted 08/21/2006] The FDA and GlaxoSmithKline notified healthcare professionals of changes to the BOXED WARNING, WARNINGS and PRECAUTIONS sections of the prescribing information for Dexedrine (dextroamphetamine sulfate), approved for the treatment of Attention-Deficit Hyperactivity Disorder and narcolepsy. The warnings describe reports of sudden death in association with CNS stimulant treatment at usual doses in children and adolescents with structural cardiac abnormalities or other serious heart problems. 202 203 204 2006 2006 Fleet Phospho-Soda and Fleet Accu-Prep Audience: Consumers, pharmacists and other healthcare professionals [Posted 05/05/2006] FDA notified healthcare professionals and consumers of reports of acute phosphate nephropathy, a type of acute renal failure, that is a rare, but serious adverse event associated with the use of oral sodium phosphates (OSP) for bowel cleansing. Documented cases of acute phosphate nephropathy include 21 patients who used an OSP solution (such as Fleet Phospho-soda or Fleet ACCU-PREP) and one patient who used OSP tablets (Visicol). Individuals at increased risk of acute phosphate nephropathy include: those of advanced age, those with kidney disease or decreased intravascular volume, and those using medicines that affect renal perfusion or function [diuretics, angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), and possibly nonsteroidal anti-inflammatory drugs (NSAIDs)]. Recommendations were offered for providers and patients when choosing and using a bowel cleanser. Tequin (gatifloxacin); Audience: Healthcare professionals and patients [Posted 02/16/2006] BMS notified FDA and healthcare professionals about proposed changes to the prescribing information for Tequin, including an updating of the existing WARNING on hypoglycemia (low blood sugar) and hyperglycemia (high blood sugar), and a CONTRAINDICATION for use in diabetic patients. The changes also include information identifying other risk factors for developing low blood sugar and high blood sugar, including advanced age, renal insufficiency, and concomitant glucose-altering medications while taking Tequin. The proposed changes are highlighted in the following "Dear Healthcare Provider" letter issued by BMS. Specific wording of these additions and revisions to the labeling is pending FDA review and approval. 2006 FDA-USA Heparin Sodium Injection; Audience: Vascular surgeons, ER personnel, pharmacists, and other healthcare professionals [Posted 12/08/2006] FDA notified healthcare professionals of revisions to the WARNINGS section of the prescribing information for Heparin to inform clinicians of the possibility of delayed onset of heparin-induced thrombocytopenia (HIT), a serious antibody-mediated reaction resulting from irreversible aggregation of platelets. HIT may progress to the development of venous and arterial thromboses, a condition referred to as heparin-induced thrombocytopenia and thrombosis (HITT). Thrombotic events may be the initial presentation for HITT which can occur up to several weeks after the discontinuation of heparin therapy. Patients presenting with thrombocytopenia or thrombosis after discontinuation of heparin should be evaluated for HIT and HITT. 205 2006 FDA-USA Product active ingredient Safety Issue (AE) Year 206 207 2006 Title Droxia, Hydrea, Droxia (hydroxyurea capsules) Audience: Pharmacists and Oncological healthcare professionals [Posted 01/26/2006] Bristol-Myers Squibb notified healthcare professionals about revisions to the WARNINGS and ADVERSE REACTIONS sections of the prescribing information to describe cutaneous vasculitic toxicities, including vasculitic ulcerations and gangrene, in patients with myeloproliferative disorders during therapy with hydroxyurea, most often reported in patients with a history of or currently receiving interferon therapy. The PRECAUTIONS and DOSING AND ADMINISTRATION sections have been revised to provide updated information on the safe handling of these products.The proposed changes are highlighted in "Dear Healthcare Provider" letters issued January 2006 by BristolMyers Squibb 2006 Ibuprofen and Aspirin Taken Together Audience: Consumers and healthcare professionals [Posted 09/08/2006] FDA notified consumers and healthcare professionals that taking Ibuprofen for pain relief and aspirin at the same time may interfere with the benefits of aspirin taken for the heart. Ibuprofen can interfere with the antiplatelet effect of low dose aspirin (81 mg per day), that may render aspirin less effective when used for cardioprotection and stroke prevention. Although it is all right to use Ibuprofen and aspirin together, FDA recommends that consumers contact their healthcare professional for more information on the timing of when to take these two medicines, so that both medicines can be effective. [September 8, 2006 - Science Paper - FDA] Regulatory Authority/Reg ion 2006 209 2006 210 2006 211 2006 212 2006 Avonex* (interferon beta-1a) [2006 version] Isotretinoin - Accutane and generic isotretinoin Audience: Dermatological, other healthcare professionals and patients [Posted 10/06/2006] FDA and the iPLEDGE program notified healthcare professionals and patients of an update to iPLEDGE, a risk management program to reduce the risk of fetal exposure to isotretinoin, that will eliminate one element of the program, the 23 day lock-out period for males and females of non-child bearing potential. This change does not affect female patients of child-bearing potential. Sotret (isotretinoin) [2006 version] Lamictal (lamotrigine) Audience: Neurologists, obstetricians, other healthcare professionals, and patients [Posted 09/29/2006] The FDA notified healthcare professionals and patients of new preliminary information from the North American Antiepileptic Drug Pregnancy Registry that suggests that babies exposed to Lamictal, indicated to treat seizures and bipolar disorder, during the first three months of pregnancy may have a higher chance of being born with a cleft lip or cleft palate. More research is needed to be sure about the possibility of the increased chance of cleft lip or cleft palate developing in babies of pregnant women who take Lamictal. Women who take Lamictal and are pregnant or are thinking of becoming pregnant should talk with their doctor. Patients should not start or stop using Lamictal without talking to their doctor Safety Issue (AE) Intervention Type FDA-USA hydroxyurea capsules Cutaneous vasculitic toxicities, including vasculitic ulcerations and gangrene EM EMDHCPL FDA-USA Ibuprofen and Aspirin Taken Together Drug interactioninterferance with aspirin effectiveness EM FDA-USA imatinib mesylate Severe congestive heart failure and left ventricular dysfunction EM FDA-USA interferon beta1a Not specified EM-MG Gleevec (imatinib mesylate); Audience: Oncology and cardiology healthcare professionals [Posted 10/19/2006] Novartis and FDA notified healthcare professionals about revisions to the PRECAUTIONS section of the prescribing information, describing the occasional occurrence of severe congestive heart failure and left ventricular dysfunction in patients taking Gleevec. Most of the patients with reported cardiac events had other co-morbidities and risk factors, including advanced age and previous medical history of cardiac disease. Patients with cardiac disease or risk factors for cardiac failure should be monitored carefully and any patients with signs or symptoms consistent with cardiac failure should be evaluated and treated. 208 Product active ingredient FDA-USA isotretinoin Teratogenicity Registry modificat ion FDA-USA isotretinoin Not specified EM-MG lamotrigine Cleft lip or cleft palate during the first 3 months of pregnancy EM FDA-USA Year 213 214 215 216 217 Title Menactra (Meningococcal Conjugate Vaccine A, C, Y, and W135) Audience: Neurological and Pediatric healthcare professionals, and consumers [Posted 10/23/2006] FDA and CDC updated an October 2005 alert to consumers and health care providers regarding reports of Guillain Barre Syndrome (GBS) following administration of Meningococcal Conjugate Vaccine A, C, Y, and W135, manufactured by Sanofi Pasteur. To date a total of 15 confirmed cases of GBS among individuals 11-19 years of age occurring within six weeks of vaccination with Menactra have been reported to the Vaccine Adverse Event Reporting System (VAERS). Two additional cases have been confirmed in persons 20 years of age and older. All individuals are reported to be recovering or have recovered. While the cases reported suggest a small increased risk of GBS following immunization with Menactra, the limitations in VAERS, and the uncertainty regarding background incidence rates for GBS require that these findings be viewed with caution. 2006 2006 Dolophine (methadone HCl) Audience: Pain management specialists, pharmacists, and other healthcare professionals Indication: Treatment of moderate to severe pain not responsive to non-narcotic analgesics; detoxification of opioid addiction; and maintenance treatment of opioid addiction [Posted 11/27/2006] FDA notified healthcare professionals of reports of death and life-threatening adverse events such as respiratory depression and cardiac arrhythmias in patients receiving methadone. These adverse events are the possible result of unintentional methadone overdoses, drug interactions, and methadone's cardiac toxicities (QT prolongation and Torsades de Pointes). The reports underscore the importance of knowing methadone's toxicities and unique pharmacologic properties, including dosing and monitoring recommendations. 2006 2006 Ortho Evra (norelgestromin/ethinyl estradiol) Audience: Gynecologists, other healthcare professionals and consumers [Posted 09/20/2006] Ortho-McNeil and FDA notified healthcare professionals and patients about revisions to the prescribing information to inform them of the results of two separate epidemiology studies that evaluated the risk of developing a serious blood clot in women using Ortho Evra compared to women using a different oral contraceptive. The first study found that the risk of non-fatal venous thromboembolism (VTE) associated with the use of Ortho Evra contraceptive patch is similar to the risk associated with the use of oral contraceptive pills containing 35 micrograms of ethinyl estradiol and norgestimate.The second study found an approximate two-fold increase in the risk of medically verified VTE events in users of Ortho Evra compared to users of norgestimate-containing oral contraceptives containing 35 micrograms of estrogen. Although the results of the two studies differ, the results of the second study support FDA's concerns regarding the potential for Ortho Evra use to increase the risk of blood clots in some women. Prescribing information for Ortho Evra continues to recommend that women with concerns or risk factors for thromboembolic disease Product active ingredient Safety Issue (AE) Intervention Type Meningococcal Conjugate Vaccine A, C, Y, and W135 Guillain Barre Syndrome (GBS) EM FDA-USA methadone HCl Death and life-threatening adverse events such as respiratory depression and cardiac arrhythmias EM FDA-USA mifepristone Deaths following abortion EM FDA-USA natalizumab Progressive multifocal leukoencephalopathy (PML), a serious viral infection of the brain RD FDA-USA norelgestromin/e thinyl estradiol Risk of non-fatal venous thromboembolism (VTE) EM FDA-USA Mifeprex (mifepristone) Audience: Reproductive healthcare professionals and consumers [Posted 03/17/2006] The FDA notified healthcare professionals of two additional deaths following medical abortion with mifepristone (Mifeprex). The Agency received verbal notification of the deaths in the United States from the manufacturer, Danco Laboratories. At this time we are investigating all circumstances associated with these cases and are not able to confirm the causes of death. However, all providers of medical abortion and their patients need to be aware of the specific circumstances and directions for use of this drug and all risks including sepsis when considering treatment. In particular, physicians and their patients should fully discuss early potential signs and symptoms that may warrant immediate medical evaluation. [March 17, 2006 – Public Health Advisory – FDA] Tysabri (natalizumab); Audience: Neurological and other healthcare professionals, patients [UPDATE 07/21/2006] Dear Healthcare Provider Letter issued. [Posted 06/05/2006] FDA notified healthcare professionals of the resumed marketing, with a special restricted distribution program of Tysabri (natalizumab), a monoclonal antibody for the treatment of patients with relapsing forms of multiple sclerosis. Tysabri was initially approved by the FDA in November 2004, but was withdrawn by the manufacturer in February 2005 after three patients in the drug’s clinical trials developed progressive multifocal leukoencephalopathy (PML), a serious viral infection of the brain. Tysabri will be available only through the Risk Management Plan, called the TOUCH Prescribing Program. In order to receive Tysabri, patients must talk to their doctor and understand the risks and benefits of Tysabri and agree to all of the instructions in the TOUCH Prescribing Program. 2006 Regulatory Authority/Reg ion Year Title talk with their healthcare professionals about using Ortho Evra versus other contraceptive options. Regulatory Authority/Reg ion Oral Sodium Phosphate (OSP) Products for Bowel Cleansing Audience: Consumers, pharmacists and other healthcare professionals [Posted 05/05/2006] FDA notified healthcare professionals and consumers of reports of acute phosphate nephropathy, a type of acute renal failure, that is a rare, but serious adverse event associated with the use of oral sodium phosphates (OSP) for bowel cleansing. Documented cases of acute phosphate nephropathy include 21 patients who used an OSP solution (such as Fleet Phospho-soda or Fleet ACCU-PREP) and one patient who used OSP tablets (Visicol). Individuals at increased risk of acute phosphate nephropathy include: those of advanced age, those with kidney disease or decreased intravascular volume, and those using medicines that affect renal perfusion or function [diuretics, angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), and possibly nonsteroidal anti-inflammatory drugs (NSAIDs)]. 218 219 220 221 2006 2006 Tamiflu (oseltamivir phosphate) Audience: Pediatric and primary care healthcare professionals and patients [Posted 11/13/2006] Roche and FDA notified healthcare professionals of revisions to the PRECAUTIONS/Neuropsychiatric Events and Patient Information sections of the prescribing information for Tamiflu, indicated for the treatment of uncomplicated acute illness due to influenza infection in patients 1 year and older who have been symptomatic for no more than 2 days and for the prophylaxis of influenza in patients 1 year and older.There have been postmarketing reports (mostly from Japan) of self-injury and delirium with the use of Tamiflu in patients with influenza. People with the flu, particularly children, may be at an increased risk of self-injury and confusion shortly after taking Tamiflu and should be closely monitored for signs of unusual behavior. A healthcare professional should be contacted immediately if the patient taking Tamiflu shows any signs of unusual behavior. Paxil (paroxetine HCl) Tablets and Oral Suspension Audience: Neuropsychiatric and other healthcare professionals [Posted 05/12/2006] GlaxoSmithKline (GSK) and FDA notified healthcare professionals of changes to the Clinical Worsening and Suicide Risk subsection of the WARNINGS section in the prescribing Information for Paxil and Paxil CR. These labeling changes relate to adult patients, particularly those who are younger adults. It is important that all patients, especially young adults and those who are improving, receive careful monitoring during paroxetine therapy regardless of the condition being treated. 2006 2006 Macugen (pegaptanib sodium injection) Audience: Ophthalmological healthcare professionals, surgical service supervisors and other healthcare professionals [Posted 04/07/2006] (OSI)Eyetech/Pfizer and FDA notified healthcare professionals of important changes in the approved product labeling for Macugen (pegaptanib sodium injection), including changes to the CONTRAINDICATIONS, PRECAUTIONS, ADVERSE EVENTS Post-Marketing, and DOSAGE and ADMINISTRATION sections. Rare reports of anaphylaxis/anaphylactoid reactions, including angioedema following the administration of Macugen along with various medications administered as part of the injection preparation, were described. Macugen is indicated for the treatment of neovascular (wet) age-related macular degeneration, and is administered once every six weeks by intravitreous injection. Healthcare professionals should evaluate the patient's medical history for hypersensitivity reactions to Macugen prior to using this product. Product active ingredient Safety Issue (AE) Intervention Type FDA-USA Oral Sodium Phosphate (OSP Acute phosphate nephropathy EM FDA-USA oseltamivir phosphate Self-injury and delirium EM FDA-USA paroxetine HCl Higher frequency of suicidal behavior in young adults treated with paroxetine compared with placebo. EM FDA-USA pegaptanib sodium injection Rare reports of anaphylaxis/anaphylactoid reactions EM Year 222 2006 223 2006 224 2006 225 2006 226 227 228 Title Elidel Cream (pimecrolimus);Protopic Ointment (tacrolimus) Audience: Dermatological and other healthcare professionals [Posted 01/20/2006] The Food and Drug Administration announced the approval of updated labeling for two topical eczema drugs, Elidel Cream (pimecrolimus) and Protopic Ointment (tacrolimus). The labeling will be updated with a boxed warning about a possible risk of cancer and a EM-MG (FDA-approved patient labeling) will be distributed to help ensure that patients using these prescription medicines are aware of this concern. The new labeling also clarifies that these drugs are recommended for use as second-line treatments. This means that other prescription topical medicines should be tried first. Use of these drugs in children under 2 years of age is not recommended. Elidel Cream (pimecrolimus) [2006 version] Promethazine HCl (marketed as Phenergan and generic products) Audience: Pediatricians, emergency service professionals and patients [Posted 04/25/2006] FDA notified healthcare professionals and patients that cases of breathing problems, some causing death, have been reported to the FDA when the drug was used in children less than two years old. Parents and caregivers should also be careful and get a doctor's advice about giving promethazine HCl in any form to children age two and older. The labeling on all products, brand name and generic, has been changed to reflect these strengthened warnings. Avandia (rosiglitazone maleate/metformin hcl) Quinine products Audience: Pharmacists, other healthcare professionals and consumers [Posted 12/12/2006] FDA informed healthcare professionals and consumers that the Agency ordered firms to stop marketing unapproved drug products containing quinine, citing serious safety concerns, including deaths associated with quinine products. There are multiple unapproved products containing quinine currently on the market, used off-label to treat leg cramps and similar conditions. Quinine drugs are associated with serious side effects, such as cardiac arrhythmias, thrombocytopenia, and severe hypersensitivity reactions. Qualaquin, manufactured by Mutual Pharmaceutical Company, is the only FDA-approved quinine product 2006 2006 2006 Regulatory Authority/Reg ion Safety Issue (AE) Intervention Type FDA-USA pimecrolimus Possible risk of cancer BBW FDA-USA pimecrolimus Not specified EM-MG FDA-USA promethazine HCl FDA-USA rosiglitazone Breathing problems, some causing death New onset and worsening diabetic macular edema Quinine products Cardiac arrhythmias, thrombocytopenia, and severe hypersensitivity reactions, including deaths associated with quinine products. EM FDA-USA Rituximab Deaths resulting from progressive multifocal leukoencephalopathy (PML) EM FDA-USA Serotonin Syndrome Selective Serotonin Reuptake Inhibitors (SSRIs) Serotonin syndrome EM FDA-USA Rituxan (Rituximab) Audience: Oncologists, Rheumatologists, other healthcare professionals, and consumers Indication: Treatment of CD20-postive, B-cell, non-Hodgkins lymphoma and for moderately-to-severely-active rheumatoid arthritis when there has been inadequate response to other treatments. [Posted 12/18/2006] FDA and Genentech informed healthcare professionals of important emerging safety information about Rituxan. Two patients died after being treated with Rituxan for systemic lupus erythematosus (SLE). Rituxan is approved for the above indication and is prescribed off-label for other serious diseases and conditions such as SLE. The cause of death was a viral infection of the brain called progressive multifocal leukoencephalopathy (PML) that is caused by reactivated JC virus which is present in about 80 percent of adults. Physicians should maintain a high index of suspicion for the development of PML in patients under treatment with Rituxan. 5-Hydroxytryptamine Receptor Agonists (Triptans) - Serotonin Syndrome Selective Serotonin Reuptake Inhibitors (SSRIs) Selective Serotonin/Norepinephrine Reuptake Inhibitors (SNRIs) Serotonin Syndrome Audience: Neuropsychiatric and other healthcare professionals, and consumers [Posted 07/19/2006] FDA notified healthcare professionals and consumers of new safety information regarding taking medications used to treat migraine headaches (triptans) together with certain types of antidepressant and mood disorder medications (selective serotonin reuptake inhibitors (SSRIs) and selective serotonin/norepinephrine reuptake inhibitors (SNRIs). A life-threatening condition called serotonin syndrome may occur when triptans are used together with a SSRI or a SNRI. Product active ingredient EM EM Year Title SSRIs and Treatment Challenges of Depression in Pregnancy Audience: Neuropsychiatric and other healthcare professionals, and consumers [Posted 07/19/2006] FDA notified healthcare professionals and consumers of important information from two recent studies that should be considered when making treatment decisions in pregnant women who take antidepressants. The studies included pregnant women who were treated with selective serotonin reuptake inhibitors (SSRIs), or in a few cases, other antidepressant medications. One study illustrated the potential risk of relapsed depression after stopping antidepressant medication during pregnancy. The second study suggests there may be additional, though rare, risks of taking SSRI medications during pregnancy. This study focused on newborn babies with persistent pulmonary hypertension (PPHN), which is a serious and life-threatening lung condition that occurs soon after birth. Babies born with PPHN have high pressure in their lung blood vessels and are not able to get enough oxygen into their bloodstream. In this study, PPHN was six times more common in babies whose mothers took an SSRI antidepressant after the 20th week of pregnancy compared to babies whose mothers did not take an antidepressant. Regulatory Authority/Reg ion Product active ingredient FDA-USA SSRIs Potential risk of relapsed depression after stopping antidepressant medication during pregnancy / may be additional, though rare, risks of taking SSRI medications during pregnancy FDA-USA SNRIs / SSRIs Serotonin syndrome EM FDA-USA tacrolimus Risk of cancer BBW Additionally, the labeling for paroxetine (Paxil) was recently changed to add information about findings in an epidemiologic study that suggests that exposure to the drug in the first trimester of pregnancy may be associated with an increased risk of cardiac birth defects. 229 2006 Safety Issue (AE) Intervention Type EM Selective Norepinephrine Reuptake Inhibitors (SNRIs) 5-Hydroxytryptamine Receptor Agonists (Triptans); Selective Serotonin Reuptake Inhibitors (SSRIs); Selective Serotonin/Norepinephrine Reuptake Inhibitors (SNRIs) Serotonin Syndrome Audience: Neuropsychiatric and other healthcare professionals, and consumers [Posted 07/19/2006] FDA notified healthcare professionals and consumers of new safety information regarding taking medications used to treat migraine headaches (triptans) together with certain types of antidepressant and mood disorder medications (selective serotonin reuptake inhibitors (SSRIs) and selective serotonin/norepinephrine reuptake inhibitors (SNRIs). A life-threatening condition called serotonin syndrome may occur when triptans are used together with a SSRI or a SNRI. 230 2006 Protopic Ointment (tacrolimus); Elidel Cream (pimecrolimus) Audience: Dermatological and other healthcare professionals [Posted 01/20/2006] The Food and Drug Administration announced the approval of updated labeling for two topical eczema drugs, Elidel Cream (pimecrolimus) and Protopic Ointment (tacrolimus). The labeling will be updated with a boxed warning about a possible risk of cancer and a EM-MG (FDA-approved patient labeling) will be distributed to help ensure that patients using these prescription medicines are aware of this concern. The new labeling also clarifies that these drugs are recommended for use as second-line treatments. This means that other prescription topical medicines should be tried first. Use of these drugs in children under 2 years of age is not recommended. 231 2006 232 2006 Protopic Ointment (tacrolimus) [2006 version] FDA-USA tacrolimus Not specified EM-MG 233 2006 Nolvadex (tamoxifen) [2006 version] Ketek (telithromycin) 06/29/2006; Audience: Infectious disease, hepatology and other healthcare professionals. [Posted 06/29/2006] The FDA notified healthcare professionals and patients that it completed its safety assessment of Ketek (telithromycin), indicated for the treatment of acute exacerbation of chronic bronchitis, acute bacterial sinusitis and community acquired pneumonia of mild to moderate severity, including pneumonia caused by resistant strep infections. The drug has been associated with rare cases of serious liver injury and liver failure with four reported deaths and one liver transplant after the administration of the drug. FDA determined that additional warnings are required and the manufacturer is revising the drug labeling to address this safety concern. FDA is advising both patients taking Ketek and their doctors to be on the alert for signs and symptoms of liver problems. Patients experiencing such signs or symptoms should discontinue Ketek and seek medical evaluation, which may include tests for liver function. FDA-USA tamoxifen Not specified EM-MG telithromycin Rare cases of serious liver injury and liver failure with four reported deaths and one liver transplant EM 234 2006 FDA-USA Year 235 236 2006 Title Aptivus (tipranavir); Audience: Infectious disease specialists, pharmacists, and other healthcare professionals; [Posted 06/30/2006] Boehringer Ingelheim and FDA informed healthcare professionals of important new safety information for Aptivus (tipranavir) capsules, co-administered with ritonavir (500mg/200mg), that includes an addition to the drug's Black Box Warning regarding reports of both fatal and non-fatal intracranial hemorrhage (ICH). Boehringer Ingelheim identified 14 reports of intracranial hemorrhage events, including 8 fatalities, in 6,840 HIV-1 infected individuals receiving Aptivus capsules in combination antiretroviral therapy in clinical trials. Many of the patients experiencing ICH in the Aptivus clinical development program had other medical conditions (CNS lesions, head trauma, recent neurosurgery, coagulopathy, hypertension or alcohol abuse) or were receiving concomitant medications, including anticoagulants and antiplatelet agents, that may have caused or contributed to these events. 2006 Effexor XR (venlafaxine HCl) Extended-Release Capsules Audience: Neuropsychiatric and other healthcare professionals [Posted 10/25/2006] Wyeth and FDA notified healthcare professionals of revisions to the OVERDOSAGE/Human Experience section of the prescribing information for Effexor (venlafaxine HCl), indicated for treatment of major depressive disorder. In postmarketing experience, there have been reports of overdose with venlafaxine, occurring predominantly in combination with alcohol and/or other drugs. Published retrospective studies report that venlafaxine overdosage may be associated with an increased risk of fatal outcome compared to that observed with SSRI antidepressant products, but lower than that for tricyclic antidepressants. Healthcare professionals are advised to prescribe Effexor and Effexor XR in the smallest quantity of capsules consistent with good patient management to reduce the risk of overdose. Regulatory Authority/Reg ion Product active ingredient Safety Issue (AE) Intervention Type tipranavir Fatal and non-fatal intracranial hemorrhage (ICH) BBW FDA-USA venlafaxine HCl Overdose leading to increased risk of fatal outcome EM FDA-USA warfarin sodium Bleeding risk EM-MG FDA-USA acitretin Not specified EM-MG alprazolam Difficulty in breathing, muscle spasms and muscle stiffness EM Antidepressant Medication Products Increased risks of suicidal thinking and behavior in young adults ages 18 to 24 years old during the first one to two months of treatment BBWupdate FDA-USA Coumadin (warfarin sodium) Audience: Pharmacists, other healthcare professionals, and patients [Posted 10/06/2006] FDA and Bristol-Myers Squibb notified pharmacists and physicians of revisions to the labeling for Coumadin, to include a new patient EM-MG as well as a reorganization and highlighting of the current safety information to better inform providers and patients. The FDA regulation 21CFR 208 requires a EM-MG to be provided with each prescription that is dispensed for products that FDA determines pose a serious and significant public health concern. See information about all currently approved EM-MGs. [October 2006 - Label (including EM-MG) - Bristol-Myers Squibb] 237 2006 238 2007 239 240 Soriatane (acitretin) [2007 version] Xanax (alprazolam) Audience: Consumers, healthcare professionals [Posted 02/16/2007] FDA informed consumers and healthcare professionals regarding the possible dangers of buying prescription medications online. Individuals who ordered Ambien, Xanax, Lexapro, and Ativan over the internet received a product that contained haloperidol, a powerful anti-psychotic drug. Several consumers experienced difficulty in breathing, muscle spasms and muscle stiffness after ingesting the suspect product and had to seek emergency medical treatment. Haloperiodol can cause muscle stiffness, spasms, agitation and sedation. Taking medication that contains an active ingredient other than what is prescribed by qualified healthcare professionals is generally unsafe. 2007 2007 FDA-USA Antidepressant Medication Products; Audience: Healthcare professionals, consumers [Posted 05/02/2007] FDA notified healthcare professionals that the Agency proposed that makers of all antidepressant medications update the existing black box warning on the prescribing information for their products to include warnings about the increased risks of suicidal thinking and behavior in young adults ages 18 to 24 years old during the first one to two months of treatment. The proposed labeling changes also state that scientific data did not show this increased risk in adults older than 24 years of age and that adults 65 years of age and older taking antidepressants have a decreased risk of suicidality. The proposed updates apply to the entire category of antidepressants. Individuals currently taking prescribed antidepressant medications should not stop taking them and should notify their healthcare professional if they have concerns. Manufacturers of antidepressant medications will have 30 days to submit their revised product labeling and revised EM-MGs to FDA for review. See the FDA press release for the list of products affected by the proposed antidepressant product labeling changes. FDA-USA Year 241 2007 242 2007 243 2007 244 2007 245 2007 Title Aprotinin Injection (marketed as Trasylol); Audience: Cardiac surgeons, other healthcare professionals [Posted 10/25/2007] FDA informed healthcare professionals of the Data Safety Monitoring Board's recommendation to stop patient enrollment in the aprotinin treatment group arm of the Blood conservation using antifibrinolytics: A randomized trial in a cardiac surgery population (BART) study. The BART study was designed to test the hypothesis that aprotinin was superior to epsilon-aminocaproic acid and tranexamic acid in decreasing the occurrence of massive bleeding in association with cardiac surgery. The preliminary findings suggest that, compared to the antifibrinolytic drugs, epsilonaminocaproic acid and tranexamic acid, aprotinin increases the risk of death. FDA anticipates re-evaluation of the overall risks and benefits of Trasylol which may result in the need to revise the prescribing information or other regulatory actions. Healthcare professionals who are considering use of Trasylol should be aware of the risks and benefits described in the prescribing information for Trasylol and the accumulating data suggesting Trasylol administration increases the risk of death compared to other antifibrinolytic drugs. Avastin (bevacizumab) April 2007; Audience: Oncological and other healthcare professionals [Posted 04/21/2007] Genentech and FDA notified healthcare professionals of important new safety information regarding tracheoesophageal (TE) fistula formation in a recent clinical study in patients with limited-stage small cell lung cancer (SCLC). This multicenter, non-randomized, single-arm phase II clinical trial study combined chemotherapy and radiation plus Avastin. There have been two confirmed serious adverse events of TE fistula (one fatal) reported in the first 29 patients enrolled in this study. A third, fatal event (upper aerodigestive tract hemorrhage and death of unknown cause), was also reported, in which TE fistula was suspected but not confirmed. All three events occurred during the Avastin maintenance phase of the study in the context of persistent esophagitis. Additionally, six other cases of TE fistula have also been reported in other lung and esophageal cancer studies using Avastin and chemotherapy alone or with concurrent radiation treatment. Carbamazepine (marketed as Carbatrol, Equetro, Tegreto and generics) Audience: Neurologists, psychiatrists, other healthcare professionals, consumers [Posted 12/12/2007] FDA informed healthcare professionals that dangerous or even fatal skin reactions (Stevens Johnson syndrome and toxic epidermal necrolysis), that can be caused by carbamazepine therapy, are significantly more common in patients with a particular human leukocyte antigen (HLA) allele, HLA-B*1502. This allele occurs almost exclusively in patients with ancestry across broad areas of Asia, including South Asian Indians. Patients with ancestry from areas in which HLA-B*1502 is present should be screened for the HLA-B*1502 allele before starting treatment with carbamazepine. If these individuals test positive, carbamazepine should not be started unless the expected benefit clearly outweighs the increased risk of serious skin reactions. Patients who have been taking carbamazepine for more than a few months without developing skin reactions are at low risk of these events ever developing from carbamazepine. This is true for patients of any ethnicity or genotype, including patients positive for HLA-B*1502. Cefepime (marketed as Maxipime); Audience: Healthcare professionals [UPDATE 05/14/2008] FDA is continuing its investigation of a possible association between the use of cefepime and an increased risk of mortality compared with similar drugs. FDA will communicate its conclusions and any resulting recommendations to the public at the completion of its review. [Posted 11/14/2007] FDA issued an early communication about the ongoing review of new safety data and the request for additional data to further evaluate the risk of death in patients treated with cefepime. An article in the May 2007 issue of The Lancet Infectious Diseases (Efficacy and safety of cefepime: a systematic review and meta-analysis) raised the question about increased mortality with the use of cefepime, a broad spectrum B-lactam antibiotic currently approved for the treatment of a variety of infections due to susceptible strains of microorganisms. The article describes a higher all-cause mortality in patients treated with cefepime compared to other B-lactam antibiotics. Rocephin (ceftriaxone sodium) for Injection Audience: Neonatologists, pediatricians, infectious disease specialists, hospital administrators, other healthcare professionals [UPDATED 09/11/2007] Roche informed healthcare professionals about revisions made to the prescribing information for Rocephin to clarify the potential risk associated with concomitant use of Rocephin with calcium or calcium-containing solutions or products. Healthcare professionals are advised that Rocephin and calcium-containing solutions including continuous calciumcontaining infusions such as parenteral nutrition, should not be mixed or co-administered to any patient irrespective of age, even via different infusion lines at different sites. Rocephin and IV calcium-containing solutions should not be administered within 48 hours of each other in any patient. No data are available on the potential interaction between ceftriaxone and oral calcium-containing products or interaction between intramuscular ceftriaxone and calciumcontaining products (IV or oral). Regulatory Authority/Reg ion Product active ingredient Safety Issue (AE) Intervention Type FDA-USA Aprotinin Increased risk of death EM FDA-USA bevacizumab Tracheoesophageal (TE) fistula formation EM FDA-USA Carbamazepine Dangerous or even fatal skin reactions (Stevens Johnson syndrome and toxic epidermal necrolysis) EM FDA-USA Cefepime Increased risk of mortality compared with similar drugs EM ceftriaxone sodium Potential risk associated with concomitant use of Rocephin with calcium or calciumcontaining solutions or products. EMlabel clarificati on FDA-USA Year Title Regulatory Authority/Reg ion Product active ingredient Safety Issue (AE) Intervention Type [Posted 07/05/2007] Roche and FDA informed healthcare professionals of revisions to the CONTRAINDICATIONS, WARNINGS, PRECAUTIONS, ADVERSE REACTIONS and DOSAGE AND ADMINISTRATION sections of the prescribing information for Rocephin for Injection. The revisions are based on new information that describes the potential risk associated with concomitant use of Rocephin with calcium or calcium containing solutions or products. Cases of fatal reactions with calcium-ceftriaxone precipitates in the lungs and kidneys in both term and premature neonates were reported. Hyperbilirubinemic neonates, especially prematures, should not be treated with Rocephin. The drug must not be mixed or administered simultaneously with calcium-containing solutions or products, even via different infusion lines. Additionally, calcium-containing solutions or products must not be administered within 48-hours of the last administration of ceftriaxone. 246 2007 Celebrex (celecoxib) [2007 version] FDA-USA 247 2007 Limbitrol (chlordiazepoxide and amitriptyline) [2007 version] FDA-USA celecoxib chlordiazepoxide and amitriptyline 248 2007 Anafranil (clomipramine HCl) [2007 version] Codeine Products Used By Nursing Mothers August 2007 Audience: Obstetricians, pediatricians, other healthcare professionals, consumers FDA-USA 249 250 2007 [Posted 08/17/2007] FDA issued a Public Health Advisory with important new information about a very rare, but serious, side effect in nursing infants whose mothers are taking codeine and are ultra-rapid metabolizers of codeine. When codeine enters the body and is metabolized, it changes to morphine, which relieves pain. Many factors affect codeine metabolism, including a person’s genetic make-up. Some people have a variation in a liver enzyme and may change codeine to morphine more rapidly and completely than other people. Nursing mothers taking codeine may also have higher morphine levels in their breast milk. These higher levels of morphine in breast milk may lead to life-threatening or fatal side effects in nursing babies. In most cases, it is unknown if someone is an ultra-rapid codeine metabolizer. Cough and Cold Medications in Children Less Than Two Years of Age January 2007 Audience: Pediatric and primary care healthcare professionals and patients [Posted 01/12/2007] The Centers for Disease Control and Prevention (CDC) issued a Morbidity and Mortality Weekly Report (MMWR) article describing three deaths in U.S. infants aged less than 12 months associated with cough and cold medications. These medications were determined by medical examiners or coroners to be the underlying cause of death. The cases described in this report underscore the need for clinicians to use caution when prescribing and caregivers to use caution when administering cough and cold medications to children aged less than 2 years. 2007 FDA-USA FDA-USA Erythropoiesis Stimulating Agents: Aranesp (darbepoetin alfa), Epogen (epoetin alfa), and Procrit (epoetin alfa) November 2007 Audience: Oncologists, nephrologists, other healthcare professionals [UPDATE 01/03/2008] FDA informed healthcare professionals of findings from two additional clinical studies, Preoperative Epirubicin Paclitaxel Aranesp Study (PREPARE), and the National Cancer Institute Gynecologic Oncology Group (COG-19), showing an increase in mortality and shorter time to tumor progression in patients with cancer receiving an Erythropoiesis-Stimulating Agent (ESA). Both the PREPARE study in breast cancer and the COG-19 study in cervical cancer showed higher rates of death and or tumor progression in patients who received an ESA compared to patients who did not receive an ESA. 251 2007 FDA-USA Not specified EM-MG Not specified EM-MG clomipramine HCl Not specified EM-MG Codeine Products Very rare, but serious, side effect in nursing infants whose mothers are taking codeine and are ultra-rapid metabolizers of codeine. EM Cough and Cold Medications Deaths in U.S. infants aged less than 12 months associated with cough and cold medications EM darbepoetin alfa,epoetin alfa, and epoetin alfa Tumor growth and shortened survival in patients with advanced breast, head and neck, lymphoid and non-small cell lung cancer EM Year Title Exjade (deferasirox) Tablets For Oral Suspension Audience: Oncologists, Hematology-Oncologists, Pediatric Hematologists, Specialty Pharmacists Regulatory Authority/Reg ion Product active ingredient Safety Issue (AE) Intervention Type [UPDATE 12/13/2007] Novartis informed healthcare professionals of changes made to the WARNINGS, ADVERSE REACTIONS, and DOSAGE and ADMINISTRATION sections of prescribing information for Exjade Tablets for Oral Suspension. The WARNINGS and ADVERSE REACTIONS sections of the labeling were revised to include information about postmarketing reports of hepatic failure, some with a fatal outcome, in patients treated with Exjade. Most of these events occurred in patients greater than 55 years of age. Most reports of hepatic failure involved patients with significant comorbidities, including liver cirrhosis and multi-organ failure. [Posted 05/22/2007] Novartis and FDA notified healthcare professionals of changes to the WARNINGS and ADVERSE REACTIONS sections of the product labeling for Exjade, a drug used to treat chronic iron overload due to blood transfusions (transfusional hemosiderosis) in patients 2 years of age and older. Cases of acute renal failure, some with a fatal outcome, have been reported following the post marketing use of Exjade. Most of the fatalities occurred in patients with multiple co-morbidities and who were in advanced stages of their hematological disorders. Additionally, there were post marketing reports of cytopenias, including agranulocytosis, neutropenia and thrombocytopenia in patients treated with Exjade where some of the patients died. The relationship of these episodes to treatment with Exjade is uncertain. Most of these patients had preexisting hematologic disorders that are frequently associated with bone marrow failure. Further, cases of leukocytoclastic vasculitis, urticaria, and hypersensitivity reactions (including anaphylaxis and angioedema) were reported. 252 2007 Healthcare professionals should monitor serum creatinine in patients who are at increased risk of complications, having preexisting renal conditions, are elderly, have co-morbid conditions, or are receiving medicinal products that depress renal function. Blood counts should also be monitored regularly and treatment should be interrupted in patients who develop unexplained cytopenia Desmopressin Acetate (marketed as DDAVP Nasal Spray, DDAVP Rhinal Tube, DDAVP, DDVP, Minirin, and Stimate Nasal Spray) December 2007 Audience: Endocrinologists, pediatricians, other healthcare professionals FDA-USA deferasirox Hepatic failure EM FDA-USA Desmopressin Acetate Certain patients, including children treated with the intranasal formulation of the drug for primary nocturnal enuresis (PNE), are at risk for developing severe hyponatremia that can result in seizures and death. EMDHCPL FDA-USA Desmopressin Acetate Severe hyponatremia and seizures EM FDA-USA dexmethylphenid ate HCl Not specified EM-MG [UPDATE 8/07/2008] The Dear Healthcare Professional Letter issued by Sanofi-aventis U.S. in December 2007 has been added as a link below. Also, links to prescribing information for healthcare professionals and patient package labeling with the safety-related revisions highlighted are included for the following DDAVP (desmopressin acetate) Sanofi-aventis, U.S. products: Nasal Spray, Rhinal Tube, Injection, and Tablets. 253 2007 [Posted 12/04/2007] FDA notified healthcare professionals and patients of the Agency's request that manufacturers update the prescribing information for desmopressin to include important new safety information about severe hyponatremia and seizures. Certain patients, including children treated with the intranasal formulation of the drug for primary nocturnal enuresis (PNE), are at risk for developing severe hyponatremia that can result in seizures and death. As such, desmopressin intranasal formulations are no longer indicated for the treatment of primary nocturnal enuresis and should not be used in hyponatremic patients or patients with a history of hyponatremia. PNE treatment with desmopressin tablets should be interrupted during acute illnesses that may lead to fluid and/or electrolyte imbalance. All desmopressin formulations should be used cautiously in patients at risk for water intoxication with hyponatremia. Desmopressin Acetate (marketed as DDAVP Nasal Spray, DDAVP Rhinal Tube, DDAVP, DDVP, Minirin, and Stimate Nasal Spray); Audience: Endocrinologists, pediatricians, other healthcare professionals [UPDATE 8/07/2008] The Dear Healthcare Professional Letter issued by Sanofi-aventis U.S. in December 2007 has been added as a link below. Also, links to prescribing information for healthcare professionals and patient package labeling with the safety-related revisions highlighted are included for the following DDAVP (desmopressin acetate) Sanofi-aventis, U.S. products: Nasal Spray, Rhinal Tube, Injection, and Tablets. 254 2007 [Posted 12/04/2007] FDA notified healthcare professionals and patients of the Agency's request that manufacturers update the prescribing information for desmopressin to include important new safety information about severe hyponatremia and seizures. 255 2007 Focalin (dexmethylphenidate HCl) [2007 version] Year Title Regulatory Authority/Reg ion Product active ingredient 256 2007 Adderall XR (dextroamphetamine saccharate, amphetamine aspartate, dextroamphetamine sulfate and amphetamine sulfate) [2007 version] FDA-USA 257 2007 Arthrotec (diclofenac sodium) [2007 version] FDA-USA dextroamphetam ine saccharate, amphetamine aspartate, dextroamphetam ine sulfate and amphetamine sulfate diclofenac sodium 258 2007 Sinequan (doxepin HCl) [2007 version] FDA-USA 259 2007 Cymbalta (duloxetine HCl) [2007 version)] Baraclude (entecavir) Tablets and Oral Solution; Audience: Infectious disease specialists and other healthcare professionals [UPDATE 08/16/2007] FDA and Bristol-Myers Squibb notified healthcare professionals of revisions to the following sections of the Baraclude prescribing information: BOXED WARNINGS, MICROBIOLOGY/Antiviral Activity against HIV (human immunodeficiency virus), WARNINGS/Co-infection with HIV, PRECAUTIONS/Information for Patients, and Patient Package Insert. Baraclude therapy is not recommended for HIV/hepatitis B virus (HBV) co-infected patients who are not also receiving highly active antiretroviral therapy (HAART) due to the potential for the development of HIV resistance. FDA-USA Not specified EM-MG Not specified EM-MG doxepin HCl Not specified EM-MG duloxetine HCl Not specified EM-MG FDA-USA entecavir Contraindication for HIV/hepatitis B virus (HBV) co-infected patients who are not also receiving highly active antiretroviral therapy (HAART) due to the potential for the development of HIV resistance EM FDA-USA epoetin alfa Serious and life-threatening side effects or death EM esomeprazole Increased the risk of heart attacks, heart failure, and heart-related sudden death EM [Posted 02/24/2007] FDA and Bristol-Myers Squibb notified healthcare professionals of revisions to the MICROBIOLOGY/Antiviral Activity and INDICATIONS AND USAGE/Description of Clinical Studies/Special Populations sections of the prescribing information for Baraclude. The revised labeling is the result of a case report in which a human immunodeficiency virus (HIV) variant containing the M184V resistance substitution was documented during Baraclude treatment for chronic hepatitis B virus (HBV) infection in an HIV/HBV co-infected patient who was not simultaneously receiving highly active antiretroviral therapy (HAART). 