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www.uspharmacist.com Psy Foc cho us o tro n pic s H EALTH S YS TEMS EDITION NO VEM B E R 20 09 T H E J O U R N A L F O R P H A R M A C I S T S ’ E D U C AT I O N Treating Alcoholism for Optimal Results Opioid Dependence & Withdrawal Controlling Schizophrenia Symptoms Prophylactic Medications in Traumatic Brain Injury 2 CE Credits Emergency Contraception: Clinical and Regulatory Update New Products in This Issue: Afinitor / Novartis Pharmaceuticals Corporation • Authorized Generics / Greenstone LLC • Distinctive Labeling / Baxter Healthcare • Embeda / King Pharmaceuticals • Injectables / Pfizer Injectables • Kapidex / Takeda Pharmaceuticals • Onglyza / AstraZeneca • Product Labeling / Teva Pharmaceuticals • Uloric / Takeda Pharmaceuticals • Welchol / Daiichi-Sankyo F OR FR EE C E, GO TO: www.uspharmacist.com A J O B S O N P U B L I C AT I O N Indication ULORIC is a xanthine oxidase (XO) inhibitor indicated for the chronic management of hyperuricemia in patients with gout. ULORIC is not recommended for the treatment of asymptomatic hyperuricemia. Important Safety Information • ULORIC is contraindicated in patients being treated with azathioprine, mercaptopurine, or theophylline. • An increase in gout flares is frequently observed during initiation of anti-hyperuricemic agents, including ULORIC. If a gout flare occurs during treatment, ULORIC need not be discontinued. Prophylactic therapy (i.e. - NSAIDs or colchicine) upon initiation of treatment may be beneficial for up to six months. • Cardiovascular Events: In randomized controlled studies, there was a higher rate of cardiovascular thromboembolic events (cardiovascular deaths, non-fatal myocardial infarctions, and non-fatal strokes) in patients treated with ULORIC [0.74 per 100 P-Y (95% CI 0.36-1.37)] than allopurinol [0.60 per 100 P-Y (95% CI 0.16-1.53)]. A causal relationship with ULORIC has not been established. Monitor for signs and symptoms of MI and stroke. • Liver Enzyme Elevations: In randomized controlled studies, transaminase elevations greater than 3 times the upper limit of normal (ULN) were observed (AST: 2%, 2%, and ULORIC® is a registered trademark of Teijin Pharma Limited and used under license by Takeda Pharmaceuticals America, Inc. ©2009 Takeda Pharmaceuticals North America, Inc. TXF-00319 08/09 ULORIC powerfully lowers serum uric acid levels for long-term control of gout. Powerfully lowers serum uric acid1 • In the largest phase 3 study (6 months): - 45% of patients who received ULORIC 40 mg achieved serum uric acid levels of <6 mg/dL (N=757) compared to 42% of patients who received allopurinol 300 mg (N=755; p=0.233) - 67% of patients who received ULORIC 80 mg achieved serum uric acid levels of <6 mg/dL (N=756) compared to 42% of patients who received allopurinol 300 mg (N=755; p<0.001) Extensively studied safety profile1 • The safety profile of ULORIC has been evaluated2 - In more than 4000 patients - In some for more than 5 years Simple, once-daily dosing1 • Available in 40- and 80-mg tablets for once-daily dosing with a starting dose of 40 mg • No dose adjustments required in patients with mild to moderate renal or hepatic impairment* *There are insufficient data in patients with severe renal dysfunction, and no studies have been conducted in patients with severe hepatic impairment. Caution should be exercised in these patients. ALT: 3%, 2% in ULORIC and allopurinol-treated patients, respectively). No dose-effect relationship for these transaminase elevations was noted. Laboratory assessment of liver function is recommended at, for example, 2 and 4 months following initiation of ULORIC and periodically thereafter. • Adverse reactions occurring in at least 1% of ULORIC-treated patients, and, at least 0.5% greater than placebo, are liver function abnormalities, nausea, arthralgia, and rash. Individual results may vary based on factors such as baseline serum uric acid levels. Please see brief summary of complete Prescribing Information on adjacent pages. References: 1. ULORIC® (febuxostat) full prescribing information, February 2009. 2. Data on file, Takeda Pharmaceuticals North America, Inc. For more information, please visit www.ULORIC.com. BRIEF SUMMARY OF FULL PRESCRIBING INFORMATION for ULORIC® (febuxostat) tablets INDICATIONS AND USAGE ULORIC® is a xanthine oxidase (XO) inhibitor indicated for the chronic management of hyperuricemia in patients with gout. ULORIC is not recommended for the treatment of asymptomatic hyperuricemia. CONTRAINDICATIONS ULORIC is contraindicated in patients being treated with azathioprine, mercaptopurine, or theophylline [see Drug Interactions]. WARNINGS AND PRECAUTIONS Gout Flare After initiation of ULORIC, an increase in gout flares is frequently observed. This increase is due to reduction in serum uric acid levels resulting in mobilization of urate from tissue deposits. In order to prevent gout flares when ULORIC is initiated, concurrent prophylactic treatment with an NSAID or colchicine is recommended. Cardiovascular Events In the randomized controlled studies, there was a higher rate of cardiovascular thromboembolic events (cardiovascular deaths, non-fatal myocardial infarctions, and non-fatal strokes) in patients treated with ULORIC [0.74 per 100 P-Y (95% CI 0.36-1.37)] than allopurinol [0.60 per 100 P-Y (95% CI 0.16-1.53)] [see Adverse Reactions]. A causal relationship with ULORIC has not been established. Monitor for signs and symptoms of myocardial infarction (MI) and stroke. Liver Enzyme Elevations During randomized controlled studies, transaminase elevations greater than 3 times the upper limit of normal (ULN) were observed (AST: 2%, 2%, and ALT: 3%, 2% in ULORIC and allopurinol-treated patients, respectively). No dose-effect relationship for these transaminase elevations was noted. Laboratory assessment of liver function is recommended at, for example, 2 and 4 months following initiation of ULORIC and periodically thereafter. ADVERSE REACTIONS Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. A total of 2757 subjects with hyperuricemia and gout were treated with ULORIC 40 mg or 80 mg daily in clinical studies. For ULORIC 40 mg, 559 patients were treated for r 6 months. For ULORIC 80 mg, 1377 subjects were treated for r 6 months, 674 patients were treated for r 1 year and 515 patients were treated for r 2 years. Most Common Adverse Reactions In three randomized, controlled clinical studies (Studies 1, 2 and 3), which were 6 to 12 months in duration, the following adverse reactions were reported by the treating physician as related to study drug. Table 1 summarizes adverse reactions reported at a rate of at least 1% in ULORIC treatment groups and at least 0.5% greater than placebo. Table 1: Adverse Reactions Occurring in r 1% of ULORIC-Treated Patients and at Least 0.5% Greater than Seen in Patients Receiving Placebo in Controlled Studies Placebo Adverse Reactions Liver Function Abnormalities Nausea Arthralgia Rash ULORIC allopurinol* (N=134) 40 mg daily (N=757) 80 mg daily (N=1279) (N=1277) 0.7% 6.6% 4.6% 4.2% 0.7% 1.1% 1.3% 0.8% 0% 1.1% 0.7% 0.7% 0.7% 0.5% 1.6% 1.6% *Of the subjects who received allopurinol, 10 received 100 mg, 145 received 200 mg, and 1122 received 300 mg, based on level of renal impairment. The most common adverse reaction leading to discontinuation from therapy was liver function abnormalities in 1.8% of ULORIC 40 mg, 1.2% of ULORIC 80 mg, and in 0.9% of allopurinol-treated subjects. In addition to the adverse reactions presented in Table 1, dizziness was reported in more than 1% of ULORIC-treated subjects although not at a rate more than 0.5% greater than placebo. Less Common Adverse Reactions In phase 2 and 3 clinical studies the following adverse reactions occurred in less than 1% of subjects and in more than one subject treated with doses ranging from 40 mg to 240 mg of ULORIC. This list also includes adverse reactions (less than 1% of subjects) associated with organ systems from Warnings and Precautions. Blood and Lymphatic System Disorders: anemia, idiopathic thrombocytopenic purpura, leukocytosis/leukopenia, neutropenia, pancytopenia, splenomegaly, thrombocytopenia; Cardiac Disorders: angina pectoris, atrial fibrillation/flutter, cardiac murmur, ECG abnormal, palpitations, sinus bradycardia, tachycardia; Ear and Labyrinth Disorders: deafness, tinnitus, vertigo; Eye Disorders: vision blurred; Gastrointestinal Disorders: abdominal distention, abdominal pain, constipation, dry mouth, dyspepsia, flatulence, frequent stools, gastritis, gastroesophageal reflux disease, gastrointestinal discomfort, gingival pain, haematemesis, hyperchlorhydria, hematochezia, mouth ulceration, pancreatitis, peptic ulcer, vomiting; General Disorders and Administration Site Conditions: asthenia, chest pain/discomfort, edema, fatigue, feeling abnormal, gait disturbance, influenza-like symptoms, mass, pain, thirst; Hepatobiliary Disorders: cholelithiasis/cholecystitis, hepatic steatosis, hepatitis, hepatomegaly; Immune System Disorder: hypersensitivity; Infections and Infestations: herpes zoster; Procedural Complications: contusion; Metabolism and Nutrition Disorders: anorexia, appetite decreased/increased, dehydration, diabetes mellitus, hypercholesterolemia, hyperglycemia, hyperlipidemia, hypertriglyceridemia, hypokalemia, weight decreased/increased; Musculoskeletal and Connective Tissue Disorders: arthritis, joint stiffness, joint swelling, muscle spasms/twitching/tightness/weakness, musculoskeletal pain/stiffness, myalgia; Nervous System Disorders: altered taste, balance disorder, cerebrovascular accident, Guillain-Barré syndrome, headache, hemiparesis, hypoesthesia, hyposmia, lacunar infarction, lethargy, mental impairment, migraine, paresthesia, somnolence, transient ischemic attack, tremor; Psychiatric Disorders: agitation, anxiety, depression, insomnia, irritability, libido decreased, nervousness, panic attack, personality change; Renal and Urinary Disorders: hematuria, nephrolithiasis, pollakiuria, proteinuria, renal failure, renal insufficiency, urgency, incontinence; Reproductive System and Breast Changes: breast pain, erectile dysfunction, gynecomastia; Respiratory, Thoracic and Mediastinal Disorders: bronchitis, cough, dyspnea, epistaxis, nasal dryness, paranasal sinus hypersecretion, pharyngeal edema, respiratory tract congestion, sneezing, throat irritation, upper respiratory tract infection; Skin and Subcutaneous Tissue Disorders: alopecia, angio edema, dermatitis, dermographism, ecchymosis, eczema, hair color changes, hair growth abnormal, hyperhidrosis, peeling skin, petechiae, photosensitivity, pruritus, purpura, skin discoloration/altered pigmentation, skin lesion, skin odor abnormal, urticaria; Vascular Disorders: flushing, hot flush, hypertension, hypotension; Laboratory Parameters: activated partial thromboplastin time prolonged, creatine increased, bicarbonate decreased, sodium increased, EEG abnormal, glucose increased, cholesterol increased, triglycerides increased, amylase increased, potassium increased, TSH increased, platelet count decreased, hematocrit decreased, hemoglobin decreased, MCV increased, RBC decreased, creatinine increased, blood urea increased, BUN/creatinine ratio increased, creatine phosphokinase (CPK) increased, alkaline phosphatase increased, LDH increased, PSA increased, urine output increased/decreased, lymphocyte count decreased, neutrophil count decreased, WBC increased/decreased, coagulation test abnormal, low density lipoprotein (LDL) increased, prothrombin time prolonged, urinary casts, urine positive for white blood cells and protein. Cardiovascular Safety Cardiovascular events and deaths were adjudicated to one of the pre-defined endpoints from the Anti-Platelet Trialists’ Collaborations (APTC) (cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke) in the randomized controlled and long-term extension studies. In the Phase 3 randomized controlled studies, the incidences of adjudicated APTC events per 100 patient-years of exposure were: Placebo 0 (95% CI 0.00-6.16), ULORIC 40 mg 0 (95% CI 0.00-1.08), ULORIC 80 mg 1.09 (95% CI 0.44-2.24), and allopurinol 0.60 (95% CI 0.16-1.53). In the long-term extension studies, the incidences of adjudicated APTC events were: ULORIC 80 mg 0.97 (95% CI 0.57-1.56), and allopurinol 0.58 (95% CI 0.02-3.24). Overall, a higher rate of APTC events was observed in ULORIC than in allopurinoltreated patients. A causal relationship with ULORIC has not been established. Monitor for signs and symptoms of MI and stroke. DRUG INTERACTIONS Xanthine Oxidase Substrate Drugs ULORIC is an XO inhibitor. Drug interaction studies of ULORIC with drugs that are metabolized by XO (e.g., theophylline, mercaptopurine, azathioprine) have not been conducted. Inhibition of XO by ULORIC may cause increased plasma concentrations of these drugs leading to toxicity [see Clinical Pharmacology]. ULORIC is contraindicated in patients being treated with azathioprine, mercaptopurine, or theophylline [see Contraindications]. Cytotoxic Chemotherapy Drugs Drug interaction studies of ULORIC with cytotoxic chemotherapy have not been conducted. No data are available regarding the safety of ULORIC during cytotoxic chemotherapy. In Vivo Drug Interaction Studies Based on drug interaction studies in healthy subjects, ULORIC does not have clinically significant interactions with colchicine, naproxen, indomethacin, hydrochlorothiazide, warfarin or desipramine. Therefore, ULORIC may be used concomitantly with these medications. USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C: There are no adequate and well-controlled studies in pregnant women. ULORIC should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Febuxostat was not teratogenic in rats and rabbits at oral doses up to 48 mg per kg (40 and 51 times the human plasma exposure at 80 mg per day for equal body surface area, respectively) during organogenesis. However, increased neonatal mortality and a reduction in the neonatal body weight gain were observed when pregnant rats were treated with oral doses up to 48 mg per kg (40 times the human plasma exposure at 80 mg per day) during organogenesis and through lactation period. Nursing Mothers Febuxostat is excreted in the milk of rats. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when ULORIC is administered to a nursing woman. Pediatric Use Safety and effectiveness in pediatric patients under 18 years of age have not been established. Geriatric Use No dose adjustment is necessary in elderly patients. Of the total number of subjects in clinical studies of ULORIC, 16 percent were 65 and over, while 4 percent were 75 and over. Comparing subjects in different age groups, no clinically significant differences in safety or effectiveness were observed but greater sensitivity of some older individuals cannot be ruled out. The Cmax and AUC24 of febuxostat following multiple oral doses of ULORIC in geriatric subjects (r 65 years) were similar to those in younger subjects (18-40 years). Renal Impairment No dose adjustment is necessary in patients with mild or moderate renal impairment (Clcr 30-89 mL per min). The recommended starting dose of ULORIC is 40 mg once daily. For patients who do not achieve a sUA less than 6 mg per dL after 2 weeks with 40 mg, ULORIC 80 mg is recommended. There are insufficient data in patients with severe renal impairment (Clcr less than 30 mL per min); therefore, caution should be exercised in these patients. Hepatic Impairment No dose adjustment is necessary in patients with mild or moderate hepatic impairment (Child-Pugh Class A or B). No studies have been conducted in patients with severe hepatic impairment (Child-Pugh Class C); therefore, caution should be exercised in these patients. Secondary Hyperuricemia No studies have been conducted in patients with secondary hyperuricemia (including organ transplant recipients); ULORIC is not recommended for use in patients whom the rate of urate formation is greatly increased (e.g., malignant disease and its treatment, Lesch-Nyhan syndrome). The concentration of xanthine in urine could, in rare cases, rise sufficiently to allow deposition in the urinary tract. OVERDOSAGE ULORIC was studied in healthy subjects in doses up to 300 mg daily for seven days without evidence of dose-limiting toxicities. No overdose of ULORIC was reported in clinical studies. Patients should be managed by symptomatic and supportive care should there be an overdose. CLINICAL PHARMACOLOGY Pharmacodynamics Effect on Uric Acid and Xanthine Concentrations: In healthy subjects, ULORIC resulted in a dose dependent decrease in 24-hour mean serum uric acid concentrations, and an increase in 24-hour mean serum xanthine concentrations. In addition, there was a decrease in the total daily urinary uric acid excretion. Also, there was an increase in total daily urinary xanthine excretion. Percent reduction in 24-hour mean serum uric acid concentrations was between 40% to 55% at the exposure levels of 40 mg and 80 mg daily doses. Effect on Cardiac Repolarization: The effect of ULORIC on cardiac repolarization as assessed by the QTc interval was evaluated in normal healthy subjects and in patients with gout. ULORIC in doses up to 300 mg daily, at steady state, did not demonstrate an effect on the QTc interval. Special Populations Renal Impairment: Following multiple 80 mg doses of ULORIC in healthy subjects with mild (Clcr 50-80 mL per min), moderate (Clcr 30-49 mL per min) or severe renal impairment (Clcr 10-29 mL per min), the Cmax of febuxostat did not change relative to subjects with normal renal function (Clcr greater than 80 mL per min). AUC and half-life of febuxostat increased in subjects with renal impairment in comparison to subjects with normal renal function, but values were similar among three renal impairment groups. Mean febuxostat AUC values were up to 1.8 times higher in subjects with renal impairment compared to those with normal renal function. Mean Cmax and AUC values for 3 active metabolites increased up to 2- and 4-fold, respectively. However, the percent decrease in serum uric acid concentration for subjects with renal impairment was comparable to those with normal renal function (58% in normal renal function group and 55% in the severe renal function group). No dose adjustment is necessary in patients with mild to moderate renal impairment [see Dosage and Administration and Use in Specific Populations]. The recommended starting dose of ULORIC is 40 mg once daily. For patients who do not achieve a sUA less than 6 mg per dL after 2 weeks with 40 mg, ULORIC 80 mg is recommended. There is insufficient data in patients with severe renal impairment; caution should be exercised in those patients [see Use in Specific Populations. ULORIC has not been studied in end stage renal impairment patients who are on dialysis. Hepatic Impairment: Following multiple 80 mg doses of ULORIC in patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment, an average of 20-30% increase was observed for both Cmax and AUC24 (total and unbound) in hepatic impairment groups compared to subjects with normal hepatic function. In addition, the percent decrease in serum uric acid concentration was comparable between different hepatic groups (62% in healthy group, 49% in mild hepatic impairment group, and 48% in moderate hepatic impairment group). No dose adjustment is necessary in patients with mild or moderate hepatic impairment. No studies have been conducted in subjects with severe hepatic impairment (Child-Pugh Class C); caution should be exercised in those patients [see Use in Specific Populations. NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis: Two-year carcinogenicity studies were conducted in F344 rats and B6C3F1 mice. Increased transitional cell papilloma and carcinoma of urinary bladder was observed at 24 mg per kg (25 times the human plasma exposure at maximum recommended human dose of 80 mg per day) and 18.75 mg per kg (12.5 times the human plasma exposure at 80 mg per day) in male rats and female mice, respectively. The urinary bladder neoplasms were secondary to calculus formation in the kidney and urinary bladder. Mutagenesis: Febuxostat showed a positive mutagenic response in a chromosomal aberration assay in a Chinese hamster lung fibroblast cell line with and without metabolic activation in vitro. Febuxostat was negative in the in vitro Ames assay and chromosomal aberration test in human peripheral lymphocytes, and L5178Y mouse lymphoma cell line, and in vivo tests in mouse micronucleus, rat unscheduled DNA synthesis and rat bone marrow cells. Impairment of Fertility: Febuxostat at oral doses up to 48 mg per kg per day (approximately 35 times the human plasma exposure at 80 mg per day) had no effect on fertility and reproductive performance of male and female rats. Animal Toxicology A 12-month toxicity study in beagle dogs showed deposition of xanthine crystals and calculi in kidneys at 15 mg per kg (approximately 4 times the human plasma exposure at 80 mg per day). A similar effect of calculus formation was noted in rats in a six-month study due to deposition of xanthine crystals at 48 mg per kg (approximately 35 times the human plasma exposure at 80 mg per day). PATIENT COUNSELING INFORMATION [see FDA-Approved Patient Labeling in the full prescribing information] General Information Patients should be advised of the potential benefits and risks of ULORIC. Patients should be informed about the potential for gout flares, elevated liver enzymes and adverse cardiovascular events after initiation of ULORIC therapy. Concomitant prophylaxis with an NSAID or colchicine for gout flares should be considered. Patients should be instructed to inform their healthcare professional if they develop a rash, chest pain, shortness of breath or neurologic symptoms suggesting a stroke. Patients should be instructed to inform their healthcare professional of any other medications they are currently taking with ULORIC, including over-the-counter medications. Distributed by Takeda Pharmaceuticals America, Inc. Deerfield, IL 60015 U.S. Patent Nos. - 6,225,474; 7,361,676; 5,614,520. ULORIC® is a registered trademark of Teijin Pharma Limited and used under license by Takeda Pharmaceuticals America, Inc. All other trademark names are the property of their respective owners ©2009 Takeda Pharmaceuticals America, Inc. February 2009 For more detailed information, see the full prescribing information for ULORIC (febuxostat) tablets (PI1114 R1; February 2009) or contact Takeda Pharmaceuticals America, Inc. at 1.877.825.3327. PI1114 R1-Brf; February 2009 L-TXF-0209-3 Straight Talk Pharmacy Technicians: Truth and Consequences ith the flu season quickly approaching, imagine an absolutely unbearable workday in your pharmacy. Anticipating the worst, you call in extra pharmacists and pharmacy technicians to help fill what are expected to be some of the busiest prescription days of the year. Sure enough, on a typical day during the flu outbreak, a line starts early at the prescription drop-off counter and continues to build throughout the day. Cars are stacked up at the drive-through prescription window as though McDonald’s were giving out free Big Macs. As physicians’ offices open, the pharmacy’s phones ring incessantly with new prescription orders and permissions to refill older prescriptions. Everyone is working to their fullest capacity, which necessitates extra effort from all pharmacy personnel. Pharmacists’ and technicians’ fingers are furiously tapping the computer keyboards trying to input data as quickly as possible while making sure important information is accurately recorded into patients’ medical records. Medication stock bottles are being pulled from every shelf in the pharmacy, with their tablets and capsules ready to be poured out into the smaller prescription containers and bottles lined up on the prescription counter, each awaiting a label with instructions to be affixed to it. Once filled, the prescriptions will be checked by a pharmacist before being dispensed to the patient. The pharmacy counter is a mess and resembles the trading floor of the New York Stock Exchange after a busy day, with notes on scrap paper strewn everywhere. Pharmacy technicians and pharmacists line up to fill the waiting prescription bottles and vials like a General Motors assembly line. And then it happens . . . a pharmacy technician prepares a prescription that contains a fatal dose of the medication. Because of the craziness in the pharmacy, the error gets passed over by a pharmacist who is sup- W posed to check each and every prescription before it is dispensed. A doomsday scenario, you say, that would never happen in your pharmacy? Maybe, but the truth is, it does happen, and it is more than likely that the pharmacist, not the technician, will pay the consequences of any error. Depending on its severity, the error could result in a hefty fine and prison time for the pharmacist. While the above scenario may be fictitious, a case reported by U.S. Pharmacist’s legal contributor, Jesse C. Vivian, BS Pharm, JD, in this month’s Legal Considerations column (page 66), is unfortunately all too real. In that case of a fatal error, the technician was charged with negligent homicide but was given a “get out of jail free” card by the court, wasn’t even fined, and actually went back to work in a retail pharmacy. The pharmacist, however, was found guilty of involuntary manslaughter and faced up to 5 years in prison and a $10,000 fine. His license was revoked, and he will probably never work again as a pharmacist. All this because he did not check the accuracy of a prescription filled by the technician. The column should be a wake-up call for every pharmacist who works closely with one or more pharmacy technicians. While it is true that each case of negligence involving a technician will be judged on the merits of the case, the message is clear. The truth is that if a pharmacist is not diligent about checking a technician’s work, the consequences could be dire. Harold E. Cohen, RPh Editor-in-Chief [email protected] 4 U.S. Pharmacist • November 2009 • www.uspharmacist.com U.S. Pharmacist What’s News Editorial Board of Advisors Joseph Bova, RPh Community Pharmacy Owner, Cary’s Pharmacy, Dobbs Ferry, New York; Member, NYS Board of Pharmacy Carmen Catizone, RPh Executive Director, National Association of Boards of Pharmacy John M. Coster, PhD, RPh Senior VP of Government Affairs National Community Pharmacists Assoc. Hewitt (Ted) W. Matthews, PhD Dean, Southern School of Pharmacy, Mercer University, Atlanta David G. Miller, RPh Pharmacy Affairs, Merck & Co., Inc., West Point, Pennsylvania Mario F. Sylvestri, PharmD, PhD Senior Director, Medical Science Liaisons, Amylin Pharmaceuticals Ray A. Wolf, PharmD Medical Education, Sanofi Aventis Mary Ann E. Zagaria, PharmD, MS, CGP Senior Care Consultant and President, MZ Associates, Inc., Norwich, New York Contributing Editors Loyd V. Allen, Jr., PhD Connie Barnes, PharmD Bruce Berger, PhD R. Keith Campbell, RPh, CDE Patrick N. Catania, PhD, RPh R. Rebecca Couris, PhD, RPh Ed DeSimone, PhD, RPh Ronald W. Maddox, PharmD Somnath Pal, BS (Pharm), MBA, PhD W. Steven Pray, PhD, DPh M. Saljoughian, PharmD, PhD Jesse C. Vivian, BS Pharm, JD Send your comments via E D I T O R @ U S P H A R M A C I S T. C O M Mail: 160 Chubb Avenue, Suite 306 Lyndhurst, NJ 07071 Telephone: (201) 623-0999 Editorial Dept. Fax: (201) 623-0991 Internet: www.uspharmacist.com FDA Approves Gardasil for Genital Warts in Men and Boys Silver Spring, MD — The FDA approved the vaccine Gardasil for the prevention of genital warts resulting from the human papillomavirus (HPV) types 6 and 11 in boys and men age 9 through 26 years. A randomized trial of 4,055 males age 16 through 26 showed that Gardasil was 90% effective in preventing genital warts, and studies measuring the immune response of males age 9 through 15 were equally positive. Each year, about two out of every 1,000 men in the United States are diagnosed with genital warts. Gardasil currently is approved for use in girls and women age 9 through 26 for the prevention of cervical, vulvar, and vaginal cancer caused by HPV types 16 and 18; precancerous lesions caused by types 6, 11, 16, and 18; and genital warts caused by types 6 and 11. Most genital warts are caused by HPV infection, which is the most common sexually transmitted infection in the U.S. IMS Predicts 4% to 6% Global Pharma Market Growth Next Year Norwalk, CT — IMS Health reported that the value of the global pharmaceutical market in 2010 is expected to grow 4% to 6% on a constant-dollar basis, exceeding $825 billion. The forecast predicts global pharmaceutical market sales to grow at a 4% to 7% compound annual rate through 2013, and considers the impact of the global macroeconomy, the changing mix of innovative and mature products, and the rising influence of health care access and funding on market demand. The value of the global pharmaceutical market is expected to expand to $975+ billion by 2013. “Overall, market growth is expected to remain at historically low levels, but stronger-than-expected demand in the U.S. is lifting both our short- and long-term forecasts,” said Murray Aitken, senior vice president, Healthcare Insight, IMS Health. FDA Warns About Illegal H1N1 Vaccines on the Web Silver Spring, MD — The FDA warned consumers about purchasing any products over the Internet that claim to diagnose, prevent, treat, or cure the H1N1 influenza virus. The warning comes after the FDA recently purchased and analyzed several products represented online as Tamiflu (oseltamivir) that may pose risks to patients. One of the orders, which arrived in an unmarked envelope with a postmark from India, consisted of unlabeled white tablets taped between two pieces of paper. When analyzed by the FDA, the tablets were found to contain talc and acetaminophen, but none of the active ingredient oseltamivir. The Web site disappeared shortly after the FDA placed the order. Smoking Bans Reduce Heart Attack Risk Washington, DC — A report from the Institute of Medicine says that smoking bans are effective at reducing the risk of heart attacks and heart disease associated with secondhand smoke. The report also provides evidence that breathing secondhand smoke boosts the risk for heart problems in nonsmokers, adding that there is evidence that relatively brief exposures could lead to a heart attack. About 43% of nonsmoking children and 37% of nonsmoking adults are exposed to secondhand smoke in the U.S., according to public health data. 5 U.S. Pharmacist • November 2009 • www.uspharmacist.com NO VEM BE R 20 Vol. 34 No. 11 PERFORATION Bipolar Disorder TEAR ALONG HEALTH SYSTEMS EDITION PATIENT TEACHING AID 09 The Journal for Pharmacists’ Education Dramatic High and Low Mood Swi ngs Bipolar disorder, sometimes called manic depression, is a mental illness that is described in mood extremes as . Patients with bipolar a fluctuation experience high disorder may (mania) and low and the lives of (depressi swings those around them. low moods and The classic picture that are dramatic, seriously affecting on) mood back again, with of bipolar disorder their lives each normal mood in includes swings between the extremes swing lasting from weeks to months from high to their days with . During and often mania, patients increased activity, are often agitated, with periods of little sleep, erratic focused. During speeding through depressio behavior, and problems with suicidal thoughts n, feelings of exhaustion, concentrating hopelessness, and . futility are common or staying The cause of bipolar , sometimes disorder is most imbalance may likely an imbalan be hereditary, since ce in brain chemical within families. s that affect mood. Diagnosis depends there is an increased risk of bipolar about 1% of the on a thorough history disorder and schizoph This population has of mood and renia been probably much higher due to misdiagndiagnosed with bipolar disorder, behavior in the past. Although the actual number Without treatmen osis. of people is The goal of treatmen t, bipolar disorder is a debilitat ing There are a variety t is to stabilize the patient’s mood condition that will not improve of on its own. to avoid drastic the cause of bipolar medications that act to even and damaging mood out the swings. ily therapy to help symptoms. Therapy for bipolar disorder imbalance of brain chemical s thought to be patients and their often includes individu ment of this condition friends and family al, group, understand the . triggers, early signs, and famand treat- U.S. Pharmacist is a Peer-Reviewed Journal Copyright Jobson Medical Informati on LLC, 2009 cont inue d FEATURES Illustration: © 2009 Teri J. McDermott, MA, CMI COVER IMAGE: Senior Care Progressive Supranuclear Palsy...20 Difficulty looking up without extending the neck or trouble using the stairs may be an initial symptom of this condition. PTA0911 Bipolar 10_14scbo.indd 1 10/15/09 12:24 PM PATIENT TEACHING AID Bipolar Disorder. See page 17 Pharmacologic Management of Alcohol Dependence ............. 60 Several medications are available that may help patients achieve abstinence and avoid relapse. Krina H. Patel, PharmD Mary Ann E. Zagaria, PharmD, MS, CGP Pharmacy Law So Many Options, So Little Difference in Efficacy: What Is the Appropriate Antidepressant? ...... 26 TeriMcDermott.com These agents are equal in effectiveness, but it is hard to predict which one will work best for a given patient. As part of the reward pathway in alcohol use, endorphins are released. Naltrexone blocks the binding of endorphins to opioid receptors, preventing dopamine release. Marjorie Rochette DeLucia, PharmD, MS, and Michael J. Schuh, PharmD, MBA CE CREDITS Emergency Contraception: An Update of Clinical and Regulatory Changes. See page 70 THIS MONTH Editorial Focus: Psychotropics NEXT MONTH Editorial Focus: Gastroenterologic Diseases Criminalization of Medication Errors ............ 66 A recent case equating a pharmacist’s mistake with manslaughter raises the question of pharmacy technician responsibility. Jesse C. Vivian, BS Pharm, JD 2 CE Credits ● Medications Used in Opioid Maintenance Treatment ............ 40 Emergency Contraception: An Update of Clinical and Regulatory Changes ................ 70 It is important to keep abreast of current therapeutic options as increasingly more patients are treated for dependence. Current information about levonorgestrel-based emergency birth control and strategies for educating consumers are discussed. Christie Choo, PharmD, BCPS Kathleen H. Besinque, PharmD, MSEd HEALT H S YS TE M S E DI TI ON Earn additional CE credits online. Visit: www.uspharmacist.com CE PROGRAMS ON THE U.S. PHARMACIST WEB SITE New: Emergency Contraception: An Update of Clinical and Regulatory Changes Recent: Ovarian Cancer: One of the Common Gynecologic Malignancies Perimenopause: Management of Common Symptoms During the Menopausal Transition An Update on the Current Treatment of HIV If you have any questions about our CE programs, call (800) 825-4696, fax (212) 219-7849, or e-mail [email protected]. Schizophrenia: A Review of Pharmacologic and Nonpharmacologic Treatments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . HS-2 Pharmacists should play an active role in the management of this complicated form of mental illness. Stacy Eon, PharmD, and Jennifer Durham, PharmD Prophylactic Therapies in Traumatic Brain Injury Management . . . . . HS-10 Clear guidelines for the proper administration of drugs used to treat this condition are lacking. Jennifer Confer, PharmD, and Jon Wietholter, PharmD Newly Approved mTOR Inhibitors for the Treatment of Metastatic Renal Cell Carcinoma . . . . . . . . . . . . . . . . . . . . . . . . . . HS-20 Temsirolimus and everolimus are now indicated as therapy for this type of cancer. Diana Hey Cauley, PharmD, BCOP In-Service Primers Nutrition and Clinical Depression . . . . . . . . . . . . . . . . . . . . . . . . . . HS-28 Manouchehr Saljoughian, PharmD, PhD U.S. PHARMACIST® (ISSN 01484818; USPS No. 333-490) is published monthly by Jobson Medical Information LLC, 100 Avenue of the Americas, New York, NY 10013-1678. Periodicals postage paid at New York, and additional mailing offices. Postmaster: Send address changes to U.S. PHARMACIST, P.O. Box 2027, Skokie, IL 60076-7927. Canada Post: Publications Mail Agreement #40612608. Canada Returns to be sent to Bleuchip International, P.O. Box 25542, London, ON N6C 6B2. Subscriptions: One-year subscription rate: USA $58.00; Faculty and Students at U.S. Colleges of Pharmacy $39.00; Canada $81.00 (U.S.); and air mail to all other countries $157.00. Single copies are $6.00 each. All subscriptions payable in U.S. dollars. Payment must accompany order. Send checks and subscription requests to U.S. PHARMACIST, P.O. Box 2027, Skokie, IL 60076-7927 or call Customer Service:1-877-529-1746 (U.S. only) or 1-847-763-9630. Copyright 2009 by Jobson Medical Information LLC, 100 Avenue of the Americas, New York, NY 10013-1678. Reproduction of articles without permission from the publisher is expressly prohibited. Acceptance of advertising by U.S. PHARMACIST does not constitute endorsement of the advertiser, its products or services. The opinions, statements and views expressed by contributors to U.S. PHARMACIST are the authors’ and do not necessarily reflect those of the publisher, editor-in-chief, editors, editorial board of advisors, or the staff of U.S. PHARMACIST. 6 U.S. Pharmacist • November 2009 • www.uspharmacist.com Q. Which Global Generic Company’s Transdermal Patches Were Most Dispensed in the U.S. Last Year? A. Mylan Pharmaceuticals.* With one of the most advanced transdermal development and manufacturing facilities in the United States—brand or generic—Mylan is well-recognized as an innovator in transdermal drug delivery technology. In fact, last year 65% of all generic patches dispensed in the U.S. carried the Mylan name.* We have developed more generic transdermal patches than any company in the U.S. and all of our patches are designed with patient safety in mind. None have a bulky, liquid, gel-filled reservoir, which eliminates any concern about the dangers associated with leakage, and none have aluminum or other metals in their backing, which may cause potential burns in MRI patients. So when you need generic transdermal patches…think Mylan. *IMS National Prescription Audit. 12 months ending December 2008. ©2009 Mylan Pharmaceuticals Inc. MYNMKT308 Vol. 34 No. 11 U.S. Pharmacist A Jobson Publication Senior Vice President–Editor-in-Chief Harold E. Cohen, RPh Executive Editor Robert Davidson Senior Editor NO VEM BE R 20 09 The Journal for Pharmacists’ Education Bonnie Ostrowski U.S. Pharmacist is a Peer-Reviewed Journal Senior Associate Editor Marjorie Borden Projects Editor Nancy Robertson, MS Consulting Clinical Editor Mary Gurnee, PharmD, RPh Senior Vice President–Publisher Harold E. Cohen, RPh (201) 623-0982 Associate Publisher Jack McAleer (201) 623-0987 East Coast Regional Sales Manager Mark Hildebrand (201) 623-0984 DEPARTMENTS Straight Talk Consult Your Pharmacist Marketing Manager Pharmacy Technicians: Truth and Consequences . . . . . . 4 Deborah Mortara (201) 623-0990 Harold E. Cohen, RPh Fatigue and Drowsiness: Everyday Exhaustion and Beyond . . . . . . . . . . . . . . 12 Midwest/West Regional Sales Manager Megan Conley (773) 450-7339 Classified Advertising Sales Heather Brennan (800) 983-7737 x106 What’s News. . . . . . . . . . . . . . 5 Design Director TrendWatch Sharyl Sand Carow Production Manager Dina Romano (201) 623-0942 Corporate Production Director John Anthony Caggiano W. Steven Pray, PhD, DPh Acute Negative Feelings Among Adults . . . . . . . . . . . . 10 Nonpositive beliefs and emotions generally occur to a similar degree across age groups. Director, Continuing Education Processing Vice President, Circulation Director Worthlessness 2.9 3.1 3.0 2.6 18-44 years Vice President, Creative Services and Production Monica Tettamanzi In lozenge form, this analgesic and anesthetic agent can be prepared to suit the patient’s individual flavor preference. 45-64 years Helplessness 3.5 4.2 3.7 65-74 years 2.7 75+ years Restlessness 5.2 Sadness 6.7 “Everything is an effort” 3.9 4.9 7.9 Loyd V. Allen, Jr, PhD 3.1 7.3 Classified Advertising . . . . . . 80 7.5 7.9 7.4 Career and business opportunities, products, and services for the pharmacist. 7.4 7.9 Chief Executive Officer Jeff MacDonald Chief Financial Officer Derek Winston Nervousness 9.6 10.1 0 5 10 15 Generic Trends . . . . . . . . . . . 54 Ketamine Hydrochloride 10-mg Troches . . . . . . . . . . . 58 Prevalence of Selected Acute Negative Feelings Emelda Barea FDA Fast Facts . . . . . . . . . . . 24 Contemporary Compounding Somnath Pal, BS (Pharm), MS, MBA, PhD Regina Combs (800) 825-4696 Prolonged tiredness and sleepiness are a concern for many people. 20 25 Product News . . . . . . . . . . . . 82 8.4 8.4 30 35 40 Percentage of adults surveyed © JUPITERIMAGES CEO, Information Services Division Marc Ferrara Senior Vice President, Operations Jeff Levitz Vice President, Human Resources Lorraine Orlando U.S. Pharmacist 160 Chubb Avenue, Suite 306 Lyndhurst, NJ 07071 Tel: (201) 623-0999 Fax: (201) 623-0991 E-mail: [email protected] Web: www.uspharmacist.com Printed on paper containing an average of 96 percent post-consumer recycled waste. New Products in This Issue Afinitor / Novartis Pharmaceuticals Corporation • Authorized Generics / Greenstone LLC • Embeda / King Pharmaceuticals • Kapidex / Takeda Pharmaceuticals • Onglyza / AstraZeneca • Uloric / Takeda Pharmaceuticals • Welchol / Daiichi-Sankyo Health Systems Edition: Distinctive Labeling / Baxter Healthcare • Injectables / Pfizer Injectables • Product Labeling / Teva Pharmaceuticals 8 U.S. Pharmacist • November 2009 • www.uspharmacist.com If key products are missing from your multi-source topical inventory perhaps you should rely on the specialist. E. FOUGERA & CO. A division of Nycomed US Inc., Melville, NY 11747 • Toll free: 800-645-9833 • www.fougera.com © 2009 Fougera. All rights reserved. Iss. 9/09 TrendWatch Acute Negative Feelings Among Adults The 2007 National Health Interview Survey for noninstitutionalized adults provides an understanding of the prevalence of acute feelings of sadness, hopelessness, worthlessness, or nervousness or that everything is an effort. Prevalence of Selected Acute Negative Feelings Worthlessness 2.9 3.1 3.0 2.6 18-44 years 45-64 years Helplessness 3.7 3.5 4.2 65-74 years 2.7 75+ years Restlessness Sadness 5.2 6.7 3.9 4.9 7.3 3.1 7.9 7.5 Sadness, Hopeless- “Everything is 7.9 7.4 7.4 7.9 an effort” ness, Worthlessness, or Everything Feeling Like Nervousness 8.4 9.6 8.4 10.1 an Effort: Ten percent of respon0 5 10 15 20 25 30 35 dents experienced Percentage of adults surveyed sadness; 6% felt © JUPITERIMAGES hopeless; 5% felt worthless; and 13% felt these feelings had at sadness, compared with that everything was an least a bachelor’s degree. 11% of those with only effort. Twelve percent of Adults in poor families Medicare coverage and women felt sad, comwere twice as likely as 8% of those with private pared with 8% of men. adults in families that health insurance. More non-Hispanic were better off to feel Divorced respondents black respondents than sad, hopeless, worthless, were more likely than non-Hispanic white or that everything is an other respondents to feel respondents felt that effort. sad or that everything is everything is an effort. Among respondents an effort. The highest percentage under age 65 years, 25% of respondents with of those with Medicaid Feelings of Nervousness these feelings had less coverage experienced or Restlessness: Thirteen than a high-school feelings of sadness, com- percent of respondents diploma, and responpared with 15% of those experienced nervousness, dents least likely to have who were uninsured and and 15% reported rest6% of those who had lessness. Sixteen percent private health insurance. of women felt nervous, Somnath Pal, BS (Pharm), MBA, PhD Among individuals aged versus 11% of men. Professor of Pharmacy 65 years and over, 19% Non-Hispanic white Administration, College of of those with Medicaid respondents had more Pharmacy & Allied Health and Medicare coverage feelings of nervousness Professions, St. John’s University, experienced feelings of than non-Hispanic black Jamaica, New York 10 U.S. Pharmacist • November 2009 • www.uspharmacist.com respondents. The highest percentage of adults with these feelings had less than a highschool diploma; those least likely to have these feelings possessed a bachelor’s degree or higher. Adults in poor families were more likely to feel nervous than adults in families that were better off. Among individuals under age 65 years, 26% of 40 those with Medicaid coverage experienced feelings of nervousness, compared with 15% of those who were uninsured and 12% of those who had private health insurance. Among adults aged 65 years and over, 25% of those with Medicaid and Medicare coverage experienced feelings of nervousness, versus 11% of those who had only Medicare coverage and 11% of those with private health insurance. Adults who were married were least likely to have feelings of nervousness or restlessness, compared with adults who were divorced or separated, never married, or living with a partner. 1,500+ Ways We Meet Your Needs 7JTJUUFWBVTBDPNUPWJFXPVSHSPXJOHQPSUGPMJP 8PNFOµT)FBMUI 1BJO.BOBHFNFOU $BSEJPWBTDVMBS "OUJ*OGFDUJWF 0ODPMPHZ $/4 888 TEVA USA s www.tevausa.com ©2009, Teva Pharmaceuticals USA 8402 A Consult Your Pharmacist Fatigue and Drowsiness: Everyday Exhaustion and Beyond atigue and drowsiness are a part of everyday life for millions of people, and prolonged fatigue is a concern for 10% to 25% of those who visit general practitioners.1 The high incidence of fatigue is due to such issues as today’s hectic lifestyle, lack of leisure time, poor sleep habits, and certain medical conditions. Pharmacists are in an ideal position to provide assistance to patients complaining about continual fatigue and daytime drowsiness. Fatigue Fatigue is commonly experienced and is the feeling of tiredness or exhaustion that follows a hard day of work or mentally and physically challenging exercise.2,3 Patients may also complain that they are weary, that their energy is gone, or that they feel lack of motivation to accomplish other tasks. Counseling Patients With Fatigue: When counseling patients with fatigue, the pharmacist W. Steven Pray, PhD, DPh Bernhardt Professor, Nonprescription Products and Devices College of Pharmacy, Southwestern Oklahoma State University Weatherford, Oklahoma © JUPITERIMAGES F Caffeine's stimulant effect is well known and is the primary reason for its ubiquitous use. The dose approved as safe and effective is 100 to 200 mg, not more often than every 3 to 4 hours. should first attempt to ascertain whether the fatigue is a normal response to overwork or a continual problem that seems unrelated to the amount or extent of effort performed that day, week, or month. If it is the former, the problem is probably a short-term, minor difficulty that will resolve on its own once the stressors have subsided. However, if the patient is able to sleep normally but still experiences continual fatigue that seems unrelated to ongoing mental or physical stress, the fatigue may be secondary to medications or a medical condition.3 For example, patients with hypothyroidism com- plain that they awaken refreshed, but that activity results in rapid onset of fatigue.3 Causes of Fatigue: Fatigue can be caused by a wide variety of medical conditions.1,3,4 As many as 40% of those reporting symptoms of chronic fatigue were eventually discovered to have a psychiatric or medical condition that had not yet been diagnosed but was ultimately treated successfully.4 Etiologies include premenstrual syndrome, premenstrual dysphoric disorder, allergic rhinitis, asthma, anemias, hypo- or hyperthyroidism, Addison’s disease, fibromyalgia, arthritis, lupus, cancer, 12 U.S. Pharmacist • November 2009 • www.uspharmacist.com Parkinson’s disease, congestive heart failure, diabetes, conditions causing persistent pain, infections (e.g., AIDS, mononucleosis), renal disease, and hepatic disease.4-8 Depression and grief induce fatigue. Sleep disorders cause fatigue, including insomnia, narcolepsy, and obstructive sleep apnea. Alcohol and other drugs of abuse (e.g., cocaine, narcotics) cause fatigue, and the patient may find that making healthier lifestyle choices will resolve the problem. Malnutrition leads to fatigue, as do anorexia and other eating disorders. The wide spectrum of potential etiologies makes it critical for pharmacists to refer patients with unexplained fatigue to a physician for a full medical evaluation. Chronic Fatigue Syndrome: Chronic fatigue syndrome (CFS) is a cause of chronic tiredness that affects 1 to 4 million Americans.4 Its ramifications are profound, in that one-fourth of sufferers are not employed and many are receiving disability benefits. It differs from normal fatigue in its sever- ✁ PATIENT INFORMATION Combating Fatigue and Drowsiness Steps You Can Take Before you take any medications for fatigue and drowsiness, you may wish to try some relatively easy solutions. You should not go to bed and arise at odd times or at different times each day. The best advice is to set a time for going to bed and also for arising and try to stick to them as much as possible. Everyone has experienced the “fun” of staying up till 4 AM or later and then sleeping in until noon the next day. Even 8 hours of sleep cannot fool your body into normalcy, and you will feel the effects of your altered schedule the next day. In addition, strive to get at least 7 to 8 hours of sleep a night. Trying to get through the next day without adequate sleep leads to daytime drowsiness that is a major cause of fatal automobile accidents. Avoid stimulants such as caffeine or oral nasal decongestants (e.g., Sudafed) too close to bedtime, as the stimulant effect may not allow you to drop off to sleep at the right time, leaving you fatigued the following day. You should always eat a healthy, balanced diet and drink sufficient water to keep fully hydrated. Avoid all alcohol, nicotine, and drugs of abuse. If you habitually drink caffeine-containing soft drinks, coffee, or tea, try to reduce the amount or eliminate them completely to determine whether they are responsible for a tired feeling. You should also be aware of any medications you are taking that may cause drowsiness, such as antihistamines, antihypertensives, corticosteroids, diuretics, and sleep aids. One method to reduce fatigue is to reduce life stresses. It may be necessary to change from a job that causes severe stress to one that allows a more relaxing day of work. When you have spare time, do not spend it playing high-stress video games that require splitsecond timing and fast reflexes. Instead, go for a walk, read a book, or have a pleasant conversation with family and friends. If you are caught in a relationship that is fraught with problems, deal with them directly or end the relationship. Nonprescription Medications The only pharmacy product proven safe and effective in helping fight fatigue and drowsiness is caffeine, found PHARMACY STAMP © JUPITERIMAGES Everyone has felt tired or sleepy during the day. Undue tiredness may be caused by a number of serious medical conditions, so if simple advice or OTC products containing caffeine do not help, it is wise to see a physician. in such OTC products as Vivarin and NoDoz. Each caplet or tablet contains 200 mg of caffeine. Take one dose not more often than every 3 to 4 hours. These products are only safe for those aged 12 years and above. They are not a substitute for healthy sleep and should never be used to keep you awake all night. They should not be used if you are pregnant or breastfeeding without speaking to your physician first. Energy Drinks Avoid the use of the popular energy drinks. Virtually all contain ingredients of unknown safety and effectiveness, such as herbs and dietary supplements. One contains such unproven ingredients as ginkgo, guarana, inositol, L-carnitine, ginseng, and milk thistle. Using products such as these is a risky gamble with your health, since they can have adverse effects and are not proven to provide a safe boost of energy. Remember, if you have questions, Consult Your Pharmacist. 13 U.S. Pharmacist • November 2009 • www.uspharmacist.com Consult Your Pharmacist ity, in the incapacitating feeling that patients experience, and in the fact that bed rest does not relieve it.1,9 The degree of fatigue limits or halts social engagements, educational efforts, work, and personal activity. Studies from the CDC reveal that the disabling effects of CFS rival those of such overwhelming conditions as chronic obstructive pulmonary disease (COPD), rheumatoid arthritis, lupus, multiple sclerosis, heart disease, and end-stage renal disease. The degree of disability varies widely among patients and in the same patient from episode to episode. Some patients experience periods where they are relatively free of symptoms, followed by a period of extreme disability.1 This cyclical pattern is often seen with CFS. To meet the formal diagnosis of CFS, patients should have experienced symptoms for 6 months or more.1 Further, the fatigue is not caused by any underlying medical conditions and is accompanied by such nonspecific ancillary symptoms as sore throat, joints that are painful but lack erythema or inflammation, unrelenting muscle pain, headaches that differ from the norm in severity or symptoms, and What’s in Red Bull? The popular product known as Red Bull claims to be an “energy drink.” The company Web site does not directly state that the taurine (an amino acid) in the product provides energy, but it does mention other beneficial effects.13 It says that “one can of Red Bull Energy Drink contains approximately the same amount of caffeine as a cup of coffee,” a vague statement that should be clarified to disclose the exact amount. The drink also contains glucuronolactone, B vitamins, sucrose, and glucose. Patients should not assume that its formula is safer or more effective than caffeine alone. lymph node tenderness (axillary or cervical).1 Patients do not feel refreshed after sleep, and they also notice that physical or mental exercise produces a malaise that persists for more than 24 hours. Their ability to concentrate on tasks is reduced, and their memory is impaired. These are referred to as the eight symptoms that define CFS. Treatment options for CFS are diverse and of variable use. The CDC urges practitioners to adapt treatment plans to the individual patient’s present symptoms.10 Sleep disturbances may be initially treated with simple sleep hygiene measures, followed by nonprescription antihistamine sleep aids such as Sominex and Unisom. If these medications are needed beyond 14 days, however, the patient should be urged to seek care from a physician. Muscle and joint pain and headache may be amenable to nonprescription acetaminophen, ibuprofen, or naproxen. The CDC alerts patients to the fallacies of using nutritional and herbal supplements for CFS.10 Although some patients report relief from these products, they are not regulated by the FDA, and thus objective data to prove their efficacy and safety are often lacking. The CDC warns patients against such herbs as comfrey, ephedra, kava, germander, chaparral, bitter orange, licorice root, and yohimbine due to reports of toxicity coupled with lack of efficacy data.10 The CDC also mentions the use of alternative therapies such as acupuncture, aquatic therapy, gentle massage, meditation, deep breathing, biofeedback, yoga, and tai chi.10 The agency urges patients to discuss these options with a health care provider to 14 U.S. Pharmacist • November 2009 • www.uspharmacist.com make sure that they have been proven safe and effective. Medications That Cause Fatigue: Medications that are reported to cause fatigue include antihistamines, antihypertensives, corticosteroids, diuretics, and sleep aids for insomnia.2 Some agents induce toxic myopathy that can lead to fatigue.11 If prescription medications are suspected to be the cause of fatigue or of CFS, patients should be asked to visit their prescriber for a full evaluation and consideration of alternative medications. Drowsiness Drowsiness differs from fatigue in that it is a subjective feeling that sleep is needed. A patient may not be tired at all, but falls prey to an overwhelming need for sleep at an inappropriate time or in an inappropriate situation.12 Counseling Patients With Drowsiness: It is normal to experience drowsiness after inadequate sleep because the patient has a “sleep debt.” However, some patients complain of abnormal sleepiness in spite of having obtained sufficient sleep the night before. The pharmacist can question these patients about their sleep patterns, how much they normally Consult Your Pharmacist sleep, whether they snore, and whether their bed partner complains that they have episodes of breathing cessation during the night (sleep apnea). If the answers to these are unrevealing, the patient should be urged to visit a physician, who may conduct sleep studies to determine the root cause of this abnormal drowsiness. If the patient’s habits seem to demonstrate poor sleep, interrupted sleep, or inadequate sleep, he or she should be advised to adopt the principles of sleep hygiene. Patients may be asked whether they are depressed, anxious, stressed, or suffering general life boredom. A trial of antidepressants may help some of these patients. Causes of Drowsiness: Drowsiness may be caused by such widely varying etiologies as rotating shift work, sedating medications (e.g., antihistamines, antidepressants, pain medications), hypothyroidism, hypercalcemia, REFERENCES 1. Chronic fatigue syndrome. Symptoms. CDC. www.cdc.gov/cfs/ cfssymptomsHCP.htm. Accessed September 30, 2009. 