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AMERICAN SOCIETY of HEMATOLOGY Join us in Atlanta, GA, for the ® 54th ASH Annual Meeting and Exposition December 8-11, 2012 blood JOURNAL OF Blood, Journal of The American Society of Hematology (print ISSN 0006-4971, online ISSN 1528-0020), is published weekly every Thursday, except for the last week in December, (51 times weekly), plus the ASH annual meeting abstracts in November, by the American Society of Hematology (ASH), 2021 L Street, NW, Suite 900, Washington, DC 20036. Printed in the United States of America. Periodicals postage paid at Washington, DC, and additional mailing offices. Postmaster: Send change-of-address information to Blood, Journal of the American Society of Hematology, Subscription Office, 2021 L Street, NW, Suite 900, Washington, DC 20036. Canadian regulations: Publications Mail Agreement No: 40038947. Return undeliverable Canadian addresses to: Circulation Dept. or DPGM, 4960-2 Walker Road, Windsor, ON N9A 6J3. 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An Option for Newly Diagnosed Chronic Phase (CP) Ph+ CML Adult Patients… Start With SPRYCEL (dasatinib) SPRYCEL: Superior Response Rates vs Imatinib s Phase III, open-label, international, multicenter, randomized* study of SPRYCEL 100 mg once daily (n=259) vs imatinib 400 mg once daily (n=260) in adults with newly diagnosed Ph+ CML in chronic phase (N=519) at a minimum follow-up of 12 months1,2 — Primary endpoint was confirmed complete cytogenetic response (CCyR) † by 12 months MMR at Any Time Major Molecular Response (MMR)‡ at Any Time1 52% SPRYCEL (95% CI, 46-58) P<0.0001§ 34% SPRYCEL (n=259) Imatinib (n=260) Imatinib (95% CI, 28-40) 0 10 20 30 40 50 60 MMR (%) 70 80 90 100 s Among responders, median time to MMR was 6.3 months with SPRYCEL (n=135) vs 9.2 months with imatinib (n=88)1 s Primary endpoint: A significantly higher rate of patients on SPRYCEL (77%) (95% CI, 71-82) achieved confirmed CCyR by 12 months vs 66% (95% CI, 60-72) of patients on imatinib (P=0.007§)1 s Among responders, median time to confirmed CCyR with SPRYCEL was 3.1 months (n=199) vs 5.6 months with imatinib (n=177)1 Select Important Safety Information s SPRYCEL is associated with the following warnings and precautions: myelosuppression; bleeding-related events; fluid retention; QT prolongation; congestive heart failure, left ventricular dysfunction, and myocardial infarction; pulmonary arterial hypertension; and use in pregnancy s The most frequently reported serious adverse events in patients with newly diagnosed CP CML included pleural effusion (2%), hemorrhage (2%), congestive heart failure (1%), and pyrexia (1%) s The most frequently reported adverse reactions reported in 10% of patients with newly diagnosed CP CML included myelosuppression, fluid retention events (pleural effusion, superficial localized edema, generalized edema), diarrhea, headache, musculoskeletal pain, and rash s Please see detailed Important Safety Information on adjacent pages Indication SPRYCEL® (dasatinib) is indicated for the treatment of adults with newly diagnosed Philadelphia chromosomepositive chronic myeloid leukemia (Ph+ CML) in chronic phase. The effectiveness of SPRYCEL is based on cytogenetic and major molecular response rates. The trial is ongoing and further data will be required to determine long-term outcome. for Superior Response vs Imatinib in 1st Line Start With Convenient Once-Daily Dosing 1 pill 100 mg 1 time per day One tablet taken consistently, either in the morning or in the evening Tablets should not be crushed or cut; they should be swallowed whole Tablet not actual size. s In clinical studies, treatment with SPRYCEL was continued until disease progression or until no longer tolerated by the patient1 SPRYCEL Can Be Taken Either With or Without Food1 SPRYCEL—the only treatment for adults with newly diagnosed Ph+ CML in chronic phase with: FASTING s No fasting requirements s No need to alter meal schedules s No need to take with food Important Safety Information About Drug Interactions s Use of concomitant strong CYP3A4 inducers may decrease plasma concentrations of SPRYCEL and should be avoided s Strong CYP3A4 inhibitors may increase plasma concentrations of SPRYCEL and should be avoided s Grapefruit juice may increase plasma concentrations of SPRYCEL and should be avoided s Concomitant use of H 2 antagonists or proton pump inhibitors with SPRYCEL is not recommended s Antacids should be considered instead. Antacids may decrease SPRYCEL drug levels. If antacid therapy is needed, the dose should be given 2 hours before or after SPRYCEL *Stratified by Hasford risk score.2 Confirmed CCyR is defined as a CCyR (0% Ph+ metaphases) noted on 2 consecutive assessments at least 28 days apart.1 ‡ MMR (at any time) was defined as BCR-ABL ratios 0.1% by real-time quantitative polymerase chain reaction (RQ-PCR) in peripheral blood samples standardized on the International Scale.1 § Adjusted for Hasford score and indicated statistical significance at a pre-defined nominal level of significance.1 † Please see detailed Important Safety Information, including Important Safety Information on Drug Interactions, on adjacent pages. Important Safety