260 2007 Epogen (epoetin alfa); Audience: Oncologists, nephrologists, other healthcare professionals [UPDATE 03/09/2007] FDA notified healthcare professionals of new safety information for erythropoiesis-stimulating agents (ESAs) Aranesp (darbepoetin alfa), Epogen (epoetin alfa), and Procrit (epoetin alfa). Four new studies in patients with cancer found a higher chance of serious and life-threatening side effects or death with the use of ESAs. These research studies were evaluating an unapproved dosing regimen, a patient population for which ESAs are not approved, or a new unapproved ESA. FDA believes these new concerns apply to all ESAs and is re-evaluating how to safely use this product class. [Posted 02/16/2007] FDA notified healthcare professionals of the results from a large clinical trial evaluating use of an erythropoiesis-stimulating agent (ESA) to treat anemia in cancer patients not receiving chemotherapy. In this study, patients received either Aranesp, an ESA, according to the approved dosing regimen or placebo. Patients treated with Aranesp had a higher death rate and no reduction in the need for transfusions compared to those treated with placebo. 261 2007 Nexium (esomeprazole); Audience: Gastroenterologists, other healthcare professionals, consumers [UPDATE 12/11/2007] FDA informed healthcare professionals of the issuance of the Agency's follow-up communication regarding its review of safety data for the drugs omeprazole and esomeprazole that raised concerns about a potential increased risk of heart problems for patients treated with these drugs. The Agency conducted a comprehensive review of the data from two studies that were submitted to FDA. FDA continues to believe that long-term use of omeprazole or esomeprazole is not likely to be associated with an increased risk of heart problems and recommends that healthcare providers continue to prescribe and patients continue to use these products in the manner described in the labeling. 262 2007 Safety Issue (AE) Intervention Type FDA-USA Year 263 2007 Title Prosom (estazolam); Audience: Healthcare professionals, consumers [Posted 03/14/2007] FDA notified healthcare professionals of its request that all manufacturers of sedative-hypnotic drug products, a class of drugs used to induce and/or maintain sleep, strengthen their product labeling to include stronger language concerning potential risks. These risks include severe allergic reactions and complex sleep-related behaviors, which may include sleep-driving. Sleep driving is defined as driving while not fully awake after ingestion of a sedativehypnotic product, with no memory of the event. FDA also requested that each product manufacturer send letters to health care providers to notify them about the new warnings, and that manufacturers develop Patient EM-MGs for the products to inform consumers about risks and advise them of potential precautions that can be taken. Regulatory Authority/Reg ion Product active ingredient Safety Issue (AE) Intervention Type estazolam Severe allergic reactions and complex sleep-related behaviors, which may include sleep-driving EM eszopiclone Severe allergic reactions and complex sleep-related behaviors, which may include sleep-driving EM FDA-USA ethchlorvynol Severe allergic reactions and complex sleep-related behaviors, which may include sleep-driving EM FDA-USA fentanyl Death and life-threatening adverse events EM FDA-USA fluoxetine HCl Not specified EM-MG FDA-USA Lunesta (eszopiclone); Audience: Healthcare professionals, consumers 264 2007 [Posted 03/14/2007] FDA notified healthcare professionals of its request that all manufacturers of sedative-hypnotic drug products, a class of drugs used to induce and/or maintain sleep, strengthen their product labeling to include stronger language concerning potential risks. These risks include severe allergic reactions and complex sleep-related behaviors, which may include sleep-driving. Sleep driving is defined as driving while not fully awake after ingestion of a sedativehypnotic product, with no memory of the event. FDA also requested that each product manufacturer send letters to health care providers to notify them about the new warnings, and that manufacturers develop Patient EM-MGs for the products to inform consumers about risks and advise them of potential precautions that can be taken. FDA-USA Placidyl (ethchlorvynol); Audience: Healthcare professionals, consumers [Posted 03/14/2007] FDA notified healthcare professionals of its request that all manufacturers of sedative-hypnotic drug products, a class of drugs used to induce and/or maintain sleep, strengthen their product labeling to include stronger language concerning potential risks. These risks include severe allergic reactions and complex sleep-related behaviors, which may include sleep-driving. Sleep driving is defined as driving while not fully awake after ingestion of a sedativehypnotic product, with no memory of the event. FDA also requested that each product manufacturer send letters to health care providers to notify them about the new warnings, and that manufacturers develop Patient EM-MGs for the products to inform consumers about risks and advise them of potential precautions that can be taken. 265 2007 Fentanyl Transdermal System (marketed as Duragesic and generics); Audience: Pain management specialists, other healthcare professionals [Posted 12/21/2007] FDA issued an update that highlights important information on appropriate prescribing, dose selection, and the safe use of the fentanyl transdermal system (patch). FDA previously issued a Public Health Advisory and Information for Healthcare Professionals in July 2005 regarding the appropriate and safe use of the transdermal system. However, the Agency continues to receive reports of death and life-threatening adverse events related to fentanyl overdose that have occurred when the fentanyl patch was used to treat pain in opioid-naive patients and when opioid-tolerant patients have applied more patches than prescribed, changed the patch too frequently, and exposed the patch to a heat source. The fentanyl patch is only indicated for use in patients with persistent, moderate to severe chronic pain who have been taking a regular, daily, around-the-clock narcotic pain medicine for longer than a week and are considered to be opioid-tolerant. Patients must avoid exposing the patch to excessive heat as this promotes the release of fentanyl from the patch and increases the absorption of fentanyl through the skin which can result in fatal overdose. Directions for prescribing and using the fentanyl patch must be followed exactly to prevent death or other serious side effects from fentanyl overdose. 266 2007 267 2007 Sarafem (fluoxetine HCl) [2007 version] Year Title Dalmane (flurazepam HCl); Audience: Healthcare professionals, consumers Regulatory Authority/Reg ion Intervention Type Product active ingredient Safety Issue (AE) EM 2007 [Posted 03/14/2007] FDA notified healthcare professionals of its request that all manufacturers of sedative-hypnotic drug products, a class of drugs used to induce and/or maintain sleep, strengthen their product labeling to include stronger language concerning potential risks. These risks include severe allergic reactions and complex sleep-related behaviors, which may include sleep-driving. Sleep driving is defined as driving while not fully awake after ingestion of a sedativehypnotic product, with no memory of the event. FDA also requested that each product manufacturer send letters to health care providers to notify them about the new warnings, and that manufacturers develop Patient EM-MGs for the products to inform consumers about risks and advise them of potential precautions that can be taken. FDA-USA flurazepam HCl Severe allergic reactions and complex sleep-related behaviors, which may include sleep-driving. 269 2007 Haloperidol (Haldol, Haldol decanoate, and Haldol lactate); Audience: Neuropsychiatric and cardiovascular specialists, other healthcare professionals [Posted 09/17/2007] Johnson and Johnson and FDA informed healthcare professionals that the WARNINGS section of the prescribing information for haloperidol has been revised to include a new Cardiovascular subsection regarding cases of sudden death, QT prolongation and Torsades de Pointes(TdP) in patients treated with haloperidol, especially when given intravenously, or at doses higher than recommended. Although injectable haloperidol is only approved by the FDA for intramuscular injection, there is considerable evidence that the intravenous administration of haloperidol is a relatively common off-label clinical practice. There are at least 28 case reports of QT prolongation and TdP, some with fatal outcome in the context of off-label intravenous haloperidol. Healthcare professionals should consider this new risk information when making individual treatment decisions for their patients. FDA-USA Haldol, Haldol decanoate, and Haldol lactate Sudden death, QT prolongation and Torsades de Pointes(TdP) EM 270 2007 Motrin (ibuprofen) [2007 version] FDA-USA ibuprofen Not specified EM-MG 271 2007 Tofranil (imipramine HCl) [2007 version] FDA-USA imipramine HCl Not specified EM-MG 272 2007 Indocin (indomethacin) [2007 version] FDA-USA indomethacin Not specified EM-MG 273 2007 Toradol (ketorolac tromethamine) [2007 version] FDA-USA ketorolac tromethamine Not specified EM-MG 274 2007 Lindane Lotion (lindane) [2007 version] Zyvox (linezolid); Audience: Infectious disease specialists, other healthcare professionals FDA-USA lindane Not specified EM-MG FDA-USA linezolid Higher chance of death EM FDA-USA lopinavir/ritonav ir Accidental overdose EMDHCPL 268 [Posted 03/16/2007] FDA notified healthcare professionals of new emerging safety concerns about Zyvox (linezolid) from a recent clinical study. This open-label, randomized trial compared linezolid to vancomycin, oxacillin, or dicloxacillin in the treatment of seriously ill patients with intravascular catheter-related bloodstream infections including those with cathetersite infections. Patients treated with linezolid had a higher chance of death than did patients treated with any comparator antibiotic, and the chance of death was related to the type of organism causing the infection. Patients with Gram positive infections had no difference in mortality according to their antibiotic treatment. In contrast, mortality was higher in patients treated with linezolid who were infected with Gram negative organisms alone, with both Gram positive and Gram negative organisms, or who had no infection when they entered the study. 275 2007 Kaletra (lopinavir/ritonavir) Oral Solution; Audience: Infectious disease specialists, pediatricians, pharmacists, other healthcare professionals [Posted 08/14/2007] Abbott Laboratories disseminated a Dear Healthcare Provider Letter throughout the world to physicians and pharmacists that prescribe/distribute Kaletra Oral Solution. The letter informed healthcare professionals of an accidental overdose that occurred with a pediatric patient taking Kaletra Oral Solution. The infant received a significantly large dose of Kaletra and subsequently died. Healthcare professionals should pay special attention to accurate calculation of the dose of Kaletra, transcription of the medication order, dispensing information and dosing instructions to minimize the risk for medication errors. 276 2007 Regulatory Authority/Reg ion 277 2007 Desoxyn (methamphetamine HCl) [2007 version] FDA-USA 278 2007 Mircera* (methoxy polyethylene glycol-epoetin beta) [2007 version] FDA-USA Product active ingredient methamphetami ne HCl methoxy polyethylene glycol-epoetin beta 279 2007 Metadate CD (methylphenidate HCl) [2007 version] FDA-USA 280 2007 Remeron (mirtazapine) [2007 version] Provigil (modafinil) Tablets; Audience: Neuropsychiatric specialists, other healthcare professionals, consumers [Posted 10/24/2007] FDA and Cephalon notified healthcare professionals of updates to the WARNINGS section of the prescribing information for Provigil (modafinil). Provigil is indicated to improve wakefulness in adult patients with excessive sleepiness associated with narcolepsy, obstructive sleep apnea/hypopnea syndrome, and shift work sleep disorder. The revised labeling updates safety information to include warnings regarding serious rash, including Stevens-Johnson Syndrome (SJS) and hypersensitivity reactions, and psychiatric symptoms. Rare cases of serious or life-threatening rash, including Toxic Epidermal Necrolysis, and Drug Rash with Eosinophilia and Systemic Symptoms have been reported in adults and children in worldwide postmarketing experience. Angioedema and multi-organ hypersensitivity reactions have also been reported in postmarketing experience. FDA-USA Year 281 282 2007 2007 Title CellCept (mycophenolate mofetil) February 2007 Audience: Cardiac transplantation healthcare professionals Indication: Prophylaxis of organ rejection in patients receiving allogeneic renal, cardiac or hepatic transplants [Posted 02/22/2007] Roche and FDA notified cardiac transplant healthcare practitioners about a clinical study (Heart Spare The Nephron) that was terminated due to an observed increased incidence of grade IIIA acute rejection in heart transplant patients switched from calcineurin inhibitor and CellCept to Rapamune (sirolimus) and CellCept at 12 weeks post heart transplantation. The safety and efficacy of CellCept in combination with sirolimus following withdrawal of initial calcineurin inhibitor therapy has not been established. FDA-USA FDA-USA CellCept (mycophenolate mofetil) October 2007 Audience: Cardiac, renal, hepatic transplantation specialists, gynecologists, obstetricians, and other healthcare professionals [UPDATE 11/27/2007] Prescribing information for Mycophenolic Acid (marketed as Myfortic Delayed Released Tablets) revised to include information that use of drug during pregnancy is associated with increased risks of pregnancy loss and congenital malformations. See the MedWatch alert for Myfortic (mycophenolic acid). [Posted 10/29/2007] Roche and FDA notified healthcare providers that use of CellCept (mycophenolate mofetil) is associated with increased risk of first trimester pregnancy loss and increased risk of congenital malformations, especially external ear and facial abnormalities including cleft lip and palate, and anomalies of the distal limbs, heart, esophagus, and kidney. Based on postmarketing data from the United States National Transplantation Pregnancy Registry and additional postmarketing data collected in women exposed to systemic mycophenolate mofetil during pregnancy, the pregnancy category for CellCept has been changed from Category C (risk of fetal harm cannot be ruled out) to Category D (positive evidence of fetal risk). Labeling changes include the following sections: BOXED WARNING, WARNINGS/Pregnancy and Pregnancy Exposure Prevention, PRECAUTIONS/Information for Patients, and ADVERSE REACTIONS/Postmarketing Experience. 283 2007 FDA-USA Safety Issue (AE) Intervention Type Not specified EM-MG Not specified EM-MG methylphenidate HCl Not specified EM-MG mirtazapine Not specified EM-MG modafinil Serious rash, including Stevens-Johnson Syndrome (SJS) and hypersensitivity reactions, and psychiatric symptoms EM mycophenolate mofeti Increased incidence of grade IIIA acute rejection in heart transplant patients switched from calcineurin inhibitor and CellCept to Rapamune (sirolimus) and CellCept at 12 weeks post heart transplantation EM mycophenolate mofeti Use of drug during pregnancy is associated with increased risks of pregnancy loss and congenital malformations EM Year 284 2007 285 2007 286 2007 287 2007 288 2007 289 2007 Title Nonprescription Cough and Cold Medicine Use in Children; Audience: Parents and caregivers of children receiving cough and cold products, pediatricians, other healthcare providers [Posted August 15, 2007] FDA announced that on October 18 - 19, 2007, the Nonprescription Drugs Advisory Committee will discuss the safety and effectiveness of cough and cold drug product use in children. Questions have been raised about the safety of these products and whether the benefits justify any potential risks from the use of these products in children, especially in children under two years of age. In preparation for the meeting, FDA is reviewing safety and efficacy data for the ingredients of these products. Some reports of serious adverse events associated with the use of these products appear to be the result of giving too much of these medicines to children. Pamelor (nortriptyline HCl) [2007 version] Xolair (omalizumab); Audience: Pulmonary healthcare professionals, asthmatic patients Indications and Usage: for treatment of adults and adolescents (12 years of age and above) with moderate to severe persistent asthma who have a positive skin test or in vitro reactivity to a perennial aeroallergen and whose symptoms are inadequately controlled with inhaled corticosteroids. Xolair has been shown to decrease the incidence of asthma exacerbations in these patients. Safety and efficacy have not been established in other allergic conditions. [UPDATE 07/02/2007] Genetech and FDA informed healthcare professionals and asthmatic patients that the prescribing information for Xolair was revised to include a new BOXED WARNING, and updated WARNINGS, PRECAUTIONS, and ADVERSE REACTIONS sections that address the risk of anaphylaxis (the onset of action can be delayed for 24 hours or more) when taking this medication. In addition, a new EM-MG was developed and will be provided to patients when a prescription for Xolair is filled or refilled at the pharmacy. Due to the risk of anaphylaxis, Xolair should only be administered to patients in a healthcare setting under direct medical supervision. Patients should be observed for an appropriate period of time following each Xolair injection. [Posted 02/21/2007] FDA notified asthmatic patients and healthcare professionals of new reports of serious and lifethreatening allergic reactions (anaphylaxis) in patients after treatment with Xolair (omalizumab). Omeprazole (marketed as Prilosec and generic products); Audience: Gastroenterologists, other healthcare professionals, consumers [UPDATE 12/11/2007] FDA informed healthcare professionals of the issuance of the Agency's follow-up communication regarding its review of safety data for the drugs omeprazole and esomeprazole that raised concerns about a potential increased risk of heart problems for patients treated with these drugs. The Agency conducted a comprehensive review of the data from two studies that were submitted to FDA. FDA continues to believe that long-term use of omeprazole or esomeprazole is not likely to be associated with an increased risk of heart problems and recommends that healthcare providers continue to prescribe and patients continue to use these products in the manner described in the labeling for the two products. See the "Update of Safety Review" for information regarding the two studies that were reviewed. [Posted August 09, 2007] FDA issued an early communication about the ongoing review of new safety data for the proton pump inhibitors, Prilosec and Nexium. The new safety data was from two small long-term clinical studies in patients with severe gastroesophageal reflux disease (GERD). In both studies, patients were randomly assigned to receive treatment with a drug (either omeprazole or esomeprazole) or to have surgery to control their GERD. Daypro Alta (oxaprozin potassium) [2007 version] Butisol Sodium Carbrital (pentobarbital and carbromal); Audience: Healthcare professionals, consumers [Posted 03/14/2007] FDA notified healthcare professionals of its request that all manufacturers of sedative-hypnotic drug products, a class of drugs used to induce and/or maintain sleep, strengthen their product labeling to include stronger language concerning potential risks. These risks include severe allergic reactions and complex sleep-related behaviors, which may include sleep-driving. Sleep driving is defined as driving while not fully awake after ingestion of a sedativehypnotic product, with no memory of the event. FDA also requested that each product manufacturer send letters to health care providers to notify them about the new warnings, and that manufacturers develop Patient EM-MGs for the products to inform consumers about risks and advise them of potential precautions that can be taken. Regulatory Authority/Reg ion Intervention Type Product active ingredient Safety Issue (AE) FDA-USA Nonprescription Cough and Cold Medicine Use in Children Serious adverse events associated with the use of these products appear to be the result of giving too much of these medicines to children EM FDA-USA nortriptyline HCl Not specified EM-MG omalizumab Risk of anaphylaxis (the onset of action can be delayed for 24 hours or more) BBW FDA-USA omeprazole Increased the risk of heart attacks, heart failure, and heart-related sudden death EM FDA-USA oxaprozin potassium Not specified EM-MG pentobarbital and carbroma Severe allergic reactions and complex sleep-related behaviors, which may include sleep-driving EM FDA-USA FDA-USA Year 290 2007 291 2007 292 2007 293 2007 294 2007 295 2007 Title Permax (pergolide) and generic equivalents; Audience: Neurologists, other healthcare professionals, consumers [Posted 03/29/2007] FDA notified healthcare professionals and patients that companies that manufacture and distribute pergolide have agreed to withdraw the drug from the market. Pergolide is a dopamine agonist (DA) used with levodopa and carbidopa to manage the signs and symptoms of Parkinson's disease. Results of two new studies showed that some patients with Parkinson's disease treated with pergolide had serious damage to their heart valves when compared to patients who did not receive the drug. These two studies confirm earlier studies that also describe this problem. Patients currently taking pergolide should contact their healthcare professional about alternate treatments and not abruptly stop taking their medication. Healthcare professionals should assess their patient's need for DA therapy. If continued treatment with a DA is needed, another DA should be substituted for pergolide. Nardil (phenelzine sulfate) [2007 version] Actos (pioglitazone); Audience: Endocrinologists, other healthcare professionals, consumers [Posted 03/09/2007] Takeda and FDA notified healthcare professionals of recent safety data concerning pioglitazonecontaining products. The results of an analysis of the manufacturer's clinical trial database of pioglitazone showed more reports of fractures in female patients taking pioglitazone than those taking a comparator (either placebo or active). The majority of fractures observed in female patients were in the distal upper limb (forearm, hand and wrist) or distal lower limb (foot, ankle, fibula and tibia). There were more than 8100 patients in the pioglitazone-treated groups and over 7400 patients in the comparator-treated groups. The duration of pioglitazone treatment was up to 3.5 years. Healthcare professionals should consider the risk of fracture when initiating or treating female patients with type 2 diabetes mellitus with pioglitazone-containing products. Actos (pioglitazone HCl) Tablets Audience: Endocrinologists, other healthcare professionals, consumers [UPDATE 11/19/2007] Information for Healthcare Professionals Sheet highlights changes to the prescribing information for rosiglitazone, including a new BOXED WARNING and changes to the WARNINGS, PRECAUTIONS, and INDICATIONS sections of the product's prescribing information about the potential increased risk of myocardial ischemia. [Posted 08/14/2007] After a review of postmarketing adverse event reports, FDA determined that an updated label with a boxed warning on the risks of heart failure was needed for the entire thiazolidinedione class of antidiabetic drugs. These drugs are used in conjunction with diet and exercise to improve blood sugar control in adults with type 2 (non-insulindependent) diabetes. Manufacturers of certain drugs have agreed to the upgraded warning. The strengthened warning advises healthcare professionals to observe patients carefully for the signs and symptoms of heart failure, including excessive, rapid weight gain, shortness of breath, and edema after starting drug therapy. Symlin (pramlintide acetate) [2007 version] Diprivan (propofol); Audience: Surgeons, anesthesiologists, healthcare professionals [Posted 06/15/2007] FDA informed healthcare professionals about several clusters of patients who experienced chills, fever, and body aches shortly after receiving propofol for sedation or general anesthesia. Multiple vials and several lots of propofol used in patients who experienced these symptoms were tested and there was no evidence that the propofol vials or prefilled syringes used were contaminated with bacteria or endotoxins. Patients who develop fever, chills, body aches or other symptoms of acute febrile reactions shortly after receiving propofol should be evaluated for bacterial sepsis. Healthcare professionals who administer propofol for sedation or general anesthesia should carefully follow the recommendations for handling and use in the product's full prescribing information. Regulatory Authority/Reg ion Product active ingredient Safety Issue (AE) Intervention Type FDA-USA pergolide Serious damage to their heart valves when compared to patients who did not receive the drug FDA-USA phenelzine sulfate Not specified EM-MG FDA-USA pioglitazone Fractures in female patients EM FDA-USA pioglitazone HCl Risk of myocardial ischemia BBW FDA-USA pramlintide acetate Not specified EM-MG propofol Chills, fever, and body aches shortly after receiving propofol for sedation or general anesthesia EM FDA-USA EM Year 296 297 Title Propofol (marketed as Diprivan and generic products); June 2007; Audience: Surgeons, anesthesiologists, healthcare professionals [Posted 06/15/2007] FDA informed healthcare professionals about several clusters of patients who experienced chills, fever, and body aches shortly after receiving propofol for sedation or general anesthesia. Multiple vials and several lots of propofol used in patients who experienced these symptoms were tested and there was no evidence that the propofol vials or prefilled syringes used were contaminated with bacteria or endotoxins. Propofol is an intravenous sedative-hypnotic agent for use in the induction and maintenance of anesthesia or sedation. To minimize the potential for bacterial contamination, propofol vials and prefilled syringes should be used within six hours of opening and one vial should be used for one patient only. Patients who develop fever, chills, body aches or other symptoms of acute febrile reactions shortly after receiving propofol should be evaluated for bacterial sepsis. Healthcare professionals who administer propofol for sedation or general anesthesia should carefully follow the recommendations for handling and use in the product's full prescribing information. 2007 2007 Vivactil (protriptyline HCl) [2007 version] Doral (quazepam); Audience: Healthcare professionals, consumers [Posted 03/14/2007] FDA notified healthcare professionals of its request that all manufacturers of sedative-hypnotic drug products, a class of drugs used to induce and/or maintain sleep, strengthen their product labeling to include stronger language concerning potential risks. These risks include severe allergic reactions and complex sleep-related behaviors, which may include sleep-driving. Sleep driving is defined as driving while not fully awake after ingestion of a sedativehypnotic product, with no memory of the event. FDA also requested that each product manufacturer send letters to health care providers to notify them about the new warnings, and that manufacturers develop Patient EM-MGs for the products to inform consumers about risks and advise them of potential precautions that can be taken. Regulatory Authority/Reg ion Product active ingredient Safety Issue (AE) Intervention Type FDA-USA Propofol Symptoms of acute febrile reactions: fever, chills, body aches FDA-USA protriptyline HCl Not specified EM-MG FDA-USA quazepam Severe allergic reactions and complex sleep-related behaviors, which may include sleep-driving EM EM 298 2007 299 2007 Doral (quazepam) [2007 version] FDA-USA quazepam Not specified EM-MG 300 2007 Evista (raloxifene HCl) [2007 version] Rozerem (ramelteon); Audience: Healthcare professionals, consumers FDA-USA raloxifene HCl Not specified EM-MG ramelteon Severe allergic reactions and complex sleep-related behaviors, which may include sleep-driving EM FDA-USA ranibizumab injection Higher incidence of stroke in the 0.5 mg dose group compared to the 0.3 mg dose group EM FDA-USA rosiglitazone maleate and glimepiride Risk of myocardial ischemia BBW [Posted 03/14/2007] FDA notified healthcare professionals of its request that all manufacturers of sedative-hypnotic drug products, a class of drugs used to induce and/or maintain sleep, strengthen their product labeling to include stronger language concerning potential risks. These risks include severe allergic reactions and complex sleep-related behaviors, which may include sleep-driving. FDA also requested that each product manufacturer send letters to health care providers to notify them about the new warnings, and that manufacturers develop Patient EM-MGs for the products to inform consumers about risks and advise them of potential precautions that can be taken 301 302 303 2007 2007 2007 FDA-USA Lucentis (ranibizumab injection); Audience: Ophthalmological healthcare professionals Indication: Treatment of patients with neovascular (wet) age-related macular degeneration [Posted 02/01/2007] Genentech informed healthcare professionals of preliminary safety information from a planned interim analysis in an ongoing study (SAILOR) which confirmed the higher incidence of stroke in the 0.5 mg dose group compared to the 0.3 mg dose group (1.2% versus 0.3%, respectively; P=0.02) of patients with neovascular (wet) age-related macular degeneration who received intravitreal Lucentis. Avandaryl (rosiglitazone maleate and glimepiride) Tablets; Audience: Endocrinologists, other healthcare professionals, consumers [UPDATE 11/19/2007] Information for Healthcare Professionals Sheet highlights changes to the prescribing information for rosiglitazone, including a new BOXED WARNING and changes to the WARNINGS, PRECAUTIONS, and INDICATIONS sections of the product's prescribing information about the potential increased risk of myocardial ischemia. [Posted 08/14/2007] After a review of postmarketing adverse event reports, FDA determined that an updated label with a boxed warning on the risks of heart failure was needed for the entire thiazolidinedione class of antidiabetic drugs. The strengthened warning advises healthcare professionals to observe patients carefully for the signs and symptoms of heart failure, including excessive, rapid weight gain, shortness of breath, and edema after starting drug therapy. Year 304 2007 305 2007 Title Avandamet (rosiglitazone maleate and metformin HCl); Audience: Endocrinologists, other healthcare professionals, consumers Indication: Treatment of type 2 diabetes mellitus [Posted 02/20/2007] Glaxo SmithKline (GSK) notified healthcare professionals of the results of a randomized, double-blind parallel group study [ADOPT] of 4,360 patients with recently diagnosed type 2 diabetes mellitus followed for 4-6 years to compare glycemic control with rosiglitazone relative to metformin and glyburide monotherapies. Significantly more female patients who received rosiglitazone experienced fractures of the upper arm, hand, or foot, than did female patients who received either metformin or glyburide. At GSK's request, an independent safety committee reviewed an interim analysis of fractures in another large; ongoing; controlled clinical trial and preliminary analysis was reported as being consistent with the observations from ADOPT. Healthcare professionals should consider the risk of fracture when initiating or treating female patients with type 2 diabetes mellitus with rosiglitazone Pentavalent vaccine (RotaTeq) June 2007; Audience: Pediatric healthcare professionals, consumers [Posted 06/15/2007] FDA informed healthcare professionals of changes to the ADVERSE REACTIONS and POSTMARKETING sections of the product's prescribing information. The ADVERSE REACTIONS section was updated to include six cases of Kawasaki disease that were observed during the Phase 3 clinical trial. Regulatory Authority/Reg ion Product active ingredient Safety Issue (AE) Intervention Type FDA-USA rosiglitazone maleate and metformin HCl Fractures EM FDA-USA rotavirus vaccine Kawasaki disease EM FDA-USA rotavirus vaccine Intussusception EM secobarbital sodium Severe allergic reactions and complex sleep-related behaviors, which may include sleep-driving EM FDA-USA sedative hypnotic drugs Severe allergic reactions and complex sleep-related behaviors, which may include sleep-driving. EM- EMMGDHCPL FDA-USA selegeline transdermal system Not specified EM-MG sildenafil Sudden hearing loss sometimes accompanied by tinnitus and dizziness. EM Rotavirus, Live, Oral, Pentavalent vaccine (RotaTeq) February 2007; Audience: Pediatric healthcare professionals, consumers 306 2007 [Posted 02/13/2007] FDA issued a Public Health Notification to inform health care providers and consumers about 28 postmarketing reports of intussusception following administration of Rotavirus, Live, Oral, Pentavalent vaccine (RotaTeq). Intussusception is a serious and potentially life-threatening condition that occurs when the intestine gets blocked or twisted. Seconal (secobarbital sodium); Audience: Healthcare professionals, consumers [Posted 03/14/2007] FDA notified healthcare professionals of its request that all manufacturers of sedative-hypnotic drug products, a class of drugs used to induce and/or maintain sleep, strengthen their product labeling to include stronger language concerning potential risks. These risks include severe allergic reactions and complex sleep-related behaviors, which may include sleep-driving. Sleep driving is defined as driving while not fully awake after ingestion of a sedativehypnotic product, with no memory of the event. FDA also requested that each product manufacturer send letters to health care providers to notify them about the new warnings, and that manufacturers develop Patient EM-MGs for the products to inform consumers about risks and advise them of potential precautions that can be taken. 307 2007 FDA-USA Ambien, Ambien CR (zolpidem tartate); Audience: Healthcare professionals, consumers [Posted 03/14/2007] FDA notified healthcare professionals of its request that all manufacturers of sedative-hypnotic drug products, a class of drugs used to induce and/or maintain sleep, strengthen their product labeling to include stronger language concerning potential risks. These risks include severe allergic reactions and complex sleep-related behaviors, which may include sleep-driving. Sleep driving is defined as driving while not fully awake after ingestion of a sedativehypnotic product, with no memory of the event. FDA also requested that each product manufacturer send letters to health care providers to notify them about the new warnings, and that manufacturers develop Patient EM-MGs for the products to inform consumers about risks and advise them of potential precautions that can be taken. 308 309 310 2007 2007 2007 Emsam (selegeline transdermal system) [2007 version] Revatio (sildenafil); Audience: Urologists, other healthcare professionals, consumers [Posted 10/18/2007] FDA informed healthcare professionals of reports of sudden decreases or loss of hearing following the use of PDE5 inhibitors Viagra, Levitra, Cialis for the treatment of erectile dysfunction, and Revatio for the treatment of pulmonary arterial hypertension. In some cases, the sudden hearing loss was accompanied by tinnitus and dizzinessThe PRECAUTIONS and ADVERSE REACTIONS sections of the approved product labeling for Viagra, Levitra, and Cialis were revised. FDA is working with the manufacturer to revise the labeling for Revatio. FDA-USA Year 311 312 2007 2007 Title Clinoril (sulindac) [2007 version] Cialis (tadalafil) October 2007 Audience: Urologists, other healthcare professionals, consumers [Posted 10/18/2007] FDA informed healthcare professionals of reports of sudden decreases or loss of hearing following the use of PDE5 inhibitors Viagra, Levitra, Cialis for the treatment of erectile dysfunction, and Revatio for the treatment of pulmonary arterial hypertension. In some cases, the sudden hearing loss was accompanied by tinnitus and dizziness. Medical follow-up on these reports was often limited which makes it difficult to determine if the loss of hearing was related to the use of one of the drugs, an underlying medical condition or other risk factors for hearing loss, a combination of these factors or other factors. The PRECAUTIONS and ADVERSE REACTIONS sections of the approved product labeling for Viagra, Levitra, and Cialis were revised. FDA is working with the manufacturer to revise the labeling for Revatio. Zelnorm (tegaserod maleate); Audience: Gastroenterologists, other healthcare professionals, consumers Regulatory Authority/Reg ion FDA-USA 2007 Not specified EM-MG tadalafil Sudden hearing loss was accompanied by tinnitus and dizziness EM tegaserod maleate Serious cardiovascular adverse events, including angina, heart attacks, and stroke, RD - for use only in CT or IND (special access) FDA-USA telithromycin Hepatotoxicity (liver injury), loss of consciousness, and visual disturbances BBW/ EMDHCPL FDA-USA telithromycin Not specified EM-MG temazepam Severe allergic reactions and complex sleep-related behaviors, which may include sleep-driving EM FDA-USA FDA-USA Ketek (telithromycin); Audience: Infectious disease and pulmonary specialists, other healthcare professionals, consumers [UPDATE 03/26/2007] Sanofi-Aventis issued a "Dear Healthcare Professional" letter. [Posted 02/12/2007] FDA and Sanofi-Aventis notified healthcare professionals of revisions to the prescribing information, including a BOXED WARNING and a new Patient EM-MG, for the antibiotic Ketek. Two of the three previously approved indications, acute bacterial sinusitis and acute bacterial exacerbations of chronic bronchitis, were removed from the prescribing information because the balance of benefits and risks no longer support approval of the drug for these indications. Ketek will remain on the market for the treatment of community acquired pneumonia of mild to moderate severity. In addition, warnings were strengthened for hepatotoxicity (liver injury), loss of consciousness, and visual disturbances. The BOXED WARNING states that Ketek is contraindicated in patients with myasthenia gravis. The Patient EM-MG, which must be distributed to all patients, informs them about the risks of the drug and how to use it safely. 314 2007 315 2007 316 2007 Ketek (telithromycin) [2007 version] Restoril (temazepam); Audience: Healthcare professionals, consumers [Posted 03/14/2007] FDA notified healthcare professionals of its request that all manufacturers of sedative-hypnotic drug products, a class of drugs used to induce and/or maintain sleep, strengthen their product labeling to include stronger language concerning potential risks. These risks include severe allergic reactions and complex sleep-related behaviors, which may include sleep-driving. Sleep driving is defined as driving while not fully awake after ingestion of a sedativehypnotic product, with no memory of the event. FDA also requested that each product manufacturer send letters to health care providers to notify them about the new warnings, and that manufacturers develop Patient EM-MGs for the products to inform consumers about risks and advise them of potential precautions that can be taken. Safety Issue (AE) Intervention Type sulindac [UPDATE 07/27/2007] FDA announced that it is permitting the restricted use of Zelnorm under a treatment investigational new drug (IND) protocol to treat irritable bowel syndrome with constipation (IBS-C) and chronic idiopathic constipation (CIC) in women younger than 55 who meet specific guidelines. In some instances, patients with a serious or life-threatening disease or condition who are not enrolled in a clinical trial may be treated with a drug not approved by the FDA. [Posted 03/30/2007] FDA notified healthcare professionals and patients that Novartis has agreed to discontinue marketing Zelnorm, a drug used for the short-term treatment of women with irritable bowel syndrome with constipation and for patients younger than 65 years of age with chronic constipation. FDA analysis of safety data pooled from 29 clinical trials involving over 18,000 patients showed an excess number of serious cardiovascular adverse events, including angina, heart attacks, and stroke, in patients taking Zelnorm compared to patients given placebo. 313 Product active ingredient FDA-USA Year 317 Title Zanaflex (tizanidine HCl) Tablets and Capsules; Audience: Healthcare professionals [Posted 04/11/2007] Acorda Therapeutics and FDA informed healthcare professionals of changes to the CONTRAINDICATIONS and WARNINGS Sections of the product labeling for Zanaflex, a drug used to treat spasticity. In pharmacokinetic studies where tizanidine was coadministered with either fluvoxamine or ciprofloxacin (CYP1A2 inhibitors), the serum concentration of tizanidine was significantly increased and potentiated its hypotensive and sedative effects. Although there are no clinical studies evaluating the effects of other CYP1A2 inhibitors on tizanidine, coadministration of tizanidine with other CYP1A2 inhibitors (zileuton, other fluroquinolones, antiarrythmics, cimetidine, famotidine, oral contraceptives, acyclovir and ticlopidine) should be avoided. 2007 Regulatory Authority/Reg ion Product active ingredient Safety Issue (AE) Intervention Type tizanidine HCl Drug interaction with fluvoxamine or ciprofloxacin; serum concentration of tizanidine was significantly increased and potentiated its hypotensive and sedative effects EM FDA-USA triazolam Severe allergic reactions and complex sleep-related behaviors, which may include sleep-driving EM FDA-USA vardenafil Sudden decreases or loss of hearing EM warfarin Genetic makeup may influence how they respond to the drug EM zaleplon Severe allergic reactions and complex sleep-related behaviors, which may include sleep-driving EM EM - MG EM-MG FDA-USA Halcion (triazolam); Audience: Healthcare professionals, consumers [Posted 03/14/2007] FDA notified healthcare professionals of its request that all manufacturers of sedative-hypnotic drug products, a class of drugs used to induce and/or maintain sleep, strengthen their product labeling to include stronger language concerning potential risks. These risks include severe allergic reactions and complex sleep-related behaviors, which may include sleep-driving. 318 2007 Levitra (vardenafil); Audience: Urologists, other healthcare professionals, consumers [Posted 10/18/2007] FDA informed healthcare professionals of reports of sudden decreases or loss of hearing following the use of PDE5 inhibitors Viagra, Levitra, Cialis for the treatment of erectile dysfunction, and Revatio for the treatment of pulmonary arterial hypertension. In some cases, the sudden hearing loss was accompanied by tinnitus and dizziness. Medical follow-up on these reports was often limited which makes it difficult to determine if the loss of hearing was related to the use of one of the drugs, an underlying medical condition or other risk factors for hearing loss, a combination of these factors or other factors. The PRECAUTIONS and ADVERSE REACTIONS sections of the approved product labeling for Viagra, Levitra, and Cialis were revised. FDA is working with the manufacturer to revise the labeling for Revatio. 319 2007 Warfarin (marketed as Coumadin); Audience: Hematologists, other healthcare providers, consumers [Posted 08/16/2007] FDA approved updated labeling to include pharmacogenomics information to the CLINICAL PHARMACOLOGY, PRECAUTIONS, and DOSAGE AND ADMINISTRATION sections of the prescribing information for the widely used blood-thinning drug, Coumadin. This new information explains that people's genetic makeup may influence how they respond to the drug. Specifically, people with variations in two genes may need lower warfarin doses than people without these genetic variations. The two genes are called CYP2C9 and VKORC1. The CYP2C9 gene is involved in the breakdown (metabolism) of warfarin and the VKORC1 gene helps regulate the ability of warfarin to prevent blood from clotting. 320 2007 FDA-USA Sonata (zaleplon); Audience: Healthcare professionals, consumers [Posted 03/14/2007] FDA notified healthcare professionals of its request that all manufacturers of sedative-hypnotic drug products, a class of drugs used to induce and/or maintain sleep, strengthen their product labeling to include stronger language concerning potential risks. These risks include severe allergic reactions and complex sleep-related behaviors, which may include sleep-driving. 321 2007 FDA-USA 322 2008 [Posted 07/24/2008] FDA informed healthcare professionals that serious and sometimes fatal hypersensitivity reactions (HSR) caused by abacavir therapy are significantly more common in patients with a particular human leukocyte antigen (HLA) allele, HLA-B*5701. FDA reviewed data from two studies that support a recommendation for pre-therapy screening for the presence of the HLA-B*5701 allele and the selection of alternative therapy in positive subjects. Genetic tests for HLA-B*5701 are available and all patients should be screened for the HLA-B*5701 allele before starting or restarting treatment with abacavir or abacavir-containing medications. Development of clinically suspected abacavir HSR requires immediate and permanent discontinuation of abacavir therapy in all patients, including patients negative for HLA-B*5701. 323 2008 Pacerone (amiodarone HCl) [2008 version] FDA-USA abacavir Serious and sometimes fatal hypersensitivity reactions (HSR) FDA-USA amiodarone HCl Not specified Year 324 2008 Title Antipsychotics, Conventional and Atypical; Audience: Neuropsychiatric and geriatrics healthcare professionals [Posted 06/16/2008] FDA notified healthcare professionals that both conventional and atypical antipsychotics are associated with an increased risk of mortality in elderly patients treated for dementia-related psychosis. In April 2005, FDA notified healthcare professionals that patients with dementia-related psychosis treated with atypical antipsychotic drugs are at an increased risk of death. Since issuing that notification, FDA has reviewed additional information that indicates the risk is also associated with conventional antipsychotics. Antipsychotics are not indicated for the treatment of dementia-related psychosis. The prescribing information for all antipsychotic drugs will now include the same information about this risk in a BOXED WARNING and the WARNINGS section Regulatory Authority/Reg ion Product active ingredient FDA-USA Antipsychotics, Conventional and Atypical FDA-USA Safety Issue (AE) Intervention Type Increased risk of mortality in elderly patients EM aprotinin injection Increased risk for death. RDlimited use in CT becaplermin Increased risk of death from cancer in patients treated with three or more tubes of Regranex BBW Trasylol (aprotinin injection); Audience: Cardiac surgeons and other healthcare professionals [UPDATE 05/14/2008] Following publication of the Blood conservation using antifibrinolytics: A randomized trial in a cardiac surgery population (BART) study in the May 14, 2008 online issue of The New England Journal of Medicine, Bayer Pharmaceuticals notified the FDA of their intent to remove all remaining supplies of Trasylol from hospital pharmacies and warehouses. Under a limited use agreement, access to Trasylol is limited to investigational use of the drug according to the procedures described in a special treatment protocol. The protocol allows treatment for certain patients who are at increased risk of blood loss and transfusions during coronary artery bypass graft surgery and who have no acceptable alternative therapy. Physicians using Trasylol in this situation must also verify that the benefits of the drug clearly outweigh the risks for their patients. [Posted 11/05/2007] FDA announced that, at the agency's request, Bayer Pharmaceuticals Corp. has agreed to a marketing suspension of Trasylol (aprotinin injection), a drug used to control bleeding during heart surgery, pending detailed review of preliminary results from a Canadian study that suggested an increased risk for death. FDA requested the suspension in the interest of patient safety based on the serious nature of the outcomes suggested in the preliminary data. FDA has not yet received full study data but expects to act quickly with Bayer, the study's researchers at the Ottawa Health Research Institute, and other regulatory agencies to undertake a thorough analysis of data to better understand the risks and benefits of Trasylol. 