2. Pray WS. Nonprescription Product Therapeutics. 2nd ed. Baltimore, MD: Lippincott Williams & Wilkins; 2006. 3. Fatigue. National Library of Medicine. www.nlm.nih.gov/medlineplus/ency/article/003088.htm. Accessed September 30, 2009. 4. Chronic fatigue syndrome. Back- hyponatremia or hypernatremia, sleep apnea, and narcolepsy.12 Nonprescription Products In addition to helping patients uncover the sources of fatigue or drowsiness and referring them when appropriate, pharmacists can also recommend nonprescription treatment. The only medication found to be safe and effective for selfuse when used as labeled is caffeine.2 Caffeine’s stimulant effect is wellknown and is the primary reason for its ubiquitous recreational use. The stimulant dose approved as safe and effective is 100 to 200 mg, not more often than every 3 to 4 hours.2 Products include Vivarin and NoDoz, both containing 200 mg of caffeine per tablet/caplet. These products are not to be recommended for anyone under the age of 12 years. Labels will warn patients that these products contain approximately as much caffeine ground. CDC. www.cdc.gov/cfs/. Accessed September 30, 2009. 5. Zanni GR. Diagnosing and treating fibromyalgia. Consult Pharm. 2009;24:572-589. 6. Cuatrecasas G. Fibromyalgic syndromes: could growth hormone therapy be beneficial? Pediatr Endocrinol Rev. 2009;6(suppl 4):529-533. 7. Rapkin AJ, Winer SA. Premenstrual syndrome and premenstrual dysphoric disorder: quality of life and burden of illness. Expert Rev Pharmacoecon Outcomes Res. as a cup of coffee and that they should limit or stop caffeine use while taking them. Failure to do so could lead to nervousness, sleeplessness, irritability, and tachycardia. Of course, a cup of coffee can contain widely divergent amounts of caffeine, so the FDA warning is only an estimate for consumer use. Labels warn patients that these products are for occasional use only and that they will not substitute for sleep. Furthermore, if drowsiness or fatigue persists or recurs, patients should consult their physician. These products are not to be used if the patient is pregnant or breastfeeding. Their optimal use is for patients who are performing boring, repetitive tasks that lead to inattention (e.g., assembly-line work). They may also be useful to maintain maximal attentiveness during driving. Some patients are already consuming the recommended amount of caffeine in the form of coffee, tea, and soft 2009;9:157-170. 8. Lou JS. Physical and mental fatigue in Parkinson’s disease: epidemiology, pathophysiology and treatment. Drugs Aging. 2009;26:195-208. 9. Chronic fatigue syndrome. National Library of Medicine. www.nlm.nih.gov/medlineplus/ chronicfatiguesyndrome.html. Accessed September 30, 2009. 10. Chronic fatigue syndrome. Treatment options. CDC. www.cdc. gov/cfs/cfstreatmentHCP.htm. 15 U.S. Pharmacist • November 2009 • www.uspharmacist.com drinks. Eight ounces of brewed coffee contains 135 mg of caffeine, and the same amount of brewed tea contains 50 mg.2 A 12-oz can of Coca-Cola or Pepsi-Cola contains 34 to 38 mg of caffeine, where the amount in other soft drinks may be as high as 55 mg/12 oz. A patient who drinks several cans of caffeinated soft drinks daily, along with a 20-oz cup of coffee from a popular coffee chain like Starbucks (480 mg of caffeine) is already consuming a considerable amount of stimulant.2 The 200 mg in a single NoDoz or Vivarin may not be enough to provide any benefit beyond the already high daily intake and could lead to unwanted effects. Conclusion Fatigue and drowsiness are common medical conditions that can be caused by a host of serious disorders. Unless the cause is trivial and shortterm, the patient should be referred to a physician for a full evaluation. Accessed September 30, 2009. 11. Dalakas MC. Toxic and druginduced myopathies. J Neurol Neurosurg Psychiatry. 2009;80:832-838. 12. Drowsiness. National Library of Medicine. www.nlm.nih.gov/medlineplus/ency/article/003208.htm. Accessed September 30, 2009. 13. Red Bull Energy Drink. Ingredients. www.redbull.com/cs/ Satellite/en_INT/Products/Red-BullEnergy-Drink-021242751115866?p= 1242745950125. Accessed September 30, 2009. Use as directed. FOR YOUR PATIENTS WITH HYPERTENSION RECOMMEND COLD MEDICINE WITH A HEART. Tell your patients about the only cold brand that won’t raise their blood pressure: Coricidin® HBP. Like many of your patients, S. Epatha Merkerson has hypertension. Since decongestants are contraindicated for hypertensive patients, they need to be careful when they get a cold. So assure your patients that Coricidin HBP is the smart choice because it’s decongestant-free and specially made to relieve cold symptoms without raising blood pressure. Recommend the full line of products from Coricidin HBP. Powerful cold medicine with a heart. ® Schering-Plough, maker of Coricidin HBP, sponsors the AHA High Blood Pressure website. ©2009 Schering-Plough HealthCare Products, Inc. PATIENT TEACHING AID TEAR ALONG PERFORATION Bipolar Disorder Bipolar disorder, sometimes called manic depression, is a mental illness that is described as a fluctuation in mood extremes. Patients with bipolar disorder may experience high (mania) and low (depression) mood swings that are dramatic, seriously affecting their lives and the lives of those around them. The classic picture of bipolar disorder includes swings from high to low moods and back again, with each swing lasting from weeks to months and often with periods of normal mood in between the extremes. During mania, patients are often agitated, speeding through their days with increased activity, little sleep, erratic behavior, and problems concentrating or staying focused. During depression, feelings of exhaustion, hopelessness, and futility are common, sometimes with suicidal thoughts. The cause of bipolar disorder is most likely an imbalance in brain chemicals that affect mood. This imbalance may be hereditary, since there is an increased risk of bipolar disorder and schizophrenia within families. Diagnosis depends on a thorough history of mood and behavior in the past. Although about 1% of the population has been diagnosed with bipolar disorder, the actual number of people is probably much higher due to misdiagnosis. Without treatment, bipolar disorder is a debilitating condition that will not improve on its own. The goal of treatment is to stabilize the patient’s mood to avoid drastic and damaging mood swings. There are a variety of medications that act to even out the imbalance of brain chemicals thought to be the cause of bipolar symptoms. Therapy for bipolar disorder often includes individual, group, and family therapy to help patients and their friends and family understand the triggers, early signs, and treatment of this condition. Dramatic High and Low Mood Swings Copyright Jobson Medical Information LLC, 2009 continued PATIENT TEACHING AID Medications Can Level the Extremes and Restore a More Normal Mood Bipolar disorder can occur in several symptom patterns. These include cyclothymia (mild mood swings), bipolar I (one period of mania sometimes following a period of depression), and the most common form, bipolar II (at least one period of mild or hypomania and one period of depression). When mania and depression occur together, it is called mixed-state bipolar disorder. The manic phase is characterized Identifying Symptoms: Bipolar symptoms typically begin in by euphoria, racing thoughts, and the late teens to early 30s and are first seen after a significant impulsiveness. stressful or traumatic event. The tendency to develop this disease may be hereditary in some cases, since many families have more than one member with this condition. Symptoms of mania include excitation, exhilaration, feelings of self-importance, confusion, racing thoughts, problems concentrating, little interest in food or rest, and impulsiveness. These symptoms take a toll on the physical and mental health of the patient. Since thoughts are jumbled and the mood is euphoric, patients often make poor decisions that make little sense. Psychosis can also be a symptom. During a psychotic episode, patients see or hear things that do not exist (hallucinations), or believe things that are not in touch with reality (delusions). Symptoms of depression include feelings of hopelessness and despondency, with little interest in activities that were once pleasurable. During the depressive phase of bipolar disorder, many patients have problems eating and sleeping, feel nervous and irritable, and consider suicide. Seeking Help: Most patients with bipolar disorder recognize that they have a problem, but not all seek help. This is for a variety of reasons. Bipolar disorder is considered a mental illness, which may evoke feelings of shame and inadequacy. Many patients also do not want to treat their mood swings with medications. However, the only reliable and effective treatment for bipolar disorder is medication to level the extremes and restore a more normal mood. Without therapy, bipolar disorder will only worsen with time. Untreated, it can lead to serious depression and suicide, problems with functioning in life, and drug or alcohol addiction. That is why it is important for patients to find support in family, friends, and therapists who can help them lead a productive, normal life. Therapy for bipolar disorder can include individual therapy to help patients understand the condition and care for themselves, group therapy to help patients understand how others are suffering from this condition, and family therapy to educate patients’ loved ones about the disorder and what to do when they observe the beginnings of mood swings that patients may or may not notice themselves. Drug therapy for bipolar disorder includes medications that rebalance the chemicals in the brain that affect mood, thereby equalizing mood. The medication cannot be discontinued during periods of normal mood, since bipolar disorder is a chronic condition that requires treatment of symptoms as well as prevention of symptoms. Although younger patients may not accept the idea of a lifetime of medication, eventually they begin to understand its importance after suffering serious relapses when they discontinue therapy. Drug therapy for bipolar disorder might start out with lithium, quetiapine, or an antiseizure medicine such as valproic acid. These drugs help stabilize mood and avoid swings. Some patients may require additional medicine for psychosis (antipsychotics such as risperidone or olanzapine) or sleep aids. Many doctors find that a combination of medicines that work in different ways is the most effective treatment. All drugs take a period of weeks to months to work best, and sometimes doses need to be increased or decreased to work better while avoiding side effects. Once the right drug therapy is established, patients need to be aware of the importance of continuing their medicines to avoid future episodes of mania or depression. Our most important ingredient is integrity. Introducing Pfizer Injectables. Dedicated to helping your business thrive with our heritage of quality, reliable manufacturing, and customer-focused flexibility—so essential injectable medicines can reach the patients who need them, making the world a healthier place. US100032 © 2009 Pfizer Inc. All rights reserved. Printed in USA/November 2009 Solutions Are Our Business.™ www.pfizerinjectables.com H E A LT H S Y S T E M S E D I T I O N Schizophrenia A Review of Pharmacologic and Nonpharmacologic Treatments © JUPITERIMAGES P atients with mental illness constitute a population that can be challenging for any health care provider, but they offer great opportunities for a pharmacist to make a meaningful contribution. The pharmacist’s role might involve assisting in the selection of medication regimens, managing adverse drug reactions, or facilitating adherence. These interventions can be particularly important for patients with schizophrenia. (see TABLE 1), involve the diminution or absence of normal functions; they often are refractory to treatment.3,4 Cognitive symptoms are highly prevalent and may include difficulties with verbal fluency, attention, and working memory.3 Antipsychotic medications have little effect on cognitive symptoms; as a result, these symptoms affect a patient’s ability to obtain employment, establish personal relationships, and function in many social settings.3 According to Diagnostic and Statistical Manual of Mental Disorders-IV-TR criteria, a patient can be diagnosed with schizophrenia if he or she presents with at least two of the following symptoms in addition to social dysfunction for a significant amount of time during a 1-month period, with some symptoms persisting for at least 6 months: delusions, hallucinations, disorganized speech, grossly disorganized or catatonic behavior, or negative symptoms.4 The diagnosis can also be made solely on the basis of bizarre delusions or hallucinations involving voices.4 DIAGNOSIS AND CLINICAL PRESENTATION Schizophrenia is a chronic, debilitating mental illness that affects approximately 1% of the population.1 Owing to the 10% lifetime prevalence of suicide in patients with the disorder, early recognition and appropriate treatment are imperative.2 Schizophrenia typically presents in late adolescence and persists throughout the patient’s life, and males typically experience symptoms 5 to 7 years earlier than females.1,3 Symptoms of schizophrenia may be classified as positive, negative, or cognitive. Positive symptoms include disorganized speech or behavior and psychotic characteristics such as delusions or hallucinations. Delu- PATHOPHYSIOLOGY sions, or fixed false beliefs, occur when a patient mis- Although the neurochemistry behind schizophrenia is not fully understood, the disorder is interprets an experience, leading to Stacy Eon, PharmD thought to be caused by increased erroneous beliefs involving paranoia PGY2 Pharmacy Resident in Psychiatry dopaminergic transmission. 1 This or persecution. Hallucinations involve University of North Carolina Hospitals increase in dopamine effect causes the more vivid sensory disruptions, with Chapel Hill, North Carolina brain to be hypersensitive to stimauditory hallucinations being the Jennifer Durham, PharmD uli, making it difficult for the patient most common.1,3 Negative symptoms, Clinical Pharmacist including affective flattening, alogia, to distinguish between reality and his Moses Cone Memorial Hospital avolition, and reduced social drive or her delusions or hallucinations.1 Greensboro, North Carolina HS-2 U.S. Pharmacist • November 2009 • www.uspharmacist.com IN THE TREATMENT OF MRSA BACTEREMIA AND MRSA COMPLICATED SKIN INFECTIONS INSIDE.OUTSIDE.ON HIS SIDE. n Landmark clinical trial of CUBICIN 6 mg/kg once daily demonstr ated efficacy in S. aureus bacteremia caused by MRSA and MSSA n Proven clinical success of CUBICIN 4 mg/kg once daily in S. aureus complicated skin infections — both MRSA and MSSA INDICATIONS AND IMPORTANT SAFETY INFORMATION CUBICIN is indicated for the following infections: Complicated skin and skin structure infections caused by susceptible isolates of the following Gram-positive microorganisms: S. aureus (including methicillin-resistant isolates), Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus dysgalactiae subspecies equisimilis, and Enterococcus faecalis (vancomycin-susceptible isolates only). Combination therapy may be clinically indicated if the documented or presumed pathogens include Gram-negative or anaerobic organisms. S. aureus bloodstream infections (bacteremia), including those with right-sided infective endocarditis, caused by methicillin-susceptible and methicillin-resistant isolates. Combination therapy may be clinically indicated if the documented or presumed pathogens include Gram-negative or anaerobic organisms. The efficacy of CUBICIN in patients with left-sided infective endocarditis due to S. aureus has not been demonstrated. The clinical trial of CUBICIN in patients with S. aureus bloodstream infections included limited data from patients with left-sided infective endocarditis; outcomes in these patients were poor. CUBICIN has not been studied in patients with prosthetic valve endocarditis or meningitis. Patients with persisting or relapsing S. aureus infection or poor clinical response should have repeat blood cultures. If a culture is positive for www.cubicin.com ©2007 Cubist Pharmaceuticals, Inc. 3974071907 September 2007 CUBICIN is a registered trademark of Cubist Pharmaceuticals,Inc. S. aureus, MIC susceptibility testing of the isolate should be performed using a standardized procedure, as well as diagnostic evaluation to rule out sequestered foci of infection. Appropriate surgical intervention (eg, debridement, removal of prosthetic devices, valve replacement surgery) and/or consideration of a change in antibiotic regimen may be required. CUBICIN is not indicated for the treatment of pneumonia. Clostridium difficile-associated diarrhea (CDAD) has been r eported with the use of nearly all antibacterial agents, including CUBICIN, and may range in severity from mild diarrhea to fatal colitis. CDAD has been reported to occur over 2 months post-antibiotic treatment. If CDAD is suspected, antibiotic treatment may need to be suspended. Patients receiving CUBICIN should be monitored for the development of muscle pain or weakness, particularly of the distal extremities. In patients who receive CUBICIN, creatine phosphokinase (CPK) levels should be monitored weekly, and more frequently in patients who received recent prior or concomitant therapy with an HMG-CoA reductase inhibitor. In patients with renal insufficiency, both renal function and CPK should be monitored more frequently. Patients who demonstrate unexplained elevations in CPK while receiving CUBICIN should be monitored more frequently. CUBICIN should be discontinued in patients with unexplained signs and symptoms of myopathy in conjunction with CPK elevation >1000 U/L (~5X ULN), or in patients without reported symptoms who have marked elevations in CPK >2000 U/L (≥10X ULN). Most adverse events reported in CUBICIN clinical trials were mild to moderate in intensity. The most common CUBICIN adverse events were anemia, constipation, diarrhea, nausea, vomiting, injection-site reactions, and headache. Please see Brief Summary of Prescribing Information on adjacent page. Brief summary of prescribing information. INDICATIONS AND USAGE CUBICIN (daptomycin for injection) is indicated for the following infections (see also DOSAGE AND ADMINISTRATION and CLINICAL STUDIES in full prescribing information): Complicated skin and skin structure infections (cSSSI) caused by susceptible isolates of the following Gram-positive microorganisms: Staphylococcus aureus (including methicillin-resistant isolates), Streptococcus pyogenes, S. agalactiae, S. dysgalactiae subsp equisimilis, and Enterococcus faecalis (vancomycin-susceptible isolates only). Combination therapy may be clinically indicated if the documented or presumed pathogens include Gram-negative or anaerobic organisms. Staphylococcus aureus bloodstream infections (bacteremia), including those with right-sided infective endocarditis, caused by methicillin-susceptible and methicillin-resistant isolates. Combination therapy may be clinically indicated if the documented or presumed pathogens include Gram-negative or anaerobic organisms. The efficacy of CUBICIN in patients with left-sided infective endocarditis due to S. aureus has not been demonstrated. The clinical trial of CUBICIN in patients with S. aureus bloodstream infections included limited data from patients with left-sided infective endocarditis; outcomes in these patients were poor (see CLINICAL STUDIES in full prescribing information). CUBICIN has not been studied in patients with prosthetic valve endocarditis or meningitis. Patients with persisting or relapsing S. aureus infection or poor clinical response should have repeat blood cultures. If a culture is positive for S. aureus, MIC susceptibility testing of the isolate should be performed using a standardized procedure, as well as diagnostic evaluation to rule out sequestered foci of infection (see PRECAUTIONS). CUBICIN is not indicated for the treatment of pneumonia. Appropriate specimens for microbiological examination should be obtained in order to isolate and identify the causative pathogens and to determine their susceptibility to daptomycin. Empiric therapy may be initiated while awaiting test results. Antimicrobial therapy should be adjusted as needed based upon test results. To reduce the development of drug-resistant bacteria and maintain the effectiveness of CUBICIN and other antibacterial drugs, CUBICIN should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy. CONTRAINDICATIONS CUBICIN is contraindicated in patients with known hypersensitivity to daptomycin. WARNINGS Clostridium difficile–associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including CUBICIN, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon, leading to overgrowth of C. difficile. C. difficile produces toxins A and B, which contribute to the development of CDAD. Hypertoxin-producing strains of C. difficile cause increased morbidity and mortality, since these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary because CDAD has been reported to occur over 2 months after the administration of antibacterial agents. If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated. PRECAUTIONS General The use of antibiotics may promote the selection of non-susceptible organisms. Should superinfection occur during therapy, appropriate measures should be taken. Prescribing CUBICIN in the absence of a proven or strongly suspected bacterial infection is unlikely to provide benefit to the patient and increases the risk of the development of drugresistant bacteria. Persisting or Relapsing S. aureus Infection Patients with persisting or relapsing S. aureus infection or poor clinical response should have repeat blood cultures. If a culture is positive for S. aureus, MIC susceptibility testing of the isolate should be performed using a standardized procedure, as well as diagnostic evaluation to rule out sequestered foci of infection. Appropriate surgical intervention (eg, debridement, removal of prosthetic devices, valve replacement surgery) and/or consideration of a change in antibiotic regimen may be required. Failure of treatment due to persisting or relapsing S. aureus infections was assessed by the Adjudication Committee in 19/120 (15.8%) CUBICIN-treated patients (12 with MRSA and 7 with MSSA) and 11/115 (9.6%) comparator-treated patients (9 with MRSA treated with vancomycin and 2 with MSSA treated with antistaphylococcal semi-synthetic penicillin). Among all failures, 6 CUBICINtreated patients and 1 vancomycin-treated patient developed increasing MICs (reduced susceptibility) by central laboratory testing on or following therapy. Most patients who failed due to persisting or relapsing S. aureus infection had deep-seated infection and did not receive necessary surgical intervention (see CLINICAL STUDIES in full prescribing information). Skeletal Muscle In a Phase 1 study examining doses up to 12 mg/kg q24h of CUBICIN for 14 days, no skeletal muscle effects or CPK elevations were observed. In Phase 3 cSSSI trials of CUBICIN at a dose of 4 mg/kg, elevations in CPK were reported as clinical adverse events in 15/534 (2.8%) CUBICIN-treated patients, compared with 10/558 (1.8%) comparator-treated patients. In the S. aureus bacteremia/endocarditis trial, at a dose of 6 mg / kg, elevations in CPK were reported as clinical adverse events in 8/120 (6.7%) CUBICIN-treated patients compared with 1/116 (<1%) comparator-treated patients. There were a total of 11 patients who experienced CPK elevations to above 500 U/L. Of these 11 patients, 4 had prior or concomitant treatment with an HMG-CoA reductase inhibitor. Skeletal muscle effects associated with CUBICIN were observed in animals (see ANIMAL PHARMACOLOGY in full prescribing information). Patients receiving CUBICIN should be monitored for the development of muscle pain or weakness, particularly of the distal extremities. In patients who receive CUBICIN, CPK levels should be monitored weekly, and more frequently in patients who received recent prior or concomitant therapy with an HMGCoA reductase inhibitor. In patients with renal insufficiency, both renal function and CPK should be monitored more frequently. Patients who develop unexplained elevations in CPK while receiving CUBICIN should be monitored more frequently. In the cSSSI studies, among patients with abnormal CPK (>500 U/L) at baseline, 2/19 (10.5%) treated with CUBICIN and 4/24 (16.7%) treated with comparator developed further increases in CPK while on therapy. In this same population, no patients developed myopathy. CUBICIN-treated patients with baseline CPK >500 U/L (N=19) did not experience an increased incidence of CPK elevations or myopathy relative to those treated with comparator (N=24). In the S. aureus bacteremia/endocarditis study, 3 (2.6%) CUBICIN-treated patients, including 1 with trauma associated with a heroin overdose and 1 with spinal cord compression, had an elevation in CPK >500 U/L with associated musculoskeletal symptoms. None of the patients in the comparator group had an elevation in CPK >500 U/L with associated musculoskeletal symptoms. CUBICIN should be discontinued in patients with unexplained signs and symptoms of myopathy in conjunction with CPK elevation >1,000 U/L (~5x ULN), or in patients without reported symptoms who have marked elevations in CPK >2,000 U/L (r10x ULN). In addition, consideration should be given to temporarily suspending agents associated with rhabdomyolysis, such as HMG-CoA reductase inhibitors, in patients receiving CUBICIN. In a Phase 1 study examining doses up to 12 mg/kg q24h of CUBICIN for 14 days, no evidence of nerve conduction deficits or symptoms of peripheral neuropathy was observed. In a small number of patients in Phase 1 and Phase 2 studies at doses up to 6 mg/kg, administration of CUBICIN was associated with decreases in nerve conduction velocity and with adverse events (eg, paresthesias, Bell’s palsy) possibly reflective of peripheral or cranial neuropathy. Nerve conduction deficits were also detected in a similar number of comparator subjects in these studies. In Phase 3 cSSSI and communityacquired pneumonia (CAP) studies, 7/989 (0.7%) CUBICIN-treated patients and 7/1,018 (0.7%) comparator-treated patients experienced paresthesias. New or worsening peripheral neuropathy was not diagnosed in any of these patients. In the S. aureus bacteremia/endocarditis trial, a total of 11/120 (9.2%) CUBICIN-treated patients had treatment-emergent adverse events related to the peripheral nervous system. All of the events were classified as mild to moderate in severity; most were of short duration and resolved during continued treatment with CUBICIN or were likely due to an alternative etiology. In animals, effects of CUBICIN on peripheral nerve were observed (see ANIMAL PHARMACOLOGY in full prescribing information). Therefore, physicians should be alert to the possibility of signs and symptoms of neuropathy in patients receiving CUBICIN. Drug Interactions Warfarin Concomitant administration of CUBICIN (6 mg/kg q24h for 5 days) and warfarin (25 mg single oral dose) had no significant effect on the pharmacokinetics of either drug, and the INR was not significantly altered. As experience with the concomitant administration of CUBICIN and warfarin is limited, anticoagulant activity in patients receiving CUBICIN and warfarin should be monitored for the first several days after initiating therapy with CUBICIN (see CLINICAL PHARMACOLOGY, Drug-Drug Interactions in full prescribing information). HMG-CoA Reductase Inhibitors Inhibitors of HMG-CoA reductase may cause myopathy, which is manifested as muscle pain or weakness associated with elevated levels of CPK. There were no reports of skeletal myopathy in a placebo-controlled Phase 1 trial in which 10 healthy subjects on stable simvastatin therapy were treated concurrently with CUBICIN (4 mg/kg q24h) for 14 days. In the Phase 3 S. aureus bacteremia/endocarditis trial, 5/22 CUBICIN-treated patients who received prior or concomitant therapy with an HMG-CoA reductase inhibitor developed CPK elevations >500 U/L. Experience with co-administration of HMG-CoA reductase inhibitors and CUBICIN in patients is limited; therefore, consideration should be given to temporarily suspending use of HMG-CoA reductase inhibitors in patients receiving CUBICIN (see ADVERSE REACTIONS, Post-Marketing Experience). Drug-Laboratory Test Interactions There are no reported drug-laboratory test interactions. Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term carcinogenicity studies in animals have not been conducted to evaluate the carcinogenic potential of daptomycin. However, neither mutagenic nor clastogenic potential was found in a battery of genotoxicity tests, including the Ames assay, a mammalian cell gene mutation assay, a test for chromosomal aberrations in Chinese hamster ovary cells, an in vivo micronucleus assay, an in vitro DNA repair assay, and an in vivo sister chromatid exchange assay in Chinese hamsters. Daptomycin did not affect the fertility or reproductive performance of male and female rats when administered intravenously at doses up to 150 mg/kg/day, which is approximately 9 times the estimated human exposure level based upon AUCs. Pregnancy Teratogenic Effects: Pregnancy Category B Reproductive and teratology studies performed in rats and rabbits at doses of up to 75 mg/kg, 2 and 4 times the 6 mg/kg human dose, respectively, on a body surface area basis, have revealed no evidence of harm to the fetus due to daptomycin. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Nursing Mothers It is not known if daptomycin is excreted in human milk. Caution should be exercised when CUBICIN is administered to nursing women. Pediatric Use Safety and efficacy of CUBICIN in patients under the age of 18 have not been established. Geriatric Use Of the 534 patients treated with CUBICIN in Phase 3 controlled clinical trials of cSSSI, 27.0% were 65 years of age or older and 12.4% were 75 years of age or older. Of the 120 patients treated with CUBICIN in the Phase 3 controlled clinical trial of S. aureus bacteremia/endocarditis, 25.0% were 65 years of age or older and 15.8% were 75 years of age or older. In Phase 3 clinical studies of cSSSI and S. aureus bacteremia/endocarditis, lower clinical success rates were seen in patients r65 years of age compared with those <65 years of age. In addition, treatment-emergent adverse events were more common in patients r65 years old than in patients <65 years of age. ADVERSE REACTIONS Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice. The adverse reaction information from clinical trials does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates. Clinical studies sponsored by Cubist enrolled 1,667 patients treated with CUBICIN and 1,319 treated with comparator. Most adverse events reported in Cubist-sponsored Phase 1, 2, and 3 clinical studies were described as mild or moderate in intensity. In Phase 3 cSSSI trials, CUBICIN was discontinued in 15/534 (2.8%) patients due to an adverse event, while comparator was discontinued in 17/558 (3.0%) patients. In the S. aureus bacteremia/endocarditis trial, CUBICIN was discontinued in 20/120 (16.7%) patients due to an adverse event, while comparator was discontinued in 21/116 (18.1%) patients. GramNegative Infections In the S. aureus bacteremia/endocarditis trial, serious Gram-negative infections and nonserious Gram-negative bloodstream infections were reported in 10/120 (8.3%) CUBICIN-treated and 0/115 comparator-treated patients. Comparator patients received dual therapy that included initial gentamicin for 4 days. Events were reported during treatment and during early and late follow-up. Gram-negative infections included cholangitis, alcoholic pancreatitis, sternal osteomyelitis/mediastinitis, bowel infarction, recurrent Crohn’s disease, recurrent line sepsis, and recurrent urosepsis caused by a number of different Gram-negative organisms. One patient with sternal osteomyelitis following mitral valve repair developed S. aureus endocarditis with a 2 cm mitral vegetation and had a course complicated with bowel infarction, polymicrobial bacteremia, and death. Other Adverse Reactions The incidence (%) of adverse events that occurred in r2% of patients in either CUBICIN 4 mg/kg (N=534) or comparator* (N=558) treatment groups in Phase 3 cSSSI studies were as follows: Gastrointestinal disorders: constipation 6.2% and 6.8%; nausea 5.8% and 9.5%; diarrhea 5.2% and 4.3%; vomiting 3.2% and 3.8%; dys- pepsia 0.9% and 2.5%; General disorders: injection site reactions 5.8% and 7.7%; fever 1.9% and 2.5%; Nervous system disorders: headache 5.4% and 5.4%; insomnia 4.5% and 5.4%; dizziness 2.2% and 2.0%; Skin/subcutaneous disorders: rash 4.3% and 3.8%; pruritus 2.8% and 3.8%; Diagnostic investigations: abnormal liver function tests 3.0% and 1.6%; elevated CPK 2.8% and 1.8%; Infections: fungal infections 2.6% and 3.2%; urinary tract infection 2.4% and 0.5%; Vascular disorders: hypotension 2.4% and 1.4%; hypertension 1.1% and 2.0%; Renal/urinary disorders: renal failure 2.2% and 2.7%; Blood/lymphatic disorders: anemia 2.1% and 2.3%; Respiratory disorders: dyspnea 2.1% and 1.6%; Musculoskeletal disorders: limb pain 1.5% and 2.0%; arthralgia 0.9% and 2.2%. *Comparators included vancomycin (1 g IV q12h) and anti-staphylococcal semi-synthetic penicillins (ie, nafcillin, oxacillin, cloxacillin, flucloxacillin; 4 to 12 g/day IV in divided doses). The incidence (%) of adverse events that occurred in r5% of patients organized by system organ class (SOC), in either CUBICIN 6 mg/kg (N=120) or comparator† (N=116) treatment groups in the S. aureus bacteremia/endocarditis study were as follows: Infections and infestations: 65 (54.2%) and 56 (48.3%); urinary tract infection NOS 8 (6.7%) and 11 (9.5%); osteomyelitis NOS 7 (5.8%) and 7 (6.0%); sepsis NOS 6 (5.0%) and 3 (2.6%); bacteraemia 6 (5.0%) and 0 (0%); pneumonia NOS 4 (3.3%) and 9 (7.8%); Gastrointestinal disorders: 60 (50.0%) and 68 (58.6%); diarrhoea NOS 14 (11.7%) and 21 (18.1%); vomiting NOS 14 (11.7%) and 15 (12.9%); constipation 13 (10.8%) and 14 (12.1%); nausea 12 (10.0%) and 23 (19.8%); abdominal pain NOS 7 (5.8%) and 4 (3.4%); dyspepsia 5 (4.2%) and 8 (6.9%); loose stools 5 (4.2%) and 6 (5.2%); gastrointestinal haemorrhage NOS 2 (1.7%) and 6 (5.2%); General disorders and administration site conditions: 53 (44.2%) and 69 (59.5%); oedema peripheral 8 (6.7%) and 16 (13.8%); pyrexia 8 (6.7%) and 10 (8.6%); chest pain 8 (6.7%) and 7 (6.0%); oedema NOS 8 (6.7%) and 5 (4.3%); asthenia 6 (5.0%) and 6 (5.2%); injection site erythema 3 (2.5%) and 7 (6.0%); Respiratory, thoracic, and mediastinal disorders: 38 (31.7%) and 43 (37.1%); pharyngolaryngeal pain 10 (8.3%) and 2 (1.7%); pleural effusion 7 (5.8%) and 8 (6.9%); cough 4 (3.3%) and 7 (6.0%); dyspnoea 4 (3.3%) and 6 (5.2%); Skin and subcutaneous tissue disorders: 36 (30.0%) and 40 (34.5%); rash NOS 8 (6.7%) and 10 (8.6%); pruritus 7 (5.8%) and 6 (5.2%); erythema 6 (5.0%) and 6 (5.2%); sweating increased 6 (5.0%) and 0 (0%); Musculoskeletal and connective tissue disorders: 35 (29.2%) and 42 (36.2%); pain in extremity 11 (9.2%) and 11 (9.5%); back pain 8 (6.7%) and 10 (8.6%); arthralgia 4 (3.3%) and 13 (11.2%); Psychiatric disorders: 35 (29.2%) and 28 (24.1%); insomnia 11 (9.2%) and 8 (6.9%); anxiety 6 (5.0%) and 6 (5.2%); Nervous system disorders: 32 (26.7%) and 32 (27.6%); headache 8 (6.7%) and 12 (10.3%); dizziness 7 (5.8%) and 7 (6.0%); Investigations: 30 (25.0%) and 33 (28.4%); blood creatine phosphokinase increased 8 (6.7%) and 1 (<1%); Blood and lymphatic system disorders: 29 (24.2%) and 24 (20.7%); anaemia NOS 15 (12.5%) and 18 (15.5%); Metabolism and nutrition disorders: 26 (21.7%) and 38 (32.8%); hypokalaemia 11 (9.2%) and 15 (12.9%); hyperkalaemia 6 (5.0%) and 10 (8.6%); Vascular disorders: 21 (17.5%) and 20 (17.2%); hypertension NOS 7 (5.8%) and 3 (2.6%); hypotension NOS 6 (5.0%) and 9 (7.8%); Renal and urinary disorders: 18 (15.0%) and 26 (22.4%); renal failure NOS 4 (3.3%) and 11 (9.5%); renal failure acute 4 (3.3%) and 7 (6.0%). †Comparator: vancomycin (1 g IV q12h) or anti-staphylococcal semi-synthetic penicillin (ie, nafcillin, oxacillin, cloxacillin, flucloxacillin; 2 g IV q4h), each with initial low-dose gentamicin. The following events, not included above, were reported as possibly or probably drug-related in the CUBICIN-treated group: Blood and Lymphatic System Disorders: eosinophilia (1.7%), lymphadenopathy (<1%), thrombocythaemia (<1%), thrombocytopenia (<1%); Cardiac Disorders: atrial fibrillation (<1%), atrial flutter (<1%), cardiac arrest (<1%); Ear and Labyrinth Disorders: tinnitus (<1%); Eye Disorders: vision blurred (<1%); Gastrointestinal Disorders: dry mouth (<1%), epigastric discomfort (<1%), gingival pain (<1%), hypoaesthesia oral (<1%); Infections and Infestations: candidal infection NOS (1.7%), vaginal candidiasis (1.7%), fungaemia (<1%), oral candidiasis (<1%), urinary tract infection fungal (<1%); Investigations: blood phosphorous increased (2.5%), blood alkaline phosphatase increased (1.7%), INR ratio increased (1.7%), liver function test abnormal (1.7%), alanine aminotransferase increased (<1%), aspartate aminotransferase increased (<1%), prothrombin time prolonged (<1%); Metabolism and Nutrition Disorders: appetite decreased NOS (<1%); Musculoskeletal and Connective Tissue Disorders: myalgia (<1%); Nervous System Disorders: dyskinesia (<1%), paraesthesia (<1%); Psychiatric Disorders: hallucination NOS (<1%); Renal and Urinary Disorders: proteinuria (<1%), renal impairment NOS (<1%); Skin and Subcutaneous Tissue Disorders: heat rash (<1%), pruritus generalized (<1%), rash vesicular (<1%). In Phase 3 studies of community-acquired pneumonia (CAP), the death rate and rates of serious cardiorespiratory adverse events were higher in CUBICIN-treated patients than in comparator-treated patients. These differences were due to lack of therapeutic effectiveness of CUBICIN in the treatment of CAP in patients experiencing these adverse events (see INDICATIONS AND USAGE). The incidence of decreased renal function based on creatinine clearance levels in CUBICIN 6 mg/kg (N=120) and comparator† (N=116) was as follows: Days 2 to 4, 2/96 (2.1%) and 6/90 (6.7%); Days 2 to 7, 6/115 (5.2%) and 16/113 (14.2%); Day 2 to End of Therapy, 13/118 (11.0%) and 30/114 (26.3%). †Comparator: vancomycin (1 g IV q12h) or anti-staphylococcal semi-synthetic penicillin (ie, nafcillin, oxacillin, cloxacillin, flucloxacillin; 2 g IV q4h), each with initial low-dose gentamicin. Post-Marketing Experience The following adverse reactions have been reported with CUBICIN in worldwide postmarketing experience. Because these events are reported voluntarily from a population of unknown size, estimates of frequency cannot be made and causal relationship cannot be precisely established. Immune System Disorders: anaphylaxis; hypersensitivity reactions, including pruritus, hives, shortness of breath, difficulty swallowing, truncal erythema, and pulmonary eosinophilia. Musculoskeletal System: rhabdomyolysis; some reports involved patients treated concurrently with CUBICIN and HMG-CoA reductase inhibitors. OVERDOSAGE In the event of overdosage, supportive care is advised with maintenance of glomerular filtration. Daptomycin is slowly cleared from the body by hemodialysis (approximately 15% recovered over 4 hours) or peritoneal dialysis (approximately 11% recovered over 48 hours). The use of high-flux dialysis membranes during 4 hours of hemodialysis may increase the percentage of dose removed compared with low-flux membranes. DOSAGE The recommended dosage of CUBICIN (daptomycin for injection) in adult patients is as follows: Creatinine clearance (CLCR ) r30 mL/min: 4 mg/kg once every 24 hours (cSSSI) or 6 mg/kg once every 24 hours (S. aureus bloodstream infections); Creatinine clearance (CLCR ) <30 mL/ min, including hemodialysis or CAPD: 4 mg/kg once every 48 hours (cSSSI) or 6 mg/kg once every 48 hours (S. aureus bloodstream infections). 3985072607 CUBICIN is a registered trademark of Cubist Pharmaceuticals, Inc. ©2003–2007 Cubist Pharmaceuticals, Inc. SCHIZOPHRENIA: A REVIEW OF TREATMENTS Affective flattening: restricted emotional expression Akathisia: uncontrollable motor restlessness Alogia: restricted speech Avolition: lack of goal-directed behavior Dystonia: abnormal muscle tone, e.g., rigidity Pseudoparkinsonism: drug-induced syndrome resembling parkinsonism Researchers continue to explore the roles that neurotransmitters other than dopamine, such a serotonin and acetylcholine, might play in schizophrenia.1 TREATMENT Owing to the complex nature of schizophrenia, treatment typically involves both pharmacologic and nonpharmacologic therapies. Nonpharmacologic Therapies Although nonpharmacologic interventions may be perceived as treatment modalities that cannot change the biochemistry of schizophrenia, they can help patients learn how to cope with their illness. Fostering healthy relationships, maintaining employment, learning from others who struggle with mental illness, and participating in cognitive behavioral therapy can all be effective components of a patient’s treatment.5 A 2-year randomized study compared the effect of integrated treatment versus standard treatment in 547 newly diagnosed schizophrenia patients. Standardtreatment patients were offered access to a community mental-health center and received minimal home visits; integrated-treatment patients received home visits from an assigned assertive community-treatment team member and were offered family treatment sessions and social-skills training. Both arms were offered antipsychotic medications. Patients in the integrated-treatment arm showed clinically significant improvement in positive and negative symptoms and substance abuse, but no improvement in depression or suicidal behavior. The integrated-treatment group had a statistically significant decrease in hospital stays during the first year, but the difference was not significant at 2 years. Finally, the mean antipsychotic dose for patients in the integrated-treatment arm was significantly lower.6 This trial illustrates that psychiatric care has a positive impact on a patient’s life when pharmacotherapy is augmented with lifestyle coaching and family involvement. Pharmacotherapy Most patients with schizophrenia require chronic treatment with medications to control symptoms and achieve remission. Once a patient attains a satisfactory clinical response, the regimen should continue indefinitely. First-line medication options include first- and secondgeneration antipsychotics.1 First-Generation Antipsychotics (FGAs): FGAs, also known as conventional or typical antipsychotics, work via dopamine receptor antagonism.1 TABLE 2 includes a list of FGAs. This class of antipsychotics is associated with movement disorders, including extrapyramidal symptoms (EPS) and tardive dyskinesia (TD). Symptoms of EPS include akathisia, dystonia, and pseudoparkinsonism (see TABLE 1). Akathisia can be treated either by lowering the antipsychotic dosage or with benzodiazepines or centrally acting beta-blockers such as propranolol; dystonia and pseudoparkinsonism can be treated with anticholinergic agents such as benztropine or diphenhydramine.1 TD, which typically presents as abnormal orofacial movements, develops in 30% of patients on long-term FGAs. Unlike EPS, TD cannot be treated with medications, and it may be irreversible even after the offending antipsychotic is discontinued.1 Second-Generation Antipsychotics (SGAs): Whereas FGAs work primarily as dopamine-2 receptor antagonists, the mechanisms are much broader for SGAs (also known as atypical antipsychotics). In addition to having an antagonistic effect on dopamine, SGAs also antagonize norepinephrine and serotonin receptors (TABLE 2). Aripiprazole has a unique mechanism of action involving mixed dopaminergic agonism and antagonism in addition to antagonism of serotonergic receptors.1 Owing to serotonergic antagonism, SGAs are not associated with high rates of EPS, with the exception of aripiprazole, which causes akathisia in approximately 10% of patients. 7 Although patients taking SGAs usually do not experience movement-disorder issues, SGAs come with new risks that may negatively affect patient adherence. Clozapine and olanzapine are associated with metabolic syndrome, specifically weight gain, diabetes, and dyslipidemia; other atypical antipsychotics, however, offer minimal to no risk of these metabolic effects. 8 Clozapine also carries a risk of seizures, anticholinergic effects, hypersalivation, myocarditis, and agranulocytosis.9 The incidence of agranulocytosis in patients taking clozapine is 0.39%, and the incidence of death from agranulocytosis is 0.012%.10 The FDA requires all providers prescribing clozapine to be registered with the Clozaril National Registry. Absolute neutrophil counts must be monitored weekly for 6 months when therapy is initiated or adjusted, and continuously throughout the course of therapy.1 Risperidone and paliperidone are associated with hyperprolactinemia, leading to acute adverse events such as galac- HS-5 U.S. Pharmacist • November 2009 • www.uspharmacist.com H E A LT H S Y S T E M S E D I T I O N Table 1 Glossary of Some Schizophrenia Symptoms SCHIZOPHRENIA: A REVIEW OF TREATMENTS H E A LT H S Y S T E M S E D I T I O N Table 2 Dosing of Conventional and Atypical Antipsychotics Drug Name Starting Daily Dose Target Daily Dose or Range Schedule Chlorpromazine (Thorazine) 50-100 mg 300-1,000 mg 3 times dailya Fluphenazine (Prolixin) 5 mg 5-20 mg 3 times dailya Haloperidol (Haldol) 2-5 mg 2-20 mg 1-3 times dailya Perphenazine (Trilafon) 4-8 mg 16-64 mg 3 times dailya Thiothixene (Navane) 4-10 mg 15-20 mg 2-3 times dailya Trifluoperazine (Stelazine) 4-10 mg 5-20 mg Twice dailya Aripiprazole (Abilify) 10-15 mg 10-15 mg Once daily Clozapine (Clozaril) 12.5-25 mg 300-450 mg 1-2 times daily Iloperidone (Fanapt) 2 mg 12-24 mg Twice dailya Olanzapine (Zyprexa) 5-10 mg 20 mg Once daily Paliperidone (Invega) 6 mg 6 mg Once daily Risperidone (Risperdal) 2 mg 2-8 mg 1-2 times dailya Quetiapine IR (Seroquel IR) 50 mg 300-400 mg 2-3 times daily Quetiapine XR (Seroquel XR) 300 mg 400-800 mg Once daily Ziprasidone (Geodon) 40 mg 40-160 mg Twice daily, with food Fluphenazine decanoate (Prolixin Decanoate) 12.5-25 mg IM every 1-3 wk 6.25-50 mg IM every 2-4 wk Every 1-3 wk Haloperidol decanoate (Haldol Decanoate) 25-50 mg IM every 2-4 wk 50-200 mg IM every 2-4 wk Every 3-4 wk Risperidone (Risperdal Consta) 12.5 mg IM every 2 wk 25 mg IM every 2 wk Every 2 wk Conventional Antipsychotics (FGAs) Atypical Antipsychotics (SGAs) Long-Acting Depot Injections a The total daily dose of most antipsychotics can be administered once daily if tolerated. Exceptions are clozapine, quetiapine, and ziprasidone, which likely will require multiple daily doses to control symptoms. FGA: first-generation antipsychotic; IM: intramuscularly; SGA: second-generation antipsychotic. Source: Reference 22. torrhea (spontaneous flow of milk from nipple), amenorrhea (absence of menses), and sexual dysfunction. Osteoporosis may be a long-term effect of hyperprolactinemia.9,11 Both conventional and atypical agents, particularly haloperidol, chlorpromazine, iloperidone, thioridazine, and ziprasidone, are associated with prolongation of the QTc interval, with the last two agents having the highest incidence.9,12,13 The incidence of QTc prolongation with these agents is approximately twice that of a healthy population not taking antipsychotics.14 Providers must always consider the side effects of antipsychotics and discuss them with their patients prior to prescribing. There is very little literature supporting the idea that SGAs are more effective than FGAs. A number of metaanalyses have been published comparing the efficacy of the two classes, as have meta-analyses comparing various SGAs with one another, but no conclusions have been made about the comparative efficacy of the various agents.9,15,16 Both CUtLASS (Cost Utility of the Latest Antipsychotic Drugs in Schizophrenia Study) and CATIE (Clinical Antipsychotic Trials of Intervention Effectiveness) showed that atypical antipsychotics offer no benefit over conventional antipsychotics; however, CATIE 2 concluded that clozapine may have an advantage over other atypical antipsychotics in treatment-refractory patients.17-19 Clozapine’s benefit may be a result of the increase in provider interaction due to monitoring for agranulocytosis.20 HS-6 U.S. Pharmacist • November 2009 • www.uspharmacist.com SCHIZOPHRENIA: A REVIEW OF TREATMENTS H E A LT H S Y S T E M S E D I T I O N • Atypical antipsychotic Stage 1 Stage 2 Stage 3 Stage 4 • Atypical or conventional antipsychotic • Not the same atypical from stage 1 • Clozapine • May try earlier if history of recurrent suicidality, violence, or substance abuse • Clozapine plus • Conventional or atypical antipsychotic or ECT will improve adherence. Exceptions to this are clozapine, quetiapine, and ziprasidone, which probably will require multiple daily doses to control symptoms. Finally, treatment with multiple antipsychotics should be considered a last resort and avoided if at all possible, as it often provides no additional efficacy and increases the risk of intolerable side effects. In general, FGAs are more affordable than SGAs, with perphenazine and fluphenazine costing more than other FGAs. Currently, the only generic SGAs are clozapine and risperidone. Cost should be a major consideration when choosing an antipsychotic, with a preference for FGAs if a patient can tolerate them. • Trial of single atypical or conventional agent not tried in stages 1 and 2 Other Medications: Whereas antipsychotics remain the primary pharmacologic treatment for schizophrenia, a • Combination therapy, such as atypical plus conventional antipsychotic; number of other medications may be combination of atypical and/or conventional antipsychotics plus ECT; used to augment them. One such class or conventional or atypical antipsychotic plus mood stabilizer Stage 6 is the mood stabilizers, which often are used in patients experiencing increased agitation or aggression. Overall, patients Source: Reference 29. Adapted with permission of the Texas Department of State with schizophrenia are not violent; Health Services. however, episodes in which positive ECT: electroconvulsive therapy. symptoms are exacerbated may lead to Figure 1. Algorithm for the treatment of schizophrenia. A patient should progress increased agitation. 3 During such to the next stage if he or she experiences a partial response or nonresponse to instances, mood stabilizers may be benthe current stage. eficial. In a meta-analysis of 11 studies comparing antipsychotic monotherImprovements in sleep disturbance and agitation apy with lithium augmentation, more patients receiving may be seen in the first 2 days of antipsychotic ther- lithium had a clinically significant response, with a apy; however, the full effect may not be seen for 6 to number needed to treat of 8.23 Two small studies have 8 weeks. If the patient reports no symptom relief in 2 compared antipsychotic monotherapy with carbato 4 weeks, either the antipsychotic dose should be mazepine augmentation; in these studies, patients on carbamazepine showed clinically significant overall increased or a new agent should be selected.1,21 Recommended doses of FGAs and SGAs are given global improvement. 24 Similarly, there is only limin TABLE 2.22 These doses have been suggested by the ited evidence to support the use of augmentation thermanufacturers of the respective agents; however, apy with valproate, including a single small study showpractitioners often prescribe outside of the recom- ing less agitation in the valproate augmentation group mended range. While this often is unavoidable in treat- versus the antipsychotic monotherapy group.25 A metament-resistant patients, the practice may result in adverse analysis of five studies evaluating the efficacy of antipsyevents and limited additional efficacy. Also, many chotic augmentation with lamotrigine showed that patients probably will not require the higher end of 20% to 30% of clozapine-resistant patients with the dosing range for FGAs. Specifically, patients schizophrenia had a clinically significant improvement experiencing their first psychotic break will likely respond when lamotrigine was added.26 In a randomized, douto much lower doses of antipsychotics and be more ble-blind, placebo-controlled study of patients with sensitive to adverse events than a patient in a more schizophrenia, the addition of topiramate resulted in advanced stage of schizophrenia.21 Additionally, it should a reduction of both positive and negative symptoms be noted that the total daily dose of most antipsychotics compared with patients on antipsychotic monothercan be administered once daily if tolerated, and this apy.27 Mood stabilizers have great potential for the Stage 5 HS-8 U.S. Pharmacist • November 2009 • www.uspharmacist.com SCHIZOPHRENIA: A REVIEW OF TREATMENTS ADHERENCE A number of studies have been designed to measure patient adherence to antipsychotics compared with other medications, but the results are difficult to interpret. This is primarily because each study defines and measures nonadherence differently. A meta-analysis REFERENCES 1. Freedman R. Schizophrenia. N Engl J Med. 2003;349:1738-1749. 2. Siris SG. Suicide and schizophrenia. J Psychopharmacol. 2001;15: 127-135. 3. Tandon R, Nasrallah HA, Keshavan MS. Schizophrenia, “just the facts” 4. Clinical features and conceptualization. Schizophr Res. 2009;110:1-23. 4. Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR). Washington, DC: American Psychiatric Association; 2000. 5. Keshavan MS, Roberts M, Wittmann D. Guidelines for clinical treatment of early course schizophrenia. Curr Psych Rep. 2006;8:329-334. 6. Petersen L, Jeppesen P, Thorup A, et al. A randomized multicentre trial of integrated versus standard treatment for patients with a first episode of psychotic illness. BMJ. 2005;331:602-608. 7. Pae CU. A review of the safety and tolerability of aripiprazole. Expert Opin Drug Saf. 2009;8:373-386. 8. Newcomer JW. Second-generation (atypical) antipsychotics and metabolic effects: a comprehensive literature review. CNS Drugs. 2005;19(suppl 1):1-93. 9. Leucht S, Corves C, Arbter D, et al. Second-generation versus firstgeneration antipsychotic drugs for schizophrenia: a meta-analysis. Lancet. 2009;373:31-41. 10. Honigfeld G, Arellano F, Sethi J, et al. Reducing clozapine-related morbidity and mortality: 5 years of experience with the Clozaril National Registry. J Clin Psychiatry. 1998;59(suppl 3):3-7. 11. Haddad PM, Wieck A. Antipsychotic-induced hyperprolactinemia: mechanisms, clinical features and management. Drugs. 2004;64: 2291-2314. 12. Cutler AJ, Kalali AH, Weiden PJ, et al. Four-week, double-blind, placebo- and ziprasidone-controlled trial of iloperidone in patients with acute exacerbations of schizophrenia. J Clin Psychopharmacol. 2008;28(2 suppl 1):S20-S28. 13. FDA Psychopharmacological Drugs Advisory Committee. Briefing document for Zeldox ® capsules (ziprasidone HCl). July 19, 2000. 14. Glassman AH, Bigger JT Jr. Antipsychotic drugs: prolonged QTc interval, torsade de pointes, and sudden death. Am J Psychiatry. 2001;158:1774-1782. 15. Leucht S, Komossa K, Rummel-Kluge C, et al. A meta-analysis of head-to-head comparisons of second-generation antipsychotics in the treatment of schizophrenia. Am J Psychiatry. 2009;166:152-163. 16. Davis JM, Chen N, Glick ID. A meta-analysis of the efficacy of second-generation antipsychotics. Arch Gen Psychiatry. 2003;60:553-564. of adherence studies reported that patients take an average of 58% of their prescribed antipsychotic doses (range 24%-90%). The meta-analysis found that patients take medications for physical ailments an average of 76% of the time (range 60%-92%), implying that adherence to antipsychotics may be lower than adherence to other medications.30 Some barriers to care in patients with schizophrenia include stigma about mental illness, lack of access to care, and fragmentation of services.5 A pharmacist can help a patient overcome these barriers through education and identification of patient-assistance programs when financial issues arise. Additionally, the pharmacist may recommend the use of long-acting depot antipsychotic injections to improve adherence to medication therapy. Recommended doses of depot antipsychotics are given in TABLE 2. CONCLUSION Despite the fact that there is no cure for schizophrenia, providing patients with guideline-based treatments supported by primary literature will afford the best opportunity for controlling the symptoms of their illness. The process of choosing appropriate medications and monitoring for appropriate adverse reactions should be facilitated by a pharmacist whenever possible. 17. Jones PB, Barnes TRE, Davies L, et al. Randomized controlled trial of the effect on quality of life of second- and first-generation antipsychotic drugs on schizophrenia: Cost Utility of the Latest Antipsychotic Drugs in Schizophrenia Study (CUtLASS I). Arch Gen Psychiatry. 2006;63:1079-1087. 18. Lieberman JA, Stroup TS, McEvoy JP, et al, for the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) Investigators. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med. 2005;353:1209-1223. 19. McEvoy JP, Lieberman JA, Stroup TS, et al, for the CATIE Investigators. Effectiveness of clozapine versus olanzapine, quetiapine, and risperidone in patients with chronic schizophrenia who did not respond to prior atypical antipsychotic treatment. Am J Psychiatry. 2006;163: 600-610. 20. Meltzer HY, Alphs L, Green AI, et al. Clozapine treatment for suicidality in schizophrenia: International Suicide Prevention Trial (InterSePT). Arch Gen Psychiatry. 2003;60:82-91. 21. APA Practice Guidelines. Lehman AF, Lieberman JA, Dixon LB, et al. Practice guideline for the treatment of patients with schizophrenia. 2nd ed. www.psychiatryonline.com/pracGuide/loadGuidelinePdf .aspx?file=Schizophrenia2e_Inactivated_04-16-09. Accessed October 13, 2009. 22. Micromedex Healthcare Series [Intranet database]. Greenwood Village, CO: Thomson Healthcare. Accessed October 13, 2009. 23. Leucht S, Kissling W, McGrath J. Lithium for schizophrenia. Cochrane Database Syst Rev. 2007;(3):CD003834. 24. Leucht S, Kissling W, McGrath J. Carbamazepine for schizophrenia. Cochrane Database Syst Rev. 2007;(3):CD001258. 25. Schwarz C, Volz A, Li C, Leucht S. Valproate for schizophrenia. Cochrane Database Syst Rev. 2008;(3):CD004028. 26. Tiihonen J, Wahlbeck K, Kiviniemi V. The efficacy of lamotrigine in clozapine-resistant schizophrenia: a systematic review and meta-analysis. Schizophr Res. 2009;109:10-14. 27. Afshar H, Roohafza H, Mousavi G, et al. Topiramate add-on treatment in schizophrenia: a randomised, double-blind, placebo-controlled clinical trial. J Psychopharmacol. 2009;23:157-162. 28. Volz A, Khorsand V, Gillies D, Leucht S. Benzodiazepines for schizophrenia. Cochrane Database Syst Rev. 2007;(1):CD006391. 29. Moore TA, Buchanan RW, Buckley PF, et al. The Texas Medication Algorithm Project antipsychotic algorithm for schizophrenia: 2006 update. J Clin Psychiatry. 2007;68:1751-1762. 30. Cramer JA, Rosenheck R. Compliance with medication regimens for mental and physical disorders. Psychiatr Serv. 1998;49:196-201. HS-9 U.S. Pharmacist • November 2009 • www.uspharmacist.com H E A LT H S Y S T E M S E D I T I O N treatment of schizophrenia, but more research is needed. Benzodiazepines have been studied for their benefits in augmenting antipsychotics. Although the studies have been small, they have shown some advantage over antipsychotic monotherapy in treating agitation in schizophrenia. This effect is short-lived, however, with a return of symptoms within 1 hour of a benzodiazepine dose.28 One of the most straightforward algorithms for the treatment of schizophrenia was published by the Texas Department of State Health Services (FIGURE 1). This algorithm is based on evidence when available, and expert consensus where no evidence exists. If a patient fails trials of two stages of this algorithm with no appreciable improvement in symptoms, the diagnosis of schizophrenia should be re-evaluated, and the possibility of co-occurring substance abuse should be considered.29 H E A LT H S Y S T E M S E D I T I O N © JUPITERIMAGES Prophylactic Therapies in Traumatic Brain Injury Management T raumatic brain injury (TBI), defined as a strong impact to the head or a penetrating head injury that alters the function of the brain, affects the lives of approximately 1.4 million people in the United States each year.1 TBI currently accounts for an estimated 1.1 million emergency department admissions and 50,000 deaths annually. Individuals at highest risk for TBI are young children 6 months to 4 years old, males between the ages of 15 and 30 years, elderly individuals (aged 75 years or older), and certain military personnel. According to the CDC, the leading causes of TBI include falls (28%), motor vehicle crashes (20%), events in which a person is struck by or against an object (19%), and assaults (11%).1 blast wounds are the result of a combination of blunt and penetrating injuries. In addition to identifying the mechanism of injury, TBI is also separated into either primary or secondary injury.2 A primary injury occurs at the time of injury and directly damages neuronal tissue. Resultant lesions from a primary injury are either focal, where the injury is in a localized area of the brain, or diffuse, in which the injury is large and widespread. The secondary injury that occurs from TBI is not initially seen; instead it is the result of a normal physiological response to the primary injury, such as tissue hypoxia, that develops over a period of time from hours to months following the primary injury.2 For decades, the concentration of TBI management Types of Injuries was on maintaining the control of intracranial pressure To appropriately treat and provide care to patients (ICP) and cerebral perfusion pressure. As will be diswith TBI, it is important to understand the mecha- cussed, the focus of TBI management no longer resides nism and pathophysiology behind the injury. There in one central area; instead, managing all aspects of are three key mechanisms of injury—blunt, pene- TBI are now important areas of therapeutic decision trating, and blast, which are further making. Building upon the 2007 Jennifer Confer, PharmD divided into primary or secondary Guidelines for the Management of Critical Care Clinical Specialist injuries.2 Blunt injuries are the most Severe Traumatic Brain Injury, this Cabell Huntington Hospital Clinical Assistant Professor, West Virginia common cause of TBI and are frearticle will focus on prophylactic University School of Pharmacy quently the result of motor vehicle therapies currently being used and Huntington, West Virginia (i.e., automobile, motorcycle, pedesrecommended in patients with TBI Jon Wietholter, PharmD trian) crashes, falls, sports-related (TABLE 1). Internal Medicine Clinical Specialist injuries, and assaults. Penetrating Cabell Huntington Hospital Prophylactic Steroids injuries result when any sharp or Clinical Assistant Professor, West Virginia Beneficial effects of corticosteroids blunt object penetrates the scalp or University School of Pharmacy in TBI were originally discovered in skull (e.g., gunshot wounds). Lastly, Huntington, West Virginia HS-10 U.S. Pharmacist • November 2009 • www.uspharmacist.com Fentanyl transdermal system should ONLY be used in patients who are already receiving opioid therapy, who have demonstrated opioid tolerance, and who require a total daily dose at least equivalent to fentanyl transdermal system 25 mcg/hr. Patients who are considered opioid-tolerant are those who have been taking, for a week or longer, at least 60 mg of morphine daily, or at least 30 mg of oral oxycodone daily, or at least 8 mg of oral hydromorphone daily or an equianalgesic dose of another opioid. Because serious or life-threatening hypoventilation could occur, fentanyl transdermal system is contraindicated: • in patients who are not opioid-tolerant • in the management of acute pain or in patients who require opioid analgesia for a short period of time • in the management of postoperative pain, including use after out patient or day surgeries (e.g., tonsillectomies) • in the management of mild pain • in the management of intermittent pain [e.g., use on an as needed basis (prn)] The safety of fentanyl transdermal system has not been established in children under 2 years of age. Fentanyl transdermal system should be administered to children only if they are opioid-tolerant and 2 years of age or older (see PRECAUTIONS: Pediatric Use). Patients using fentanyl transdermal system should avoid exposure to external heat sources, such as heating pads, hot tubs, long hot baths, and sunbathing. An increase in body temperature may result in a sudden and possible dangerous rise in their body fentanyl level. Fentanyl transdermal system may cause death from overdosage; therefore, it is important for healthcare professionals, patients and caregivers to know the signs of fentanyl overdose, which can include trouble breathing and extreme sleepiness. Fentanyl transdermal system should be stored in a safe place and kept out of the reach of children. Used, unneeded or defective fentanyl patches should be safely disposed of by folding the sticky side of the patch together (until it sticks to itself) and flushing it down the toilet. The most common adverse events reported in clinical trials were fever, nausea, vomiting, constipation, dry mouth, somnolence, confusion, asthenia, and sweating. Please see adjacent Brief Summary of Prescribing Information, including BOXED WARNING. In the management of persistent, moderate to severe chronic pain that requires continuous, around-the-clock opioid administration for an extended period of time and cannot be managed by other means* Why Take A Chance With Other Fentanyl Patches? One patch can cause burns. This matrix patch contains aluminum in its backing, which can overheat during a magnetic resonance imaging (MRI) scan and burn the patient who is wearing it. Other patches can leak. They contain a reservoir of fentanyl gel that can leak and cause potentially life-threatening complications. Mylan FENTANYL is the first marketed fentanyl patch designed to avoid the risks associated with burns and leaks. The Mylan FENTANYL TRANSDERMAL SYSTEM CII has no aluminum or other metals in its backing. Also important to patient safety, Mylan Fentanyl has a proprietary matrix design without a liquid, gel-filled reservoir that can leak. It is an innovative solution in transdermal drug delivery. *Other means include non-steroidal analgesics, opioid combination products, or immediate-release opioids. ©2009 Mylan Pharmaceuticals Inc. MYNFEN031 No metal. No burns. No leaks. FENTANYL TRANSDERMAL SYSTEM BRIEF SUMMARY: Please see package insert for full prescribing information. FOR USE IN OPIOID-TOLERANT PATIENTS ONLY Fentanyl transdermal system contains a high concentration of a potent Schedule II opioid agonist, fentanyl. Schedule II opioid substances which include fentanyl, hydromorphone, methadone, morphine, oxycodone, and oxymorphone have the highest potential for abuse and associated risk of fatal overdose due to respiratory depression. Fentanyl can be abused and is subject to criminal diversion. The high content of fentanyl in the patches (fentanyl transdermal system) may be a particular target for abuse and diversion. Fentanyl transdermal system is indicated for management of persistent, moderate to severe chronic pain that: • requires continuous, around-the-clock opioid administration for an extended period of time, and • cannot be managed by other means such as non-steroidal analgesics, opioid combination products, or immediate-release opioids Fentanyl transdermal system should ONLY be used in patients who are already receiving opioid therapy, who have demonstrated opioid tolerance, and who require a total daily dose at least equivalent to fentanyl transdermal system 25 mcg/hr. Patients who are considered opioid-tolerant are those who have been taking, for a week or longer, at least 60 mg of morphine daily, or at least 30 mg of oral oxycodone daily, or at least 8 mg of oral hydromorphone daily or an equianalgesic dose of another opioid. Because serious or life-threatening hypoventilation could occur, fentanyl transdermal system is contraindicated: • in patients who are not opioid-tolerant • in the management of acute pain or in patients who require opioid analgesia for a short period of time • in the management of postoperative pain, including use after out patient or day surgeries (e.g., tonsillectomies) • in the management of mild pain • in the management of intermittent pain [e.g., use on an as needed basis (prn)] (See CONTRAINDICATIONS for further information.) Since the peak fentanyl levels occur between 24 and 72 hours of treatment, prescribers should be aware that serious or life-threatening hypoventilation may occur, even in opioid-tolerant patients, during the initial application period. The concomitant use of fentanyl transdermal system with all cytochrome P450 3A4 inhibitors (such as ritonavir, ketoconazole, itraconazole, troleandomycin, clarithromycin, nelfinavir, nefazodone, amiodarone, amprenavir, aprepitant, diltiazem, erythromycin, fluconazole, fosamprenavir, grapefruit juice, and verapamil) may result in an increase in fentanyl plasma concentrations, which could increase or prolong adverse drug effects and may cause potentially fatal respiratory depression. Patients receiving fentanyl transdermal system and any CYP3A4 inhibitor should be carefully monitored for an extended period of time and dosage adjustments should be made if warranted (see CLINICAL PHARMACOLOGY: Drug Interactions, WARNINGS, PRECAUTIONS and DOSAGE AND ADMINISTRATION in full prescribing information for further information). The safety of fentanyl transdermal system has not been established in children under 2 years of age. Fentanyl transdermal system should be administered to children only if they are opioid-tolerant and 2 years of age or older (see PRECAUTIONS: Pediatric Use in full prescribing information). Fentanyl transdermal system is ONLY for use in patients who are already tolerant to opioid therapy of comparable potency. Use in non-opioid-tolerant patients may lead to fatal respiratory depression. Overestimating the fentanyl transdermal system dose when converting patients from another opioid medication can result in fatal overdose with the first dose. Due to the mean elimination half-life of 17 hours of fentanyl transdermal system, patients who are thought to have had a serious adverse event, including overdose, will require monitoring and treatment for at least 24 hours. Fentanyl transdermal system can be abused in a manner similar to other opioid agonists, legal or illicit. This risk should be considered when administering, prescribing, or dispensing fentanyl transdermal system in situations where the healthcare professional is concerned about increased risk of misuse, abuse or diversion. Persons at increased risk for opioid abuse include those with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (e.g., major depression). Patients should be assessed for their clinical risks for opioid abuse or addiction prior to being prescribed opioids. All patients receiving opioids should be routinely monitored for signs of misuse, abuse and addiction. Patients at increased risk of opioid abuse may still be appropriately treated with modified-release opioid formulations; however, these patients will require intensive monitoring for signs of misuse, abuse, or addiction. Fentanyl transdermal system patches are intended for transdermal use (on intact skin) only. Do not use a fentanyl transdermal system if the seal is broken or the patch is cut, damaged, or changed in any way. Avoid exposing the fentanyl transdermal system application site and surrounding area to direct external heat sources, such as heating pads or electric blankets, heat or tanning lamps, saunas, hot tubs, and heated water beds, while wearing the system. Avoid taking hot baths or sunbathing. There is a potential for temperaturedependent increases in fentanyl released from the system resulting in possible overdose and death. Patients wearing fentanyl transdermal systems who develop fever or increased core body temperature due to strenuous exertion should be monitored for opioid side effects and the fentanyl transdermal system dose should be adjusted if necessary. INDICATIONS AND USAGE: Fentanyl transdermal system is indicated for management of persistent, moderate to severe chronic pain that: • requires continuous, around-the-clock opioid administration for an extended period of time, and • cannot be managed by other means such as non-steroidal analgesics, opioid combination products, or immediate-release opioids Fentanyl transdermal system should ONLY be used in patients who are already receiving opioid therapy, who have demonstrated opioid tolerance, and who require a total daily dose at least equivalent to fentanyl transdermal system 25 mcg/hr (see DOSAGE AND ADMINISTRATION in full prescribing information). Patients who are considered opioid-tolerant are those who have been taking, for a week or longer, at least 60 mg of morphine daily, or at least 30 mg of oral oxycodone daily, or at least 8 mg of oral hydromorphone daily, or an equianalgesic dose of another opioid. Because serious or life-threatening hypoventilation could result, fentanyl transdermal system is contraindicated for use on an as needed basis (i.e., prn), for the management of postoperative or acute pain, or in patients who are not opioid-tolerant or who require opioid analgesia for a short period of time (see BOX WARNING and CONTRAINDICATIONS). An evaluation of the appropriateness and adequacy of treating with immediate-release opioids is advisable prior to initiating therapy with any modified-release opioid. Prescribers should individualize treatment in every case, initiating therapy at the appropriate point along a progression from non-opioid analgesics, such as non-steroidal anti-inflammatory drugs and acetaminophen, to opioids, in a plan of pain management such as outlined by the World Health Organization, the Agency for Health Research and Quality, the Federation of State Medical Boards Model Policy, or the American Pain Society. Patients should be assessed for their clinical risks for opioid abuse or addiction prior to being prescribed opioids. Patients receiving opioids should be routinely monitored for signs of misuse, abuse, and addiction. Persons at increased risk for opioid abuse include those with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (e.g., major depression). Patients at increased risk may still be appropriately treated with modified-release opioid formulations; however these patients will require intensive monitoring for signs of misuse, abuse, or addiction. CONTRAINDICATIONS: Because serious or life-threatening hypoventilation could occur, fentanyl transdermal system is contraindicated: • in patients who are not opioid-tolerant • in the management of acute pain or in patients who require opioid analgesia for a short period of time • in the management of postoperative pain, including use after out-patient or day surgeries (e.g., tonsillectomies) • in the management of mild pain • in the management of intermittent pain [e.g., use on an as needed basis (prn)] • in situations of significant respiratory depression, especially in unmonitored settings where there is a lack of resuscitative equipment • in patients who have acute or severe bronchial asthma Fentanyl transdermal system is contraindicated in patients who have or are suspected of having paralytic ileus. Fentanyl transdermal system is contraindicated in patients with known hypersensitivity to fentanyl or any components of this product. WARNINGS: Fentanyl transdermal systems are intended for transdermal use (on intact skin) only. Do not use a fentanyl transdermal system if the seal is broken or the patch is cut, damaged, or changed in any way. The safety of fentanyl transdermal system has not been established in children under 2 years of age. Fentanyl transdermal system should be administered to children only if they are opioid-tolerant and 2 years of age or older (see PRECAUTIONS: Pediatric Use in full prescribing information). Fentanyl transdermal system is ONLY for use in patients who are already tolerant to opioid therapy of comparable potency. Use in non-opioid-tolerant patients may lead to fatal respiratory depression. Overestimating the fentanyl transdermal system dose when converting patients from another opioid medication can result in fatal overdose with the first dose. The mean elimination half-life of fentanyl transdermal system is 17 hours. Therefore, patients who have experienced serious adverse events, including overdose, will require monitoring for at least 24 hours after fentanyl transdermal system removal since serum fentanyl concentrations decline gradually and reach an approximate 50% reduction in serum concentrations 17 hours after system removal. Fentanyl transdermal system should be prescribed only by persons knowledgeable in the continuous administration of potent opioids, in the management of patients receiving potent opioids for treatment of pain, and in the detection and management of hypoventilation including the use of opioid antagonists. All patients and their caregivers should be advised to avoid exposing the fentanyl transdermal system application site and surrounding area to direct external heat sources, such as heating pads or electric blankets, heat or tanning lamps, saunas, hot tubs, and heated water beds, etc., while wearing the system. Patients should be advised against taking hot baths or sunbathing. There is a potential for temperature-dependent increases in fentanyl released from the system resulting in possible overdose and death. Based on a pharmacokinetic model, serum fentanyl concentrations could theoretically increase by approximately one-third for patients with a body temperature of 40°C (104°F) due to temperature-dependent increases in fentanyl released from the system and increased skin permeability. Patients wearing fentanyl transdermal systems who develop fever or increased core body temperature due to strenuous exertion should be monitored for opioid side effects and the fentanyl transdermal system dose should be adjusted if necessary. Death and other serious medical problems have occurred when people were accidentally exposed to fentanyl transdermal system. Examples of accidental exposure include transfer of a fentanyl transdermal system from an adult’s body to a child while hugging, accidental sitting on a patch and possible accidental exposure of a caregiver’s skin to the medication in the patch while the caregiver was applying or removing the patch. Placing fentanyl transdermal system in the mouth, chewing it, swallowing it, or using it in ways other than indicated may cause choking or overdose that could result in death. Misuse, Abuse and Diversion of Opioids Fentanyl is an opioid agonist of the morphine-type. Such drugs are sought by drug abusers and people with addiction disorders and are subject to criminal diversion. Fentanyl can be abused in a manner similar to other opioids, legal or illicit. This should be considered when prescribing or dispensing fentanyl transdermal system in situations where the physician or pharmacist is concerned about an increased risk of misuse, abuse or diversion. Fentanyl transdermal system has been reported as being abused by other methods and routes of administration. These practices will result in uncontrolled delivery of the opioid and pose a significant risk to the abuser that could result in overdose and deaths (see WARNINGS and DRUG ABUSE AND ADDICTION). Concerns about abuse, addiction and diversion should not prevent the proper management of pain. However, all patients treated with opioids require careful monitoring for signs of abuse and addiction, since use of opioid analgesic products carries the risk of addiction even under appropriate medical use. Healthcare professionals should contact their state professional licensing board or state controlled substances authority for information on how to prevent and detect abuse or diversion of this product. Hypoventilation (Respiratory Depression): Serious or life-threatening hypoventilation may occur at any time during the use of fentanyl transdermal system especially during the initial 24 to 72 hours following initiation of therapy and following increases in dose. Because significant amounts of fentanyl are absorbed from the skin for 17 hours or more after the patch is removed, hypoventilation may persist beyond the removal of fentanyl transdermal system. Consequently, patients with hypoventilation should be carefully observed for degree of sedation and their respiratory rate monitored until respiration has stabilized. The use of concomitant CNS active drugs requires special patient care and observation. Respiratory depression is the chief hazard of opioid agonists, including fentanyl the active ingredient in fentanyl transdermal system. Respiratory depression is more likely to occur in elderly or debilitated patients, usually following large initial doses in non-tolerant patients, or when opioids are given in conjunction with other drugs that depress respiration. Respiratory depression from opioids is manifested by a reduced urge to breathe and a decreased rate of respiration, often associated with the “sighing” pattern of breathing (deep breaths separated by abnormally long pauses). Carbon dioxide retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids. This makes overdoses involving drugs with sedative properties and opioids especially dangerous. Fentanyl transdermal system should be used with extreme caution in patients with significant chronic obstructive pulmonary disease or cor pulmonale, and in patients having a substantially decreased respiratory reserve, hypoxia, hypercapnia, or preexisting respiratory depression. In such patients, even usual therapeutic doses of fentanyl transdermal system may decrease respiratory drive to the point of apnea. In these patients, alternative non-opioid analgesics should be considered, and opioids should be employed only under careful medical supervision at the lowest effective dose. Chronic Pulmonary Disease: Because potent opioids can cause serious or life-threatening hypoventilation, fentanyl transdermal system should be administered with caution to patients with preexisting medical conditions predisposing them to hypoventilation. In such patients, normal analgesic doses of opioids may further decrease respiratory drive to the point of respiratory failure. Head Injuries and Increased Intracranial Pressure: Fentanyl transdermal system should not be used in patients who may be particularly susceptible to the intracranial effects of CO2 retention such as those with evidence of increased intracranial pressure, impaired consciousness, or coma. Opioids may obscure the clinical course of patients with head injury. Fentanyl transdermal system should be used with caution in patients with brain tumors. Interactions with other CNS Depressants: The concomitant use of fentanyl transdermal system with other central nervous system depressants, including but not limited to other opioids, sedatives, hypnotics, tranquilizers (e.g., benzodiazepines), general anesthetics, phenothiazines, skeletal muscle relaxants, and alcohol, may cause respiratory depression, hypotension, and profound sedation or potentially result in coma. When such combined therapy is contemplated, the dose of one or both agents should be significantly reduced. Interactions with Alcohol and Drugs of Abuse: Fentanyl may be expected to have additive CNS depressant effects when used in conjunction with alcohol, other opioids, or illicit drugs that cause central nervous system depression. Interactions with CYP3A4 Inhibitors: The concomitant use of transdermal fentanyl with all CYP3A4 inhibitors (such as ritonavir, ketoconazole, itraconazole, troleandomycin, clarithromycin, nelfinavir, nefazadone, amiodarone, amprenavir, aprepitant, diltiazem, erythromycin, fluconazole, fosamprenavir, grapefruit juice, and verapamil) may result in an increase in fentanyl plasma concentrations, which could increase or prolong adverse drug effects and may cause potentially fatal respiratory depression. Patients receiving fentanyl transdermal system and any CYP3A4 inhibitor should be carefully monitored for an extended period of time, and dosage adjustments should be made if warranted (see BOX WARNING, CLINICAL PHARMACOLOGY: Drug Interactions in full prescribing information, PRECAUTIONS, and DOSAGE AND ADMINISTRATION in full prescribing information for further information). PRECAUTIONS: General: Fentanyl transdermal system should not be used to initiate opioid therapy in patients who are not opioid-tolerant. Children converting to fentanyl transdermal system should be opioid-tolerant and 2 years of age or older (see BOX WARNING). Page 1 of 3 Patients, family members and caregivers should be instructed to keep patches (new and used) out of the reach of children and others for whom fentanyl transdermal system was not prescribed. A considerable amount of active fentanyl remains in fentanyl transdermal system even after use as directed. Accidental or deliberate application or ingestion by a child or adolescent will cause respiratory depression that could result in death. Cardiac Disease: Fentanyl may produce bradycardia. Fentanyl should be administered with caution to patients with bradyarrhythmias. Hepatic or Renal Disease: Insufficient information exists to make recommendations regarding the use of fentanyl transdermal system in patients with impaired renal or hepatic function. If the drug is used in these patients, it should be used with caution because of the hepatic metabolism and renal excretion of fentanyl. Use in Pancreatic/Biliary Tract Disease: Fentanyl transdermal system may cause spasm of the sphincter of Oddi and should be used with caution in patients with biliary tract disease, including acute pancreatitis. Opioids like fentanyl transdermal system may cause increases in the serum amylase concentration. Tolerance: Tolerance is a state of adaptation in which exposure to a drug induces changes that result in a diminution of one or more of the drug’s effects over time. Tolerance may occur to both the desired and undesired effects of drugs, and may develop at different rates for different effects. Physical Dependence: Physical dependence is a state of adaptation that is manifested by an opioid specific withdrawal syndrome that can be produced by abrupt cessation, rapid dose reduction, decreasing blood level of the drug, and/or administration of an antagonist. The opioid abstinence or withdrawal syndrome is characterized by some or all of the following: restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, piloerection, myalgia, mydriasis, irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, or increased blood pressure, respiratory rate, or heart rate. In general, opioids should not be abruptly discontinued (see DOSAGE AND ADMINISTRATION: Discontinuation of Fentanyl Transdermal System in full prescribing information). Ambulatory Patients: Strong opioid analgesics impair the mental or physical abilities required for the performance of potentially dangerous tasks, such as driving a car or operating machinery. Patients who have been given fentanyl transdermal system should not drive or operate dangerous machinery unless they are tolerant to the effects of the drug. Information for Patients: Patients and their caregivers should be provided with a Medication Guide each time fentanyl transdermal system is dispensed because new information may be available. Patients receiving fentanyl transdermal system should be given the following instructions by the physician: 1. Patients should be advised that fentanyl transdermal systems contain fentanyl, an opioid pain medicine similar to morphine, hydromorphone, methadone, oxycodone, and oxymorphone. 2. Patients should be advised that each fentanyl transdermal system may be worn continuously for 72 hours, and that each patch should be applied to a different skin site after removal of the previous transdermal patch. 3. Patients should be advised that fentanyl transdermal system should be applied to intact, nonirritated, and nonirradiated skin on a flat surface such as the chest, back, flank, or upper arm. Additionally, patients should be advised of the following: • In young children or persons with cognitive impairment, the patch should be put on the upper back to lower the chances that the patch will be removed and placed in the mouth. • Hair at the application site should be clipped (not shaved) prior to patch application. • If the site of fentanyl transdermal system application must be cleansed prior to application of the patch, do so with clear water. • Do not use soaps, oils, lotions, alcohol, or any other agents that might irritate the skin or alter its characteristics. • Allow the skin to dry completely prior to patch application. 4. Patients should be advised that fentanyl transdermal system should be applied immediately upon removal from the sealed package and after removal of the protective liner. Additionally the patient should be advised of the following: • The fentanyl transdermal system should not be used if the seal is broken or the patch is cut, damaged, or changed in any way. • The transdermal patch should be pressed firmly in place with the palm of the hand for 30 seconds, making sure the contact is complete, especially around the edges. • The patch should not be folded so that only part of the patch is exposed. 5. Patients should be advised that the dose of fentanyl transdermal system or the number of patches applied to the skin should NEVER be adjusted without the prescribing healthcare professional’s instruction. 6. Patients should be advised that while wearing the patch, they should avoid exposing the fentanyl transdermal system application site and surrounding area to direct external heat sources, such as: • heating pads, • electric blankets, • sunbathing, • heat or tanning lamps, • saunas, • hot tubs or hot baths, and • heated water beds, etc. 7. Patients should also be advised of a potential for temperature-dependent increases in fentanyl release from the patch that could result in an overdose of fentanyl; therefore, patients who develop a high fever or increased body temperature due to strenuous exertion while wearing the patch should contact their physician. 8. Patients should be advised that if they experience problems with adhesion of the fentanyl transdermal system, they may tape the edges of the patch with first aid tape. If problems with adhesion persist, patients may overlay the patch with a transparent adhesive film dressing (e.g., Bioclusive® or Askina®Derm). 9. Patients should be advised that if the patch falls off before 72 hours a new patch may be applied to a different skin site. 10. Patients should be advised to fold (so that the adhesive side adheres to itself) and immediately flush down the toilet used fentanyl transdermal systems after removal from the skin. 11. Patients should be advised that fentanyl transdermal system may impair mental and/or physical ability required for the performance of potentially hazardous tasks (e.g., driving, operating machinery). 12. Patients should be advised to refrain from any potentially dangerous activity when starting on fentanyl transdermal system or when their dose is being adjusted, until it is established that they have not been adversely affected. 13. Patients should be advised that fentanyl transdermal system should not be combined with alcohol or other CNS depressants (e.g., sleep medications, tranquilizers) because dangerous additive effects may occur, resulting in serious injury or death. 14. Patients should be advised to consult their physician or pharmacist if other medications are being or will be used with fentanyl transdermal system. 15. Patients should be advised of the potential for severe constipation. 16. Patients should be advised that if they have been receiving treatment with fentanyl transdermal system and cessation of therapy is indicated, it may be appropriate to taper the fentanyl transdermal system dose, rather than abruptly discontinue it, due to the risk of precipitating withdrawal symptoms. 17. Patients should be advised that fentanyl transdermal system contains fentanyl, a drug with high potential for abuse. 18. Patients, family members and caregivers should be advised to protect fentanyl transdermal system from theft or misuse in the work or home environment. 19. Patients should be instructed to keep fentanyl transdermal system in a secure place out of the reach of children due to the high risk of fatal respiratory depression. 20. Patients should be advised that fentanyl transdermal system should never be given to anyone other than the individual for whom it was prescribed because of the risk of death or other serious medical problems to that person for whom it was not intended. 21. Patients should be informed that, if the patch dislodges and accidentally sticks to the skin of another person, they should immediately take the patch off, wash the exposed area with water and seek medical attention for the accidentally exposed individual. 22. When fentanyl transdermal system is no longer needed, the unused patches should be removed from their pouches, folded so that the adhesive side of the patch adheres to itself, and flushed down the toilet. 23. Women of childbearing potential who become, or are planning to become pregnant, should be advised to consult a physician prior to initiating or continuing therapy with fentanyl transdermal system. 24. Patients should be informed that accidental exposure or misuse may lead to death or other serious medical problems. Drug Interactions: Agents Affecting Cytochrome P450 3A4 Isoenzyme System: Fentanyl is metabolized mainly via the human cytochrome P450 3A4 isoenzyme system (CYP3A4), therefore potential interactions may occur when fentanyl transdermal system is given concurrently with agents that affect CYP3A4 activity. Coadministration with agents that induce CYP3A4 activity may reduce the efficacy of fentanyl transdermal system. The concomitant use of transdermal fentanyl with all CYP3A4 inhibitors (such as ritonavir, ketoconazole, itraconazole, troleandomycin, clarithromycin, nelfanivir, nefazadone, amiodarone, amprenavir, aprepitant, diltiazem, erythromycin, fluconazole, fasamprenavir, grapefruit juice, and verapamil) may result in an increase in fentanyl plasma concentrations, which could increase or prolong adverse drug effects and may cause fatal respiratory depression. Patients receiving fentanyl transdermal system and any CYP3A4 inhibitor should be carefully monitored for an extended period of time, and dosage adjustments should be made if warranted (see BOX WARNING, CLINICAL PHARMACOLOGY: Drug Interactions in full prescribing information, WARNINGS, and DOSAGE AND ADMINISTRATION in full prescribing information for further information). Central Nervous System Depressants: The concomitant use of fentanyl transdermal system with other central nervous system depressants, including but not limited to other opioids, sedatives, hypnotics, tranquilizers (e.g., benzodiazepines), general anesthetics, phenothiazines, skeletal muscle relaxants, and alcohol, may cause respiratory depression, hypotension, and profound sedation, or potentially result in coma or death. When such combined therapy is contemplated, the dose of one or both agents should be significantly reduced. MAO Inhibitors: Fentanyl transdermal system is not recommended for use in patients who have received MAOI within 14 days because severe and unpredictable potentiation by MAO inhibitors has been reported with opioid analgesics. Carcinogenesis, Mutagenesis, and Impairment of Fertility: Studies in animals to evaluate the carcinogenic potential of fentanyl HCl have not been conducted. There was no evidence of mutagenicity in the Ames Salmonella mutagenicity assay, the primary rat hepatocyte unscheduled DNA synthesis assay, the BALB/c 3T3 transformation test, and the human lymphocyte and CHO chromosomal aberration in vitro assays. The potential effects of fentanyl on male and female fertility were examined in the rat model via two separate experiments. In the male fertility study, male rats were treated with fentanyl (0, 0.025, 0.1 or 0.4 mg/kg/day) via continuous intravenous infusion for 28 days prior to mating; female rats were not treated. In the female fertility study, female rats were treated with fentanyl (0, 0.025, 0.1 or 0.4 mg/kg/day) via continuous intravenous infusion for 14 days prior to mating until day 16 of pregnancy; male rats were not treated. Analysis of fertility parameters in both studies indicated that an intravenous dose of fentanyl up to 0.4 mg/kg/day to either the male or the female alone produced no effects on fertility (this dose is approximately 1.6 times the daily human dose administered by a 100 mcg/hr patch on a mg/m2 basis). In a separate study, a single daily bolus dose of fentanyl was shown to impair fertility in rats when given in intravenous doses of 0.3 times the human dose for a period of 12 days. Pregnancy: Teratogenic Effects: Pregnancy Category C: No epidemiological studies of congenital anomalies in infants born to women treated with fentanyl during pregnancy have been reported. The potential effects of fentanyl on embryo-fetal development were studied in the rat, mouse, and rabbit models. Published literature reports that administration of fentanyl (0, 10, 100, or 500 mcg/kg/day) to pregnant female Sprague-Dawley rats from day 7 to 21 via implanted microosmotic minipumps did not produce any evidence of teratogenicity (the high dose is approximately 2 times the daily human dose administered by a 100 mcg/hr patch on a mg/m2 basis). In contrast, the intravenous administration of fentanyl (0, 0.01, or 0.03 mg/kg) to bred female rats from gestation day 6 to 18 suggested evidence of embryotoxicity and a slight increase in mean delivery time in the 0.03 mg/kg/day group. There was no clear evidence of teratogenicity noted. Pregnant female New Zealand White rabbits were treated with fentanyl (0, 0.025, 0.1, 0.4 mg/kg) via intravenous infusion from day 6 to day 18 of pregnancy. Fentanyl produced a slight decrease in the body weight of the live fetuses at the high dose, which may be attributed to maternal toxicity. Under the conditions of the assay, there was no evidence for fentanyl induced adverse effects on embryo-fetal development at doses up to 0.4 mg/kg (approximately 3 times the daily human dose administered by a 100 mcg/hr patch on a mg/m2 basis). There are no adequate and well controlled studies in pregnant women. Fentanyl transdermal system should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Nonteratogenic Effects: Chronic maternal treatment with fentanyl during pregnancy has been associated with transient respiratory depression, behavioral changes, or seizures characteristic of neonatal abstinence syndrome in newborn infants. Symptoms of neonatal respiratory or neurological depression were no more frequent than expected in most studies of infants born to women treated acutely during labor with intravenous or epidural fentanyl. Transient neonatal muscular rigidity has been observed in infants whose mothers were treated with intravenous fentanyl. The potential effects of fentanyl on prenatal and postnatal development were examined in the rat model. Female Wistar rats were treated with 0, 0.025, 0.1, or 0.4 mg/kg/day fentanyl via intravenous infusion from day 6 of pregnancy through 3 weeks of lactation. Fentanyl treatment (0.4 mg/kg/day) significantly decreased body weight in male and female pups and also decreased survival in pups at day 4. Both the mid-dose and high-dose of fentanyl animals demonstrated alterations in some physical landmarks of development (delayed incisor eruption and eye opening) and transient behavioral development (decreased locomotor activity at day 28 which recovered by day 50). The mid-dose and the high-dose are 0.4 and 1.6 times the daily human dose administered by a 100 mcg/hr patch on a mg/m2 basis. Labor and Delivery: Fentanyl readily passes across the placenta to the fetus; therefore, fentanyl transdermal system is not recommended for analgesia during labor and delivery. Nursing Mothers: Fentanyl is excreted in human milk; therefore, fentanyl transdermal system is not recommended for use in nursing women because of the possibility of effects in their infants. Pediatric Use: The safety of fentanyl transdermal system was evaluated in three open-label trials in 291 pediatric patients with chronic pain, 2 years of age through 18 years of age. Starting doses of 25 mcg/hr and higher were used by 181 patients who had been on prior daily opioid doses of at least 45 mg/day of oral morphine or an equianalgesic dose of another opioid. Initiation of fentanyl transdermal system therapy in pediatric patients taking less than 60 mg/day of oral morphine or an equianalgesic dose of another opioid has not been evaluated in controlled clinical trials. Approximately 90% of the total daily opioid requirement (fentanyl transdermal system plus rescue medication) was provided by fentanyl transdermal system. Fentanyl transdermal system was not studied in children under 2 years of age. Fentanyl transdermal system should be administered to children only if they are opioid-tolerant and 2 years of age or older (see DOSAGE AND ADMINISTRATION in full prescribing information and BOX WARNING). To guard against accidental ingestion by children, use caution when choosing the application site for fentanyl transdermal system (see DOSAGE AND ADMINISTRATION in full prescribing information) and monitor adhesion of the system closely. Geriatric Use: Information from a pilot study of the pharmacokinetics of IV fentanyl in geriatric patients (N = 4) indicates that the clearance of fentanyl may be greatly decreased in the population above the age of 60. The relevance of these findings to fentanyl transdermal system is unknown at this time. Respiratory depression is the chief hazard in elderly or debilitated patients, usually following large initial doses in nontolerant patients, or when opioids are given in conjunction with other agents that depress respiration. Fentanyl transdermal system should be used with caution in elderly, cachectic, or debilitated patients as they may have altered pharmacokinetics due to poor fat stores, muscle wasting or altered clearance (see DOSAGE AND ADMINISTRATION in full prescribing information). ADVERSE REACTIONS: In post-marketing experience, deaths from hypoventilation due to inappropriate use of fentanyl transdermal system have been reported (see BOX WARNING and CONTRAINDICATIONS). Premarketing Clinical Trial Experience: Although fentanyl transdermal system use in postoperative or acute pain and in patients who are not opioid-tolerant is CONTRAINDICATED, the safety of fentanyl transdermal system was originally evaluated in 357 postoperative adult patients for 1 to 3 days and 153 cancer patients for a total of 510 patients. The duration of fentanyl transdermal system use varied in cancer patients; 56% of patients used fentanyl transdermal system for over 30 days, 28% continued treatment for more than 4 months, and 10% used fentanyl transdermal system for more than 1 year. Hypoventilation was the most serious adverse reaction observed in 13 (4%) postoperative patients and in 3 (2%) of the cancer patients. Hypotension and hypertension were observed in 11 (3%) and 4 (1%) of the opioid-naive patients. Various adverse events were reported; a causal relationship to fentanyl transdermal system was not always determined. The frequencies presented here reflect the actual frequency of each adverse effect in patients who received fentanyl transdermal system. There has been no attempt to correct for a placebo effect, concomitant use of Page 2 of 3 other opioids, or to subtract the frequencies reported by placebo-treated patients in controlled trials. Adverse reactions reported in 153 cancer patients at a frequency of 1% or greater are presented in Table 1; similar reactions were seen in the 357 postoperative patients. In the pediatric population, the safety of fentanyl transdermal system has been evaluated in 291 patients with chronic pain 2 to 18 years of age. The duration of fentanyl transdermal system use varied; 20% of pediatric patients were treated for ) 15 days; 46% for 16 to 30 days; 16% for 31 to 60 days; and 17% for at least 61 days. Twenty-five patients were treated with fentanyl transdermal system for at least 4 months and 9 patients for more than 9 months. There was no apparent pediatric-specific risk associated with fentanyl transdermal system use in children as young as 2 years old when used as directed. The most common adverse events were fever (35%), vomiting (33%), and nausea (24%). Adverse events reported in pediatric patients at a rate of * 1% are presented in Table 1. TABLE 1: ADVERSE EVENTS (at rate of ≥ 1%) Adults (N = 380) and Pediatric (N = 291) Clinical Trial Experience Body System Body as a Whole Cardiovascular Digestive Nervous Respiratory Skin and Appendages Urogenital Adults Abdominal pain*, headache*, fatigue*, back pain, fever, influenza-like symptoms*, accidental injury, rigors Arrhythmia, chest pain Nausea**, vomiting**, constipation**, dry mouth**, anorexia*, diarrhea*, dyspepsia*, flatulence Somnolence**, insomnia, confusion**, asthenia**, dizziness*, nervousness*, hallucinations*, anxiety*, depression*, euphoria*, tremor, abnormal coordination, speech disorder, abnormal thinking, abnormal gait, abnormal dreams, agitation, paresthesia, amnesia, syncope, paranoid reaction Dyspnea*, hypoventilation*, apnea*, hemoptysis, pharyngitis*, hiccups, bronchitis, rhinitis, sinusitis, upper respiratory tract infection* Sweating**, pruritus*, rash, application site reaction – erythema, papules, itching, edema Urinary retention*, micturition disorder Pediatrics Pain*, headache*, fever, syncope, abdominal pain, allergic reaction, flushing Hypertension, tachycardia Nausea**, vomiting**, constipation*, dry mouth, diarrhea Somnolence*, nervousness*, insomnia*, asthenia*, hallucinations, anxiety, depression, convulsions, dizziness, tremor, speech disorder, agitation, stupor, confusion, paranoid reaction Dyspnea, respiratory depression, rhinitis, coughing Pruritus*, application site reaction*, sweating increased, rash, rash erythematous, skin reaction localized Urinary retention *Reactions occurring in 3% to 10% of fentanyl transdermal system patients **Reactions occurring in 10% or more of fentanyl transdermal system patients The following adverse effects have been reported in less than 1% of the 510 adult postoperative and cancer patients studied: Cardiovascular: bradycardia Digestive: abdominal distention Nervous: aphasia, hypertonia, vertigo, stupor, hypotonia, depersonalization, hostility Respiratory: stertorous breathing, asthma, respiratory disorder Skin and Appendages, General: exfoliative dermatitis, pustules Special Senses: amblyopia Urogenital: bladder pain, oliguria, urinary frequency Post-Marketing Experience: Adults: The following adverse reactions have been reported in association with the use of fentanyl transdermal system and not reported in the premarketing adverse reactions section above: Body as a Whole: edema Cardiovascular: tachycardia Metabolic and Nutritional: weight loss Special Senses: blurred vision Urogenital: decreased libido, anorgasmia, ejaculatory difficulty DRUG ABUSE AND ADDICTION: Fentanyl transdermal system contains a high concentration of fentanyl, a potent Schedule II opioid agonist. Schedule II opioid substances, which include hydromorphone, methadone, morphine, oxycodone, and oxymorphone, have the highest potential for abuse and risk of fatal overdose due to respiratory depression. Fentanyl, like morphine and other opioids used in analgesia, can be abused and is subject to criminal diversion. The high content of fentanyl in the patches (fentanyl transdermal system) may be a particular target for abuse and diversion. Addiction is a primary, chronic, neurobiologic disease, with genetic, psychosocial, and environmental factors influencing its development and manifestations. It is characterized by behaviors that include one or more of the following: impaired control over drug use, compulsive use, continued use despite harm, and craving. Drug addiction is a treatable disease, utilizing a multidisciplinary approach, but relapse is common. “Drug seeking” behavior is very common in addicts and drug abusers. Drug-seeking tactics include emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing or referral, repeated “loss” of prescriptions, tampering with prescriptions and reluctance to provide prior medical records or contact information for other treating physician(s). “Doctor shopping” to obtain additional prescriptions is common among drug abusers and people suffering from untreated addiction. Abuse and addiction are separate and distinct from physical dependence and tolerance. Physicians should be aware that addiction may be accompanied by concurrent tolerance and symptoms of physical dependence. In addition, abuse of opioids can occur in the absence of true addiction and is characterized by misuse for nonmedical purposes, often in combination with other psychoactive substances. Since fentanyl transdermal system may be diverted for nonmedical use, careful record keeping of prescribing information, including quantity, frequency, and renewal requests is strongly advised. Proper assessment of the patient, proper prescribing practices, periodic re-evaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs. Fentanyl transdermal systems are intended for transdermal use (to be applied on the skin) only. Do not use a fentanyl transdermal system if the seal is broken or the patch is cut, damaged, or changed in any way. OVERDOSAGE: Clinical Presentation: The manifestations of fentanyl overdosage are an extension of its pharmacologic actions with the most serious significant effect being hypoventilation. Treatment: For the management of hypoventilation, immediate countermeasures include removing the fentanyl transdermal system and physically or verbally stimulating the patient. These actions can be followed by administration of a specific narcotic antagonist such as naloxone. The duration of hypoventilation following an overdose may be longer than the effects of the narcotic antagonist’s action (the half-life of naloxone ranges from 30 to 81 minutes). The interval between IV antagonist doses should be carefully chosen because of the possibility of renarcotization after system removal; repeated administration of naloxone may be necessary. Reversal of the narcotic effect may result in acute onset of pain and the release of catecholamines. Always ensure a patent airway is established and maintained, administer oxygen and assist or control respiration as indicated and use an oropharyngeal airway or endotracheal tube if necessary. Adequate body temperature and fluid intake should be maintained. If severe or persistent hypotension occurs, the possibility of hypovolemia should be considered and managed with appropriate parenteral fluid therapy. Page 3 of 3 MYLAN® Mylan Pharmaceuticals Inc. Morgantown, WV 26505 REVISED JUNE 2008 BS:FTS:R16 READER INPUT FORM U.S. PHARMACIST Jobson Medical Information LLC • 160 Chubb Avenue • Suite 306 • Lyndhurst, NJ 07071 • Fax 201-623-0921 Which two articles in this issue did you like the most? 1. 