325 2008 Until FDA can review the data from the terminated study it is not possible to determine and identify a population of patients undergoing cardiac surgery for which the benefits of Trasylol outweigh the risks. However, understanding that individual doctors may identify specific cases where benefit outweighs risk, FDA is committed to exploring ways for those doctors to have continued, limited access to Trasylol. There are not many treatment options for patients at risk for excessive bleeding during cardiac surgery. Thus, FDA is working with Bayer to phase Trasylol out of the marketplace in a way that does not cause shortages of other drugs used for this purpose. Regranex (becaplermin) Gel Audience: Endocrinologists, other healthcare professionals, patients [UPDATE 06/06/2008] FDA informed healthcare professionals that a Boxed Warning was added to prescribing information for Regranex that describes an increased risk of death from cancer in patients treated with three or more tubes of Regranex compared with those patients who did not use the product. FDA recommends that Regranex be used only when the benefits can be expected to outweigh the risks. [Posted 03/27/2008] The FDA is conducting a safety review based on study data suggesting there may be an increased risk of death from cancer in diabetic patients using Regranex (becaplermin) Gel, a skin product used to heal leg and foot ulcers. While the review is ongoing, the FDA recommends health care professionals discuss the potential risks and benefits of using Regranex with their patients. 326 2008 This communication is in keeping with FDA’s commitment to inform the public about its ongoing safety reviews of drugs. As soon as this review is complete, FDA will communicate the conclusions and recommendations to the public. FDA-USA Year Title Regulatory Authority/Reg ion Product active ingredient Safety Issue (AE) Intervention Type Avastin (bevacizumab) Audience: Oncologists, other healthcare professionals 327 328 2008 2008 [Posted 07/14/2008] Genentech, Inc. informed healthcare professionals of reports of several cases of microangiopathic hemolytic anemia (MAHA) in patients with solid tumors receiving Avastin in combination with sunitinib malate. Avastin is not approved for use in combination with sunitinib malate and this combination is not recommended. Twenty-five patients were enrolled in a Phase I dose-escalation study combining Avastin and sunitinib malate. The study consisted of 3 cohorts using a fixed dose of Avastin at 10mg/kg/IV every 2 weeks and escalating doses of sunitinib that included 25, 37.5, and 50 mg orally daily given in a 4 weeks on/ 2 weeks off schedule. Five of 12 patients at the highest sunitinib dose level exhibited laboratory findings consistent with MAHA. Two of these cases were considered severe with evidence of thrombocytopenia, anemia, reticulocytosis, reductions in serum haptoglobin, schistocytes on peripheral smear, modest increases in serum creatinine levels, and severe hypertension, reversible posterior leukoencephalopathy syndrome, and proteinuria. The findings in these two cases were reversible within three weeks upon discontinuation of both drugs without additional interventions. Healthcare professionals should report cases of MAHA or any serious adverse events suspected to be associated with the use of Avastin. Bisphosphonates marketed as Alendronate (Fosamax, Fosamax Plus D) Etidronate (Didronel) Ibandronate (Boniva) Pamidronate (Aredia) Risedronate (Actonel, Actonel W/Calcium) Tiludronate (Skelid) Zoledronic acid (Reclast, Zometa) Audience: Geriatricians, gynecologists, orthopedic surgeons, other healthcare professionals [Posted 11/12/2008] FDA issued an update to the Agency's review of safety data regarding the potential increased risk of atrial fibrillation in patients treated with a bisphosphonate drug. Bisphosphonates are a class of drugs used primarily to increase bone mass and reduce the risk for fracture in patients with osteoporosis, slow bone turnover in patients with Paget’s disease of the bone, and to treat bone metastases and lower elevated levels of blood calcium in patients with cancer. FDA reviewed data on 19,687 bisphosphonate-treated patients and 18,358 placebo-treated patients who were followed for 6 months to 3 years. The occurrence of atrial fibrillation was rare within each study, with most studies containing 2 or fewer events. Across all studies, no clear association between overall bisphosphonate exposure and the rate of serious or nonserious atrial fibrillation was observed. Additionally, increasing dose or duration of bisphosphonate therapy was not associated with an increase rate of atrial fibrillation. Healthcare professionals should not alter their prescribing patterns for bisphosphonates and patients should not stop taking their bisphosphonate medication. Botox, Botox Cosmetic (Botulinum toxin Type A), Myobloc (Botulinum toxin Type B) Audience: Cosmetic Surgeons, neurologists, other healthcare professionals, consumers 329 2008 [Posted 02/08/2008] FDA issued an early communication about an ongoing safety review regarding Botox and Botox Cosmetic. FDA has received reports of systemic adverse reactions including respiratory compromise and death following the use of botulinum toxins types A and B for both FDA-approved and unapproved uses. The reactions reported are suggestive of botulism, which occurs when botulinum toxin spreads in the body beyond the site where it was injected. The most serious cases had outcomes that included hospitalization and death, and occurred mostly in children treated for cerebral palsy-associated limb spasticity. Use of botulinum toxins for treatment of limb spasticity (severe arm and leg muscle spasms) in children or adults is not an approved use in the U.S. See the FDA's "Early Communication about an Ongoing Safety Review" for Agency recommendations and additional information for healthcare professionals. 330 2008 Aplenzin (buproprion hydrobromide [2008 version] FDA-USA Microangiopathic hemolytic anemia (MAHA) EM Increased risk of atrial fibrillation EM FDA-USA bevacizumab Bisphosphonates marketed as Alendronate (Fosamax, Fosamax Plus D) Etidronate (Didronel) Ibandronate (Boniva) Pamidronate (Aredia) Risedronate (Actonel, Actonel W/Calcium) Tiludronate (Skelid) Zoledronic acid (Reclast, Zometa) FDA-USA Botox, Botox Cosmetic (Botulinum toxin Type A), Myobloc (Botulinum toxin Type B) Systemic adverse reactions including respiratory compromise and death EM FDA-USA buproprion hydrobromide Not specified EM-MG Year Title Regulatory Authority/Reg ion Product active ingredient Safety Issue (AE) Intervention Type Cefepime (marketed as Maxipime) November 2007 Audience: Healthcare professionals [UPDATE 05/14/2008] FDA is continuing its investigation of a possible association between the use of cefepime and an increased risk of mortality compared with similar drugs. FDA will communicate its conclusions and any resulting recommendations to the public at the completion of its review. 331 332 2008 2008 333 2008 334 2008 335 2008 [Posted 11/14/2007] FDA issued an early communication about the ongoing review of new safety data and the request for additional data to further evaluate the risk of death in patients treated with cefepime. An article in the May 2007 issue of The Lancet Infectious Diseases (Efficacy and safety of cefepime: a systematic review and meta-analysis) raised the question about increased mortality with the use of cefepime, a broad spectrum B-lactam antibiotic currently approved for the treatment of a variety of infections due to susceptible strains of microorganisms. The article describes a higher all-cause mortality in patients treated with cefepime compared to other B-lactam antibiotics. Until FDA's evaluation is completed, healthcare professionals who are considering the use of cefepime should be aware of the risks and benefits described in the product's prescribing information and the new information from this meta-analysis. Cimzia (certolizumab pegol) Lyophilized powder for solution for subcutaneous injection (PDF - 250KB) Phosphocol P 32 (Chromic Phosphate P 32 Suspension) Audience: Oncologists, other healthcare professionals [Posted 09/18/2008] Covidien and Mallinckrodt Inc. informed healthcare professionals of important new safety information in prescribing Phosphocol P 32. Phosphocol P 32 is approved for the intracavitary instillation for the treatment of peritoneal or pleural effusions caused by metastatic disease. Phosphocol P 32 may increase the risk for leukemia in certain situations. Two children (ages 9 and 14) with hemophilia developed acute lymphocytic leukemia approximately 10 months after intra-articular injections of Phosphocol P 32 (0.6 and 1.5 mCi total dose). This drug is not indicated in the intra-articular treatment of hemarthroses. Additionally, post marketing experience identified radiation injury (necrosis and fibrosis) to the small bowel, cecum, and bladder following administration of P 32 into the peritoneal cavity. Healthcare professionals should refer to the product's revised prescribing information for updated information regarding the appropriate use of Phosphocol P 32. Cipro (ciprofloxacin) [2008 version] Over The Counter Cough and Cold Medications Audience: Pediatric and primary healthcare professionals, consumers [Posted 10/09/2008] FDA notified healthcare professionals and consumers that the Consumer Healthcare Products Association (CHPA) is voluntarily modifying the product labels for consumers of over the counter (OTC) cough and cold medicines to state "do not use" in children under 4 years of age. FDA supports CHPA members to help prevent and reduce misuse and to better inform consumers about the safe and effective use of these products for children. FDA continues to assess the safety and efficacy of these products and to revise its OTC list of approved ingredients and amounts for these medicines. Parents and care givers should adhere to the dosage instructions and warnings on the label that FDA-USA cefepime Increased risk of mortality EM FDA-USA certolizumab pegol Not specified EM-MG, communi cation plan FDA-USA Chromic Phosphate P 32 Suspension Potential increased risk for leukemia EM FDA-USA ciprofloxacin Not specified EM-MG FDA-USA Cough and Cold Medications Do not use in children under 4 years of age RD Year Title accompanies OTC cough and cold medications before giving the product to children, and should consult their healthcare professionals if they have any questions or concerns. Regulatory Authority/Reg ion Product active ingredient Safety Issue (AE) Intervention Type Erythropoiesis Stimulating Agents: Aranesp (darbepoetin alfa), Epogen (epoetin alfa), and Procrit (epoetin alfa) Audience: Oncological healthcare professionals 336 2008 [Posted 03/12/2008] Amgen and FDA notified healthcare professionals of changes to the Boxed Warnings/WARNINGS: Increased Mortality and/or Tumor Progression section of the Aranesp and EPOGEN/PROCRIT labeling to update information describing the results of two additional studies showing increased mortality and more rapid tumor progression in patients with cancer receiving ESAs. Based on the results of these studies, the prescribing information has been revised as follows: ESAs shortened overall survival and/or time to tumor progression in clinical studies in patients with breast, non-small cell lung, head and neck, lymphoid, and cervical cancers when dosed to target a hemoglobin of ≥ 12 g/dL. Prezista (darunavir) Audience: Infectious disease healthcare professionals FDA-USA darbepoetin alfa, epoetin alfa, and Procrit, epoetin alfa Increased mortality and more rapid tumor progression in patients with cancer r BBW FDA-USA darunavir Drug-induced hepatitis EM FDA-USA dextroamphetam ine sulfate Not specified EM-MG FDA-USA didanosine AND abacavir Higher risk of heart attack EM [UPDATE 3/21/2008] FDA issued a new "Information for Healthcare Professionals" sheet highlighting the addition of hepatotoxicity information to the WARNINGS section of prescribing information for Prezista. 337 2008 338 2008 [Posted 03/12/2008] FDA and Tibotec Therapeutics notified healthcare professionals of changes to the WARNINGS section of the prescribing information for Prezista (darunavir) tablets regarding the risk of hepatotoxicity. In clinical trials and postmarketing experience, drug induced hepatitis has been reported in patients receiving combination therapy with Prezista/ritonavir. Appropriate laboratory testing should be conducted prior to initiating therapy with Prezista/ritonavir and patients should be monitored during treatment. Increased AST/ALT monitoring should be considered in patients with underlying chronic hepatitis, cirrhosis, or in patients who have pretreatment elevations of transaminases, especially during the first several months of Prezista/ritonavir treatment. Dexedrine (dextroamphetamine sulfate) [2008 version] Videx (didanosine) and Ziagen (abacavir) Audience: Infectious disease and medical genetics healthcare professionals [Posted 03/27/2009] The FDA issued an Early Communication about recent findings of The Data Collection on Adverse Events of Anti-HIV Drugs Study. Data analyses from this study indicate a higher risk of heart attack in patients infected with HIV-1 who were taking Ziagen (abacavir) or Videx (didanosine) as part of their drug therapy. The study is a large observational study of 33,347 HIV-1 infected patients living in North America, Europe and Australia. Patients in this study are being followed to evaluate the short and long term adverse effects of treatment with anti-HIV drugs. FDA continues to evaluate the overall risks and benefits of abacavir and didanosine. This evaluation may result in the need to revise labeling for the products. Until the FDA’s review is complete, health care professionals should evaluate the potential risks and benefits of each HIV-1 antiretroviral drug their patients are taking. 339 2008 This early communication is in keeping with FDA’s commitment to inform the public about its ongoing safety reviews of Year Title drugs. As soon as this review is complete, FDA will communicate the conclusions and recommendations to the public. Regulatory Authority/Reg ion Product active ingredient Safety Issue (AE) Intervention Type Raptiva (efalizumab) October 2008 Audience: Dermatological healthcare professionals, patients [Posted 10/17/2008] FDA notified healthcare professionals of extensive labeling changes, including a Boxed Warning, to highlight the risks of life-threatening infections, including bacterial sepsis, viral meningitis, invasive fungal disease, progressive multifocal leukoencephalopathy and other opportunistic infections with the use of Raptiva. In addition, the prescribing information will be updated to describe a potential risk for the permanent suppression of the immune system with repeat administration of Raptiva in children. Raptiva is not approved for children under 18 years of age. Risks of life-threatening infections, including bacterial sepsis, viral meningitis, invasive fungal disease, progressive multifocal leukoencephalopathy and other opportunistic infections BBW eltrombopag Risk of fungal infections EM-MG, elements to assure safe use, impleme ntation system Epoetin alfa Increased mortality in patients who received epoetin alfa compared to patients who received the placebo EM EM-MG Doctors and other prescribers should carefully evaluate and weigh the risk/benefit profile of Raptiva for patients who would be more susceptible to these risks. Health care professionals should monitor patients treated with Raptiva for the signs and symptoms of these adverse events and also instruct patients to report any such signs and symptoms to them without delay. Patients identified to begin therapy with Raptiva should have received all their age-appropriate vaccinations before starting the drug. 340 341 2008 2008 Patients with pre-existing infections or who have a compromised immune system should notify their health care professional before beginning treatment with Raptiva. Promacta (eltrombopag) Tablets (PDF - 4180KB) Section Contents Menu MedWatch The FDA Safety Information and Adverse Event Reporting Program Safety Information Safety Alerts for Human Medical Products FDA-USA FDA-USA efalizumab Medical Products - Epoetin alfa - Early Communication about an Ongoing Safety Review Audience: Neurological healthcare professionals [Posted 09/23/2008] FDA has been made aware of preliminary safety findings from a clinical trial conducted in Germany investigating the use of epoetin alfa to treat acute ischemic stroke. The clinical trial utilized doses of epoetin alfa that were considerably higher than the doses recommended for the treatment of anemia as described in the FDA-approved labeling for the product. Over a period of ninety days after the start of the trial, there were more deaths in the group of patients who received epoetin alfa compared to patients who received the placebo (16% versus 9%). Roughly half of all deaths in both groups occurred within the first seven days after starting the drug, with death from intracranial hemorrhage (bleeding within the brain) occurring among approximately 4% of patients who received epoetin alfa compared to 1% of patients in the placebo group. 342 2008 FDA anticipates the receipt of additional data within the next several weeks. As soon as the review of these data is complete, FDA will communicate our conclusions and recommendations to the public. The finding of increased mortality FDA-USA Year Title in patients receiving epoetin alfa in the German trial suggests the need to closely monitor patients enrolled in other ongoing trials for adverse outcomes and to evaluate whether the potential benefits for enrolled patients outweigh the risks in these trials. Regulatory Authority/Reg ion Product active ingredient Safety Issue (AE) Intervention Type Tarceva (erlotinib) Audience: Oncological healthcare professionals 343 2008 [Posted 09/23/2008] OSI and Genentech notified healthcare professionals that cases of hepatic failure and hepatorenal syndrome, including fatalities, have been reported during use of Tarceva, particularly in patients with baseline hepatic impairment. Patients with hepatic impairment receiving Tarceva should be closely monitored during therapy and the product should be used with extra caution in patients with total bilirubin >3x ULN. Dosing should be interrupted or discontinued if changes in liver function are severe, such as doubling of total bilirubin and/or tripling of transaminases in the setting of pretreatment values outside the normal range. New information from a pharmacokinetic study in patients with moderate hepatic impairment associated with significant liver tumor burden has been provided in the revised prescribing information, and other recommendations are included in the WARNINGS and DOSAGE AND ADMINISTRATION sections. 344 2008 Lexapro (escitalopram oxalate) [2008 version] FDA-USA escitalopram oxalate Not specified EM-MG 345 2008 Lunesta (eszopiclone) [2008 version] Section Contents Menu MedWatch The FDA Safety Information and Adverse Event Reporting Program Safety Information Safety Alerts for Human Medical Products FDA-USA eszopiclone Not specified EM-MG etanercept Infections, including serious infections leading to hospitalization or death EMDHCPL FDA-USA erlotinib Hepatic failure and hepatorenal syndrome, including fatalities, EM Medical Products - Enbrel (etanercept) Audience: Rheumatologists, dermatologists, other healthcare professionals, patients 346 2008 [Posted 05/01/2008] Amgen and Wyeth Pharmaceuticals informed healthcare professionals of revisions to prescribing information for Enbrel. The revisions include a BOXED WARNING about infections, including serious infections leading to hospitalization or death that have been observed in patients treated with Enbrel. Infections have included bacterial sepsis and tuberculosis. The ADVERSE REACTIONS section of the label was updated to include information regarding global clinical studies and the rate of occurrence of tuberculosis in patients treated with Enbrel. Healthcare professionals should screen patients for latent tuberculosis infection before beginning Enbrel. Patients should be educated about the symptoms of infection and closely monitored for signs and symptoms of infection during and after treatment with the FDA-USA Year 347 2008 Title drug. Patients who develop an infection should be evaluated for appropriate antimicrobial treatment and, in patients who develop a serious infection, Enbrel should be discontinued. Enbrel* (etanercept) [2008 version] Byetta (exenatide) October 2007 Audience: Endocrinologists, other healthcare professionals, consumers Regulatory Authority/Reg ion Product active ingredient Safety Issue (AE) Intervention Type FDA-USA etanercept Not specified EM-MG, communi cation plan FDA-USA exenatide Hemorrhagic or necrotizing pancreatitis EMDHCPL FDA-USA exenatide hemorrhagic or necrotizing pancreatitis EMDHCPL [UPDATED 08/18/2008] Since issuing Information for Healthcare Professionals in October 2007, FDA has received reports of 6 cases of hemorrhagic or necrotizing pancreatitis in patients taking Byetta. Byetta is a medicine given by subcutaneous injection to help treat adults with type 2 diabetes. Of the 6 cases of hemorrhagic or necrotizing pancreatitis, all patients required hospitalization, two patients died and four patients were recovering at time of reporting. Byetta was discontinued in all 6 cases. Byetta and other potentially suspect drugs should be promptly discontinued if pancreatitis is suspected. There are no signs or symptoms that distinguish acute hemorrhagic or necrotizing pancreatitis associated with Byetta from the less severe form of pancreatitis. If pancreatitis is confirmed, initiate appropriate treatment and carefully monitor the patient until recovery. Byetta should not be restarted. Consider antidiabetic therapies other than Byetta in patients with a history of pancreatitis. [UPDATED 02/27/2008] Dear Healthcare Professional letter posted. [Posted 10/16/2007] FDA has reviewed 30 postmarketing reports of acute pancreatitis in patients taking Byetta (exenatide), a drug used to treat adults with type 2 diabetes. An association between Byetta and acute pancreatitis is suspected in some of these cases. Amylin Pharmaceuticals, Inc. has agreed to include information about acute pancreatitis in the PRECAUTIONS section of the product label. Healthcare professionals should be alert to the signs and symptoms of acute pancreatitis and instruct patients taking Byetta to seek prompt medical care if they experience unexplained, persistent, severe abdominal pain which may or may not be accompanied by vomiting. If pancreatitis is suspected, Byetta should be discontinued. If pancreatitis is confirmed, Byetta should not be restarted unless an alternative etiology is identified. 348 2007 Byetta (exenatide) Audience: Endocrinologists, other healthcare professionals, consumers [UPDATED 08/18/2008] Since issuing Information for Healthcare Professionals in October 2007, FDA has received reports of 6 cases of hemorrhagic or necrotizing pancreatitis in patients taking Byetta. Byetta is a medicine given by subcutaneous injection to help treat adults with type 2 diabetes. Of the 6 cases of hemorrhagic or necrotizing pancreatitis, all patients required hospitalization, two patients died and four patients were recovering at time of reporting. Byetta was discontinued in all 6 cases. Byetta and other potentially suspect drugs should be promptly discontinued if pancreatitis is suspected. There are no signs or symptoms that distinguish acute hemorrhagic or necrotizing pancreatitis associated with Byetta from the less severe form of pancreatitis. If pancreatitis is confirmed, initiate appropriate treatment and carefully monitor the patient until recovery. Byetta should not be restarted. Consider antidiabetic therapies other than Byetta in patients with a history of pancreatitis. 349 2008 [UPDATED 02/27/2008] Dear Healthcare Professional letter posted. Year 350 2008 Title Trilipix (fenofibric acid) Delayed-Release Capsules (PDF - 91KB) Fluoroquinolone Antimicrobial Drugs Audience: Healthcare professionals, consumers Regulatory Authority/Reg ion FDA-USA Product active ingredient Safety Issue (AE) Intervention Type fenofibric acid Not specified EM-MG FDA-USA Fluoroquinolone Antimicrobial Drugs Strengthen existing warnings about the increased risk of developing tendinitis and tendon rupture in patients taking fluoroquinolones for systemic use. BBW Not specified EM-MG [Posted 07/08/2008] FDA notified healthcare professionals that a BOXED WARNING and EM-MG are to be added to the prescribing information to strengthen existing warnings about the increased risk of developing tendinitis and tendon rupture in patients taking fluoroquinolones for systemic use. 351 2008 Fluoroquinolones are associated with an increased risk of tendinitis and tendon rupture. This risk is further increased in those over age 60, in kidney, heart, and lung transplant recipients, and with use of concomitant steroid therapy. Physicians should advise patients, at the first sign of tendon pain, swelling, or inflammation, to stop taking the fluoroquinolone, to avoid exercise and use of the affected area, and to promptly contact their doctor about changing to a non-fluoroquinolone antimicrobial drug. Selection of a fluoroquinolone for the treatment or prevention of an infection should be limited to those conditions that are proven or strongly suspected to be caused by bacteria. 352 2008 Advair Diskus (fluticasone propionate and salmeterol xinafoate inhalation powder) (PDF - 35KB) FDA-USA fluticasone propionate and salmeterol xinafoate inhalation powder 353 2008 Luvox CR (fluvoxamine mealeate) [2008 version] Fosphenytoin Sodium (marketed as Cerebyx and generics) Phenytoin (marketed as Dilantin, Phenytek and generics) and Fosphenytoin Sodium (marketed as Cerebyx and generics) FDA-USA fluvoxamine mealeate Not specified EM-MG fosphenytoin sodium Increased risk of serious skin reactions including Stevens Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) EM 354 2008 Audience: Neurological healthcare professionals [Posted 11/24/2008] FDA is investigating new preliminary data regarding a potential increased risk of serious skin reactions including Stevens Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) from phenytoin therapy in Asian patients positive for human leukocyte antigen (HLA) allele, HLA-B*1502. This allele occurs almost exclusively in patients with ancestry across broad areas of Asia, including Han Chinese, Filipinos, Malaysians, South Asian Indians, and Thais. Until the FDA evaluation is completed, healthcare providers who are considering the use of phenytoin or fosphenytoin should be aware of the risks and benefits described in the current prescribing information for this drug. Healthcare providers should consider avoiding phenytoin and fosphenytoin as alternatives for carbamazepine in patients who test positive for HLA-B*1502. A summary of the data currently being analyzed by FDA, and information for patients and healthcare professionals to consider, can be found in the links provided below. FDA-USA Year 355 356 2008 2008 Title Factive (gemifloxacin) [2008 version] Exubera (insulin human rDNA origin) Inhalation Powder Audience: Endocrinologists, pulmonologists, pharmacists, patients [Posted 04/09/2008] Pfizer informed healthcare professionals and patients of updated safety information in the WARNINGS section of prescribing information for Exubera, a short-acting insulin you breathe in through your mouth using the Exubera inhaler that helps to control high blood sugar in adults with diabetes. There have been 6 newly diagnosed cases of primary lung malignancies in clinical trials among Exubera-treated patients, and 1 newly diagnosed case among comparator treated patients. There has also been 1 post-marketing report of a primary lung malignancy in an Exubera-treated patient. There were too few cases to determine whether the emergence of these events is related to Exubera. All patients who were diagnosed with lung cancer had a prior history of cigarette smoking. Because of limited availability of Exubera, healthcare professionals should seek alternative treatment options to maintain patients' glycemic control. Regulatory Authority/Reg ion Product active ingredient Safety Issue (AE) Intervention Type FDA-USA gemifloxacin Not specified EM-MG FDA-USA insulin human rDNA origin Primary lung malignancies EM Not specified EM-MG 357 2008 Exubera (insulin recombinant human) [2008 version] FDA-USA insulin recombinant human 358 2008 Roferon-A* (interferon alfa-2a recombinant) [2008 version] FDA-USA interferon alfa2a recombinant Not specified EM-MG 359 2008 Intron A* (interferon alfa-2b) [2008 version] FDA-USA interferon alfa2b Not specified EM-MG Year 360 2008 Title Marplan (isocarboxazid) [2008 version] Bisphosphonates (marketed as Actonel, Actonel+Ca, Aredia, Boniva, Didronel, Fosamax, Fosamax+D, Reclast, Skelid, and Zometa) Audience: Pharmacists, other healthcare professionals Regulatory Authority/Reg ion Product active ingredient Safety Issue (AE) Intervention Type FDA-USA isocarboxazid Not specified EM-MG Severe and sometimes incapacitating bone, joint, and/or muscle (musculoskeletal) pain EM [Posted 01/07/2008] FDA informed healthcare professionals and patients of the possibility of severe and sometimes incapacitating bone, joint, and/or muscle (musculoskeletal) pain in patients taking bisphosphonates. Although severe musculoskeletal pain is included in the prescribing information for all bisphosphonates, the association between bisphosphonates and severe musculoskeletal pain may be overlooked by healthcare professionals, delaying diagnosis, prolonging pain and/or impairment, and necessitating the use of analgesics. The severe musculoskeletal pain may occur within days, months, or years after starting a bisphosphonates. Some patients have reported complete relief of symptoms after discontinuing the bisphosphonate, whereas others have reported slow or incomplete resolution. The risk factors for and incidence of severe musculoskeletal pain associated with bisphosphonates are unknown. 361 2008 Healthcare professionals should consider whether bisphosphonate use might be responsible for severe musculoskeletal pain in patients who present with these symptoms and consider temporary or permanent discontinuation of the drug. FDA-USA isphosphonates (marketed as Actonel, Actonel+Ca, Aredia, Boniva, Didronel, Fosamax, Fosamax+D, Reclast, Skelid, and Zometa) 362 2008 Vimpat (lacosamide) Injection, Oral Solution, and Tablets (PDF - 35KB) FDA-USA lacosamide Not specified EM-MG 363 2008 Levaquin (levofloxacin) [2008 version] FDA-USA levofloxacin Not specified EM-MG 364 2008 Ponstel (mefenamic acid) [2008 version] FDA-USA mefenamic acid Not specified EM-MG Year Title Regulatory Authority/Reg ion Product active ingredient Safety Issue (AE) Intervention Type 365 2008 Avandamet (metformin HCl and rosiglitazone maleate) [2008 version] FDA-USA metformin HCl and rosiglitazone maleate 366 2008 Concerta (methylphenidate HCl) [2008 version] Mitoxantrone HCl (marketed as Novantrone and generics) Audience: Neurological and Oncological healthcare professionals, risk managers FDA-USA methylphenidate HCl Not specified EM-MG FDA-USA Mitoxantrone HCl Recommendations that left ventricular ejection fraction (LVEF) be evaluated before initiating treatment and prior to administering each dose of mitoxantrone. FDA offered additional recommendations for cardiac monitoring to detect lateoccurring cardiac toxicity, and provided information for patients with multiple sclerosis who receive the drug. TDM FDA-USA moxifloxacin Not specified EM-MG FDA-USA mycophenolate mofeti Progressive Multifocal Leukoencephalopathy (PML) EM [Posted 07/29/2008] FDA reminded health care professionals who treat patients with mitoxantrone about recommendations that left ventricular ejection fraction (LVEF) be evaluated before initiating treatment and prior to administering each dose of mitoxantrone. FDA offered additional recommendations for cardiac monitoring to detect lateoccurring cardiac toxicity, and provided information for patients with multiple sclerosis who receive the drug. These recommendations were established in 2005 in response to post-marketing reports and case reports in the medical literature that described decreases in LVEF or frank congestive heart failure in patients with MS who had received cumulative doses of mitoxantrone that were lower than 100 mg/m2. Since that time, FDA has received information from a post-marketing safety study that demonstrated there is poor adherence to these recommendations in clinical practice. FDA is working with the manufacturers to educate healthcare providers to adhere to cardiac monitoring recommendations for patients with MS. 367 2008 368 2008 Avelox (moxifloxacin) [2008 version] CellCept (mycophenolate mofetil) Audience: Transplantation specialists, infectious disease specialists, other healthcare professional Not specified EM-MG [Update] Novartis informed healthcare professionals of changes to the WARNINGS and ADVERSE REACTIONS sections of the Myfortic prescribing information. The changes are based on postmarketing data regarding cases of Progressive Multifocal Leukoencephalopathy (PML) in patients treated with Myfortic. 369 2008 [Update] Roche Laboratories informed healthcare professionals of changes to the WARNINGS and ADVERSE REACTIONS sections of the CellCept prescribing information. The changes are based on postmarketing data regarding cases of Progressive Multifocal Leukoencephalopathy (PML) in patients treated with CellCept. Year Title Regulatory Authority/Reg ion Product active ingredient Safety Issue (AE) Intervention Type [Posted 04/10/2008] FDA informed healthcare professionals that the Agency is investigating a potential association between the use of CellCept and Myfortic, medicines used to prevent organ rejection, and the development of progressive multifocal leukoencephalopathy (PML), a life-threatening disease. PML is a rare disorder that affects the central nervous system usually occurring in patients with immune systems suppressed by disease or medicines. FDA is reviewing data submitted by Roche, including postmarketing reports it has received of PML in patients who took CellCept or Myfortic, and the proposed revisions to the CellCept prescribing information. FDA has asked Novartis, the maker of Myfortic, for data on PML cases and to revise the Myfortic prescribing information to include the same information about PML included in the CellCept prescribing information. FDA anticipates it may take about 2 months to complete its review of the postmarketing reports and the proposed revisions to the prescribing information. As soon as the review is completed, FDA will communicate the conclusions and recommendations to the public. Until further information is available, patients and healthcare professionals should be aware of the possibility of PML, such as localized neurologic signs and symptoms in the setting of a suppressed immune system, including during therapy with CellCept and Myfortic. Mycophenolate Mofetil [MMF] (marketed as CellCept) Mycophenolic Acid [MPA] (marketed as Myfortic) Inosine Monophosphate Dehydrogenase Inhibitors (IMPDH) Immunosuppressants Audience: Transplantation specialists, infectious disease specialists, other healthcare professionals [Posted 05/16/2008] FDA is aware of reports of infants born with serious congenital anomalies, including microtia and cleft lip and palate, following exposure to mycophenolate mofetil (MMF) during pregnancy. MMF, the active drug substance in CellCept, is an ester of the active metabolite mycophenolic acid (MPA), the active drug substance in Myfortic. In most cases, the mothers were taking MMF following an organ transplant to prevent organ rejection. However, some mothers taking MMF were being treated for immune-mediated conditions such as systemic lupus erythematosus (SLE) and erythema multiforme. Treatment began before their pregnancies and continued into the first trimester or until the pregnancy was detected. MMF and MPA increase the risk of spontaneous abortion in the first trimester and can cause congenital malformations in the offspring of women who are treated during pregnancy. 370 2008 FDA is continuing to work with the manufacturers of these drug products to develop and implement means to mitigate the risks of fetal exposure. See the FDA Healthcare Professional Information Sheet containing considerations and recommendations for clinicians prior to prescribing MMF or MPA to women of childbearing potential. Vivitrol (naltrexone) Audience: Primary healthcare physicians, internists, other healthcare professionals 371 2008 [Posted 08/12/2008] FDA informed healthcare professionals of the risk of adverse injection site reactions in patients receiving naltrexone. Naltrexone is indicated for the treatment of alcohol dependence in patients who are able to abstain from alcohol in an outpatient setting prior to initiation of treatment. Naltrexone is administered as an intramuscular gluteal injection and should not be administered intravenously, subcutaneously, or inadvertently into fatty tissue. Physicians should instruct patients to monitor the injection site and contact them if they develop pain, swelling, tenderness, induration, bruising, pruritus, or redness at the injection site that does not improve or worsens within two weeks. Physicians should promptly refer patients with worsening injection site reactions to a surgeon. Read the FDA recommendations for healthcare professionals to consider regarding the use of Naltrexone injection. 372 2008 Anaprox (naproxen sodium) [2008 version] FDA-USA mycophenolate mofetil Serious congenital anomalies, including microtia and cleft lip and palate, following exposure to mycophenolate mofetil (MMF) during pregnancy. EM EM EM-MG FDA-USA naltrexone Pain, swelling, tenderness, induration, bruising, pruritus, or redness FDA-USA naproxen sodium Not specified Year 373 374 2008 2008 Title Treximet (naproxen sodium and sumatriptan succinate) [2008 version] Tysabri (natalizumab) Audience: Neurologists, other healthcare professionals, patients [Posted 08/25/2008] FDA informed healthcare professionals of two new cases of progressive multifocal leukoencephalopathy (PML) in European patients receiving Tysabri monotherapy for multiple sclerosis for more than one year. PML, which is usually fatal, is a known risk of Tysabri treatment, but previous cases in patients with multiple sclerosis were seen in combination with other immunomodulatory therapies. Approximately 39,000 patients have received treatment with Tysabri worldwide, with approximately 12,000 patients receiving treatment for a least one year. No new cases have been seen in the US, where about 7,500 patients have received the drug for greater than one year and approximately 3,300 patients have received the drug for at least one and one-half years. In the U.S., Tysabri is available only to patients with relapsing multiple sclerosis or Crohn's disease who are enrolled in the risk minimization plan called the TOUCH Prescribing Program. Under this program, every Tysabri-treated patient is closely monitored and followed for the occurrence of PML and other serious opportunistic infections. While the two patients who developed PML were on monotherapy, the FDA still believes that Tysabri monotherapy may confer a lower risk of PML than when Tysabri is used together with other immunomodulatory medications. Prescribing information for Tysabri will be revised to include information informing prescribers and patients that cases of PML have occurred in patients taking Tysabri as monotherapy. Healthcare professionals should continue to monitor patients for sign and symptoms of PML. Additionally, Tysabri should not be infused if PML is suspected. Tysabri (natalizumab) Feb 2008 Audience: Neurologists, other healthcare professionals, patients Regulatory Authority/Reg ion Product active ingredient Safety Issue (AE) Intervention Type FDA-USA naproxen sodium and sumatriptan succinate Not specified EM-MG FDA-USA natalizumab Progressive multifocal leukoencephalopathy (PML) EM EM 375 2008 [Posted 02/27/2008] Biogen Idec, Elan and FDA notified healthcare professionals of reports of clinically significant liver injury, including markedly elevated serum hepatic enzymes and elevated total bilirubin, occurred as early as six days after the first dose of Tysabri. The combination of transaminase elevations and elevated bilirubin without evidence of obstruction is recognized as an important predictor of severe liver injury that may lead to death or the need for a liver transplant in some patients. Tysabri should be discontinued in patients with jaundice or other evidence of significant liver injury. Physicians should inform patients that Tysabri may cause liver injury. 376 2008 Tyasbri (natalizumab) [2008 version] FDA-USA natalizumab Not specified EM-MG 377 2008 Viramune (nevirapine) Tablets and Oral Suspension (PDF - 16KB) FDA-USA nevirapine Not specified EM-MG FDA-USA natalizumab Clinically significant liver injury, including markedly elevated serum hepatic enzymes and elevated total bilirubin, Year Title Regulatory Authority/Reg ion Product active ingredient Safety Issue (AE) Intervention Type 378 2008 Noroxin (norfloxacin) [2008 version] FDA-USA norfloxacin Not specified EM-MG 379 2008 Floxin (ofloxacin) [2008 version] Oral Sodium Phosphate (OSP) Products for Bowel Cleansing (marketed as Visicol and OsmoPrep, and oral sodium phosphate products available without a prescription) Audience: All healthcare professionals, consumers FDA-USA ofloxacin Not specified EM-MG FDA-USA Oral Sodium Phosphate (OSP Acute phosphate nephropathy, a type of acute kidney injury EM FDA-USA Ortho Evra Contraceptive Transdermal Patch Higher risk of developing serious blood clots, also known as venous thromboembolism (VTE), EM [Posted 12/11/2008] FDA has become aware of reports of acute phosphate nephropathy, a type of acute kidney injury, associated with the use of oral sodium phosphate products (OSP) for bowel cleansing prior to colonoscopy or other procedures. These products include the prescription products, Visicol and OsmoPrep, and OSPs available over-thecounter without a prescription as laxatives (e.g., Fleet Phospho-soda). In some cases when used for bowel cleansing, these serious adverse events have occurred in patients without identifiable factors that would put them at risk for developing acute kidney injury. 380 2008 FDA is requiring the manufacturer of Visicol and OsmoPrep, the two OSPs available by prescription only, to add a Boxed Warning to the labeling for these products. FDA is also requiring that the manufacturer develop and implement a risk evaluation and mitigation strategy (REMS), which will include a EM-MG, to ensure that the benefits of these products outweigh the risk of acute phosphate nephropathy, and to conduct a postmarketing clinical trial to further assess the risk of acute kidney injury with use of these products. FDA recommends, in light of the risk of acute phosphate nephropathy, over-the-counter laxative OSP products should not be used for bowel cleansing. Consumers should only use OSPs for bowel cleansing pursuant to a prescription from a healthcare professional. Ortho Evra Contraceptive Transdermal Patch Audience: Reproductive healthcare professionals, patients [Posted 01/19/2008] FDA modified the prescribing information for the Ortho Evra Contraceptive Transdermal (Skin) Patch to include the results of a new epidemiology study that found that users of the birth control patch were at higher risk of developing serious blood clots, also known as venous thromboembolism (VTE), than women using birth control pills. VTE can lead to pulmonary embolism. The label changes are based on a study conducted by the Boston Collaborative Drug Surveillance Program on behalf of Johnson and Johnson. The patch was studied in women aged 15-44. These findings support an earlier study that also said women in this group were at higher risk for VTE. 381 2008 FDA believes that Ortho Evra is a safe and effective method of contraception when used according to the labeling, which recommends that women with concerns or risk factors for serious blood clots talk with their health care provider about using Ortho Evra versus other contraceptive options Year Title Tamiflu (oseltamivir phosphate) Audience: Pediatric and infectious disease healthcare professionals Regulatory Authority/Reg ion Product active ingredient Safety Issue (AE) Intervention Type 382 2008 [Posted 03/04/2008, UPDATED 03/04/2008] Roche and FDA informed healthcare professionals of neuropsychiatric events associated with the use of Tamiflu, in patients with influenza.The label has been revised as follows: Influenza can be associated with a variety of neurologic and behavioral symptoms which can include events such as hallucinations, delirium, and abnormal behavior, in some cases resulting in fatal outcomes. These events may occur in the setting of encephalitis or encephalopathy but can occur without obvious severe disease. There have been postmarketing reports (mostly from Japan) of delirium and abnormal behavior leading to injury, and in some cases resulting in fatal outcomes, in patients with influenza who were receiving Tamiflu. Because these events were reported voluntarily during clinical practice, estimates of frequency cannot be made but they appear to be uncommon based on Tamiflu usage data. These events were reported primarily among pediatric patients and often had an abrupt onset and rapid resolution. The contribution of Tamiflu to these events has not been established. Patients with influenza should be closely monitored for signs of abnormal behavior. If neuropsychiatric symptoms occur, the risks and benefits of continuing treatment should be evaluated for each patient. 383 2008 Paxil (paroxetine HCl) [2008 version] FDA-USA paroxetine HCl Not specified EM-MG 384 2008 Pegasys* (peginterferon alfa-2a) [2008 version] FDA-USA peginterferon alfa-2a Not specified EM-MG FDA-USA peginterferon alfa-2b and ribavirin Not specified EM-MG phenytoin Increased risk of serious skin reactions including Stevens Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) EM 385 386 2008 2008 PegIntron*/Rebetol Combo Pack (peginterferon alfa-2b and ribavirin) [2008 version] Phenytoin (marketed as Dilantin, Phenytek and generics) and Fosphenytoin Sodium (marketed as Cerebyx and generics) Audience: Neurological healthcare professionals [Posted 11/24/2008] FDA is investigating new preliminary data regarding a potential increased risk of serious skin reactions including Stevens Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) from phenytoin therapy in Asian patients positive for human leukocyte antigen (HLA) allele, HLA-B*1502. This allele occurs almost exclusively in patients with ancestry across broad areas of Asia, including Han Chinese, Filipinos, Malaysians, South Asian Indians, and Thais. Until the FDA evaluation is completed, healthcare providers who are considering the use of phenytoin or fosphenytoin should be aware of the risks and benefits described in the current prescribing information for this drug. Healthcare providers should consider avoiding phenytoin and fosphenytoin as alternatives for carbamazepine in patients who test positive for HLA-B*1502. A summary of the data currently being analyzed by FDA, and information for patients and healthcare professionals to consider, can be found in the links provided below. FDA-USA oseltamivir phosphate Delirium and abnormal behavior leading to injury EM FDA-USA Year Title Regulatory Authority/Reg ion Product active ingredient Safety Issue (AE) Intervention Type 387 2008 Rozerem (ramelteon) [2008 version] FDA-USA ramelteon Not specified EM-MG 388 2008 Ribasphere (ribavirin) [2008 version] Rituxan (rituximab) Audience: Oncologists, rheumatologists, other healthcare professionals, consumers FDA-USA ribavirin Not specified EM-MG FDA-USA rituximab Progressive multifocal leukoencephalopathy (PML) EM 389 390 2008 2008 [Posted 09/11/2008] Genentech informed healthcare professionals of revisions to prescribing information for Rituxan regarding a case of progressive multifocal leukoencephalopathy (PML) leading to death in a patient with rheumatoid arthritis who received Rituxan in a long-term safety extension clinical study. The patient developed a JC virus infection with resultant PML and death 18 months after taking the last dose of Rituxan. Healthcare professionals treating patients with Rituxan should consider PML in any patient presenting with new onset neurologic manifestations. Additionally, consultation with a neurologist, brain MRI and lumbar puncture should be considered as clinically indicated. Nplate (romiplostim) [2008 version] Avandia (rosiglitazone maleate) Audience: Endocrinologists, pharmacists, patients FDA-USA romiplostim Not specified EM-MG, communi cation plan FDA-USA rosiglitazone maleate New or worse heart failure EM-MG [Posted 02/26/2008] FDA and GlaxoSmithKline notified pharmacists and physicians of a new EM-MG for Avandia (rosiglitazone maleate). The FDA regulation 21CFR 208 requires a EM-MG to be provided with each prescription that is dispensed for products that FDA determines pose a serious and significant public health concern. The EM-MG and current Prescribing Information for Avandia are provided below. 391 2008 Year 392 2008 Title Avandia (rosiglitazone maleate) [2008 version] Regulatory Authority/Reg ion Product active ingredient Safety Issue (AE) Intervention Type FDA-USA rosiglitazone maleate Not specified EM-MG Not specified EM-MG 393 2008 Avandamet (rosiglitazone maleate and metformin HCl) Tablets (PDF - 96KB) FDA-USA rosiglitazone maleate and metformin 394 2008 Banzel (rufinamide) [2008 version] FDA-USA rufinamide Not specified EM-MG EMcommuni cation plan, elements to assure safe use, impleme ntation system EM-MG 395 2008 Sucraid (sacrosidase) Oral Solution (PDF - 100KB) FDA-USA sacrosidase Increase in allergy related adverse events following a manufacturing change 396 2008 Zoloft (sertraline HCl) [2008 version] FDA-USA sertraline HCl Not specified Year 397 2008 Title Section Contents Menu MedWatch The FDA Safety Information and Adverse Event Reporting Program Safety Information Safety Alerts for Human Medical Products 2010 Safety Alerts for Human Medical Products 2009 Safety Alerts for Human Medical Products 2008 Safety Alerts for Human Medical Products 2007 Safety Alerts for Human Medical Products 2006 Safety Alerts for Human Medical Products 2005 Safety Alerts for Human Medical Products 2004 Safety Alerts for Human Medical Products 2003 Safety Alerts for Human Medical Products 2002 Safety Alerts for Human Medical Products 2001 Safety Alerts for Human Medical Products 2000 Safety Alerts for Human Medical Products - Simvastatin Used With Amiodarone Audience: Cardiologic healthcare professionals, pharmacists, other healthcare professionals [Posted 08/08/2008] FDA notified healthcare professionals of the risk of muscle injury, rhabdomyolysis, which can lead to kidney failure or death, when simvastatin is used with amiodarone. This risk is dose-related and increases when a dose of simvastatin greater than 20 mg per day is given with amiodarone. Although a revision of the simvastatin labeling in 2002 described an increased risk of rhabdomyolysis when amiodarone is taken with simvastatin doses greater than 20 mg daily, FDA continues to receive reports of rhabdomyolysis in patients treated concurrently with amiodarone and simvastatin. Prescribers should be aware of the increased risk of rhabdomyolysis when simvastatin is prescribed with amiodarone, and they should avoid doses of simvastatin greater than 20 mg per day in patients taking amiodarone. Regulatory Authority/Reg ion Product active ingredient FDA-USA simvastatin Risk of muscle injury, rhabdomyolysis, EM Not specified EM-MG Not specified EM-MG 398 2008 Treximet (sumatriptan succinate and naproxen sodium) Tablets (PDF - 112KB) FDA-USA sumatriptan succinate and naproxen sodium 399 2008 Tapentadol Tablets (PDF - 222KB) FDA-USA tapentadol 400 2008 Xenazine (tetrabenazine) [2008 version] Innohep (tinzaparin sodium injection) Audience: Hematological and Nephrological healthcare professionals, hospital risk managers Safety Issue (AE) Intervention Type FDA-USA tetrabenazine Not specified EM-MG, communi cation plan FDA-USA tinzaparin sodium injection May increase the risk for death EMDHCPL [UPDATE 12/31/2008] Celgene has issued a Dear Healthcare Professional letter describing a controlled clinical study suggesting that Innohep may increase the risk for death, compared to unfractionated heparin when used to treat elderly patients with renal insufficiency. It recommended consideration of alternatives to Innohep when treating these patients for deep vein thrombosis with or without pulmonary embolism. 401 2008 [Posted 12/02/2008] FDA has received information about the clinical study: Innohep in Renal Insufficiency Study (IRIS) Year Title that was stopped in February, 2008 by the study’s Data Safety Monitoring Committee because of an interim finding of an increase in all-cause mortality in patients who received Innohep. Information on the patients enrolled in the study, on the heparin used to manufacture Innohep, and on the heparin used in the study is still being collected and analyzed. Regulatory Authority/Reg ion Product active ingredient Safety Issue (AE) Intervention Type In July 2008, the company revised the prescribing information to restrict the use of Innohep in patients 90 years of age or older. FDA is concerned that the preliminary data from the IRIS study suggest that the increased risk of mortality is not limited only to patients 90 years of age or older. Therefore, FDA has requested that the company revise the labeling for Innohep to better describe the overall study results which suggest that, when compared to unfractionated heparin, Innohep increases the risk of death for elderly patients (i.e., 70 years of age and older) with renal insufficiency. Healthcare professionals should consider the use of alternative treatments to Innohep when treating elderly patients over 70 years of age with renal insufficiency and DVT, PE, or both. This communication is in keeping with FDA’s commitment to inform the public about its ongoing safety reviews of drugs. FDA anticipates submission of the final IRIS study report in January, 2009 and plans to complete its review soon thereafter. FDA will communicate its conclusions and any resulting recommendations to the public at that time. FDA will consider additional regulatory actions as appropriate after thorough review of all applicable data from the manufacturer of Innohep. Tiotropium (marketed as Spiriva HandiHaler) Audience: Pulmonary care health professionals and patients [01/14/2010] FDA issued a Follow-Up to the previous Early Communications issued in 2008, describing a potential increase in the risk of stroke, heart attack, or death from a cardiovascular cause related to the use of tiotropium, which is marketed as Spiriva HandiHaler. FDA has now completed its review and believes the available data do not support an association between the use of Spiriva HandiHaler and an increased risk for these serious adverse events. FDA is advising healthcare professionals to continue to prescribe Spiriva HandiHaler as recommended in the drug label. [UPDATE 10/07/2008] FDA informed healthcare professionals that FDA has reviewed preliminary data from UPLIFT (Understanding the Potential Long-Term Impacts on Function with Tiotropium), a large, 4-year, placebo controlled clinical trial with Spiriva HandiHaler in approximately 6000 patients with chronic obstructive pulmonary disease. The preliminary results reported by Boehringer Ingelheim to the FDA showed that there was no increased risk of stroke with tiotropium bromide compared to placebo. Two recent publications reported increased risk for mortality and/or cardiovascular events in patients who received tiotropium or inhaled anticholinergics. Both studies examined cardiovascular outcomes. FDA expects to receive the complete report for UPLIFT in November 2008. Results from this trial will also help to address some issues raised about tiotropium in the two recent publications. Due to the amount of data collected in UPLIFT, a complete review of the results could take several months, at which time FDA will update this communication with the final results of the UPLIFT analysis, as well as all the available data regarding tiotropium and stroke risk. [Posted 03/18/2008] Boehringer Ingelheim and FDA notified healthcare professionals that ongoing safety monitoring has identified a possible increased risk of stroke in patients who take Spiriva. This product contains tiotropium bromide and is used to treat bronchospasm associated with chronic obstructive pulmonary disease. Boehringer Ingelheim reported to the FDA that it has conducted an analysis of the safety data from 29 placebo controlled clinical studies (“pooled analysis”). Based on data from these studies, the preliminary estimates of the risk of stroke are 8 patients per 1000 patients treated for one year with Spiriva, and 6 patients per 1000 patients treated for one year with placebo. This means that the estimated excess risk of any type of stroke due to Spiriva is 2 patients for each 1000 patients using Spiriva over a one year period. 402 2008 It is important to interpret these preliminary results with caution. FDA is working with Boehringer Ingelheim to further evaluate the potential association between Spiriva and stroke. FDA has not confirmed these analyses and while pooled analyses can provide early information about potential safety issues, these analyses have inherent limitations and uncertainty that require further investigation using other data sources. Patients should not stop taking Spiriva HandiHaler before talking to their doctor, if they have questions about this new information. This early communication is in keeping with FDA’s commitment to inform the public about its ongoing safety reviews of drugs FDA-USA tiotropium Potential increase in the risk of stroke, heart attack, or death from a cardiovascular cause EM Year Title Regulatory Authority/Reg ion Product active ingredient Safety Issue (AE) Intervention Type 403 2008 Tolectin (tolmetin sodium) [2008 version] FDA-USA tolmetin sodium Not specified EM-MG 404 2008 Parnate (tranylcypromine sulfate) [2008 version] FDA-USA tranylcypromine sulfate Not specified EM-MG 405 2008 Halcion (triazolam) [2008 version] Tumor Necrosis Factor (TNF) Blockers (marketed as Remicade, Enbrel, Humira, and Cimzia) Audience: Rheumatologists, gastroenterologists, oncologists, other healthcare professionals FDA-USA triazolam Not specified EM-MG Development of lymphoma and other cancers EM Pulmonary and disseminated histoplasmosis, coccidioidomycosis, blastomycosis and other opportunistic infections EM 406 407 2008 2008 [Posted 06/03/2008] FDA issued an Early Communication About an Ongoing Safety Review to inform healthcare professionals that the Agency is investigating a possible association between the use of Tumor Necrosis Factor (TNF) blockers and the development of lymphoma and other cancers in children and young adults. FDA is investigating approximately 30 reports of cancer in children and young adults. These reports were submitted to FDA's Adverse Event Reporting System over a ten-year interval, beginning in 1998 through April 29, 2008. These reports describe cancer occurring in children and young adults who began taking TNF blockers (along with other immuno-suppressive medicines such as methotrexate, azathioprine or 6-mercaptopurine), when they were ages 18 or less, to treat juvenile idiopathic arthritis, Crohn's disease or other diseases. Approximately half of the cancers were lymphomas, including both Hodgkin's and non-Hodgkin's lymphoma. Long-term studies are necessary to provide definitive answers about whether TNF blockers increase the occurrence of cancers in children because cancers may take a long time to develop and may not be detected in short-term studies. Until the evaluation is completed, healthcare providers, parents, and caregivers should be aware of the possible risk of lymphoma and other cancers in children and young adults when deciding how to best treat these patients. Tumor necrosis factor-alpha blockers (TNF blockers), Cimzia (certolizumab pegol), Enbrel (etanercept), Humira (adalimumab), and Remicade (infliximab) Sept 2008 Audience: Rheumatological, gastroenterological and infectious disease healthcare professionals [Posted 09/04/2008] FDA notified healthcare professionals that pulmonary and disseminated histoplasmosis, coccidioidomycosis, blastomycosis and other opportunistic infections are not consistently recognized in patients taking tumor necrosis factor-α blockers (TNF blockers). This has resulted in delays in appropriate treatment, sometimes resulting in death. For patients taking TNF blockers who present with signs and symptoms of possible systemic fungal infection, such as fever, malaise, weight loss, sweats, cough, dypsnea, and/or pulmonary infiltrates, or other serious systemic illness with or without concomitant shock, healthcare professionals should ascertain if patients live in or have traveled to areas of endemic mycoses. For patients at risk of histoplasmosis and other invasive fungal infections, clinicians should consider empiric antifungal treatment until the pathogen(s) are identified. FDA-USA FDA-USA Tumor Necrosis Factor (TNF) Blockers (marketed as Remicade, Enbrel, Humira, and Cimzia) Tumor necrosis factor-alpha blockers (TNF blockers), Cimzia (certolizumab pegol), Enbrel (etanercept), Humira (adalimumab), and Remicade (infliximab) Year Title Regulatory Authority/Reg ion Product active ingredient Safety Issue (AE) Intervention Type Chantix (Varenicline) November 2007 Audience: Healthcare professionals, consumers [UPDATE 05/16/2008] FDA informed healthcare professionals and patients that as the Agency’s review of Chantix safety data has progressed, it appears increasingly likely that there is an association between Chantix and serious neuropsychiatric symptoms. Prescribing information for Chantix was revised to include this safety information in the WARNINGS and PRECAUTIONS sections of the label, and a EM-MG for patients is also available. If patients, their families, or caregivers notice agitation, depressed mood, or changes in behavior that are not typical for the patient or if the patient has suicidal thoughts or actions, the patient should stop taking Chantix and contact their healthcare professional. [Posted 11/20/2007] FDA informed healthcare professionals of reports of suicidal thoughts and aggressive and erratic behavior in patient who have taken Chantix, a smoking cessation product. There are also reports of patients experiencing drowsiness that affected their ability to drive or operate machinery. FDA is currently reviewing these cases, along with other recent reports. A preliminary assessment reveals that many of the cases reflect new-onset of depressed mood, suicidal ideation, and changes in emotion and behavior within days to weeks of initiating Chantix treatment. The role of Chantix in these cases is not clear because smoking cessation, with or without treatment, is associated with nicotine withdrawal symptoms and has also been associated with the exacerbation of underlying psychiatric illness. However, not all patients described in the cases had preexisting psychiatric illness and not all had discontinued smoking. Healthcare professionals should monitor patients taking Chantix for behavior and mood changes. Patients taking this product should report behavior or mood changes to their doctor and use caution when driving or operating machinery until they know how quitting smoking with Chantix may affect them. 408 2007 FDA-USA varenicline Serious neuropsychiatric symptom EM EM-MG EM Varenicline (marketed as Chantix) Audience: Neuropsychiatric and other healthcare professionals, consumers 409 2008 [Posted 02/01/2008] FDA informed healthcare professionals and consumers of important revisions to the WARNINGS and PRECAUTIONS sections of the prescribing information for Chantix regarding serious neuropsychiatric symptoms experienced in patients taking Chantix. These symptoms include changes in behavior, agitation, depressed mood, suicidal ideation, and attempted and completed suicide. While some patients may have experienced these types of symptoms and events as a result of nicotine withdrawal, some patients taking Chantix who experienced serious neuropsychiatric symptoms and events had not yet discontinued smoking. In most cases, neuropsychiatric symptoms developed during Chantix treatment, but in others, symptoms developed following withdrawal of Chantix therapy. See the FDA Information for Healthcare Professionals Sheet for recommendations and considerations for healthcare professionals on using Chantix therapy for patients. 410 2008 Effexor (venlafaxine HCl) [2008 version] FDA-USA venlafaxine HCl Not specified EM-MG 411 2008 Vicoprofen (vicoprofen and ibuprofen) [2008 version] FDA-USA vicoprofen and ibuprofen Not specified EM-MG FDA-USA varenicline Neuropsychiatric symptoms experienced in patients taking Chantix. These symptoms include changes in behavior, agitation, depressed mood, suicidal ideation, and attempted and completed suicide Year Title Relenza (zanamivir) Audience: Pediatric and infectious disease healthcare professionals Regulatory Authority/Reg ion Product active ingredient Safety Issue (AE) Intervention Type [Posted 04/01/2008] GlaxoSmithKline informed healthcare professionals of changes to the WARNINGS AND PRECAUTIONS sections of prescribing information for Relenza regarding information from postmarketing reports (mostly from Japan) of delirium and abnormal behavior leading to injury in patients with influenza who are receiving neuraminidase inhibitors, including Relenza. These events were reported primarily among pediatric patients and often had an abrupt onset and rapid resolution. The contribution of Relenza to these events has not been established. Influenza can be associated with a variety of neurologic and behavioral symptoms which can include seizures, hallucinations, delirium, and abnormal behavior, in some cases resulting in fatal outcomes. These events may occur in the setting of encephalitis or encephalopathy but can occur without obvious severe disease. 412 2008 Patients with influenza should be closely monitored for signs of abnormal behavior. If neuropsychiatric symptoms occur, the risks and benefits of continuing treatment should be evaluated for each patient. FDA-USA zanamivir Delirium and abnormal behavior leading to injury EM 413 2008 Zolpidem (zolpidem tartrate) [2008 version] FDA-USA zolpidem tartrate Not specified EM-MG FDA-USA abacavir sulfate, lamivudine and zidovudine Not specified EM-MG 414 415 416 2009 2009 2009 Trizivir (abacavir sulfate, lamivudine and zidovudine) [2009 version] Dysport* (abobotulinumtoxinA) [2009 version] Darvocet (acetaminophen and propoxyphene napsylate) [2009 version] FDA-USA abobotulinumtox inA Not specified EM-MG, communi cation plan FDA-USA acetaminophen and propoxyphene napsylate Not specified EM-MG Year Title Regulatory Authority/Reg ion Product active ingredient Safety Issue (AE) Intervention Type 417 2009 Humira* (adalimumab) [2009 version] FDA-USA adalimumab Not specified 418 2009 Entereg (alvimopan) Capsules (PDF - 2120KB) FDA-USA alvimopan Risk of myocardial infarction observed with longer use EM-MG EMcommuni cation plan, elements to assure safe use, impleme ntation system 419 2009 Letairis (ambrisentan) [2009 version] FDA-USA ambrisentan Not specified EM-MG; elements to assure safe use, impleme ntation system 420 2009 Cordarone (amiodarone HCl) [2009 version] FDA-USA amiodarone HCl Not specified EM-MG Year Title Antiepileptic Drugs Audience: Neuropsychiatric healthcare professionals, other healthcare professionals, patients Regulatory Authority/Reg ion Product active ingredient Safety Issue (AE) Intervention Type [UPDATE 09/15/2009] Dear Healthcare Professional Letter for Klonopin (clonazepam) added below. [UPDATE 05/05/2009] FDA notified healthcare professionals that it approved updated labeling for antiepileptic drugs used to treat epilepsy, psychiatric disorders, and other conditions (e.g., migraine and neuropathic pain syndromes). FDA also required development of a EM-MG, to be issued to patients each time the product is dispensed. Since issuing safety alerts on December 16, 2008 and January 31, 2008, FDA has been working with the manufacturers of drugs in this class to better understand the suicidality risk. Eleven antiepileptic drugs were included in a pooled analysis of placebo-controlled clinical studies in which these drugs were used to treat epilepsy as well as psychiatric disorders and other conditions. The increased risk of suicidal thoughts or behavior was generally consistent among the eleven drugs, with varying mechanisms of action and across a range of indications. This observation suggests that the risk applies to all antiepileptic drugs used for any indication. [UPDATE 12/16/2008] The FDA has completed its analysis of reports of suicidality (suicidal behavior or ideation [thoughts]) from placebo-controlled clinical trials of drugs used to treat epilepsy, psychiatric disorders, and other conditions. Based on the outcome of this review, FDA is requiring that all manufacturers of drugs in this class include a Warning in their labeling and develop a EM-MG to be provided to patients prescribed these drugs to inform them of the risks of suicidal thoughts or action. [Posted 01/31/2008] FDA informed healthcare professionals that the Agency has analyzed reports of suicidality (suicidal behavior or ideation) from placebo-controlled clinical studies of eleven drugs used to treat epilepsy as well as psychiatric disorders, and other conditions. In the FDA's analysis, patients receiving antiepileptic drugs had approximately twice the risk of suicidal behavior or ideation (0.43%) compared to patients receiving placebo (0.22%). The increased risk of suicidal behavior and suicidal ideation was observed as early as one week after starting the antiepileptic drug and continued through 24 weeks. The results were generally consistent among the eleven drugs. The relative risk for suicidality was higher in patients with epilepsy compared to patients who were given one of the drugs in the class for psychiatric or other conditions. Healthcare professionals should closely monitor all patients currently taking or starting any antiepileptic drug for notable changes in behavior that could indicate the emergence or worsening of suicidal thoughts or behavior or depression. The drugs included in the analyses include (some of these drugs are also available in generic form): Carbamazepine (marketed as Carbatrol, Equetro, Tegretol, Tegretol XR) Felbamate (marketed as Felbatol) Gabapentin (marketed as Neurontin) Lamotrigine (marketed as Lamictal) Levetiracetam (marketed as Keppra) Oxcarbazepine (marketed as Trileptal) Pregabalin (marketed as Lyrica) Tiagabine (marketed as Gabitril) Topiramate (marketed as Topamax) Valproate (marketed as Depakote, Depakote ER, Depakene, Depacon) Zonisamide (marketed as Zonegran) 421 2009 Although the 11 drugs listed above were the ones included in the analysis, FDA expects that the increased risk of suicidality is shared by all antiepileptic drugs and anticipates that the class labeling changes will be applied broadly. FDA-USA antiepileptic drugs carbamazepine, felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, regabalin, tiagabine, topiramate, valproate, zonisamide Suicidality (suicidal behavior or ideation [thoughts]) EM Year 422 423 2009 2009 Title Abilify (aripiprazole) [2009 version] Tracleer (bosentan) [2009 version] Botox and Botox Cosmetic (Botulinum toxin Type A) and Myobloc (Botulinum toxin Type B) Audience: Cosmetic surgeons, neurologists, consumers Regulatory Authority/Reg ion FDA-USA Product active ingredient aripiprazole Safety Issue (AE) Intervention Type Not specified EM-MG FDA-USA bosentan Not specified EM-MG, elements to assure safe use, impleme ntation system FDA-USA Botox and Botox Cosmetic (Botulinum toxin Type A) and Myobloc (Botulinum toxin Type B) Risk of adverse events when the effects of the toxin spread beyond the site where it was injected EM FDA-USA budesonide and formoterol fumarate dihydrate Not specified EM-MG [UPDATED 08/03/2009] FDA notified healthcare professionals of changes to the established drug names for Botox/Botox Cosmetic, Dysport and Myobloc to reinforce individual potencies and prevent medication errors, and provided recommendations for healthcare professionals to consider, plus information for patients, family members, and caregivers. [Posted 04/30/2009] FDA notified healthcare professionals that after an ongoing safety review initiated in February 2008, the manufacturers of licensed botulinum toxin products will be required by FDA to strengthen warnings in product labeling and add a boxed warning regarding the risk of adverse events when the effects of the toxin spread beyond the site where it was injected. FDA will also require that manufacturers develop and implement a Risk Evaluation and Mitigation Strategy [REMS], including a communication plan to provide more information regarding the risk for distant spread of botulinum toxin effects after local injection, as well as information to explain that botulinum toxin products cannot be interchanged. The REMS would also include a EM-MG that explains the risks to patients, their families, and caregivers. FDA is requiring the manufacturers to submit safety data after multiple administrations of the product in a specified number of children and adults with spasticity to assess the signal of serious risk regarding distant spread of toxin effects. 424 425 2009 2009 FDA’s evaluation of the data continues to support the recommendations made in the 2008 Early Communication. Symbicort (budesonide and formoterol fumarate dihydrate) [2009 version] Year Title Cefepime (marketed as Maxipime) Update of Ongoing Safety Review Audience: Infectious disease healthcare professionals Regulatory Authority/Reg ion Product active ingredient Safety Issue (AE) Intervention Type FDA notified healthcare professionals that it has finished its analysis of a possible risk of higher death with cefepime, an antibiotic, following publication of a study that suggested a higher rate of death in patients treated with this drug, as compared to patients treated with similar drugs. FDA reviewed this study data and conducted additional analyses based on additional data, including data submitted by Bristol Meyers Squibb. FDA has determined that the data do not indicate a higher rate of death in cefepime-treated patients. Cefepime remains an appropriate therapy for its approved indications. 426 2009 FDA will continue to review the safety of cefepime. As part of this ongoing review, both FDA and Bristol Meyers Squib are conducting separate analyses of death potentially associated with cefepime, using hospital drug use data. The results of these analyses likely will be reported in approximately one year. Ceftriaxone (marketed as Rocephin and generics) Audience: Neonatology, infectious disease healthcare professionals, hospital risk managers FDA-USA cefepime Higher rate of death EM EMDHCPL [UPDATE 06/11/2009] Dear Healthcare Professional Letter issued by Roche. 427 2009 [Posted 04/14/2009] FDA notified healthcare professionals of an update to a previous alert that addresses the interaction of ceftriaxone with calcium-containing products, based on previously reported fatal cases in neonates. At the request of FDA, the manufacturer of ceftriaxone (Roche) conducted two in vitro studies to assess the potential for precipitation of ceftriaxone-calcium when ceftriaxone and calcium-containing products are mixed in vials and in infusion lines. These two in vitro studies were conducted in neonatal and adult plasma to assess the potential for precipitation of ceftriaxone-calcium using varying ceftriaxone and calcium concentrations, including concentrations in excess of those achieved in vivo. Based on the results from these studies, FDA now recommends that ceftriaxone and calcium-containing products may be used concomitantly in patients >28 days of age, using the precautionary recommendations noted because the risk of precipitation is low in this population. FDA had previously recommended, but no longer recommends, that in all age groups ceftriaxone and calcium-containing products should not be administered within 48 hours of one another. 428 2009 Cimzia* (certolizumab pegol) [2009 version] FDA-USA certolizumab pegol Not specified EM-MG 429 2009 Cipro (ciprofloxacin) Tablets, Oral Suspension, I.V. Solution, and Extended-Release Tablets) (PDF - 19KB) FDA-USA ciprofloxacin Not specified EM-MG 430 2009 Celexa (citalopram hydrobromide) [2009 version] FDA-USA citalopram hydrobromide Not specified EM-MG FDA-USA ceftriaxone Interaction of ceftriaxone with calcium-containing products, based on previously reported fatal cases in neonates Year Title Clopidogrel (marketed as Plavix) and Omeprazole (marketed as Prilosec) - Drug Interaction Audience: Cardiovascular healthcare professionals, pharmacists Regulatory Authority/Reg ion [Posted 11/17/2009] FDA notified healthcare professionals of new safety information concerning an interaction between clopidogrel (Plavix), an anti-clotting medication, and omeprazole (Prilosec/Prilosec OTC), a proton pump inhibitor (PPI) used to reduce stomach acid. New data show that when clopidogrel and omeprazole are taken together, the effectiveness of clopidogrel is reduced. Patients at risk for heart attacks or strokes who use clopidogrel to prevent blood clots will not get the full effect of this medicine if they are also taking omeprazole. Separating the dose of clopidogrel and omeprazole in time will not reduce this drug interaction. 2009 Recommendations for healthcare professionals are provided in the "Information for Healthcare Professionals" sheet. Clopidogrel bisulfate (marketed as Plavix) Audience: Cardiovascular healthcare professionals, Pharmacists Safety Issue (AE) Intervention Type FDA-USA clopidogrel (marketed as Plavix) and omeprazole (marketed as Prilosec) - Drug Interaction Drug interaction effectiveness of clopidogrel is reduced EM FDA-USA clopidogrel bisulfate Differences in effectiveness may be due to genetic differences EM FDA-USA Colchicine Cases of fatal colchicine toxicity EM Other drugs that are expected to have a similar effect and should be avoided in combination with clopidogrel include: cimetidine, fluconazole, ketoconazole, voriconazole, etravirine, felbamate, fluoxetine, fluvoxamine, and ticlopidine. 431 Product active ingredient [Posted 01/26/2009] FDA notified healthcare professionals that the makers of Plavix have agreed to work with FDA to conduct studies to obtain additional information that will allow a better understanding and characterization of the effects of genetic factors and other drugs (especially the proton pump inhibitors (PPIs)) on the effectiveness of clopidogrel. FDA is aware of published reports that clopidogrel (marketed as Plavix) is less effective in some patients than it is in others. Differences in effectiveness may be due to genetic differences in the way the body metabolizes clopidogrel or that using certain other drugs with clopidogrel can interfere with how the body metabolizes clopidogrel. These studies should lead to a better understanding about how to optimize the use of clopidogrel. The FDA recognizes the importance of obtaining these data promptly. The drug manufacturers have agreed to a timeline for completing the studies and FDA will review the new information expeditiously and will communicate its conclusions and any recommendations to the public at that time. It could take several months to complete the studies and analyze the results. Until further information is available FDA recommends the following: 432 2009 Healthcare providers should continue to prescribe and patients should continue to take clopidogrel as directed, because clopidogrel has demonstrated benefits in preventing blood clots that could lead to a heart attack or stroke. Healthcare providers should re-evaluate the need for starting or continuing treatment with a PPI, including Prilosec OTC, in patients taking clopidogrel. Patients taking clopidogrel should consult with their healthcare provider if they are currently taking or considering taking a PPI, including Prilosec OTC. Colchicine (marketed as Colcrys) Audience: Rheumatological healthcare professionals [Posted 07/30/2009] FDA notified healthcare professionals of the approval of the first single-ingredient oral colchicine product, Colcrys, for the treatment of familial Mediterranean fever (FMF) and acute gout flares and of two previously uncharacterized safety concerns associated with the use of colchicine. Oral colchicine has been used for many years as an unapproved drug with no FDA-approved prescribing information, dosage recommendations, or drug interaction warnings. FDA analyzed safety data for colchicine from adverse events reported to the Agency, the published literature, and company-sponsored pharmacokinetic and drug interaction studies. This analysis revealed cases of fatal colchicine toxicity reported in certain patients taking standard therapeutic doses of colchicine and concomitant medications that interact with colchicine, such as clarithromycin. These reports suggest that drug interactions affecting the gastrointestinal absorption and/or hepatic metabolism of colchicine play a central role in the development of colchicine toxicity. Data submitted supporting the safety and efficacy of Colcrys in acute gout flares demonstrated that a substantially lower dose of colchicine was as effective as the higher dose traditionally used. Moreover, patients receiving the lower dose experienced significantly fewer adverse events compared to the higher dose. 433 2009 Based on this information, FDA has included important safety considerations in the approved prescribing information to assure safe use of Colcrys and is providing background information, a data summary and recommendations in this alert. Year 434 2009 Title Colcrys (colchicine) [2009 version] Exjade (deferasirox) - Early Communication Audience: Hematology-Oncology healthcare professionals Regulatory Authority/Reg ion FDA-USA Product active ingredient Safety Issue (AE) Intervention Type colchicine Not specified EM-MG deferasirox Adverse events and deaths in patients using Exjade who are over sixty years old who have myelodysplastic syndrome (MDS) EM FDA-USA desipramine HCl Extreme caution should be used when this drug is given to patients who have a family history of sudden death, cardiac dysrhythmias, and cardiac conduction disturbances; and that seizures precede cardiac dysrhythmias and death in some patients. EMDHCPL [Posted 09/25/2009] FDA notified healthcare professionals of an Early Communication regarding an ongoing review of safety issues with Exjade (deferasirox). New safety data suggests there may be a greater number of adverse events and deaths in patients using Exjade who are over sixty years old who have myelodysplastic syndrome (MDS). Exjade, an iron chelator, is an oral medication approved in 2005 for patients aged two and older with chronic anemia (low red blood cell counts) and iron overload as a result of receiving blood transfusions. FDA is working with Novartis to add new information in the Contraindications, Warnings, and Precautions sections of the prescribing information, to alert healthcare professionals of the risks and adverse events, including acute renal failure and gastrointestinal hemorrhages that in rare cases, especially in older patients with blood-related malignancies and/or low platelet counts, have been fatal. 435 2009 Any adverse events or quality problems that may be related to the use of this product should be reported to the FDA's MedWatch Adverse Event Reporting program online, by phone [1-800-332-1088 begin_of_the_skype_highlighting 1-800-332-1088 end_of_the_skype_highlighting], or by returning the postage-paid FDA Form 3500 by mail or fax [1800-FDA-0178]. Norpramin (desipramine HCl) - Dear Healthcare Professional Letter Audience: Psychiatric healthcare professionals FDA-USA [Posted 12/02/2009] Sanofi-Aventis and FDA notified healthcare professionals of changes to the Warnings and Overdosage sections of the Prescribing Information for Norpramin (desipramine HCl), indicated for the treatment of depression. The new safety information states that extreme caution should be used when this drug is given to patients who have a family history of sudden death, cardiac dysrhythmias, and cardiac conduction disturbances; and that seizures precede cardiac dysrhythmias and death in some patients. 436 2009 437 2009 Norpramin (desipramine HCl) [2009 version] FDA-USA desipramine HCl Not specified EM-MG 438 2009 Pennsaid (diclofenac sodium) [2009 version] FDA-USA diclofenac sodium Not specified EM-MG Year Title Voltaren Gel (diclofenac sodium topical gel) 1% - Hepatic Effects Labeling Changes Audience: Rheumatological healthcare professionals, pharmacists Regulatory Authority/Reg ion Product active ingredient Safety Issue (AE) Intervention Type [Posted 12/04/2009] Endo, Novartis and FDA notified healthcare professionals of revisions to the Hepatic Effects section of the prescribing information to add new warnings and precautions about the potential for elevation in liver function tests during treatment with all products containing diclofenac sodium. In postmarketing reports, cases of drug-induced hepatotoxicity have been reported in the first month but can occur at any time during treatment with diclofenac. Postmarketing surveillance has reported cases of severe hepatic reactions, including liver necrosis, jaundice, fulminant hepatitis with and without jaundice, and liver failure. Some of these reported cases resulted in fatalities or liver transplantation. 439 440 2009 2009 Physicians should measure transaminases periodically in patients receiving long-term therapy with diclofenac. The optimum times for making the first and subsequent transaminase measurement are not known. Based on clinical trial data and postmarketing experiences, transaminases should be monitored within 4 to 8 weeks after initiating treatment with diclofenac. Multaq (dronedarone) [2009 version] Xigris (Drotrecogin alfa [activated]) - Early Communication about an Ongoing Safety Review Audience: Critical care healthcare professionals FDA-USA diclofenac sodium topical gel Hepatic effects EM FDA-USA dronedarone Not specified EM-MG, communi cation plan FDA-USA Drotrecogin alfa [activated] Reduction of mortality EM Not specified EM-MG, communi cation plan [Posted 02/04/2009] FDA is aware of a recently published study, a retrospective medical record review of 73 patients who receive Drotrecogin alfa (activated), marketed as Xigris, indicated for the reduction of mortality in adult patients with severe sepsis who have a high risk of death (Gentry et al.; Crit Care Med 2009).The study reported an increased risk of serious bleeding events and of death in patients with sepsis and baseline bleeding risk factors who received this product. Serious bleeding events occurred in 7 of 20 patients (35%) who had a bleeding risk factor vs. only 2 of 53 (3.8%) patients without any bleeding risk factors. The finding by Gentry et al. of an increased risk of death and serious bleeding events in patients treated with Xigris who also have baseline bleeding risk factors is consistent with the information in the current product label. Prescribers should refer to the product label for the specific contraindications, warnings, and, precautions and carefully weigh the increased risk of bleeding against the benefits of Xigris. 441 442 2009 2009 FDA is working with the manufacturer to further evaluate the incidence of serious bleeding events and mortality in patients who received Xigris. FDA will communicate its conclusions and any resulting recommendations to the public when the review is completed, which may take several months.The FDA urges both healthcare professionals and patients to report side effects from the use of Xigris to the FDA's MedWatch Adverse Event Reporting program. Kalbitor* (ecallantide) [2009 version] FDA-USA ecallantide Year 443 2009 Title Soliris (eculizumab) [2009 version] Raptiva (efalizumab) Feb 2009 Audience: Dermatological healthcare professionals, patients Regulatory Authority/Reg ion Product active ingredient Safety Issue (AE) Intervention Type FDA-USA eculizumab Not specified EM-MG FDA-USA efalizumab Progressive multifocal leukoencephalopathy (PML) EM erlotinib Gastrointestinal perforation (including fatalities), bullous, blistering and exfoliative skin conditions including cases suggestive of StevensJohnson syndrome/toxic epidermal necrolysis, in some cases fatal, and ocular disorders, including corneal perforation or ulceration EM [UPDATE 04/08/2009] Genentech and FDA notified healthcare professionals of the voluntary, phased withdrawal of Raptiva, a medication for treatment of psoriasis, from the U.S. market due to a potential risk to patients of developing progressive multifocal leukoencephalopathy (PML). By June 8, 2009, Raptiva will no longer be available in the United States. Prescribers are being asked not to initiate Raptiva treatment for any new patients. Prescribers should immediately begin discussing with patients currently using Raptiva how to transition to alternative therapies. The FDA strongly recommends that patients work with their health care professional to transition to alternative therapies for psoriasis. 444 2009 [Posted 02/19/2009] FDA issued a Public Health Advisory to notify healthcare professionals of three confirmed, and one possible report of progressive multifocal leukoencephalopathy (PML), a rare brain infection, in patients using the psoriasis drug Raptiva. In October 2008, the labeling for Raptiva was changed to highlight, in a Boxed Warning, the risks of lifethreatening infections, including PML. In addition, FDA directed Genentech, the manufacturer of Raptiva, to develop a Risk Evaluation and Mitigation Strategy, or REMS, to ensure that patients receive risk information about Raptiva. The FDA is reviewing this latest information. The agency will take appropriate steps to ensure that the risks of Raptiva do not outweigh its benefits, that patients prescribed Raptiva are clearly informed of the signs and symptoms of PML, and that health care professionals carefully monitor patients for the possible development of PML. The Public Health Advisory provides recommendations for healthcare providers and patients when treatment with this product is considered. Tarceva (erlotinib) May 2009 Audience: Oncological, dermatological and ophthalmological healthcare professionals [Posted 05/08/2009] OSI, Genentech and FDA notified healthcare professionals of new safety information added to the WARNINGS AND PRECAUTIONS sections of the prescribing information for Tarceva. Gastrointestinal perforation (including fatalities), bullous, blistering and exfoliative skin conditions including cases suggestive of Stevens-Johnson syndrome/toxic epidermal necrolysis, in some cases fatal, and ocular disorders, including corneal perforation or ulceration have been reported during use of Tarceva. The new safety information comes from routine pharmacovigilance activities of clinical study and postmarketing reports. Tarceva monotherapy is indicated for the treatment of patients with locally advanced or metastatic non-small cell lung cancer after failure of at least one prior chemotherapy regimen. In combination with gemcitabine, Tarceva is also indicated for the first-line treatment of patients with locally advanced, unresectable, or metastatic pancreatic cancer. 445 2009 FDA-USA Year Title Intelence (etravirine) Audience: Infectious disease healthcare professionals, patients Regulatory Authority/Reg ion Product active ingredient [Posted 08/27/2009] Tibotec Therapeutics and FDA notified healthcare professionals of revisions to the WARNINGS AND PRECAUTIONS section of the prescribing information for Intelence (etravirine). There have been postmarketing reports of cases of Stevens-Johnson syndrome, toxic epidermal necrolysis and erythema multiforme, as well as hypersensitivity reactions characterized by rash, constitutional findings, and sometimes organ dysfunction, including hepatic failure. Intelence therapy should be immediately discontinued when signs and symptoms of severe skin or hypersensitivity reactions develop. 446 2009 FDA-USA Safety Issue (AE) Intervention Type etravirine Stevens-Johnson syndrome, toxic epidermal necrolysis and erythema multiforme, as well as hypersensitivity reactions characterized by rash, constitutional findings, and sometimes organ dysfunction, including hepatic failure EM TDM Byetta (exenatide) - Renal Failure Audience: Endocrine and nephrology healthcare professionals [Posted 11/02/2009] FDA notified healthcare professionals of revisions to the prescribing information for Byetta (exenatide) to include information on post-marketing reports of altered kidney function, including acute renal failure and insufficiency. Byetta, an incretin-mimetic, is approved as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. From April 2005 through October 2008, FDA received 78 cases of altered kidney function (62 cases of acute renal failure and 16 cases of renal insufficiency), in patients using Byetta. Some cases occurred in patients with pre-existing kidney disease or in patients with one or more risk factors for developing kidney problems. Labeling changes include: 447 2009 Information regarding post-market reports of acute renal failure and insufficiency, highlighting that Byetta should not be used in patients with severe renal impairment (creatinine clearance <30 ml/min) or end-stage renal disease. Recommendations to healthcare professionals that caution should be applied when initiating or increasing doses of Byetta from 5 mcg to 10 mcg in patients with moderate renal impairment (creatinine clearance 30 to 50 ml/min). Recommendations that healthcare professionals monitor patients carefully for the development of kidney dysfunction, and evaluate the continued need for Byetta if kidney dysfunction is suspected while using the product. Information about kidney dysfunction in the patient EM-MG to help patients understand the benefits and potential risks associated with Byetta. 448 2009 Byetta (exenatide) [2009 version] 449 2009 Byetta (exenatide) Injection (PDF - 30KB) FDA-USA exenatide Altered kidney function, including acute renal failure and insufficiency FDA-USA exenatide Not specified EM-MG Pancreatitis; renal failure EM-MG, communi cation plan FDA-USA exenatide Year Title Section Contents Menu MedWatch The FDA Safety Information and Adverse Event Reporting Program Safety Information Safety Alerts for Human Medical Products - Ezetimibe/Simvastatin (marketed as Vytorin, Simvastatin (marketed as Zocor), Ezetimibe (marketed as Zetia) Audience: Endocrinologists, cardiologists, other healthcare professionals, patients Regulatory Authority/Reg ion Product active ingredient Safety Issue (AE) Intervention Type [UPDATED 12/22/2009] Follow-up to Early Communication posted. [Posted 08/21/2008] FDA informed healthcare professionals that the Agency is investigating a report from the Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) trial of a possible association between the use of Vytorin and a potentially increased incidence of cancer. Vytorin is a combination product of simvastatin and ezetimibe used to decrease the production of cholesterol by the liver and inhibit the absorption of cholesterol in the intestine to reduce LDL-cholesterol levels and reduce the risk of cardiovascular events. Recently, FDA obtained preliminary results from the SEAS trial. The clinical trial tested whether lowering LDL-cholesterol with Vytorin would reduce the risk of cardiovascular events in individuals with aortic stenosis. A lower overall cardiovascular risk was not found with Vytorin. However, there was an additional observation that a larger percentage of subjects treated with Vytorin were diagnosed with and died from all types of cancer combined when compared to placebo during the 5-year study. 