2. Which two articles in this issue did you like the least? 1. 2. Which areas of pharmacy would you like us to address in the future? Would you be interested in writing a review article? If so, please indicate your areas of expertise. Other comments or suggestions? If you would like to help us occasionally with a project, please attach your business card here and mail, or photocopy and fax, to us. We value your input. Thanks! HS-14 U.S. Pharmacist • November 2009 • www.uspharmacist.com TRAUMATIC BRAIN INJURY Prophylaxis Category 2007 Guideline Recommendations Recommended Dosages for Prophylaxis Steroid Steroids do not improve outcome or lower ICP in severe TBI and are not recommended for TBI Steroid prophylaxis should not be given to patients who present with severe TBI Infection There is no support for the use of prolonged antibiotics for systemic infection prophylaxis in intubated TBI patients Infection prophylaxis should not be routinely prescribed for patients with severe TBI. If the patient does require antibiotics for an infection that presents, choice of medication and dosage should be made appropriately based on local susceptibility and resistance patterns Venous thromboembolism The use of compression stockings for VTE prophylaxis should be placed for patients with severe TBI, unless lower extremity injuries prevent their use. Pharmacologic therapies with either LMWH or UFH should also be initiated in patients with no contraindications Heparin: 5,000 units SQ every 8 h Dalteparin: 5,000 units SQ once daily Enoxaparin: 30 mg SQ twice daily (or 40 mg SQ once daily) Fondaparinux: 2.5 mg SQ once daily (for patients ≥50 kg) LMWH should not be given to patients with CrCl <30 mL/min Seizure Early antiseizure prophylaxis is typically initiated in patients with phenytoin. Although valproate may have a comparable effect to phenytoin for early seizures, this is not a recommended, FDA-labeled use for this medication. Antiseizure prophylaxis given later than 1 wk following TBI is not recommended Early: Phenytoin 10-20 mg/kg IV bolus, followed by 5-6 mg/kg/day IV in 3 divided doses (can be switched to oral when patient can tolerate at an equivalent dose) Late: Routine seizure prophylaxis later than 1 wk following TBI is not recommended CrCl: creatinine clearance; ICP: intracranial pressure; LMWH: low-molecular-weight heparin; SQ: subcutaneously; TBI: traumatic brain injury; UFH: unfractionated heparin; VTE: venous thromboembolism. Source: References 5, 7, 10, 14. the 1960s. At that time, corticosteroids were thought to be favorable through a significant reduction in brain edema, a decrease of cerebrospinal fluid production, and the lessening of free radical production. Since then, there have been numerous clinical studies examining the role that corticosteroids play in neurological procedures, as well as in TBI. In 1976, two trials were conducted comparing low- and high-dose glucocorticoids in patients with severe TBI.3,4 Results of these trials demonstrated favorable response to high-dose glucocorticoid groups and favorable dose-related effects on mortality. Successively, in the 1980s and 1990s, there were further trials that evaluated clinical outcomes in patients with TBI, ICP, or both. None of the studies demonstrated a sizeable benefit in using glucocorticoids in those patients.5 More recently, in 2004, the CRASH (Corticosteroid Randomization After Significant Head Injury) trial authors described the results of an international randomized, controlled trial in patients with TBI using high-dose methylprednisolone (2-g IV methylprednisolone followed by 0.4 mg/h for 48 h) or placebo.6 The study was concluded early due to an interim analysis that demonstrated a harmful effect of methylprednisolone, particularly with regard to mortality. The authors thus concluded that although the cause of increase in mortality was unclear, the detrimental effects were not different among groups of patients further classified by injury severity. In general, the use of prophylactic corticosteroids is not recommended at this time for improving patient outcomes or reducing ICP/edema in patients with TBI.5 Furthermore, it is concluded that high-dose methylprednisolone may be correlated with an increase in mortality. Due to the results of recent trials, there is little interest in pursuing further research in this area at this time. Infection Prophylaxis With an increased incidence of mechanical ventilation and other invasive aspects of patient monitoring and treatment, patients with TBI are at a significantly increased likelihood of developing infections. The issue of infection prophylaxis has been evaluated by numerous sources and has revolved around different possibilities of infection development. One possible infection source is through the insertion of ICP devices. The incidence of ICP device infection can range from less than 1% to 27%.7 Even with these striking infection rates, there are conflicting data HS-15 U.S. Pharmacist • November 2009 • www.uspharmacist.com H E A LT H S Y S T E M S E D I T I O N Table 1 Current Dose Recommendations for Prophylaxis Based on 2007 Guidelines for the Management of Severe Traumatic Brain Injury TRAUMATIC BRAIN INJURY H E A LT H S Y S T E M S E D I T I O N concerning what the appropriate prophylactic measures should contain for patients with TBI. Most studies cited by the 2007 guidelines evaluating prophylactic antibiotic usage in patients with external ventricular drainage have shown no difference in infection rates. Additionally, one study showed that patients receiving bacitracin flushes experienced a significantly higher infection rate than those without prophylactic measures.7 Prophylactic antibiotic use in patients with TBI have shown no meaningful reduction in nosocomial infections.7 In addition, an increase in serious gram-negative infections was noted in this population. The guidelines also cite data showing an increase in resistant or gram-negative nosocomial pneumonias. This was seen when prophylactic antibiotics were given for longer than 48 hours in general trauma patients. In contrast, one study showed a decrease in pneumonias when prophylactic antibiotics were given to patients with TBI. No difference in mortality was noted, so it is difficult to assess the usefulness of this therapeutic avenue.7 Since publication of the 2007 guidelines, one further study in patients with TBI has been completed.8 This study retrospectively evaluated the use of antibiotic prophylaxis in patients with ICP monitor implantation. Of the 155 patients included in the analysis, only two developed CNS infections, and these were both in the group that received prophylactic antibiotics. Additionally, both complications from infections and multidrug resistant infections were significantly increased in the group that received antibiotics. In summary, there are currently no convincing data to support infection prophylaxis in patients with TBI, especially in light of data suggesting that prophylaxis might predispose patients to more severe infections when infections would arise.7,8 To be fair, there is a relative lack of data to give any definitive statement on the use of prophylactic antibiotics, but at this time this practice cannot be supported. Venous Thromboembolism Prophylaxis Venous thromboembolism (VTE) is a topic that is very pertinent to patients with TBI, as they are at an increased risk of developing blood clots due to their typically persistent immobile state. The development of deep vein thrombosis (DVT) in patients with TBI who do not receive prophylaxis is as high as 25%.9 However, there remains some uncertainty about the appropriateness of VTE prophylaxis due to the questionable safety of anticoagulation in patients who have TBI. Mechanical means of VTE prophylaxis such as sequential compression devices seem to carry less risk in patients with TBI, but concomitant lower limb injuries can prevent their use in some patients. Per the 2007 guidelines, mechanical VTE prophylaxis is recommended in all severe patients with TBI who have no contraindications to usage, such as an intracranial bleed.10 Concerning pharmacologic options, the guidelines suggest that low-molecular-weight heparin (LMWH) or low-dose unfractionated heparin (UFH) should be used in addition to mechanical means of VTE prophylaxis when no contraindications to LMWH or UFH exist. It is important to note, however, that the guidelines do not elicit a preferred agent, dosage, or timing of pharmacologic prophylaxis and also warn of the increased risk of intracranial hemorrhage expansion.10 Three studies have been published since the guidelines on pharmacologic VTE prophylaxis in patients with TBI.11-13 A 2007 prospective study evaluated the use of dalteparin in trauma patients in which 23% were patients with TBI.11 These patients received prophylactic dalteparin (5,000 units SQ once daily) if there was no active or progressing bleed on CT scan. No patients developed or had increased intracranial bleeding after initiation of dalteparin, while only 3.9% of patients had evidence of DVT and 0.8% had evidence of pulmonary embolism. A second prospective study published in 2008 evaluated the use of enoxaparin (30 mg SQ twice daily) in patients with TBI. 12 Progressive hemorrhagic injury was seen in 3.4% of the TBI population, with 67% of those patients having clinically insignificant hemorrhagic changes. In addition, one patient died from a potential side effect from enoxaparin usage. The authors of these two studies concluded that enoxaparin and dalteparin are safe options in patients with TBI and that both agents have a relatively low risk of significant bleeding complications.11,12 A retrospective study published in 2009 looked at a comparison of the risk of DVT in patients with and without TBI utilizing either LMWH or UFH (doses not specified).13 This study showed a three- to fourfold increase in DVTs in patients with TBI using relative risks with 95% confidence intervals. The highest rate was noted when prophylaxis was started greater than 48 hours after insult. In summary, it is currently acceptable to recommend mechanical and pharmacologic VTE prophylaxis in patients with TBI that have no contraindications to usage.10-13 The evidence is shifting in favor of quick initiation of prophylactic agents regardless of product selection. However, the breakpoint for deciding between mechanical and pharmacologic choices or agents is still unknown and should be a course of future study. Seizure Prophylaxis Posttraumatic seizure (PTS) is a common occurrence in patients with TBI. These seizures are broken into two groups: early (within 7 days of injury) and late (after 7 days). Certain risk factors have been shown to place patients with TBI at increased risk for PTS. These risk factors include: Glasgow Coma Score (a HS-16 U.S. Pharmacist • November 2009 • www.uspharmacist.com TRAUMATIC BRAIN INJURY REFERENCES 1. Langlois JA, Rutland-Brown W, Thomas KE. Traumatic Brain Injury in the United States: Emergency Department Visits, Hospitalizations, and Deaths. Atlanta, GA: Centers for Disease Control and Prevention, National Center for Injury Prevention and Control; 2006. 2. Nolan S. Traumatic brain injury: a review. Crit Care Nurs Q. 2005;28:188-194. 3. Faupel G, Reulen HJ, Muller D, et al. Double-blind study on the effects of steroids on severe closed head injury. In: Pappius HM, Feindel W, eds. Dynamics of Brain Edema. New York, NY: Springer-Verlag; 1976:337-343. 4. Gobiet W, Bock WJ, Liesgang J, et al. Treatment of acute cerebral edema with high dose of dexamethasone. In: Beks JW, Bosch DA, Brock M, eds. Intracranial Pressure III. New York, NY: Springer-Verlag; 1976:231-235. 5. Brain Trauma Foundation, American Association of Neurological Surgeons, Congress of Neurological Surgeons, et al. Guidelines for the management of severe traumatic brain injury. XV. Steroids. J Neurotrauma. 2007;24(suppl 1):S91-S95. 6. Roberts I, Yates D, Sandercock P, et al. Effect of intravenous corticosteroids on death within 14 days in 10,008 adults with clinically significant head injury (MRC CRASH trial): randomised placebo-controlled trial. Lancet. 2004;364:1321-1328. 7. Brain Trauma Foundation, American Association of Neurological Surgeons, Congress of Neurological Surgeons, et al. Guidelines for the management of severe traumatic brain injury. IV. Infection prophylaxis. J Neurotrauma. 2007;24(suppl 1):S26-S31. 8. Stoikes NF, Magnotti LJ, Hodges TM, et al. Impact of intracranial pressure monitor prophylaxis on central nervous system infections and bacterial prophylaxis developed late PTS, while only 13% of patients who did not receive prophylaxis developed late PTS. While the retrospective data were not statistically significant, the prospective data were even more striking. A significant difference was noted in the prospective group, where 39% of patients treated with antiseizure prophylaxis developed late PTS, while none of the patients who were not treated with antiseizure prophylaxis developed late PTS. However, phenobarbital is not commonly used in the U.S. in this regard because of its adverse-effect profile and multiple drug interactions, and because more appropriate antiepileptic selections are available; therefore, results must not be generalized too drastically. In summary, current literature including the 2007 guidelines indicates that the incidence of early PTS appears to be reduced with the addition of prophylactic antiseizure medications.14 However, there is currently no evidence to indicate that prophylactic antiseizure medications alter mortality or incidence of late PTS, and it is still unknown whether or not this course of therapeutic prophylaxis is currently benefitting patients. Conclusion Traumatic brain injury can be overwhelming and distressing to both patients and their family members. In addition to the emotional and social impacts that accompany TBI, it is important to identify and deliver prompt attention to the physical needs of the patient. Prophylactic medications play an important role in patients with TBI, yet as of now many categories lack definitive data to direct appropriate therapeutic choices. Future studies are needed to clarify this important issue in the management of patients with this condition. multi-drug resistance. Surg Infect (Larchmt). 2008;9:503-508. 9. Denson K, Morgan D, Cunningham R, et al. Incidence of venous thromboembolism in patients with traumatic brain injury. Am J Surg. 2007;193:380-384. 10. Brain Trauma Foundation, American Association of Neurological Surgeons, Congress of Neurological Surgeons, et al. Guidelines for the management of severe traumatic brain injury. V. Deep vein thrombosis prophylaxis. J Neurotrauma. 2007;24(suppl 1):S32-S36. 11. Cothren CC, Smith WR, Moore EE, Morgan SJ. Utility of once-daily dose of low-molecular-weight heparin to prevent venous thromboembolism in multisystem trauma patients. World J Surg. 2007;31:98-104. 12. Norwood SH, Berne JD, Rowe SA, et al. Early venous thromboembolism prophylaxis with enoxaparin in patients with blunt traumatic brain injury. J Trauma. 2008;65:1021-1027. 13. Reiff DA, Haricharan RN, Bullington NM, et al. Traumatic brain injury is associated with the development of deep vein thrombosis independent of pharmacological prophylaxis. J Trauma. 2009;66:1436-1440. 14. Brain Trauma Foundation, American Association of Neurological Surgeons, Congress of Neurological Surgeons, et al. Guidelines for the management of severe traumatic brain injury. XIII. Antiseizure prophylaxis. J Neurotrauma. 2007;24(suppl 1):S83-S86. 15. Jones KE, Puccio AM, Harshman KJ, et al. Levetiracetam versus phenytoin for seizure prophylaxis in severe traumatic brain injury. Neurosurg Focus. 2008;25:E3. 16. Formisano R, Barba C, Buzzi MG, et al. The impact of prophylactic treatment on post-traumatic epilepsy after severe traumatic brain injury. Brain Injury. 2007;21:499-504. HS-19 U.S. Pharmacist • November 2009 • www.uspharmacist.com H E A LT H S Y S T E M S E D I T I O N neurological scale used to assess level of consciousness) less than 10; cortical contusion; depressed skull fracture; subdural, intracerebral, and epidural hematoma; penetrating head wound; or seizure within 24 hours after injury.14 Phenytoin and valproate sodium have been studied in the prevention of early and late PTS. One study cited by the 2007 guidelines showed a significant reduction in early PTS without showing any significant effect on late PTS or survival with the use of phenytoin.14 In contrast, a randomized, double-blind study showed no early or late PTS benefit by using phenytoin. Valproate sodium has shown a similar rate of early PTS reduction when compared to phenytoin. However, a trend toward higher mortality in the valproate sodium group was noted and could be cause for concern.14 Since the publication of the guidelines, there have been two pertinent studies completed regarding seizure prophylaxis.15-16 The first, a study from 2008, compared the incidence of seizures in patients with TBI when randomized to either phenytoin or levetiracetam.15 Results indicated that there was no significant difference in seizure incidence. However, patients receiving levetiracetam showed increased incidence of electroencephalogram (EEG) abnormalities. An EEG was indicated if patients displayed persistent coma, decreased mental status, or clinical signs of seizures. The second study evaluated the incidence of late PTS in patients with TBI who did or did not receive antiseizure prophylaxis upon initial presentation. 16 This study was carried out in Italy, with phenobarbital being one of the main agents used in antiseizure prophylaxis. Interestingly, in the retrospective portion of the study, 29% of patients who received antiseizure H E A LT H S Y S T E M S E D I T I O N Newly Approved mTOR Inhibitors for the Treatment of Metastatic Renal Cell Carcinoma © JUPITERIMAGES T about 30% of these patients will have disease recurrence. Surgery is a good choice for patients with advanced disease, benefiting quality of life by reducing pain or bleeding, and sometimes even improving survival.4 For many years, immunotherapy with the biologic response modifiers interleukin-2 (IL-2) and interferonalpha (IFN-A) has been the mainstay of systemic treatment for metastatic disease. Treatment with these agents alone or in combination yields a median survival of 12 to 17.5 months.3 High-dose IL-2, which was FDAapproved in 1992 for advanced RCC, provides durable complete response in a small fraction of patients. Conventional chemotherapy yields response rates of less than 10% and often is used in a palliative context. High-dose nonmyeloablative chemotherapy followed by allogeneic stem-cell transplantation remains experimental.2,4 Targeted therapies have been developed to interfere with intracellular signaling, tumor-cell proliferation, differentiation, and angiogenesis. The small-molecule tyrosine kinase (TK) inhibitors bind to receptor TKs (RTKs) located on cell-surface growth factor receptors (GFRs), thereby inhibiting tumor growth.2 Sorafenib, which was approved in 2005 for advanced RCC, inhibits multiple intracellular and cell-surface kinases, including Raf; vascular endothelial GFR types 1 to 3 (VEGFR 1-3); platelet-derived GFR (PDGFR)Diana Hey Cauley, PharmD, BCOP beta; the stem cell factor receptor (c-kit); Clinical Pharmacy Specialist, Fms-like TK-3 (Flt3); and glial cell Genitourinary Medical Oncology line–derived neurotrophic factor recepDivision of Pharmacy, University of Texas tor (RET).4,5 Sunitinib, approved for M.D. Anderson Cancer Center advanced RCC in 2006, also inhibits Houston, Texas he American Cancer Society has estimated that 57,760 new cases of kidney cancer and 12,980 deaths due to kidney cancer will occur in the United States in 2009. Included in these statistics are renal cell carcinoma (RCC) and transitional cell carcinoma of the renal pelvis. Kidney cancer is one of the 10 most common types of cancer in men and women, with men at higher risk than women. The overall lifetime risk of developing kidney cancer is approximately 1 in 75 (1.34%).1 RCC constitutes 90% of kidney cancers, and the peak incidence is in the sixth decade of life. The histology is primarily clear cell carcinoma (85%); the remaining 15% comprises papillary, chromophobe, and collecting-duct carcinomas. The incidence of RCC is increasing, and about 30% of patients present with metastatic disease. Risk factors include smoking, hypertension, obesity, cystic kidney disease, and genetic abnormalities. One genetic abnormality is the mutation of the von HippelLindau tumor-suppressor gene often seen in clear-cell carcinomas.2 Patients with metastatic RCC have an estimated 10% survival rate at 5 years. A prognostic model to predict survival was developed to stratify patients into low-risk (no risk factors), intermediate-risk (1-2 risk factors), and poor-risk categories (>2 risk factors).2 See TABLE 1 for predictors of short survival.3 Current Treatment Options Surgery is an important option for patients with RCC. Localized disease can be cured with surgery; unfortunately, HS-20 U.S. Pharmacist • November 2009 • www.uspharmacist.com Introducing Teva’s New and Improved Product Labeling NDC#s are prominently placed in top left corner Lot number is imprinted for easier tracking TALLman lettering, used when appropriate, helps reduce dispensing errors Strength is highlighted in color for better visibility. Products with multiple strengths are distinguished by different colors. Bar Coded with a scannable Standard RSS bar code Expiration Date Manufacturing location of product For up-to-date information on all of our products, including many latex-free and preservative-free injectables, visit www.tevausa.com ©2009, Teva Pharmaceuticals USA 8430 A 19 Hughes • Irvine, California 92618 800.729.9991 • www.tevausa.com MTOR INHIBITORS FOR METASTATIC RENAL CELL CARCINOMA H E A LT H S Y S T E M S E D I T I O N Figure 1. mTOR signaling pathway. mTOR: mammalian target of rapamycin; PI3K: phosphoinositide 3-kinase. multiple kinases, including VEGFR 1–3, PDGFR-alpha and -beta, c-kit, Flt3, colony-stimulating factor receptor type 1, and RET.4,6 Bevacizumab is a monoclonal recombinant humanized antibody that binds to and neutralizes circulating VEGF ligand, which prevents activation of the kinase VEGFR.2 It was FDA-approved in July 2009 in combination with IFN-A for patients with metastatic RCC. Clinical trials also demonstrate activity as single-agent therapy.4 Mammalian Target of Rapamycin (mTOR) Pathway Three primary signaling pathways associated with RTKs are currently identified in cancer cells. One of them is the phosphoinositide 3-kinase (PI3K)/Akt/mTOR protein cascade (FIGURE 1); the other two are the protein kinase C family and the Ras/mitogen-activated protein kinase cascades. Activation of RTK leads to stepwise activation of PI3K, then Akt, and then mTOR, directly promoting tumor growth. The mutation and overexpression of RTK, as well as growth receptors, are common in RCC.7 Table 1 Predictors of Short Survival Risk Factors Description LDH level >1.5 × ULN HB <LLN Corrected serum calcium level >10 mg/dL Interval from original diagnosis to start of systemic treatment <1 yr Karnofsky performance score ≤70 Number of metastatic sites ≥2 HB: hemoglobin; LDH: lactate dehydrogenase; LLN: lower limit of normal; ULN: upper limit of normal. Source: Reference 3. mTOR regulates essential signal-transduction pathways, tying growth stimuli to cell-cycle progression.7 It also integrates signals involving nutrient availability, energy status, and stress.8 There are two multiprotein complexes (mTORCs): mTORC-1 and mTORC-2. mTORC-1 is rapamycin-sensitive; mTORC-2 is rapamycin-insensitive.7 The mTOR pathway is important with regard to glucose and lipid metabolism. Interruption of the pathway by mTOR inhibitors increases the frequency of hyperglycemia and hyperlipidemia.7 mTOR Inhibitors Rapamycin, also known as sirolimus, originally was developed as an antifungal drug, but it was initially used as an immunosuppressive agent in transplant patients because it inhibits T-cell proliferation after activation.9 In Europe, rapamycin also is used to prevent restenosis after percutaneous coronary interventions. Rapamycin was not studied for its anticancer activity until the late 1990s, when it was identified as the first mTOR inhibitor.7 To inhibit mTOR, rapamycin must bind to an abundant intracellular binding protein, FKBP-12; the drug:FKPB-12 complex binds at the rapamycin binding domain.8 The result of mTOR inhibition is cell-growth arrest, decreased protein synthesis, and reduced growth signaling. Rapamycin decreases the activity of mTORC-2 with sustained exposure.7 Rapalogues, or rapamycin derivatives, which were developed later, include temsirolimus and everolimus. The primary difference between the rapalogues is their pharmacokinetic and pharmacologic properties.7 Temsirolimus was created by adding an ester to a rapamycin carbon, and adding an ether created everolimus; the result was increased solubility and bioavailability.8 Notably, the rapalogues do not induce immunosuppression, as is seen with rapamycin.7,9 Temsirolimus Temsirolimus, also known as CCI-779, is an IV-administered mTOR kinase inhibitor. The dosing is 25 mg once weekly as a 30- to 60-minute infusion. To prevent a hypersensitivity reaction, the patient should receive diphenhydramine 25 mg or 50 mg, or a similar antihistamine, about 30 minutes before the start of each dose. The dose should be held in the event of low neutrophil or platelet counts or severe adverse reactions.3,10 Temsirolimus binds to FKBP-12, forms a complex, and inhibits mTOR signaling. The agent inhibits cell division, halts growth signaling, and reduces hypoxia inducible factor (HIF-1 and HIF-2 alpha) and VEGF expression.3,10 It is hydrolyzed to the active metabolite sirolimus, which also likely inhibits mTOR. Temsirolimus has a terminal half-life of 12 to 15 hours; that of sirolimus is 40 to 50 hours.8 Temsirolimus is metabolized hepatically via CYP450 3A4. Drug interactions can occur HS-22 U.S. Pharmacist • November 2009 • www.uspharmacist.com Lilly is committed to meeting the ever-changing needs of our hospital customers. And this commitment drives us to continue working on more innovations for the future. HI59949 1009 PRINTED IN USA ©2009, LILLY USA, LLC. ALL RIGHTS RESERVED. MTOR INHIBITORS FOR METASTATIC RENAL CELL CARCINOMA H E A LT H S Y S T E M S E D I T I O N The dose of everolimus may also be reduced to 5 mg in the presence of moderate hepatic impairment or severe adverse events. The mean half-life is about 30 hours. There Outcome Temsirolimus Temsirolimus IFN-A are six main metabolites of everolimus; Measure Arm + IFN-A Arm Arm they are 100 times less potent than the Median OS 10.9 mo 8.4 mo 7.3 mo parent compound. Grapefruit juice should Median PFS 5.5 mo 4.7 mo 3.1 mo be avoided.11 Phase I and II studies established the Clinical benefita 32.1% 28.1% 15.5% safety and efficacy of everolimus admina Proportion of patients with objective response or stable disease for ≥24 wk. istered on a daily oral dosing schedule. IFN-A: interferon-alpha; OS: overall survival; PFS: progression-free survival. They also demonstrated disease stabilizaSource: Reference 3. tion or tumor reduction in metastatic with strong inducers and inhibitors, so these medications RCC.4,7,9,12 Responding to the need for active cancer should be avoided. If coadministration is unavoidable, medications after traditional agents have failed, a phase the dose of temsirolimus should be increased to 50 mg III study investigated the role of everolimus in second- or when given with a strong CYP450 3A4 inducer and third-line dosing.12 Motzer and colleagues conducted a phase III trial in reduced to 12.5 mg when given with a strong inhibitor.2 Grapefruit juice should be avoided because it may increase 410 patients with metastatic clear cell RCC assigned in sirolimus levels. Use temsirolimus with caution in patients a 2-to-1 ratio to two treatment arms: oral everolimus 10 with hypersensitivity to polysorbate 80.10 mg daily plus best supportive care or placebo plus best Phase I and II clinical trials determined that temsiro- supportive care.12 Patients had to have progressed by or limus 25 mg IV could be given safely on a weekly basis within 6 months of stopping sunitinib, sorafenib, or both and had promising activity in RCC. Researchers also drugs; previous therapy with bevacizumab, IL-2, or IFN-A found that patients with treatment-refractory, poor- was allowed. At progression, placebo patients could prognosis RCC who were receiving temsirolimus had a transition to active open-label everolimus treatment for median overall survival of 8.2 months versus 4.9 months ethical reasons. At the second interim safety analysis, the for IFN-A.7 Subsequently, Hudes and colleagues conducted study was halted early because the prolongation in proa phase III trial comparing three treatment arms in 626 gression-free survival (PFS) was greater than expected. patients with metastatic RCC: temsirolimus 25 mg IV See TABLE 3 for results.12,13 The crossover from placebo weekly; temsirolimus 15 mg IV weekly with IFN-A at to everolimus at disease progression would likely confound 3 to 6 MU subcutaneously (SC) three times weekly; and the median overall survival data for the everolimus group; IFN-A 3 to 18 MU SC three times weekly. Patients had therefore, the endpoint was not reached.12 In a follow-up to the phase III everolimus study, to be treatment-naïve and have at least three predictors researchers collected 4.5 months of additional blinded of short survival.3 See TABLE 2 for results.3 Dose reductions and delays were least common in the data for a total of 416 patients. The results of this study temsirolimus single-agent arm.3 The FDA approved demonstrated persistence of PFS prolongation.13 In March 2009, the FDA approved everolimus for temsirolimus for metastatic RCC in May 2007. As a result of the phase II and III trials, temsirolimus is now the treatment of advanced RCC after failure of treatment favored as first-line treatment for patients with poor- with sunitinib or sorafenib.11 The drug also is FDAapproved as a medical device as a component of the prognosis metastatic RCC.9 everolimus-eluting coronary stent system for coronary Everolimus artery disease.14 Everolimus is approved in Europe as an Everolimus, also known as RAD001, is an orally admin- immunosuppressant for the prevention of solid organ istered mTOR kinase inhibitor. It forms a complex with transplant rejection.9 the intracellular protein FKBP-12 and inhibits the mTOR kinase. Everolimus reduces cell proliferation, cell growth, Adverse Events angiogenesis, and glucose uptake, and it inhibits HIF-1 The primary adverse-events profile of the mTOR inhibitors includes hyperglycemia, hypercholesterolemia, and expression and reduces VEGF expression.7,8,11 Everolimus is administered once daily as a 10-mg hyperlipidemia. This reflects the blockade of mTOR, the tablet, at the same time every day, with or without food. primary signaling conduit for insulin and insulin growth It is metabolized hepatically via CYP450 3A4. Drug factor. Other common adverse events for temsirolimus interactions with CYP450 3A4 inducers and inhibitors and everolimus include fatigue, stomatitis, diarrhea, should be avoided. If treatment with a strong CYP450 hypophosphatemia, low red blood cells and platelets, and inducer cannot be avoided, the dose of everolimus may peripheral edema. These adverse events are commonly be increased from 10 mg to 20 mg in 5-mg increments. reversible upon treatment discontinuation. Less common Table 2 Temsirolimus Phase III Study Results HS-24 U.S. Pharmacist • November 2009 • www.uspharmacist.com Please see us at Booth #1201 at the ASHP Convention in Las Vegas! MTOR INHIBITORS FOR METASTATIC RENAL CELL CARCINOMA H E A LT H S Y S T E M S E D I T I O N Table 3 Everolimus Phase III Study Resultsa Outcome Measure Everolimus + Best Supportive Care Placebo + Best Supportive Care Median PFS 4.9 mo 1.9 mo Median OS Not reached 8.8 mo Patients with PR 1% 0% Patients with stable disease 63% 32% Patients with progressive disease 19% 46% a active treatment and for 3 months after the final dose. Women taking everolimus should use contraception while receiving active treatment and for 8 weeks after the final dose.10,11 Patients being treated with mTOR inhibitors should not receive live vaccines. Patients should also avoid close contact with individuals who have received live vaccines.10,11 Investigational Combination Studies The goal of combining different therapies is to achieve greater efficacy. Strategies often involve combining agents with different mechanisms of action and sideeffect profiles. Investigational combinations in phase I and II studies include bevacizumab with either everolimus or temsirolimus; other studies are examining temsirolimus with sorafenib or IFN-A.4,8 Certain combinations require up-front dose reductions, such as temsirolimus with sorafenib, or are not safe, such as temsirolimus with sunitinib.15 Including 4.5-mo follow-up. OS: overall survival; PFS: progression-free survival; PR: partial response. Source: References 12, 13. symptoms are renal insufficiency, interstitial pneumonitis, and low white blood cells.8 Fatigue is experienced by more than 50% of patients taking mTOR inhibitors. About 10% have dose-limiting fatigue to the degree of warranting dose reduction.9 Hyperglycemia is experienced by more than 50% of treated patients. Owing to the rising incidence of obesity and metabolic syndrome, it is important to identify these adverse events quickly. Up to 10% of patients develop severe symptoms and require medical intervention with an oral hypoglycemic agent or SC insulin. Regular monitoring of triglycerides is recommended, with early dietary interventions for minor elevations and initiation of a lipid-lowering agent for levels exceeding 500 mg/dL. Severe hypertriglyceridemia is associated with acute pancreatitis.9 Impairment of renal function and interstitial pulmonary fibrosis are rare but important events. Serum creatinine should be monitored regularly. The pulmonary fibrosis is often steroid-responsive and frequently fully reversible. If symptoms of progressive dyspnea or lung infiltrates are present, the dose may be reduced or the treatment discontinued.9 Both temsirolimus and everolimus are classified as pregnancy category D. Men and women receiving temsirolimus should use contraception while receiving REFERENCES 1. American Cancer Society. Detailed Guide: Kidney Cancer. What are the key statistics for kidney cancer? www.cancer.org/docroot/CRI/content/CRI_2_4_1X_What_ are_the_key_statistics_for_kidney_cancer_22.asp?sitearea=. Accessed July 25, 2009. 2. Reeves DJ, Liu CY. Treatment of metastatic renal cell carcinoma. Cancer Chemother Pharmacol. 2009;64:11-25. 3. Hudes G, Carducci M, Tomczak P, et al. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med. 2007;356:2271-2281. 4. Basso M, Cassano A, Barone C. A survey of therapy for advanced renal cell carcinoma. Urol Oncol. Epub July 6, 2009. www.urologiconcology.org/article/S10781439(09)00142-2/abstract [registration required]. Accessed July 20, 2009. 5. Nexavar (sorafenib) package insert. Wayne, NJ: Bayer Cost The average wholesale price (AWP) of the temsirolimus injection kit 25 mg IV weekly is $1,499, or $5,996 per month. The respective monthly AWPs of everolimus 5 mg and 10 mg orally daily are $6,400 and $6,700. The manufacturers offer assistance programs for eligible patients. Prior authorization often is required for these high-cost medications. Summary There are two recently approved novel mTOR inhibitors with activity in metastatic RCC. Temsirolimus is FDAapproved for first-line treatment of metastatic RCC and is favored for poor-prognosis patients. Everolimus is FDA-approved for second-line treatment of metastatic RCC after sunitinib or sorafenib failure. These agents provide a valuable choice for providers and patients with limited treatment options. HealthCare Pharmaceuticals, Inc; February 2009. 6. Sutent (sunitinib) package insert. New York, NY: Pfizer Labs; July 2009. 7. Wysocki P. mTOR in renal cell cancer: modulator of tumor biology and therapeutic target. Expert Rev Mol Diagn. 2009;9:231-241. 8. Hudes GR. Targeting mTOR in renal cell carcinoma. Cancer. 2009;115(suppl 10):2313-2320. 9. Dasanu CA, Clark BA III, Alexandrescu DT. mTORblocking agents in advanced renal cancer: an emerging therapeutic option. Expert Opin Investig Drugs. 2009;18(2): 175-187. 10. Torisel (temsirolimus) injection package insert. Philadelphia, PA: Wyeth Pharmaceuticals Inc; September 2008. 11. Afinitor (everolimus) package insert. East Hanover, NJ: Novartis Pharmaceuticals Corp; March 2009. 12. Motzer RJ, Escudier B, Oudard S, et al. Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet. 2008;372:449-456. 13. Kay A, Motzer R, Figlin R, et al. Updated data from a phase III randomized trial of everolimus (RAD001) versus PBO in metastatic renal cell carcinoma (mRCC). Proc Am Soc Clin Oncol. 2009. Abstract 278 [presented at 2009 ASCO Genitourinary Cancers Symposium]. 14. FDA. XIENCE™ V everolimus eluting coronary stent on the over-the-wire (OTW) or rapid exchange (RX) stent delivery systems–P070015. www.fda.gov/medicaldevices/productsandmedicalprocedures/ deviceapprovalsandclearances/recently-approveddevices/ ucm074025.htm. Accessed July 15, 2009. 15. Sosman J, Puzanov I. Combination targeted therapy in advanced renal cell carcinoma. Cancer. 2009;115(suppl 10):2368-2375. HS-26 U.S. Pharmacist • November 2009 • www.uspharmacist.com building on our promises Visit our Booth #2003 at the ASHP Midyear Meeting. Sagent’s product line growth helps to meet evolving customer needs Sagent is delivering on our promises made to hospitals and healthcare providers – a commitment to ongoing product quality, safety and growth – through an ever-expanding portfolio of products and presentations. In the last few months alone, Sagent has launched ADENOSINE Injection, USP single-dose vials, ONDANSETRON in 5% Dextrose Injection premix bags, AZITHROMYCIN for Injection in single-dose vials and more. In addition to a growing product line and multiple packaging forms, Sagent offers enhanced safety features on every product label and package to help reduce the risk of medication errors. Each uniquely designed Sagent product label features a bar code, easy-to-read drug name and prominently displayed dosage information. The choices you want, the products you need. That’s Injectables Excellence. Find out more at www.SagentPharma.com. Sagent Pharmaceuticals, Inc., Schaumburg, Illinois 60195 www.SagentPharma.com SAGENT PHARMACEUTICALS, SAGENT, INJECTABLES EXCELLENCE and DISCOVER INJECTABLES EXCELLENCE are registered trademarks of Sagent Pharmaceuticals, Inc. ©2009 Sagent Pharmaceuticals, Inc. 1191 H E A LT H S Y S T E M S E D I T I O N Nutrition and Clinical Depression In-Service Primers OVERVIEW Research results in the emerging area of nutritional neuroscience point to a link between what people eat and the quality of their mental state. hile the connection between nutritional deficiencies and physical illness is more obvious, few people see the connection between nutrition and depression. This is because depression is more typically thought of as either biochemicaly based or emotionally rooted. It is now proven that nutrition can play a key role in the onset, as well as severity and duration, of depression. Nutritional neuroscience is an emerging discipline that is shedding light on the link between nutritional factors and human cognition, behavior, and emotions.1 There are two types of depression. Behavioral depression or “the blues” results from various causes, and most people experience it at some point in their lives. Clinical depression, on the other hand, is much more serious. It is usually caused by a chemical imbalance in the brain and requires medical attention.2 Nutrition plays an important role in every aspect of well-being, and improper nutrition can lead to poor bodily function. There are many reports that people with clinical depression also suffer from malnutrition. The dietary habits of the general population in the United States and many Asian countries reveal that people are often deficient in many nutrients, especially essential amino acids, vitamins, minerals, and omega-3 fatty acids. People who are depressed often lose all sense Manouchehr Saljoughian, PharmD, PhD, Alta Bates Summit Medical Center, Department of Pharmacy, Berkeley, California W of self and stop eating and caring. Food alone cannot prevent depression, but poor nutrition makes the body incapable of healing itself. Supplements containing amino acids have been found to reduce symptoms of depression, as they are converted to neurotransmitters, which in turn alleviate depression and other mental health problems.3 Since most antidepressant prescription drugs have side effects, it is possible that some patients who are not being observed by psychiatrists will skip taking their medications. Such noncompliance can put patients at a higher risk for committing suicide or being hospitalized. An alternate and effective way for psychiatrists to circumvent noncompliance is to familiarize themselves with alternative or complementary nutritional therapies. Psychiatrists can recommend doses of dietary supplements based on efficacious studies and adjust the doses based on the results obtained by closely observing the changes in the patient.4 If a person with depression suffers from loss of sleep, clinicians will either increase the amount of amino acids in their diet or add iron for loss of appetite. There are foods that should be included in the diet of a person with clinical depression. Meat and amino acids such as phenylalanine, tryptophan, choline, and tyrosine—which help the nervous system function properly—should be added to the HS-28 U.S. Pharmacist • November 2009 • www.uspharmacist.com Providing Affordable and Innovative Medicines for Healthier Lives Affordable Medicines High-quality, low-cost generic ANDA alternatives Innovative Medicines _ First Indian company to fully develop an in-house biosimilar – NCEs for unmet medical needs – OTCs for a more complete selection Global Presence...Local Focus Dr. Reddy’s Laboratories, Inc. 3600 Arco Corporate Drive, Charlotte, NC 28273-7104 (866) 733-3952 www.DRREDDYS.com © 2009 Dr. Reddy’s Laboratories, Inc. Planning Our Future to Meet Your Future – Robust generic pipeline – Supply-chain excellence – 41 Rx generic product families available – Rx-to-OTC switches – Vertically integrated – Customer focused Visit us at ASHP booth # 3118 to pick up your Generic to Brand Conversion Guide! Or contact us directly to order your copy. DRFO / 11/09 NUTRITION AND CLINICAL DEPRESSION H E A LT H S Y S T E M S E D I T I O N diet. Choline and tryptophan can be found in many freshwater fish, and tyrosine can be found in cheese.5 Foods that should be avoided are alcohol and caffeine. Alcohol acts as a central nervous system depressant, which makes the situation worse, and caffeine interferes with sleep and promotes nervousness. Signs and Symptoms of Depression Many people attribute the feelings induced by depression to other causes such as inability to handle stress, social stigma, and alcoholism. However, depression is not difficult to spot, and specific signs and symptoms exhibited by a person are helpful in identifying its presence (see TABLE 1). 6 Brain Biochemical Imbalance Neurotransmitters are the natural biochemicals that facilitate communication between brain cells. These substances control our emotions, memory, moods, behavior, sleep, and learning abilities. Neurotransmitters are manufactured in the brain from the amino acid precursors we receive from food. Without adequate amino acid conversion, sufficient amounts of neurotransmitters are not produced.7 Alcohol destroys these essential precursor amino acids, which is probably why alcoholics seem so emotionally down and depressed. The two major neurotransmitters involved in preventing depression are serotonin (from the amino acid L-tryptophan) and norepinephrine (from the amino acids L-phenylalanine and L-tyrosine). It is interesting that the depressive symptoms exhibited indicate which amino acids are lacking: If the symptoms are sleeplessness, anxiety, or irritability, then L-tryptophan is low; if the symptoms are lethargy, Table 1 Signs of Depression • Indecisiveness • Continual fatigue and lethargy • Loss of appetite or binge eating • Withdrawal from daily activities • Inability to concentrate • Lack of motivation and unresponsiveness to people • Feeling helpless, immobilized • Sleeping too much; using sleep to escape reality • Insomnia, particularly earlymorning insomnia • Lack of response to good news • Ongoing anxiety • An “I don’t care” attitude • Easily upset or angered • Listening to mood music persistently • Self-destructive behavior Source: Reference 6. fatigue, sleeping too much, or feelings of immobility, L-tyrosine or L-phenylalanine is lacking.7 Conversion of Amino Acids to Neurotransmitters The amino acid tyrosine, found in large amounts in cheese, has an amazing effect on depression. Tyrosine is a nonessential amino acid that is synthesized in the body from phenylalanine. As a building block for several important brain chemicals, tyrosine is needed to make epinephrine, norepinephrine, serotonin, and dopamine, all of which work to regulate mood. Tyrosine also aids in the production of melanin (the pigment responsible for hair and skin color) and in the function of organs responsible for making and regulating hormones, including the adrenal, thyroid, and pituitary glands. Tyrosine is also involved in the synthesis of enkephalins, substances that have pain-relieving effects in the body. 8 Low levels of tyrosine have been associated with low blood pressure, low body temperature, and an underactive thyroid. Because tyrosine binds to free radicals, it is considered a mild antioxidant. Thus, tyrosine may be useful for individuals who have been exposed to harmful chemicals (such as from smoking) and radiation. The usual dose is 3 to 6 g per day, taken on an empty stomach. Vitamins B6 and C need to be taken to facilitate the conversion of tyrosine to norepinephrine.8 An alternative to tyrosine is the amino acid L-phenylalanine, which can also be converted into norepinephrine. L-phenylalanine is converted to a substance called 2-phenylethylamine (2-PEA). Low brain levels of 2-PEA are also responsible for some depression. 2-PEA is converted to tyrosine, which then converts to norepinephrine. L-phenylalanine is a better start than tyrosine, but if it causes the brain to race due to the formation of 2-PEA, the patient should start with tyrosine. A disadvantage to taking Lphenylalanine is its slight potential for raising blood pressure. There is also some evidence that excess L-phenylalanine can cause headaches, insomnia, and irritability. For these reasons, it is important to start with a low dose. L-phenylalanine doses can range from 500 mg to 1,500 mg daily and should be taken on an empty stomach.8 The FDA prohibited the manufacture and sale of tryptophan in the United States in the fall of 1980. Although the FDA continues to enunciate its concern about the use of L-tryptophan as a single product and related compounds such as L-5-hydroxytryptophan, the agency does not prohibit the marketing of dietary supplements that contain lower HS-30 U.S. Pharmacist • November 2009 • www.uspharmacist.com sepd`eopej_ph]^ahejcbnki>]tpan* ?kiejcokkjÄ`eopej_perah]^ahejcbnki>]tpan* Pkha]njikna(_kjp]_pukqn>]tpannalnaoajp]perakn_]hh-)4,,)0)>=TPAN$-)4,,)0..)54/3%* Baxter, Committed to a Safer Healthcare Environment, and the distinctive product label design are trademarks of Baxter International Inc. Baxter Healthcare Corporation, Route 120 and Wilson Road, Round Lake, IL 60073 www.baxter.com 111085 03/09 NUTRITION AND CLINICAL DEPRESSION H E A LT H S Y S T E M S E D I T I O N doses of L-tryptophan. 5-hydroxytryptophan (a direct precursor to serotonin) has been offered as an alternative. The amino acid tryptophan is the precursor for serotonin and it is found in large amounts in milk and turkey (see TABLE 2). Serotonin controls mood, sleep, sexual ability, appetite, and pain threshold. Increasing serotonin can lift depression and end insomnia.8 Prostaglandin E1 and Depression Another biochemical cause of depression is a genetic inability to manufacture enough prostaglandin E1 (PGE1), an important brain metabolite derived from essential fatty acids (EFAs). The problem is the result of an inborn deficiency in omega6 essential fatty acids. Alcohol stimulates temporary production of PGE1 and lifts the depression. When drinking is stopped, PGE1 levels fall again and depression returns. To banish it, the patients turn again to alcohol. Thus, a downward spiral toward alcoholism begins. During the past 15 years, researchers have found that if they restore the PGE1 levels to normal range in patients suffering from alcoholism, they can eliminate both the depression and the need to drink for relief. Research shows that nutritional deficiencies in brain chemistry can result in depression, anger, hopelessness, and paranoia. This can be achieved with a substance called gamma-linolenic acid, which can be easily converted to PGE1. 9 The Effect of Nutrition Research shows that nutritional deficiencies in brain chemistry can result in depression, anger, hopelessness, and paranoia. This is because the connection Table 2 Important Points About Tryptophan • Tryptophan alone will not be converted to serotonin. To ensure that it is properly used, you must also take vitamins C and B6. • Tryptophan is converted to niacin before its final conversion into serotonin. If your body is deficient in niacin, the tryptophan you take will supply you with niacin, not serotonin. For this reason, it is a good idea to take a Bcomplex vitamin daily. This will give you both vitamin B6 and niacin and allow the tryptophan to be converted to serotonin. • Unlike serotonin, tryptophan (or more accurately, its breakdown product 5hydroxytryptophan, or 5-HTP) can pass through the blood–brain barrier. Thus, supplementation of tryptophan would appear to be a simple and natural alternative to selective serotonin reuptake inhibitor drugs. • Since it is not stored in the body, tryptophan cannot accumulate to toxic levels. Taking high doses of supplements containing tryptophan, however, can produce some side effects such, as drowsiness, increased blood pressure, and bad dreams. between depression and vitamin and mineral deficiencies is often missed. A closer look at the diet of patients suffering from depression indicates that their nutrition is far from adequate. They make poor food choices and frequently select foods that contribute to depression. 10 The B-complex vitamins are essential to mental and emotional well-being. They cannot be stored in our bodies, so we depend entirely on our daily diet to supply them. B vitamins are destroyed by alcohol, refined sugars, nicotine, and caffeine. Continued vitamin C deficiency causes chronic depression, fatigue, and vague ill health, and insufficient amounts of minerals also cause mental problems. The relationship between vitamins B and C and minerals and depression is shown in TABLE 3. Carbohydrates Carbohydrates, or polysaccharides, play an important role in the structure and function of an organism. In humans, they have been found to affect mood and behavior. Food rich in carbohydrates triggers the release of insulin in the body. Insulin facilitates the release of blood sugar into the cells, where it can be used for energy, and simultaneously triggers the entry of tryptophan to the brain. Tryptophan in the brain affects neurotransmitter levels. Consumption of diets low in carbohydrates tends to precipitate depression, since the production of the brain chemicals serotonin and tryptophan, which promote the feeling of well-being, is reduced. It is suggested that low glycemic index (GI) foods such as some fruits and vegetables, whole grains, and pasta are more likely to provide a moderate but lasting effect on brain chemistry, mood, and energy level than the high GI foods.10 HS-32 U.S. Pharmacist • November 2009 • www.uspharmacist.com NUTRITION AND CLINICAL DEPRESSION Vitamin Bs • • • • • • • Vitamin B1 (thiamine): Deficiencies trigger depression and irritability and can cause neurologic and cardiac disorders among alcoholics. Vitamin B2 (riboflavin): Adequate riboflavin may be required for cognitive function. Riboflavin has been reported to improve depression scores in patients taking TCA drugs. Vitamin B3 (niacin): Depletion causes anxiety, depression, apprehension, and fatigue. Vitamin B5 (pantothenic acid): Symptoms of deficiency are fatigue, chronic stress, and depression. Vitamin B5 is needed for hormone formation and for the uptake of amino acids and the brain chemical acetylcholine, which combine to prevent certain types of depression. Vitamin B6 (pyridoxine): Deficiency can disrupt formation of neurotransmitters. Vitamin B6 is a coenzyme needed for conversion of tryptophan to serotonin and of phenylalanine and tyrosine to norepinephrine. Folic acid (B9): Folate and MTHF work best together by helping to regulate the neurotransmitters that affect depression. Vitamin B12: This vitamin controls blood levels of the amino acid homocysteine. Elevated levels of this substance appear to be linked with heart disease and, possibly, depression and Alzheimer’s disease. Vitamin C Continued vitamin C deficiency causes chronic depression, fatigue, and vague ill health. Minerals Deficiencies in a number of minerals can also cause mental problems. • Calcium: Depletion affects the central nervous system. Low levels of calcium cause nervousness, apprehension, irritability, and numbness. • Zinc: Deficiencies result in lack of appetite and lethargy. When zinc is low, copper in the body can increase to toxic levels, resulting in paranoia and fearfulness. Zinc also protects the brain cells against the potential damage caused by free radicals. • Iron: Depression is often a symptom of chronic iron deficiency. Other symptoms include general weakness, exhaustion, lack of appetite, and headaches. • Manganese: This metal is needed for proper use of the B-complex vitamins and vitamin C. Since it also plays a role in amino acid formation, a deficiency may contribute to depression resulting from low levels of the neurotransmitters serotonin and norepinephrine. Manganese also helps stabilize blood sugar and prevent hypoglycemic mood swings. • Potassium: Depletion is frequently associated with depression, tearfulness, weakness, and fatigue. A 1981 study found that depressed patients were more likely than controls to have decreased intracellular potassium. Decreased brain levels of potassium have also been found on autopsy of suicides. Potassium levels can be boosted by using one teaspoon of Morton’s Lite-Salt every day. • Magnesium: Symptoms of deficiency include confusion, apathy, loss of appetite, weakness, and insomnia. • Selenium: Low selenium intake is associated with lowered mood status. Intervention studies with selenium with other patient populations reveal that selenium improves mood and diminishes anxiety. MTHF: methyltetrahydrofolate; TCA: tricyclic antidepressant. Source: References 11-14. Proteins and Amino Acids Many of the neurotransmitters in the brain are made from amino acids. Proteins are made up of amino acids and are important building blocks of life. As many as 12 amino acids are manufactured in the body and the remaining eight (essential amino acids) must be supplied through diet. A high-quality protein diet contains all of the essential amino acids. Foods rich in high-quality protein include meat, milk and other dairy products, and eggs. Plant proteins in beans, peas, and grains may be low in one or two essential amino acids. Protein intake and in turn the individual amino acids can affect the brain function and mental health. The neurotransmitter dopamine is made from the amino acid tyrosine, and the neurotransmitter serotonin is made from tryptophan. If there is a lack of either of these amino acids, there will lack of neurotransmitter synthesis, which is associated with low mood and aggression in patients. The excessive buildup of amino acids may also lead to brain damage and mental retardation. For example, excessive amounts of phenylalanine in individuals with the disease called phenylketonuria can cause brain damage and mental retardation.10 Omega-3 Fatty Acids The brain is one of the organs with the highest level of lipids (fats). Brain lipids are composed of fatty acids and are a major part of its membranes. It has been estimated that gray matter contains 50% fatty acids that are polyunsaturated in nature (about 33% belong to the omega-3 family) and hence are supplied through the diet. In one of the first experimental demonstrations of the effect of nutrients on the structure and function of the HS-33 U.S. Pharmacist • November 2009 • www.uspharmacist.com H E A LT H S Y S T E M S E D I T I O N Table 3 Effects of Vitamins and Minerals on Depression NUTRITION AND CLINICAL DEPRESSION H E A LT H S Y S T E M S E D I T I O N brain, the omega-3 fatty acid alpha-linolenic was found to have a major role. An important trend has been observed from the findings of some recent studies that lowering plasma cholesterol by diet and medications might increase depression. Among the significant factors involved are the quantity and ratio of omega6 and omega-3 polyunsaturated fatty acids (PUFAs) that affect serum lipids and alter the biochemical and biophysical properties of cell membranes. It has been hypothesized that sufficient long-chain PUFAs, especially DHA, may decrease the development of depression.15 The glycerophospholipids in the brain consist of a high proportion of PUFAs derived from the essential fatty acids, linoleic acid, and alpha-linolenic acid. The main PUFAs in the brain are DHA, derived from the omega-3 fatty acid alphalinolenic acid, arachidonic acid, and docosatetraenoic acid, both derived from the omega-6 fatty acid and linoleic acid. Experimental studies have also revealed that diets lacking omega-3 PUFAs lead to considerable disturbance in neural function. 16 REFERENCES 1. Shaheen Lakhan SE, Vieira KF. Nutritional therapies for mental disorders. Nutr J. 2008;7:2. 2. National Institute of Mental Health. Depression. Bethesda, MD: US Department of Health and Human Services; 2000 [reprinted September 2002]. 3. Bourre JM. Effect of nutrients (in food) on the structure and function of the nervous system: update on dietary requirements for brain, part 1: nicronutrients. J Nutr Health Aging. 2006; 10:377-385. 4. Massimo CM, Ferrara A, Boscati L, et al. Plasma and platelet amino acid concentrations in patients affected by major depression and under Fluvoxamine treatment. Neuropsychobiology. 1998;37:124-129. 5. Shaw K, Turner J, Del Mar C. Tryptophan and 5-hydroxytryptophan for depression. Cochrane Database of Systematic Reviews. 2002;1:article CD003198. 6. Rush AJ. The varied clinical presentations of major depressive disorder. J Clin Psychiatry. 2007;68:4-10. Age, Depression, and CAM Anorexia in the elderly may play an important role in precipitating depression, either by reducing food intake directly or in response to such adverse factors as age-associated reductions in sensory perception (taste and smell), poor dentition, use of multiple prescription drugs, and depression. Currently, to tackle the problem of depression, many people are following the complementary and alternative medicine (CAM) interventions. CAM therapies are defined by the National Center for Complementary and Alternative Medicine as “a group of diverse medical and health systems, practices, and products that are not considered to be a part of conventional medicine.”17 Mental health professionals need to be aware that it is likely that a fair number of their patients with bipolar disorder might use CAM interventions. Some clinicians judge these interventions to be attractive and safe alternatives or adjuncts to conventional psychotropic medications. Current research in psychoneuroimmunology and brain biochemistry indicates the possibility of communication path7. Firk C, Markus CR. Serotonin by stress interaction: a susceptibility factor for the development of depression? J Psychopharmacol. 2007;21: 538-544. 8. Ruhe HG, Mason NS, Schene AH. Mood is indirectly related to serotonin, norepinephrine and dopamine levels in humans: a meta-analysis of monoamine depletion studies. Mol Psychiatry. 2007;12:331-359. 9. Horrobin DF, Manku MS. Possible role of prostaglandin E1 in the affective disorders and in alcoholism. Br Med J. 1980;280(6228): 1363-1366. 10. Bourre JM. Effect of nutrients (in food) on the structure and function of the nervous system: update on dietary requirements for brain, part 1: micronutrients. J Nutr Health Aging. 2006;10:377-385. 11. Abou-Saleh MT, Coppen A. Folic acid and the treatment of depression. J Psychosom Res. 2006;61:285-287. 12. Levenson CW. Zinc, the new antidepressant? Nutr Rev. 2006;6:39-42. 13. Eby GA, Eby KL. Rapid recovery from major ways that can provide a clearer understanding of the association between nutritional intake, the central nervous system, and immune function, thereby influencing an individual’s psychological health status. These findings may lead to greater acceptance of the therapeutic value of dietary intervention among health practitioners and health care providers in addressing depression and other psychological disorders.18 The Safety of Vitamin Supplements Vitamin C and the B-complex vitamins, discussed above, are all water soluble; therefore, they cannot accumulate in the body or be stored for future use. Amounts above and beyond current nutritional needs are excreted through urine. As a result, there is little danger of overdosing. Unlike water-soluble vitamins, lipid-soluble vitamins and minerals can be stored in body tissues. For therapeutic doses of these compounds, the advice of a qualified nutrition consultant is required. Do not exceed the recommended therapeutic doses, since accumulation of certain minerals in the body can be dangerous. 19 depression using magnesium treatment. Med Hypotheses. 2006;67:362-370. 14. Benton D. Selenium intake, mood and other aspects of psychological functioning. Nutr Neurosci. 2002;5:363-374. 15. Bourre JM. Dietary omega-3 fatty acids and psychiatry: mood, behavior, stress, depression, dementia and aging. J Nutr Health Aging. 2005;9:31-38. 16. Sinclair AJ, Begg D, Mathai M, Weisinger RS. Omega-3 fatty acids and the brain: review of studies in depression. Asia Pac J Clin Nutr. 2007;16:391-397. 17. Roberts SB. Energy regulation and aging: recent findings and their implications. Nutr Rev. 2000;58:91-97. 18. Andreescu C, Mulsant BH, Emanuel JE. Complementary and alternative medicine in the treatment of bipolar disorder: a review of the evidence. J Affect Disord. May 2, 2008 [Epub ahead of print]. 19. Eritsland J. Safety considerations of polyunsaturated fatty acids. Am J Clin Nutr. 2000;71:197S-201S. HS-34 U.S. Pharmacist • November 2009 • www.uspharmacist.com Progressive Supranuclear Palsy PARKINSON’S-LIKE SYMPTOMS Difficulty looking up without extending the neck or difficulty climbing up and down stairs may signal this condition. P Disability develops in PSP patients within 3 to 5 years of diagnosis; death usually occurs within 10 years of symptom onset, often secondary to infection (e.g., pneumonia) or other complications of immobility.2,6,7 Advance directives, such as a living will or durable power of attorney (see Reference 8), should be prepared by patients diagnosed with PSP so that they have the opportunity to indicate the type of medical treatment they wish to receive as part of their end-of-life care plan.6,8 Mary Ann E. Zagaria, PharmD, MS, CGP Senior Care Consultant Pharmacist and President of MZ Associates, Inc. Norwich, New York www.mzassociatesinc.com Recipient of the Excellence in Geriatric Pharmacy Practice Award from the Commission for Certification in Geriatric Pharmacy Pathophysiology and Diagnosis While PD is slowly progressive and primarily involves the substantia nigra, patients with PSP show a degeneration of neurons that occurs in the basal ganglia— the part of the brain that helps coordinate and ensure smooth body movements—and in the brain stem, the part of the brain that controls vital body functions (e.g., breathing, heart rate, swallowing) and eye movements.1,6 In addition, neurofibrillary tangles are detected (containing abnormal tau protein), and strokes (lacunar) may occur in the basal ganglia and deep white matter.1 According to Schneider and Mandelkow, neurofibrillary tangles are a hallmark of Alzheimer’s and other neurodegenerative diseases (e.g., PSP, Pick’s disease, frontotemporal dementia, and parkinsonism linked to chromosome 17) referred to as rogressive supranuclear palsy (PSP) is an uncommon neurodegenerative disorder often misdiagnosed, most frequently as Parkinson’s disease (PD).1,2 Although PSP is less common than PD, both are characterized by progressive loss of selected neurons in certain areas of the brain, which causes disease.3,4 Approximately 4% of patients experiencing parkinsonian symptoms have PSP.2 Few clinicians are proficient at recognizing the nonclassic presentations of PSP and also at treating it.5 Pharmacists should be aware of this distinct condition with an unknown cause, also known as Steele-Richardson-Olszewski syndrome. Although PSP usually strikes individuals after age 50 years, some patients can develop signs in their fourth decade.1,2 tauopathies, since neurofibrillary tangles are composed of intracellular aggregates of the microtubule-associated protein tau.9 While the mechanisms underlying tau-mediated neurotoxicity are not well understood, neurodegeneration and neuronal dysfunction are associated with pathologic hyperphosphorylation and aggregation of tau.9 A shared characteristic of PD and PSP is the presence of Lewy bodies (abnormal intracytoplasmic inclusion deposits), although Lewy bodies are found in a minority of PSP cases.3 Diagnosis of PSP is clinical, by history and physical examination.2 Neuroimaging is not required for diagnosis since findings are not specific.2 Signs and Symptoms A core feature of PSP is known as vertical supranuclear gaze palsy, where the voluntary vertical gaze is impaired; this causes difficulty looking up or down without extending or flexing the neck, or difficulty climbing up and down stairs, and may be the first noticeable symptom of the disease.1,2 Shortly after onset of the disorder, patients present with postural instability, causing gait unsteadiness and falls (typically backward).2,3 A staring, astonished appearance may be caused by retraction of the upper eyelids.2 Other findings (TABLE 1) may include dysphagia and dysarthria with emotional lability (pseudobulbar palsy). Emotional 20 U.S. Pharmacist • November 2009 • www.uspharmacist.com PROGRESSIVE SUPRANUCLEAR PALSY lability (with a propensity to laugh or cry easily) is referred to as pseudobulbar affect.2 Rigidity, bradykinesia, and dystonic neck extension may be present, and language functions resemble those evident in PD (i.e., speech may become incomprehensible, repetitive/babbling, or mute).1-3,7 While only occasional, a subtle resting tremor may be present.2 Deficits, similar to those secondary to multiple strokes, occur in a progressive and usually rapid fashion.2 In terms of the patient’s cognition, mental slowing, executive dysfunction (i.e., impairment of volitional activities such as planning, organizing, self-awareness, self-regulation, and initiation of action), and memory impairment (less severe than in Alzheimer’s disease) occur.1,3,6 Later in the disease, depression and dementia are common, causing some individuals to experience sleep disturbances, agitation, and irritability.2,3 Eventually, most PSP patients require a wheelchair and a feeding tube.7 Upon initially seeing a patient with symptoms of PSP, pharmacists may recognize symptoms that resemble drug-induced pseudoparkinsonism, most commonly seen with the use of firstgeneration antipsychotic agents of the phenothiazine (e.g., chlorpromazine), thioxanthene (e.g., thiothixene), or butyrophenone (e.g., haloperidol) classes. Based on the parkinsonian signs and symptoms and considering that the core symptom of vertical supranuclear gaze palsy is not always present in the early stage of PSP, it is not difficult to understand how this disease may be misdiagnosed as PD, especially since diagnosis is determined clinically and not by any substantiating diagnostic test. Schmidt et al note the most important features that characterize and differentiate PSP from other parkinsonian syndromes as Table 1 Potential Symptoms of Progressive Supranuclear Palsy • • • • • • • • • • • Loss of voluntary eye movements; particular difficulty with vertical movements, referred to as vertical supranuclear gaze palsy; inability to fix gaze on a stationary or moving object (square wave jerks). Reflexive eye movements are unaffected Other ophthalmic signs and symptoms include blurred vision, diplopia, photophobia, burning, tearing, and upper eyelid retraction Postural instability causing falls (specifically a tendency to fall backward) Bradykinesia Muscular rigidity with progressive dyskinetic movements due to disordered tonicity of muscle (e.g., dystonic neck extension); subtle resting tremor (usually absent) Pseudobulbar palsy: difficulty swallowing (dysphagia) and speech disturbance (dysarthria) with emotional lability Cognitive impairment (e.g., mental slowing, executive dysfunction, memory impairment) Sleep disturbances (insomnia or hyposomnia) Agitation, irritability, disinhibition Depression (late in course) Dementia (eventually occurs) Source: References 1-3, 6, 7, 16. the following: 1) supranuclear gaze palsy; 2) postural instability; 3) pseudobulbar palsy; and 4) cognitive disturbances.10 Litvan et al indicate that which specifically differentiates PSP from other diseases: 1) PSP from PD is unstable gait, absence of tremordominant disease, and absence of a response to levodopa; 2) PSP from diffuse Lewy body disease is supranuclear vertical gaze palsy, gait instability, and the absence of delusions; 3) PSP from Pick’s disease is postural instability; 4) PSP from multiple system atrophy is supranuclear vertical gaze palsy and increased age at symptom onset; and 5) PSP from corticobasal degeneration is gait abnormality, severe upward gaze palsy, bilateral bradykinesia, and absence of alien limb syndrome. 11 Significant autonomic dysfunction may be seen in patients with PSP as well as in patients with PD.10 According to Schmidt et al, the parasympathetic cardiovascular system appears to be involved to a similar extent in patients with PD and patients with PSP, as compared to sympathetic cardiovascular dysfunction, which is more frequent and severe in patients with PD but can also be seen in patients with PSP.10 Treatment PSP is an incurable condition. Treatment is supportive and far less effective than that for Parkinson’s disease.2 The treatment of PSP remains unsatisfactory, since only occasionally do levodopa, dopamine agonists (TABLE 2), amantadine, or amitriptyline partially relieve rigidity.1,2 It is presumed that the reason PSP is not responsive to dopamine replacement or dopamine agonist therapies is that dopamine receptors are decreased as a result of postsynaptic damage beyond pathological changes seen in PD.12 Symptomatic treatment with drugs and other therapies should be targeted at reducing morbidity and improving quality of life (e.g., depression can be treated with 21 U.S. Pharmacist • November 2009 • www.uspharmacist.com PROGRESSIVE SUPRANUCLEAR PALSY selective serotonin reuptake the short-term effects of Table 2 inhibitors).5,7 Pharmacists coenzyme Q10 in PSP.15 should note that prior to Dopamine Agonists Used in the Results indicated significant initiating any treatment, the Treatment of Parkinson’s Diseasea changes in the occipital lobe and a consistent trend in the overall benefit-to-risk ratio Apomorphine (Apokyn) basal ganglia.15 Coenzyme Q to the individual patient Bromocriptine (Parlodel) 10 treatment compared to must be considered. Pramipexole (Mirapex) placebo showed clinical Due to adverse effects Ropinirole (Requip, Requip XL) improvement according to associated with dopamine b Rotigotine transdermal (Neupro [DSC]) the PSP rating scale and the agonists—including nausea, a Refer to manufacturer’s prescribing information for comFrontal Assessment Battery; hypotension, confusion, and plete dosing guidelines. although the improvement hallucinations—their utility b Currently unavailable in the United States. was slight, it was noted as is severely limited.4 A Source: References 4, 14, 17. recently published reassesssignificant.15 The researchers concluded that since coenzyme Q ment of risks and benefits of the central nervous system effects 10 appears to improve cerebral dopamine agonists in PD has of amantadine; the use of two energy metabolism in PSP, longrevealed the occurrence of increas- divided daily doses may minimize ingly recognized adverse effects this effect.14 In patients with renal term treatment might have a disimpairment, amantadine requires ease-modifying, neuroprotective such as lower extremity edema, renal dosing based on estimated effect.15 daytime somnolence, impulse 13 creatinine clearance. Monitoring control disorders, and fibrosis. The antiviral agent amantaparameters for amantadine therapy Conclusion dine was accidentally discovered include renal function, Parkinson’s In PSP, neurodegenerative changes take place in the brain to have an antiparkinsonism symptoms, mental status, and stem, basal ganglia, and elseaction (e.g., increasing release of blood pressure.14 Nonpharmacologic measures where; neurofibrillary tangles are dopamine among other effects).4 Adverse effects associated with introduced early in the course of present. While PSP continues to amantadine therapy include rest- disease may include weighted be an underrecognized disorder lessness, agitation, confusion, walking aids or wheelchairs to pre- and is often misdiagnosed, it can and hallucinations; high doses vent falls, and adaptive eyeglasses be differentiated from other akimay result in an acute toxic psy(e.g., bifocals, prisms) to improve netic rigid syndromes such as chosis.4 Peripheral edema, ortho- vision.2 Also important in the PD.5 Diagnosis of this debilitating static hypotension, urinary reten- early stage of the illness is the disorder is clinical and treatment is tion, dry mouth, and livedo introduction of physical therapy, supportive. Risks associated with reticularis (i.e., red to blue skin occupational therapy, and speech potential adverse effects of treatdiscoloration on the limbs and therapy as supportive measures.2 ment should be considered in the trunk that intensifies upon expo- Thus far, surgical approaches to formulation of an individualized PSP have proven ineffective.5 sure to cold) may also occur.1,4 pharmaceutical care plan. Early The geriatric patient populaA randomized, placebo-condiscussion about end-of-life issues tion may be more susceptible to trolled trial in Germany looked at is advised. REFERENCES 1. Beers MH, Porter RS, Jones TV, et al. The Merck Manual of Diagnosis and Therapy. 18th ed. Whitehouse Station, NJ: Merck Research Laboratories; 2006:1885. 2. Progressive Supranuclear Palsy. In: Beers MH, Jones TV, Berkwits M, et al, eds. The Merck Manual of Geriatrics. Updated June 2006. www.merck.com/mkgr/mmg/sec6/ch46/ch46d.jsp. Accessed October 19, 2009. 3. Craft S, Cholerton B, Reger M. Aging and cognition: what is normal? In: Hazzard WR, Blass JP, Halter JB, et al, eds. Principles of Geriatric Medicine and Gerontology. 5th ed. New York, NY: McGraw-Hill, Inc; 2003:13551372. 4. Howland RD, Mycek MJ. Pharmacology. 3rd ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2006:91-101. 5. Lubarsky M, Juncos JL. Progressive supranuclear palsy: a current review. Neurologist. 2008 Mar;14(2):79-88. 6. Beers MH, Jones TV, Berkwits M, et al, eds. The Merck Manual of Health & Aging. Whitehouse Station, NJ: Merck Research Laboratories; 2004:367-369. 7. Chand P, Litvan I. Progressive supranuclear palsy and corticobasal degeneration: similarities and differences. Future Neurol. May 2008. www.medscape.com/viewarticle/578084. Accessed October 21, 2009. 8. Zagaria ME. The dying patient: choices, control, and communication. U.S Pharm. 2009;34(10):32-34. 9. Schneider A, Mandelkow E. Tau-based treatment strategies in neurodegenerative diseases. Neurotherapeutics. 2008;5(3):443-457. 10. Schmidt C, Herting B, Prieur S, et al. Autonomic dysfunction in patients with progressive supranuclear palsy. Mov Disord. 2008;23(14):2083-2089. 11. Litvan I, Campbell G, Mangone CA, et al. Which clinical features differentiate progressive supranuclear palsy (Steele-Richardson-Olszewski syndrome) from related disorders? A clinicopathological study. Brain. 1997;120(pt 1):65-74. 12. Nelson MV, Berchou RC, LeWitt PA. Parkinson’s disease. In: DiPiro JT, Talbert RL, Yee GC, et al, eds. Pharmacotherapy: A Pathophysiologic Approach. 6th ed. New York, NY: McGraw-Hill, Inc; 2005:1075-1088. 13. Antonini A, Tolosa E, Mizuno Y, et al. A reassment of risks and benefits of dopamine agonists in Parkinson’s disease. Lancet Neurol. 2009;8:929-937. 14. Semla TP, Beizer JL, Higbee MD. Geriatric Dosage Handbook. 14th ed. Hudson, OH: Lexi-Comp, Inc; 2009. 15. Stamelou M, Reuss A, Pilatus U, et al. Short-term effects of coenzyme Q10 in progressive supranuclear palsy: a randomized, placebo-controlled trial. Mov Disord. 2008;23(7):942-949. 16. Dorland’s Pocket Medical Dictionary. 28th ed. Elsevier Saunders; 2009. 17. My Epocrates. Version 1.0. Updated October 6, 2009. 22 U.S. Pharmacist • November 2009 • www.uspharmacist.com FDA Fast Facts New Leukemia Treatment Fast Tracked The FDA approved ofatumumab (Arzerra) for treating patients with chronic lymphocytic leukemia (CLL), a blood and bone marrow cancer. Ofatumumab was approved using the accelerated approval process for patients with CLL whose cancer is uncontrolled by other types of chemotherapy. The effectiveness of the drug was evaluated in 59 patients with CLL whose disease no longer responded to the available therapies. CLL, which arises from B cells found in the body’s immune system, mainly afflicts patients older than 50 years, killing about 4,400 people each year. “The approval of Arzerra illustrates FDA’s commitment to using the accelerated approval process to approve drugs for patients who have limited therapeutic options,” said Richard Pazdur, MD, director of the Office of Oncology Drug Products in the FDA’s Center for Drug Evaluation and Research. The manufacturer, GlaxoSmithKline, is currently conducting a clinical trial to verify that ofatumumab added to standard chemotherapy delays CLL progression. Marketing of Illegal Opioids Halted The FDA warned four FDA Marks AIDS Program Milestone The U.S. Department of Health and Human Services (HHS) marked the recent approval of the 100th antiretroviral drug in association with the President’s Emergency Plan for AIDS Relief (PEPFAR), which is designed to prevent HIV/AIDS and to treat and care for patients and those affected by the disease worldwide. The PEPFAR program is a joint effort involving the FDA and other HHS agencies, the State Department’s Office of the U.S. Global AIDS Coordinator, the U.S. Department of Defense, other federal agencies, host country governments, and other international partners. “This milestone exemplifies the dedication, caring, and hard work of all who strive to better the lives of those infected with or affected by HIV/AIDS,” said HHS Secretary Kathleen Sebelius. Drug products used in PEPFAR receive a tentative approval and cannot be approved for marketing in the United States due to current patents and marketing exclusivity, yet the drugs must meet the same manufacturing, safety, and efficacy standards required for marketing in this country. As of October 6, 2009, more than 100 products had been assessed by the FDA as part of the PEPFAR program and either fully or tentatively approved. Of these, 29 were new products, 71 were versions of drugs approved in the U.S., and 22 were new combinations or regimens not previously authorized in the U.S. In 2008, PEPFAR provided almost $1.6 billion in support of HIV/AIDS treatment programs. companies that they must stop marketing unapproved codeine sulfate tablets, opioid analgesics used to treat pain. These particular products have not received FDA approval, and the agency has no evidence that they are safe and effective. Another manufacturer, Roxane Laboratories, markets approved codeine sulfate tablets, and the FDA does not expect a shortage in the supply of these drugs. The products and the manufacturers and distributors that received the warning letters are: Codeine Sulfate Tablets, 30 mg, 60 mg (Lehigh Valley Technologies Inc., Allentown, Pennsylva- nia); Codeine Sulfate Tablets, 30 mg, 60 mg (Cerovene Inc., Valley Cottage, New York); Codeine Sulfate Tablets, 30 mg (Dava International Inc., Fort Lee, New Jersey); and Codeine Sulfate Tablets, 30 mg, 60 mg (Glenmark Generics Inc. USA, Mahwah, New Jersey). Companies receiving the warning letters have 15 days to give the FDA a plan to discontinue marketing the unapproved drugs. New Web Page Details Disposal Instructions The FDA launched a Web page for consumers with information on 24 U.S. Pharmacist • November 2009 • www.uspharmacist.com how to dispose of certain drugs, including high-potency opioids and other potentially harmful controlled substances. The FDA recommends that these medicines be disposed of by flushing them down the sink or toilet to keep them away from children and others. Medicines not listed should be thrown away in the household trash after mixing them with some unpalatable substance, such as coffee grounds, and sealing them in a bag or other container. Another option is to dispose of them through drug take-back programs, federal and state law permitting. 6 at 64 us h 1 sit ot Vi Bo HP AS QS/1 ® When you think you need a miracle cure for managing your outpatient pharmacy, think QS/1. Until there’s a miracle cure for the aches and pains of managing an outpatient pharmacy, count on real pharmacy management solutions from QS/1. QS/1 has the industry’s most complete suite of pharmacy management tools, all designed to work together to improve efficiency, safety and operations in busy pharmacies like yours. Join the thousands of pharmacies backed by the leader in pharmacy management. Think QS/1. © 2009, J M SMITH CORPORATION. QS/1 is a registered trademark of the J M Smith Corporation. 1-800-231-7776 www.qs1.com So Many Options, So Little Difference in Efficacy What Is the Appropriate Antidepressant? © JUPITERIMAGES ncertainty is high when it comes to selecting What Is Depression? the appropriate antidepressant for patients diag- Depression can be a chronic or recurrent mental disnosed with major depressive disorder (MDD), order that presents with several symptoms such as not only because studies have reported no differences in depressed mood, loss of interest or pleasure, feelings efficacy between agents, but also because only 11% to of guilt, disturbed sleep or appetite, low energy, and 30% of patients will reach remission with initial treat- difficulty thinking.7 Depression can lead to substanment, even after a year.1,2 This consequently has led clin- tial impairment in an individual’s ability to take care icians to practice in a trial-and-error fashion to treat of everyday responsibilities. Depression can also lead to depression.3 Furthermore, the last major revision of the suicide, a tragedy accounting for the loss of about Diagnostic and Statistical Manual of Mental Disorders 850,000 lives worldwide every year.7 (DSM-IV-TR) was produced in 2000.4 In 2005, a guideline watch was published to review important safety con- Prevalence and At-Risk Populations cerns that had emerged about some agents, such as There are an estimated 121 million people worldwide nefazodone, as well as to review two new antidepressants affected with depression.7 In 2000, depression was the approved that year, escitalopram and duloxetine.5 Revi- fourth leading contributor to the global burden of dission and update of the DSM-IV-TR (DSM-V manuscript) ease among all diseases, and by 2020 it is anticipated is not due until May 2012. Therefore, there is need for that it will rise to the number-two leading contributor an up-to-date review to assist clinicians in deciding on to the global burden of disease, second only to heart the appropriate agents to treat individual patients. disease.7 Populations at higher risk for developing depression The 2007 Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study attempted to develop and include women, people between the ages of 24 and 45 evaluate feasible treatment strategies to improve clinical years, and those with first-degree relatives with depresoutcomes for patients with treatment-resistant depres- sion. Women are at increased risk for depression until sion who were identified with a current major depressive their 50s, and their lifetime risk is two times greater than episode.6 Specifically, STAR*D aimed to determine which men’s. People between the ages of 24 and 45 years of several treatments is the most effective “next step” for experience the highest rate of depression. Finally, firstpatients who do not reach remission with an initial or degree relatives of depressed patients are 1.5 to 3 times subsequent treatment or who cannot tolerate the treat- more likely to experience depression than others.4,8 ment. The overall results of this study demonstrated that pharmacologic differences between psychotropic medi- Pathophysiology and cations did not translate into substantial clinical differ- Pharmacotherapy Rationale Biological and psychosocial causes have been hypothences, although tolerability differed.6 The purpose of this article is to review treatment evi- esized in an attempt to describe the pathophysiology of dence available in the literature in depression. Pharmacologic agents will Rochette DeLucia, PharmD, MS order to provide a quick reference that Marjorie target the biological causes linked to PGY1 Pharmacy Practice Resident will help clinicians decide on the dysregulation in the neurotransmitBaptist Medical Center appropriate agent, taking into conters. This dysregulation is often Jacksonville, Florida sideration adverse effects, drug interdescribed as a deficiency in brain neuMichael J. Schuh, PharmD, MBA actions, and medication safety, as well rotransmitter levels. Norepinephrine, Ambulatory Pharmacist, Mayo Clinic as patient characteristics. serotonin, and dopamine levels Jacksonville, Florida U 26 U.S. Pharmacist • November 2009 • www.uspharmacist.com WHAT IS THE APPROPRIATE ANTIDEPRESSANT? Table 1 Selective Serotonin Reuptake Inhibitors Medications Initial/Max Dose Comments Adverse Effects Citalopram (Celexa) 20 mg/60 mg daily (40 mg max effective) t1/2 = 35 h; weak CYP2D6 inhibitor; anxiety symptoms significantly improved compared to other SSRIs Escitalopram (Lexapro) 10 mg/20 mg daily (10 mg max effective) t1/2 = 35 h; most potent SSRI; like citalopram, fewer drug interactions Fluoxetine (Prozac) 20 mg/80 mg daily Long t1/2 = 7-15 days; active metabolite norfluoxetine; potent CYP2D6 inhibitor = drug interactions; may cause weight loss Fluvoxamine (Luvox) 50 mg/300 mg in divided doses t1/2 = 16 h adults, 26 h elderly; potent CYP3A4, 2C19, 1A2 inhibitor = most drug interactions; primarily used to treat OCD and panic disorders Weight gain, insomnia, tremors, prolonged QT interval, dizziness, constipation, dry mouth, nausea, lightheadedness, syncope, confusion, agitation, sexual dysfunction Paroxetine (Paxil) 20 mg/60 mg daily (50 mg max effective) t1/2 = 26 h; potent CYP2D6 inhibitor; mild affinity for muscarinic receptors = more anticholinergic side effects than other SSRIs; sedating Sertraline (Zoloft) 50 mg/200 mg daily t1/2 = 26 h; absorption increases when taken with food; weak CYP2D6 inhibitor = less potential drug interactions; more likely than other SSRIs to cause nausea; most cited reason for d/c d/c: discontinuation; max: maximum; OCD: obsessive compulsive disorder; SSRI: selective serotonin reuptake inhibitor; t1/2: half-life. Source: References 4, 10. may be decreased in patients with depression, thus associating a decreased amount of neurotransmitters with the disorder. 8 The pharmacotherapy rationale has been to boost these deficiencies by blocking the reuptake or preventing enzymatic metabolism of neurotransmitters via antidepressants. Overall, these mechanisms aim at increasing the level of neurotransmitters either by forcing the neuron to fire more often and produce more neurotransmitters or by preventing degradation of the neurotransmitter itself. Pharmacologic Agents Several classes of agents are currently available to treat depression. They include selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants (TCAs), monoamine oxidase inhibitors (MAOIs), and serotoninnorepinephrine reuptake inhibitors (SNRIs), among others. Antidepressants have been associated with an increased risk of suicidal thinking and suicidality in children, adolescents, and young adults in short-term placebo controlled studies of MDD. Anyone considering the use of any antidepressant in a child, adolescent, or young adult must balance this risk with the clinical need. Shortterm studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24 years, and there was a reduction in risk with antidepressants compared to placebo in adults aged 65 years and older. Depression and other psychiatric disorders are themselves associated with increased risk of suicide. Patients of all ages who are started on antidepressant therapy should be monitored appropriately and observed closely for clinical worsening, suicidality, or unusual changes in behavior.9 Selective Serotonin Reuptake Inhibitors4,10: SSRIs are considered first-line agents when it comes to treating patients with depression. These drugs include citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline (TABLE 1). The major adverse effects of this class include nausea, vomiting, and diarrhea, which are dose-dependent effects and tend to dissipate after the first weeks of treatment. In some patients, SSRIs can cause agitation and sleep disturbances, which will also dissipate with time. Sexual dysfunction is a side effect present with all antidepressants, but seems to be most common with SSRIs. Serotonin syndrome (i.e., abdominal pain, diarrhea, sweating, mental status change, renal failure, cardiovascular shock, and possibly death) is a rare adverse effect of SSRIs. Serotonin syndrome can occur with an increase in SSRI dose or by taking SSRIs with herbals such as St. John’s wort or with illicit drugs. Finally, combining SSRIs with MAOIs can also lead to lethal drug interactions with development of serotonin syndrome. When clinicians feel the need to switch from one class of agent to the other, it is suggested that at least five half-lives elapse between the time the SSRI is stopped and the MAOI is started.4 Of all agents in the class, fluvoxamine has the highest rate of drug interactions, since it 29 U.S. Pharmacist • November 2009 • www.uspharmacist.com WHAT IS THE APPROPRIATE ANTIDEPRESSANT? Table 2 Tertiary and Secondary Amine Tricyclic Antidepressants Medications Initial/Max Dose Comments Adverse Effects Amitriptyline (Elavil) 25-75 mg/200 mg daily 5HT > NE Amoxapine (Asendin) 50 mg bid/400 mg daily 5HT = NE, weak DA Orthostatic hypotension, drowsiness, weight gain, anticholinergic, QT prolongation (in overdose) Tertiary Amine TCAs Clomipramine (Anafranil) 25 mg/250 mg daily 5HT > NE Doxepin (Sinequan) 50-75 mg/300 mg daily 5HT = NE; highly sedating Imipramine (Tofranil) 50-100 mg/200 mg daily 5HT = NE Secondary Amine TCAs Desipramine (Norpramin) 100-200 mg/300 mg daily NE > 5HT; metabolite of imipramine Maprotiline (Ludiomil) 25 mg tid/225 mg daily NE > 5HT Nortriptyline (Pamelor) 25-50 mg/150 mg daily NE > 5HT; metabolite of amitriptyline Same as above, but with more drowsiness, somnolence, and weight gain than tertiary DA: dopamine; 5HT: serotonin; max: maximum; NE: norepinephrine; TCA: tricyclic antidepressant. Source: References 4, 10. inhibits several hepatic enzymes such as CYP450 1A2, 2C19, 2C9, 2D6, and 3A4. Fluoxetine follows fluvoxamine’s drug interaction rate closely with inhibition of CYP 2C9, 2D6, and 3A4. Finally, citalopram and escitalopram have the least drug interactions, since they inhibit 2D6 enzymes to a lesser extent. When considering patient characteristics and safety, SSRIs are safe to use in most patient groups, including those with preexisting cardiac disease, asthma, dementia, and hypertension. The elderly, who are particularly prone to orthostatic hypotension as well as weight loss, may benefit most from using SSRIs since those agents produce weight gain and lack anticholinergic activity. Tricyclic Antidepressants4,10: TCAs block norepinephrine and serotonin reuptake, but they also have affinity for alpha1, H1, and muscarinic receptors, thus causing anticholinergic adverse effects. There are two subclasses of agents available within this class, the tertiary and secondary amine TCAs (TABLE 2). The secondary amine TCAs (desipramine, maprotiline, nortriptyline) have less affinity for the alpha1, H1, and muscarinic receptors, therefore causing fewer anticholinergic adverse effects than the tertiary amine TCAs (e.g., amitriptyline, amoxapine, clomipramine, doxepin, imipramine). The main adverse effects of this class of agents are orthostatic hypotension, QT prolongation, drowsiness, dry mouth, blurred vision, constipation, and weight gain. In general, tertiary amine TCAs have more serotonin activity versus secondary amine TCAs, which have more norepinephrine activity, thus causing less drowsiness, somnolence, and weight gain. It is known that TCAs inhibit both CYP 2C19 and 2D6 enzymes.11 They are also metabolized to a lesser extent by CYP 1A2 and 3A4 enzymes.12 For this reason, although drug–drug interactions with these agents might not be the primary concern, it is advised to use caution when combining TCAs with SSRIs, since the drug plasma level of TCAs has the potential to increase by up to fourfold, possibly leading to toxic effects.13,14 When considering patient characteristics and safety, TCAs are contraindicated in some specific cardiac conditions such as patients with a history of arrhythmias, sinus node dysfunction, or conduction defects. Caution is advised with the elderly, as they are more sensitive to cholinergic blockade as well as orthostatic hypotension. Furthermore, individuals also suffering from dementia will be particularly susceptible to the toxic effects of muscarinic blockade on memory and attention span and would generally do best if given antidepressants with the lowest degree of anticholinergic effects. Finally, caution should be exercised when considering starting TCAs in patients with suicidal thoughts due to high lethality risks with overdose. The lethal dose is only eight times the therapeutic dose, so if TCAs are ingested in an overdose, they may block the sinoatrial node in the heart. Monoamine Oxidase Inhibitors4,10: The MAOIs that are available include isocarboxazid, phenelzine, selegiline, and tranylcypromine (TABLE 3). Aside from selegiline, which is a selective MAO B inhibitor, all other agents inhibit both MAO A and B enzymes responsible for serotonin, norepinephrine, and dopamine metabolism in the brain. Due to severe adverse effects and required diet restrictions, MAOIs are generally reserved for patients who have failed other antidepressants. Hypertensive crisis can occur when patients taking MAOIs ingest foods containing tyramine, such as beer, 30 U.S. Pharmacist • November 2009 • www.uspharmacist.com WHAT IS THE APPROPRIATE ANTIDEPRESSANT? Table 3 Monoamine Oxidase Inhibitors Medications Initial/Max Dose Isocarboxazid (Marplan) Phenelzine (Nardil) Selegiline (Emsam)a Tranylcypromine (Parnate) Comments Dietary restrictions: no 10 mg bid/60 mg daily foods containing tyramine 15 mg tid/90 mg daily (e.g., beer, wine, aged 6 mg/12 mg (24-h transdermal patch) cheese, soy sauce, bananas, smoked meat) 30 mg/60 mg (divided doses) Adverse Effects HTN crisis: palpitations, chest pain, muscle rigidity; 5HT syndrome: nausea, sedation, diaphoresis, confusion, HTN a Selective monoamine oxidase B inhibitor. 5HT: serotonin; HTN: hypertension; max: maximum. Source: References 4, 10. wine, aged cheese, and smoked meat. This reaction presents as an acute onset of severe headache, nausea, neck stiffness, heart palpitations, chest pain, and confusion. MAOIs can also cause serotonin syndrome. As mentioned previously, this syndrome most commonly occurs when MAOIs are taken concomitantly with other serotonergic agents such as SSRIs or if venlafaxine, an SNRI, is administered soon after an MAOI. When patients are switched from an SSRI with a short halflife to an MAOI, it is important that a 2-week washout period be respected between the discontinuation of the SSRI and the start of the MAOI. If fluoxetine is the SSRI, which has a long half-life, the washout period should be 5 weeks.4 Other adverse effects can occur with MAOIs such as orthostatic hypotension, weight gain, sexual dysfunction, and insomnia. Due to the high rate of drug interactions with these agents, caution should be used when prescribed to patients with asthma using sympathomimetic bronchodilators. In patients with hypertension, MAOIs may induce orthostatic hypotension, especially with concurrent diuretic treatments. Serotonin-Norepinephrine Reuptake Inhibitors4,10: The SNRIs such as desvenlafaxine, duloxetine, and venlafaxine may also be used as first-line agents (TABLE 4). These medications are safer than TCAs, and their adverse effects are similar to those of SSRIs, including nausea, vomiting, and sexual dysfunction, as well as elevated blood pressure. Venlafaxine has been shown to cause an increase in blood pressure in 3% to 13% of cases, while desvenlafaxine was reported to cause an increase in blood pressure in only 1% to 2% of cases.10 Thus, it is recommended to avoid using venlafaxine in patients with uncontrolled hypertension since the agent can exacerbate the condition. Duloxetine has more norepinephrine activity than both of the aforementioned agents, thus being useful with physical symptoms such as muscle aches, headaches, stomach issues, and generalized pain, often occurring with severely depressed patients. Due to its effectiveness in pain symptoms, duloxetine has also been approved for other indications such as fibromyalgia and diabetic peripheral neuropathic pain.15 Finally, all three agents have more serotonin than norepinephrine Table 4 Serotonin-Norepinephrine Reuptake Inhibitors Medications Initial/Max Dose Comments Adverse Effects Desvenlafaxine (Pristiq) 50 mg/100 mg daily (50 mg max effective dose) Active metabolite of venlafaxine; BP elevation reported to be less common than with venlafaxine Duloxetine (Cymbalta) 40 mg/ 60 mg daily t1/2 = 12 h; moderate inhibitor of CYP2D6; GI adverse effects (nausea, dry mouth, constipation) are common; unique beneficial treatment for physical pain associated with depression Similar adverse effects to SSRIs, except more incidence of BP elevation with SNRIs Venlafaxine (Effexor) 25 mg tid/ 225 mg daily 5HT > NE at lower doses; NE > 5HT at higher doses; t1/2 = 11 h; inhibitor of CYP2D6 BP: blood pressure; 5HT: serotonin; GI: gastrointestinal; max: maximum; NE: norepinephrine; SNRI: serotonin-norepinephrine reuptake inhibitor; SSRI: selective serotonin reuptake inhibitor; t1/2: half-life. Source: References 4, 10. 36 U.S. Pharmacist • November 2009 • www.uspharmacist.com WHAT IS THE APPROPRIATE ANTIDEPRESSANT? Table 5 Other Antidepressants Medications Initial/Max Dose Comments Adverse Effects Bupropion IR (Wellbutrin) 100 mg bid/ 150 mg tid Contraindicated in patients with anorexia, bulimia, or seizure disorders Bupropion SR (Budeprion SR, Wellbutrin SR, Buproban) 150 mg/ 200 mg bid Bupropion XL (Wellbutrin XL, Budeprion XL) 150 mg/ 450 mg daily Similar to SSRIs but with less 5HT adverse effects such as nausea, somnolence, and weight gain; no sexual dysfunction NDRIs Mixed-Action Antidepressants Mirtazapine (Remeron) 15 mg/ 45 mg daily Blocks alpha2, 5HT2a,c, 5HT3, and H1 receptors More weight gain, less sexual dysfunction, insomnia Nefazodone (Serzone) 100 mg bid/ 300 mg bid Blocks 5HT2a and 5HT reuptake; 3A4 inhibitor = many drug interactions will limit use Black box warning = hepatotoxicity Trazodone (Desyrel) 150 mg/ 600 mg daily Blocks 5HT2 and alpha1 receptors Too much sedation limits use 5HT: serotonin; IR: immediate release; max: maximum; NDRI: norepinephrine-dopamine reuptake inhibitor; SR: sustained release; SSRI: selective serotonin reuptake inhibitor; XL: extended release. Source: References 4, 10. activity at lower doses and more norepinephrine than serotonin activity at higher doses, thus having dosedependent adverse effects. ory impairment, dry mouth, and constipation may occur. Caution is also advised with trazodone use in men due to risk of priapism. Other Antidepressants4,10: Several other antidepressants are available that differ in their mechanism of action from the classes of medications described previously. The norepinephrine-dopamine reuptake inhibitors (NDRIs) such as bupropion immediate-release (IR) branded Wellbutrin (also available in long-acting dosage forms such as Wellbutrin XL, Wellbutrin SR, Budeprion SR, Budeprion XL, and Buproban) may be used as first-line agents to treat depression (TABLE 5). Their adverse effects are similar to those of SSRIs, with minimal serotonin effects such as nausea and weight gain and little or no sexual dysfunction. Bupropion has been shown to exert beneficial effects on Parkinson’s disease symptoms in some patients, but it may also induce some psychotic symptoms, perhaps because of its agonistic action on the dopaminergic system.16 Finally, there are three more antidepressants with mixed action available: mirtazapine, nefazodone, and trazodone (TABLE 5). All three agents block different serotonin receptors, thus having distinct effects. Mirtazapine causes more weight gain by increasing appetite. Nefazodone has limited uses because of hepatotoxicity and CYP3A4 enzyme inhibition, which leads to drug interactions. Trazodone blocks serotonin receptors to a great extent, with poor binding to muscarinic receptors. Adverse effects such as sedation, headache, mem- Conclusion In general, antidepressant medications have been shown to be equally efficacious; therefore, medication choice should be based on adverse effects, drug interactions, safety, and patient preferences. Several algorithms are available to guide the clinician during the patient’s treatment, particularly the recently updated Texas Department of State Health Services algorithm for the treatment of MDD (updated July 2008).17 If patients show partial response, clinicians may choose to increase the dose, change to an alternative agent, or give a combination of antidepressants. On the contrary, if patients do not respond or cannot tolerate the drug, switching to an alternative agent is also appropriate, taking into consideration that therapeutic effects will usually occur between 4 to 6 weeks, even though adverse effects might appear after 1 week of treatment.4,17 In addition, while the adverse effects appear early in treatment, they generally dissipate after 2 to 3 weeks.4,17 Nonetheless, the antidepressant that will most likely ensure a patient’s improvement and safety may be determined, at least partially, by trial and error. Given the difficulty in predicting what medication will be both efficacious for and tolerated by an individual patient, familiarity with a broad spectrum of antidepressants is prudent and useful. References available online at www.uspharmacist.com. 39 U.S. Pharmacist • November 2009 • www.uspharmacist.com Medications Used in Opioid Maintenance Treatment F or the community pharmacist, the ability to aid in the management of opioid dependence is vital to closing the gap between treated and untreated opioid-dependent individuals. In the United States, approximately 2 million adults are dependent on heroin or other nonmedically prescribed opioids, yet only about 14% receive treatment.1,2 In an effort to provide care to a greater number of patients with dependence or addiction treatment needs, the Drug Addiction Treatment Act of 2000 (DATA 2000) was passed. DATA 2000 states that physicians who qualify can treat opioid dependence in the office setting with a schedule III, IV, or V drug that is FDA-approved for this indication.3 In 2002, buprenorphine (Subutex) and buprenorphine/naloxone (Suboxone) sublingual tablets were approved for the management of opioid dependence. As the practice of treating opioid dependence expands, pharmacists must become familiar with this chronic condition and stay up-to-date with current treatment options for patients on maintenance therapy. © MEDI-MATION LTD / PHOTO RESEARCHERS, INC Many characteristics of opioids, especially onset of action and half-life, contribute to the potential for dependence and to the onset of withdrawal. Withdrawal may present as anxiety, bone pain, chills, piloerection, sweating, nervousness, nausea, diarrhea, rhinorrhea, or constant yawning. More severe symptoms include hot and cold flashes, increased blood pressure and pulse, mydriasis, abdominal and muscle cramps, and vomiting. Symptoms continue for 48 to 96 hours after the last dose, but may persist for weeks to months in some individuals.6 See TABLE 1 for withdrawal profiles of various opioids. PHARMACOLOGIC TREATMENT There are three major approaches to opioid dependence: opioid detoxification, agonist maintenance, and antagonist maintenance. Opioid detoxification, also known as medically supervised withdrawal, is utilized mainly to transition into or out of a maintenance program, over a very short period of time. In antagonist maintenance, naltrexone—an opioid antagonist like naloxone—is used. Unlike naloxone, it can be used orally because of its supeNEUROBIOLOGY OF OPIOID rior bioavailability. Unfortunately, neither opioid DEPENDENCE AND WITHDRAWAL detoxification nor antagonist maintenance has proved to Over the past 30 years, much has been discovered be as efficacious as agonist maintenance for producing about opioid dependence that has improved our under- long-term abstinence.7 However, research is being constanding of addiction as a chronic disease. Opioids acti- ducted using novel approaches like rapid detoxification vate specific opioid receptors (mu, delta, and kappa). Ini- under general anesthesia and subcutaneous naltrexone tially, when heroin or other short-acting opioids are taken, implantation.8,9 To be an effective option for maintenance treatment, receptor agonists induce euphoria. Subsequent doses will quickly produce tolerance—the need for increasingly an agent must be able to do the following: block the higher doses to induce the same effect—and physical euphoric and sedating effects of dependent opioids; relieve dependence. Currently, it is believed that tolerance is a the cravings (the major cause of relapse); relieve and result of a reduction in either the number or the prevent withdrawal symptoms; permit the patient to participate in society; and allow for at least once-daily dosresponsivity of opioid receptors.4,5 Chronic exposure to opioids causes upregulation of the ing.10 The pharmacologic agents that embody these charcyclic adenosine monophosphate signaling pathways in acteristics and have proven their efficacy are buprenorphine, neurons that are responsible for the buprenorphine/naloxone, and methadone Christie Choo, PharmD, BCPS release of noradrenaline. When the (see TABLE 2). Assistant Clinical Professor inhibitory opioid is no longer present, College of Pharmacy and Allied Health Methadone and Levo-Alpha the firing rates of these neurons are Professions, St. John’s University Jamaica, New York Acetyl Methadol (LAAM) unopposed and result in adrenergic overClinical Manager–Internal Medicine activation, which manifests as the con- New York–Presbyterian/Columbia University Methadone, a schedule II controlled substance, has been the most frequently stellation of withdrawal symptoms.4,5 Medical Center, New York, New York 40 U.S. Pharmacist • November 2009 • www.uspharmacist.com OPIOID MAINTENANCE TREATMENT Table 1 Comparison of Opioid Withdrawal Profiles Drug Dose Equivalent to Methadone 1 mg Time for Effects to Wear off Onset of Withdrawal Peak of Withdrawal End of Withdrawal Fentanyl Meperidine Oxycodone Hydromorphone