450 2009 FDA anticipates receiving a final SEAS study report in about 3 months and the Agency's review and evaluation of the clinical trial data and other relevant information should take approximately 6 months. FDA will communicate its conclusions and recommendations at that time. Healthcare professionals and caregivers should continue to monitor patients taking Vytorin and report side effects from the use of this drug to the Agency. 451 2009 Nalfon (fenoprofen calcium) [2009 version] FDA-USA ezetimibe/simvas tatin Increased incidence of cancer EM FDA-USA fenoprofen calcium Not specified EM-MG 452 2009 Onsolis (fentanyl buccal soluble film) [2009 version] FDA-USA fentanyl buccal soluble film Not specified EM-MG; elements to assure safe use, impleme ntation system 453 2009 Actiq (fentanyl citrate) [2009 version] FDA-USA fentanyl citrate Not specified EM-MG Year Title Regulatory Authority/Reg ion Product active ingredient Safety Issue (AE) Intervention Type 454 2009 Prozac (fluoxetine HCl) [2009 version] FDA-USA fluoxetine HCl Not specified EM-MG 455 2009 Dalmane (flurazepam HCl) [2009 version] Lexiva (fosamprenavir calcium) - Dear Healthcare Professional Letter Audience: HIV/Infectious Disease healthcare professionals, cardiovascular healthcare professionals FDA-USA flurazepam HCl Not specified EM-MG FDA-USA fosamprenavir calcium Myocardial infarction and dyslipidemia in HIV infected adults EMDHCPL 456 2009 [Posted 12/03/2009] GlaxoSmithKline and FDA notified healthcare professionals of a potential association between Lexiva and myocardial infarction and dyslipidemia in HIV infected adults. GSK has modified the existing Warnings and Precautions section of the Prescribing Information to note that increases in cholesterol have occurred with treatment, the importance of lipids management, and a recommendation that triglyceride and cholesterol testing be performed prior to initiating therapy with LEXIVA and at periodic intervals during therapy. The Dear Healthcare Professional letter also provides key messages, actions required by healthcare professionals and supporting information from a case-control study reported at a February 2009 international HIV conference. 457 2009 Factive (gemifloxacin) Tablets (PDF - 48KB) FDA-USA gemifloxacin Not specified EM-MG 458 2009 Duetact (glimepiride and pioglitazone) [2009 version] FDA-USA glimepiride and pioglitazone Not specified EM-MG Year 459 2009 Title Avandaryl (glimepiride and rosiglitazone maleate) [2009 version] Simponi (golimumab) Audience: Rheumatological healthcare professionals 460 2009 [Posted 05/27/2009] Centocor Ortho Biotech and FDA reminded healthcare professionals of the risk of serious fungal infections associated with TNF-α blockers, including Simponi [golimumab]. FDA has reported that histoplasmosis and other invasive fungal infections are not consistently recognized in patients taking other TNF-α blockers including Cimzia (certolizumab pegol), Enbrel (etanercept), Humira (adalimumab), and Remicade (infliximab). This has resulted in delays in appropriate antifungal treatment, sometimes even resulting in death. It is important that all adverse events potentially associated with Simponi be reported so that the adverse event profile reported in the prescribing information can be updated appropriately as post-approval experience is gathered. Centocor encourages reporting adverse events to Centocor at 1-800-457-6399 begin_of_the_skype_highlighting 1-800-457-6399 end_of_the_skype_highlighting or to the FDA MedWatch program at 1-800-332-1088 begin_of_the_skype_highlighting 1-800-332-1088 end_of_the_skype_highlighting. 461 2009 Extraneal (icodextrin) [2009 version] 462 2009 Remicade* (infliximab) [2009 version] Lantus (insulin glargine) Audience - Diabetes healthcare professionals, patients Regulatory Authority/Reg ion FDA-USA Product active ingredient Safety Issue (AE) Intervention Type glimepiride and rosiglitazone maleate Not specified EM-MG EM, communi cation plan FDA-USA golimumab Histoplasmosis and other invasive fungal infections are not consistently recognized FDA-USA icodextrin Not specified EM-MG FDA-USA infliximab Not specified EM-MG; communi cation plan FDA-USA insulin glargine Possible risk for cancer in patients with diabetes. EM FDA notified healthcare professionals and patients that it is aware of four recently-published observational studies that looked at the use of Lantus (insulin glargine) and possible risk for cancer in patients with diabetes. Three of the four studies suggest an increased risk for cancer associated with use of Lantus. Based on the currently available data, the FDA recommends that patients should not stop taking their insulin therapy without consulting a physician, since uncontrolled blood sugar levels can have both immediate and long-term serious adverse effects. 463 2009 FDA is currently reviewing many sources of safety data for Lantus, including these newly published observational studies, data from all completed controlled clinical trials, and information about ongoing controlled clinical trials, to better understand the risk, if any, for cancer associated with use of Lantus. Discussions are also ongoing between FDA and the manufacturer of Lantus as to whether any additional studies evaluating the safety and efficacy of this drug will need to be performed. FDA will communicate the results on its ongoing review to the public, as appropriate, as our review continues. Year Title Regulatory Authority/Reg ion Product active ingredient Safety Issue (AE) Intervention Type The FDA encourages both healthcare professionals and patients to report side effects from the use of insulin glargine to the FDA's MedWatch Adverse Event Reporting Program. 464 2009 Infergen (interferon alfacon-1) (PDF - 77KB) FDA-USA interferon alfacon-1 Not specified EM-MG 465 2009 Betaseron*(interferon beta-1b) [2009 version] Dexferrum (iron dextran injection) - Labeling Change Audience: Hematological healthcare professionals, hospital risk managers FDA-USA interferon beta1b Not specified EM-MG FDA-USA iron dextran injection Anaphylactic-type reactions, including fatalities BBWmodified FDA-USA lacosamide Not specified EM-MG 466 2009 [Posted 10/16/2009] American Regent and FDA notified healthcare professionals that anaphylactic-type reactions, including fatalities, have followed the parenteral administration of iron dextran injection. The Boxed Warning has been modified to recommend administering a test dose prior to the first therapeutic dose and observing for signs or symptoms of anaphylactic-type reactions during administration of Dexferrum. Fatal reactions have followed the test dose of iron dextran injection, even in situations where the test dose was tolerated. Patients with a history of drug allergy or multiple drug allergies may be at increased risk of anaphylactic-type reactions. It is recommended that resuscitation equipment and personnel trained in the detection and treatment of anaphylactic-type reactions be readily available during Dexferrum administration. 467 2009 Vimpat (lacosamide) [2009 version] Year Title Regulatory Authority/Reg ion Product active ingredient Safety Issue (AE) Intervention Type 468 2009 Lamictal (lamotrigine) [2009 version] FDA-USA lamotrigine Not specified EM-MG 469 2009 Prevacid NapraPac (lansoprazole and naproxen) [2009 version] FDA-USA lansoprazole and naproxen Not specified EM-MG 470 2009 Revlimid (lenalidomide) [2009 version] Leukotriene Inhibitors: Montelukast (marketed as Singulair), Zafirlukast (marketed as Accolate), and Zileuton (marketed as Zyflo and Zyflo CR) Audience: Pulmonology healthcare professionals FDA-USA lenalidomide Not specified EM-MG FDA-USA Leukotriene Inhibitors: Montelukast (marketed as Singulair), Zafirlukast (marketed as Accolate), and Zileuton (marketed as Zyflo and Zyflo CR) Neuropsychiatric events include postmarket cases of agitation, aggression, anxiousness, dream abnormalities and hallucinations, depression, insomnia, irritability, restlessness, suicidal thinking and behavior (including suicide), and tremor. EM FDA-USA levetiracetam Not specified EM-MG [UPDATED 08/28/2009] The June 12, 2009 Healthcare Professional Sheet has been updated. FDA provided healthcare professionals with updated information on the original March 2008 early communication and January 2009 follow-up communication about the ongoing safety review for the leukotriene inhibitors, montelukast, zafirlukast and zileuton. Neuropsychiatric events have been reported in some patients taking montelukast (Singulair), zafirlukast (Accolate), and zileuton (Zyflo and Zyflo CR). FDA has requested that manufacturers include a precaution in the drug prescribing information (drug labeling). The reported neuropsychiatric events include postmarket cases of agitation, aggression, anxiousness, dream abnormalities and hallucinations, depression, insomnia, irritability, restlessness, suicidal thinking and behavior (including suicide), and tremor. FDA recommends that: 471 2009 Patients and healthcare professionals should be aware of the potential for neuropsychiatric events with these medications. Patients should talk with their healthcare providers if these events occur. Healthcare professionals should consider discontinuing these medications if patients develop neuropsychiatric symptoms. 472 2009 Keppra (levetiracetam) [2009 version] Year 473 2009 Title Levaquin (levofloxacin) Tablets, Injection, and Oral Solution (PDF - 34KB) Local Anesthetics, Continuously Infused (marketed as bupivacaine, chlorprocaine, lidocaine, mepivacaine, procaine, ropivacaine) - Chondrolysis Audience: Orthopedic and Anesthesia healthcare professionals, hospital risk managers Regulatory Authority/Reg ion Product active ingredient Safety Issue (AE) Intervention Type FDA-USA levofloxacin Not specified EM-MG Joint pain, stiffness, and loss of motion were reported as early as the second month after receiving the infusion. EM [Posted 11/13/2009] FDA notified healthcare professionals of 35 reports of chondrolysis (necrosis and destruction of cartilage) in patients given continuous intra-articular infusions of local anesthetics with elastomeric infusion devices to control post-surgical pain. The local anesthetics (with and without epinephrine) were infused for extended periods of time (48 to 72 hours) directly into the intra-articular space using an elastomeric pump. Joint pain, stiffness, and loss of motion were reported as early as the second month after receiving the infusion. In more than half of these reports, the patients required additional surgery, including arthroscopy or arthroplasty (joint replacement). 474 2009 This notice provides further management considerations for healthcare professionals, information for patients, a data summary of the 35 reports, and references. FDA-USA Local Anesthetics, Continuously Infused (marketed as bupivacaine, chlorprocaine, lidocaine, mepivacaine, procaine, ropivacaine) Chondrolysis 475 2009 Kaletra (lopinavir and ritonavir) Tablets and Oral Solution (PDF - 187KB) Updated! FDA-USA lopinavir and ritonavir Not specified EM-MG 476 2009 Lariam (mefloquine HCl) [2009 version] FDA-USA mefloquine HCl Not specified EM-MG Local anesthetics are approved as injections for the production of local or regional anesthesia or analgesia. The approved drug labels for local anesthetics do not include an indication for continuous intra-articular postoperative infusions or use of infusion devices, such as elastomeric pumps. The FDA has not cleared any infusion devices with an indication for use in intra-articular infusion of local anesthetics. Health care professionals are encouraged to follow the instructions for use of elastomeric infusion devices, and to not use these devices for continuous intra-articular infusion of local anesthetics after orthopedic surgery. Year 477 2009 Title Actoplus Met (metformin HCl and pioglitazone HCl) [2009 version] Regulatory Authority/Reg ion Product active ingredient Safety Issue (AE) Intervention Type FDA-USA metformin HCl and pioglitazone HCl Not specified EM-MG Not specified EM-MG 478 2009 Actoplus Met XR (metformin HCl and pioglitazone HCl) [2009 version] FDA-USA metformin HCl and pioglitazone HCl 479 2009 Reglan (metoclopramide HCl) tablets [2009 version] Metoclopramide-Containing Drugs Audience: Healthcare professionals, consumers FDA-USA metoclopramide HCl tablets Not specified EM-MG Risk of its long-term or highdose use. Chronic use of metoclopramide has been linked to tardive dyskinesia, which may include involuntary and repetitive movements of the body, even after the drugs are no longer taken BBW Not specified EM-MG 480 2009 [Posted 02/26/2009] FDA notified healthcare professionals that manufacturers of metoclopramide, a drug used to treat gastrointestinal disorders, must add a boxed warning to their drug labels about the risk of its long-term or high-dose use. Chronic use of metoclopramide has been linked to tardive dyskinesia, which may include involuntary and repetitive movements of the body, even after the drugs are no longer taken. These symptoms are rarely reversible and there is no known treatment. Metoclopramide is available in a variety of formulations including tablets, syrups and injections. Names of metoclopramide-containing products include Reglan Tablets, Reglan Oral Disintegrating Tablets, Metoclopramide Oral Solution, and Reglan Injection. Manufacturers will be required to implement a risk evaluation and mitigation strategy [REMS] to ensure patients are provided with a EM-MG that discusses this risk. Current product labeling warns of the risk of tardive dyskinesia with chronic metoclopramide treatment. 481 2009 Savella (milnacipran HCl) FDA-USA MetoclopramideContaining Drugs FDA-USA milnacipran HCl Year Title Singulair (montelukast) Audience: Pulmonologists, respiratory therapists, other healthcare professionals, patients Regulatory Authority/Reg ion Product active ingredient Safety Issue (AE) Intervention Type [UPDATE 01/13/2009] FDA provided updated information to its March 2008 Early Communication. FDA is continuing to review clinical trial data to assess other neuropsychiatric events, (mood and behavioral adverse events) related to drugs that act through the leukotriene pathway (montelukast, zafirlukast, zileuton). As a result, FDA has not yet reached a definitive conclusion regarding the clinical trial data on mood and behavioral adverse events associated with montelukast, zafirlukast, and zileuton. [Posted 03/27/2008] FDA informed healthcare professionals and patients of the Agency's investigation of the possible association between the use of Singulair and behavior/mood changes, suicidality (suicidal thinking and behavior) and suicide. Singulair is a leukotriene receptor antagonist used to treat asthma and the symptoms of allergic rhinitis, and to prevent exercise-induced asthma. Patients should not stop taking Singulair before talking to their doctor if they have questions about the new information. Healthcare professionals and caregivers should monitor patients taking Singulair for suicidality (suicidal thinking and behavior) and changes in behavior and mood. 482 2009 This early communication is in keeping with FDA’s commitment to inform the public about its ongoing safety reviews of drugs. Due to the complexity of the analyses, FDA anticipates that it may take up to 9 months to complete the ongoing evaluations. As soon as this review is complete, FDA will communicate the conclusions and recommendations to the public. Behavior/mood changes, suicidality (suicidal thinking and behavior) and suicide EM FDA-USA montelukast Not specified EM-MG, communi cation plan 483 2009 Embeda (morphine sulfate and naltrexone HCl) [2009 version] FDA-USA morphine sulfate and naltrexone HCl 484 2009 Avelox (moxifloxacin) Tablets and I.V. Solution (PDF - 20KB) FDA-USA moxifloxacin Not specified EM-MG FDA-USA mycophenolate mofetil Pure Red Cell Aplasia (PRCA) EM Medical Products - CellCept (mycophenolate mofetil) August 2009 Audience: Renal, cardiac, and hepatic transplantation healthcare professionals [Posted 08/14/2009] Roche notified healthcare professionals that cases of Pure Red Cell Aplasia (PRCA) have been reported in patients treated with CellCept. The WARNINGS and ADVERSE REACTIONS sections of the CellCept Prescribing Information have been revised to reflect this new safety information. 485 2009 PRCA is a type of anemia in which there is a selective reduction of red blood cell precursors on bone marrow examination. Patients with PRCA may present with fatigue, lethargy, and/or abnormal paleness of the skin (pallor). In some cases, PRCA was found to be reversible with dose reduction or cessation of CellCept therapy. In transplant patients, however, reduced immunosuppression may place the graft at risk. Year Title CellCept (mycophenolate mofetil) and Myfortic (mycophenolic acid) Audience: Renal, cardiac, and hepatic transplantation healthcare professionals Regulatory Authority/Reg ion Product active ingredient Safety Issue (AE) Intervention Type [UPDATE 03/24/2009] FDA and Novartis notified healthcare professionals of the introduction of a Myfortic EM-MG to provide important safety information in language that patients can easily comprehend. By May 15, 2009, a copy of the Myfortic EM-MG will be enclosed with every Myfortic bottle. Pharmacists are required to distribute a copy of the EMMG with every Myfortic prescription. 486 2009 [Posted 02/12/2009] FDA and Roche Laboratories notified healthcare professionals of the introduction of a CellCept EMMG to provide important safety information in language that patients can easily comprehend. FDA regulations require a pharmacist to distribute a copy of the EM-MG to every patient who fills a CellCept prescription from this point forward. FDA has also required the introduction of a EM-MG for mycophenolic acid, marketed as Myfortic by Novartis. 487 2009 Cellcept (mycophenolate mofetil) [2009 version] FDA-USA mycophenolate mofetil Not specified EM-MG 488 2009 Noroxin (norfloxacin) Tablets (PDF - 22KB) FDA-USA norfloxacin Not specified EM-MG EM-MG, communi cation plan, elements to assure safe use, impleme ntation system EM-MG FDA-USA mycophenolate mofetil General safety EM-MG 489 2009 Zyprexa, Zyprexa Zydis (olanzapine) Tablets (PDF - 41KB) FDA-USA olanzapine Risks of hyperglycemia, hyperlipidemia, and weight gain. 490 2009 Symbyax (olanzapine and fluoxetine) Capsules (PDF - 10KB) FDA-USA olanzapine and fluoxetine Not specified Year Title Omalizumab (marketed as Xolair) - Early Communication about an Ongoing Safety Review Audience: Pediatricians, cardiology, pulmonology healthcare professionals Regulatory Authority/Reg ion Product active ingredient [07/16/2009] FDA is evaluating interim safety findings from an ongoing study of Xolair (omalizumab) titled Evaluating the Clinical Effectiveness and Long-Term Safety in Patients with Moderate to Severe Asthma (EXCELS) that suggests a disproportionate increase in ischemic heart disease, arrhythmias, cardiomyopathy and cardiac failure, pulmonary hypertension, cerebrovascular disorders, and embolic, thrombotic and thrombophlebitic events in patients treated with Xolair compared to the control group of patients not given the drug. Xolair is approved for use by adults and adolescents (12 years of age and above) with moderate to severe persistent asthma who test positive for reactivity to a perennial airborne allergen, and whose symptoms are inadequately controlled with inhaled corticosteroids. 491 2009 FDA is not recommending any changes to the prescribing information for Xolair and is not advising patients to stop taking Xolair at this time. Until the evaluation of the EXCELS study is completed, healthcare providers and patients should be aware of the risks and benefits described in the prescribing information, as well as the new information from the ongoing EXCELS study that may suggest a risk of cardiovascular and cerebrovascular adverse events. 492 2009 Xolair (omalizumab) Injection (PDF - 135KB) 493 2009 Botox/Botox Cosmetic (onabotulinumtoxinA) Injection (PDF - 35KB) Orlistat (marketed as Alli and Xenical): Early Communication about an Ongoing Safety Review Audience: Endocrinological healthcare professionals, patients Safety Issue (AE) Intervention Type FDA-USA omalizumab Increase in ischemic heart disease, arrhythmias, cardiomyopathy and cardiac failure, pulmonary hypertension, cerebrovascular disorders, and embolic, thrombotic and thrombophlebitic events FDA-USA omalizumab Not specified EM-MG FDA-USA onabotulinumtox inA Potential occurrence of spread of toxin effect beyond the injection site. EM-MG, communi cation plan EM FDA notified healthcare professionals and patients that it is reviewing new safety information regarding reports of liverrelated adverse events in patients taking orlistat. Orlistat is marketed in the United States as a prescription product, Xenical, and as an over-the-counter (OTC) product, Alli. Between 1999 and October 2008, 32 reports of serious liver injury, including 6 cases of liver failure, in patients using orlistat were submitted to FDA’s Adverse Event Reporting System. The most commonly reported adverse events described in the 32 reports of serious liver injury were jaundice, weakness, and abdominal pain. FDA is reviewing other data on suspected cases of liver injury submitted by the manufacturers of orlistat, analysis of these data is ongoing and no definite association between liver injury and orlistat has been established at this time. FDA is not advising healthcare professionals to change their prescribing practices with orlistat. Consumers currently taking Xenical should continue to take it as prescribed and those using over-the-counter Alli should continue to use the product as directed. 494 2009 FDA urges both healthcare professionals and consumers to report side effects from the use of orlistat (Alli and Xenical) to FDA's MedWatch Adverse Event Reporting program. FDA-USA orlistat Liver-related adverse events in patients taking orlistat. EM 495 2009 Zenpep (pancrelipase) [2009 version] FDA-USA pancrelipase Not specified EM-MG Year Title Regulatory Authority/Reg ion Product active ingredient Safety Issue (AE) Intervention Type 496 2009 Votrient (pazopanib) Tablets (PDF - 17KB) FDA-USA pazopanib Not specified EM-MG 497 2009 Pegintron* (peginterferon alfa-2b) [2009 version] Peramivir IV Audience: Infectious disease healthcare professionals, hospital risk managers FDA-USA peginterferon alfa-2b Not specified EM-MG FDA-USA peramivir IV Safety not well known, limited use EM FDA-USA pioglitazone hydrchloride Not specified EM-MG [UPDATED 10/30/2009] Questions and Answers web page posted. [Posted 10/24/2009] FDA notified healthcare professionals that, in response to a request from the U.S. Centers for Disease Control and Prevention, it has issued an emergency use authorization (EUA) for the investigational antiviral drug peramivir intravenous in certain adult and pediatric patients with confirmed or suspected 2009 H1N1 influenza infection who are admitted to a hospital. IV peramivir is authorized only for hospitalized adult and pediatric patients for whom therapy with an IV drug is clinically appropriate, based on one or more of the following: 1] the patient is not responding to either oral or inhaled antiviral therapy, 2] when drug delivery by a route other than an intravenous route is not expected to be dependable or feasible, or 3] for adults only, when the clinician judges IV therapy is appropriate due to other circumstances. 498 2009 Given there are limited safety data on peramivir, mandatory reporting requirements are important to defining the safety profile of this unapproved drug. As part of the conditions of the EUA, health care providers (or designee) must report adverse events and all medication errors associated with peramivir to FDA’s MedWatch program within 7 calendar days from the onset of the adverse event. Additionally, healthcare providers (or designee) must conduct follow-up requested by FDA or CDC related to peramivir adverse event or medication error reports submitted to FDA. 499 2009 Actos (pioglitazone hydrchloride) [2009 version] 500 2009 Effient (prasugrel) [2009 version] FDA-USA prasugrel Not specified EM-MG, communi cation plan 501 2009 Lyrica (pregabalin) [2009 version] Promethazine HCl Injection Audience: All healthcare professionals FDA-USA pregabalin Not specified EM-MG FDA-USA promethazine HCl Risks of severe tissue injury, including gangrene, requiring amputation BBW [Posted 09/16/2009] FDA notified healthcare professionals that a Boxed Warning is being added to the prescribing information for Promethazine HCl products, describing the risks of severe tissue injury, including gangrene, requiring amputation following intravenous administration of promethazine. The Boxed Warning will remind practitioners that due to the risks of intravenous injection, the preferred route of administration is deep intramuscular injection and that subcutaneous injection is contraindicated. 502 2009 Year 503 2009 Title Perivascular extravasation, unintentional intra-arterial injection and intraneuronal or perineuronal infiltration of the drug may result in irritation and tissue damage. Healthcare professionals should be alert for signs and symptoms of potential tissue injury including burning or pain at the site of injection, phlebitis, swelling, and blistering. Darvon (propoxyphene HCl) [2009 version] Propoxyphene-containing Products Audience: Pharmacists, pain management healthcare professionals Regulatory Authority/Reg ion Product active ingredient Safety Issue (AE) Intervention Type FDA-USA propoxyphene HCl Not specified EM-MG FDA-USA Propoxyphenecontaining Products Risk of overdose EM FDA-USA propylthiouracil Severe liver injury and acute liver failure, BBW FDA notified healthcare professionals that it is taking several actions to reduce the risk of overdose in patients using pain medications that contain propoxyphene because of data linking propoxyphene and fatal overdoses. The agency will require manufacturers of propoxyphene-containing products to strengthen the label, including the boxed warning, emphasizing the potential for overdose when using these products and to provide a EM-MG to patients stressing the importance of using the drugs as directed. 504 2009 FDA is requiring a new safety study assessing unanswered questions about the effects of propoxyphene on the heart at higher than recommended doses. Findings from this study, as well as other data, could lead to additional regulatory action. To further evaluate the safety of propoxyphene, FDA plans to work with several groups including the Centers for Medicare & Medicaid Services and the Veterans Health Administration to study how often the elderly are prescribed propoxyphene instead of other pain relievers and the difference in the safety profiles of propoxyphene compared to other drugs. Propylthiouracil Audience: Endocrine healthcare professionals, Pharmacists, Pediatricians [Updated 04/21/2010] FDA has added a Boxed Warning to the label for propylthiouracil, to include information about reports of severe liver injury and acute liver failure, some of which have been fatal, in adult and pediatric patients using this medication. 505 2009 [Posted 06/04/2009] FDA notified healthcare professionals of the risk of serious liver injury, including liver failure and death, with the use of propylthiouracil in adult and pediatric patients. Reports to FDA’s Adverse Event Reporting System (AERS) suggest there is an increased risk of hepatotoxicity with proplythiouracil when compared to methimazole. FDA has identified 32 (AERS) cases (22 adult and 10 pediatric) of serious liver injury associated with propylthiouracil use. Although both proplythiouracil and methimazole are indicated for the treatment of hyperthyroidism due to Graves’ disease, healthcare professionals should carefully consider which drug to initiate in a patient recently diagnosed with Graves’ disease. Physicians should closely monitor patients on propylthiouracil therapy for symptoms and signs of liver injury, especially during the first six months after initiation of therapy. Propylthiouracil should not be used in pediatric patients unless the patient is allergic to or intolerant of methimazole, and there are no other treatment options available. Year Title Regulatory Authority/Reg ion Product active ingredient Safety Issue (AE) Intervention Type 506 2009 Seroquel (quetiapine fumarate) [2009 version] FDA-USA quetiapine fumarate Not specified EM-MG 507 2009 Qualaquin (quinine sulfate) [2009 version] FDA-USA quinine sulfate Not specified EM-MG 508 2009 Rebetol (ribavirin) [2009 version] FDA-USA ribavirin Not specified EM-MG 509 2009 Myobloc* (rimabotulinumtoxinB) [2009 version] Rituxan (rituximab) - PML Audience: Rheumatological healthcare professionals FDA-USA rimabotulinumto xinB Not specified EM-MG, communi cation plan FDA-USA rituximab Progressive multifocal leukoencephalopathy (PML) EM [Posted 10/23/2009] Genentech and FDA notified healthcare professionals about a third case of progressive multifocal leukoencephalopathy [PML], the first case of PML in a patient with rheumatoid arthritis [RA] treated with Rituxan who has not previously received treatment with a TNF antagonist. Information to date suggests that patients with RA who receive Rituxan have an increased risk of PML. 510 2009 Physicians should consider PML in any patient being treated with Rituxan who presents with new onset neurologic manifestations. Consultation with a neurologist, brain MRI, and lumbar puncture should be considered as clinically indicated. Year 511 512 513 2009 2009 2009 Title Rituxan* (rituximab) [2009 version] Meridia (sibutramine HCl): Early Communication about an Ongoing Safety Review Audience: Cardiology and endocrinology healthcare professionals [11/20/2009] FDA notified healthcare professionals and patients that it is reviewing preliminary data from a recent study suggesting that patients using sibutramine have a higher number of cardiovascular events (heart attack, stroke, resuscitated cardiac arrest, or death) than patients using a placebo (sugar pill). Sibutramine is marketed as Meridia, a prescription drug, in the United States. Meridia was approved by FDA in 1997 for the management of obesity, including weight loss and maintenance of weight loss, in conjunction with a reduced calorie diet. Meridia is only recommended for obese patients with an initial body mass index (BMI) ≥ 30 kg/m2, or BMI ≥ 27 kg/m2 with other risk factors (e.g., diabetes, high cholesterol, controlled high blood pressure).The analysis of these data is ongoing and FDA is making no conclusions about the preliminary findings at this time. These findings highlight the importance of avoiding the use of sibutramine in patients with a history of coronary artery disease (heart disease), congestive heart failure (CHF), arrhythmias, or stroke, as recommended in the current sibutramine labeling. Sirolimus (marketed as Rapamune) Audience: Transplantation healthcare professionals FDA notified healthcare professionals of clinical trial data that suggest increased mortality in stable liver transplant patients after conversion from a calcineurin inhibitor (CNI)-based immunosuppressive regimen to sirolimus (Rapamune). The trial was conducted by sirolimus manufacturer, Wyeth. The Agency will continue to examine the data on mortality and other adverse events in this study, and will make further recommendations, as appropriate. The FDA is determining whether a labeling change for sirolimus is needed. In the interim, physicians should continue to use the drug’s professional labeling as a guide to therapy. See the FDA Healthcare Professional Information sheet for current FDA recommendations. Regulatory Authority/Reg ion FDA-USA Not specified EM-MG FDA-USA sibutramine HCl Higher number of cardiovascular events (heart attack, stroke, resuscitated cardiac arrest, or death) than patients using a placebo EM FDA-USA sirolimus sirolimus (marketed as Rapamune), Cyclosporine (marketed as Sandimmune and generics), Cyclosporine modified (marketed as Neoral and generics), Mycophenolate mofetil (marketed as Cellcept and generics), Mycophenolic acid (marketed as Myfortic) Increased mortality EM Immunosuppressed patients are at increased risk for opportunistic infections, such as activation of latent viral infections, including BK virus-associated nephropathy EM Audience: Transplant and nephrology healthcare professionals [Posted 07/14/2009] The FDA is requiring the makers of certain immunosuppressant drugs to update their labeling to reflect that immunosuppressed patients are at increased risk for opportunistic infections, such as activation of latent viral infections, including BK virus-associated nephropathy. These immunosuppressant drugs are used to protect against the rejection of certain organ transplants. The association of BK virus-associated nephropathy has previously been reported for another immunosuppressant drug, tacrolimus (marketed as Prograf). Monitoring for this serious risk and early intervention by the health care provider is critical. Adjustments in immunosuppression therapy should be considered for patients who develop BK virus-associated nephropathy. 514 2009 Safety Issue (AE) Intervention Type rituximab Immunosuppressant Drugs: Required Labeling Changes Sirolimus (marketed as Rapamune), Cyclosporine (marketed as Sandimmune and generics), Cyclosporine modified (marketed as Neoral and generics), Mycophenolate mofetil (marketed as Cellcept and generics), Mycophenolic acid (marketed as Myfortic) FDA is continuing to review the safety of immunosuppressant drug products used in renal transplantation. The FDA urges both healthcare professionals and patients to report side effects from the use of immunosuppressant drug products to the FDA's MedWatch Adverse Event Reporting program. Product active ingredient FDA-USA Year 515 516 2009 2009 Title Sitagliptin (marketed as Januvia and Janumet) - acute pancreatitis Audience: Diabetes healthcare professionals, patients [Posted 09/25/2009] FDA notified healthcare professionals and patients of revisions to the prescribing information for Januvia (sitagliptin) and Janumet (sitagliptin/metformin) to include information on reported cases of acute pancreatitis in patients using these products. Eighty-eight post-marketing cases of acute pancreatitis, including two cases of hemorrhagic or necrotizing pancreatitis in patients using sitagliptin, were reported to the Agency between October 2006 and February 2009. It is recommended that healthcare professionals monitor patients carefully for the development of pancreatitis after initiation or dose increases of sitagliptin or sitagliptin/metformin. Sitagliptin has not been studied in patients with a history of pancreatitis. Therefore, it is not known whether these patients are at an increased risk for developing pancreatitis and the medication should be used with caution and with appropriate monitoring in patients with a history of pancreatitis. Considerations for healthcare professionals, information for patients, and a Data Summary are provided. Osmoprep (sodium phosphate dibasic anhydrous and sodium phosphate monobasic monohydrate) [2009 version] Stimulant Medications used in Children with Attention-Deficit/Hyperactivity Disorder - Communication about an Ongoing Safety Review Products involved include: Focalin, Focalin XR (dexmethylphenidate HCl ); Dexedrine, Dexedrine Spansules, Dextroamphetamine ER, Dextrostat (dextroamphetamine sulfate); Vyvanse (lisdexamfetamine dimesylate); Desoxyn (methamphetamine); Concerta, Daytrana, Metadate CD, Metadate ER, Methylin, Methylin ER, Ritalin, Ritalin-LA, Ritalin-SR (methylphenidate); Adderall, Adderall XR (mixed salts amphetamine); Cylert (pemoline) and generics. Regulatory Authority/Reg ion Product active ingredient FDA-USA sitagliptin Safety Issue (AE) Intervention Type Acute pancreatitis EM FDA-USA sodium phosphate dibasic anhydrous and sodium phosphate monobasic monohydrate Not specified EM-MG, communi cation plan FDA-USA Stimulant Medications used in Children with AttentionDeficit/Hyperacti vity Disorder Sudden death in healthy children EM Audience: Pediatricians, Neuropsychiatric healthcare professionals [Posted 06/15/2009] FDA notified healthcare professionals that it is providing its perspective on study data published in the American Journal of Psychiatry on the potential risks of stimulant medications used to treat AttentionDeficit/Hyperactivity Disorder (ADHD) in children. This study, funded by the FDA and the National Institute of Mental Health (NIMH), compared the use of stimulant medications in 564 healthy children from across the United States who died suddenly to the use of stimulant medications in 564 children who died as passengers in a motor vehicle accident.The study authors concluded that there may be an association between the use of stimulant medications and sudden death in healthy children. Given the limitations of this study’s methodology, the FDA is unable to conclude that these data affect the overall risk and benefit profile of stimulant medications used to treat ADHD in children. FDA believes that this study should not serve as a basis for parents to stop a child’s stimulant medication. Parents should discuss concerns about the use of these medicines with the prescribing healthcare professional. Any child who develops cardiovascular symptoms (such as chest pain, shortness of breath or fainting) during stimulant medication treatment should immediately be seen by a doctor. 517 2009 FDA is continuing its review of the strengths and limitations of this and other epidemiological studies that evaluate the risks of stimulant medications used to treat ADHD in children. FDA and the Agency for Healthcare Research and Quality are sponsoring a large epidemiological study that will provide further information about the potential risks associated with stimulant medication use in children. The data collection for this study will be complete later in 2009. Year 518 2009 Title Nucynta (tapentadol HCl) [2009 version] Regulatory Authority/Reg ion FDA-USA Product active ingredient tapentadol HCl Safety Issue (AE) Intervention Type Not specified EM-MG 519 2009 Vibativ (telavancin) [2009 version] FDA-USA telavancin Not specified EM-MG, communi cation plan 520 2009 Tyzeka (telbivudine) Oral Solution (PDF - 119KB) FDA-USA telbivudine Not specified EM-MG teriparatide Not specified EM-MG, communi cation plan testosterone Secondary exposure to testosterone in children ranging in age from nine months to five years inappropriate enlargement of the genitalia (penis or clitoris), premature development of pubic hair, advanced bone age, increased libido and aggressive behavior EM 521 2009 Forteo (teriparatide) [2009 version] Testosterone gel products (AndroGel 1% and Testim 1% ) Audience: Urological and Endocrinological healthcare professionals, pediatricians FDA-USA [Posted 05/07/2009] FDA notified healthcare professionals that it will require two prescription topical testosterone gel products, AndroGel 1% and Testim 1%, to include a boxed warning on the products’ labels after receiving reports of adverse effects in children who were inadvertently exposed to testosterone through contact with another person being treated with these products. Despite the currently labeled precautions, FDA has received reports of eight cases of secondary exposure to testosterone in children ranging in age from nine months to five years. Since that time, additional reports of secondary exposure have been received by the agency and are presently under review. Of the fully reviewed cases, adverse events reported in these children included inappropriate enlargement of the genitalia (penis or clitoris), premature development of pubic hair, advanced bone age, increased libido and aggressive behavior. The gels are approved for use in men who either no longer produce testosterone or produce it in very low amounts. Both products are applied once daily, to the shoulders or upper arms. FDA has provided recommendations and precautions to minimize the potential for secondary exposure 522 2009 FDA-USA Year Title Regulatory Authority/Reg ion Product active ingredient Safety Issue (AE) Intervention Type 523 2009 Androgel (testosterone) [2009 version] FDA-USA testosterone Not specified EM-MG 524 2009 Thalomid (thalidomide) [2009 version] FDA-USA thalidomide Not specified EM-MG 525 2009 Actemra * (tocilizumab) [2009 version] FDA-USA tocilizumab Not specified EM-MG tolvaptan Risk of osmotic demyelination syndrome (ODS) by EM-MG, communi cation plan Topical Anesthetics Serious, life-threatening adverse effects, such as irregular heartbeat, seizures, breathing difficulties, coma and even death, when applied to a large area of skin or when the area of application is covered EM 526 527 2009 2009 Samsca (tolvaptan) Tablets (PDF - 305KB) Topical Anesthetics Audience: Consumers, radiological healthcare professionals, emergency room healthcare professionals, risk managers [Posted 01/16/2009] FDA issued a public health advisory to remind patients, healthcare professionals, and caregivers about potentially serious hazards of using skin numbing products, also known as topical anesthetics, for relieving pain from mammography and other medical tests and conditions. FDA is concerned about the potential for these products to cause serious, life-threatening adverse effects, such as irregular heartbeat, seizures, breathing difficulties, coma and even death, when applied to a large area of skin or when the area of application is covered. FDA is working with healthcare professional organizations and other media that distribute healthcare information to spread the message about the potential hazards and safe use of topical anesthetics. The Advisory and the Dear Colleague letter provide recommendations to both doctors and patients on safe use of these products FDA-USA FDA-USA Year 528 2009 Title Topamax (topiramate) [2009 version] Tumor Necrosis Factor (TNF) Blockers (marketed as Remicade, Enbrel, Humira, Cimzia, and Simponi) August 2009 Audience: Rheumatologists, gastroenterologists, oncologists, dermatologists Regulatory Authority/Reg ion Product active ingredient Safety Issue (AE) Intervention Type FDA-USA topiramate Not specified EM-MG FDA-USA Tumor Necrosis Factor (TNF) Blockers (marketed as Remicade, Enbrel, Humira, and Cimzia) Increased risk of lymphoma and other cancers EM [UPDATED 08/31/2009] Supplemental Q&As added [Posted 08/04/2009] FDA notified healthcare professionals that it has completed its analysis of tumor necrosis factor (TNF) blockers and has concluded that there is an increased risk of lymphoma and other cancers associated with the use of these drugs in children and adolescents. This new safety information is now being added to the Boxed Warning for these products. FDA has also identified new safety information related to the occurrence of leukemia and new-onset psoriasis in patients treated with TNF blockers. The current prescribing information for TNF blockers does contain a warning for malignancies, but does not specifically mention leukemia. FDA is also requiring updates to the current EM-MG to help patients understand the risks associated with TNF blocker therapy. 529 530 2009 2009 TNF blockers are approved for the treatment of one or more of a number of immune system diseases including juvenile idiopathic arthritis (JIA), rheumatoid arthritis, psoriatic arthritis, plaque psoriasis, Crohn’s disease, and ankylosing spondylitis. Stelara* (ustekinumab) [2009 version] Valproate Sodium and related products (valproic acid and divalproex sodium): Risk of Birth Defects Audience: Neuropsychiatric and Obstetrical healthcare professionals FDA-USA ustekinumab Not specified EM-MG, communi cation plan FDA-USA valproic acid and divalproex sodium Risk of Birth Defects EM [Posted 12/03/2009] The FDA notified health care professionals and patients about the increased risk of neural tube defects and other major birth defects, such as craniofacial defects and cardiovascular malformations, in babies exposed to valproate sodium and related products (valproic acid and divalproex sodium) during pregnancy. Healthcare practitioners should inform women of childbearing potential about these risks, and consider alternative therapies, especially if using valproate to treat migraines or other conditions not usually considered life-threatening. Women of childbearing potential should only use valproate if it is essential to manage their medical condition. Those who are not actively planning a pregnancy should use effective contraception, as birth defect risks are particularly high during the first trimester, before many women know they are pregnant. A valproate EM-MG, provided with each outpatient prescription, will explain the benefits and risks of valproate and encourage patients to discuss options with their healthcare professional. 531 2009 Pregnant women using valproate or other AEDs should be encouraged to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry (1-888-233-2334 begin_of_the_skype_highlighting 1-888-233-2334 end_of_the_skype_highlighting; www.aedpregnancyregistry.org). Year 532 2009 Title Chantix (varenicline) Tablets (PDF - 85KB) Varenicline (marketed as Chantix) and Bupropion (marketed as Zyban, Wellbutrin, and generics) Audience: Neuropsychiatric healthcare professionals, patients Regulatory Authority/Reg ion Product active ingredient Safety Issue (AE) Intervention Type FDA-USA varenicline Not specified EM-MG FDA-USA varenicline, bupropion Risk of serious neuropsychiatric symptoms FDA-USA vigabatrin Not specified BBW EM-MG, communi cation plan, elements to assure safe use, impleme ntation system FDA-USA Zicam Cold Remedy Nasal Products (Cold Remedy Nasal Gel, Cold Remedy Nasal Swabs, and Cold Remedy Swabs, Kids Size) Loss of sense of smell EM FDA notified healthcare professionals and patients that it has required the manufacturers of the smoking cessation aids varenicline (Chantix) and bupropion (Zyban and generics) to add new Boxed Warnings and develop patient EM-MGs highlighting the risk of serious neuropsychiatric symptoms in patients using these products. These symptoms include changes in behavior, hostility, agitation, depressed mood, suicidal thoughts and behavior, and attempted suicide. The added warnings are based on the continued review of postmarketing adverse event reports for varenicline and bupropion received by the FDA. These reports included those with a temporal relationship between the use of varenicline or bupropion and suicidal events and the occurrence of suicidal ideation and suicidal behavior in patients with no history of psychiatric disease. 533 2009 534 2009 535 2009 Healthcare professionals should advise patients to stop taking varenicline or bupropion and contact a healthcare provider immediately if they experience agitation, depressed mood, and any changes in behavior that are not typical of nicotine withdrawal, or if they experience suicidal thoughts or behavior. Sabril (vigabatrin) [2009 version] Zicam Cold Remedy Nasal Products (Cold Remedy Nasal Gel, Cold Remedy Nasal Swabs, and Cold Remedy Swabs, Kids Size) Audience: Consumers [Posted 06/16/2009] FDA notified consumers and healthcare professionals to discontinue use of three Zicam Nasal Gel/Nasal Swab products sold over-the-counter as cold remedies because they are associated with the loss of sense of smell that may be long-lasting or permanent. The FDA has received more than 130 reports of loss of sense of smell associated with the use of the three Zicam products. In these reports, many people who experienced a loss of smell said the condition occurred with the first dose; others reported a loss of the sense of smell after multiple uses of the products. People who have experienced a loss of sense of smell or other problems after use of the affected Zicam products should contact their health care professional. The loss of sense of smell can adversely affect a person’s quality of life, and can limit the ability to detect the smell of gas or smoke or other signs of danger in the environment Year 536 2009 Title Edluar (zolpidem tartrate) [2009 version] Zonisamide (marketed as Zonegran, and generics) Audience: Neurological healthcare professionals 537 2009 [Posted 02/23/2009] FDA notified healthcare professionals that updated clinical data has determined that treatment with zonisamide, indicated as adjunctive therapy in the treatment of partial seizures in adults with epilepsy, can cause metabolic acidosis in some patients. Patients with predisposing conditions or therapies may be at greater risk for developing metabolic acidosis and the risk of zonisamide-induced metabolic acidosis appears to be more frequent and severe in younger patients. FDA recommends that healthcare professionals measure serum bicarbonate before starting treatment and periodically during treatment with zonisamide, even in the absence of symptoms and is working with the makers of zonisamide to revise the product labeling to reflect this new safety information. The notification includes recommendations for healthcare providers, information for patients, and a data summary. 