Heroin Morphine Codeine Hydrocodone Methadone 0.01 mg 20 mg 1.5 mg 0.5 mg 1-2 mg 3-4 mg 30 mg 0.5 mg NA 1h 2-3 h 3-6 h 4-5 h 4h 4-5 h 4h 4-8 h 8-12 h 3-5 h 4-6 h 8-12 h 4-5 h 8-12 h 8-12 h 8-12 h 8-12 h 36-72 h 8-12 h 8-12 h 36-72 h 36-72 h 36-72 h 36-72 h 36-72 h 36-72 h 96-144 h 4-5 days 4-5 days ≈7-10 days ≈7-10 days 7-10 days 7-10 days ≈7-10 days ≈7-10 days 14-21 days NA: not applicable. Source: Reference 6. used medication in opioid treatment programs. Access to methadone for the treatment of opioid dependence is available only through DEA-licensed methadone clinics. LAAM is no longer being produced or marketed because of the increased risk of cardiac death. Clinical Pharmacology: Both methadone and LAAM are synthetic mu-opioid receptor agonists, like heroin, and serve to replace heroin or other opioids’ occupation of mu-opioid receptors. Methadone also is an N-methylD-aspartate antagonist. Methadone is a highly fat-soluble drug that is rapidly and extensively absorbed. The oral suspension has variable bioavailability (range 36% to 100%) and reaches its peak effects 1 to 7.5 hours after intake.11 Methadone is a 50:50 racemic mixture. The R-enantiomer has a significantly higher affinity to mu and kappa receptors. Methadone has an average half-life of 24 hours (range 13 to 50 hours). Metabolism of the drug occurs through the CYP450 system—mainly CYP3A4, but also CYP2B6, CYP2C9, CYP2C19, and CYP2D6. Methadone is an inhibitor of CYP2D6.12,13 Dosing: In an opioid-naïve patient beginning methadone maintenance, the first dose should not exceed 40 mg owing to the risk of death from respiratory depression. A common starting dose is 20 mg to 30 mg. The patient usually is monitored for 2 to 4 hours to allow the methadone to peak. After the first day, additional doses of 5 mg to 10 mg may be given if withdrawal symptoms persist. The dose may be slowly titrated over the next couple of weeks to achieve a dose that prevents withdrawal and drug cravings without oversedating or causing other side effects. Most patients can be maintained on a dose of 60 mg to 120 mg, although some patients will need doses outside this range.6 For maintenance, methadone should be dispensed to the patient as a 1-mg/mL solution. Doses of less than 50 mg/day have been associated with increased relapse rates and less retention in programs.14,15 Side Effects: Because methadone acts upon central opioid receptors, its side-effect profile mirrors that of other opioids. These effects include sweating, somnolence, dizziness, mild nausea, anorexia, constipation, and pruritus. The most serious adverse effects are respiratory depression and cardiac arrhythmias. There also have been reports of increased risk of cardiac death. Patients should be counseled regarding possible weight gain, sexual dysfunction, and oligomenorrhea or amenorrhea.10,14 Interactions: There are numerous potential drug interactions with methadone (see TABLE 3). Methadone’s drug interactions occur primarily through inhibition or induction of liver enzymes and changes in protein binding.12,13 No clinically significant protein-binding drug interaction has been reported. Giving methadone with opioid antagonists, mixed agonist/antagonists, and partial agonists (i.e., naloxone, naltrexone, pentazocine, nalbuphine, butorphanol, and buprenorphine) may precipitate withdrawal. Somnolence and respiratory depression may be potentiated if methadone is taken with other opioids. Buprenorphine and Naloxone Some of the drawbacks of methadone treatment are that the drug has increased risks of respiratory depression, death from overdose, QT prolongation, divergence, and difficult withdrawal. Buprenorphine is a partial agonist that carries fewer risks than methadone.16 Naloxone is formulated in combination with buprenorphine to decrease the abuse potential: When taken correctly sublingually, naloxone has no clinical effect because of poor bioavailability; if injected, however, naloxone precipitates withdrawal. Pharmacology: Buprenorphine is a synthetic opioid with partial mu-opioid receptor agonism and kappa-receptor antagonism. It has a higher affinity for mu-opioid receptors; therefore, it displaces morphine, methadone, and other full agonists from the receptor site. This partial 41 U.S. Pharmacist • November 2009 • www.uspharmacist.com KAPIDEX WORKS A SECOND SHIFT TO HELP SHUT DOWN ACID PUMPS KAPIDEX is the first and only PPI with a Dual Delayed Release™ (DDR) formulation, which provides a second release of drug Mean plasma concentration (in healthy subjects; day 5; ng/mL)1 1200 1000 800 600 400 KAPIDEX KA K A 60 mg 200 KAPIDEX 30 mg KA KA 0 0 6 12 18 24 Time (h) • KAPIDEX 30 mg provided full 24-hour heartburn relief in a majority of symptomatic non-erosive gastroesophageal reflux disease patients at week 41 • KAPIDEX 60 mg provided consistently high erosive esophagitis healing rates at week 81 • KAPIDEX offers a safety and tolerability profile similar to lansoprazole1 • KAPIDEX can be taken without regard to food1 KAPIDEX should be swallowed whole. Alternatively, capsules can be opened, sprinkled on 1 tablespoon of applesauce, and swallowed immediately. While KAPIDEX can be taken without regard to food, some patients may benefit from administering the dose prior to a meal if post-meal symptoms do not resolve under post-fed conditions. Conclusions of comparative efficacy cannot be drawn from this information. Indications KAPIDEX is indicated for healing all grades of erosive esophagitis (EE) for up to 8 weeks, maintaining healing of EE for up to 6 months, and treating heartburn associated with symptomatic non-erosive gastroesophageal reflux disease (GERD) for 4 weeks. Important Safety Information KAPIDEX is contraindicated in patients with known hypersensitivity to any component of the formulation. Hypersensitivity and anaphylaxis have been reported with KAPIDEX use. Symptomatic response with KAPIDEX does not preclude the presence of gastric malignancy. Most commonly reported treatment-emergent adverse reactions (≥2%): diarrhea (4.8%), abdominal pain (4.0%), nausea (2.9%), upper respiratory tract infection (1.9%), vomiting (1.6%), and flatulence (1.6%). Do not co-administer atazanavir with KAPIDEX because atazanavir systemic concentrations may be substantially decreased. KAPIDEX may interfere with absorption of drugs for which gastric pH is important for bioavailability (e.g., ampicillin esters, digoxin, iron salts, ketoconazole). Patients taking concomitant warfarin may require monitoring for increases in international normalized ratio (INR) and prothrombin time. Increases in INR and prothrombin time may lead to abnormal bleeding, which can lead to serious consequences. Please see adjacent brief summary of prescribing information for KAPIDEX. BRIEF SUMMARY OF FULL PRESCRIBING INFORMATION KAPIDEX™ (dexlansoprazole) delayed release capsules INDICATIONS AND USAGE KAPIDEX is indicated for: sTHEHEALINGOFALLGRADESOFEROSIVEESOPHAGITIS%%FORUPTOWEEKS sMAINTAININGHEALINGOF%%FORUPTOMONTHSAND sTHETREATMENTOFHEARTBURNASSOCIATEDWITHNONEROSIVEGASTROESOPHAGEAL REmUXDISEASE'%2$FORWEEKS CONTRAINDICATIONS +!0)$%8ISCONTRAINDICATEDINPATIENTSWITHKNOWNHYPERSENSITIVITYTOANY COMPONENTOFTHEFORMULATION(YPERSENSITIVITYANDANAPHYLAXISHAVEBEEN REPORTEDWITH+!0)$%8USE [see Adverse Reactions] WARNINGS AND PRECAUTIONS Gastric Malignancy 3YMPTOMATIC RESPONSE WITH +!0)$%8 DOES NOT PRECLUDE THE PRESENCE OF GASTRICMALIGNANCY ADVERSE REACTIONS Clinical Trials Experience 4HE SAFETY OF +!0)$%8 WAS EVALUATED IN PATIENTS IN CONTROLLED AND UNCONTROLLEDCLINICALSTUDIESINCLUDINGPATIENTSTREATEDFORATLEAST MONTHSANDPATIENTSTREATEDFORONEYEAR0ATIENTSRANGEDINAGEFROM TOYEARSMEDIANAGEYEARSWITHFEMALE#AUCASIAN "LACK !SIAN AND OTHER RACES 3IX RANDOMIZED CONTROLLED CLINICAL TRIALSWERECONDUCTEDFORTHETREATMENTOF%%MAINTENANCEOFHEALED%%AND SYMPTOMATIC'%2$WHICHINCLUDEDPATIENTSONPLACEBOPATIENTS ON+!0)$%8MGPATIENTSON+!0)$%8MGANDPATIENTSON LANSOPRAZOLEMGONCEDAILY DRUGREACTIONASTHENIACHESTPAINCHILLSFEELINGABNORMALINmAMMATION MUCOSALINmAMMATIONNODULEPAINPYREXIAHepatobiliary Disorders:BILIARY COLICCHOLELITHIASISHEPATOMEGALYImmune System Disorders: HYPERSENSI TIVITY Infections and Infestations: CANDIDA INFECTIONS INmUENZA NASOPHAR YNGITIS ORAL HERPES PHARYNGITIS SINUSITIS VIRAL INFECTION VULVOVAGINAL INFECTION Injury, Poisoning and Procedural Complications: FALLS FRACTURES JOINTSPRAINSOVERDOSEPROCEDURALPAINSUNBURNLaboratory Investigations: !,0INCREASED!,4INCREASED!34INCREASEDBILIRUBINDECREASEDINCREASED BLOODCREATININEINCREASEDBLOODGASTRININCREASEDBLOODGLUCOSEINCREASED BLOOD POTASSIUM INCREASED LIVER FUNCTION TEST ABNORMAL PLATELET COUNT DECREASEDTOTALPROTEININCREASEDWEIGHTINCREASEMetabolism and Nutrition Disorders:APPETITECHANGESHYPERCALCEMIAHYPOKALEMIA Musculoskeletal and Connective Tissue Disorders: ARTHRALGIA ARTHRITIS MUSCLE CRAMPS MUSCULOSKELETAL PAIN MYALGIA Nervous System Disorders: ALTERED TASTE CONVULSION DIZZINESS HEADACHES MIGRAINE MEMORY IMPAIRMENT PARES THESIAPSYCHOMOTORHYPERACTIVITYTREMORTRIGEMINALNEURALGIAPsychiatric Disorders: ABNORMALDREAMSANXIETYDEPRESSIONINSOMNIALIBIDOCHANGES Renal and Urinary Disorders: DYSURIA MICTURITION URGENCY Reproductive System and Breast Disorders: DYSMENORRHEA DYSPAREUNIA MENORRHAGIA MENSTRUALDISORDER; Respiratory, Thoracic and Mediastinal Disorders:ASPIRA TION ASTHMA BRONCHITIS COUGH DYSPNOEA HICCUPS HYPERVENTILATION RESPIRATORY TRACT CONGESTION SORE THROAT Skin and Subcutaneous Tissue Disorders: ACNE DERMATITIS ERYTHEMA PRURITIS RASH SKIN LESION URTICARIA Vascular Disorders:DEEPVEINTHROMBOSISHOTmUSHHYPERTENSION !DDITIONALADVERSEREACTIONSTHATWEREREPORTEDINALONGTERMUNCONTROLLED STUDY AND WERE CONSIDERED RELATED TO +!0)$%8 BY THE TREATING PHYSICIAN INCLUDED ANAPHYLAXIS AUDITORY HALLUCINATION "CELL LYMPHOMA CENTRAL OBESITY CHOLECYSTITIS ACUTE DECREASED HEMOGLOBIN DEHYDRATION DIABETES MELLITUSDYSPHONIAEPISTAXISFOLLICULITISGASTROINTESTINALPAINGOUTHERPES !SCLINICALTRIALSARECONDUCTEDUNDERWIDELYVARYINGCONDITIONSADVERSERE ZOSTERHYPERGLYCEMIAHYPERLIPIDEMIAHYPOTHYROIDISMINCREASEDNEUTROPHILS ACTIONRATESOBSERVEDINTHECLINICALTRIALSOFADRUGCANNOTBEDIRECTLYCOM -#(# DECREASE NEUTROPENIA ORAL SOFT TISSUE DISORDER RECTAL TENESMUS PAREDTORATESINTHECLINICALTRIALSOFANOTHERDRUGANDMAYNOTREmECTTHE RESTLESSLEGSSYNDROMESOMNOLENCETHROMBOCYTHEMIATONSILLITIS RATESOBSERVEDINPRACTICE /THER ADVERSE REACTIONS NOT OBSERVED WITH +!0)$%8 BUT OCCURRING WITH -OST#OMMONLY2EPORTED!DVERSE2EACTIONS THERACEMATELANSOPRAZOLECANBEFOUNDINTHELANSOPRAZOLEPACKAGEINSERT 4HE MOST COMMON ADVERSE REACTIONS r THAT OCCURRED AT A HIGHER !$6%23%2%!#4)/.3SECTION INCIDENCEFOR+!0)$%8THANPLACEBOINTHECONTROLLEDSTUDIESAREPRESENTED DRUG INTERACTIONS IN4ABLE Drugs with pH-Dependent Absorption Pharmacokinetics Table 2: Incidence of Treatment-Emergent Adverse +!0)$%8 CAUSES INHIBITION OF GASTRIC ACID SECRETION +!0)$%8 IS LIKELY TO Reactions in Controlled Studies SUBSTANTIALLY DECREASE THE SYSTEMIC CONCENTRATIONS OF THE ()6 PROTEASE Placebo KAPIDEX KAPIDEX KAPIDEX Lansoprazole INHIBITORATAZANAVIRWHICHISDEPENDENTUPONTHEPRESENCEOFGASTRICACIDFOR ABSORPTIONANDMAYRESULTINALOSSOFTHERAPEUTICEFFECTOFATAZANAVIRAND 30 mg 60 mg Total 30 mg THE DEVELOPMENT OF ()6 RESISTANCE 4HEREFORE +!0)$%8 SHOULD NOT BE (N=896) (N=455) (N=2218) (N=2621) (N=1363) Adverse Reaction % % % % % COADMINISTEREDWITHATAZANAVIR $IARRHEA !BDOMINAL0AIN .AUSEA 5PPER2ESPIRATORY Tract Infection 6OMITING &LATULENCE )TISTHEORETICALLYPOSSIBLETHAT+!0)$%8MAYINTERFEREWITHTHEABSORPTIONOF OTHERDRUGSWHEREGASTRICP(ISANIMPORTANTDETERMINANTOFORALBIOAVAILABILITY EGAMPICILLINESTERSDIGOXINIRONSALTSKETOCONAZOLE Warfarin #OADMINISTRATIONOF+!0)$%8MGANDWARFARINMGDIDNOTAFFECTTHE PHARMACOKINETICSOFWARFARINOR).2(OWEVERTHEREHAVEBEENREPORTSOF INCREASED).2ANDPROTHROMBINTIMEINPATIENTSRECEIVING00)SANDWARFARIN CONCOMITANTLY)NCREASESIN).2ANDPROTHROMBINTIMEMAYLEADTOABNORMAL BLEEDING AND EVEN DEATH 0ATIENTS TREATED WITH +!0)$%8 AND WARFARIN CONCOMITANTLY MAY NEED TO BE MONITORED FOR INCREASES IN ).2 AND PROTHROMBINTIME !DVERSE2EACTIONS2ESULTINGIN$ISCONTINUATION )NCONTROLLEDCLINICALSTUDIESTHEMOSTCOMMONADVERSEREACTIONLEADINGTO USE IN SPECIFIC POPULATIONS DISCONTINUATIONFROM+!0)$%8THERAPYWASDIARRHEA Pregnancy /THER!DVERSE2EACTIONS /THER ADVERSE REACTIONS THAT WERE REPORTED IN CONTROLLED STUDIES AT AN Teratogenic Effects 0REGNANCY #ATEGORY " 4HERE ARE NO ADEQUATE AND WELLCONTROLLED STUDIES INCIDENCEOFLESSTHANARELISTEDBELOWBYBODYSYSTEM Blood and Lymphatic System Disorders:ANEMIALYMPHADENOPATHYCardiac WITHDEXLANSOPRAZOLEINPREGNANTWOMEN4HEREWERENOADVERSEFETALEFFECTS Disorders:ANGINAARRHYTHMIABRADYCARDIACHESTPAINEDEMAMYOCARDIAL INANIMALREPRODUCTIONSTUDIESOFDEXLANSOPRAZOLEINRABBITS"ECAUSEANIMAL INFARCTION PALPITATION TACHYCARDIA Ear and Labyrinth Disorders: EAR PAIN REPRODUCTIONSTUDIESARENOTALWAYSPREDICTIVEOFHUMANRESPONSE+!0)$%8 TINNITUSVERTIGOEndocrine Disorders: GOITEREye Disorders:EYEIRRITATION SHOULDBEUSEDDURINGPREGNANCYONLYIFCLEARLYNEEDED EYESWELLINGGastrointestinal Disorders: ABDOMINALDISCOMFORTABDOMINAL !REPRODUCTIONSTUDYCONDUCTEDINRABBITSATORALDEXLANSOPRAZOLEDOSESUP TENDERNESS ABNORMAL FECES ANAL DISCOMFORT "ARRETTS ESOPHAGUS BEZOAR TOMGPERKGPERDAYAPPROXIMATELYFOLDTHEMAXIMUMRECOMMENDED BOWEL SOUNDS ABNORMAL BREATH ODOR COLITIS MICROSCOPIC COLONIC POLYP HUMANDEXLANSOPRAZOLEDOSE;MG=BASEDONBODYSURFACEAREA;"3!= CONSTIPATIONDRYMOUTHDUODENITISDYSPEPSIADYSPHAGIAENTERITISERUC REVEALEDNOEVIDENCEOFHARMTOTHEFETUSDUETODEXLANSOPRAZOLE)NADDITION TATION ESOPHAGITIS GASTRIC POLYP GASTRITIS GASTROENTERITIS GASTROINTESTINAL REPRODUCTION STUDIES PERFORMED IN PREGNANT RATS WITH ORAL LANSOPRAZOLE AT DISORDERS GASTROINTESTINAL HYPERMOTILITY DISORDERS '%2$ ') ULCERS AND DOSESUPTOMGPERKGPERDAYTIMESTHERECOMMENDEDHUMANDOSE PERFORATION HEMATEMESIS HEMATOCHEZIA HEMORRHOIDS IMPAIRED GASTRIC BASEDON"3!ANDINPREGNANTRABBITSATORALLANSOPRAZOLEDOSESUPTOMG EMPTYING IRRITABLE BOWEL SYNDROME MUCUS STOOLS NAUSEA AND VOMITING PERKGPERDAYTIMESTHERECOMMENDEDHUMANDOSEBASEDON"3!REVEALED ORALMUCOSALBLISTERINGPAINFULDEFECATIONPROCTITISPARESTHESIAORALRECTAL NOEVIDENCEOFIMPAIREDFERTILITYORHARMTOTHEFETUSDUETOLANSOPRAZOLE HEMORRHAGEGeneral Disorders and Administration Site Conditions:ADVERSE Nursing Mothers )TISNOTKNOWNWHETHERDEXLANSOPRAZOLEISEXCRETEDINHUMANMILK(OWEVER LANSOPRAZOLEANDITSMETABOLITESAREPRESENTINRATMILKFOLLOWINGTHEADMINIS TRATIONOFLANSOPRAZOLE!SMANYDRUGSAREEXCRETEDINHUMANMILKANDBECAUSE OFTHEPOTENTIALFORTUMORIGENICITYSHOWNFORLANSOPRAZOLEINRATCARCINOGENICITY STUDIES[see Carcinogenesis, Mutagenesis, Impairment of Fertility]ADECISION SHOULD BE MADE WHETHER TO DISCONTINUE NURSING OR TO DISCONTINUE THE DRUG TAKINGINTOACCOUNTTHEIMPORTANCEOFTHEDRUGTOTHEMOTHER WERETREATEDORALLYWITHLANSOPRAZOLEATDOSESOFTOMGPERKGPERDAY ABOUTTOTIMESTHEEXPOSUREONABODYSURFACEMGMBASISOFAKG PERSON OF AVERAGE HEIGHT M "3! GIVEN THE RECOMMENDED HUMAN DOSEOFLANSOPRAZOLEMGPERDAY OVERDOSAGE 4HERE HAVE BEEN NO REPORTS OF SIGNIlCANT OVERDOSE OF +!0)$%8 -ULTIPLE DOSESOF+!0)$%8MGANDASINGLEDOSEOF+!0)$%8MGDIDNOT RESULT IN DEATH OR OTHER SEVERE ADVERSE EVENTS $EXLANSOPRAZOLE IS NOT EXPECTEDTOBEREMOVEDFROMTHECIRCULATIONBYHEMODIALYSIS)FANOVERDOSE OCCURSTREATMENTSHOULDBESYMPTOMATICANDSUPPORTIVE 4HE POTENTIAL EFFECTS OF DEXLANSOPRAZOLE ON FERTILITY AND REPRODUCTIVE PERFORMANCEWEREASSESSEDUSINGLANSOPRAZOLESTUDIES,ANSOPRAZOLEATORAL DOSESUPTOMGPERKGPERDAYTIMESTHERECOMMENDEDLANSOPRAZOLE HUMAN DOSE BASED ON "3! WAS FOUND TO HAVE NO EFFECT ON FERTILITY AND REPRODUCTIVEPERFORMANCEOFMALEANDFEMALERATS PATIENT COUNSELING INFORMATION CLINICAL PHARMACOLOGY [see FDA-Approved Patient Labeling in the full prescribing information] Pharmacodynamics !NTISECRETORY!CTIVITY 4HEEFFECTSOF+!0)$%8MGNORLANSOPRAZOLEMGNONCE DAILY FOR lVE DAYS ON HOUR INTRAGASTRIC P( WERE ASSESSED IN HEALTHY SUBJECTSINAMULTIPLEDOSECROSSOVERSTUDY Information for Patients 4O ENSURE THE SAFE AND EFFECTIVE USE OF +!0)$%8 THIS INFORMATION AND INSTRUCTIONS PROVIDED IN THE &$!APPROVED PATIENT LABELING SHOULD BE DISCUSSEDWITHTHEPATIENT)NFORMPATIENTSOFTHEFOLLOWING ,ANSOPRAZOLE PRODUCED DOSERELATED GASTRIC %#, CELL HYPERPLASIA AND %#, CELLCARCINOIDSINBOTHMALEANDFEMALERATS[see Clinical Pharmacology]. )NRATSLANSOPRAZOLEALSOINCREASEDTHEINCIDENCEOFINTESTINALMETAPLASIAOF THEGASTRICEPITHELIUMINBOTHSEXES)NMALERATSLANSOPRAZOLEPRODUCEDA Pediatric Use 3AFETYANDEFFECTIVENESSOF+!0)$%8INPEDIATRICPATIENTSLESSTHANYEARS DOSERELATEDINCREASEOFTESTICULARINTERSTITIALCELLADENOMAS4HEINCIDENCEOF THESEADENOMASINRATSRECEIVINGDOSESOFTOMGPERKGPERDAYTO OFAGEHAVENOTBEENESTABLISHED TIMES THE RECOMMENDED LANSOPRAZOLE HUMAN DOSE BASED ON "3! Geriatric Use EXCEEDEDTHELOWBACKGROUNDINCIDENCERANGETOFORTHISSTRAIN )NCLINICALSTUDIESOF+!0)$%8OFPATIENTSWEREAGEDYEARSANDOVER OFRAT4ESTICULARINTERSTITIALCELLADENOMAALSOOCCURREDINOFRATSTREATED .O OVERALL DIFFERENCES IN SAFETY OR EFFECTIVENESS WERE OBSERVED BETWEEN THESEPATIENTSANDYOUNGERPATIENTSANDOTHERREPORTEDCLINICALEXPERIENCE WITHMGLANSOPRAZOLEPERKGPERDAYTIMESTHERECOMMENDEDLANSO HASNOTIDENTIlEDSIGNIlCANTDIFFERENCESINRESPONSESBETWEENGERIATRICAND PRAZOLEHUMANDOSEBASEDON"3!INAYEARTOXICITYSTUDY YOUNGERPATIENTSBUTGREATERSENSITIVITYOFSOMEOLDERINDIVIDUALSCANNOTBE )N A MONTH CARCINOGENICITY STUDY #$ MICE WERE TREATED ORALLY WITH RULEDOUT] LANSOPRAZOLEDOSESOFMGTOMGPERKGPERDAYTOTIMESTHE RECOMMENDEDHUMANDOSEBASEDON"3!,ANSOPRAZOLEPRODUCEDADOSE Renal Impairment .O DOSAGE ADJUSTMENT OF +!0)$%8 IS NECESSARY IN PATIENTS WITH RENAL RELATEDINCREASEDINCIDENCEOFGASTRIC%#,CELLHYPERPLASIA)TALSOPRODUCED IMPAIRMENT4HEPHARMACOKINETICSOFDEXLANSOPRAZOLEINPATIENTSWITHRENAL AN INCREASED INCIDENCE OF LIVER TUMORS HEPATOCELLULAR ADENOMA PLUS IMPAIRMENTARENOTEXPECTEDTOBEALTEREDSINCEDEXLANSOPRAZOLEISEXTENSIVELY CARCINOMA 4HE TUMOR INCIDENCES IN MALE MICE TREATED WITH MG AND METABOLIZED IN THE LIVER TO INACTIVE METABOLITES AND NO PARENT DRUG IS MG LANSOPRAZOLE PER KG PER DAY TO TIMES THE RECOMMENDED RECOVEREDINTHEURINEFOLLOWINGANORALDOSEOFDEXLANSOPRAZOLE. LANSOPRAZOLE HUMAN DOSE BASED ON "3! AND FEMALE MICE TREATED WITH MG TO MG LANSOPRAZOLE PER KG PER DAY TO TIMES THE Hepatic Impairment .ODOSAGEADJUSTMENTFOR+!0)$%8ISNECESSARYFORPATIENTSWITHMILDHEPATIC RECOMMENDED HUMAN DOSE BASED ON "3! EXCEEDED THE RANGES OF BACK IMPAIRMENT#HILD0UGH#LASS!+!0)$%8MGSHOULDBECONSIDEREDFOR GROUNDINCIDENCESINHISTORICALCONTROLSFORTHISSTRAINOFMICE,ANSOPRAZOLE PATIENTSWITHMODERATEHEPATICIMPAIRMENT#HILD0UGH#LASS".OSTUDIES TREATMENT PRODUCED ADENOMA OF RETE TESTIS IN MALE MICE RECEIVING TO HAVEBEENCONDUCTEDINPATIENTSWITHSEVEREHEPATICIMPAIRMENT#HILD0UGH MG PER KG PER DAY TO TIMES THE RECOMMENDED LANSOPRAZOLE HUMANDOSEBASEDON"3! #LASS#. 3ERUM'ASTRIN%FFECTS 4HE EFFECT OF +!0)$%8 ON SERUM GASTRIN CONCENTRATIONS WAS EVALUATED IN APPROXIMATELYPATIENTSINCLINICALTRIALSUPTOWEEKSANDINPATIENTS FORUPTOTOMONTHS4HEMEANFASTINGGASTRINCONCENTRATIONSINCREASED FROMBASELINEDURINGTREATMENTWITH+!0)$%8MGANDMGDOSES)N PATIENTSTREATEDFORMORETHANMONTHSMEANSERUMGASTRINLEVELSINCREASED DURINGAPPROXIMATELYTHElRSTMONTHSOFTREATMENTANDWERESTABLEFORTHE REMAINDEROFTREATMENT-EANSERUMGASTRINLEVELSRETURNEDTOPRETREATMENT LEVELSWITHINONEMONTHOFDISCONTINUATIONOFTREATMENT +!0)$%8ISAVAILABLEASADELAYEDRELEASECAPSULE +!0)$%8MAYBETAKENWITHOUTREGARDTOFOOD +!0)$%8SHOULDBESWALLOWEDWHOLE s!LTERNATIVELY+!0)$%8CAPSULESCANBEOPENEDANDADMINISTEREDASFOLLOWS n/PENCAPSULE n3PRINKLEINTACTGRANULESONONETABLESPOONOFAPPLESAUCE n3WALLOWIMMEDIATELY $ISTRIBUTEDBY %NTEROCHROMAFlN,IKE#ELL%#,%FFECTS Takeda Pharmaceuticals America, Inc. 4HEREWERENOREPORTSOF%#,CELLHYPERPLASIAINGASTRICBIOPSYSPECIMENS $EERlELD), OBTAINEDFROMPATIENTSTREATEDWITH+!0)$%8MGMGORMGFOR 530ATENT.OS UPTOMONTHS AND $URINGLIFETIMEEXPOSUREOFRATSDOSEDDAILYWITHUPTOMGPERKGPERDAY OF LANSOPRAZOLE MARKED HYPERGASTRINEMIA WAS OBSERVED FOLLOWED BY %#, +!0)$%8ISATRADEMARKOF4AKEDA0HARMACEUTICALS.ORTH!MERICA)NCAND CELLPROLIFERATIONANDFORMATIONOFCARCINOIDTUMORSESPECIALLYINFEMALERATS USEDUNDERLICENSEBY4AKEDA0HARMACEUTICALS!MERICA)NC !LLOTHERTRADEMARKNAMESARETHEPROPERTYOFTHEIRRESPECTIVEOWNERS [see Nonclinical Toxicology ] Ú4AKEDA0HARMACEUTICALS!MERICA)NC %FFECTON#ARDIAC2EPOLARIZATION !STUDYWASCONDUCTEDTOASSESSTHEPOTENTIALOF+!0)$%8TOPROLONGTHE &OR MORE DETAILED INFORMATION SEE THE FULL PRESCRIBING INFORMATION FOR 1414cINTERVALINHEALTHYADULTSUBJECTS+!0)$%8DOSESOFMGORMG +!0)$%8 0) 2 *ANUARY OR CONTACT 4AKEDA 0HARMACEUTICALS DIDNOTDELAYCARDIACREPOLARIZATIONCOMPAREDTOPLACEBO4HEPOSITIVECONTROL !MERICA)NCAT MOXImOXACINPRODUCEDSTATISTICALLYSIGNIlCANTLYGREATERMEANMAXIMUMAND 0)2"RF*ANUARY TIMEAVERAGED1414 INTERVALSCOMPAREDTOPLACEBO c NONCLINICAL TOXICOLOGY ,,0$ Carcinogenesis, Mutagenesis, Impairment of Fertility 4HECARCINOGENICPOTENTIALOFDEXLANSOPRAZOLEWASASSESSEDUSINGLANSOPRA ZOLESTUDIES)NTWOMONTHCARCINOGENICITYSTUDIES3PRAGUE$AWLEYRATS KAPIDEX™ and Dual Delayed Release™ are trademarks of Takeda Pharmaceuticals North America, Inc., and are used under license by Takeda Pharmaceuticals America, Inc. Reference: 1. KAPIDEX (dexlansoprazole) package insert, Takeda Pharmaceuticals America, Inc. ©2009 Takeda Pharmaceuticals North America, Inc. LPD-00250 6/09 Printed in U.S.A. OPIOID MAINTENANCE TREATMENT Table 2 Characteristics of Options for Maintenance Treatment Buprenorphine and Buprenorphine/Naloxone Methadone Pharmacologic Action Buprenorphine: partial agonist Naloxone: full antagonist Full agonist Route of Administration Sublingual Oral Dosing Buprenorphine: 2-32 mg; naloxone: 0.5-8 mg; combination: 4:1 ratio 20-30 mg initially, then 60-120 mg Administration Daily to 3 times/wk Daily Common Side Effects Headache, nausea, sweating, rhinitis, constipation Cardiac dysrhythmia, hypotension, diaphoresis, constipation, nausea, vomiting, dizziness, sedation Contraindications Need for ongoing opioid agonists for pain relief, hypersensitivity Hypersensitivity Pregnancy Concerns Category C; combination not recommended in pregnancy—replace with methadone or buprenorphine Category C; current standard of care in pregnancy Accessibility Physician’s office or opioid treatment program Opioid treatment program Regulatory Concerns Physician may prescribe only with DEA-issued registration certificate code; 30-patient census/prescriber, then 100patient census after 1st y; pharmacy may dispense up to 30-day supply based on schedule III Physician may prescribe only to opioiddependent patients for up to 72 h as bridge to treatment entry; only licensed opioid treatment programs may dispense; federal regulations govern dispensing frequency (e.g., daily, 3 times/wk, wkly) Insurance Coverage Specific to type of insurance Specific to type of insurance DEA: Drug Enforcement Administration. Source: Reference 25. agonism allows buprenorphine to have a ceiling effect on the opioid effects at higher doses, making it safer in the event of overdose. Naloxone is a mu-opioid receptor antagonist with poor oral bioavailability owing to limited absorption and extensive first-pass metabolism. It has a rapid onset of action when given intravenously. Because it has a higher affinity for mu-opioid receptors than heroin, morphine, or methadone, naloxone displaces these drugs from receptors and blocks their effects.17 Buprenorphine/naloxone (Suboxone) is available as a 4:1 fixed combination. Subutex (buprenorphine), a white tablet, is available in 2-mg and 8-mg strengths; Suboxone is an orange tablet and is available in 2/0.5mg and 8/2-mg formulations. Buprenorphine is rapidly absorbed sublingually, and peak effects are reached 90 minutes after administration. Naloxone does not affect the pharmacokinetics of buprenorphine. The mean half-life of buprenorphine is 37 hours; that of naloxone is 1.1 hours.18 Dosing: Because buprenorphine displaces the other opioid from mu-receptor sites and induces withdrawal, it should be initiated only when the patient already has evident signs of withdrawal; otherwise, the patient might associate the buprenorphine with withdrawal, thereby reducing adherence. The buprenorphine/naloxone combination is the drug of choice for initiating therapy in both U.S. and European guidelines. Buprenorphine may be started alone at doses of 4 mg to 8 mg or in combination in a 4:1 ratio to naloxone. A second dose of 4 mg may be given in 2 to 4 hours, and the patient may be given an additional dose of 2 mg to 4 mg to take home in case of withdrawal within the next 24 hours. The physician should monitor for buprenorphine-precipitated withdrawal while the patient is in the office. This is not to be confused with withdrawal from underdosing of buprenorphine, which usually occurs in the second half of the 24-hour dosing interval.16 The maintenance dose may be achieved by doubling the dose each day, to a maximum of 24 mg to 32 mg. If withdrawal symptoms arise at any time during the 24-hour dosing interval, the dose is too low and needs to be increased. If induction occurs too slowly, the patient may prematurely terminate treatment. Therefore, it is important for the practitioner to be diligent in monitoring the patient. When converting to or from the naltrexone combination, a 1:1 ratio of the buprenorphine dose may be used.16 When the maintenance dose is achieved, buprenor- 46 U.S. Pharmacist • November 2009 • www.uspharmacist.com OPIOID MAINTENANCE TREATMENT Table 3 Potential Drug Interactions for Methadone and Buprenorphine Interaction Methadone Buprenorphine Increase Effects of Opioid Substitute Alcohol Antidepressants • Fluoxetine • Fluvoxamine • Paroxetine • Sertraline Anti-infectives • Ciprofloxacin • Erythromycin • Fluconazole • Ketoconazole Benzodiazepines Cimetidine Alcohol Antiretrovirals • Atazanavir • Indinavir • Nevirapine • Ritonavir • Saquinavir Benzodiazepines Fluvoxamine Ketoconazole Interactions: Buprenorphine goes through hepatic metabolism via CYP3A4. The drug has the potential for many of the same interactions as methadone (see TABLE 3). One dangerous interaction to monitor for is the potentially fatal interaction with benzodiazepines.19 Concomitant administration should be avoided. Compared with methadone, buprenorphine may be a safer choice in patients receiving antiretrovirals.20 CLINICAL EFFICACY OF METHADONE VERSUS BUPRENORPHINE It is well established that both methadone and buprenorphine are effective for decreasing illicit drug use. It is worthwhile to consider the results of studies examining the efficacy of methadone versus buprenorphine.7 The 2008 Cochrane review determined that Decrease Effects Anti-infectives Carbamazepine methadone dosed at 60 mg/day to 120 mg/day of Opioid Substitute • Fusidic acid Phenobarbital has superior efficacy compared with buprenor• Rifampin Phenytoin Antiretrovirals Rifampin phine.21 The specific studies yield varied results. • Abacavir One study found less illicit heroin use with • Amprenavir buprenorphine than with methadone, but the • Efavirenz methadone arm had higher retention rates. 22 • Nevirapine Another study concluded that high-dose methadone • Ritonavir • Saquinavir had a higher retention rate and less illicit opioid Barbiturates use compared with buprenorphine 8 mg.23 A douCarbamazepine ble-blind, randomized trial comparing an averPhenytoin age dose of buprenorphine (10 mg/day) versus Source: References 12, 16. methadone (70 mg/day) showed a higher retention rate with methadone, but found that the phine may be administered from every other day to 3 drugs had equal efficacy in reducing illicit heroin use.24 times weekly (e.g., Monday, Wednesday, and Friday) in However, a study from 1992 concluded that buprenororder to increase compliance and patient satisfaction. phine had better retention rates than methadone at 25 Every-4-day regimens have been associated with increased weeks.26 Overall, it is accepted that buprenorphine and withdrawal symptoms. The daily dose may be doubled methadone have comparable efficacy and that treatment for every-other-day dosing and also for thrice-weekly dos- should be individualized. ing, but Friday’s dose would be 2.5 times the daily dose.16 New patients should be advised that sublingual tablets CONCLUSION must be dissolved under the tongue, as the medication Because of DATA 2000 and ongoing research on opiis much less effective if swallowed.18 No more than two oid dependence, pharmacists must be prepared to face tablets should be taken at one time, to avoid swallow- an increase in the number of prescriptions being writing them by mistake. Wetting the mouth before placing ten for opioid maintenance treatment. When presented the tablets under the tongue may help them dissolve with a new prescription, a pharmacist may visit the site faster. Full absorption may take up to 10 minutes. Patients www.buprenorphine.samhsa.gov to confirm physician should refrain from smoking for 10 to 15 minutes before eligibility. Pharmacists must monitor and counsel patients taking the medication, as this seems to help the tablets about withdrawal symptoms and overdose possibilities. dissolve faster.18 Because buprenorphine is a partial agonist, the risk of overdose is smaller, and its use in combination with naloxSide Effects: Buprenorphine/naloxone is generally well one further reduces the risk of intravenous abuse. Histolerated. Side effects are associated mainly with buprenor- torically, daily visits to methadone clinics have been the phine, since naloxone is not readily absorbed. In clinical most frequently utilized method of treating opioid depentrials, the most common adverse effects were headache, dence, but with the current availability of sublingual withdrawal syndrome, pain, nausea, insomnia, sweating, buprenorphine products, more patients will be able to rhinitis, constipation, abdominal pain, flulike syndrome, receive treatment in a convenient office-based setting. and flushing.17 References available online at www.uspharmacist.com. 53 U.S. Pharmacist • November 2009 • www.uspharmacist.com Generic Trends Generics Will Have Modest Negative Impact on Hypertension Drug Market Sales Through 2018 Despite the generic erosion of many hypertension drug products expected over the next decade, it is estimated that the overall hypertension drug market will experience only a modest decline. According to Decision Resources, a research and advisory firm for pharmaceutical and health care issues, the market will decrease 1.4% annually through 2013, and thereafter the annual decline will slow to 1% through 2018 in the United States, France, Germany, Italy, Spain, the United Kingdom, and Japan. According to a company report, a major contributor to the market decline will be an increase in the generic availability of antihypertensive agents. For example, by 2018, Novartis’s Diovan alone will lose more than $1 billion in sales beginning next year when the drug goes off patent. Other hypertension drug classes will suffer as well, including angiotensin-converting enzyme inhibitors (ACE inhibitors), angiotensin II receptor antagonists, Hatch-Waxman Act Turns 25 Twenty-five years ago a bill introduced by Senator Orrin Hatch and Rep. Henry Waxman that would change the generic industry forever was signed into law at a White House Rose Garden ceremony. While not perfect, the Hatch-Waxman Act continues to receive accolades from industry observers and government officials. “Our industry is proud of how far it has come in the past 25 years,” said Kathleen Jaeger, president and CEO of the Generic Pharmaceutical Association, commenting on the law. “Today, generic medicines represent 72% of the total prescriptions dispensed in the U.S., but only 17% of all dollars spent on prescription drugs. One billion dollars is saved every three days by using generics. That’s extraordinary savings—far more than anyone predicted or could have even imagined 25 years ago.” Health and Human Services Secretary Kathleen Sebelius also offered kudos, particularly in the context of health care reform proposals currently in front of Congress. “I think that it’s appropriate this year that as we look at what’s pending in Congress on health reform that we are also celebrating the quarter century anniversary of the Hatch-Waxman Act, which really began to transform the pharmaceutical industry and made generic drugs much more widely available to Americans.” And from the bill’s authors comes admission that they didn’t always see eye-to-eye from across the aisle, but were able to still produce a bipartisan piece of legislation that has withstood many challenges over its relatively short 25-year history. “Henry and I put our differences aside to work in a bipartisan manner to get the bill passed,” admits Senator Hatch. “In the end, we passed a bill that has not only worked well, but has saved consumers, state, and federal governments billions of dollars.” “When Senator Hatch and I developed the legislation 25 years ago to produce generic drugs, we thought that the result of this law would save perhaps a billion dollars…in reality generic drugs have saved consumer and businesses, and state and federal governments $734 billion,” said Representative Waxman. calcium channel blockers, and diuretics. Mylan Settles With Pfizer Over Vfend Generic Mylan Pharmaceuticals and Matrix Laboratories have entered into a settlement and license agreement with Pfizer Inc. relating to voricona- zole tablets, 50 mg and 200 mg, the generic version of Pfizer’s Vfend Tablets, a triazole antifungal agent. Mylan’s Matrix was the first company to submit a substantially complete Abbreviated New Drug Application containing a Paragraph IV certification to the 54 U.S. Pharmacist • November 2009 • www.uspharmacist.com FDA and therefore believes it will be eligible for 180 days of marketing exclusivity upon commercial marketing of the product. Pursuant to the agreement, Mylan will have the right to market voriconazole tablets in the U.S. in the first quarter of 2011. Providing Affordable and Innovative Medicine for Healthier Lives Affordable Medicines High-quality, low cost generic ANDA alternatives Innovative Medicines _ First Indian company to fully develop an in-house biosimilar – NCEs for unmet medical needs – OTCs for a more complete selection Planning Our Future to Meet Your Future – Robust generic pipeline – Supply chain excellence – 41 Rx generic product families available – Rx-to-OTC switches – Vertically integrated – Customer focused Global Presence...Local Focus Dr. Reddy’s Laboratories, Inc. 3600 Arco Corporate Drive, Charlotte, NC 28273-7104 (866) 733-3952 www.DRREDDYS.com DRCO / 09/09 R Generic Trends “Free Generic Fill” Provision in Health Care Reform Legislation Applauded by GPhA “GPhA applauds the Senate Finance Committee for approving the ‘Free Generic Fill’ provision [in health care reform legislation], which would save patients and the federal government more than $6 billion over 10 years,” commented Kathleen Jaeger, president and CEO of the Generic Pharmaceutical Association (GPhA). The “free generic fill” provision creates an exception that would allow health plan sponsors to encourage beneficiaries to utilize generic drugs by allowing them to waive copays as an incentive to try a generic drug. “Clearly, Congress has recognized that expanding access to generic medicines is the key to lowering health care costs...,” said Jaeger. Innovative Pharmacy Benefit Plan Design Can Optimize Generic Utilization Data from research con- ducted by CVS Caremark and presented at the Academy of Managed Care Pharmacy (AMCP) Annual Educational Conference showed that innovative pharmacy benefit plan design can impact generic utilization. Specifically, the study found that implementing a $0 copay structure for generic medications can be an effective strategy to increase generic dispensing, with the generic dispensing rate increasing to 60.8% (which represents a 4.2% increase). “The data presented at AMCP illustrate an example of how we can work with our plan sponsors to change and optimize participant behavior in order to achieve increased generic utilization,” said Jack Bruner, executive vice president, CVS Caremark. Some other data uncovered by the study showed that the average participant cost share for generic medications decreased almost 10% and the average plan cost per 30 days of therapy also exhibited a slight decline, despite the reduction in generic copayment rates. Call for Papers U.S. Pharmacist is seeking authors to write clinical articles and continuing education lessons on a variety of topics. While we will entertain all subject matter, we are particularly interested in articles that correspond to our “Editorial Focus” therapeutic areas. The therapeutic categories and the months for which they are planned are listed below: Cardiovascular Diseases – February Endocrinology – June Gastroenterologic Diseases – December Infectious Diseases – August Neurologic Diseases – January New Drugs – October Ophthalmology – April Pain Management – May Pediatric and Adolescent Health – March Psychotropics – November Respiratory Diseases – July Women’s Health – September In addition to these topics, we also publish supplements each year covering oncology and hematology, diabetes, the generic drug industry, and OTC drugs. In the majority of cases, articles are peer-reviewed and an honorarium is offered based on their complexity and length. As a general guideline, we would like the articles to be approximately 2,500 –2,800 words, including references and tables. Continuing education lessons should be approximately 6,000 words, including references, tables, and exam. Prospective authors are urged to review the “Author Guidelines” on the U.S. Pharmacist Web site at www.uspharmacist.com. Interested authors should contact Rob Davidson, Executive Editor ([email protected]), with the topic(s) they would like to cover. All articles must be original and exclusive to U.S. Pharmacist. GREENSTONE LLC Watch Our Product Line Recently Introduced ANDA Products GREENL LSCTONE ou ne Offers Y o t s n e e r G What ess model in s u b e iv s s re g New and pro lier ndustry supp -i c ri e n e g g Leadin orate integrity rp o c d n a y tr s Indu in expertise a h -c ly p p u s Dedicated in every dose ty li a u q to d Committe ther suppliers o n e h w — ort Market supp can’t supply folio product port g in w ro g ly Rapid ucts d ANDA prod n a s c ri e n e g Authorized pricing Competitive ommitment c g in is m ro mp AND…Unco to service • Amoxicillin Tablets • Bisoprolol Fumarate Tablets • Cefadroxil Capsules • Cefdinir Capsules • Cefprozil Tablets • Cefuroxime Axetil Tablets • Lamotrigine Tablets • Levetiracetam Tablets • Ondansetron HCl Tablets • Topiramate Tablets Authorized Generic Products • Alprazolam Tablets • Alprazolam XR Tablets • Amlodipine Besylate Tablets • Azithromycin: Tablets & Powder for Oral Suspension • Clindamycin HCl Capsules • Colestipol HCl Micronized Tablets • Eplerenone Tablets • Fluconazole: Tablets & Powder for Oral Suspension • Gabapentin: Capsules & Tablets • Glipizide XL Tablets • Sulfasalazine DR Tablets • Sulfasalazine Tablets • Triazolam Tablets ... and More GREENSTONE LLC 800-447-3360 www.GreenstoneLLC.com GST00073 © GREENSTONE LLC 2009 GSP I04 Contemporary Compounding Ketamine Hydrochloride 10-mg Troches In lozenge form, this analgesic and anesthetic agent can be prepared to suit the patient’s individual flavor preference. G FORMULA Ketamine Hydrochloride 10-mg Troches Rx (for 100 troches): Ingredient Ketamine hydrochloride Silica gel Stevia Acacia Citric acid Flavor Polyethylene glycol 1450 Method of Preparation: Calibrate the mold being used to determine the amount of polyethylene glycol (PEG) 1450 needed. Calculate the quantity of each ingredient for the amount to be prepared. Accurately weigh or measure each ingredient. Melt the PEG 1450 at 50°-55°C. Blend the powders (ketamine hydrochloride [HCl], silica gel, stevia, acacia, citric acid) and slowly sprinkle into melted base while mixing; mix until uniform. Remove from heat, add flavor (which can be based on the patient’s preference), and mix well. Pour into molds and let mixture cool. Trim (if necessary), package, and label. Loyd V. Allen, Jr, PhD Professor Emeritus, College of Pharmacy, University of Oklahoma, Oklahoma City 1g 1g 750 mg 1.65 g 1.2 g qs qs Use: Ketamine HCl troches have been used to treat moderate-tosevere pain. Packaging: Package in well-sealed, light-resistant containers. Labeling: Keep out of the reach of children. Use only as directed. Stability: A beyond-use date of up to 6 months may be used for this preparation.1 Quality Control: Quality-control assessment can include weight, specific gravity, active drug assay, color, texture–surface, appearance, feel, melting test, dissolution test, physical observation, and physical stability.2 Discussion: Ketamine HCl (C13H16ClNO.HCl, MW 274.2), an analgesic and anesthetic, occurs as a white, crystalline powder with a slight characteristic odor. ≈1.15 mg is equivalent to 1 mg ketamine base. It is soluble 1 g in 4 mL water, 14 mL alcohol, and 60 mL absolute alcohol.1,3 Silica gel is obtained by insolubilizing the dissolved silica in sodium silicate solution. It occurs as a fine, white, hygroscopic, odorless, amorphous powder with a usual particle size of 2-10 mu. It is insoluble in alcohol, other organic solvents, and water, and soluble in hot solutions of alkali hydroxides. It is used as a desiccant, suspending agent, and viscosity-increasing agent.4 Stevia (honey leaf, yerba dulce) is a natural sweetening agent extracted from the Stevia rebaudiana Bertoni plant. Nontoxic and safe, it occurs as a white, crystalline, hygroscopic powder. It can be used in hot and cold preparations.5 Acacia (gum acacia, gum arabic) is the dried gummy exudate obtained from some species of the acacia tree. It is a complex aggregate of sugars and 58 U.S. Pharmacist • November 2009 • www.uspharmacist.com hemicelluloses, with MW from 240,000 to 580,000. It is used as an emulsifying agent (5%-10% concentration[conc]), pastille base (10%-30% conc), suspending agent (5%10% conc), and tablet binder (1%-5% conc), as well as in cosmetics and food products. It should be preserved when in aqueous solution, as it is subject to bacterial or enzymatic degradation. Boiling its solution briefly will inactivate any enzymes and enhance its stability. Some substances that are incompatible with acacia are cresol, ethanol (95%), morphine, phenol, and thymol. Some salts reduce the viscosity of aqueous acacia solutions. Since acacia is negatively charged in solution, it will form a coacervate with positively charged molecules such as those in gelatin. Acacia may coagulate in the presence of trivalent salts.6 Citric acid (citric acid monohydrate, C6H8O7.H2O) occurs as colorless or translucent crystals or as a white, crystalline, efflorescent, odorless powder with a strong, tart, acidic taste. It is present at about the 5%-8% Contemporary Compounding level in lemon juice. In 0.3%-2% concentration, it is used to improve flavor in liquid formulations and as a sequestering agent. It may be used to prepare effervescent granules and solid and semisolid (chewable) dosage forms. The hydrated form may contain up to 8.8% water, and the pH of a 1% w/v aqueous solution is ≈2.2. Its density is REFERENCES 1. USP Pharmacists’ Pharmacopeia. 2nd ed. Rockville MD: US Pharmacopeial Convention, Inc; 2008:217,775-779,1444. 2. Allen LV Jr. Standard operating procedure for performing physical quality assessment of suppositories, troches, lollipops and sticks. IJPC. 1999;3:56-57. 1.542 g/mL. The hydrated form will effloresce and the anhydrous form will be hygroscopic, depending upon the humidity. If stored in air that is too dry, it may lose its water if the temperature reaches ≈40°C. Its melting point is ≈100°C, but it softens at ≈75°C. One g is soluble in <1 mL water and 1.5 mL ethanol. It is incompatible with potassium tartrate, alkali and alkaline earth carbonates, bicarbonates, acetates, and sulfides. If included in a syrup formulation, it may induce sucrose to crystallize.7 PEG 1450 (Carbowax, polyoxyethylene glycol) is an addition polymer of ethylene oxide and water. At room temperature, it occurs as a solid or as white or off-white waxy 3. Sweetman SC, ed. Martindale: The Complete Drug Reference. 33rd ed. London, England: Pharmaceutical Press (PP); 2002:1262-1263. 4. Owen SC. Colloidal silicon dioxide. In: Rowe RC, Sheskey PJ, Owen SC, eds. Handbook of Pharmaceutical Excipients. 5th ed. Washington, DC: American Pharma- ceutical Association (APA); 2006:188-191. 5. Reynolds JEF, ed. Martindale: The Extra Pharmacopoeia. 30th ed. London, England: PP; 1993:1049. 6. Kibbe AH. Acacia. In: Rowe RC, Sheskey PJ, Owen SC, eds. Handbook of Pharmaceutical Excipients. 5th ed. Washington, DC: APA; 2006:1-3. flakes or powder. Its density ranges from 1.151.21 g/mL; its melting point is 40°-48°C. It is soluble in water; miscible in all ratios with other PEGs; soluble in acetone, dichloromethane, ethanol, and methanol; and slightly soluble in aliphatic hydrocarbons and ether. It is insoluble in fats, fixed oils, and mineral oil.8 7. Amidon GE. Citric acid. In: Rowe RC, Sheskey PJ, Owen SC, eds. Handbook of Pharmaceutical Excipients. 5th ed. Washington, DC: APA; 2006:185-187. 8. Price JC. Polyethylene glycol. In: Rowe RC, Sheskey PJ, Owen SC, eds. Handbook of Pharmaceutical Excipients. 5th ed. Washington, DC: APA; 2006:545-550. Pharmacologic Management of Alcohol Dependence © JUPITERIMAGES A lcohol dependence is a serious health concern that is associated with many long-term consequences. Alcohol dependence not only affects an individual’s physical health, but also may impact mental health and social well-being. Alcohol use is common in the American population. According to the 2008 National Survey on Drug Use and Health, more than 50% of Americans aged 12 and older reported drinking, 23% reported binge drinking, and 6.9% were heavy alcohol drinkers.1 The prevalence rate of alcohol abuse or dependence in the United States is estimated at 5% to 14%.1-3 Alcohol dependence is a chronic disorder that may require maintenance treatment, similar to other medical conditions such as hyperlipidemia and diabetes.4 It is believed that multiple neurotransmitters such as endogenous opioids, dopamine, serotonin, gammaaminobutyric acid (GABA), and glutamate may be either directly or indirectly affected by alcohol.4 Risk factors such as genetics, environmental factors, and cultural attitudes may play a significant role in the development of alcohol dependence.2 The intent of this article is to review the pharmacologic management of alcohol dependence; therefore alcohol withdrawal, although a crucial part of treatment, will not be discussed. Pharmacologic Therapy The ultimate goals for patients with alcohol dependence are to achieve abstinence and prevent relapse. Currently, the four pharmacologic agents that may aid in accomplishing these goals are disulfiram, oral naltrexone, injectable extended-release naltrexone, and acamprosate. sion, arrhythmia, convulsions, respiratory depression, and myocardial infarction.4-6 The effects of this drug are sufficiently unpleasant to the patient to serve as a deterrent to consuming alcohol. Disulfiram in the absence of alcohol tends to cause minimal effects; however, drowsiness, metallic aftertaste, and hepatotoxicity may occur.5 Severe cardiovascular disease and concurrent use of metronidazole are two major contraindications associated with disulfiram.5 It is important not to administer disulfiram until the patient has abstained from alcohol for at least 12 hours. Furthermore, since disulfiram irreversibly inhibits ALDH, alcohol consumption must be avoided for 2 weeks after the last dose.5 There is a substantial amount of literature regarding the use of disulfiram for alcohol dependence, but many of these trials have significant methodologic weaknesses.6,7 Some of the data are inconsistent and may be conflicting.4,6 A Veterans Administration Cooperative Study assessed 605 subjects assigned to disulfiram 250 mg, disulfiram 1 mg, or placebo. 8 This study, conducted over 1 year, concluded that there were no significant between-group differences in abstinence rates or time to first drink. The study did find, however, that patients receiving disulfiram 250 mg who ended up drinking reported fewer drinking days compared with the other two groups.8 Disulfiram is still utilized despite the conflicting data. Disulfiram’s unique mechanism of action may be a powerful advantage for patients. Disulfiram may help with drinking outcomes such as reduced drinking days or frequency; however, other outcomes, such as time to first drink, abstinence, and alcohol consumption per unit of time, lack consistent evidence. 4,6 Although not appropriate for all patients, disulfiram has a place in therapy for individuals seeking help with cessation of heavy drinking. Disulfiram: Disulfiram is an aversion-based treatment that acts by blocking aldehyde dehyKrina H. Patel, PharmD drogenase (ALDH). This results in Assistant Professor an increase in acetaldehyde levels Pharmacy Practice when alcohol is consumed and induces Nesbitt College of Pharmacy and Nursing negative effects such as dizziness, Wilkes University flushing, nausea, vomiting, hypotenWilkes Barre, Pennsylvania Naltrexone: Naltrexone is a competitive opioid receptor antagonist. Endogenous opioids are released in response to alcohol intake, thereby 60 U.S. Pharmacist • November 2009 • www.uspharmacist.com PHARMACOLOGIC MANAGEMENT OF ALCOHOL DEPENDENCE causing alcohol’s acute rewarding properties. Naltrexone’s mechanism of action reduces cravings and also is likely to minimize the “high” that individuals experience with alcohol intake, which may result in lower alcohol consumption.7,9-12 Naltrexone’s adverse-effect profile tends to be mild, but gastrointestinal side effects, headache, dizziness, anxiety, and decreased appetite may occur.5 Rarely, naltrexone may cause dose-related hepatotoxicity, so frequent monitoring is recommended. Owing to naltrexone’s mechanism of action, current opiate treatment may induce withdrawal symptoms, so patients should be opioid-free for at least 7 to 10 days before naltrexone is initiated.5 Several studies have concluded that naltrexone is an effective treatment option for alcohol dependence. In a 12-week, double-blind, placebo-controlled trial, 70 male patients were treated with naltrexone or placebo.9 Patients who received naltrexone experienced fewer cravings and consumed less alcohol. The percentage of patients who relapsed was significantly less in the naltrexone group compared with the placebo group (54% vs. 23%). Additionally, 95% of placebo patients who sampled alcohol relapsed, versus 50% of naltrexone patients.9 Another trial established that naltrexone was superior to placebo when outcomes such as number of drinking days, abstinence rates, relapse rates, and severity of alcohol-related problems were compared.12 This study found that abstinence rates were higher in the naltrexone group versus the placebo group (61% vs. 19%).12 There are also some less compelling data regarding naltrexone. One trial evaluated the use of naltrexone for 3 months or 12 months in 627 veterans.13 Naltrexone was not significantly better than placebo in decreasing percentage of drinking days or drinks per day, and it did not improve days to relapse. The trial concluded that the use of naltrexone in this population base was not supported.13 Overall, naltrexone is an effective treatment option for patients with alcohol dependence. Based on the literature, naltrexone can help improve outcomes by lessening cravings, decreasing heavy alcohol consumption, decreasing relapse, and potentially enhancing abstinence rates.7,9-12 Intramuscular (IM) Naltrexone: In 2006, the FDA approved a long-acting IM formulation of naltrexone. Previous trials of naltrexone suggested that nonadherence to treatment may be a concern, resulting in decreased effectiveness and suboptimal treatment outcomes. 10,14 Use of the IM formulation may help overcome problems with adherence. One concern regarding this formulation is the potential for injection-site reactions such as cellulitis, hematoma, and necrosis.5 Several trials support positive outcomes associated with the use of IM naltrexone. In one multicenter, randomized, placebo-controlled trial, 315 patients received either IM naltrexone or placebo.15 The trial, conducted over 3 months, found that IM naltrexone significantly improved abstinence rates compared with placebo (18% vs. 10%), and also prolonged the time to first drinking day.15 Overall, IM naltrexone appears to be a safe and effective treatment option that may be especially beneficial for patients who have adherence problems.16 Acamprosate: In 2004, acamprosate became available in the U.S. for the treatment of alcohol dependence. It is hypothesized that acamprosate restores GABA and glutamate imbalances caused by alcohol intake.5,11 It also is proposed that acamprosate has some effects on the N-methyl-D-aspartic acid receptor.11 Some common adverse effects associated with acamprosate are diarrhea, headache, insomnia, anxiety, and muscle weakness.5 Patients treated with acamprosate should try their best to avoid alcohol; however, alcohol intake does not affect the pharmacokinetics of acamprosate, and therefore no disulfiram-type reaction will occur.5 In addition, acamprosate may be a safer option than disulfiram or naltrexone in patients with hepatic impairment. The drug should be used with caution in patients with renal impairment, however.5 Currently, there is insufficient U.S. literature strongly evidencing the effectiveness of acamprosate, although an adequate amount of European literature supports its use.17-20 The COMBINE study, conducted in the U.S., concluded that acamprosate failed to show evidence of efficacy with regard to time to first heavy drink or abstinent days.17 In another U.S.-based double-blind, placebo-controlled study, patients received acamprosate 2 g, acamprosate 3 g, or placebo.18 This study found that percentage of abstinent days did not differ among treatment groups; however, a post-hoc analysis that controlled baseline covariates and measured highly motivated patients as a subset found that acamprosate yielded a greater number of abstinent days than placebo.18 A European meta-analysis of 20 trials suggested that continuous abstinence rates at 6 months were significantly higher for acamprosate-treated patients versus patients given placebo (36.1% vs. 23.4%). 19 Data also indicate that acamprosate confers improved abstinence rates for up to 48 weeks.20 It is not clear why outcomes associated with acamprosate are inconsistent between the U.S. and European studies. Certain factors, such as the severity of the alcohol dependence, may be potential reasons. 4 Based on the literature, acamprosate is associated with an improved rate of complete abstinence and may have other positive outcomes, such as decreased drinking frequency and rate of relapse.7,18-20 The drug appears 61 U.S. Pharmacist • November 2009 • www.uspharmacist.com Day 1 Day 2 Day 3 Day 4 Day 5 TAKE Z-PAK® FOR 5 DAYS1 OR... (azithromycin) 250 mg TAKE AZITHROMYCIN TO 1 DAY. 1 DOSE. 2 Please see accompanying Zmax brief summary. Zmax is indicated for mild to moderate acute bacterial sinusitis in adults due to Haemophilus influenzae, Moraxella catarrhalis, or Streptococcus pneumoniae and is also indicated for community-acquired pneumonia due to Chlamydophila pneumoniae, Haemophilus influenzae, Mycoplasma pneumoniae,or or Streptococcus pneumoniae in adult and pediatric patients aged 6 months and over, deemed appropriate for oral therapy. epidermal necrolysis in patients on other formulations of azithromycin therapy. Rarely, fatalities have been reported. Zmax and Zithromax are contraindicated in patients with known hypersensitivity to azithromycin, erythromycin, or any macrolide or ketolide antibiotic. If an allergic reaction occurs, appropriate therapy should be instituted. Physicians should be aware that reappearance of the allergic symptoms may occur when symptomatic therapy is discontinued. Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including azithromycin, and may range in severity from mild diarrhea to fatal colitis. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents. If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued, and appropriate management and treatment of C. difficile should be instituted as clinically indicated. There have been rare reports of serious allergic reactions including angioedema, anaphylaxis, Stevens Johnson syndrome, and toxic As with all macrolides, including Zmax, exacerbations of myasthenia gravis have been reported. Zmax: 1 product — indicated for both adult and pediatric patients2 Pediatric patients A higher incidence of gastrointestinal adverse events (8 of 19 subjects) was observed when Zmax was administered to a limited number of subjects with GFR <10 mL/min. Overall, the most common treatment-related adverse reactions in: -Adult patients receiving a single 2-g dose of Zmax were diarrhea/loose stools (12%), nausea (4%), abdominal pain (3%), headache (1%), and vomiting (1%). Adult patients -Pediatric patients receiving the recommended Zmax dose of 1 mL/lb were vomiting (11.9%), diarrhea (8%), loose stools (5.6%), abdominal pain (3%), rash (2.8%), nausea (1.7%), and anorexia (1.2%). References: 1. Zithromax (prescribing information). New York, NY: Pfizer Inc; 2007. 2. Zmax (prescribing information). New York, NY: Pfizer Inc; 2009. Zmax® (azithromycin extended release) for oral suspension Brief Summary of Prescribing Information INDICATIONS AND USAGE Zmax is indicated for the treatment with mild to moderate infections caused by susceptible isolates of the designated microorganisms in the specific conditions listed below. Acute bacterial sinusitis in adults due to Haemophilus influenzae, Moraxella catarrhalis or Streptococcus pneumoniae. Community-acquired pneumonia in adults and pediatric patients six months of age or older due to Chlamydophila pneumoniae, Haemophilus influenzae, Mycoplasma pneumoniae or Streptococcus pneumoniae, in patients appropriate for oral therapy. Pediatric use in this indication is based on extrapolation of adult efficacy. To reduce the development of drug-resistant bacteria and maintain the effectiveness of Zmax and other antibacterial drugs, Zmax should be used only to treat infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy. Appropriate culture and susceptibility tests should be performed before treatment to determine the causative organism and its susceptibility to Zmax.Therapy with Zmax may be initiated before results of these tests are known; once the results become available, antimicrobial therapy should be adjusted accordingly. CONTRAINDICATIONS Zmax is contraindicated in patients with known hypersensitivity to azithromycin, erythromycin or any macrolide or ketolide antibiotic. WARNINGS AND PRECAUTIONS Allergic and skin reactions Serious allergic reactions, including angioedema, anaphylaxis, Stevens Johnson syndrome, and toxic epidermal necrolysis have been reported rarely in patients on azithromycin therapy using other formulations. Although rare, fatalities have been reported. Despite initially successful symptomatic treatment of the allergic symptoms, when symptomatic therapy was discontinued, the allergic symptoms recurred soon thereafter in some patients without further azithromycin exposure.These patients required prolonged periods of observation and symptomatic treatment. The relationship of these episodes to the long tissue half-life of azithromycin and subsequent exposure to antigen has not been determined. If an allergic reaction occurs, appropriate therapy should be instituted. Physicians should be aware that reappearance of the allergic symptoms may occur when symptomatic therapy is discontinued. Clostridium difficile-associated diarrhea Clostridium difficile-associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including Zmax, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile. C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents. If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated. Exacerbation of myasthenia gravis Exacerbation of symptoms of myasthenia gravis and new onset of myasthenic syndrome have been reported in patients receiving azithromycin therapy. Gastrointestinal Disturbances A higher incidence of gastrointestinal adverse events (8 of 19 subjects) was observed when Zmax was administered to a limited number of subjects with GFR <10 mL/min. Prolongation of the QT interval Prolonged cardiac repolarization and QT interval, imparting a risk of developing cardiac arrhythmia and torsades de pointes, have been seen in treatment with other macrolides. A similar effect with azithromycin cannot be completely ruled out in patients at increased risk for prolonged cardiac repolarization. Development of drug resistant bacteria Prescribing Zmax in the absence of a proven or strongly suspected bacterial infection is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria. ADVERSE REACTIONS Clinical studies experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adults: The data described below reflect exposure to Zmax in 728 adult patients. All patients received a single 2-g oral dose of Zmax. The population studied had community-acquired pneumonia and acute bacterial sinusitis. In controlled clinical trials with Zmax, the majority of the reported treatment-related adverse reactions were gastrointestinal in nature and mild to moderate in severity. Overall, the most common treatment-related adverse reactions in adult patients receiving a single 2-g dose of Zmax were diarrhea/loose stools (12%), nausea (4%), abdominal pain (3%), headache (1%), and vomiting (1%). The incidence of treatment-related gastrointestinal adverse reactions was 17% for Zmax and 10% for pooled comparators. Treatment-related adverse reactions following Zmax treatment that occurred with a frequency of <1% included the following: Cardiovascular: palpitations, chest pain Gastrointestinal: constipation, dyspepsia, flatulence, gastritis, oral moniliasis Genitourinary: vaginitis Nervous System: dizziness, vertigo General: asthenia Allergic: rash, pruritus, urticaria Special Senses: taste perversion Laboratory Abnormalities In subjects with normal baseline values, the following clinically significant laboratory abnormalities (irrespective of drug relationship) were reported in Zmax clinical trials: - with an incidence of greater than or equal to 1%: reduced lymphocytes and increased eosinophils; reduced bicarbonate; - with an incidence of less than 1%: leukopenia, neutropenia, elevated bilirubin, AST, ALT, BUN, creatinine, alterations in potassium. Where follow-up was provided, changes in laboratory tests appeared to be reversible. Pediatric Patients: The data described below reflect exposure to Zmax in 907 pediatric patients. The population was 3 months to 12 years of age. All patients received a single 60 mg/kg oral dose of Zmax. As in adults, the most common treatment-related adverse reactions in pediatric subjects were gastrointestinal in nature. The pediatric subjects all received a single 60 mg/kg dose (equivalent to 27 mg/lb) of Zmax. In a study with 450 pediatric subjects (ages 3 months to 48 months), vomiting (11%), diarrhea (10%) loose stools (9%), and abdominal pain (2%) were the most frequently reported treatment-related gastrointestinal adverse reactions. Many treatment related gastrointestinal adverse reactions with an incidence greater than 1% began on the day of dosing in these subjects [43%(68/160)] and most [53%(84/160)] resolved within 48 hours of onset. Treatment-related adverse events that were not gastrointestinal, occurring with a frequency ≥ 1% were: rash (5%), anorexia (2%), fever (2%), and dermatitis (2%). In a second study of 337 pediatric subjects, ages 2 years to 12 years, the most frequently reported treatment-related adverse reactions also included vomiting (14%), diarrhea (7%), loose stools (2%), nausea (4%) and abdominal pain (4%). A third study investigated the tolerability of two different concentrations of azithromycin oral suspension in 120 pediatric subjects (ages 3 months to 48 months), all of whom were treated with azithromycin.The study evaluated the hypothesis that a more dilute, less viscous formulation (the recommended 27 mg/mL concentration of Zmax) is less likely to induce vomiting in young children than a more concentrated suspension used in other pediatric studies. The vomiting rate for subjects taking the dilute concentration azithromycin was 3% (2/61). The rate was numerically lower but not statistically different from the vomiting for the more concentrated suspension. Across both treatment arms, the only treatmentrelated adverse events with a frequency of ≥1% were vomiting (6%, 7/120) and diarrhea (2%, 2/120). Treatment-related adverse reactions with a frequency of <1% following Zmax treatment in all 907 pediatric subjects in the Phase 3 studies were: Body as a whole: chills, fever, flu syndrome, headache; Digestive: abnormal stools, constipation, dyspepsia, flatulence, gastritis, gastrointestinal disorder, hepatitis; Hemic and Lymphatic: leukopenia; Nervous System: agitation, emotional liability, hostility, hyperkinesia, insomnia, irritability, parasthesia, somnolence; Respiratory: asthma, bronchitis, cough increased, dyspnea, pharyngitis, rhinitis; Skin and Appendages: dermatitis, fungal dermatitis, maculopapular rash, pruritus, urticaria; Special Senses: otitis media, taste perversion; Urogenital: dysuria. Laboratory Abnormalities In subjects with normal baseline values, the following clinically significant laboratory abnormalities (irrespective of drug relationship) were reported in Zmax pediatric clinical trials: - with an incidence of greater than or equal to 1%: elevated eosinophils, BUN, and potassium; decreased lymphocytes; and alterations in neutrophils; - with an incidence of less than 1%: elevated SGOT, SGPT and creatinine; decreased potassium; and alterations in sodium and glucose. Postmarketing experience with other azithromycin products Because these reactions are reported voluntarily from a population of uncertain size, reliably estimating their frequency or establishing a causal relationship to drug exposure is not always possible. Adverse events reported with azithromycin immediate release formulations during the post-marketing period for which a causal relationship may not be established include: Allergic: arthralgia, edema, urticaria and angioedema Cardiovascular: palpitations and arrhythmias including ventricular tachycardia and hypotension There have been rare reports of QT prolongation and torsades de pointes. Gastrointestinal: anorexia, constipation, dyspepsia, flatulence, vomiting/diarrhea rarely resulting in dehydration, pseudomembranous colitis, pancreatitis, oral candidiasis and rare reports of tongue discoloration General: asthenia, paresthesia, fatigue, malaise and anaphylaxis (rarely fatal) Genitourinary: interstitial nephritis, acute renal failure, moniliasis and vaginitis Hematopoietic: thrombocytopenia, mild neutropenia Liver/Biliary: abnormal liver function including hepatitis and cholestatic jaundice, as well as rare cases of hepatic necrosis and hepatic failure, some of which have resulted in death Nervous System: convulsions, dizziness/vertigo, headache, somnolence, hyperactivity, nervousness, agitation and syncope Psychiatric: aggressive reaction and anxiety Skin/Appendages: pruritus, rash, photosensitivity, rarely serious skin reactions including erythema multiforme, Stevens-Johnson syndrome and toxic epidermal necrolysis Special Senses: hearing disturbances including hearing loss, deafness and/or tinnitus and rare reports of taste/smell perversion and/or loss DRUG INTERACTIONS Warfarin Although, in a study of 22 healthy men, a 5-day course of azithromycin did not affect the prothrombin time from a subsequently administered dose of warfarin, spontaneous post-marketing reports suggest that concomitant administration of azithromycin may potentiate the effects of oral anticoagulants. Prothrombin times should be carefully monitored while patients are receiving azithromycin and oral anticoagulants concomitantly. USE IN SPECIFIC POPULATIONS Pregnancy Teratogenic Effects. Pregnancy Category B: Reproduction studies have been performed in rats and mice at doses up to moderately maternally toxic dose concentrations (i.e., 200 mg/kg/day). These daily doses in rats and mice, based on mg/m2, are estimated to be approximately equivalent to one or onehalf of, respectively, the single adult oral dose of 2 g. In the animal studies, no evidence of harm to the fetus due to azithromycin was found. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, azithromycin should be used during pregnancy only if clearly needed. Nursing Mothers It is not known whether azithromycin is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when azithromycin is administered to a nursing woman. Pediatric Use Safety and effectiveness in the treatment of pediatric patients under 6 months of age have not been established. Community-Acquired Pneumonia: The safety and effectiveness of Zmax have been established in pediatric patients 6 months of age or older with community-acquired pneumonia due to Chlamydophila pneumoniae, Mycoplasma pneumoniae, Haemophilus influenzae or Streptococcus pneumoniae. Use of Zmax for these patients is supported by evidence from adequate and well-controlled studies of Zmax in adults with additional safety and pharmacokinetic data in pediatric patients. Acute bacterial sinusitis: Safety and effectiveness in the treatment of pediatric patients with acute bacterial sinusitis have not been established. Geriatric Use Data collected from the azithromycin capsule and tablet formulations indicate that a dosage adjustment does not appear to be necessary for older patients with normal renal function (for their age) and hepatic function receiving treatment with Zmax. In clinical trials of Zmax, 17% of subjects were at least 65 years of age (214/1292) and 5% of subjects (59/1292) were at least 75 years of age. No overall differences in safety or effectiveness were observed between these subjects and younger subjects. Renal Impairment No dosage adjustment is recommended for patients with GFR >10 mL/min. Caution should be exercised when Zmax is administered to patients with GFR <10 mL/min, due to a higher incidence of gastrointestinal adverse events (8 of 19 subjects) observed in a limited number of subjects with GFR <10 mL/min. Gender The impact of gender on the pharmacokinetics of azithromycin has not been evaluated for Zmax. However, previous studies have demonstrated no significant differences in the disposition of azithromycin between male and female subjects. No dosage adjustment of Zmax is recommended based on gender. OVERDOSAGE Adverse events experienced in higher than recommended doses were similar to those seen at normal doses. In the event of overdosage, general symptomatic and supportive measures are indicated as required. Please see full Prescribing Information for additional information about Zmax. ZMU00173 ©2009 Pfizer Inc. All rights reserved. Printed in USA/November 2009 PHARMACOLOGIC MANAGEMENT OF ALCOHOL DEPENDENCE to be a logical option given the evidence of lasting effects and improved drinking outcomes.20 Combination Treatment It has been proposed that combination therapy may result in improved efficacy compared with monotherapy. 17,21,22 Owing to their different mechanisms of action, it may be theoretically appropriate to combine these agents for added benefit. Based on the literature, the combination of disulfiram and naltrexone appears to offer no additional benefits over treatment with either medication alone. 23 Studies examining the combination of disulfiram and acamprosate indicate that this combination may result in improved efficacy, but there is not much literature regarding concomitant use of these drugs.21 The bulk of the literature centers on the combination of naltrexone and acamprosate. The COMBINE trial concluded that the concomitant use of these two medications appeared to be safe and well tolerated, but provided no additional therapeutic benefit versus naltrexone alone.17 In another trial, 160 patients were randomized to receive acamprosate, naltrexone, naltrexone plus acamprosate, or placebo.22 The combination group had significantly lower relapse rates compared with the placebo group and the acamprosate group, but the combination was not more effective than naltrexone only.22 Overall, the combination of naltrexone and acamprosate appears to be safe and well tolerated, but there may be an increase in certain adverse effects, such as diarrhea and nausea.22 The combination seems to provide some benefit compared with acamprosate alone. Combination therapy may be a valid option for some patients who are not responding to monotherapy. Further research is needed to clarify the utility of combination therapy in the treatment of alcohol dependence. Off-Label and Investigational Treatments Recently there has been a growing interest in exploring other potential treatments for alcohol dependence. Most new research focuses on agents that are proposed to target neurotransmitters that are affected by alcohol. These different classes of medications have been used off-label in the hope that some new agents may provide promising treatments in the future. Topiramate, oxcarbazepine, lithium, carbamazepine, gabapentin, and divalproex are some of the mood stabilizers and anticonvulsants that have been evaluated for the treatment of alcohol dependence. 4,6,10 It is believed that some anticonvulsants, such as topiramate, are responsible for enhancing GABA activity and antagonizing glutamate activity, which may lead to decreased alcohol consumption.4,10,24 Topiramate appears to be the best studied of the anticonvulsants thus far. Several randomized, controlled trials of topiramate have reported positive drinking outcomes (such as decreased heavy drinking days and drinks per day) and increased abstinent days compared with placebo.10,24,25 One trial found that patients treated with topiramate achieved 26% more abstinent days than patients given placebo.24 Topiramate appears to hold promise as a treatment for alcohol dependence. Most of the other abovementioned drugs, such as oxcarbazepine and divalproex, do not have conclusive data concerning their utility in treating alcohol dependence, and further research is needed.10 Lithium currently does not have supportive evidence as a treatment for alcohol dependence.7 Serotonergic agents constitute another medication class that has been researched for its value in treating alcohol dependence. It is theorized that serotonin plays a role in alcohol consumption.4,26 Literature exists concerning the use of selective serotonin reuptake inhibitors (SSRIs) for the treatment of alcohol dependence; however, results are inconsistent and do not support the use of SSRIs to treat alcohol dependence as a primary condition.4,6,7,26 It is thought that SSRIs may improve psychiatric illness, which may have an effect on drinking behavior.27 Ondansetron has been associated with positive drinking outcomes such as fewer drinks per day, fewer drinks per drinking day, more abstinent days, and more abstinent days per week.6 Dopamine antagonists may be involved in the treatment of alcohol dependence. Olanzapine has exhibited some positive outcomes.10 Other agents, such as baclofen and galantamine, also have been researched, but data regarding their use are either mixed or negative.10 Currently, there are only a few options available for the treatment of alcohol dependence. The agents mentioned above may hold some promise for the future, but more research is needed. Many of the current trials of these agents are methodologically weak or have inconclusive findings. For those reasons, further investigation is needed before these agents can be recommended or used for the treatment of alcohol dependence. There is a great need for the discovery of new potential options to treat alcohol dependence. Conclusion Alcohol dependence is a chronic disorder that has many consequences. Optimal treatment with pharmacologic agents may help achieve desired outcomes. The currently available treatments for alcohol dependence are all valid options, and their use should be individualized. Pharmacists can optimize treatment by recommending agents based on the expected outcomes associated with each medication. Pharmacists also can provide care by educating patients regarding expected outcomes, adverse effects, and precautions associated with the pharmacologic agents. References available online at www.uspharmacist.com. 65 U.S. Pharmacist • November 2009 • www.uspharmacist.com Criminalization of Medication Errors A recent case that equates a pharmacist’s mistake with manslaughter also raises the question of pharmacy technician responsibility. H ere is a sobering thought. A pharmacist makes a mistake. The error results in the death of a patient, and the pharmacist is charged with negligent homicide. He is found guilty of involuntary manslaughter and faces up to 5 years in prison and a maximum fine of $10,000. Of course, his pharmacist license is revoked and chances are he will never work in the profession again. His crime? He did not check the accuracy of calculations used by a pharmacy technician under his charge to compound the concentration of sodium chloride in a prescription for a cancer chemotherapy solution. Negligent? Yes. Accountability and responsibility? Yes and Yes. Malpractice? Yes. Loss of license? Yes. Guilty? Yes. But a crime? Prison term? For a mistake, albeit a mistake with a worst-case outcome? That is tough medicine to swallow. More Jesse C. Vivian, BS Pharm, JD Professor, Department of Pharmacy Practice College of Pharmacy and Health Sciences Wayne State University Detroit, Michigan important, how is justice served by putting this pharmacist in jail? The message to pharmacists and perhaps all other health care practitioners— watch out. There may be prosecutors out there just itching to put you away. Facts of the Case On February 24, 2006, while working at the Rainbow Babies and Children’s Hospital in Cleveland, Ohio, licensed pharmacist Eric Cropp received a prescription for a chemotherapy solution of Eposin (etoposide phosphate) that was supposed to be mixed in an IV bag of normal saline containing 0.9% sodium chloride.1 The patient, Emily Jerry, was diagnosed with a yolk sac tumor when she was about a year and a half old. The tumor was the size of a grapefruit and stemmed from the base of her spine into her abdomen. Her team of doctors and nurses assured the parents that Emily’s cancer was not only treatable but curable. Emily endured months of surgeries, testing, and rigorous chemotherapy sessions, each of which lasted for 5 or 6 days. Emily’s treatment had been so successful that her last MRI clearly showed that the tumor had shrunk dramatically, with minimal residual scar tissue. However, her physicians still felt one final treatment was necessary to prevent the tumor from reappearing. She was scheduled to begin her last chemotherapy session on her second birthday. This last treatment was just to be sure that there were no traces of cancer left. The medication was to be the fourth and final round of treatment. Two days later, after the IV therapy was started, the child collapsed in her mother’s arms, crying in pain and vomiting. She grabbed her head and said, “Mommy, it hurts, it hurts.” The IV was started at 4:30 PM. By 5:30 PM, she was on life support. She went into a coma and died on March 1, 2006.2 The infusion caused intense cerebral edema. For reasons that have never been explained, the technician who made the mixture, Katie Dudash, used a saline base solution of 23.4% sodium chloride instead of the commercially available standard bag of normal saline. She told investigators that she did not recall why she decided to make a new solution of saline from scratch instead of grabbing a premade bag of normal saline that was available right there in the pharmacy. She said she was distracted because she was talking on her cell phone just before the incident happened, busy making plans for her upcoming wedding. An investigation into the incident disclosed that many circumstances contributed to the error’s occurrence. The pharmacy computer system was not working and a backlog of physician orders was piling up. The pharmacy was shortstaffed and everyone in the pharmacy was busy. The employee shortage meant that normal work and meal breaks were altered or not available. The technician was distracted from her normal routine. A floor nurse called the pharmacy and asked the pharmacist to send the 66 U.S. Pharmacist • November 2009 • www.uspharmacist.com CRIMINALIZATION OF MEDICATION ERRORS solution early. As a result, he felt rushed. Ironically, it was later determined that the IV bag was not needed for several hours. As can well be imagined, this incident took a terrible toll on the parents. They sued the hospital for malpractice and obtained a $7 million settlement.3 Soon afterward, the parents separated, and they divorced a year later. The mother, Kelly Jerry, had to obtain restraining orders against Emily’s father, Chris Jerry. He violated at least one of the orders and lost custody of both of his other children. In 2008, he was arrested for possession of marijuana and charged with resisting arrest. His case was diverted to a mental health court for sentencing. He sought psychological counseling as he looked for a way to work through his problems. Then, in 2009, Chris Jerry found a way to make something out of this tragedy. Mr. Jerry began counseling families in local hospitals whose children were on life-support systems. He made himself present simply as one who understands what they were going through. “I can speak to these people because I have gone through something similar, I know what they need to hear,” he said. “I can relate to them in every way.”4 He also started Emily’s Foundation, a charity he hopes to use to push for a national law to govern the work of pharmacy technicians and help prevent medical errors like the one that killed his daughter.5 Kelly Jerry attended all of the civil and criminal proceedings and made a compelling statement at the board of pharmacy hearing on the administrative complaint against the pharmacist. Chris Jerry did not attend any of the legal actions, although now he no longer feels any anger against the pharmacist. In fact he has been quoted as saying, “I feel very sorry for the pharmacist. This guy is facing a prison sentence, and I know it was an accident.”6 Unprofessional Conduct The pharmacist and the technician were dismissed by the hospital about 1 month after the incident. The tech went to back to work at CVS/pharmacy where she had been employed before working at the hospital. The pharmacist found a job at a local retail pharmacy just a few weeks later. There, according to records, he made an additional 13 more dispensing errors over a 10month period. One of those errors caused harm to another child.7 The Ohio State Board of Pharmacy held a hearing on a formal complaint against the pharmacist on April 11, 2007, a little over a year after the incident that caused the death of Emily Jerry.8 For this error, State regulations vary tremendously with respect to pharmacy technicians. the board found him responsible for misbranding and mislabeling a drug in violation of Ohio law.9 But this incident was actually only the beginning of Mr. Cropp’s problems. On April 26, 2006, while working at a community pharmacy, Eric Cropp misbranded a prescription for Compazine (prochlorperazine) 10-mg tablets prescribed for “nausea and vomiting.”10 He typed the label indicating the medication was to be taken “as needed for pain.” While at the same store, on July 18, he dispensed tramadol with acetaminophen instead of the prescribed Vicoprofen (hydrocodone and ibuprofen). On July 25, he dispensed metformin ER 500-mg tablets to a patient instead of the Biaxin XL (clarithromycin) 500-mg tablets that were prescribed. On that same day, he gave the Biaxin to the patient who should have been given the metformin. On August 18, he received a prescription for Phenergan (promethazine) 25-mg suppositories with directions to be used “rectally every 8 hours.” Instead, he typed a label indicating the medication was to be “taken by mouth.” On September 19, he dispensed Adderall XR (amphetamine and dextroamphetamine) 5-mg capsules to an 8-year-old child who had been prescribed Focalin XR (dexmethylphenidate) 5-mg capsules. The child suffered undisclosed injuries. On November 13, he received a prescription for Disalcid (salsalate) 500 mg. He dispensed Azulfidine (sulfasalazine) 500 mg instead. On November 18, he received a prescription for VoSol HC (hydrocortisone and acetic acid) from an ear, nose, and throat physician with indications that the medication was to be used “in the ear.” He labeled the drug as for use “in the eye.” On December 12, he received a prescription for Zoloft (sertraline) 100-mg tablets with directions that the patient should take “two tablets every evening.” He labeled the medication to be taken “twice daily.” On December 15, he received a prescription for Avelox (moxifloxacin) 400 mg. He labeled and dispensed the drug to the wrong patient. On December 26, he received a prescription for Zoloft (sertraline) 100-mg tablets. Instead, he dispensed 50-mg tablets. On February 3, 2007, he received a prescription for E.E.S. (erythromycin ethylsuccinate) 200 mg/5 mL suspension. Instead, he dispensed erythromycin with sulfisoxazole suspension. Finally, on the following day, he received a prescription for two boxes of Imitrex (sumatriptan) 6 mg/0.5 mL and dispensed a quantity less than what was called for by the prescription. The Ohio Board of Pharmacy found that all of the above conduct constitutes “unprofessional conduct” in violation of state law and then permanently revoked the pharma- 67 U.S. Pharmacist • November 2009 • www.uspharmacist.com CRIMINALIZATION OF MEDICATION ERRORS cist’s license.11 The vote was six in favor of this resolution with two board members in opposition. In May 2009, the pharmacist pleaded no contest to a charge of involuntary manslaughter for improperly supervising the technician. On August 14, 2009, Mr. Cropp was sentenced to 6 months in prison, 6 months of home confinement with electronic monitoring, 400 hours of community service, a $5,000 fine, and payment of court costs.12 Part of the community service sentence requires him to seek out medical and legal organizations where he can tell his story and, hopefully, help prevent others from making a similar mistake. Remember that his pharmacist license was permanently revoked, so he will have a significant loss of future income. And then, of course, there are the undisclosed attorney fees that the pharmacist incurred in his hearing in front of the Board of Pharmacy and his criminal prosecution. Oh, and by the way, what happened to the pharmacy tech that made the fatal error? Katie Dudash was charged by the prosecutor with negligent homicide, but the grand jury gave her a “get out of jail free card.” She gets off with no real penalty and is now working in a retail pharmacy. She was not licensed, registered, or certified by the state to work as a technician, so REFERENCES 1. Emily’s Story. Emily Jerry Foundation. http://emilyjerryfoundation.org/emilys-story/. Accessed October 11, 2009. 2. Robins M. Fatal dose: Ohio girl is killed by medical mistake. January 31, 2007. www.firstcoastnews.com/ news/usworld/news-article.aspx?storyid=75102. Accessed October 4, 2009. 3. Whitley M. Chris Jerry, whose daughter Emily died from a pharmacy technician’s mistake, starts foundation to push for national law. June 13, 2009. http://blog. cleveland.com/metro/2009/06/chris_jerry_whose_ daughter_emi.html. Accessed October 11, 2009. 4. News. Emily Jerry Foundation. October 7, 2009. http://emilyjerryfoundation.org/chris-jerry-whosedaughter-emily-died-from-a-pharmacy-techniciansmistake-starts-foundation-to-push-for-national-law/. Accessed October 11, 2009. 5. See note 4, supra. The Web site states, in part: “The core of the Emily Jerry Foundation focuses on protecting our nation’s babies and children from the all too redun- there were no administrative sanctions available. She has no accountability or responsibility. She was just an employee doing a job. She did not do her job right, but there were no consequences—other than losing her job and maybe having to live with the idea that her actions directly caused the death of another human being. Emily’s Law At the time, Ohio was one of many states that had no minimum training, licensing, registration, or certification requirements for pharmacy technicians. State regulations vary tremendously with respect to pharmacy technicians. Currently, only eight states license technicians, 31 states have registration, and five states certify techs. Twenty states have no educational requirements (training, continuing education, or certification exam) for technicians.13 On January 7, 2009, the governor of Ohio signed SB 203, known as “Emily’s Law,” which establishes standards for qualified pharmacy technicians and requires them to undergo a criminal background check.14 They must also pass a competency test. It also establishes penalties for certain activities, including compounding, packaging, and preparing a drug by an individual who is not a pharmacist, pharmacy intern, or qualified pharmacy technician.15 dant medical errors that keep occurring over and over again in hospitals across the nation. These countless mistakes are killing our children and are most often avoidable. We are increasing public awareness of these issues and striving to get better legislation in place across the United States. The Emily Jerry Foundation is helping to save countless lives, as well as make our world-renowned medical facilities much safer.” 6. See note 4, supra. 7. Failure to track pharmacy mistakes may be “prescription for trouble.” NewsNet5. March 23, 2009. www.newsnet5.com/news/18917359/detail.html. Accessed October 11, 2009. 8. Minutes of the April 9-11, 2007 meeting of the Ohio State Board of Pharmacy. Docket Number D-061108-012. http://pharmacy.ohio.gov/minutes/mins07040911.pdf. Accessed October 11, 2009. 9. ORC § 3715.52(A)(2) and OHC Rule 4729-17-10. 10. See note 8, supra. 11. ORC § 4729.16. 12. Not a wonderful life: no George Bailey for pharmacist The downside of making this mistake, awful as it was, into a criminal case with incarceration for the offender is that it discourages others from ever wanting to report errors with serious consequences. “We need to change the system. I’m hopeful that we can find something meaningful in terms of safety from this child’s death,” said Bona Benjamin, director of medication use quality improvement at the American Society of Health-System Pharmacists (ASHP).16 Some pharmacy groups are beginning to push for greater standardization of technician training. ASHP has developed a model curriculum for pharmacy technician training program accreditation as the first effort to develop a national standard. In addition, the National Pharmacy Technician Association, the Institute for the Certification of Pharmacy Technicians, and the Pharmacy Technician Certification Board have all worked to develop technician training standards.17 If nothing else, this case should send a loud and serious message to pharmacists. You can delegate activities associated with the practice of pharmacy to technicians and others. But you can never delegate responsibility or accountability. It is your name on the license, and there are no excuses for mistakes of this type. Eric Cropp or his patient. September 5, 2009. http://jparadisirn.com/2009/09/05/not-a-wonderful-lifeno-george-bailey-for-pharmacist-eric-cropp-or-his-patient/. Accessed October 4, 2009. 13. Reid P. Former pharmacist indicted for manslaughter after med error. Drug Topics. September 17, 2007. http://drugtopics.modernmedicine.com/drugtopics/ Community+Pharmacy/Former-pharmacist-indicted-formanslaughter-after-/ArticleStandard/Article/detail/456584. Accessed October 11, 2009. 14. Sangiacomo M. Ohio governor signs “Emily’s Law” forcing standards for pharmacy technicians. Cleveland Plain Dealer. January 7, 2009. www.cleveland.com/ medical/index.ssf/2009/01/emilys_law_enacted_by_gov_ stri.html. Accessed October 11, 2009. 15. Governor signs “Emily’s Law” legislation. www.governor.ohio.gov/News/PressReleases/2009/ January2009/News1709/tabid/956/Default.aspx. Accessed October 11, 2009. 16. See note 13, supra. 17. See note 13, supra. 68 U.S. Pharmacist • November 2009 • www.uspharmacist.com & are excited to launch: www.PharmQD.com Join 160,000 pharmacists, techs, and students who are being invited to check out the new professional and social networking site for the pharmacy community: ã ã ã ã Create and maintain connections Job listings !.# UGRF PC?JRGKC ACPRGdžA?RCQ Breaking pharmaceutical and pharmacy news ã ã ã ã Blogs on current topics Forums for in-depth discussion Market research opportunities .PMDCQQGML?J ?LB NCPQML?J NPMdžJCQ MD ?JJ KCK@CPQ PharmQD.com – Your Daily Dose of Pharmacy News and Networking 2 CE Credits This activity is supported by an educational grant from Teva Women’s Health. © JUPITERIMAGES Emergency Contraception An Update of Clinical and Regulatory Changes E mergency contraception (EC), sometimes referred to as the “morning-after pill,” is a safe and effective method of preventing pregnancy after intercourse. Levonorgestrel, a hormone found in many birth control pills, is the active ingredient in most emergency contraceptive products used in the U.S. The Food and Drug Administration (FDA) approved the first levonorgestrel-only emergency contraceptive, Plan B (levonorgestrel 0.75 mg oral tablets), in 1999 for prescription use. In 2006, the FDA widened access to EC by approving over-the-counter (OTC) sale to consumers 18 years of age or older.1,2 At the time, Plan B was the first product to be approved in the U.S. with dual status (a single product approved for OTC sale or prescription-only access to consumers based on age). More recently, the FDA further increased access to EC by reducing the age for OTC access to anyone 17 years and older, continuing access to girls under age 17 by prescription only. Two new EC products recently became available in the U.S. In July 2009, the FDA approved a one-dose emergency contraceptive, Plan B One-Step (levonorgestrel 1.5 mg tablet) for OTC Kathleen H. Besinque, PharmD, MSEd Associate Professor of Clinical Pharmacy School of Pharmacy University of Southern California Los Angeles, California U.S. Pharmacist Continuing Education GOAL: The goals of this educational program are to update pharmacists and other health care professionals on the current clinical and regulatory information related to levonorgestrelbased emergency contraception and to provide effective strategies for educating consumers about emergency contraception. OBJECTIVES: After completing this activity, participants should be able to: 1. Discuss the clinical indications for emergency contraception.* 2. Compare available levonorgestrel-only emergency contraceptive regimens and the requirements associated with the nonprescription sale of these products.* 3. Describe the evidence for the mechanism of action and safety profile of levonorgestrel-only emergency contraceptive regimens.* 4. Discuss opportunities for pharmacists to provide improved access to emergency contraception, including identification of and reduction of barriers in the pharmacy environment.* 5. Describe strategies to improve education and counseling of consumers regarding the effective use of levonorgestrel emergency contraception regimens.* * Also applies to pharmacy technicians. sale to consumers age 17 and older and by prescription to girls under age 17.3 Next Choice (levonorgestrel 0.75 mg tablets) was also approved in 2009 and is a generic formulation of the original Plan B. Although three levonorgestrel EC products may be currently available—Plan B, Plan B OneStep, and Next Choice— the distribution of Plan B will cease as Plan B OneStep launches into the marketplace. All EC products are approved to prevent pregnancy when a contraceptive method has failed or was not used during intercourse. Unintended pregnancies are associated with many personal and public health related consequences. In the U.S., approximately half of all pregnancies occurring each year are unintended and as many as half of the unintended pregnancies are terminated by elective abortion.4 When taken within 72 hours of unprotected intercourse, levonorgestrel-only EC reduces the risk of pregnancy by as much as 89%.2,3 Studies to date have not been able to show that having EC available without a prescription has reduced the rates of unintended pregnancy in the U.S. as was originally anticipated.5,6 The reason for the lower-than-anticipated impact on unintended pregnancy rates may be related to the persistence of barriers to EC access, including misunderstanding by consumers about when to use EC. Pharmacists and other health care professionals can help to reduce bar- 70 U.S. Pharmacist • November 2009 • www.uspharmacist.com EMERGENCY CONTRACEPTION: AN UPDATE imen initiated within 72 hours of unprotected intercourse. Despite FDA approval, an increase in the utilization of EC by women was hampered by a number of barriers (TABLE 1). To improve access, a request was made to move Plan • Lack of awareness by consumers that a method to B to OTC status. Plan B appeared to satisfy FDA requireprevent pregnancy after intercourse was available ments for conversion from prescription to OTC sta• Failure of doctors to discuss EC during medical tus, which include a minimum of two years of prescripappointments tion use with a high degree of safety and studies establishing • Lack of information about EC among health care that consumers can interpret labeled instructions corprofessionals rectly. Although an FDA Advisory Committee voted in • Misconceptions about how EC works 2003 in support of the request for nonprescription • Confusion of EC and the “abortion pill” status, the FDA approved a change for Plan B in 2006 • Difficulty obtaining EC by prescription within the to “dual status” instead.11 Under dual status, Plan B was narrow window of efficacy made available without prescription to consumers at or above a certain age (originally 18 years but now 17) and riers that limit the use of EC by improving patient access remained available by prescription to younger women. and being available to answer questions about the use Packaging for the product was approved to meet the of EC. Pharmacists, as the “most accessible” health requirements for both prescription and nonprescription care provider, are in a unique position and play a cru- products. Since then, Next Choice and Plan B Onecial role in providing timely access to and information Step have also been approved for dual status distribuabout EC to consumers. OTC availability in the phar- tion in pharmacies and clinics (TABLE 2). Before the approval of dedicated products for EC, macy to consumers age 17 and over improves access to EC by reducing the delays that were associated with commercially available oral contraceptives containing obtaining a prescription in the limited time frame needed ethinyl estradiol with either norgestrel or levonorgestrel (often referred to as the “Yuzpe regimen”) were used for for efficacy of the product. EC. More recent studies have shown these combinaBackground and Clinical History of EC tions to be less effective (ranging from 49% to 75%) Levonorgestrel has been extensively studied as an than levonorgestrel-only regimens. 7,9 Furthermore, emergency contraceptive worldwide since the 1970s. the Yuzpe regimen has more side effects, especially nauAfter almost 40 years of EC use, the high degree of sea and vomiting, which often require the addition of efficacy in preventing pregnancy (up to 89% reduction) an antiemetic medication. Production of Preven, a comand the low rate of adverse effects have been well doc- mercially available equivalent to the Yuzpe regimen, was umented.5,7-10 A 2009 update to a Cochrane review of stopped in 2004. Because of its lower efficacy and EC interventions included more than 88 studies and increased frequency of side effects, use of the Yuzpe type concluded that levonorgestrel is both safe and effective combination regimens has declined but remains an in preventing pregnancy after intercourse.7 option when levonorgestrel is not available. The first products approved by the FDA for EC were Several other methods have been evaluated for EC, Preven (ethinyl estradiol 0.25 mg/levonorgestrel 0.5 mg including combinations of estrogen with norethindrone, tablets) in 1998 and Plan B (levonorgestrel 0.75 mg combining levonorgestrel with the COX-2 inhibitor tablets) one year later. Both products were approved for meloxicam, Yuzpe or levonorgestrel regimens using difuse by prescription and to be taken in a two-dose reg- ferent time intervals or doses, insertion of a copper IUD, an investigational progesterone modulator ulipristal (availTable 2 able as ellaOne in Europe) and Products Approved for Emergency Contraception low doses of mifepristone.7,12 Combination regimens using Levonorgestrel norethindrone appear to be less Brand Manufacturer Dose per Dose (mg) effective than levonorgestrel One-Dose Regimen regimens. 13 Regimens using mifepristone in doses ranging Plan B One-Step Barr Pharmaceuticals 1 tablet per dose 1.5 from 10 mg to 50 mg appear Two-Dose Regimens (administered immediately and 12 h later) to be effective; however, these Plan B Barr Pharmaceuticals doses are not available in the Next Choice Watson Pharmaceuticals 1 tablet per dose 0.75 U.S.7 Insertion of a copper IUD up to 10 days after intercourse Table 1 Early Barriers Preventing Utilization of EC Methods 71 U.S. Pharmacist • November 2009 • www.uspharmacist.com EMERGENCY CONTRACEPTION: AN UPDATE appears to have a low failure rate (0.01% to 0.02%), but IUD insertion requires a clinician visit and may not be suitable for some women.8 The investigational progesterone receptor modulator recently approved in Europe, ulipristal, may be as effective with similar side effects as levonorgestrel.14 Studies evaluating the use of levonorgestrel as a single dose (1.5 mg) did not find a significant difference in efficacy compared with 0.75 mg two-dose regimens.7 The newly approved Plan B One-Step (1.5 mg) is a single-dose regimen that may be more convenient and easier to use. Mechanism of Action Levonorgestrel, the only active ingredient in Plan B, Plan B One-Step, and Next Choice, is a synthetic progestin also available in hormonal contraceptives. The mechanisms by which levonorgestrel prevent pregnancy are likely similar to those of other hormonal contraceptives. All currently available hormonal methods of contraception have been shown to act by one or more of the following mechanisms: altering the endometrial lining, altering cervical mucus, interfering with fertilization or transport of an egg, or preventing implantation. There is good evidence that levonorgestrel prevents or delays ovulation as its primary mechanism of action; however, it is possible that additional mechanisms may be involved.15-20 There are no data supporting the view that levonorgestrel can impair the development of the embryo or prevent implantation.20 A number of publications have shed light on the mechanisms of action for levonorgestrel-only EC.15-20 Levonorgestrel-only EC has been shown to inhibit the preovulatory surge of luteinizing hormone (LH), thereby inhibiting follicular development and/or the release of the egg. A properly timed and sufficient surge of LH is required for the release of an ovum or ovulation. Ovulation must take place for fertilization to be possible. Research has demonstrated that EC inhibits the midcycle surge of LH from the pituitary and, if taken at least two days before ovulation, ovulation is delayed or pre- Table 3 Indications for Use of Emergency Contraception • • • • • • • Unprotected intercourse (including forgetting to use a condom or diaphragm) If a condom breaks or tears during intercourse Missing one or more doses of an oral contraceptive Being 2 or 3 days late to resume an ongoing hormonal contraceptive regimen While taking medication that may reduce the effectiveness of a hormonal contraceptive After exposure to a teratogen After a sexual assault vented. Ovulation may occur if the administration of levonorgestrel is delayed until ovulation is imminent.20 If levonorgestrel is taken later in the cycle, the effect on the LH surge may be equal to that of a placebo and pregnancy may occur. These time-sensitive events may explain why taking EC as soon as possible after unprotected intercourse is critical for maximizing its effectiveness. Studies of levonorgestrel and its potential effects on endometrial function have not shown changes that would prevent the implantation of a fertilized ovum.17 Women who have used Plan B to prevent a pregnancy early in their menstrual cycle remain at risk for pregnancy later in the same cycle if contraception is not resumed or fails again. This indicates that the endometrium is still intact and capable of implanting a fertilized ovum.19 It has been speculated that levonorgestrel may alter the movement of a fertilized egg, which would be expected to increase the risk of an ectopic pregnancy. Studies have not supported this assumption. The risk of an ectopic pregnancy after levonorgestrel use may be slightly lower than national ectopic pregnancy rates. 21 The Cochrane review found only five cases of ectopic pregnancy reported in more than 45,000 uses of EC and concluded that ectopic pregnancy was not associated with any specific type of EC or a likely consequence from using EC.7 The International Consortium for Emergency Contraception (ICEC), in a 2008 Policy Statement on mechanism of action, reported that levonorgestrel-only EC pills inhibit, delay, or interfere with ovulation and may possibly prevent the sperm and egg from meeting by affecting cervical mucus or the ability of sperm to bind to the egg.22 The ICEC also stated that there are no direct clinical data to support mechanisms other than the inhibition, delay, or alteration of ovulation.22 Levonorgestrelonly EC does not cause abortion or interfere with an established pregnancy and, if inadvertently taken by a woman who is pregnant, the pregnancy will not be harmed. The ICEC noted that EC might actually prevent abortions by reducing unplanned pregnancies.22 Indications and Contraindications EC is the use of a contraceptive method to prevent pregnancy after intercourse. Levonorgestrel products are approved for use within 72 hours after intercourse. There is evidence that taking EC as soon as possible may maximize its effectiveness and that use up to 120 hours may be effective. Consumers who are unsure of when to use EC or whether EC is needed may ask the pharmacist about its appropriateness. Circumstances where EC is indicated are listed in TABLE 3. Pharmacists can reassure women that EC is safe and effective and can be used when needed to prevent pregnancy after unprotected intercourse. A myth that may present a barrier to access to EC is belief that it can only be used once in a lifetime, once per year, or 72 U.S. Pharmacist • November 2009 • www.uspharmacist.com EMERGENCY CONTRACEPTION: AN UPDATE only once during a menstrual cycle. Pharmacists should not restrict the purchase of EC based on prior use or out of concern that repeated use of EC is not safe.12 There is no evidence that repeat use of EC poses increased risk to patients.23 Because EC is less effective as birth control than ongoing methods of contraception (such as condoms or birth control pills), it is recommended only as a backup method and not as a substitute for ongoing, more effective methods. EC can be purchased in advance and kept at home in case the need arises, as this avoids the delay of going to the pharmacy. There are few contraindications to the use of EC. The WHO Medical Criteria for Contraceptive Use 2005 stated that there are “no conditions where the risks of EC outweigh the benefits.”23 Product labeling lists the contraindications as an established pregnancy or known allergy to the ingredients in EC. There are no studies of EC use by women with migraine headaches, smokers over age 35, or other precautions applicable to the regular use of combination oral contraceptives. However, these conditions should not limit the use of EC. Timing of the EC Dose Levonorgestrel is thought to be more effective the sooner it is taken, therefore pharmacists should encourage women take EC as soon as possible after unprotected intercourse.24 The FDA-approved dosing recommends initiating therapy within 72 hours of unprotected intercourse. For levonorgestrel 0.75 mg tablets, a second dose is required 12 hours after the initial dose.5,8 Although there is evidence of efficacy as late as 120 hours after intercourse, women should be encouraged to seek treatment as soon as possible, preferably within the 72-hour timeframe.21,25-28 Since the time required from intercourse or ovulation to implantation is approximately 6 to 7 days, use of hormonal EC beyond 120 hours is not likely to be effective.13 Studies evaluating single-dose levonorgestrel (1.5 mg) have concluded that the single dose is not less effective than the two-dose regimen.21,28,29 Plan B One-Step has been approved for use as a single 1.5 mg dose for EC. The single dose formula may improve compliance by simplifying the EC regimen and will replace the Plan B 0.75 mg levonorgestrel preparation. Concerns have been raised that providing EC to women in advance of need to keep on hand “just in case” of a contraceptive failure might lead to an increase in unprotected intercourse or encourage women to discontinue the use of their usual method of contraception. However, studies evaluating the outcomes of providing EC in advance of need have not found that women engage in more unprotected intercourse or abandon their usual method. 