538 2009 Zonegran (zonisamide) Capsules (PDF - 28KB) 539 540 2000 2000 Warning - Prepulsid® (cisapride) - Health Products and Food Branch Indinavir and other antiretroviral agents, Interaction with St John's Wart Regulatory Authority/Reg ion Product active ingredient Safety Issue (AE) Intervention Type FDA-USA zolpidem tartrate Not specified EM-MG FDA-USA zonisamide Metabolic acidosis EM FDA-USA zonisamide Not specified EM-MG HC-CAN cisapride Serious cardiac arrhythmias (e.g. ventricular tachycardia, torsades de pointes, and ventricular fibrillation) and sudden cardiac deaths. EMDHCPL HC-CAN Indinavir and other antiretroviral agents with St John's Wart Drug interaction - decreased the blood levels of some concomitantly administered drugs EM Year 541 2000 Title Important Drug Warning - VIRAMUNE - Boehringer Ingelheim (Canada) Ltd. Regulatory Authority/Reg ion Product active ingredient Safety Issue (AE) Intervention Type HC-CAN nevirapine Severe, life-threatening and in some cases, fatal hepatotoxicity Thrombotic events or excessive bleeding EM EM 542 2000 Important Drug Warning on Plas+SD - Vitex Inc. HC-CAN Pooled Plasma, (Human) Solvent Detergent Treated (plas + SD) 543 2000 Important Drug Warning on Serentil - Novartis - Health Products and Food Branch HC-CAN mesoridazine besylate Thrombotic events or excessive bleeding EMDHCPL HC-CAN phenylpropanola mine Increased risk of stroke in younger women EM EMDHCPL thioridazone HCl Prolonged QTc interval in a dose related manner & torsade de pointes-type arrhythmias and sudden death EMDHCPL 544 545 2000 2000 Health Canada issues health advisory regarding phenylpropanolamine (PPA) Important Drug Warning on Mellaril HC-CAN Year 546 547 548 2001 2001 2001 Title Important Safety Information on Amiodarone Intravenous -Sabex Inc. Health Canada advises consumers about additional products that contain Aristolochic Acid Safety Information for Patients Taking ZYBAN®(bupropion) -Glaxo Smithkline Regulatory Authority/Reg ion HC-CAN HC-CAN HC-CAN Safety Issue (AE) Amiodarone HCl Amiodarone HCl for Injection has been found to leach out plasticizers, such as DEHP [di-(2-ethylhexyl) phthalate] from intravenous tubing (including PVC tubing). "gasping syndrome" in neonates, which may be fatal, following the administration of intravenous solutions containing the preservative benzyl alcohol. EMDHCPL aristolochic acid Discontinue use due to permanent kidney damage, sometimes resulting in kidney failure that has required kidney dialysis or kidney transplantation EM bupropion The most common side effects are dry mouth and difficulty sleeping. These effects are usually mild and temporary. Other side effects that have commonly been reported include nausea, constipation, headache, shakiness and altered taste EM bupropion serum sickness/serum sickness-like reactions. Some with fatal outcome EMDHCPL Important Drug Warning - ZYBAN® - GlaxoSmithKline 549 2001 HC-CAN Intervention Type Product active ingredient Year Title Regulatory Authority/Reg ion Product active ingredient 2001 551 2001 552 2001 553 2001 Health Canada - Advisory not to use products containing Ephedra or Ephedrine HC-CAN cervastatin HC-CAN ephedra/ ephedrine containing products Cardiovascular symptomsHypertension, palpitations, tachycardia, or both; stroke; and nervous system problems - seizures. EM HC-CAN epoetin Alfa Pure red blood cell aplasia (PRCA) EMDHCPL HC-CAN glitazones Liver toxicity EM Important Safety Information - EPREXTM (Epoetin Alfa) - Janssen-Ortho Inc. Health Canada Advisory - Important Safety Reminder for Patients taking Oral Diabetes Drugs of the Glitazone Class, AVANDIA® and ACTOS® Withdra wal / DHCPL Increased reporting rate of rhabdomyolysis with Baycol relative to other statins, especially when gemfibrozil is co-prescribed. Market withdrawal of Baycol (cerivastatin) - Bayer Inc. 550 Safety Issue (AE) Intervention Type Year Title Regulatory Authority/Reg ion Product active ingredient hydroxyurea Potentially fatal hepatotoxicity and pancreatitis in patients treated for HIV infection with HYDREA (hydroxyurea) in combination with didanosine and/or stavudine, with or without other antiretroviral agents. EMDHCPL imatinib Only to be administered under the supervision of a physician experienced with the use of chemotherapy and with treatment of CML. EMDHCPL irinotecan HCl EDMC recommended temporary suspension of enrollment because the absolute number of deaths was higher, although the control arm mortality rate was not statistically significantly different from the other two arms of the study. EMDHCPL Depression and/or suicidal ideation in young people. TDM/ EP/ IC/ EMDHCPL Important Drug Warning : Hydrea (hydroxyurea) in Combination with Didanosine and/or Stavudine - Bristol-Myers Squibb Canada Inc. 554 555 556 557 HC-CAN 2001 2001 2001 2001 Conditional Approval of Gleevec (IMATINIB) - Novartis Pharma Canada Inc. Important Information-Camptosar - Pharmacia Important Safety Information on ACCUTANE - Hoffman La Roche Limited, Canada HC-CAN HC-CAN HC-CAN Safety Issue (AE) Intervention Type isotretinoin Year 558 559 2001 2001 Title Important New Safety Information SPORANOX (itraconazole) - Janssen-Ortho Inc. Important Safety Information Severe and Serious Hepatic Reactions ARAVA - Aventis Pharma Inc. Regulatory Authority/Reg ion HC-CAN HC-CAN Safety Issue (AE) Intervention Type itraconazole Rare cases of congestive heart failure (CHF) and pulmonary edema EMDHCPL leflunomide 296 cases of hepatic reactions among patients exposed to leflunomide for an estimated 104,000 patient years (77,200 US, 17,200 European Union, 300 Canada, 9,600 rest of world). By Regulatory definition, 129 of these events were considered as serious and included 2 cases of liver cirrhosis and 15 cases of liver failure, 9 with fatal outcome. EMDHCPL EMDHCPL EM Product active ingredient 560 2001 Important Safety Information Regarding Carnitor® - Sigma-tau Pharmaceuticals, Inc. HC-CAN levocarnitine Recent addition to the Precautions : "Administration of high doses of the oral formulations of levocarnitine for long periods of time is not recommended in patients with severely compromised renal function or in ESRD patients on dialysis" 561 2001 Health Canada advising of possible interaction between warfarin and vaginal miconazole HC-CAN miconazole and warfarin Drug interaction- prolonged prothrombin time Year 562 563 564 2001 2001 2001 Title Important Safety Information on Nefazodone HCI: Severe and Serious Hepatic Events - Apotex Inc. VIRAMUNE PEP - Health Products and Food Branch Notice to hospitals Important Drug Safety Information - ACTOS (Pioglitazone HCl) - Eli Lilly Regulatory Authority/Reg ion HC-CAN HC-CAN HC-CAN Product active ingredient Safety Issue (AE) Intervention Type nefazodone Severe liver injury temporally associated with nefazodone EM EMDHCPL nevirapine HIV-uninfected individuals receiving multiple doses of VIRAMUNE in the setting of post-exposure prophylaxis (PEP) and serious liver and skin toxicity. EMDHCPL pioglitazone HCl In clinical trials, an increased incidence of cardiac failure and other cardiovascular adverse events was seen in patients receiving the thiazolidinedione and insulin compared to insulin alone. It is recommended that patients be treated for an adequate period of time to evaluate change in HbA1c unless glycemic control deteriorates. Actos is not indicated for combination therapy with other antidiabetic agents. Actos is not currently indicated for use in combination with insulin. EMDHCPL Year 565 2001 Title Health Canada withdraws drug products containing phenylpropanolamine (PPA) from the market Regulatory Authority/Reg ion HC-CAN Product active ingredient Safety Issue (AE) Intervention Type phenylpropanola mine Increased risk of stroke in younger women Withdra wal/EM EMDHCPL 566 2001 Important Safety Information - Propofol - Health Products and Food Branch HC-CAN propofol Long- term propofol infusions, metabolic acidosis, rhabdomyolysis and cardiac failure 567 2001 Important Safety Concerns re Use of Propofol for Sedation in Pediatric Patients - Health Products and Food Branch Notice to Hospitals HC-CAN propofol Not approved for use in pediatric ICU EMDHCPL remicade Moderate to severe (NYHA class III-IV) congestive heart failure (CHF), higher incidences of mortality and hospitalization for worsening heart failure. EMDHCPL 568 2001 Important Drug Warning On RemicadeTM - Schering Canada Inc. HC-CAN Year 569 570 571 572 2001 2001 2001 2001 Title Important Drug Warning - RITUXAN - Hoffmann-La Roche Ltd. Important Warnings from the Manufacturer Novartis on Drug Product Exelon - Novartis Important Safety Information Regarding AVANDIA® (Rosiglitazone Maleate) - GlaxoSmithKline Inc. Important Drug Warning - VIDEX-ZERIT - Bristol-Myers Squibb Regulatory Authority/Reg ion HC-CAN HC-CAN HC-CAN HC-CAN Safety Issue (AE) Intervention Type rituximab Severe mucocutaneious reactions EMDHCPL rivastigmine Proposed changes to the monograph provide guidelines for reinitiating therapy in patients who have interrupted treatment with EXELON to reduce the risk of severe vomiting and its potential serious sequelae. EMDHCPL rosiglitazone maleate Can cause fluid retention, which can exacerbate or lead to congestive heart failure &Patients at risk for heart failure (particularly those on insulin) should be monitored for signs and symptoms of heart failure. EMDHCPL stavudine and didanosine Fatal lactic acidosis has recently been reported in three pregnant women treated throughout gestation. two with and one without pancreatitis. EMDHCPL Product active ingredient Year 573 2001 Title Important Drug Warning - Lamisil - (terbinafine HCL) - Novartis Regulatory Authority/Reg ion Product active ingredient Safety Issue (AE) HC-CAN terbinafine HCl Product Monograph being revised to provide more detailed information regarding the use of Lamisil tablets in patients with liver disease.1.Rare cases of hepatic failure, some leading to death or liver transplant, have occurred with the use of LAMISIL (terbinafine HCl) Tablets for the treatment of onychomycosis and dermatomycosis in individuals with and without pre-existing liver disease. 2.Caution should be exercised in patients receiving concomitant therapy with drugs metabolized by CYP 2D6, especially those with a narrow therapeutic window. HC-CAN topiramate Ocular syndrome Association of TOPAMAX* (Topiramate) with Acute Myopia and Secondary Angle Closure Glaucoma - Janssen-Ortho Inc. 574 2001 Intervention Type EMDHCPL EMDHCPL Year 575 576 577 2002 2002 2002 Title Important Safety Information: Use of Kineret (anakinra) in Combination with Etanercept - Amgen Canada Inc. Important Safety Information Regarding Lioresal* Intrathecal (Baclofen) - Health Products and Food Branch Important Drug Safety Information on Celebrex - Pharmacia Canada Inc. and Pfizer Canada Inc Regulatory Authority/Reg ion HC-CAN HC-CAN HC-CAN Product active ingredient Safety Issue (AE) Intervention Type anakinra Patients receiving concurrent Kineret® and etanercept resulted in a higher incidence of serious infections than in patients receiving etanercept alone. # no therapeutic benefit of the combination treatment over etanercept alone EM EMDHCPL baclofen Rare cases of intrathecal baclofen withdrawal that can lead to life threatening sequelae and/or death in patients who abruptly discontinue therapy. EMDHCPL celecoxib Incidence of complicated ulcers (gastrointestinal bleeding, perforation or obstruction). Additional protocol specified endpoints included the incidence of symptomatic ulcers (gastroduodenal ulcers identified based on upper gastrointestinal symptoms such as abdominal pain, dyspepsia, nausea, diarrhea or vomiting) and clinically relevant decreases in hemoglobin (>2 g/dl) and/or hematocrit (>10 points).No statistically significant differences were demonstrated for the incidence of complicated ulcers at the doses studied among the three treatment groups in all patients. EMDHCPL Year 578 2002 Title Health Canada Advisory - Important safety information for patients taking CELEBREX® (celecoxib) Regulatory Authority/Reg ion HC-CAN Product active ingredient Safety Issue (AE) Intervention Type celecoxib Additional contraindications due to cardiovascular and renal effects: •Active peptic ulcer, active GI bleeding, or active inflammatory disease of the bowel •Significant hepatic impairment or active liver disease •Severe renal impairment (creatinine clearance < 0.5 mL/sec: 30 mL/min) or deteriorating renal disease (individuals with less degrees of renal impairment are at risk of deterioration of their renal function when prescribed NSAIDs and must be monitored). EM EM EMDHCPL 579 2002 Association of CLOZARIL (clozapine) with Cardiovascular Toxicity - Novartis HC-CAN clozapine Cardiovascular toxicity :myocarditis, Pericarditis, pericardial effusion and cardiomyopathy have also been reported 580 2002 Important Safety Concerns on the use of Diane-35 HC-CAN cyproterone acetate Risk of venous thromboembolism EM 581 2002 Cardiovascular Toxicity with Injectable Droperidol - Health Products and Food Branch HC-CAN droperidol Cardiovascular toxicity EMDHCPL Year 582 2002 Title Health Canada requests recall of certain products containing Ephedra/ephedrine Regulatory Authority/Reg ion HC-CAN Product active ingredient Safety Issue (AE) Intervention Type ephedra/ ephedrine containing products Risk of nausea, vomiting, psychiatric symptoms such as anxiety and change in mood, autonomic hyperactivity, and palpitations EM EMDHCPL 583 2002 EPREX (epoetin alfa) - Pure Red Cell Aplasia (PRCA, Erythroblastopenia) - Janssen-Ortho Inc. HC-CAN epoetin alfa Pure red cell aplasia (PRCA, erythroblastopenia) in patients with chronic renal failure (CRF) after months to years of treatment 584 2002 Safety update: updated information about EPREX* (epoetin alfa) provided to Canadian healthcare professionals- JanssenOrtho Inc. and Ortho Biotech HC-CAN epoetin alfa severe anemia EM famotidine Dosage adjustments for patients with moderate (creatinine clearance 30-50 ml/minute) and severe (creatinine clearance < 30 ml/minute) renal insufficiency TDM / EMDHCPL gentamicinsulfate containing ear drops Ototoxic effect (e.g., vertigo, imbalance, ataxia, oscillating vision, hearing loss and tinnitus) when used by patients with perforated tympanic membranes or tympanostomy tubes. EM 585 586 2002 2002 Important Safety Iinformaton - Famotidine - Health Products and Food Branch Health Canada Advisory - Important safety reminder for patients using gentamicin sulfate-containing ear drops HC-CAN HC-CAN Year Title Regulatory Authority/Reg ion Important Drug Warning - Garasone / Garamycin - Schering Canada Inc. 587 588 589 590 2002 2002 2002 2002 HC-CAN Thrombotic Events and Immune Globulin Intravenous (IGIV) - Baxter Important Safety Information regarding REFLUDAN® - Berlex Canada Inc. Important Safety Information Regarding Sodium Phosphates Oral Solution - Pharmascience Inc. HC-CAN HC-CAN HC-CAN Intervention Type Product active ingredient Safety Issue (AE) gentamicinsulfate GARASONE® and GARAMYCIN® Risk of ototoxicity in patients with perforated tympanic membranes. EMDHCPL IGIV Thrombotic events. The exact cause of this is unknown; therefore, caution should be exercised in the prescribing and infusion of IGIV in patients with a history of cardiovascular disease or thrombotic episodes. EMDHCPL lepirudin (rDNA) Allergic and hypersensitivity reactions, including anaphylaxis, In rare instances, shock and death have been reported. Rare cases of intracranial bleeding in the absence of concomitant thrombolytic therapy have been reported following REFLUDAN administration. EMDHCPL Phosphates Solutions Electrolyte shifts, Hypocalcermia, hyperphosphatemia, hypernatremia, hypokalemia, and acidosis EM EMDHCPL Year 591 592 2002 2002 Title Important Safety Information - PLAS+SD PLASMA (Human) - Precision Pharma Services Inc. Important Drug Safety Update for Patients Using MATULANE® (Procarbazine HCl) Capsules (Formerly Marketed Under the Name NATULAN®) - Sigma-Tau Pharmaceuticals, Inc. Regulatory Authority/Reg ion HC-CAN HC-CAN Product active ingredient PLAS+®SD Thrombotic events including deep vein thrombosis and pulmonary embolism in patients with acute TTP undergoing plasma exchange following infusion of PLAS+®SD; EMDHCPL procarbazine HCl Results suggest an increased risk of lung cancer in a dosedependent fashion which is multiplied with tobacco use. Patients are advised to cease smoking before starting MOPP therapy.the development of lung cancer as a secondary nonlymphoid malignancy in Hodgkin's patients receiving the MOPP regimen (mechlorethamine, vincristine, procarbazine and prednisone) as therapy. Matulane (procarbazine HCl) is one component of the MOPP regimen. EM EMDHCPL Propofol Propofol is contraindicated for the sedation of children 18 years or younger receiving intensive care. Three of the six cases had a fatal outcome, and all cases were characterized by metabolic acidosis, hemodynamic instability, and cardiac conduction abnormalities. EMDHCPL Propofol Contraindicated for Sedation in Pediatric Patients Receiving Intensive Care Health Products and Food Branch Notice to Hospitals 593 2002 HC-CAN Safety Issue (AE) Intervention Type Year 594 595 2002 2002 Title Important Drug Safety Information: RISPERDAL* (risperidone) and Cerebrovascular Adverse Events in Placebocontrolled Dementia Trials - Janssen-Ortho Inc. Important Drug Safety Information on Vioxx - Merck Frosst Canada Inc. Regulatory Authority/Reg ion HC-CAN HC-CAN Product active ingredient Safety Issue (AE) risperidone Cerebrovascular adverse events (CVAEs) such as stroke and transient ischemic attacks (TIAs), including fatalities. EM EMDHCPL rofecoxib Caution should be exercised when VIOXX® is used in patients with a medical history of ischemic heart disease. In patients with fluid retention, hypertension, or heart failure, VIOXX® should be used with caution and introduced at the lowest recommended dose. EM EMDHCPL 596 2002 Health Canada investigates safety of MERIDIA® (Sibutramine) HC-CAN sibutramine 597 2002 Important Drug Safety Information on Rapamune - Wyeth-Ayerst Canada Inc. HC-CAN sirolimus Blood pressure and heart rate elevations; increased risk of non-fatal cardiovascular events Liver Transplantation Excess Mortality, Graft Loss, and Hepatic Artery Thrombosis (HAT): The use of sirolimus in combination with tacrolimus was associated with excess mortality and graft loss in a study in de novo liver transplant recipients. Many of these patients had evidence of infection at or near the time of death. stavudine, d4T Rapidly ascending neuromuscular weakness, mimicking the clinical presentation of GuillainBarré syndrome (including respiratory failure), in HIVinfected patients receiving stavudine in combination with other antiretrovirals. 598 2002 Symptoms Mimicking The Clinical Presentation of Guillain-Barré Syndrome Associated with ZERIT®(stavudine, d4T) Bristol-Myers Squibb HC-CAN Intervention Type EM EMDHCPL EMDHCPL Year Title Regulatory Authority/Reg ion Product active ingredient Safety Issue (AE) Intervention Type 599 2002 Important Safety Information on the use of Tamoxifen and the Incidence of Uterine Malignancies, Stroke and Pulmonary Embolism - Health Products and Food Branch 600 2002 Important Safety Information regrading BEXTRA (valdecoxib) - Pharmacia and Pfizer HC-CAN valdecoxib Higher incidences of uterine malignancies, stroke and pulmonary embolism Rare cases of serious skin reactions and cases of hypersensitivity reactions in patients with and without a history of allergic-type reactions to sulfonamides. BEXTRATM should not be given to patients who have experienced prior allergictype reactions to sulfonamides and should be discontinued at the first appearance of a skin rash or any other sign of hypersensitivity reaction 601 2002 Important Safety Information regarding ACCOLATE® (Zafirlukast) and Hepatic Effects- AstraZeneca HC-CAN zafirlukast Liver dysfunction EMDHCPL 602 2003 Health Canada is advising Canadians about the safe use of products containing Acetaminophen HC-CAN acetaminophen Safe use promotion EM 603 2003 Important Information Regarding ETHYOL (AMIFOSTINE) and Severe Cutaneous Reactions - Health Products and Food Branch HC-CAN amifostine Severe cutaneous reaction EMDHCPL beta-interferon Serious hepatic injury, including autoimmune hepatitis, hepatitis, and hepatic failure EM EMDHCPL Accelerated deaths in patients with localized prostate cancer EMDHCPL HC-CAN tamoxifen 2003 Important New Safety Information: Hepatic Injury Associated with Beta-Interferon Treatment for Multiple Sclerosis Biogen Idec Canada, Inc., Berlex Canada, Inc., and Serono Canada, Inc. 605 2003 Accelerated deaths using Casodex 150 mg in patients with localized prostate cancer otherwise undergoing watchful waiting - Health Canada withdraws approval -AstraZeneca Canada Inc. HC-CAN bicalutamide 606 2003 Important Safety Information Regarding Casodex 150 mg -AstraZeneca Canada Inc. HC-CAN casodex 607 2003 Important Safety Information Regarding the Dispensing of Clozapine HC-CAN clozapine 604 HC-CAN Increased fatality Switching of a patient from one brand of clozapine to another should not be done EM EMDHCPL EMDHCPL EM EMDHCPL Year Title Regulatory Authority/Reg ion Product active ingredient Safety Issue (AE) unless the pharmacist obtains a new, registryspecific patient registration form filled out by the prescribing physician. Intervention Type 608 2003 Important New Safety Information Regarding ZENAPAX (daclizumab) - Hoffmann-La Roche Limited - Notice to Hospitals HC-CAN daclizumab 609 2003 Diane®-35 and the Risk of Venous Thromboembolism - Berlex Canada Inc. HC-CAN Diane 35 610 2003 Important Safety Information regarding DIATHERMY THERAPY - Health Products and Food Branch Notice to Hospitals HC-CAN diathermy therapy Increase in mortality in cardiac transplant patients Risk of venous thromboembolism (blood clots) Contraindicated for patients who have an implanted metallic (electrical) lead or any implant that may contain such a lead, may cause excessive heating in the surrounding tissue, resulting in serious injury and death 611 2003 Advisory on Diethylstilbestrol (DES) and the Risk of Genital and Obstetrical Complications - Health Products and Food Branch HC-CAN diethylstilbestrol (DES) Genital and obstetrical complications EMDHCPL HC-CAN ergotamine and dihydroergotami ne-containing drugs Cerebral and/ or peripheral ischemia EMDHCPL HC-CAN ergotamine and dihydroergotami ne-containing drugs Many drug contraindications EM HC-CAN estrogen, progestin Increased risk of developing dementia EM EMDHCPL 612 613 614 2003 2003 2003 New CONTRAINDICATION regarding Ergotamine- and Dihydroergotamine-containing Drugs: Risk of Cerebral and/or Peripheral Ischemia - Novartis New contraindications for medications containing ergotamine and dihydroergotamine Novartis Pharmaceuticals Canada Inc. Important Safety Information on Estrogen plus Progestin (PremplusTM Tablets) - Wyeth Pharmaceuticals EMDHCPL EM EMDHCPL Year Title Regulatory Authority/Reg ion Product active ingredient 615 2003 Important Safety Information about DIANE®-35 and the Risk of Venous Thromboembolism - Berlex Canada Inc. HC-CAN estrogen/progest ogen DIANE®35, 616 2003 Important Safety Information Regarding Early Virologic Non-response in Patients with HIV Infection Treated with 3TC® (lamivudine), Ziagen® (abacavir) and VireadTM (tenofovir) - GlaxoSmithKline Inc. HC-CAN lamivudine &abacavir 617 2003 Important Safety Information about ReFacto® (moroctocog alfa), Antihemophilic Factor (Recombinant) [BDDrFVIII]) Wyeth Canada HC-CAN moroctocog alfa) Safety Issue (AE) Contraindicated in women with thrombophlebitis, thromboembolic disorders. elevated risk of venous thromboembolic events In combination with VireadTM (tenofovir, should not be used as a triple antiretroviral therapy when considering a new treatment regimen for naïve or pretreated HIV-1 infected patients. high rate of early virologic non-response observed in a GSKsponsored clinical study Lack of effect, mainly in prophylaxis patients, lack of effect has been described as bleeding into target joints, bleeding into new joints, other bleeding or a subjective feeling by the patient of new onset bleeding. Intervention Type EMDHCPL EMDHCPL EMDHCPL 618 2003 Important Safety Information Regarding the Discontinuation of Sales of Nefazodone in Canada: Letter to Pharmacists and Wholesalers - Bristol-Myers Squibb Canada HC-CAN nefazodone Discontinuation of sales Withdra wal / EM/ EMDHCPL 619 2003 Important Safety Information Regarding the Discontinuation of Sales of Nefazodone in Canada - Bristol-Myers Squibb Canada HC-CAN nefazodone Adverse hepatic events including liver failure EMDHCPL 620 2003 Letter to Healthcare Professionals re Synagis (palivizumab) - Abbott Laboratories Limited HC-CAN palivizumab Use in children EMDHCPL paroxetine HCl Possible increased risk of suicide-related adverse events in children and adolescents under 18 years of age EM EMDHCPL 621 2003 Important Drug Warning - Paxil® - Until further information is available, PAXIL® (paroxetine HCl) should not be used in children and adolescents under 18 years of age - GlaxoSmithKline HC-CAN Year Title 2003 Important Safety Information Regarding PERMAX® (pergolide mesylate) and Cardiac Valvulopathy - Eli Lilly Canada Inc. and Draxis Health Inc. 2003 Important safety information on the concomitant use of GlucoNorm® (repaglinide) and gemfibrozil. - Novo Nordisk Canada Inc. 624 622 623 Regulatory Authority/Reg ion HC-CAN Product active ingredient pergolide mesylate HC-CAN repaglinide 2003 Important safety information regarding Serevent® in Asthma (salmeterol xinafoate) and cessation of the SMART (Salmeterol Multi-center Asthma Research Trial) -GlaxoSmithKline Inc. HC-CAN salmeterol xinafoate 625 2003 New Safety Information Associated with the use of ZOLOFT in Patients taking Pimozide - Pfizer Canada Inc. HC-CAN sertraline HCl 626 2003 Health Canada reports back to public on safety profile of MERIDIA® (sibutramine) HC-CAN 2003 New Warning Regarding RAPAMUNE® (sirolimus) and Bronchial Anastomotic Dehiscence including Fatal Cases - Wyeth Pharmaceuticals 628 2003 Important Drug Warning - Reports of Oligohidrosis (decreased sweating) and Hyperthermia in patients treated with TOPAMAX* (topiramate) - Janssen Ortho, Inc. HC-CAN topiramate 629 2003 Important Safety Information Regarding the Use of Effexor® (venlafaxine HCI) Tablets and Effexor® XR (venlafaxine HCI) Capsules in Children and Adolescents Wyeth Pharmaceuticals HC-CAN HC-CAN 627 630 2004 Association of Absorbable Hemostatic Agents with paralysis or other neural deficits Notice to Hospitals HC-CAN Safety Issue (AE) Cardiac valvulopathy involving one or more valves The concomitant use of GlucoNorm® (repaglinide) and gemfibrozil is contraindicated. blood glucose-lowering effects risk of severe and prolonged hypoglycemia Asthma deaths Intervention Type EM EMDHCPL EM EMDHCPL EM EMDHCPL sibutramine Drug interaction with pimozide Blood pressure and heart rate elevations; increased risk of non-fatal cardiovascular events EMDHCPL EM sirolimus Bronchial anastomotic dehiscence EM EMDHCPL EM EMDHCPL venlafaxine HCl Oligohidrosis (decreased sweating) and Hyperthermia Tablets and Capsules have not been and are not recommended for use in patients under 18 years EMDHCPL absorbable hemostatic agents Paralysis EMDHCPL Year 631 2004 Title Important drug safety information for WELLBUTRIN® SR and ZYBAN® (bupropion HCI): warning for SSRIs and other newer anti-depressants regarding the potential for behavioural and emotional changes, including risk of self-harm Biovail Pharmaceuticals Canada Regulatory Authority/Reg ion HC-CAN Product active ingredient bupropion Safety Issue (AE) Intervention Type Behavioural and emotional changes EMDHCPL HC-CAN celecoxib Increasd CV risk EM EMDHCPL Important drug safety information for CELEXA: warning for SSRIs and other newer anti-depressants regarding the potential for behavioural and emotional changes, including risk of self-harm Lundbeck Canada Inc. HC-CAN citalopram hydrobromide Behavioural and emotional changes EMDHCPL 2004 Health Canada releases important information on the dispensation of CLOZAPINE products in Canada HC-CAN clozapine Agranulocytosis - changes to pateint registration form RD 2004 Safety information regarding selective COX-2 inhibitor NSAIDs: Vioxx (rofecoxib), Celebrex (celecoxib), Bextra (valdecoxib), Mobicox (meloxicam) and generic forms of meloxicam HC-CAN cox-2 inhibitors and meloxicam Increased heart attack and stroke EM Important safety information on CELEBREX (celecoxib), increased cardiovascular risk Pfizer Canada Inc. 632 2004 633 2004 634 635 636 2004 Association of EPREX (epoetin alfa) with thrombotic vascular events Janssen-Ortho Inc. HC-CAN epoetin alfa Thrombotic vascular events 637 2004 Important Drug Safety Information: EPREX (epoetin alfa) sterile solution: revised prescribing information for patients with chronic renal failure. Janssen-Ortho Inc. HC-CAN epoetin alfa PRCA EM EMDHCPL EM EMDHCPL 638 2004 Important drug safety information for PROZAC: warning for SSRIs and other newer anti-depressants regarding the potential for behavioural and emotional changes, including risk of self-harm Eli Lilly Canada Inc. HC-CAN fluoxetine HCl Behavioural and emotional changes EMDHCPL 639 2004 Important safety information regarding a drug interaction between fluticasone propionate (Flonase /Flovent /Advair ) and ritonavir (Norvir /Kaletra) GlaxoSmithKline Inc. HC-CAN fluticasone propionate Drug interaction with ritonavir EMDHCPL Year 640 641 642 Title 2004 Important drug safety information for LUVOX: warning for SSRIs and other newer anti-depressants regarding the potential for behavioural and emotional changes, including risk of self-harm Solvay Pharma Inc. 2004 Updated Safety Information addressing the risk of malignancies associated with REMICADE (infliximab) Schering Canada Inc. 2004 Important safety information for patients taking LAMICTAL (lamotrigine) GlaxoSmithKline Inc. Regulatory Authority/Reg ion HC-CAN HC-CAN HC-CAN Product active ingredient fluvoxamine maleate Safety Issue (AE) Intervention Type Behavioural and emotional changes EMDHCPL infliximab Risk of malignancies EM EMDHCPL lamotrigine Breakthrough seizures with concomitant use of hormonal contraceptives with Lamictal; decrease serum lamotrigine levels. EMDHCPL 643 2004 ARAVA (leflunomide) and interstitial lung disease HC-CAN leflunomide ILD EM EMDHCPL 644 2004 Important Safety Update: Potential Effect of DEPO-PROVERA* (medroxyprogesterone acetate) on Bone Pfizer Canada Inc.Mineral Density HC-CAN medroxyprogeste rone acetate Bone mineral densisty effects EMDHCPL 2004 Important drug safety information for REMERON RDTM/REMERON® : warning for SSRIs and other newer antidepressants regarding the potential for behavioural and emotional changes, including risk of self-harm Organon Canada Ltd/Ltée HC-CAN mirtazapine 2004 Serious adverse reactions in pediatric patients treated with ORTHOCLONE OKT*3 (muromonab-CD3) Janssen-Ortho Inc. Notice to Hospital HC-CAN muromonabCD3 behavioural and emotional changes SAEs in paediatric patients; increased risk of nervous system complications, most notably a build-up of excess fluid in the brain (cerebral edema) that may result in a fatal condition called cerebral herniation. 647 2004 Important New Safety Information Clarifying Risk Factors for Severe, Life-threatening and Fatal Hepatotoxicity with VIRAMUNE® (nevirapine) Boehringer Ingelheim (Canada) Ltd. HC-CAN Nevirapine Servere life-threatening and fatal hepatotoxicity clarification EMDHCPL 648 2004 Health Canada advises Canadians under the age of 18 to consult physicians if they are being treated with newer antidepressants HC-CAN New antidepressants Suicidality in childre and adolescents EM 645 646 EMDHCPL EM EMDHCPL Year Title Regulatory Authority/Reg ion Product active ingredient Norvir/Kaletra Safety Issue (AE) Drug interaction - Reports of adrenal suppression, greatly increased concentrations of fluticasone propionate in the blood with ritonavir and fluticasone propionate simultaneously. EM EMDHCPL PUBLIC ADVISORY - Information for patients regarding a drug interaction between RITONAVIR (Norvir/Kaletra) and FLUTICASONE propionate (Flonase, Flovent, Advair) - GlaxoSmithKline Inc. 649 2004 HC-CAN Intervention Type 650 2004 Important Drug Safety Information: ZYPREXA (olanzapine) and Cerebrovascular Adverse Events in Placebo-Controlled Elderly Dementia Trials Eli Lilly Canada Inc. HC-CAN olanzapine Cerebrovascular AEs; strokes and related events in elderly patients with dementia-related psychosis 651 2004 Important Safety Information Regarding TAMIFLU® (oseltamivir phosphate) and prescription in children less than 1 year of age Hoffmann-La Roche Limited HC-CAN oseltamivir phosphate Possible safety concerns and toxicity EMDHCPL 652 2004 Updated safety : Possible relationship of Aredia and/or Zometa with osteonecrosis of the jaw - Novartis Pharma Canada Inc. HC-CAN pamidronate disodium and/or zoledronic acid Osteonecrosis of the jaw EMDHCPL 653 2004 Important drug safety information for Paroxetine: warning for SSRIs and other newer anti-depressants regarding the potential for behavioural and emotional changes, including risk of self-harm GlaxoSmithKline Inc. HC-CAN paroxetine HCl Behavioural and emotional changes EMDHCPL Cardiac valvulopathy / fibrosis EM EMDHCPL Sudden onsent of sleep EMDHCPL 654 2004 New Safety Information Regarding PERMAX and Occurrence of Cardiac Valvulopathy / Fibrosis. Shire BioChem Inc. HC-CAN pergolide mesylate 655 2004 Important Safety Information Regarding the Antiparkinson Drug PERMAX® (pergolide mesylate): Sudden Onset of Sleep Shire BioChem Inc. HC-CAN pergolide mesylate 656 2004 Serious liver injury with TEBRAZID (pyrazinamide) or PMS-pyrazinamide and rifampin for the treatment of latent tuberculosis ICN Canada Limited and Pharmascience Inc. HC-CAN pyrazinamide Serious liver injury EM EMDHCPL 657 2004 Possible Association of RITUXAN (rituximab) with Hepatitis B reactivation Hoffmann-La Roche Limited HC-CAN rituximab Hep B reactivation EMDHCPL Increased relative risk for confirmed cardiovascular (CV) events, such as heart attack and stroke, Voluntar y withdraw al /EM/ EMDHCPL 658 2004 Merck Sharp & Dohme (MSD) Announces Voluntary Worldwide Withdrawal of VIOXX® (rofecoxib) Merck Frosst Canada Ltd HC-CAN rofecoxib Year Title Regulatory Authority/Reg ion Product active ingredient Safety Issue (AE) Intervention Type 659 2004 Important safety information regarding the association between CRESTOR (rosuvastatin) and rhabdomyolysis HC-CAN rosuvastatin Rhabdomyolysis EM EMDHCPL 660 2004 Important drug safety information for ZOLOFT: warning for SSRIs and other newer anti-depressants regarding the potential for behavioural and emotional changes, including risk of self-harm Pfizer Canada Inc. HC-CAN sertraline HCl Behavioural and emotional changes EMDHCPL EM 661 2004 Health Canada advises of potential adverse effects of SSRIs and other anti-depressants on newborns HC-CAN SSRIs Newborns whose mothers took these medications during pregnancy have developed complications at birth requiring prolonged hospitalization, breathing support and tube feeding 662 2004 Health Canada advises Canadians of stronger warnings for SSRIs and other newer anti-depressants HC-CAN SSRIs Behavioural and emotional changes EM 2004 Important Safety Update: Diarrhea and Ischemic Colitis in Patients Using ZELNORM (tegaserod hydrogen maleate) Novartis Pharmaceuticals Canada Inc. HC-CAN tegaserod hydrogen maleate diarrhea and ischemic colities EM EMDHCPL HC-CAN tenofovir disoproxil fumarate Conditional approval with renal function monitoring TDM topiramate metabolic acidosis EM EMDHCPL EM EMDHCPL 663 664 665 2004 Conditional Approval of Viread (tenofovir disoproxil fumarate) Gilead Sciences, Inc. 2004 TOPAMAX* (topiramate) use is associated with Metabolic Acidosis Janssen-Ortho Inc. HC-CAN 666 2004 Association of DESYREL (trazodone) with drug interactions with medications that alter CYP 3A4 Bristol-Myers Squibb Canadametabolism HC-CAN trazodone drug interactions with CYP 3A4 drugs 667 2004 Bextra (valdecoxib) - Cardiovascular Risks and Serious Skin Reactions Pfizer Canada Inc HC-CAN valdecoxib CV risks and serious skin reactions EMDHCPL 668 2004 Important drug safety information for EFFEXOR®: Warning for SSRIs and other newer anti-depressants regarding the potential for behavioural and emotional changes, including risk of self-harm Wyeth Pharmaceuticals HC-CAN venlafaxine behavioural and emotional changes EMDHCPL Year Title 669 2004 Important Safety Information Regarding Reports of Serious Hepatic Events in Patients Receiving ACCOLATE® (zafirlukast) AstraZeneca Canada Inc. 670 2005 Updated safety information on hematologic events associated with HUMIRA and the risk of infections associated with the concurrent use of HUMIRA and anakinra - Abbott Laboratories, Limited Regulatory Authority/Reg ion Product active ingredient Safety Issue (AE) Intervention Type HC-CAN zafirlukast serious hepatic events EM EMDHCPL HC-CAN adalimumab Hematologic events/ drug interaction with ankinra EMDHCPL EMDHCPL 671 2005 Important Safety Information on Albumin Therapy in Critically-ill Patients HC-CAN albumin Previous warning of 1998 retracted: neither increases nor decreases mortality in hypovolaemic patients. 672 2005 Health Canada has suspended market authorization of ADDERALL XRTM (amphetamine salts), a drug approved for Attention Deficit Hyperactivity Disorder (ADHD) in Children. -HPFB HC-CAN amphetmine salts Withdrawal EMDHCPL 2005 Important Safety Information on Strattera (atomoxetine HCl) and the potential for behavioral and emotional changes, including risk of self-harm - Eli Lilly Canada Inc. HC-CAN atmoxetine HCl Behavioural and emotional changes, including risk of self-harm EMDHCPL HC-CAN Atypical antipsychotic drugs Increased risk for all-cause mortality. EMDHCPL celecoxib Increased risk of cardiovascular events EM EMDHCPL PRCA EM EMDHCPL Drug interaction - high rate of virological failure and emergence of resistance EMDHCPL High risk of death EMDHCPL 673 674 2005 Important Safety Information on Atypical Antipsychotic Drugs and Dementia 2005 Important Safety Information on Celebrex (celecoxib) ◦Pfizer Canada Inc 2005 Important Safety Information on the Association of Aranesp (darbepoetin alfa) with pure red cell aplasia ◦Amgen Canada Inc. 677 2005 New Safety Information regarding the co-administration of Videx and Viread, and either Sustiva or Viramune - BristolMyers Squibb Canada and Gilead Sciences, Inc. HC-CAN darbepoetin alfa didanosine, tenofovir disoproxil fumarate [TDF]), and either efavirenz [EFV]) or (nevirapine [NVP]). 678 2005 Health Canada Endorsed Important Safety Information on Xigris [drotrecogin alfa (activated)] - Eli Lilly Canada Inc. HC-CAN Drotrecogin Alfa (activated) 675 676 HC-CAN HC-CAN Year 679 680 681 Title 2005 Important Safety Information on the discontinuation of Climacteron Injection (estradiol dienanthate, estradiol benzoate and testosterone enanthate benzilic acid hydrazone) - Sandoz Canada Inc. 2005 Association of Ezetrol (ezetimibe) with myalgia, rhabdomyolysis, hepatitis, pancreatitis, and thrombocytopenia - Merck Frosst/Schering Pharmaceuticals 2005 Important safety information on Duragesic (fentanyl transdermal system) Regulatory Authority/Reg ion Withdrawal Withdra wal/ EMDHCPL HC-CAN ezetimibe Myalgia, rhabdomyolysis, hepatitis, pancreatitis, and thrombocytopenia EMDHCPL HC-CAN fentanyl transdermal system Serious or life-threatening hypoventilation, including fatalities EM EMDHCPL EMDHCPL EMDHCPL HC-CAN Safety Issue (AE) 682 2005 Important Safety Information on Oxeze (formoterol fumarate dihydrate) Turbuhaler - AstraZeneca Canada Inc. HC-CAN formoterol fumarate Increased risks of asthma related death and other serious respiratory related outcomes 683 2005 Safety information from Investigational Studies with REMINYL (galantamine hydrobromide) in Mild Cognitive Impairment - Janssen-Ortho Inc. HC-CAN galantamine hydrobromide Mild cognitive impairment 684 685 686 2005 2005 2005 Association of Tequin (gatifloxacin) with serious hypoglycemia and hyperglycemia ◦Bristol-Myers Squibb Canada Important Safety Information on Iressa (gefitinib) 250 mg Tablets ◦AstraZeneca Canada Inc. Important Safety Information on the Association of Zevalin (ibritumomab tiuxetan) with severe mucocutaneous reactions Intervention Type Product active ingredient estradiol dienanthate, estradiol benzoate, testosterone enenthate benzilic acid hydrazone HC-CAN gefitinib Serious hypoglycemia and hyperglycemia Health Canada recommends restricting the indication for IRESSA® to patients whose tumours are EGFR expression status positive or unknown HC-CAN ibritumomab tiuxetan Severe mucocutaneious reactions (SJS) HC-CAN gatifloxacin EM EMDHCPL EM EMDHCPL EM EMDHCPL Year Title Regulatory Authority/Reg ion Product active ingredient Safety Issue (AE) Intervention Type 687 2005 Association of icodextrin-containing peritoneal dialysis solutions with falsely elevated blood glucose monitor readings HC-CAN icodextrincontaining peritoneal dialysis solutions 688 2005 Important Safety Information on the Dosage and Administration of Refludan (lepirudin) - Berlex Canada Inc. HC-CAN lepirudin Serious thrombotic events EMDHCPL letrozole Contraindication in premenopausal women congenital anomalies in infants of mothers exposed to Femara* for the treatment of infertility EM EMDHCPL HC-CAN mefloquine Rare but potentially serious psychiatric, or neurological, or cardiac adverse events preceded by sudden onset of unexplained anxiety, depression, restlessness, irritability, confusion, a persistently abnormal heart beat, or palpitations. EMDHCPL HC-CAN mixed salts amphetamine extended release capsules Sudden death reported with amphetamine treatment at therapeutic doses in children with structural cardiac abnormalities EMDHCPL 689 690 691 2005 2005 Important Safety Information on the contraindication of Femara (letrozole) in premenopausal women ◦Novartis Pharmaceuticals Canada Inc. Availability of a revised Patient Information Leaflet for Apo-Mefloquine (mefloquine). - Apotex Inc. HC-CAN Falsely elevated blood glucose monitor readings EMDHCPL 2005 Important Safety Information on Adderall XR - Shire BioChem Inc. - Report of the Adderall XR New Drug Committee 692 2005 Association of TRILEPTAL (oxcarbazepine) with life-threatening dermatological reactions and multi-organ hypersensitivity - Novartis Pharmaceuticals Canada Inc. HC-CAN oxcarbazepine Life threatening dermatological reactions and multi-organ hypersensitivity 693 2005 Important safety information on Paxil (paroxetine) and increased risk of cardiac defects following exposure during first trimester of pregnancy ◦GlaxoSmithKline Inc HC-CAN paroxetine HCl Increased risk of congenital Increased Cardiac Defects EMDHCPL EM EMDHCPL Drug interaction with pimozide - increase plasma pimozide levels EMDHCPL Contraindication due to drug interaction with ritonavir / saquinavir EMDHCPL 694 695 2005 Important Safety Information on Concomitant Use of PAXIL or PAXIL CR and pimozide (Orap) - GlaxoSmithKline Inc. 2005 New Safety Information Regarding Fortovase and Invirase and Occurrence of Drug-Induced Hepatitis in Healthy Volunteers receiving Rifampin in combination with ritonavir boosted saquinavir. - Hoffmann-La Roche Limited HC-CAN HC-CAN paroxetine HCl rifampin in combination with ritonavir/saquina vir (ritonavir boosted saquinavir Year Title 696 2005 Association of Avandia (rosiglitazone) and Avandamet (rosiglitazone/metformin) with new onset and/or worsening of macular edema GlaxoSmithKline Inc. 697 2005 Association of CRESTOR® (rosuvastatin) with muscle related adverse events - AstraZeneca Canada Inc. 698 Regulatory Authority/Reg ion Product active ingredient HC-CAN HC-CAN rosuvastatin New onset and/or worsening of macular edema Contraindication for predisposing factors for myopathy/rhabdomyolysis HC-CAN salmeterol Respiratory-related death and life-threatening experience EMDHCPL Kidney impairment and nephrocalcinosis EM EMDHCPL Intraoperative floppy iris syndrome EMDHCPL Important Safety Information on Serevent - GlaxoSmithKline Inc. 699 2005 Important safety information on pms-Sodium Phosphates Oral Solution with kidney impairment and nephrocalcinosis ◦◦Pharmascience Inc. HC-CAN sodium phosphates 700 2005 Important Safety Information on Flomax (tamsulosin) and Intraoperative Floppy Iris Syndrome (IFIS) - Boehringer Ingelheim (Canada) Ltd. HC-CAN tamsulosin 2005 Important Safety Information on Thioridazine EM EMDHCPL rosiglitazone maleate 2005 701 Safety Issue (AE) Intervention Type EMDHCPL HC-CAN thioridazone HCl QT prolongation Withdra wal / EM / EMDHCPL Risk of Serious Allergic Reactions Following TUBERSOL [Tuberculin Purified Protein Derivative (Mantoux) EMDHCPL Serious, potentially life threatening skin reactions Withdra wal 702 2005 Risk of Serious Allergic Reactions Following TUBERSOL [Tuberculin Purified Protein Derivative (Mantoux)] Administration - Sanofi Pasteur Limited HC-CAN Tuberculin Purified Protein Derivative (mantoux) 703 2005 Association of Bextra (valdecoxib) with serious adverse drug reactions - Pfizer Canada Inc. HC-CAN valdecoxib 704 2005 Updated Renal Safety Information on Zometa (Zoledronic Acid) and Aclasta (Zoledronic Acid) ◦Novartis Pharmaceuticals Canada inc. HC-CAN zoledronic acid Reports of renal dysfunction EM EMDHCPL 705 2006 Health Canada reminds women not to use ACE inhibitors during pregnancy HC-CAN ACE inhibitors Teratogenicity EMDHCPL 706 2006 New information regarding uncommon psychiatric adverse events for all ADHD drugs HC-CAN ADHD drugs Uncommon psychiatric AEs EMDHCPL Year 707 708 2006 2006 Title Important Safety Information on Trasylol - Bayer Inc. Association of Benzocaine Sprays with Methemoglobinemia 709 2006 Association of Avastin (bevacizumab) with hypertensive encephalopathy and reversible posterior leukoencephalopathy syndrome (RPLS) 710 2006 Important Safety Information on Anzemet (dolasetron mesylate): New Contraindications 711 712 713 714 2006 Important Safety Information on anti-TNFα Therapy: ENBREL (etanercept), HUMIRA (adalimumab), and REMICADE (infliximab) Amgen Canada, Inc., Abbott Laboratories, Ltd., and Schering Canada, Inc. 2006 Health Canada update on status of Evra contraceptive skin patch in Canada 2006 Association of Nephrogenic Systemic Fibrosis / Nephrogenic Fibrosing Dermopathy (NSF/NFD) with the use of gadolinium (Omniscan) 2006 Update regarding the association of Tequin (gatifloxacin) with serious hypoglycemia and hyperglycemia Bristol-Myers Squibb Canada Regulatory Authority/Reg ion Product active ingredient HC-CAN aprotinin HC-CAN benzocaine sprays Intervention Type Safety Issue (AE) Increased risk for renal dysfunction or failure; association of Trasylol with increased risk of cardiovascular events (myocardial infarction or heart failure), cerebrovascular events such as stroke, encephalopathy or coma, and renal dysfunction or failure in patients undergoing CABG surgery EMDHCPL Methemoglobinemia EM EMDHCPL Hypertensive encephalopathy and reversible posterior leukoencephalopathy syndrome (RPLS Cases of sustained supraventricular and ventricular arrhythmias, myocardial infarction and one case of fatal cardiac arrest have been reported in association with ANZEMET® (dolasetron mesylate) use in both children and adolescent EM EMDHCPL HC-CAN bevacizumab HC-CAN dolasetron mesylate HC-CAN etanercept), HUMIRA (adalimumab), and REMICADE (infliximab) Hepatitis B Reactivation EM EMDHCPL HC-CAN Evra contraceptive skin patch Risk of blood clots approximately two-fold increase EMDHCPL gadolinium Nephrogenic Systemic Fibrosis / Nephrogenic Fibrosing Dermopathy EMDHCPL gatifloxacin Serious hypoglycemia and hyperglycemia EM EMDHCPL HC-CAN HC-CAN EMDHCPL Year 715 2006 Title For Health Professionals Important Safety Information on Iressa (gefitinib) Regulatory Authority/Reg ion HC-CAN Product active ingredient Safety Issue (AE) Lack of Survival Benefit and Increased Incidence of Tumour Haemorrhage in Association with IRESSA® in Patients with Squamous Cell Carcinoma of the Head and Neck (SCCHN) gefitinib Intervention Type EMDHCPL 716 2006 Important Safety and Efficacy Information on Iressa (gefitinib) 250 mg Tablets AstraZeneca Canada Inc. HC-CAN gefitinib 717 2006 Notice to Hospitals Increased mortality and risk of serious adverse events when prophylactic heparin is abruptly discontinued in patients to be started on Xigris [drotrecogin alfa (activated)] for severe sepsis HC-CAN heparin Restricted indication of IRESSA® to patients currently benefiting from IRESSA treatment and whose tumours are EGFR positive or unknown. Increased mortality and risk of serious adverse events when prophylactic heparin is abruptly discontinued in patients to be started on Xigris [drotrecogin alfa (activated)] for severe sepsis HC-CAN imatinib mesylate Left Ventricular Ejection Fraction reduction and Congestive Heart Failure EM EMDHCPL infliximab Hepatosplenic T-cell lymphoma EM EMDHCPL HC-CAN lamotrigine Increased risk of nonsyndromic oral clefts in infants born to patients EM EMDHCPL Higher rate of acute rejection in cardiac transplant patients 718 719 720 2006 Important Safety Information on Gleevec (imatinib mesylate) Novartis Pharmaceuticals Canada Inc. 2006 Possible Association of Remicade (infliximab) with hepatosplenic T-cell lymphoma in pediatric and young adult patients with Crohn's disease Schering Canada Inc HC-CAN EM EMDHCPL EMDHCPL 2006 Association of Lamictal (lamotrigine) with an increased risk of non-syndromic oral clefts GlaxoSmithKline Inc. 721 2006 Association of CellCept (mycophenolate mofetil) and sirolimus containing immunosuppressant regimen with higher rate of acute rejection in cardiac transplant patients switched from calcineurin inhibitors Hoffmann-La Roche Limited HC-CAN mycophenolate mofetil 722 2006 Newer antidepressants linked to serious lung disorder in newborns HC-CAN New antidepressants Serious lung disorder in newborns EM EMDHCPL EM EMDHCPL HC-CAN norelgestromin and ethinyl estradio The risk of venous thromboembolism (VTE) EM EMDHCPL HC-CAN pegaptanib sodium injection Hypersensitivity reactions EM EMDHCPL 723 724 2006 2006 New safety information about Evra (norelgestromin and ethinyl estradiol) Transdermal System Janssen-Ortho Inc. Association of Macugen (pegaptanib sodium injection) with hypersensitivity reactions Pfizer Canada Inc Year 725 Title 2006 Important Safety Information on Evista (raloxifene HCl) Eli Lilly Canada Inc 726 727 728 Regulatory Authority/Reg ion 730 731 732 Safety Issue (AE) Increased Risk of Mortality Due to Stroke in Postmenopausal Women at Increased Risk for Cardiovascular Disease Intervention Type EM EMDHCPL HC-CAN raloxifene HCl 2006 Association of WinRho SDF [Rho(D) Immune Globulin (Human)] with Intravascular Hemolysis in the treatment of Immune Thrombocytopenic Purpura Cangene Corporation HC-CAN Rho(D) Immune Globulin (Human)] Hypersensitivity reactions 2006 Reports of Bowel Obstruction and Gastrointestinal Perforation with Rituxan (rituximab) Hoffmann - La Roche Limited HC-CAN rituximab Gastrointestinal Perforation EM EMDHCPL EM EMDHCPL 2006 Association of a Rapamune (sirolimus) containing immunosuppressant regimen with a high rate of acute rejection in de novo renal transplant patients Wyeth Pharmaceuticals HC-CAN sirolimus High rate of acute rejection in de novo renal transplant patients EM EMDHCPL HC-CAN tadalafil, vardenafil HCl, sildenafil citrate Vision problems EM EMDHCPL Tamiflu Hallucinations and abnormal behaviour, including self harm, EMDHCPL Association of the erectile dysfunction medications Cialis (tadalafil), Levitra (vardenafil HCl) and Viagra (sildenafil citrate) with visual problems Eli Lilly Canada Inc. Bayer Inc. Pfizer Canada Inc. 729 Product active ingredient 2006 2006 New information regarding Tamiflu 2006 Updated Safety Information on Ketek (telithromycin) and hepatic events, aggravation of myasthenia gravis and syncope sanofi-aventis Canada Inc. HC-CAN HC-CAN HC-CAN telithromycin tequin Hepatic events, aggravation of myasthenia gravis and syncope Blood glucose disorders, after serious cases of both low blood sugar (hypoglycemia) and high blood sugar (hyperglycemia EM EMDHCPL EM EMDHCPL 2006 Health Canada advises diabetic patients not to use the antibiotic Tequin 733 2006 Important Safety Information Regarding Intracranial Hemorrhage in Patients Receiving Aptivus (tipranavir) Capsules Boehringer Ingelheim (Canada) Ltd HC-CAN tipranavir Intracranial Hemorrhage EM EMDHCPL 734 2007 Association of Trasylol (aprotinin) with hypersensitivity reactions and renal dysfunction - Bayer Inc. HC-CAN aprotinin Hypersensitivity reactions and renal dysfunction EM 735 2007 Important Safety Information and availability of Trasylol (aprotinin) Bayer Inc. HC-CAN aprotinin Increase in all-cause mortality EMDHCPL Year 736 2007 Title Association of AVASTIN (bevacizumab) with tracheo-esophageal fistula - Hoffman-La Roche Ltd. Regulatory Authority/Reg ion HC-CAN Product active ingredient Safety Issue (AE) Intervention Type bevacizumab Tracheo-esophageal fistula EM EMDHCPL EM EMDHCPL 737 2007 Health Canada Endorsed Important Safety Information on Sensipar (cinacalcet HCl) - Amgen Canada Inc. HC-CAN cinacalcet HCl Contraindication in patients with secondary hyperparathyroidism and CKD not receiving dialysis 738 2007 Recommendations for the Appropriate Use of Cough and Cold Products in Children HC-CAN Cough and cold products No use in children under 2yo EM deferasirox Acute renal failure (severe kidney problems) and reports of cytopenias; GI hemhorrage EM EMDHCPL 739 740 2007 Association of acute renal failure (severe kidney problems) and reports of cytopenias (low blood cell counts) with Exjade (deferasirox) - Novartis Pharmaceuticals Canada Inc 2007 Information Regarding Baraclude (entecavir) - Bristol-Myers Squibb Canada 741 HC-CAN HC-CAN entecavir 2007 Important safety information and new prescribing information for the erythropoiesis-stimulating agents (ESAs), Aranesp (darbepoietin alfa) and Eprex (epoetin alfa) - Amgen Canada and Janssen-Ortho, Inc. 742 2007 743 EM EMDHCPL HC-CAN erythropoiesisstimulating agents (ESAs) Resistance to Hepatitis B Increased the risk of death and of serious cardiovascular adverse events in patients with cancer or renal failure, when treated to a target hemoglobin level of greater than 120 g/L EM EMDHCPL Health Canada reviewing new safety information on cardiac events in patients taking Losec (omeprazole) or Nexium (esomeprazole) HC-CAN esomeprazole Cardiac events EM 2007 Important Safety Information on IRESSA (gefitinib) ◦AstraZeneca Canada Inc. HC-CAN gefitinib Deaths due to interstitial lung disease (ILD) 744 2007 Withdrawal of Market Authorization for Prexige (lumiracoxib) - Novartis Pharmaceuticals Canada Inc. HC-CAN lumiracoxib Risk of serious hepatotoxicity EMDHCPL Withdra wal / EM / EMDHCPL 745 2007 New safety information regarding Prexige (Lumiracoxib) HC-CAN lumiracoxib Serious liver AEs (withdrawn in Australia) EM HC-CAN modafinil Serious rash, allergic reactions, and mental problems EM EMDHCPL HC-CAN Perflutren Injectable Suspension Serious cardiopulmonary reactions, including fatalities EMDHCPL 746 747 2007 2007 New warnings regarding ALERTEC (modafinil) and serious rash, allergic reactions, and mental problems - Shire Canada Inc. Important safety information on Definity (Perflutren Injectable Suspension) ◦Bristol-Myers Squibb Canada Year 748 749 750 Title 2007 Health Canada reviewing link between Parkinson's drug Permax and heart valve conditions 2007 Association between Long-Term Treatment with Actos (pioglitazone HCl) Tablets for Type 2 Diabetes Mellitus and Fractures in Women - Eli Lilly Canada Inc. 2007 Important Safety Information on RITUXAN (rituximab) - Hoffmann-La Roche Limited 2007 New restrictions on the use of rosiglitazone products due to cardiac safety concerns (Avandia, Avandamet, Avandaryl) GlaxoSmithKline Inc 752 753 751 754 755 756 HC-CAN HC-CAN HC-CAN Product active ingredient pergolide pioglitazone HCl rituximab Safety Issue (AE) Intervention Type Heart valve conditions EM fractures in women EM EMDHCPL Fatal Progressive Multifocal Leukoencephalopathy (PML) New restrictions on the use of rosiglitazone products due to cardiac safety concerns --•Rosiglitazone (no longer approved as monotherapy for type 2 diabetes, EM EMDHCPL EM EMDHCPL HC-CAN rosiglitazone 2007 Important safety information on rosiglitazone-containing products: Avandia, Avandamet and Avandaryl GlaxoSmithKline Inc. (GSK) HC-CAN rosiglitazone maleate 2007 VENTOLIN I.M. injection and VENTOLIN I.V. infusion solution for pregnant women & labour and delivery ◦GlaxoSmithKline Inc HC-CAN salbutomal sulphate Increased Incidence of Fractures in Female Patients Incidence of myocardial ischemia in pregnant women who receive PrVENTOLIN® I.M. injection or HC-CAN sitaxsentan sodium Liver toxicity, risks to the fetus, and important drugdrug interactions. EMDHCPL HC-CAN tegaserod hydrogen maleate Cardiovascular ischemic events EM EMDHCPL telithromycin Removal of indications; due to severe liver injury EM EMDHCPL 2007 2007 2007 Important Safety Information on THELIN (sitaxsentan sodium) ◦Encysive Canada, Inc. Voluntary suspension of sales of Zelnorm due to cardiovascular ischemic events - Novartis Pharmaceuticals Canada Inc. Important Safety Information on KETEK (telithromycin) - sanofi-aventis Canada Inc. 757 2008 Association of abacavir-containing medicinal products (ZIAGEN, KIVEXA and TRIZIVIR) with a potential increased risk of myocardial infarction GlaxoSmithKline 758 2008 Important Safety Information on Accusol 35 Haemodialysis Solutions for Acute Renal Therapy Edwards Lifesciences (Canada) Inc. 759 Regulatory Authority/Reg ion 2008 Infection-related deaths were reported with the use of MabCampath (alemtuzumab) following initial combination therapy with anti-leukemia drugs which also suppress the body's immune response - Bayer HealthCare and Genzyme HC-CAN HC-CAN HC-CAN HC-CAN EM EMDHCPL EMDHCPL abacavircontaining medicinal product Accusol 35 Haemodialysis Solutions for Acute Renal Therapy Increased risk of myocardial infarction EM EMDHCPL Risk of precipitate formation (calcium carbonate) EMDHCPL alemtuzumab Infection-related deaths with anti-leukemia drugs which also suppress the body's immune response EM EMDHCPL Year 760 761 762 Title 2008 Important Safety Information on Argatroban - Glaxo Operations UK Limited and Shopper's Drug Mart Specialty Health Network 2008 Reports of Eye Inflammation, Endophthalmitis, and Toxic Anterior Segment Syndrome (TASS) Following Off-label Intravitreal Use of Avastin (bevacizumab) - Hoffmann-La Roche Limited 2008 Association of Microangiopathic anemia with the combined use of AVASTIN (bevacizumab) and sunitinib malate in metastatic renal cell carcinoma Hoffmann-La Roche Limited Regulatory Authority/Reg ion HC-CAN HC-CAN HC-CAN Product active ingredient argatroban bevacizumab bevacizumab Safety Issue (AE) Risk of infection and underdosing Eye Inflammation, Endophthalmitis, and Toxic Anterior Segment Syndrome (TASS) Contraindication microangiopathic anemia with concomitant use of sunitinib malate Serious and sometimes fatal dermatologic reactions, including Toxic Epidermal Necrolysis (TEN) and Stevens-Johnson Syndrome (SJS Intervention Type EMDHCPL EM EMDHCPL EM EMDHCPL EM EMDHCPL 763 2008 New Safety Information for the anti-epileptic drug TEGRETOL (carbamazepine) Novartis Pharmaceuticals Canada Inc. HC-CAN carbamazepine 764 2008 Fatal interactions ceftriaxone-calcium HC-CAN ceftriaxone 765 2008 Important Safety Information on Tylenol with Codeine in Nursing Mothers and Ultra-Rapid Metabolizers of Codeine Janssen-Ortho Incorporated HC-CAN codeine + acetaminophen Drug interactions with calcium-containing products The babies of nursing mothers who rapidly metabolize codeine may be at increased risk for morphine overdose due to higher-thanexpected morphine levels in breast milk. 766 2008 Health Canada Releases Decision on the Labelling of Cough and Cold Products for Children HC-CAN Cough and cold products No use in children under 6mo 767 2008 Association of Prezista (darunavir) with hepatotoxicity Janssen-Ortho Inc. HC-CAN darunavir Hepatotoxicity 768 2008 Reports of Hepatic Failure with EXJADE (deferasirox) HC-CAN deferasirox Hepatic failure EM EM EMDHCPL EM EMDHCPL Desmopressin nasal sprays Increased risk of serious side effects involving water retention and decreased blood sodium levels (hyponatremia) EM EMDHCPL efalizumab Progressive multifocal leukoencephalopathy EM EMDHCPL erlotinib Moderate hepatic impairment and advanced solid tumours EM EMDHCPL 769 770 771 2008 Desmopressin nasal sprays (including Apo-Desmopressin Spray) are associated with an increased risk of serious side effects involving water retention and decreased blood sodium levels (hyponatremia). Apotex Inc. 2008 Association of Raptiva (efalizumab) with serious infections, including progressive multifocal leukoencephalopathy in patients with psoriasis - EMD Serono Canada Inc. 2008 Health Canada Endorsed Important Safety Information on Tarceva (erlotinib) - Hoffmann-La Roche Limited HC-CAN HC-CAN HC-CAN EMDHCPL EM EMDHCPL Year Title Regulatory Authority/Reg ion Product active ingredient Safety Issue (AE) Intervention Type Liver Injury and Hypersensitivity EM EMDHCPL 2008 New Safety Information Regarding Liver Injury and Hypersensitivity Associated with TYSABRI (natalizumab) Biogen Idec Canada Inc. 773 2008 Increased risk of marked hepatic enzyme elevations in patients taking SOMAVERT (pegvisomant) in combination with a somatostatin analogue Pfizer Canada Inc. HC-CAN pegvisomant Hepatic enzyme elevations EM EMDHCPL 774 2008 Updated Labelling for Diabetes Drug Actos and Risk of Heart Failure HC-CAN pioglitazone Cardiac risks EM 2008 Risk of peripheral neuropathy in patients treated with telbivudine (SEBIVO) and interferon Novartis Pharmaceuticals Canada Inc. telbivudine Risk of peripheral neuropathy interaction with interferon EM EMDHCPL 2008 Association between TORISEL (temsirolimus) concentrate for injection and hypersensitivity/infusion reactions Wyeth Canada 772 775 776 777 2008 New safety information regarding Champix (varenicline tartrate) Pfizer Canada Inc. HC-CAN HC-CAN natalizumab HC-CAN temsirolimus HC-CAN varenicline tartrate Serious adverse effects of muscle weakness remote to the site of injection, also referred to as possible distant spread of toxin. EM EMDHCPL Ceftriaxone is contraindicated in neonates. EMDHCPL 778 2009 Additional safety information related to Botox / Botox Cosmetic (botulinum toxin type A) - Allergan Canada HC-CAN botulinum toxin type A 779 2009 Health Canada issued important safey information on CEFTRIAXONE HC-CAN ceftriaxone HC-CAN Chromic Phosphate P32 780 781 2009 Association of Phosphocol P32 (Chromic Phosphate P32) with acute lymphocytic leukemia (ALL) - Tyco Healthcare 2009 Potential interaction of Proton Pump Inhibitors (PPIs) with Plavix (clopidogrel) - sanofi-aventis Canada Inc. and BristolMyers Squibb Canada Co. For Health Professionals [2009-08-20] EM EMDHCPL Hypersensitivity/Infusion reactions Serious neuropsychiatric adverse events, including depressed mood, agitation, hostility, changes in behaviour, suicidal ideation and suicide, as well as worsening of pre-existing psychiatric illness (previously diagnosed or not). HC-CAN clopidogrel Acute lymphocytic leukemia Potential interaction with PPIs - could lead to a reduction in the level of clopidogrel's active metabolite and therefore, it is conceivable that the therapeutic response to clopidogrel may be affected EM EMDHCPL EM EMDHCPL EM EMDHCPL Year 782 Title Safety Issue (AE) Intervention Type Withdra wal / EM / EMDHCPL Progressive multifocal leukoencephalopathy HC-CAN erlotinib Gastrointestinal perforation, Stevens-Johnson syndrome, and corneal perforation Association of Enbrel (etanercept) with Histoplasmosis and Other Invasive Fungal Infections - Amgen Canada Inc. HC-CAN etanercept Histoplasmosis and other Invasive Fungal Infections EM EMDHCPL EM EMDHCPL 2009 New Safety Information Regarding Intelence (etravirine) and Severe Skin and Hypersensitivity Reactions - Tibotec, a division of Janssen-Ortho Inc. HC-CAN etravirine Severe Skin and Hypersensitivity Reactions EMDHCPL 2009 Association of Telzir (fosamprenavir) with a potential increased risk of myocardial infarction (heart attack) GlaxoSmithKline Inc. HC-CAN fosamprenavir Increasd risk of myocardial infarction EM EMDHCPL HC-CAN mycophenolate sodium PRCA EM EMDHCPL EM EMDHCPL Market withdrawal of Raptiva (efalizumab) in Canada - EMD Serono Canada Inc. 783 2009 Association of TARCEVA (erlotinib) with cases of gastrointestinal perforation, Stevens-Johnson syndrome, and corneal perforation - Hoffmann-La Roche Limited 784 2009 785 787 Product active ingredient efalizumab 2009 786 Regulatory Authority/Reg ion HC-CAN 2009 Myfortic (mycophenolate sodium) - Reports of Pure Red Cell Aplasia in Patients - Novartis Pharmaceuticals Canada Inc. 788 2009 New Safety Information Regarding Progressive Multifocal Leukoencephalopathy (PML) Associated with Tysabri (natalizumab) - Biogen Idec Canada Inc. HC-CAN natalizumab Progressive Multifocal Leukoencephalopathy (PML) 789 2009 Health Canada Reviewing Possible Association of Asthma Drug Xolair (Omalizumab) with Increased Risk of Cardiovascular Problems HC-CAN omalizumab Increased risk of CV problems EMDHCPL 790 2009 Oral sodium phosphate products are no longer authorized for purgative use - Pharmascience Inc. and Odan Laboratories Ltd. HC-CAN oral sodium phosphate products No longer autorised for purative use EM EMDHCPL 791 2009 Updated Labelling for Piroxicam - Drug No Longer to be Used for Acute Pain or Inflammation HC-CAN piroxicam No longer to be used for acute pain or inflammation EMDHCPL 792 2009 Association of Rituxan (rituximab) with Progressive Multifocal Leukoencephalopathy (PML) - Hoffmann-La Roche Limited HC-CAN rituximab Multifocal Leukoencephalopathy (PML) EM EMDHCPL 793 2009 Important Safety Information Regarding the Use of Sleep Aid Drugs and the Risk of Complex Sleep-Related Behaviours HC-CAN sleep aid medications Complex sleep-related behaviours EMDHCPL TNF blocers Increased risk of cancer in children and young adults EM EMDHCPL 794 2009 Safety Update on TNF Blockers and Risk of Cancer in Children and Young Adults HC-CAN Year 795 2009 Title Safety information regarding topical anesthetics and serious adverse events - AstraZeneca Canada Inc. and Smith & Nephew Inc Regulatory Authority/Reg ion HC-CAN Product active ingredient topical anesthetics Safety Issue (AE) Intervention Type Serious adverse events including fatalities that have been associated with excessive topical application of local anesthetics in both adult and pediatric patients EM EMDHCPL 796 2009 Association of Herceptin (trastuzumab) with Oligohydramnios - Hoffman-La Roche Limited HC-CAN trastuzumab Oligohydramnios EM EMDHCPL 797 2000 Ziagen (abacavir) - urgent safety restriction MHRA - EU abcavir Hypersensitivity reactions EM 798 2000 European withdrawal of anoretctic agents/appetite suppressants MHRA - EU Anorectic agents Cardiovascular symptoms & seizures EM 799 2000 Infliximab (Remicade) - urgent safety restriction MHRA - EU infliximab Tuberculosis (TB) or other opportunistic infections EM 800 2000 Safety of Meningitis C vaccines MHRA - EU Meningitis Vaccine Death following Meningitis C vaccination EM 801 2000 Phenylpropanolamine and haemorrhagic stroke - update MHRA - EU phenylpropanola mine Haemorrhagic stroke EM 802 2000 Suspension of Cisapride MHRA - EU prepulsid Prolonged QT interval, which may lead to rare but life-threatening ventricular arrhythmias. 803 2000 Thioridazine: restricted indications and new warnings on cardiotoxicity MHRA - EU thioridazine Cardiotoxicity EM RDrestrictio n to 2nd line treatmen t 804 2001 Safety of Zyban - statement released by Professor Alasdair Breckenridge, Chair of the Committee on the Safety of Medicines MHRA - EU bupropion Increase in fatal reports EM 805 2001 Zyban (bupropion HCl) -safety update MHRA - EU bupropion Dose-related risk of seizure EM 806 2001 Cerivastatin (Lipobay) and rhabdomyolysis. Contraindication of concomitant use of gemfibrozil and restriction of maximum dose MHRA - EU cerivastatin Myopathy and Rhabdomyolysis EM Year Title Regulatory Authority/Reg ion Product active ingredient Safety Issue (AE) Intervention Type 807 2001 Withdrawal of cerivastatin (Lipobay) by Bayer plc MHRA - EU cerivastatin rhabdomyolysis Withdra wal / EM 808 2001 Discontinuation of Droleptan tablets, suspension and injection (droperidol) MHRA - EU droperidol Cardiac QT interval effects EM 809 2001 Important safety information - Eprex (epoetin alfa): reports of pure red cell aplasia (PRCA) MHRA - EU epoetin alfa PRCA EM 810 2001 Leflunomide (Arava) - urgent safety restriction MHRA - EU leflunomide Liver injury EM 811 2001 Orlaam (levacetylmethadol) - CPMP opinion to suspend the marketing authorisation (MA) MHRA - EU levacetylmethado l EM 812 2001 Update on MMR vaccine MHRA - EU MMR vaccine QTc prolongation Risk of life-threatening infection MHRA - EU oral contraceptives 3rd generation Venous thromboembolism EM Tachycardia (increased heart rate) and elevated blood pressure Withdra wal EM 2001 Venous thromboembolism (blood clots in the veins) and third generation oral contraceptives - advice and information from the Department of Health 814 2001 European withdrawal of anorectic agents/appetite suppressants: new legal developments, no new safety issues: Licences for phentermine and amfepramone being withdrawn May 2001 MHRA - EU phentermine and amfepramone 815 2002 Zyban (bupropion HCl) - safety update MHRA - EU bupropion Seizures EM Contraindicated in patients with previous or current seizure disorder EM 813 816 2002 Zyban (bupropion HCl) - safety udate MHRA - EU bupropion 817 2002 Risks and benefits of HRT - message to health professionals from Dr Pat Troop, Deputy Chief Medical Officer, Department of Health and the Committee on Safety of Medicines press release MHRA - EU HRT 818 2002 Report of the Committe on Safety of Medicines Expert Working Group on Meningococcal Group C Conjugate Vaccine MHRA - EU Meningitis Vaccine Increase in risk of breast cancer Headache, nausea and vomiting, rash, dizziness, faints, malaise, lymphadenopathy and allergic reactions including anaphylactoid reactions and seizures in older children and adolescents 819 2002 Restricted re-introduction of the atypical antipsychotic sertindole (Serdolect) MHRA - EU sertindole Risks of cardiac dysrhythmias 820 2003 Aspirin and Reye's Syndrome MHRA - EU ASA Reye's syndrome in children under 16 EM EM RDrestricted to pts in CT Tempora ry suspensio n Year Title Regulatory Authority/Reg ion Product active ingredient 821 2003 Casodex 150mg (bicalutamide): No longer indicated for treatment of localised prostate cancer MHRA - EU casodex 822 2003 Hormone replacement therapy (HRT) and breast cancer - results of the UK Million Women Study MHRA - EU HRT 823 2003 Use of hormone replacement therapy in the prevention of osteoporosis: important new information MHRA - EU 824 2003 Oral contraceptives and cervical cancer MHRA - EU Safety Issue (AE) Increase in the number of deaths Intervention Type EM HRT Breast cancer Increased risk of breast cancer, endometrial cancer and ovarian cancer in a duration-dependent manner EM EM Oral contraceptives Cervical cancer EM EM 825 2003 Safety of Seroxat (paroxetine) in children and adolescents under 18 years - contraindication in the treatment of depressive illness - Epinet message from Professor G Duff, Chairman of Committee on Safety of Medicines (CSM) MHRA - EU paroxetine Increased risk of harmful outcomes including episodes of self-harm and potentially suicidal behaviour, lack of efficacy 826 2003 Interim report of the Committee on Safety of Medicines Expert Working Group on Selective Serotonin Reuptake Inhibitors MHRA - EU SSRIs Withdrawal reactions and suicidal behaviour EM 827 2003 Selective Serotonin Reuptake Inhibitors (SSRIs): Overview of regulatory status and CSM advice relating to major depressive disorder (MDD) in children and adolescents including a summary of available safety and efficacy data MHRA - EU SSRIs Increased rate of self-harm and suicidal thoughts EM 828 2003 Safety of venlafaxine in children and adolescents under 18 years in the treatment of depressive illness - message from Professor G Duff, Chairman of the Commiittee on Safety of Medicines MHRA - EU venlafaxine Hostility, suicidal ideation and self-harm EM 829 2004 Atypical antipsychotic drugs and stroke MHRA - EU Atypical antipsychotics Stroke EM 830 2004 New data on cardiovascular risk with celecoxib (celebrex): MHRA statement MHRA - EU celecoxib CV risk 831 2004 Updated guidance on the use of Depo-Provera contraception MHRA - EU depo provera Slight thinning of the bones EM Withdra wal 832 2004 Paroxetine (Seroxat): reminder to use the recommended dose MHRA - EU paroxetine Evidence of detrimental effects with increased dose EM 833 2004 Seroxat (paroxetine) MHRA - EU paroxetine Withdrawal reactions and suicidal behaviour EM 834 2005 MHRA issues new advice on use of Strattera (atomoxetine) MHRA - EU atmoxetine Rare, but sometimes severe, cases of hepatic disorder Withdra wal Year Title Regulatory Authority/Reg ion Product active ingredient Safety Issue (AE) Intervention Type Wider access in at-risk populations: The decision to use NRT should be made following a risk-benefit assessment as early in pregnancy as possible EM 835 2005 New advice on use of nicotine replacement therapy (NRT): wider access in at-risk populations MHRA - EU NRT (nicotine replacement therapy) 836 2005 Review of the cardiovascular safety of non-steroidal anti-inflammatory drugs (NSAIDs) MHRA - EU NSAIDS CV EM 837 2005 Paroxetine (Seroxat) - safety in pregnancy MHRA - EU paroxetine Pregnancy safety EM salmeterola & formoterol Patients taking long-acting beta2 agonists should also be taking inhaled steroids, and should be monitored closely for therapeutic response in the early months of treatment. EM Voluntar y suspensio n EM 838 2005 Reminder: Salmeterol (Serevent) and formoterol (Oxis, Foradil) in asthma management MHRA - EU 839 2005 Voluntary suspension of Valdecoxib MHRA - EU valdecoxib Serious skin reactions in addition to the established risk of cardiovascular reactions (including heart attack and strokes) 840 2006 New prescribing advice: restricted indication and risk of renal dysfunction MHRA - EU aprotinin Restricted indications and risk of renal dysfunction Year Title Regulatory Authority/Reg ion Product active ingredient Safety Issue (AE) Intervention Type deferiprone Risk of agranulocytosis, and risk of eurological disorders on chronic overdose RD 841 2006 Important Safety Information: Risk of agranulocytosis, and risk of neurological disorders on chronic overdose with use of Ferriprox 842 2006 Dianette and depression: MHRA update MHRA - EU dianette Depression EM 843 2006 Dopamine agonists: Pathological gambling and increased libido are potential class effects of these drugs MHRA - EU dopamine agonists Pathological gambling and increased libido EM gadodiamide Nephrogenic fibrosing dermopathy / nephrogenic systemic fibrosis EM MHRA - EU imatinib Congestive Heart Failure and Left Ventricular Dysfunction EM MHRA - EU Rotarix (live attenuated human rotavirus oral vaccine) Non-serious adverse events reported in association with the improper route of administration EM MHRA - EU Selective and non selectiv NSAIDs Risk of arterial thrombotic events, such as heart attack or stroke EM 844 845 846 847 2006 2006 2006 2006 Risk of nephrogenic fibrosing dermopathy or nephrogenic systemic fibrosis Need for careful monitoring in patients with cardiac disease or risk factors for cardiac failure Correct route of administration of oral vaccine - letters for doctors, nurses and healthcare professionals Safety of selective and non-selective non-steroidal anti-inflammatory drugs (NSAIDs) MHRA - EU MHRA - EU Year Title Regulatory Authority/Reg ion Product active ingredient Safety Issue (AE) Intervention Type 848 2006 Important information about: contraindications for use; cautions for use; reports of visual defects; and about a lack of data for efficacy and safety when given with other treatment for pulmonary arterial hypertension MHRA - EU sildenafil Visual defects, lack of efficacy EM 849 2006 Risk of intraoperative floppy iris syndrome during cataract surgery MHRA - EU tamsulosin Intraoperative floppy iris syndrome EM 850 2006 Risk of intracranial haemorrhage MHRA - EU tipranavir Intracranial Haemorrhage EM venlafaxine Higher rate of fatal overdose (fatal toxicity index) with the antidepressant venlafaxine, when compared with SSRIs. EM EM EM 851 2006 Updated prescribing advice for venlafaxine (Efexor/Efexor XL): Information for healthcare professionals MHRA - EU 852 2007 Trasylol (aprotinin) - worldwide suspension of marketing pending full review of risks and benefits MHRA - EU aprotinin Adverse effects on the kidney, possible increased risk of heart and cerebral disorders and death 853 2007 Occurrence of tracheoesophaegeal fistula during study of chemotherapy plus radiotherapy plus Avastin in patients with limited-stage small-cell lung cancer (unapproved indication) MHRA - EU bevacizumab Tracheoesophaegeal fistula Year 854 2007 Title Serious adverse events related to distant spread of toxin; need for extreme caution on administration to patients with neurological disorders or with history of dysphagia or aspiration Regulatory Authority/Reg ion MHRA - EU Product active ingredient Safety Issue (AE) Intervention Type botulinum toxin (Botox, Dysport, NeuroBloc, Vistabel) Serious adverse events related to distant spread of toxin EM EM 855 2007 Position on the sale and supply of co-proxamol following cancellation of the marketing authorisations at the end of 2007 MHRA - EU co-proxamol Risk of toxicity in overdose, both accidental and deliberatethe, efficacy of coproxamol is poorly established 856 2007 Removal of primary nocturnal enuresis indication MHRA - EU desmopressin Hyponatraemia EM dibotermin alfa Risk of fluid collection during unapproved use in posterior lumbar spine surgery EM MHRA - EU entecavir Risk of HIV resistance in patients co-infected with HIV and hepatitis B viru EM MHRA - EU Gadoliniumcontaining MRI contrast agents Risk of nephrogenic systemic fibrosis with some agents. EM 857 858 859 2007 Reminder of correct dose and placement of product during anterior spine fusion surgery; risk of fluid collection during unapproved use in posterior lumbar spine surgery 2007 Risk of HIV resistance in patients co-infected with HIV and hepatitis B virus who are not receiving highly active antiretroviral therapy (HAART) 2007 Letter from Marketing Authorisation Holder for Omniscan (gadodiamide) MHRA - EU Year Title Regulatory Authority/Reg ion Product active ingredient Safety Issue (AE) Intervention Type 860 2007 Risk of nephrogenic systemic fibrosis MHRA - EU gadoteric acid Risk of nephrogenic systemic fibros EM 861 2007 Lenalidomide is teratogenic and therefore contraindicated in pregnancy; it is also contraindicated in women of childbearing potential unless all conditions of the Pregnancy Prevention Programme are met MHRA - EU lenalidomide Teratogenicity EM 862 2007 Restriction of indication in complicated skin and soft-tissue infections MHRA - EU linezolid Increased number of deaths EM 863 2007 New (interim) restrictions on prescription of lumiracoxib, following concerns over liver safety MHRA - EU lumiracoxib Liver adverse reactions TDM/ EM MHRA - EU Lumiracoxib Risk of severe, potentially life-threatening hepatotoxicity Withdra wal MHRA - EU Mycophenolate mofetil (CellCept) Congenital malformations EM MHRA - EU Pioglitazonecontaining products (Actos, Glustin, Competact, Tandemact) Pathological gambling and increased libido EM piroxicam Gastrointestinal and cutaneous complications RDrestricted prescripti on/ EM Increase the risk of death and serious cardiovascular events in patients with chronic kidney disease. Increasd risk of thrombosis and related complications in patients with cancer EM Depression EM 864 865 866 867 2007 2007 2007 2007 Drug safety information: Lumiracoxib - Suspension of UK licences with immediate effect Congenital malformations after use in pregnancy Pathological gambling and increased libido are potential class effects of dopamine agonists New prescribing restrictions: treatment should be initiated only by specialists in the management of arthritic disorders as a second-line treatment for osteoarthritis, rheumatoid arthritis, or ankylosing spondylitis only MHRA - EU 868 2007 Recombinant human erythropoietins: New prescribing advice MHRA - EU recombinant human erythropoietins 869 2007 Reports of depression. Information includes new contraindication in patients with ongoing major depressive illness or those taking antidepressive treatment MHRA - EU rimonabant Year Title Regulatory Authority/Reg ion Product active ingredient Safety Issue (AE) Intervention Type 870 2007 Reports of progressive multifocal leukoencephalopathy in unapproved indications of systemic lupus erythematosus and vasculitis MHRA - EU Rituximab Progressive multifocal leukoencephalopathy EM 871 2007 Risk of fractures in women on long-term treatment MHRA - EU rituximab Fractures EM 872 2007 MHRA statement on cardiac safety of rosiglitazone (brand name Avandia) MHRA - EU CV risk EM 873 2007 Risk of fractures in feet, hands, and upper arms in women MHRA - EU rosiglitazone Rosiglitazonecontaining products (Avandia, Avandamet, and Avaglim) Fractures EM 874 2007 New prescribing advice for obstetric use in the management of preterm labour and for use in respiratory disease MHRA - EU salbutamol Myocardial ischaemia EM 875 2007 Hypersensitivity syndromes in postmenopausal women MHRA - EU Strontium ranelate Hypersensitivity syndrome EM telithromycin Serious liver reactions and contraindicated usein patients with a previous history of liver disorders. EM EM 876 2007 Important information about restricted indications, contraindications, and safety measures MHRA - EU 877 2007 Cases of endophthalmitis, eye inflammation, increased intraocular pressure, and visual disturbances after unapproved route of intraocular administration MHRA - EU triamcinolone acetonide Endophthalmitis, eye inflammation, increased intraocular pressure, and visual disturbances 878 2007 Europe-wide review recommends updates to product information for varenicline (brand name Champix▼) MHRA - EU varenicline Suicidal thoughts and behaviour EM 879 2008 Six infection-related deaths in clinical trial of fludarabine and rituximab treatement followed by alemtuzumab for remission consolidation in patients with previously untreated symptomatic B-cell chronic lymphocytic leukaemia MHRA - EU alemtuzumab Infection-related deaths EM Year Title Regulatory Authority/Reg ion Product active ingredient Safety Issue (AE) Congenital malformations: functional impairment, or cerebral palsy Intervention Type 880 2008 ORACLE children study: Outcomes after use of antibiotics in preterm labour MHRA - EU Antibiotics EM 881 2008 New advice on interactions and on risk of haemorrhagic stroke in patients who have had recent stroke MHRA - EU atorvastatin 882 2008 Fibrotic cardiac valvulopathy MHRA - EU cabergoline Haemorrhagic stroke Fibrotic cardiac valvulopathy 883 2008 Association with progressive multifocal leukoencephalopathy MHRA - EU efalizumab Progressive multifocal leukoencephalopathy 884 2008 Updated and strengthened safety recommendations: Do not use in patients with high blood pressure persistently elevated above 140/90 mm/Hg and which is not adequately controlled All patients who start treatment should have blood pressure monitored within 2 weeks of starting and periodically thereafter MHRA - EU etoricoxib Hypertension 885 2008 Restricted indications due to risk of hepatotoxicity MHRA - EU ketoconazole Hepatotoxicity EM Voluntar y withdraw al 886 2008 Reminder of contraindication in children younger than 2 years and of calculation of doses for children MHRA - EU lopinavir with ritonavir Accidental overdose EM 887 2008 Serious skin rash and psychiatric symptoms MHRA - EU modafinil Serious skin rash and psychiatric symptoms EM 888 2008 Serious hepatic reactions and bullous skin reactions MHRA - EU moxifloxacin Serious hepatic reactions and bullous skin reactions EM 889 2008 Reports of progressive multifocal leukoenecephalopathy MHRA - EU mycophenolate mofetil Progressive multifocal leukoenecephalopathy EM 890 2008 Progressive multifocal leukoencephalopathy MHRA - EU natalizumab Progressive multifocal leukoenecephalopathy EM EM EM EM Year 891 2008 Title Fibrotic reactions, including cardiovalvulopathy, associated with chronic use Regulatory Authority/Reg ion Product active ingredient Safety Issue (AE) MHRA - EU pergolide Fibrotic reactions, including cardiovalvulopathy, associated with chronic use Depression and psychiatric effects Intervention Type EM Withdra wal Suspension of marketing authorisation because of concerns about psychiatric side-effects: 892 2008 Do not issue, renew, or dispense any prescriptions for rimonabant See also: https://www.cas.dh.gov.uk/Home.aspx MHRA - EU rimonabant 893 2008 Association with progressive multifocal leukoencephalopathy MHRA - EU Rituximab 894 2008 New prescribing and storage requirements MHRA - EU Rotigotine patch (Neupro) Progressive multifocal leukoenecephalopathy Patients must not abruptly discontinue therapy. Abrupt withdrawal of dopamine agonists is associated with a syndrome resembling neuroleptic malignant syndrome or akinetic crisis. 895 2008 Risk of peripheral neuropathy MHRA - EU telbivudine Peripheral neuropathy EM EM EM EM 896 2008 Use in patients with impaired renal function only if benefits of treatment outweigh potential risks MHRA - EU tenofovir Lactic acidosis/severe hepatomegaly with steatosis and post treatment exacerbation of hepatitis 897 2008 Safety information on medicines for healthcare professionals sent in August 2008; preclinical data for teratogenicity MHRA - EU lenalidomide Teratogenicity EM 898 2009 Reports of severe eye inflammation and sterile endophthalmitis after off-label intravitreal use in Canada MHRA - EU bevacizumab Eye inflammation and sterile endophthalmitis EM 899 2009 Interactions between the use of clopidogrel and proton pump inhibitors MHRA - EU clopidogrel 900 2009 Updated advice on non-prescription medicines containing codeine or dihydrocodeine (DHC) MHRA - EU 901 2009 Efalizumab (Raptiva): Recommendation to suspend Marketing Authorisation as risks outweigh benefits 902 2009 Pseudoephedrine and ephedrine: Controlling the risk of misuse of medicines EM codeinecontaining Drug interactions Risk of addiction, and importance of not taking these medicines for longer than three days. MHRA - EU efalizumab Progressive multifocal leukoencephalopathy Withdra wal MHRA - EU ephedrine Misuse Withdra wal Withdra wal Year Title Regulatory Authority/Reg ion Product active ingredient Safety Issue (AE) Intervention Type 903 2009 New safety information about the following risks: gastrointestinal perforation; bullous and exfoliative skin disorders; and ocular disorders. MHRA - EU erlotinib 904 2009 Cases of toxic epidermal necrolysis and drug rash with eosinophilia and systemic symptoms (DRESS) syndrome MHRA - EU etravirine Gastrointestinal perforation; bullous and exfoliative skin disorders; and ocular disorders Toxic epidermal necrolysis and drug rash with eosinophilia and systemic symptoms (DRESS) syndrome 905 2009 Finasteride and the risk of male breast cancer MHRA - EU finasteride Male breast cancer TDM 906 2009 Letter to healthcare professionals: Swine flu - Reporting suspected adverse reactions to Tamiflu, Relenza and future Swine flu H1N1 vaccines MHRA - EU Flu vaccine Guillain-Barré Syndrome (GBS) EM orciprenaline Cardiac adverse reactions such as tachycardiad and palpitations Withdra wal MHRA - EU orlistat Interaction with levothyroxine, and interaction with antiepileptic drugs EM MHRA - EU ReFacto® moroctocog alfa (Recombinant Coagulation Factor VIII Risk of viral contamination EM Difficulty with approval due to safety issues including intravascular hemolysis Withdra wal 907 908 909 2009 2009 2009 Orciprenaline sulphate: Planned withdrawal from the UK market following a risk-benefit analysis Warnings on oxalate nephropathy, interaction with levothyroxine, and interaction with antiepileptic drugs Refacto AF is a successor product to Refacto and is scheduled to be introduced in June 2009: advance information for discussion with staff and patients MHRA - EU RD EM 910 2009 Withdrawal of marketing authorisation - product is no longer available in the UK (see also letter below) MHRA - EU Rho immune globin 911 2009 A third case of progressive multifocal leukoencephalopathy in patients with rheumatoid arthritis receiving MabThera MHRA - EU Rituximab Progressive multifocal leukoencephalopathy EM statins Sleep disturbances, memory loss, sexual dysfunction, depression and interstitial lung disease EM 912 2009 Statins: Updates to product safety information MHRA - EU Year Title Regulatory Authority/Reg ion Product active ingredient Safety Issue (AE) Intervention Type 913 2009 Hypersensitivity/infusion reactions (including some life-threatening and rare fatal reactions) have been associated with the administration of temsirolimus (Torisel) MHRA - EU temsirolimus: Torisel Hypersensitivity/infusion reactions EM 914 2009 Risk of QT prolongation See also Drug Safety Update February 2009, p 7 MHRA - EU toremifene QT prolongation EM MHRA - EU warfarin Interactions with herbal products, and food supplements EM EMA-EU fluticasone furoate Systemic corticosteroid effects EM EMA-EU zoledronic acid Osteonecrosis of the jaw EP EMA-EU exenatide Dehydration and Acute Renal Impairment Registry EMA-EU natalizumab PML; Opportunistic Infections PtAC / EM EMA-EU rilonacept Increased risk of Injection site reaction Registry EMA-EU rosiglitazone/gli mepiride Macular Oedema EM EMA-EU tenofovir disoproxil Renal toxicity EP / EMDHCPL 915 916 2009 Warfarin: changes to safety information Systemic corticosteroid effects - Routine pharmacovigilance including targeted questionnaire Potential cataract development 24 month ocular study 2005 Osteonecrosis of the jaw - Enhanced risk minimization activities An ONJ educational program is in place, and it delivers on a country by country bases key messages on ONJ prevention and management 917 2005 Dehydration and Acute Renal Impairment • Routine pharmacovigilance. • Targeted surveillance of dehydration, hypovolaemia, and acute renal impairment Pregnant women • Pregnancy registry 918 2006 PML; Opportunistic Infections - Educational materials including physician Prescribing Guidelines and Patient Alert Card. 919 2006 Increased risk ofInjection sitereaction Additional: Severe injection site reactions will be included as anevent of special interest in the Global Patient Registry Infection Routine: post-marketing surveillance (PSURs in accordance with EMEA timetable, based on the EU approval date and/or International Birth Date). Additional: infection, including serious infection, will be ncluded as an event of special interest in the Global Patient Registry. 920 2006 Macular Oedema Routine pharmacovigilance Examine incidence of macular oedema over longer RSG exposure in ADOPT and RECORD Implementation of targeted follow up questionnaires Continue to closely monitor spontaneous reports of macular oedema 921 2006 Furthermore the MAH will distribute a Direct Healthcare Professional Communication (DHPC) to all new concerned Health Care professionals Appropriate management of patients (including dosing of tenofovir DF in patients with abnormal renal function) - Planned distribution of a Dear Healthcare Provider Letter (following approval of HBV indication) Events resulting from tenofovir DF renal toxicity; Incidence of, and risk factors for tenofovir DF renal toxicity; Genetic pre-disposition to tenofovir DF renal toxicity; Mechanism of tenofovir DF renal toxicity; Safety in children.; Safety in elderly patients; Update of educational program as appropriate 922 2006 Year 923 Title Congestive heart failure (CHF); Other Malignancies (except lymphoma and NMSC); Central Nervous System (CNS) demyelinating disorders; Non melanoma skin cancer (NMSC); Lymphoma; Risk Minimisation actions in the form of an educational programme followed by measurement and communication of its effectiveness is planned 2007-07-02 - Tuberculosis (TB) and other opportunistic infections - Congestive heart failure - Serious infections - CNS demyelination - Fatal outcomesTB educational programme extended to physicians treating patients with CD and development of tool to measure effectiveness of educational programme. - Lupus and lupus likeillness Vasculitis - Patient alert card. 2007 Regulatory Authority/Reg ion Product active ingredient Safety Issue (AE) Intervention Type EMA-EU adalimumab Congestive heart failure (CHF) PtAC/EP / EM EMA-EU alglucosidase alfa Late-Onset Pompe disease EM EMA-EU entecavir ETV resistance TDM EMA-EU 5-aminolevulinic acid HCl Neurological disorders (e.g. hemiparesis, aphasia, convulsions, hemianopsia EP EMA-EU Human Papillomavirus1 type 16 L1 protein / Human Papillomavirus1 type 18 L1 protein Contraindication with pregnancy Registry EMA-EU hydroxycarbami de Effect on growtha at end of puberty EM EMA-EU lamivudine / zidovudine Side effects related to inhomogenous dosing EP 2007-05-31 - Infusion Associated Reactions IAR management guidelines Development of antibodies; Possibility for teratogenic effect- Educational material will be provided. 924 2007 Resistance: Genotypic analysis of clinical failures and patients with detectable HBV DNA and additional analysessuch as predictive host and viral factors and cross-resistance to better estimate the impact of ETV resistance. 925 2007 Neurological disorders (e.g. hemiparesis, aphasia, convulsions, hemianopsia Routine pharmacovigilance Restriction in 4.2 of the SPC that Gliolan should only be used by neurosurgeons that have attended a training course in fluorescence-guided surgery. Warning in section 4.4 of the SPC for special care in patients with tumours in the vicinity of an important neurological function Listed as undesirable effects in section 4.8 of the SPC. 926 2007 Training courses for neurosurgeons Pregnancy outcomes after vaccination Ongoing Study HPV 008; Ongoing Study HPV 009; Ongoing Study HPV-007; Ongoing Study HPV-015 SPC proposed wording “These data are insufficient to recommend use of Cervarix during pregnancy. Vaccination should, therefore, be postponed until after completion of pregnancy.” US-based Pregnancy Register HPV-040 CRT (Finland) Post-licensure prospective cohort study (Scotland) 927 2007 Influence of hydroxycarbamide in child and adolescent growth (end of puberty) - Physician, nurse, etc. and patient’ information via dedicated leaflets describing - how to treat children - the need of continuous follow-up of the growth of treated children. (special warning is the difference is upper to 2sd) 928 2007 For inhomogeneous dosing regimen in children weighing 21 to 30 kg, the MAH is considering the usefulness of an educational program to prescribers and caregivers. Planned activities include consultation with paediatric experts and Key Opinion Leaders as well as careful consideration of the practical needs for implementation of any program. 929 2007 Year 930 Title Exposure during Pregnancy Routine Pharmacovigilance In-utero exposure is captured via the SAE reporting process and will be reported annually in the PSUR In order to perform developmental assessments following inadvertent in-utero exposure of infants it is proposed to enrol such infants where geographically possible into current long term studies in the US and Europe following in utero exposed infants. Post authorization in-utero exposure will also be captured within the US antiretroviral registry. The registry will provide a report which will be submitted with the PSUR annually. 2007 Regulatory Authority/Reg ion EMA-EU Product active ingredient maraviroc teratogenicity Registry EMA-EU mecasermin Hypoglycaemia, Lipohypertrophy at Injection Sites, Hypertentions PtAC/E M EMA-EU melatonin Not specified EM EMA-EU nelfinavir EMA-EU nilotinib teratogenicity QT Prolongation; Myelosuppression; Severe haemorrhage; Severe infections; Hepatic transaminase and bilirubin elevations; Lipase and amylase elevations; Rash; Fluid retention; Hypophosphataemia; Ischemic heart disease; Cardiac failure; Drug induced liver injury; pancreatits; photosensitivity; diabetes mellitus; Food; Important potential interactions (Drugs that may prolong the QT interval; Strong CYP3A4 Inducers) ; Important missing information (pregnancy, paediatric patients; Patients with uncontrolled or significant cardiac disease) - Education Material **Hypoglycaemia - Education material: Patient card for weight and dose. Dose calculator Education material: **Lipohypertrophy at Injection Sites - Patient card for Lipohypertrophy**Tonsillar hypertrophy and Associated Adverse Events - Educational material: Patient card for Tonsillar hypertrophy and Associated Adverse Events **Headache and Intracranial Hypertension (Papilloedema) - Educational material: Patient card for Headache and Intracranial Hypertension (Papilloedema) ** Immunogenicity - Educational material: Immunogenicity sampling information will be provided to physicians ** Allergic Reactions - Educational material: Patient card for Allergic reactions **Scoliosis and Slipped Capital Femoral Epiphysis - Patient card for Scoliosis ** Neoplasia - Education material: Patient card for neoplasia 931 2007 Safety Issue (AE) Intervention Type Produce educational packs for GPs 932 2007 Exposure of pregnant women (EMS impurity) - DHCP letter was sent to inform providers and patients. 