6,7,30,31 These studies have reported that women are more likely to use EC after unprotected intercourse if it is provided in advance of need. Based upon the findings of the studies, provid- ing EC in advance of need can be recommended to improve timely access to the product. Dual Status: EC in the Pharmacy The dual status of levonorgestrel-only EC necessitates that products be kept within the pharmacy or behind the counter. In the pharmacy a consumer has access to the pharmacist, a knowledgeable health care provider, to answer questions regarding the use of EC. EC products must only be sold in pharmacies or licensed clinics and are not available at other types of retail establishments. Keeping EC hidden behind the pharmacy counter may pose a barrier to some consumers because they may expect to find the products on pharmacy shelves or within sight behind the pharmacy counter. Pharmacists are encouraged to provide shelf tags or display EC products in a conspicuous location to facilitate access by consumers who may be reluctant to ask if they do not easily see the product in the pharmacy. “CARE” Program: Convenient Access, Responsible Education The terms of the FDA approval of Plan B for OTC access by consumers age 17 and older included requirements restricting the distribution of EC, meeting labeling requirements for both OTC and prescription use, and for the manufacturer to provide support and education about the use of the product to health care providers and consumers and to continue ongoing monitoring. The dual-labeled, behind-the-counter labeling launched with the approval of Plan B was the first time the FDA had approved the same product package for both OTC and prescription-only use. The approved packaging includes room for a prescription label (to be used when the product is dispensed by prescription), as well as the required Drug Facts box for OTC sales. The CARE program specifies that EC is to be sold only from behind the counter in the pharmacy and not be available through nonpharmacy retail outlets. The FDA approval allows EC to be sold without a prescription to women or men 17 or over as long as they can show proof of age.2 Pharmacies must have a pharmacist on duty and available for consumer consultation in order to sell EC. Although the pharmacist must be available, it is not required that the pharmacist be the person who sells the product, or for the consumer to consult with the pharmacist. Any member of the pharmacy staff working behind the pharmacy counter may sell the products to eligible consumers as long as a pharmacist is on duty and available for consultation if requested by the purchaser. Medical clinics may also sell EC if there is a licensed health care provider on the premises for consumer consultation at the time of sale. Retail outlets with pharmacies where the retail store has longer 73 U.S. Pharmacist • November 2009 • www.uspharmacist.com EMERGENCY CONTRACEPTION: AN UPDATE ask for EC (e.g., the “morning-after pill”), and to respect the confidential nature of and need for privacy that may accompany the request. Pharmacy staff may offer but should not require consultation with Most Common Plan B (levonorPlan B One-Step the pharmacist to consumers asking about Adverse Events in gestrel 0.75 mg (levonorgestrel 1.5 EC. Pharmacists may want to inform the >4% of Women oral tablets) (%) mg oral tablet) (%) entire staff that some consumers may preNausea 23.1 13.7 sent an “EC request card” (available online Abdominal pain 17.6 13.3 at www.PlanBOne-Step.com/how-to-getFatigue 16.9 13.3 plan-b.asp or www.pharmacyaccess.org/ Headache 16.8 10.3 ECPromotionalOpps.htm) to avoid being Heavier menstrual bleeding 13.8 30.9 overheard or because they are embarrassed a Lighter menstrual bleeding 12.5 to ask for EC at the pharmacy counter. a Dizziness 11.2 Keeping EC in an area where consumers Breast tenderness 10.7 9.6 can easily see that the products are availa Other complaints 9.7 a able in the pharmacy may also be helpVomiting 5.6 a ful to consumers. Diarrhea 5.0 a Although consultation with the pharDelay of menses >7 days 4.5 macist is not required for the OTC pura Reported in <4% of users. chase of EC, many consumers will have Source: Reference 3. questions for the pharmacist. Common questions about EC include its effechours of business than the pharmacy are not able to sell tiveness, possible side effects, and how to know if the EC when the pharmacy is closed. product was effective. When consumers ask the pharThere is no limit to the number of packages that macist about what to expect after taking EC, the pharmay be sold to an eligible consumer. A consumer may macist should include information about possible side purchase one or more packages of the product in a effects, when to expect her next menstrual period, single transaction. In addition, there is no require- how to resume routine birth control methods (e.g., oral ment that this OTC product must be used by the pur- contraceptives), and when follow-up care is indicated chaser, and men may purchase it as long as they are at (see FAQ). least 17 years of age. There is no requirement for purMost women who take EC will not experience side chasers of EC to sign a registry in the pharmacy or to effects. The most commonly experienced side effects provide photo identification for purchases. (nausea, dizziness, fatigue, headache, and breast tenderness) are mild (TABLE 4).3 The side effects resolve Pharmacist Consultation quickly after the regimen is completed and do not Providing an environment where consumers can feel require treatment. Most women will have their next comfortable asking questions can greatly improve access menses within one week of the originally expected to EC. Because all members of the pharmacy staff can date. However, other menstrual changes can occur, provide EC to consumers, they should be aware of where including spotting or changes to the menstrual flow it is stocked in the pharmacy, how consumers might volume during the next cycle. Pharmacists may reas- Table 4 Most Common Adverse Events Experienced by Women Receiving Plan B and Plan B One-Step Table 5 Combination Hormonal Contraceptives Used for Emergency Contraception Number of Tablets per Dosea 5 4 4 4 2 Dosage Regimen 2 doses 12 h apart 2 doses 12 h apart 2 doses 12 h apart 2 doses 12 h apart 2 doses 12 h apart Estrogen Dose 100 mcg 120 mcg 120 mcg 120 mcg 100 mcg Progestin Dose b 0.50 mg LNG 0.60 mg LNGb 0.60 mgc 0.50 mg LNGb 0.50 mgc a Brand Names Alesse, Aviane, Levlite, Levlen, Levora, Nordette, Lo/Ovral, Low-Ogestrel Tri-Levlen, Triphasil, Trivora Ovral, Ogestrel Only active hormone-containing tablets can be used. Consult product information to verify the color/hormone content before making recommendations. levonorgestrel. cNorgestrel. bLNG: 74 U.S. Pharmacist • November 2009 • www.uspharmacist.com EMERGENCY CONTRACEPTION: AN UPDATE sure women that changes in menses, while common, are self-limiting. Women can be advised to obtain follow-up care if menses does not occur within seven days of the expected onset date or, for women with irregular menses, within three weeks after using EC. Emergency contraceptives are less effective and are more costly than routine methods of contraception and thus should not be relied upon as an ongoing method of contraception. Contraceptive use is needed for future acts of intercourse if pregnancy is not desired. Women may resume the use of barrier or oral con- traceptives right away after taking EC. The pharmacist should be aware that using EC reduces the risk of pregnancy but does not provide protection from sexually transmitted infections (STIs). When requested, the pharmacist should be prepared to make referral to clinics or health care providers that provide testing and treatment for STIs. The use of condoms for protection from STIs should be encouraged, when applicable. Pharmacists may advise consumers to keep EC products at home and available in case of a contraceptive failure. Keeping EC at home may be more convenient Frequently Asked Questions (FAQ) About Emergency Contraception A Reference for Pharmacists Who can use levonorgestrel for emergency contraception (EC)? Levonorgestrel can be used by women after unprotected intercourse to prevent pregnancy. Women who are already pregnant or who have experienced an allergic reaction to a levonorgestrel-containing product in the past should not use this form of EC. Women with a history of migraine headaches, smokers over age 35, or other contraindications to the use of combination oral contraceptives may use EC. EC should not be used by women who are already pregnant because it is not effective. If EC is taken by a woman who is already pregnant or becomes pregnant after taking EC, it will not harm the fetus or disrupt the pregnancy. Women who are pregnant should consult a health care provider. How effective is levonorgestrel for EC? Plan B and Plan B One-Step have been shown to reduce the risk of pregnancy by up to 89% when taken within 3 days (72 hours) of a contraceptive failure or unprotected intercourse. If taken within the first 24 hours after unprotected sex, EC may be more effective. One way to explain the effectiveness of EC is: if 100 women had unprotected intercourse during week 2 or 3 of their menstrual cycle and no contraception was used, eight women would be expected to become pregnant. If all 100 women used EC, only one woman would be pregnant, thus there is an 89% reduction in the pregnancy rate (one instead of 8 women become pregnant). The effectiveness of EC for an individual may vary depending on the timing of intercourse, delay in taking EC, and the inherent fertility of the couple. How long should I wait to take EC? For best results, EC should be taken as soon as possible after unprotected intercourse or contraceptive failure. For Plan B and Next Choice, the first tablet (0.75 mg levonorgestrel) should be taken within 72 hours of unprotected intercourse followed by a second tablet 12 hours later. For Plan B One-Step, a single tablet (1.5 mg levonorgestrel) should be taken within 72 hours of unprotected intercourse. Taking EC as soon as possible is highly recommended. What if it has been more than 72 hours since intercourse? Although EC has only been approved for use up to 72 hours after unprotected intercourse, the available research indicates that levonorgestrel retains significant activity in reducing the risk of pregnancy for at least 120 hours after unprotected intercourse.6 While EC is more effective when taken earlier, using it up to 120 hours after intercourse may still prevent pregnancy. (Please note that the use of levonorgestrel only EC products after 72 hours for EC has not been approved by the FDA.) Users of EC should be aware that the product may be less effective when taken later than 72 hours after unprotected intercourse. What can I expect after using EC? Most women do not experience side effects from taking EC. Some mild side effects that may occur include: nausea, headache, fatigue, mild abdominal discomfort, or a change in the timing/bleeding of the next menstrual cycle. These are self-limited and do not require treatment. Most women should expect to have their period within about 1 week of when it would be expected. If a woman does not menstruate within 3 weeks of using EC, she should consult her health care provider and/or use a home pregnancy test. Is EC also known as the “abortion pill”? No, the “abortion pill,” Mifeprex (mifepristone) or RU486, is completely different from EC. Levonorgestrel (the hormone in EC) does not cause an abortion and will not be effective if taken by a woman who is already pregnant. Similar to oral contraceptives, EC has been shown to work by preventing ovulation. Once implantation of an embryo begins, EC is not effective. What if I have taken EC more than once? Women may use EC once or more than once depending on their regular birth control method and their personal circumstances. Levonorgestrel for EC is safe and may be used when needed to prevent pregnancy. EC is not as effective as other methods of contraception (such as condoms, oral contraceptives) and therefore the routine use of EC is not recommended. EC is intended to be a backup method of contraception. 75 U.S. Pharmacist • November 2009 • www.uspharmacist.com EMERGENCY CONTRACEPTION: AN UPDATE and better facilitate timely administration. Although EC is indicated for use after unprotected intercourse, consumers do not need to wait to purchase it until after they have experienced a contraceptive emergency. Pharmacists who are available to consumers with questions about EC will have an opportunity to make referrals to community resources. Pharmacists are in an excellent position to serve as a resource for consumers and provide information about other methods of contraception that, when used before or during intercourse, are more effective than EC in preventing unintended pregnancies. Pharmacists should have available the name, address, and phone number for local referral services when the consumer’s contraceptive needs cannot be met in the pharmacy. This may include consumers lacking proof of age needed to purchase EC without a prescription, girls under the age of 17, consumers unable to pay for EC, or those who want to be examined for STIs. In the event that the pharmacy does not have EC in stock, the pharmacy staff should be prepared to provide consumers with contact information for a nearby pharmacy, after verifying the product is in stock, to avoid delays in starting therapy. Pharmacists should be aware that some women seeking EC may be victims of sexual assault. If a woman discloses violence to the pharmacist, whether in the context of purchasing EC or first aid supplies such as bandages, offering access to a private phone and referral information for support services is indicated. Every pharmacist should also have national and local domestic and sexual violence service agency contact information readily available for consumers. Pharmacy Access Programs In states with pharmacy access programs, women seeking EC who are unable to show proof of age or who need a prescription for insurance purposes may be able to have a prescription for EC initiated by a pharmacist. Direct access from a pharmacist is currently permitted in nine states: Alaska, California, Hawaii, Maine, Massachusetts, New Mexico, New Hampshire, REFERENCES 1. FDA. Plan B (levonorgestrel 0.75 mg) [Letter FDA to Sponsor]. August 26, 2005. www.fda.gov/bbs/topics/news/2005/duramed_ ltr.html. Accessed September 2009. 2. FDA. Plan B (levonorgestrel 0.75 mg) [Approval letter]. August 24, 2006. www.fda.gov/cder/foi/nda/2006/021045s011_Plan_B_APPROV.pdf. Accessed September 2009. 3. FDA. Plan B One-Step (levonorgestrel 1.5 mg) [Approval letter]. July 10, 2009. www.accessdata.fda.gov/drugsatfda_docs/appletter/2009/ 021998s000ltr.pdf. Accessed September 2009. 4. Finer LB, Henshaw SK. Disparities in the rates of unintended pregnancy in the United States 1994-2001. Perspect Sex Reprod Health. 2006;38:90-96. 5. Plan B One-Step (levonorgestrel 1.5 mg tablets) package insert. Pomona, New York: Duramed Pharmaceuticals, Inc. July 2009. 6. Trussell J, Schwarz EB, Guthrie K, Raymond E. No such thing as an easy (or EC) fix. Contraception. 2008;78:351-354. 7. Cheng L, Gulmezoglu AM, Piaggio G, et al. Interventions for emergency contraception. Cochrane Database Syst Rev. 2008;(2):CD001324. Vermont, and Washington. 3 1 States permitting pharmacists to initiate prescriptions have specific requirements for pharmacist participation that may include training and/or collaborative protocol arrangements. In some states with pharmacy access it may be permitted to provide other prescription oral contraceptive products for use as EC under certain circumstances, such as when levonorgestrel-only products are unavailable (TABLE 5). Pharmacy access programs are not available to males under age 17 seeking EC because only the person taking the medication can receive a prescription from the pharmacist. If EC products are out of stock or otherwise unavailable, there are alternative regimens such as oral contraceptive combinations that can be provided by the pharmacist under some access programs. These regimens have more side effects and may be less effective; however, if there are no other options (such as referral to a nearby pharmacy or clinic) they may serve as a backup option.8,25,32 Summary and Conclusions Levonorgestrel-only EC is safe and effective for preventing unintended pregnancy after intercourse. The OTC sale to consumers at least 17 years of age is a major step toward improving access and removing barriers to the use of EC in the U.S. The timesensitive nature of EC means that ready access to women is an essential component of successful use. Pharmacists serve a critical role in expanding access to EC and are relied upon for up-to-date information regarding the safety and efficacy of EC. The role of the pharmacist includes: providing information and counseling to consumers seeking EC, maintaining an adequate supply of EC at all times, and in states where collaborative practice allows pharmacists to provide EC directly to those under age 17, becoming an ECdirect provider. By understanding the appropriate use and distribution of EC products, pharmacists can significantly reduce barriers preventing consumers from using these products. 8. ACOG Practice Bulletin. Clinical Management Guidelines for Obstetrician-Gynecologists, Number 69, December 2005. Emergency oral contraception. Obstet Gynecol. 2005;106:1443-1452. 9. Task Force on Postovulatory Methods of Fertility Regulation. Randomised controlled trial of levonorgestrel versus the Yuzpe regimen of combined oral contraceptives for emergency contraception. Lancet. 1998;352:428-433. 10. Turner A, Ellertson C. How safe is emergency contraception? Drug Safety. 2002;25;695-706. 11. Minutes of the FDA Joint Advisory Committee Meeting December 16, 2003. www.fda.gov/ohrms/dockets/ac/03/transcripts/4015T1.htm. Accessed September 2009. 12. Abuabara K, Becker D, Ellertson C, Blanchard K, et al. As often as needed: appropriate use of emergency contraceptive pills. Contraception. 2004:69:339-342. 13. Ellertson C, Webb A, Blanchard K, et al. Modifying the Yuzpe regimen of emergency contraception: a multicenter randomized controlled trail. Obstet Gynecol. 2003;101:1160-1167. 76 U.S. Pharmacist • November 2009 • www.uspharmacist.com EMERGENCY CONTRACEPTION: AN UPDATE 14. Creinin MD, Schlaff W, Archer DF, et al. Progesterone receptor modulator for emergency contraception. A randomized controlled trial. Obstet Gynecol. 2006;108:1089-1097. 15. Croxatto HB. Emergency contraception pills: how do they work? IPPF Med Bull. 2002;36:1-2. 16. Gemzell-Danielsson K, Marions L. Mechanisms of action of mifepristone and levonorgestrel when used for emergency contraception. Hum Reprod Update. 2004;10:341-348. 17. Croxatto HB, Brache V, Pavez M, et al. Pituitary-ovarian function following the standard levonorgestrel emergency-contraception dose or a single 0.75 mg dose given on the days preceding ovulation. Contraception. 2004;70:442-450. 18. Durand M, del Carmen Cravioto M, Raymond EG, et al. On the mechanisms of action of short-term levonorgestrel administration in emergency contraception. Contraception. 2001;64:227-234. 19. Davidoff F, Trussell J. Plan B and the politics of doubt. JAMA. 2006;296:1775-1778. 20. Baird DT. Emergency contraception: how does it work? Reprod Biomed Online. 2009;18(suppl 1):32-36. 21. Trussell J, Hedley A, Raymond E. Ectopic pregnancy following use of progestin-only ECPs. J Fam Plann Reprod Health Care. 2003;29:249. 22. International Consortium for Emergency Contraception and the International Federation of Gynecology & Obstetrics. How do levonorgestrelonly emergency contraceptive pills work to prevent pregnancy? October 2008. www.cecinfo.org. Accessed September 2009. 23. WHO Fact Sheet 244. Emergency contraception. Revised October 2005. www.who.int/mediacentre/factsheets/fs244/en/ index.html. Accessed October 2009. 24. Piaggio G, Von Hertzen H, Grimes DA, Van Look PF. Timing of emergency contraception with levonorgestrel or the Yuzpe regimen. Lancet. 1999;353:721. 25. Ellertson C, Evans M, Ferden S, et al. Extending the time limit for starting the Yuzpe regimen of emergency contraception to 120 hours. Obstet Gynecol. 2003;101:1168-1171. 26. Rodrigues I, Grou F, Joly J. Effectiveness of emergency contraceptive pills between 72 and 120 hours after unprotected sexual intercourse. Am J Obstet Gynecol. 2001;184:531-537. 27. Von Hertzen H, Piaggio G, Ding J, et al. Low dose mifepristone and two regimens of levonorgestrel for emergency contraception: a WHO multicentre randomized trial. Lancet. 2002;360:1803-1810. 28. Arowojulu AO, Okewolw IA, Adekunle AO. Comparative evaluation of the effectiveness and safety of two regimens of levonorgestrel for emergency contraception in Nigerians. Contraception. 2002;66:269-273. 29. Hamoda H, Ashok PW, Stalder C, et al. A randomized trial of mifepristone (10 mg) and levonorgestrel for emergency contraception. Obstet Gynecol. 2004;104:1307-1313. 30. Raine TR, Harper CC, Rocca CH, et al. Direct access to emergency contraception through pharmacies and effect on unintended pregnancy and STIs: a randomized controlled trial. JAMA. 2005;293:54-62. 31. GO2EC. Comparison of EC pharmacy access states. Models for EC pharmacies. www.go2ec.org/ModelsForECPharmacies.htm. Accessed September 2009. 32. International Consortium for Emergency Contraception. Emergency Contraceptive Pills: Medical and Service Delivery Guidelines. 2nd ed. Washington, DC; 2004. www.cecinfo.org/publications/PDFs/resources/MedicalServiceD liveryGuidelines_Eng.pdf. Accessed September 2009. Disclosure Statements: Kathleen H. Besinque, PharmD, MSEd, has no real or apparent conflicts of interest in relation to this program. U.S. Pharmacist does not view the existence of relationships as an implication of bias or that the value of the material is decreased. The content of the activity was planned to be balanced, objective, and scientifically rigorous. Occasionally, authors may express opinions that represent their own viewpoint. Conclusions drawn by participants should be derived from objective analysis of scientific data. Disclaimer: EXAMINATION Select one correct answer for each question and record your responses on the examination answer sheet. Mail it to U.S. Pharmacist, address shown on the answer sheet (photocopies are acceptable). Please allow four weeks for processing. Alternatively, this exam can be taken online at www.uspharmacist.com. Please contact CE Customer Service at (800) 825-4696 or [email protected] with any questions. 2 CE Credits Emergency Contraception: An Update of Clinical and Regulatory Changes 1. Which of the following statements accurately describes emergency contraception (EC) with levonorgestrel? A. A hormonal method of contraception after intercourse B. A method of contraception that has Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by clinicians without evaluation of their patients’ conditions and possible contraindications or dangers in use, review of any applicable manufacturer’s product information, and comparison with recommendations of other authorities. been studied since the 1970s C. A safe and effective method for preventing unintended pregnancy D.All of the above 2. Which of the following describes when EC is indicated? A. After a condom fails (dislodges/breaks) during intercourse B. After a sexual encounter when a woman has missed one or more doses of her oral contraceptive C. When a contraceptive method was not used during intercourse D.All of the above 3. Clinical studies have demonstrated that levonorgestrel-based emergency contraceptives prevent pregnancy by which of the following mechanisms? A. Inhibition or delay of ovulation B. Disruption of an implanted embryo C. Changes to endometrial lining of the uterus D.All of the above 77 U.S. Pharmacist • November 2009 • www.uspharmacist.com EMERGENCY CONTRACEPTION: AN UPDATE 4. Which of the following statements best describes the effectiveness of levonorgestrel EC regimens? A. Efficacy is increased by initiating EC as soon as possible after unprotected intercourse B. Studies have shown a 30% reduction in the risk of pregnancy when EC is taken within 72 hours of unprotected intercourse C. The products have demonstrated efficacy when taken up to 7 days after unprotected intercourse D.The products are as effective as barrier methods of contraception 5. The FDA approved regimen for Plan B One-Step is: A. One tablet to be taken within 120 hours after unprotected intercourse B. Two doses of one tablet taken 12 hours apart, started within 72 hours of unprotected intercourse C. One tablet to be taken within 72 hours of unprotected intercourse D.Two doses of one tablet taken 12 hours apart, started within 120 hours of unprotected intercourse 6. The most common side effects resulting from the use of levonorgestrel for EC include: A. Severe headache or eye pain B. Mild nausea and fatigue C. Increased risk of blood clots D.All of the above 7. The use of levonorgestrel for EC between 72 and 120 hours after unprotected intercourse: A. Has been shown to be ineffective B. Is less effective than when used within 72 hours and has not been approved by the FDA C. Has been shown to cause more side effects than use within 72 hours D.Is not permitted in the U.S. 8. Medical contraindications to the use of levonorgestrel-based emergency contraception include: A. A history of migraine headaches B. An established pregnancy C. Age over 35 years D.All of the above 9. Outcomes reported in studies evaluating advanced provision of EC include: A. A reduction in the use of other contraceptive methods B. An increase in the frequency of unprotected intercourse C. An increase in the use EC after unprotected intercourse D.An increased rate of sexually transmitted infections 10. Which statement best describes requirements for nonprescription sales of EC in a pharmacy? A. Only one package can be sold at a time to consumers without a prescription B. Plan B but not Plan B One-Step can be sold to men C. EC can be provided to a 17-year-old without a prescription D.EC products can be kept on shelves with other OTC products for women 11. Pharmacy staff members able to sell nonprescription EC to eligible consumers include: A. A licensed pharmacist B. A pharmacy technician C. A pharmacy clerk working behind the pharmacy counter D.All of the above 12. When selling EC without a prescription to a man, pharmacists: A. Need to check for proof that he is at least 17 years of age B. Must limit sales to one package C. Must ask for the name and age of the woman who will be taking the product D.Keep a log with his name and signature at the point of purchase 13. Which of the following is appropriate for a pharmacist to say to a woman asking to purchase nonprescription EC? A. Have you had unprotected intercourse? EC can only be sold after a contraceptive emergency B. It is important to take a pregnancy test before using EC C. You may not purchase more than one package at a time D.Do you have any questions about the use of this product? 14. Nonprescription sale of EC requires: A. The purchaser to present proof that he/she is at least 17 years of age B. The person who will be taking the medication to come to the pharmacy C. The purchaser’s signature on a registry kept in the pharmacy D.Consultation by the pharmacist 78 U.S. Pharmacist • November 2009 • www.uspharmacist.com EMERGENCY CONTRACEPTION Examination Answer Sheet Credits: 2.0 hours (0.20 ceu) Expires: November 30, 2011 This exam can be taken online at www.uspharmacist.com. Upon passing, you can print out your statement immediately and view your test history. Alternatively, you can mail this answer sheet to the address below. Please contact CE Customer Service at (800) 825-4696 or [email protected] with any questions. Emergency Contraception: An Update of Clinical and Regulatory Changes Directions: Select one answer for each question in the exam and completely darken the appropriate circle. A minimum score of 70% is required to earn credit. An identifier is required to process your exam. This is used for internal processing purposes only. Mail to: U.S. Pharmacist–CE, PO Box 487, Canal Street Station, New York, NY 10013 Supported by an educational grant from Teva Women’s Health. 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. A B C D 1 = Excellent A B C D Rate the effectiveness of how well the activity: 2 = Very Good 3 = Good A B C D A B C D A B C D 4 = Fair 5 = Poor 21. Met objective 1:* 1 2 3 4 5 22. Met objective 2:* 1 2 3 4 5 23. Met objective 3:* 1 2 3 4 5 24. Met objective 4:* 1 2 3 4 5 A B C D A B C D A B C D 25. Met objective 5:* 1 2 3 4 5 A B C D 26. Related to your educational needs: 1 2 3 4 5 A B C D A B C D 27. The active learning strategies (questions, cases, discussions) were appropriate and effective learning tools: 1 2 3 4 5 A B C D 28. Avoided commercial bias: 1 2 3 4 5 29. How would you rate the overall usefulness of the material presented? A B C D A B C D A B C D A B C D A B C A B A A 1 2 3 4 5 30. How would you rate the quality of the faculty? 1 2 3 4 5 D 31. How would you rate the appropriateness of the examination for this activity? 2 3 4 5 C D 32. Comments on this activity: B C D B C D 1 * Also applies to pharmacy technicians. Please retain a copy for your records. Please print clearly. You must choose and complete ONE of the following three identifier types: 1 SS # - - 2 Last 4 digits of your SS # and date of birth - 3 State Code and License # (Example: FL12345678) First Name Last Name E-Mail The following is your: Home Address Business Address Business Name Address City State 15. Which of the following may be barriers for consumers to access EC? A. The requirement to keep EC behind the pharmacy counter B. Embarrassment about asking the pharmacy staff for the product C. Misinformation about when to use EC D.All of the above 16. Which of the following actions should be taken when a woman requests EC, but the pharmacy is out of stock? A. Tell her you will order the medication and she should come back in a couple of days B. Direct her to a nearby pharmacy where the medication is available C. Tell her you are out of stock D.A and C only 17. Which of the following emergency contraceptive products contains a single dose of 1.5 mg levonorgestrel? A. Plan B B. Plan B One-Step C. Next Choice D.All of the above 18. Pharmacists can improve access to EC by: A. Placing emergency contraceptive products in an easy to see location in the pharmacy B. Educating the pharmacy staff about EC C. Being available to answer consumer questions D.All of the above 19. In states with Pharmacist Access programs for EC, the participating pharmacist is able to: A. Provide Plan B or Plan B One-Step to men of all ages B. Initiate a prescription for Plan B to those without proof of age or who need a prescription for insurance purposes C. Provide women of any age with routine hormonal contraception D.Test women for STIs in the pharmacy ZIP Telephone # - - Fax # - - Profession: Pharmacist Pharmacy Technician Other By submitting this answer sheet, I certify that I have read the lesson in its entirety and completed the self-assessment exam personally based on the material presented. I have not obtained the answers to this exam by any fraudulent or improper means. Signature ® Date Postgraduate Healthcare Education, LLC is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. Lesson 106417 Type of Activity: Knowledge 0430-0000-09-027-H01-P 0430-0000-09-027-H01-T 20. Which of the following statement(s) are important for consumer education regarding the use of EC? A. Taking EC as soon as possible may increase its effectiveness B. EC is not intended to replace your other methods of birth control C. Taking EC reduces the risk of pregnancy but not the risk of sexually transmitted infections D.All of the above 79 U.S. Pharmacist • November 2009 • www.uspharmacist.com U.S. Pharmacist Classifieds CAREER OPPORTUNITIES We are currently hiring for the following positions: G Director of Pharmacy DE – Smyrna KY – Prestonburg LA – Shreveport (2) MD – Baltimore MD – Rockville MT – Libby RI – Westerly TN – Springfield G Assistant Director of Pharmacy NC – Wilmington G Clinical Manager NY – Valhalla G System Clinical Manager LA – Shreveport G Clinical Staff Pharmacist AZ – Phoenix; Tempe G Staff Pharmacist DE – Smyrna FL– Tampa (PRN) NV – North Las Vegas (4) PRN PA – Waynesburg G G G TX – Odessa; Port Arthur WV – Princeton WY – Jackson Hole • Leading, global provider of information, products, services and technologies for the health care industry • Ranked 18th in Fortune 500 • 30,000 employees worldwide • $87 billion global company TX – Bryan TX - Odessa; San Antonio TX – Sulphur Springs (PRN); San Antonio (1) F/T, (1) PRN; TX – The Woodlands UT – Layton (PRN) Salt Lake City (PRN) WV – Bluefield (P/T) (PRN) Pharmacy Technicians AZ – Mesa; Phoenix DE – Smyrna FL – Port St. Lucie TX – The Woodlands UT – Layton Rxe-sourceSM (Staff Pharmacists at Remote Centers, 7on/7 off Overnight) CA – Glendale NC – Cary MA – Marlborough Pharmacy Intern AZ – Phoenix (2) CAREER OPPORTUNITIES Nome, Alaska Where else might you see musk oxen and sled dogs on your way to work and still pan for gold on the beach? Serve the people of northwest Alaska in a unique, comprehensive health system in a vast, stark and fiercely beautiful yet surprisingly livable Seward Peninsula. Director of Pharmacy: $140,000+ DOE, benefits, relocation allowance and potential for student loan repayment from the Indian Health Service. Norton Sound Health Corporation Steve Brock [email protected] | 877-538-3142 (NO Recruitment firms or agency reps) PRODUCTS AND SERVICES FILL RXS FASTER- TIME IS LIFE phone or fax NOW: 1-800-487-5024 Improved...Shake & Roll speedy tab/cap counter. Durable, maintenance-free, over 20,000 sold. $129.85+ frght, 30-day free trial. (eliminate CountFatigue forever - be happy). Chem-Pharm Corp Who is Cardinal Health? Box 6246, West Palm Beach, FL 33405. Who is Pharmacy Services? • We bring 40 years of expertise in helping hospitals and healthcare systems improve both the financial predictability of pharmacies and the quality of patient care. • 1,000 pharmacists employed, including 110 clinical specialists • Participate in more than 140 accreditation survey reviews each year • We process four million order lines remotely each year and identified 20,000 patient safety events through our Rxe-sourceSM centers in 2008 • Rxe-viewTM solution is an automated medication order management and clinical intervention tracking tool • We also offer a customized portfolio of drug contracts For information or to apply, call 800-231-9807 ext. 1315 or fax 281-749-2026 CAREER OPPORTUNITIES U.S. Pharmacist Classifieds CAREER OPPORTUNITIES To place a classified ad, call: Toll Free: (800) 983-7737 Phone: (610) 854-3770 Fax: (610) 854-3780 AD INDEX National Health Systems New Products - National AstraZeneca . . . . . . . . . . . . . . . CV4 Coca-Cola Co. . . . . . . . . . . . . . . . . 23 Daiichi-Sankyo. . . . . . . . . . . . . . . . 37 Dr. Reddy's . . . . . . . . . . . . . . . . . . 55 Fougera . . . . . . . . . . . . . . . . . . . . . . 9 Greenstone LLC . . . . . . . . . . . . . . 57 King Pharmaceuticals, Inc. . . . . . . 31 Mylan Pharmaceuticals Inc. . . . . . . 7 Novartis Pharmaceuticals . . . . . . . 27 Paddock Laboratories . . . . . . . . . . 59 Pfizer Inc. . . . . . . . . . . . . . . . . . . . 62 QS/1 Data System. . . . . . . . . . . . . 25 Schering-Plough . . . . . . . . . . . . . . 16 ScriptPro . . . . . . . . . . . . . . . . . . . . 19 Takeda Pharmaceuticals North America . . . . . . . . . . . . . . . . CV2, 42 Teva Pharmaceuticals . . . . . . . . . . 11 Baxter Healthcare . . . . . . . . . . HS31 Cubist Pharmaceuticals. . . . . . HS03 Dr. Reddy's . . . . . . . . . . . . . . . HS29 Eli Lilly and Company . . . . . . . HS23 Medi-Dose Group . . . . . . . . . . HS25 Mylan Pharmaceuticals Inc. . . .HS11 Ortho-McNeil . . . . . . . . . . . . . . HS17 Pfizer Injectables . . . . . . . . . . . HS01 Sagent Pharmaceuticals . . . . . HS27 Teva Pharmaceuticals . . . . . . . HS21 Waste Management - Segments . . HS07 Embeda / King Pharmaceuticals, Inc. . . . . . . . .31 Kapidex / Takeda Pharmaceuticals North America. . . . . . . . . . . . . . . . . . .42 Onglyza / AstraZeneca . . . . . . . . . CV4 Uloric / Takeda Pharmaceuticals North America. . . . . . . . . . . . . . . . . CV2 Welchol / Daiichi-Sankyo . . . . . . . . . .37 New Products - Health Systems New Products - National Distinctive Labeling / Baxter Healthcare . . . . . . . . . . HS31 Authorized Generics / Greenstone LLC . . . . . . . . . . . . . . . . .57 Product Labeling / Teva Pharmaceuticals . . . . . . . HS21 Afinitor / Novartis Pharmaceuticals . .27 Injectables / Pfizer Injectables . . . HS01 Product News Valstar Reintroduction Fills Bladder Cancer Treatment Gap Endo Pharmaceuticals announced the reintroduction and availability of a reformulated version of Valstar. Widely used to treat an aggressive type of recurrent bladder cancer before it became unavailable in 2002, the drug was reapproved by the FDA in February 2009 for bacille CalmetteGuérin (BCG) vaccine–refractory carcinoma in situ of the urinary bladder. Valstar represents a new treatment option for patients who may otherwise have exhausted all other FDA-approved treatment alternatives, including BCG. Medi-Dose/EPS Announces Three New Products To complement their popular Butterfly labels for syringes, ampules, and small containers, Medi-Dose, Inc., has introduced Butterfly labels in five new colors to call attention to medication requiring special handling. MediDose labels can be printed with a regular laser printer, and their unique hourglass design provides practitioners with ample area for medication identification. To reduce the number of errors in operating rooms due to mishandling of look-alike medications, EPS, Inc., has released two new ShrinkSafe ID Bands for chemotherapy and high-alert drugs. ShrinkSafe was designed to easily wrap around various-sized able by prescription only, hyoscyamine tablets come in bottles of 100 in 0.375-mg strength. vials and is available in bright colors to indicate medications requiring special handling. In addition to its English Pharmacy Warning and Instruction Labels, Medi-Dose/EPS has introduced a line of Spanish Pharmacy and Nursing Auxiliary Labels. These labels call attention to the same special information and indications for medications as the company’s English versions. CBI Announces TruTag Technology Cellular Bioengineering, Inc., announced the development of a novel technology that can help prevent counterfeiting of medicine and pharmaceutical products. TruTag is an edible, microscopic, nanoporous silica microtag that can be used to safely and directly mark medicine. Bioniche and Synerx Launch Fomepizole Injection Bioniche Pharma and Synerx Pharma, LLC, announced the launch of fomepizole injection, the generic equivalent of Antizol (Paladin Labs, Inc.). Fomepizole is available in 1.5-g/1.5-mL vials. Par Receives Approval to Market Starlix Par Pharmaceutical Companies, Inc., has received FDA approval for nateglinide tablets. Nateglinide is a generic version of Starlix (Novartis) and is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Perrigo Announces Approval for Polyethylene Glycol 3350 Perrigo Company announced FDA approval for OTC Polyethylene Glycol 3350, Powder for Solution. The product is indicated for the treatment of occasional constipation and is comparable to MiraLax Products (Schering-Plough). Paddock Labs Releases New Product Paddock Laboratories, Inc., announced the addition of hyoscyamine sulfate extended-release tablets to its product line. Avail- 82 U.S. Pharmacist • November 2009 • www.uspharmacist.com ONGLYZA™ (saxagliptin) tablets Brief Summary of Prescribing Information. For complete prescribing information consult official package insert. INDICATIONS AND USAGE Monotherapy and Combination Therapy ONGLYZA (saxagliptin) is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. [See Clinical Studies (14).] Important Limitations of Use ONGLYZA should not be used for the treatment of type 1 diabetes mellitus or diabetic ketoacidosis, as it would not be effective in these settings. ONGLYZA has not been studied in combination with insulin. CONTRAINDICATIONS None. WARNINGS AND PRECAUTIONS Use with Medications Known to Cause Hypoglycemia Insulin secretagogues, such as sulfonylureas, cause hypoglycemia. Therefore, a lower dose of the insulin secretagogue may be required to reduce the risk of hypoglycemia when used in combination with ONGLYZA. [See Adverse Reactions (6.1).] Macrovascular Outcomes There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with ONGLYZA or any other antidiabetic drug. ADVERSE REACTIONS Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Monotherapy and Add-On Combination Therapy In two placebo-controlled monotherapy trials of 24-weeks duration, patients were treated with ONGLYZA 2.5 mg daily, ONGLYZA 5 mg daily, and placebo. Three 24-week, placebo-controlled, add-on combination therapy trials were also conducted: one with metformin, one with a thiazolidinedione (pioglitazone or rosiglitazone), and one with glyburide. In these three trials, patients were randomized to add-on therapy with ONGLYZA 2.5 mg daily, ONGLYZA 5 mg daily, or placebo. A saxagliptin 10 mg treatment arm was included in one of the monotherapy trials and in the add-on combination trial with metformin. In a prespecified pooled analysis of the 24-week data (regardless of glycemic rescue) from the two monotherapy trials, the add-on to metformin trial, the add-on to thiazolidinedione (TZD) trial, and the add-on to glyburide trial, the overall incidence of adverse events in patients treated with ONGLYZA 2.5 mg and ONGLYZA 5 mg was similar to placebo (72.0% and 72.2% versus 70.6%, respectively). Discontinuation of therapy due to adverse events occurred in 2.2%, 3.3%, and 1.8% of patients receiving ONGLYZA 2.5 mg, ONGLYZA 5 mg, and placebo, respectively. The most common adverse events (reported in at least 2 patients treated with ONGLYZA 2.5 mg or at least 2 patients treated with ONGLYZA 5 mg) associated with premature discontinuation of therapy included lymphopenia (0.1% and 0.5% versus 0%, respectively), rash (0.2% and 0.3% versus 0.3%), blood creatinine increased (0.3% and 0% versus 0%), and blood creatine phosphokinase increased (0.1% and 0.2% versus 0%). The adverse reactions in this pooled analysis reported (regardless of investigator assessment of causality) in ≥5% of patients treated with ONGLYZA 5 mg, and more commonly than in patients treated with placebo are shown in Table 1. Table 1: Adverse Reactions (Regardless of Investigator Assessment of Causality) in Placebo-Controlled Trials* Reported in 5% of Patients Treated with ONGLYZA 5 mg and More Commonly than in Patients Treated with Placebo Number (%) of Patients ONGLYZA 5 mg Placebo N=882 N=799 Upper respiratory tract infection 68 (7.7) 61 (7.6) Urinary tract infection 60 (6.8) 49 (6.1) Headache 57 (6.5) 47 (5.9) * The 5 placebo-controlled trials include two monotherapy trials and one add-on combination therapy trial with each of the following: metformin, thiazolidinedione, or glyburide. Table shows 24-week data regardless of glycemic rescue. In patients treated with ONGLYZA 2.5 mg, headache (6.5%) was the only adverse reaction reported at a rate ≥5% and more commonly than in patients treated with placebo. In this pooled analysis, adverse reactions that were reported in ≥2% of patients treated with ONGLYZA 2.5 mg or ONGLYZA 5 mg and ≥1% more frequently compared to placebo included: sinusitis (2.9% and 2.6% versus 1.6%, respectively), abdominal pain (2.4% and 1.7% versus 0.5%), gastroenteritis (1.9% and 2.3% versus 0.9%), and vomiting (2.2% and 2.3% versus 1.3%). In the add-on to TZD trial, the incidence of peripheral edema was higher for ONGLYZA 5 mg versus placebo (8.1% and 4.3%, respectively). The incidence of peripheral edema for ONGLYZA 2.5 mg was 3.1%. None of the reported adverse reactions of peripheral edema resulted in study drug discontinuation. Rates of peripheral edema for ONGLYZA 2.5 mg and ONGLYZA 5 mg versus placebo were 3.6% and 2% versus 3% given as monotherapy, 2.1% and 2.1% versus 2.2% given as add-on therapy to metformin, and 2.4% and 1.2% versus 2.2% given as add-on therapy to glyburide. The incidence rate of fractures was 1.0 and 0.6 per 100 patient-years, respectively, for ONGLYZA (pooled analysis of 2.5 mg, 5 mg, and 10 mg) and placebo. The incidence rate of fracture events in patients who received ONGLYZA did not increase over time. Causality has not been established and nonclinical studies have not demonstrated adverse effects of saxagliptin on bone. An event of thrombocytopenia, consistent with a diagnosis of idiopathic thrombocytopenic purpura, was observed in the clinical program. The relationship of this event to ONGLYZA is not known. Adverse Reactions Associated with ONGLYZA (saxagliptin) Coadministered with Metformin in Treatment-Naive Patients with Type 2 Diabetes Table 2 shows the adverse reactions reported (regardless of investigator assessment of causality) in ≥5% of patients participating in an additional 24-week, active-controlled trial of coadministered ONGLYZA and metformin in treatment-naive patients. Table 2: Initial Therapy with Combination of ONGLYZA and Metformin in Treatment-Naive Patients: Adverse Reactions Reported (Regardless of Investigator Assessment of Causality) in 5% of Patients Treated with Combination Therapy of ONGLYZA 5 mg Plus Metformin (and More Commonly than in Patients Treated with Metformin Alone) Number (%) of Patients ONGLYZA 5 mg + Metformin* Metformin* N=320 N=328 Headache 24 (7.5) 17 (5.2) Nasopharyngitis 22 (6.9) 13 (4.0) * Metformin was initiated at a starting dose of 500 mg daily and titrated up to a maximum of 2000 mg daily. Hypoglycemia Adverse reactions of hypoglycemia were based on all reports of hypoglycemia; a concurrent glucose measurement was not required. In the add-on to glyburide study, the overall incidence of reported hypoglycemia was higher for ONGLYZA 2.5 mg and ONGLYZA 5 mg (13.3% and 14.6%) versus placebo (10.1%). The incidence of confirmed hypoglycemia in this study, defined as symptoms of hypoglycemia accompanied by a fingerstick glucose value of ≤50 mg/dL, was 2.4% and 0.8% for ONGLYZA 2.5 mg and ONGLYZA 5 mg and 0.7% for placebo. The incidence of reported hypoglycemia for ONGLYZA 2.5 mg and ONGLYZA 5 mg versus placebo given as monotherapy was 4.0% and 5.6% versus 4.1%, respectively, 7.8% and 5.8% versus 5% given as add-on therapy to metformin, and 4.1% and 2.7% versus 3.8% given as add-on therapy to TZD. The incidence of reported hypoglycemia was 3.4% in treatment-naive patients given ONGLYZA 5 mg plus metformin and 4.0% in patients given metformin alone. Hypersensitivity Reactions Hypersensitivity-related events, such as urticaria and facial edema in the 5-study pooled analysis up to Week 24 were reported in 1.5%, 1.5%, and 0.4% of patients who received ONGLYZA 2.5 mg, ONGLYZA 5 mg, and placebo, respectively. None of these events in patients who received ONGLYZA required hospitalization or were reported as life-threatening by the investigators. One saxagliptin-treated patient in this pooled analysis discontinued due to generalized urticaria and facial edema. Vital Signs No clinically meaningful changes in vital signs have been observed in patients treated with ONGLYZA. Laboratory Tests Absolute Lymphocyte Counts There was a dose-related mean decrease in absolute lymphocyte count observed with ONGLYZA. From a baseline mean absolute lymphocyte count of approximately 2200 cells/microL, mean decreases of approximately 100 and 120 cells/microL with ONGLYZA 5 mg and 10 mg, respectively, relative to placebo were observed at 24 weeks in a pooled analysis of five placebo-controlled clinical studies. Similar effects were observed when ONGLYZA 5 mg was given in initial combination with metformin compared to metformin alone. There was no difference observed for ONGLYZA 2.5 mg relative to placebo. The proportion of patients who were reported to have a lymphocyte count ≤750 cells/microL was 0.5%, 1.5%, 1.4%, and 0.4% in the saxagliptin 2.5 mg, 5 mg, 10 mg, and placebo groups, respectively. In most patients, recurrence was not observed with repeated exposure to ONGLYZA although some patients had recurrent decreases upon rechallenge that led to discontinuation of ONGLYZA. The decreases in lymphocyte count were not associated with clinically relevant adverse reactions. The clinical significance of this decrease in lymphocyte count relative to placebo is not known. When clinically indicated, such as in settings of unusual or prolonged infection, lymphocyte count should be measured. The effect of ONGLYZA on lymphocyte counts in patients with lymphocyte abnormalities (e.g., human immunodeficiency virus) is unknown. Platelets ONGLYZA did not demonstrate a clinically meaningful or consistent effect on platelet count in the six, double-blind, controlled clinical safety and efficacy trials. DRUG INTERACTIONS Inducers of CYP3A4/5 Enzymes Rifampin significantly decreased saxagliptin exposure with no change in the area under the time-concentration curve (AUC) of its active metabolite, 5-hydroxy saxagliptin. The plasma dipeptidyl peptidase-4 (DPP4) activity inhibition over a 24-hour dose interval was not affected by rifampin. Therefore, dosage adjustment of ONGLYZA is not recommended. [See Clinical Pharmacology (12.3).] Inhibitors of CYP3A4/5 Enzymes Moderate Inhibitors of CYP3A4/5 Diltiazem increased the exposure of saxagliptin. Similar increases in plasma concentrations of saxagliptin are anticipated in the presence of other moderate CYP3A4/5 inhibitors (e.g., amprenavir, aprepitant, erythromycin, fluconazole, fosamprenavir, grapefruit juice, and verapamil); however, dosage adjustment of ONGLYZA is not recommended. [See Clinical Pharmacology (12.3).] Strong Inhibitors of CYP3A4/5 Ketoconazole significantly increased saxagliptin exposure. Similar significant increases in plasma concentrations of saxagliptin are anticipated with other strong CYP3A4/5 inhibitors (e.g., atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir, and telithromycin). The dose of ONGLYZA should be limited to 2.5 mg when coadministered with a strong CYP3A4/5 inhibitor. [See Dosage and Administration (2.3) and Clinical Pharmacology (12.3).] USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category B There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, ONGLYZA (saxagliptin), like other antidiabetic medications, should be used during pregnancy only if clearly needed. Saxagliptin was not teratogenic at any dose tested when administered to pregnant rats and rabbits during periods of organogenesis. Incomplete ossification of the pelvis, a form of developmental delay, occurred in rats at a dose of 240 mg/kg, or approximately 1503 and 66 times human exposure to saxagliptin and the active metabolite, respectively, at the maximum recommended human dose (MRHD) of 5 mg. Maternal toxicity and reduced fetal body weights were observed at 7986 and 328 times the human exposure at the MRHD for saxagliptin and the active metabolite, respectively. Minor skeletal variations in rabbits occurred at a maternally toxic dose of 200 mg/kg, or approximately 1432 and 992 times the MRHD. When administered to rats in combination with metformin, saxagliptin was not teratogenic nor embryolethal at exposures 21 times the saxagliptin MRHD. Combination administration of metformin with a higher dose of saxagliptin (109 times the saxagliptin MRHD) was associated with craniorachischisis (a rare neural tube defect characterized by incomplete closure of the skull and spinal column) in two fetuses from a single dam. Metformin exposures in each combination were 4 times the human exposure of 2000 mg daily. Saxagliptin administered to female rats from gestation day 6 to lactation day 20 resulted in decreased body weights in male and female offspring only at maternally toxic doses (exposures ≥1629 and 53 times saxagliptin and its active metabolite at the MRHD). No functional or behavioral toxicity was observed in offspring of rats administered saxagliptin at any dose. Saxagliptin crosses the placenta into the fetus following dosing in pregnant rats. Nursing Mothers Saxagliptin is secreted in the milk of lactating rats at approximately a 1:1 ratio with plasma drug concentrations. It is not known whether saxagliptin is secreted in human milk. Because many drugs are secreted in human milk, caution should be exercised when ONGLYZA is administered to a nursing woman. Pediatric Use Safety and effectiveness of ONGLYZA in pediatric patients have not been established. Geriatric Use In the six, double-blind, controlled clinical safety and efficacy trials of ONGLYZA, 634 (15.3%) of the 4148 randomized patients were 65 years and over, and 59 (1.4%) patients were 75 years and over. No overall differences in safety or effectiveness were observed between patients ≥65 years old and the younger patients. While this clinical experience has not identified differences in responses between the elderly and younger patients, greater sensitivity of some older individuals cannot be ruled out. Saxagliptin and its active metabolite are eliminated in part by the kidney. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection in the elderly based on renal function. [See Dosage and Administration (2.2) and Clinical Pharmacology (12.3).] OVERDOSAGE In a controlled clinical trial, once-daily, orally-administered ONGLYZA in healthy subjects at doses up to 400 mg daily for 2 weeks (80 times the MRHD) had no dose-related clinical adverse reactions and no clinically meaningful effect on QTc interval or heart rate. In the event of an overdose, appropriate supportive treatment should be initiated as dictated by the patient’s clinical status. Saxagliptin and its active metabolite are removed by hemodialysis (23% of dose over 4 hours). PATIENT COUNSELING INFORMATION See FDA-approved patient labeling. Instructions Patients should be informed of the potential risks and benefits of ONGLYZA and of alternative modes of therapy. Patients should also be informed about the importance of adherence to dietary instructions, regular physical activity, periodic blood glucose monitoring and A1C testing, recognition and management of hypoglycemia and hyperglycemia, and assessment of diabetes complications. During periods of stress such as fever, trauma, infection, or surgery, medication requirements may change and patients should be advised to seek medical advice promptly. Physicians should instruct their patients to read the Patient Package Insert before starting ONGLYZA therapy and to reread it each time the prescription is renewed. Patients should be instructed to inform their doctor or pharmacist if they develop any unusual symptom or if any existing symptom persists or worsens. Laboratory Tests Patients should be informed that response to all diabetic therapies should be monitored by periodic measurements of blood glucose and A1C, with a goal of decreasing these levels toward the normal range. A1C is especially useful for evaluating long-term glycemic control. Patients should be informed of the potential need to adjust their dose based on changes in renal function tests over time. Manufactured by: Princeton, NJ 08543 USA Marketed by: Bristol-Myers Squibb Company Princeton, NJ 08543 and AstraZeneca Pharmaceuticals LP Wilmington, DE 19850 1256316 1256317 SA-B0001A-07-09 Iss July 2009 For your adult patients with type 2 diabetes struggling to gain glycemic control Significant reductions in A1C when partnered with key oral antidiabetic agents* • Onglyza is weight neutral • Discontinuation of therapy due to adverse events occurred in 3.3% and 1.8% of patients receiving Onglyza and placebo, respectively • Convenient, once-daily dosing • Rapidly growing formulary access1 Indication and Important Limitations of Use ONGLYZA is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. ONGLYZA should not be used for the treatment of type 1 diabetes mellitus or diabetic ketoacidosis. ONGLYZA has not been studied in combination with insulin. Important Safety Information • Use with Medications Known to Cause Hypoglycemia: Insulin secretagogues, such as sulfonylureas, cause hypoglycemia. Therefore, a lower dose of the insulin secretagogue may be required to reduce the risk of hypoglycemia when used in combination with ONGLYZA • Macrovascular Outcomes: There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with ONGLYZA or any other antidiabetic drug Most common adverse reactions (regardless of investigator assessment of causality) reported in ≥5% of patients treated with ONGLYZA and more commonly than in patients treated with control were upper respiratory tract infection (7.7%, 7.6%), headache (7.5%, 5.2%), nasopharyngitis (6.9%, 4.0%) and urinary tract infection (6.8%, 6.1%). When used as add-on combination therapy with a thiazolidinedione, the incidence of peripheral edema for ONGLYZA 2.5 mg, 5 mg, and placebo was 3.1%, 8.1% and 4.3%, respectively. *metformin, glyburide, or thiazolidinedione (pioglitazone or rosiglitazone) Onglyza – A Welcome Partner Please read the adjacent Brief Summary of the Product Information. For more information about Onglyza, a DPP-4 inhibitor, visit www.onglyza.com. Reference: 1. Fingertip Formulary® data as of October 2, 2009. Data on File, October 2009. ©2009 Bristol-Myers Squibb 422US09AB12901 10/09 Onglyza™ is a trademark of Bristol-Myers Squibb 278130