933 2007 QT Prolongation; Myelosuppression; Severe haemorrhage; Severe infections; Hepatic transaminase and bilirubin elevations; Lipase and amylase elevations; Rash; Fluid retention; Hypophosphataemia; Ischemic heart disease; Cardiac failure; Drug induced liver injury; pancreatits; photosensitivity; diabetes mellitus; Food; Important potential interactions (Drugs that may prolong the QT interval; Strong CYP3A4 Inducers) ; Important missing information (pregnancy, paediatric patients; Patients with uncontrolled or significant cardiac disease) - Education Material 934 2007 EMDHCPL EM Year 935 Title Infections tuberculosis, COPD: - Alert Card will be used to inform patients of the need for an adequate history and screening for infections 2007 Regulatory Authority/Reg ion Product active ingredient panitumumab Infections tuberculosis, COPD Dehydration; Lack of response intumours with KRAS mutation; Integument and eye toxicities Stomatitis and oral mucositi EMDHCPL EMA-EU sorafenib Dermatological toxicities EMDHCPL EMA-EU telbivudine Myopathy EM EMA-EU vildagliptin / metformin HCl Transaminase elevations, Drug-induced liver injury (DILI) TDM EMA-EU alemtuzumab Opportunistic infections EM EMA-EU epoetin alfa Additional measures to avoid s.c. application in renal anaemia patients EM EMA-EU epoetin zeta Increased risk of PRCA EM EMA-EU fentanyl human papillomavirus type 11 L1 protein, human papillomavirus type 16 L1 protein, human papillomavirus type 18 L1 protein, human papillomavirus type 6 L1 protein Misuse, abuse RD Not specified Registry EMA-EU nitisinone EMA-EU Dehydration; Lack of response intumours with KRAS mutation; Integument and eye toxicities Stomatitis and oral mucositis Risk communication will be through Direct Healthcare Professional Communication* 936 2007 Safety Issue (AE) 17/12/2007- Dermatological toxicities: Provision of information on symptom management to prescribers. 04/03/2007 - YES / NO 937 2007 Intervention Type PtAC/ TDM Myopathy - A proposal for an educational material to physicians to enhance the understanding of identified risks of muscular effects (CK elevations and myopathy) will be submitted to the CHMP for consideration 938 939 2007 2007 Transaminase elevations, Drug-induced liver injury (DILI) Therefore, as per routine clinical practice, it is recommended that liver function tests be performed prior to the initiation of treatment with vildagliptin and metformin periodically thereafter. Patients who develop increased transaminase levels should be monitored with a second liver function evaluation to confirm the finding and be monitored until the abnormalit(ies) return to normal. Should an increase in AST or ALT of 3x ULN or greater persist, withdrawal of therapy with vildagliptin and metformin is recommended. Vildagliptin and metformin should not be used in patients with hepatic impairment 2008-02-06 - Infusion-related events; Opportunistic infections - Educational Material. 940 2008 2008-12-16 - NO; 2007-09-13 Additional measures to avoid s.c. application in renal anaemia patients - Educational leaflet; Cool boxes with visual label 941 2008 Increased risk of PRCA with off-label subcutaneous administration in renal failure patients - educational leaflet 942 943 2008 2008 The applicant submitted a risk management plan which included a risk minimisation plan. However, in view of the restricted conditions of use (indication, experienced physicians) and of the writo healthcare professionals) proposed by the applicant should The identified potential risks with Effentora in the RMP are: • Misuse, abuse Use of Effentora in patients who are not already31/ 2008-08-11 The MAH has supplied a revised RMP updated with safety data. The MAH as committed to provide a revised RMP by the next PSUR submission due on 30 July 2008. Vaccination during pregnancy Pregnancy Registry, on a voluntary basis, in USA and France. 944 2008 2006-10-05 EMA-EU Year 945 Title 2010-06-09 - HEPATOBILIARY EVENTS - Core hepatic risk management information for prescribers on the importance of monitoring liver function.; DECREASED LVEF - Core cardiac risk management information to inform prescribers on the importance of cardiac monitoring ; DIARRHEA - Core diarrhoea risk management information for prescribers and patients (see Appendix 9).; RASH Core rash risk management information for prescribers and patients 2008-06-26 - yes / no 2008 Regulatory Authority/Reg ion 2008 lapatinib Hepatobiliary events TDM EMA-EU methylnaltrexon e bromide Adverse events from off-label use EMDHCPL EMA-EU micafungin Potential for liver tumour development EM EMA-EU olanzapine pamoate Weight gain, glucose dysregulation TDM ranolazine Constipation, nausea, vomiting; Dizziness and Syncope; Identified Risk: QT prolongation; PtAC IC/ Registry/ EP/ PtAC/ EMDHCPL Relevance in humans of the development of liver tumours in rats; Prescriber checklist Nurse administration and monitoring guide 947 2008 Weight Gain • Glucose Dysregulation • Dyslipidemia Promote awareness of appropriate metabolic monitoring by • Distributing utilized published guidelines • Referencing metabolic monitoring in the post injection syndrome Healthcare Awareness Program 948 2008 SEE - Identified Risk: Constipation, nausea, vomiting; Dizziness and Syncope; Identified Risk: QT prolongation; Important Missing Information: Safety information for patients with moderate and severe hepatic impairment; Important Missing Information: Patients with severe and endstage renal disease requiring dialysis; Important Missing Information: (Drug-drug interactions with Class Ia and Class III antiarrhythmics except amiodarone); Important Missing Information: Antihistamines (eg, terfenadine, astemizole, mizolastine), certain antiarrhythmics (eg, quinidine, disopyramide, procainamide), erythromycin, and tricyclic antidepressants (eg, imipramine, doxepin, amitriptyline); Important Missing Information: Real-world safety information for drugdrug interactions with potent CYP3A inhibitors; Important Missing Information: Drug-drug Interactions with CYP2D6 substrates which may need to be downtitrated (tricyclic antidepressants and antipsychotics) - Patient Alert Card 949 2008 950 2008 951 2009 952 2009 EMA-EU TERATOGENICITY - Reference to educational materials; Pregnancy Prevention Programme o Educational Programme - Direct HCP communication prior to launch - Educational material for healthcare professionals and patients � HCP booklets, patient assessment algorithm, patient treatment initiation forms, patient card or equivalent tools. � Patient booklets o Therapy management: - Criteria for determining women of childbearing potential (WCBP), effective contraceptive measures for WCBP, regular pregnancy testing for WCBP - Advise provided by SPC, outlined in direct HCP communication and detailed in Educational materials. PERIPHERAL NEUROPATHY; Thromboembolic events; Severe skin reactions; Bradycardia/syncope; Somnolence; Off-label use- Direct HCP communication prior to launch. • Educational material for healthcare professionals and patients Elevated Transaminases; Interactions with potent CYP 1A2 inhibitors (e.g.fluvoxamine, ciprofloxacin - Educational material to be provided to prescribers, with a prescription survey to follow this program. 2009-08-05 - TERATOGENICITY - Educational material as Prescriber Kit for prescribers. ; Patient Reminder Card specifically aimed at informing patients of the need to avoid pregnancy and to ensure effective contraceptive measures are used. Sending a ‘Reminder Letter’ to all Tracleer prescribers identified via the controlled distribution system to reinforce these messages; HEPATOTOXICITY - Patient Reminder Card specifically aimed at facilitating patient’s awareness of the need for regular blood tests for liver function. Safety Issue (AE) Intervention Type EMA-EU Off-label use - Sales force detailing and journal advertisements will address specific messages to appropriate healthcare providers regarding indication and populations for use. 946 Product active ingredient EMA-EU thalidomide Teratogenicity, peripheral neuropathy, thromboembolic events EMA-EU agomelatine Elevate transaminases EMDHCPL EMA-EU bosentan monohydrate Teratogenicity PtAC / EM Year 953 Title SEE A laminated card highlighting the appropriate dosing regimen, the approved therapeutic indications and the key warning and precautionary statements from the SPC will be made available for neonatal units that may use the product. Toxicity due to maternal caffeine ingestion; Healthcare Professional Communication; study / registry to monitor normal use and collect ADRs. Increase in caffeine plasma levels in premature infants with cholestatic hepatits or with clinically relevant renal insufficiency; cardiac disorders; treatment-related convulsions / seizures; - Healthcare Professional Communication; study / registry to monitor normal use and collect ADRs Card for neonatal intensive care units stating precautions; - Restricted prescription status limiting use to physician experienced in neonatal intensive care and administration only in a neonatal intensive care unit. Decrease in weight gain / failure to thrive; Caffeine withdrawal; necrotising enterocolitis; drug interactions - Healthcare Professional Communication; study / registry to monitor normal use and collect ADRs - Card for neonatal intensive care units stating precautions; - Restricted prescription status limiting use to physician experienced in neonatal intensive care and administration only in a neonatal intensive care unit. 2009 Infections An alert card for patients to highlight the key safety findings and thus further promote safety use of Ilaris are being prepared. This risk comunication/minimization initiative is subject to national laws and thus will be discussed and agreed upon with the national HAs prior to Ilaris launch in each countries. Physicians Educational Program Hypercholesterolemia - Physicians Educational Program potential interaction) - The Alert Card informs the patients to tell their doctors if they are scheduled to receive any vaccine. Physicians Educational Program 954 Regulatory Authority/Reg ion Product active ingredient Safety Issue (AE) Intervention Type EMA-EU caffeine citrate Toxicity due to maternal caffeine ingestion Registry/ RD/ PtAC/ EMDHCPL EMA-EU canakinumab Infections PtAC/EP / EM EMA-EU Transient small increase in blood pressure, lack of effect EP EMA-EU capsaicin certolizumab pegol Not specified EP EMA-EU Characterised viable autologous cartilage cells expanded ex vivo expressing specific marker proteins Not specified RD / EP EMA-EU degarelix CV disease EM Neutropenia; Vaccines important 2009 Transient small increase in blood pressure during patch application; Lack of response to opioid medication; - Establish an educational programme, including a supply of appropriate training materials addressing the need to monitor blood pressure during the treatment procedure and directions for supportive treatment for patients who experience increased pain during Qutenza administration. This programme will also address the need to evaluate the risk of adverse cardiovascular reactions due to the potential stress of the procedure in patients with unstable or poorly controlled hypertension or recent cardiovascular events prior to initiating Qutenza treatment 955 2009 Educational program 956 2009 Pro-active training in the framework of a controlled distribution system. 957 2009 Injection site reactions _ educational material; CV disease _ educational material 958 2009 Year 959 Title Inappropriate management of the signal of serum creatinine increase-Communication process on appropriate usage of MULTAQ®: An educational program with a goal to alert the prescriber on the appropriate utilization of serum creatinine testing in patients treated with dronedarone will be implemented. In each country, educational vehicles will be developed, seeking the collaboration of scientific societies, targeting physicians likely to initiate the treatment with MULTAQ® Drug-Drug Interactions with potent CYP3A4 inhibitors Communication process on appropriate usage of MULTAQ®: An educational program with a goal to prevent the concomitant use with dronedarone of potent CYP3A inhibitors will be implemented. In each country, educational vehicles will be developed, seeking the collaboration of scientific societies, targeting physicians likely to initiate the treatment with MULTAQ®. The educational material will include a drug interaction check card to be used in all EU countries that will be communicated to the Health care professionals (ie, doctors and pharmacists) for preventing these drug-drug interactions (see Annex II of the Marketing Authorisation). Use in unstable hemodynamic condition including patients with symptoms of heart failure at rest or with minimal exertion (corresponding with NYA class IV and unstable class III patients). Communication process on appropriate usage of MULTAQ®: An educational program will be implemented, with the goals to prevent the use of dronedarone in patients in unstable hemodynamic conditions including patients with symptoms of heart failure at rest or with minimal exertion (corresponding with NYHA class IV and unstable class III patients), and to limit use in stable patients with recent (1 to 3 months) NYHA class III heart failure or with LVEF <35%. In each country, educational vehicles will be developed, seeking the collaboration of scientific societies, targeting physicians likely to initiate the treatment with MULTAQ®. 2009 Regulatory Authority/Reg ion EMA-EU Product active ingredient dronedarone Drug-drug interactions EP EMA-EU fentanyl citrate Tolerance and physical and / or psychological dependance, accidental overdose EM EMA-EU golimumab Opportunistic infections and TB PtAC / EP EMA-EU lasofoxifene Not specified EP EMA-EU miglustat EMA-EU prasugrel Tolerance and physical and / or psychological dependance. Educational Material Accidental overdose - educational material 960 2009 Serious infections including opportunistic infections and TB (class effect) - Patient Alert Card • Golimumab Educational Program Additional PV activities • TB follow-up questionnaire Malignancy - Lymphoma follow-up questionnaire HBV reactivation (class effect); CHF (class effect) - Patient Alert Card • Golimumab Educational Program 961 2009 962 2009 Safety Issue (AE) Intervention Type Educational programme 2009-04-28 - Diarrhea and other GI ADRs; CNS AEs such as tremors, peripheral neuropathy; - Educational Material as prescribing kit for prescribers. Use in paediatric patients; Seizure activity in patients with NP-C disease treated with miglustat; Growth disturbance in the paediatric patients with NP-C disease treated with miglustat; reduced platelet counts in patients with NP-C disease treated with miglustat - Information package to prescribrers 963 2009 1. Haemorahage: (Intracranial haemorrhage, Gastrointestinal haemorrhage, Intraocular haemorrhage Percutaneous Coronary Intervention-Related Haemorrhage, Coronary Artery Bypass Graft-Related HaemorrhageOther ProcedureRelated Haemorrhage, Epistaxis) • Routine pharmacovigilance: monitor AEs and SAEs through routine clinical trial and spontaneous post-marketing surveillance. • Targeted surveillance for specific AEs preidentified for targeted follow-up. • In-hospital registry to monitor prasugrel use and bleeding risk during the index hospitalization compared to clopidogrel in a real life EU clinical setting. Subjects with severe hepatic impairment. • Continue to analyse AE reports in clinical trials • Periodically review and analyse safety database for any spontaneously reported case associated with severe hepatic impairment • In –hospital registry will allow for identification of subjects with possible liver damage. 964 2009 Diarrhea and other GI ADRs; CNS AE Haemorahage: (Intracranial haemorrhage, Gastrointestinal haemorrhage, Intraocular haemorrhage Percutaneous Coronary Intervention-Related Haemorrhage, Coronary Artery Bypass Graft-Related Haemorrhage Other Procedure- Related Haemorrhage, Epistaxis) EM Registry Year 965 Title SEE Reoccurence of thrombocytopenia; Increased bone marrow reticulum; thrombocytosis; thrombotic, thromboembolitic complications; progression of existing hematological malignancies or MDS; --- romiplostim Patient Safety Registry (US and Canada) Prospective registry to assess safety of romiplostim treatment in adult patients with ITP (Study 20070797) Routine risk communication; Routine physician education REMS (US only); …. Pregnancy registry proposed; neutralizing antibodies - immunogenicity registry 2009 Regulatory Authority/Reg ion Product active ingredient Intervention Type EMA-EU romiplostim Safety Issue (AE) Reoccurence of thrombocytopenia; Increased bone marrow reticulum; thrombocytosis; thrombotic, thromboembolitic complications; progression of existing hematological malignancies or MDS EMA-EU tacrolimus Risk of cutaneous malignancy and lymphoma EMDHCPL EMA-EU ulipristal Adverse pregnancy effects Registry EMA-EU ustekinumab Infections EP EMA-EU Whole virion influenza virus, strain A/California/07/2 009 (H1N1)v Adverse pregnancy effects Registry EMA-EU duloxetine hepatic risks/ suicidality/ Hyperglycemia EM EMA-EU betaine anhydrous EMA-EU bivalirudin Registry/ EM SEE - 2009-07-06: risk of cutaneous malignancy and lymphoma The MAH was therefore requested to commit to providing a DHPC to be reviewed by the CHMP (see letter of undertaking attached to this report); Theoretical risk of cutaneous malignancy including Cutaneous T-cell lymphoma; Theoretical risk of other lymphoma; Children below 2 years of age; Safety of maintenance treatment beyond 12 months (children above 2 years of age) 966 2009 Other adverse pregnancy effects (eg perinatal/neonatal effects) depending on time of foetal exposure: Registry of exposed pregnancies 967 2009 Infecctions - STELARA Education Program including TB screening, appropriate patient selection, key efficacy and safety information 968 969 2009 2009 Data in pregnant women Observational Study 820901will includes individuals in a variety of risk groups. This study will also include pregnant women in the second or third trimester Spontaneous reports regarding AEs in pregnant women will be considered as medically significant, and will be followed up. Baxter will collaborate with MHRA (post-marketing data) as well as pregnancy registries in the UK Targeted questionnaire for follow-up investigation of hepatic events ongoing activity on a case-by-case basis; Targeted questionnaire for follow-up investigation of suicide-related events 970 2008 Uncommon cases of severe cerebral edema and hypermethioninemia were reported within 2 weeks to 6 months of starting betaine therapy (see section 4.8). Complete recovery was seen after treatment discontinuation: - Plasma methionine level should be monitored, at start of treatment and periodically thereafter. The plasma methionine concentrations should be kept below 1000 μM. - If any symptoms of cerebral oedema like morning headaches with vomiting and/or visual changes appear, plasma ethionine level and compliance to the diet should be checked and treatment with Cystadane interrupted. - If symptoms of cerebral oedema recur after re-introduction of treatment then betaine therapy should be discontinued indefinitely. 971 2007 Angiox is contraindicated in patients with active bleeding or increased risk of bleeding because of haemostasis disorders and/or irreversible coagulation disorders 972 2007 cerebral edema Bleeding events; Serious immunological events; INR increase following coadministration of warfarin and bivalirudin RD EMDHCPL Year 973 2009 974 2009 975 2009 Title SEE ; Splenomegaly and splenic rupture ; Malignant cell growth in patients with severe chronic neutropenia; Cutaneous vasculitis Osteoporosis; Exacerbation of rheumatoid arthritis; Allergic type reactions; Sweet's syndrome; Acute respiratory distress syndrome (ARDS); Alveolar haemorrhage manifesting as pulmonary infiltrates and hemoptysis ; Severe sickle cell crises (PT - sickle cell anaemia with crisis); Transformation to leukaemia or myelodysplastic syndrome in chronic severe leukaemia patients - Follow up of patients through SCN registry Increased risk of GvHD (PT - graft versus host disease, chronic graft versus host disease, acute graft versus host disease); Interaction withMyelosuppressive cytotoxic chemotherapy (Decreased effectiveness of filgrastim) (PT - Drug interaction); Interaction with Lithium (PT - Drug interaction); Immunogenicity which may manifest as lack of effect; Malignant cell growth (haematological malignancy and myelodysplastic syndrome) associated with GCSF use in normal donors. (PT - haematological malignancy, myelodyspla Targeted questionnaire Treatment with Diacomit must be excluded for patient with hepatic and renal impairment and liver function tests should be checked on a regular basis; Caution should be exercised when prescribing stiripentol to women of childbearing potential (adolescents) and efficient methods of contraception should be considered; Appropriate risk warning as regards use in pregnancy; Aptivus use should rule out breast-feeding Regulatory Authority/Reg ion Product active ingredient Safety Issue (AE) Intervention Type EMA-EU stiripentol Splenomegaly and splenic rupture; Malignant cell growth in patients with severe chronic neutropenia ; Cutaneous vasculitis; Exacerbation of rheumatoid arthritis; Allergic type reactions; Sweet's syndrome Acute respiratory distress Hepatic and renal impairment; teratogenicity; neurological disorders;GI events; neutropenia EMA-EU tripranavir Teratogenicity EM EMA-EU sildenafil Hypotension EP buprenorphine/n aloxone Neonatal withdrawal syndrome, other newborn conditions / Hepatitis, other liver abnormalities EP/ EM EMA-EU filgrastim Registry RD/ EP/ EM DHCPL 2010-01-20 - Hypotension - Educational programme for Health Care providers 2009-08-17 976 977 2009 2006 The CHMP, having considered the data submitted in the application is of the opinion that the following risk minimisation activities are necessary for the safe and effective use of the medicinal product: - Educational material to eye surgeons including the following: • the Direct Healthcare Professional Communication (DHPC) on the association of Silodosin with Intraoperative Floppy Iris Syndrome and the two literature references mentioned in the text of the communication (at launch); • a flow-chart describing the management of patients for which cataract surgery is scheduled (at launch and after launch); • an educational programme on the prevention and management of IFIS (at launch and after launch); covering the following topics: 1. clinically relevant literature references on the prevention and management of IFIS; 2. pre-operative assessment: eye surgeons and ophthalmic teams should establish whether patients scheduled for cataract surgery are being or have been treated with silodosin in order to ensure that appropriate measures are in place to manage IFIS during surgery. 3. recommendation to surgeons and ophthalmic teams: discontinuing treatment with α1adrenoceptor antagonists 2 weeks prior to cataract surgery has been recommended, but the benefit and duration of stopping therapy prior to cataract surgery has not yet been established. EMA-EU Year 978 979 Title Hepatic reactions ; Restricted distribution with initiation and supervision of treatment by a specialist experienced in the treatment of rheumatoid arthritis and psoriatic arthritis ([Section 4.2] of SPC). Communication and Educational Program to emphasize to prescribers the importance of monitoring liver function. Blood cytopenia; Severe skin reactions (Restricted distribution through legal status of prescription). Infections: (Restricted distribution through legal status of prescription). Communication and Educational Program to emphasize to prescribers the immunosuppressive properties of leflunomide, the risk of infections including opportunistic infections and the contraindication for use in immuno-compromised patients. Interstitial Lung Disease: (Restricted distribution through legal status of prescription). Teratogenicity: Communication and Educational Program to communicate the risk of teratogenicity and to emphasize the recommendation to patients to avoid pregnancy until leflunomide levels are at an appropriate level. Ad hoc information service to provide patients and prescribers with information on the testing of plasma leflunomide levels after the waiting period. Restricted distribution with initiation and supervision of treatment by a specialist experienced in the treatment of rheumatoid arthritis and psoriatic arthritis ([Section 4.2] of SPC). Hypotension: (Restricted distribution through legal status of prescription). Interactions with other DMARDs (methotrexate): Restricted distribution with initiation and supervision of treatment by a specialist experienced in the treatment of rheumatoid arthritis and psoriatic arthritis ([Section 4.2] of SPC). Communication and educational activities to ensure the safe and effective use of leflunomide in the appropriate patient population, particularly with regard to combination with other DMARDs. Male-mediated foetal toxicity ; Lympho-proliferative disorders; Progressive multifocal leuko-encephalopathy; Use in children - (Restricted distribution through legal status of prescription). 2009 2009 Regulatory Authority/Reg ion EMA-EU Neutropenia and thrombocytopenia; Infection; Bleeding Events; Thrombosis / Thromboembolism; Peripheral Neuropathy - Direct Healthcare Professional Communication prior to launch • Health Care Professional Kit • Patient Brochure Foetal Exposure - Details of Pregnancy Prevention Programme including: o Criteria for women of non childbearing potential; o Counselling; Contraception; Pregnancy testing; Precautions for men o Additional precautions; o Reference to the company providing; Educational materials----- Pregnancy Prevention Programme o Educational Programme; • Direct Healthcare Professional; Communication prior to launch • Educational Health Care; Professional Kit to include HCP; booklet, Treatment Algorithm, Pregnancy Reporting Form, Patient; Card and Checklists; • Patient Brochure; o Therapy Management • Criteria for determining women of childbearing potential (WCBP), effective contraceptive measuresfor WCBP, regular pregnancy testing for WCBP • Advise provided on SPC, outlined in Direct Healthcare Professional Communication and detailed inEducational Materials o System to ensure all appropriatemeasures have been completed • Patient card to document childbearing status, counsellingand pregnancy testing EMA-EU Product active ingredient Safety Issue (AE) Intervention Type leflunomide Hepatic reactions, Blood cytopenia, Infectins, Interstitial lung disease, teratogenicity RD/ EP/ EM lenalidomide Neutropenia and thrombocytopenia; Infection; Bleeding Events; Thrombosis / Thromboembolism; Peripheral Neuropathy PtAC /EP/ EMDHCPL/ REGIST RY 980 2004 Important Safety Information PMDA-JPN argatroban 981 2004 Important Safety Information PMDA-JPN clarithromycin Fulminant hepatitis, hepatic function disorder and jaundice: Fulminant hepatitis, hepatic dysfunction, jaundice, hepatic failure: Since fulminant hepatitis; Thrombocytopenia, pancytopenia, hemolytic anemia, leukopenia, agranulocytosis; Pseudomembranous colitis, hemorrhagic colitis; Convulsion; Allergic purpura; Acute renal failure EM EM Year Title Regulatory Authority/Reg ion Product active ingredient Safety Issue (AE) Oculomucocutaneous syndrome (Stevens-Johnson syndrome), erythema multiforme exudativum Reports of death resulting from aggravation of pathological conditions after administration of this drug for treatment of brain oedema in patients with adult-onset type II citrullinemia Intervention Type 982 2004 Important Safety Information PMDA-JPN clofedanol HCl 983 2004 Important Safety Information PMDA-JPN Concentrated Glycerin/Fructo 984 2004 Important Safety Information PMDA-JPN doxazosin mesilate 985 2004 Important Safety Information PMDA-JPN flavoxate HCl Hepatitis, hepatic function disorder, jaundice Hepatic function disorder, jaundice (initial symptoms: general malaise, anorexia, pyrexia, itching, yellow ocular colouring, etc.): PMDA-JPN fluorouracil (injectable dosage form) Hyperammonemia accompanying consciousness disturbed PMDA-JPN imatinib mesilate EM infliximab (Genetical recombination) Injectable antibiotics Tumor haemorrhage, gastrointestinal perforation; Interstitial pneumonia, pulmonary fibrosis; Pericarditis; Brain oedema, intracranial pressure increased; Ileus paralytic; Thrombosis, embolism. Sepsis, pneumonia (including pnemocystis carinii pneumonia), and opportunistic infections such as fungal infectious disorders; Interstitial pneumonia: Shock EM Severe infection such as sepsis, pneumonia etc.; Aseptic meningitis [In case for subacute sclerosing panencephalitis by intrathecal (or intraventricular) administration EM 986 987 2004 2004 Important Safety Information Important Safety Information 988 2004 Important Safety Information PMDA-JPN 989 2004 Safety measures for shock etc. due to injectable antibiotics etc. PMDA-JPN 990 2004 Important Safety Information PMDA-JPN interferon alfa (NAMALWA) EM EM EM EM EM EM Year 991 2004 Title Important Safety Information Regulatory Authority/Reg ion PMDA-JPN Product active ingredient Safety Issue (AE) Intervention Type melphalan (injectable dosage form) Shock, anaphylactoid symptoms; Serious hepatic function disorder, jaundice: EM EM EM 992 2004 Important Safety Information PMDA-JPN monoethanolami ne oleate Acute respiratory distress syndrome and pulmonary oedema 993 2004 Important Safety Information PMDA-JPN mosapride citrate Hepatitis fulminant, hepatic function disorder, jaundice: 994 2004 Important Safety Information PMDA-JPN oseltamivir phosphate 995 2004 Important Safety Information PMDA-JPN paclitaxel 996 2004 Important Safety Information PMDA-JPN 997 2004 Important Safety Information PMDA-JPN phtharal salicylamide/acet aminophen/anhy drous caffeine /promethazine methylenedisalic ylate Pneumonia; Psychoneurological symptoms (e.g. disturbances in consciousness, abnormal behaviour, delirium, hallucination, delusion, convulsions) Myocardial infarction, cardiac failure congestive, cardiac conduction disorders, pulmonary embolism, thrombophlebitis, cerebral apoplexy, pulmonary oedema; Gastrointestinal necrosis, gastrointestinal perforation, haemorrhage of digestive tract, gastrointestinal ulcer; Serious enterocolitis; Intestinal obstruction, paralysis intestinal. EM EM Bullous keratopathy; Anaphylactic shock EM Glaucoma EM Year 998 999 1000 2004 2004 2004 Title Important Safety Information Important Safety Information Important Safety Information Regulatory Authority/Reg ion Product active ingredient Safety Issue (AE) Intervention Type PMDA-JPN sodium rabeprazole Pancytopenia, agranulocytosis, thrombocytopenia and hemolytic anemia; Fulminant hepatitis, hepatic function disorders and jaundice; Toxic epidermal necrolysis (Lyell syndrome), oculomucocutaneous syndrome (Stevens-Johnson syndrome) and erythema multiforme; Interstitial pneumonia PMDA-JPN sodium risedronate hydrate Hepatic function disorder, jaundice. EM PMDA-JPN tacrolimus hydrate (oral dosage form, injectable dosage form) Pancreatitis EM Tegafur/Gimerac il/Oteracil Potassium Serious stomatitis, gastrointestinal ulceration, haemorrhage of digestive tract, gastrointestinal perforation EM Loss of consciousness; Hepatic function disorder EM EM 1001 2004 Important Safety Information PMDA-JPN 1002 2004 Important Safety Information PMDA-JPN 1003 2004 Important Safety Information PMDA-JPN telithromycin vinorelbine ditartrate Acute pancreatitis EM PMDA-JPN Adsorbed DiphtheriaPurified PertussisiTetanus Combined Vaccine Encephalopathy; Convulsions EM PMDA-JPN alprostadil, alprostadil Alfadex (20 ug injectable dosage form) Myocardial infarction EM amiodarone HCl Hepatitis fulminant, hepatic cirrhosis, liver disorder. EM 1004 1005 1006 2005 2005 2005 Important Safety Information Important Safety Information Important Safety Information PMDA-JPN Year 1007 1008 1009 1010 2005 2005 2005 2005 Title Important Safety Information Important Safety Information Important Safety Information Important Safety Information Regulatory Authority/Reg ion Product active ingredient Safety Issue (AE) Intervention Type PMDA-JPN barium sulfate (excepting preparation for CT) Shock, anaphylactoid symptoms; Gastrointestinal perforation, intestinal obstruction, and peritonitis: EM PMDA-JPN Blood Glucose Self-monitoring Kit(those using the glucose dehydrogenase method and coenzyme pyroloquinoline quinone) Hypoglycaemia EM PMDA-JPN candesartan cilexetil, telmisartan, valsartan, losartan potassium Hypoglycemia EM carboplatin Hepatic failure, hepatic function disorder, and jaundice; Gastrointestinal necrosis, gastrointestinal perforation, haemorrhage of digestive tract, and gastrointestinal ulcer; Enterocolitis haemorrhagic and pseudomembranous colitis; Enterocolitis haemorrhagic and pseudomembranous colitis; Acute respiratory distress syndrome; Disseminated intravascular coagulation (DIC); Acute pancreatitis EM EM PMDA-JPN 1011 2005 Important Safety Information PMDA-JPN ceftriaxone sodium Gallstones, intrabiliary debris; Calculus renal and calculus urinary: 1012 2005 Important Safety Information PMDA-JPN donepezil HCl Rhabdomyolysis EM epirubicin HCl Bone marrow depression; Liver and biliary tract disorders; Gastric ulcer, duodenal ulcer: EM 1013 2005 Important Safety Information PMDA-JPN Year 1014 1015 1016 2005 2005 2005 Title Important Safety Information Important Safety Information Important Safety Information Regulatory Authority/Reg ion Product active ingredient Safety Issue (AE) Intervention Type ethionamide Fulminant hepatitis and acute hepatitis etc. EM PMDA-JPN etodolac Oculomucocutaneous syndrome (Stevens-Johnson syndrome) and toxic epidermal necrolysis (Lyell syndrome) EM PMDA-JPN fludarabine phosphate Autoimmune thrombocytopenia; Aplasia pure red cell EM Thromboembolism; Cardiac failure EM PMDA-JPN 1017 2005 Important Safety Information PMDA-JPN Freeze-dried Sulfonated Human Normal Immunoglobulin, pH4 Treated Acidic Human Normal Immunoglobulin, Polyethylene Glycol Treated Human Normal Immunoglobulin, Freeze-dried Polyethylene Glycol Treated Human Normal Immunoglobulin 1018 2005 Important Safety Information PMDA-JPN gemcitabine HCl Myocardial infarction EM 1019 2005 Important Safety Information PMDA-JPN Hochuekkito Interstitial pneumonia EM Idiopathic thrombocytopenic purpura; Encephalopathy; Convulsions EM 1020 2005 Important Safety Information PMDA-JPN Japanese Encephalitis Vaccine 1021 2005 Leflunomide-related interstitial pneumonia PMDA-JPN leflunomide Interstitial pneumonia EM PMDA-JPN leuprorelin acetate Pituitary apoplexy has been reported in patients with pituitary adenoma. EM 1022 2005 Important Safety Information Year 1023 1024 2005 2005 Title Important Safety Information Important Safety Information Regulatory Authority/Reg ion PMDA-JPN PMDA-JPN Intervention Type Product active ingredient Safety Issue (AE) lopinavir/ritonav ir Bradyarrhythmia; Erythema multiforme, oculomucocutaneous syndrome (Stevens-Johnson syndrome) EM mizoribine Gastrointestinal ulceration, digestive tract haemorrhage, gastrointestinal perforation; Severe skin disorder; Pancreatitis; Hyperglycaemia and diabetes mellitus: EM Agranulocytosis, pancytopenia, haemolytic anaemia, platelets decreased; Nephritis interstitial, acute renal failure EM 1026 2005 Important Safety Information PMDA-JPN omeprazole, omeprazole sodium phenytoin, phenytoin Sodium, phenytoin/pheno barbital, phenytoin/pheno barbital/caffeine and sodium benzoate 1027 2005 Important Safety Information PMDA-JPN phtharal Hepatitis fulminant, hepatic function disorder, and jaundice; Cerebellar atrophy: Shock and anaphylactoid symptoms PMDA-JPN pranoprofen (oral dosage form) Interstitial pneumonia, eosinophilic pneumonia EM Tendon rupture: EM Agranulocytosis, leucopenia EM 1025 1028 2005 2005 Important Safety Information Important Safety Information PMDA-JPN EM EM 1029 2005 Important Safety Information PMDA-JPN 1030 2005 Important Safety Information PMDA-JPN prednisolone (oral dosage form) quetiapine fumarate 1031 2005 Important Safety Information PMDA-JPN raloxifene HCl Hepatic function disorder: EM sevoflurane Rhabdomyolysis; Hepatic function disorder, jaundice; Serious arrhythmia: EM 1032 2005 Important Safety Information PMDA-JPN Year Title Regulatory Authority/Reg ion Product active ingredient Safety Issue (AE) Intervention Type 1033 2005 Important Safety Information PMDA-JPN sodium valproate 1034 2005 Important Safety Information PMDA-JPN telithromycin Hypersensitivity syndrome: rash, pyrexia or other initial symptoms which are followed by swollen glands, hepatic function disorder, increased white blood cell count, increased eosinophil count or appearance of atypical lymphocytes Loss of consciousness, accommodation disorder, vision blurred, etc. may occur torasemide Hepatic function disorder, jaundice; Hypokalaemia, hyperkalaemia: EM Whole Human Blood, Blood Respiratory disorder and transfusion-related acute lung injury; Cardiac function disturbance/arrhythmia; Renal impairment; Hepatic function disorder: EM Zedoary Powder and Japanese Tangle Powder Preparation Skin symptoms; Gastrointestinal symptoms;Anaphylactoid symptoms; Hepatic function disorder EM PMDA-JPN selegiline HCl Neuroleptic malignant syndrome; Hypoglycaemia; Gastric ulcer: EM PMDA-JPN alteplase (Genetical recombination) Acute ischemic cerebrovascular disorder; Aortic aneurysm rupture EM PMDA-JPN amiodarone HCl (oral dosage form) Hyperthyroidism, thyroiditis, hypothyroidism: EM 1035 1036 1037 1038 1039 1040 2005 2005 2005 2006 2007 2007 Important Safety Information Important Safety Information Important Safety Information Important Safety Information Important Safety Information Important Safety Information PMDA-JPN PMDA-JPN PMDA-JPN EM EM Year 1041 2007 Title Important Safety Information Regulatory Authority/Reg ion PMDA-JPN Product active ingredient amiodarone HCl (oral dosage form), Amiodarone HCl (injectable dosage form) Safety Issue (AE) Pulmonary alveolar haemorrhage: Intervention Type EM 1042 2007 Important Safety Information PMDA-JPN atorvastatin Calcium Hydrate 1043 2007 Important Safety Information PMDA-JPN cabergoline Agranulocytosis, pancytopenia, thrombocytopenia Pleurisy, pleural effusion, pleural fibrosis, pulmonary fibrosis, pericarditis, pericardial effusion; Cardiac valvulopathy; Retroperitoneal fibrosis: 1044 2007 Important Safety Information PMDA-JPN cefcapene pivoxil HCl Hepatitis fulminant, hepatic function disorder, jaundice EM cibenzoline succinate (oral dosage form) Interstitial pneumonia: EM Fulminant hepatitis, hepatic dysfunction, jaundice: Nephrogenic systemic fibrosis (NSF): EM EM 1045 2007 Important Safety Information PMDA-JPN 1046 2007 Important Safety Information PMDA-JPN 1047 2007 Important Safety Information PMDA-JPN edaravone gadodiamide hydrate 1048 2007 Important Safety Information PMDA-JPN Junchoto Interstitial pneumonia EM Nephritis interstitial leading to acute renal failure may occur, EM 1049 2007 Important Safety Information PMDA-JPN lansoprazole, lansoprazole / amoxicillin / clarithromycin 1050 2007 Important Safety Information PMDA-JPN meropenem trihydrate 1051 2007 Important Safety Information PMDA-JPN Nyoshinsan 1052 2007 Important Safety Information PMDA-JPN 1053 2007 Important Safety Information PMDA-JPN oxycodone HCl Hydrate pergolide mesilate Hepatitis fulminant, hepatic function disorder, jaundice: Hepatic function disorder, jaundice: EM EM EM EM Hepatic function disorder: EM Cardiac valvulopathy: EM Year 1054 2007 Title Important Safety Information Regulatory Authority/Reg ion PMDA-JPN Product active ingredient risperidone Safety Issue (AE) Hyperglycaemia, diabetic ketoacidosis, diabetic coma; Diabetic ketoacidosis Intervention Type EM 1055 2007 Important Safety Information PMDA-JPN rituximab (Genetical recombination) 1056 2007 Important Safety Information PMDA-JPN Seihaito Hepatitis fulminant or exacerbation of hepatitis caused by hepatitis B virus; Hepatic function disorder, jaundice; Gastrointestinal perforation: Hepatic function disorder, jaundice EM EM EM 1057 2007 Important Safety Information PMDA-JPN thiamazole Pancytopaenia, aplastic anaemia, agranulocytosis, white blood cell decreased: 1058 2007 Important Safety Information PMDA-JPN tizanidine HCl Hepatitis, hepatic function disorder, jaundice: EM zolpidem Tartrate Psychiatric symptoms, consciousness disturbed; Transient anterograde amnesia, twilight state: EM EM 1059 2007 Important Safety Information PMDA-JPN 1060 2007 Important Safety Information PMDA-JPN zopiclone Psychiatric symptoms, consciousness disturbed; Transient anterograde amnesia, twilight state: 1061 2008 Important Safety Information PMDA-JPN azelnidipine Hepatitis fulminant EM Hepatic function disorder, jaundice; Renal failure acute; Myocardial disorder, cardiac failure, cardiac tamponade, pericarditis: EM 1062 2008 Important Safety Information PMDA-JPN cyclophosphamid e (oral dosage form), cyclophosphamid e (injectable dosage form) 1063 2008 Interstitial pneumonia from interferon preparations (preparations with the indication for “improvement of viraemia in chronic hepatitis C”) PMDA-JPN interferon preparations interstitial pneumonia EM 1064 2008 Hypermagnesaemia following the administration of magnesium oxide PMDA-JPN magnesium oxide Hypermagnesaemia EM sudden onset of sleep EM Ileus EM 1065 2008 Sudden onset of sleep, etc. associated with non-ergoline dopamine agonists (patients must be advised to refrain from driving, etc.) PMDA-JPN non-ergoline dopamine agonist 1066 2008 Important Safety Information PMDA-JPN tiotropium bromide hydrate Year 1067 1068 1069 2009 2009 2009 Title Important Safety Information Important Safety Information Important Safety Information Regulatory Authority/Reg ion Product active ingredient Safety Issue (AE) Intervention Type PMDA-JPN bevacizumab (genetical recombination) Interstitial pneumonia EM PMDA-JPN ciprofloxacin, ciprofloxacin HCl Fulminant hepatitis, hepatic function disorder, jaundice: EM PMDA-JPN Enteral nutrition (Elental, Elental P, Ensure・H, Ensure Liquid, Enterued, Twinline, Harmonic-F, Harmonic-M, Racol) Shock, anaphylactoid symptoms: EM Oculomucocutaneous syndrome (Stevens-Johnson syndrome), toxic epidermal necrolysis (Lyell syndrome), erythema multiforme EM Progressive multifocal leukoencephalopathy (PML); BK viral nephropathy: EM 1071 2009 Important Safety Information PMDA-JPN Etanercept (genetical recombination) everolimus, gusperimus HCl, cyclosporine (oral dosage form, injectable dosage form), tacrolimus hydrate (oral dosage form, injectable dosage form), basiliximab (genetical recombination), mycophenolate mofetil, muromonabCD3 1072 2009 Skin necrosis/ulcer following injection of hydroxyzine HCl PMDA-JPN hydroxyzine Skin necrosis / ulcer EM EM EM 1070 2009 Important Safety Information PMDA-JPN 1073 2009 anaphylaxis and anaphylactoid symptoms associated with injectable antibiotics PMDA-JPN injectable antibiotics Anaphylaxis and anaphylactoid symptoms associated with injectable antibiotics 1074 2009 Association between use of human insulin and insulin analogues and risk of cancer PMDA-JPN insulin Risk of cancer Year Title Regulatory Authority/Reg ion Product active ingredient Safety Issue (AE) Intervention Type 1075 2009 Important Safety Information PMDA-JPN isoflurane 1076 2009 Important Safety Information PMDA-JPN ivermectin Shock, anaphylactoid symptoms; Hepatitis, hepatic function disorder: Hepatic function disorder, jaundice: PMDA-JPN iornoxicam Hepatitis fulminant, hepatic function disorder, and jaundice: Serious hepatitis such as hepatitis fulminant, EM PMDA-JPN monobasic sodium phosphate monohydrate and anhydrous dibasic sodiumpPhospha te Acute renal failure or acute phosphate nephropathy (nephrocalcinosis); Acute renal failure, acute phosphate nephropathy EM PMDA-JPN pethidine HCl, pethidine HCl/levallorphan tartrate Shock, Anaphylactic shock EM PMDA-JPN phenytoin,pPhen ytoin/phenobarbi tal, phenytoin/pheno barbital/caffeine and sodium benzoate, phenytoin sodium Rhabdomyolysis; Acute renal failure, interstitial nephritis: EM Pancytopenia, leukopenia, neutropenia, thrombocytopenia; Progressive multifocal leucoencephalopathy (PML): EM Thrombocytopenia EM Hepatitis fulminant EM 1077 1078 1079 1080 2009 2009 2009 2009 Important Safety Information Important Safety Information Important Safety Information Important Safety Information EM EM 1081 2009 Rituximab (genetical recombination) PMDA-JPN 1082 2009 Important Safety Information PMDA-JPN 1083 2009 Important Safety Information PMDA-JPN rituximab (genetical recombination) rosuvastatin calcium salazosulfapyridi ne 1084 2009 Important Safety Information PMDA-JPN sorafenib tosilate Renal failure EM 1085 2009 Important Safety Information PMDA-JPN sorafenib tosilate Acute lung disorder and interstitial pneumonia EM SSRIs Hostility, aggression, and relevant harmful behavior to other EM 1086 2009 SSRIs/SNRIs and harmful behavior to others PMDA-JPN Year Title Regulatory Authority/Reg ion Product active ingredient Safety Issue (AE) Intervention Type 1087 2009 Selective serotonin reuptake inhibitors (SSRIs) and aggression PMDA-JPN SSRIs Aggression EM 1088 2009 Important Safety Information PMDA-JPN sunitinib malate Disseminated intravascular coagulation (DIC): EM Heart failure EM 1089 2009 Important Safety Information PMDA-JPN Tegafur/gimeraci l/oteracil potassium 1090 2009 Important Safety Information PMDA-JPN telmisartan Interstitial pneumonia: EM 1091 2009 Important Safety Information PMDA-JPN temozolomide Interstitial pneumonia EM Interstitial pneumonia: EM EM 1092 2009 Important Safety Information PMDA-JPN 1093 2009 Tricyclic and tetracyclic antidepressants, associated with aggression PMDA-JPN tocilizumab (Genetical recombination) Tricyclic and tetracyclic antidepressants, associated with aggression 1094 2009 Important Safety Information PMDA-JPN varenicline tartrate aggression May exacerbate pre-existing psychiatric illnesses; depressed mood, anxiety, feeling irritated, excitement, change in behavior or idea, mental disorder, mood variable, aggressive behavior, hostility, suicide ideation, and suicide EM EM 1095 2001 Bupropion (Zyban SR) (31 August 2001) TGA-AUS bupropion Suspected adverse reactions to bupropion where the patient died 1096 2001 Cerivastatin (withdrawal from sale) (10 August 2001) TGA-AUS cerivastatin Rhabdomyolysis Withdra wal 1097 2002 Oestrogen replacement therapy and increased risk of ovarian cancer (7 August 2002) TGA-AUS HRT Risk of ovarian cancer EM 1098 2004 Review of Aspirin / Reye's syndrome warning statement TGA-AUS Aspirin (ASA) Reye's syndrome EM 1099 2004 Potential safety risks with Celebrex (18 December 2004) TGA-AUS celecoxib Possible heart attacks EM 1100 2004 Doctors urged to keep check on daughters of women who used pregnancy drug three decades ago (media statement, 4 June 2004) TGA-AUS diethylstilboestro l (DES) Vaginal abnormalities EM Year Title Regulatory Authority/Reg ion 1101 2004 Use of SSRI antidepressants in children and adolescents (ADRAC, 15 October 2004) TGA-AUS 1102 2005 Regulator takes tough action on arthritis drugs (25 February 2005) TGA-AUS Product active ingredient SSRIs Coxibs (celecoxib; lumiracoxib; meloxicam) Safety Issue (AE) Intervention Type Suicidality EM Increased risk of heart attacks and strokes EM EM 1103 2005 Advice for women taking paroxetine intending to become pregnant or in early preganancy (7 September 2005) TGA-AUS paroxetine Increased risk of some congenital malformations in babies 1104 2006 Phenylpropanolamine (7 March 2006) TGA-AUS phenylpropanola mine Haemorrhagic stroke EM 1105 2007 Bisphosphonate drugs and osteonecrosis of the jaw (ONJ) TGA-AUS Bisphosphonate drugs Osteonecrosis of the jaw EM 1106 2007 Urgent advice regarding management of patients taking lumiracoxib (Prexige) (advice for health professionals, 13 August 2007) TGA-AUS lumiracoxib Serious liver adverse reactions Withdra wal 1107 2007 Trasylol (aprotinin) injection (9 November 2007) TGA-AUS aprotinin 1108 2008 TGA announcement regarding the use of cough and cold medicines in children (17 April 2008 TGA-AUS Cough & Cold medicines 1109 2008 Screening guidelines for women exposed in utero to diethylstilboestrol (DES) (23 April 2008) TGA-AUS Diethylstilboestr ol (DES) 1110 2008 Stilnox: Zolpidem (Stilnox) (21 February 2008) TGA-AUS Safety concerns Misuse, medication error, accidental overdose, accidental exposure and concurrent use of multiple products Withdra wal EM TDM zolpidem Cervical cancer Bizarre and sometimes dangerous sleep related behaviours such as sleep walking and sleep driving Increased cancer risk EM Serious adverse reactions, including liver toxicity EM 1111 2008 Vytorin and cancer risk (4 September 2008) TGA-AUS ezetimibe / simvastatin 1112 2009 Advice to consumers regarding Hydroxycut products (8 May 2009) TGA-AUS hydroxycut EM