Information Myelosuppression: s Treatment with SPRYCEL® (dasatinib) can cause severe (NCI CTC Grade 3/4) thrombocytopenia, neutropenia, and anemia. Myelosuppression was reported in patients with normal baseline laboratory values as well as in patients with pre-existing laboratory abnormalities — Perform complete blood counts (CBCs) weekly for the first 2 months and then monthly thereafter, or as clinically indicated — Myelosuppression was generally reversible and usually managed by dose interruption, dose reduction, or discontinuation — Hematopoietic growth factor has been used in patients with resistant myelosuppression Bleeding-Related Events: s SPRYCEL caused platelet dysfunction in vitro and thrombocytopenia in humans — In all clinical trials, severe central nervous system (CNS) hemorrhage, including fatalities, occurred in 1% of patients. Severe gastrointestinal (GI) hemorrhage, including fatalities, occurred in 4% of patients receiving SPRYCEL, which generally required treatment interruptions and transfusions. Other cases of severe hemorrhage occurred in 2% of patients s Most bleeding events were associated with severe thrombocytopenia — Exercise caution in patients required to take medications that inhibit platelet function or anticoagulants Fluid Retention: s SPRYCEL is associated with fluid retention — In clinical trials, fluid retention was severe in up to 10% of patients. Ascites (<1%), generalized edema (<1%), and severe pulmonary edema (1%) were also reported s Patients who develop symptoms suggestive of pleural effusion such as dyspnea or dry cough should be evaluated by chest X-ray s Severe pleural effusion may require thoracentesis and oxygen therapy s Fluid retention was typically managed by supportive care measures that included diuretics or short courses of steroids QT Prolongation: s In vitro data suggest that SPRYCEL has the potential to prolong cardiac ventricular repolarization (QT interval) s In 865 patients with leukemia treated with SPRYCEL in five phase 2 single-arm studies, the maximum mean changes in QTcF (90% upper bound CI) from baseline ranged from 7.0 ms to 13.4 ms s In clinical trials of patients treated with SPRYCEL (N=2440), 15 patients (<1%) had QTc prolongation as an adverse reaction. Twenty-two patients (1%) experienced a QTcF >500 ms s Administer SPRYCEL with caution to patients who have or may develop prolongation of QTc, including patients with hypokalemia, hypomagnesemia, or congenital long QT syndrome and patients taking anti-arrhythmic drugs, other medicinal products that lead to QT prolongation, and cumulative high-dose anthracycline therapy — Correct hypokalemia or hypomagnesemia prior to SPRYCEL administration Congestive Heart Failure, Left Ventricular Dysfunction, and Myocardial Infarction: Cardiac adverse reactions were reported in 5.8% of 258 patients taking SPRYCEL, including 1.6% of patients with cardiomyopathy, heart failure congestive, diastolic dysfunction, fatal myocardial infarction, and left ventricular dysfunction. Monitor patients for signs or symptoms consistent with cardiac dysfunction and treat appropriately. Pulmonary Arterial Hypertension (PAH): SPRYCEL may increase the risk of developing PAH, which may occur anytime after initiation, including after more than one year of treatment. Manifestations include dyspnea, fatigue, hypoxia, and fluid retention. PAH may be reversible on discontinuation of SPRYCEL. Evaluate patients for signs and symptoms of underlying cardiopulmonary disease prior to initiating SPRYCEL and during treatment. If PAH is confirmed SPRYCEL should be permanently discontinued. Use in Pregnancy: SPRYCEL may cause fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies of SPRYCEL in pregnant women. Women of childbearing potential should be advised of the potential hazard to the fetus and to avoid becoming pregnant when taking SPRYCEL. Nursing Mothers: It is unknown whether SPRYCEL is excreted in human milk. Because of the potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or to discontinue SPRYCEL. Drug Interactions: SPRYCEL (dasatinib) is a CYP3A4 substrate and a weak time-dependent inhibitor of CYP3A4. s Drugs that may increase SPRYCEL plasma concentrations are: — CYP3A4 inhibitors: Concomitant use of SPRYCEL and drugs that inhibit CYP3A4 should be avoided. If administration of a potent CYP3A4 inhibitor cannot be avoided, close monitoring for toxicity and a SPRYCEL dose reduction or temporary discontinuation should be considered Strong CYP3A4 inhibitors (eg, ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole). If SPRYCEL must be administered with a strong CYP3A4 inhibitor, a dose decrease should be considered Grapefruit juice may also increase plasma concentrations of SPRYCEL and should be avoided s Drugs that may decrease SPRYCEL plasma concentrations are: — CYP3A4 inducers: If SPRYCEL must be administered with a CYP3A4 inducer, a dose increase in SPRYCEL should be considered Strong CYP3A4 inducers (eg, dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, phenobarbital) should be avoided. Alternative agents with less enzyme induction potential should be considered. If the dose of SPRYCEL is increased, the patient should be monitored carefully for toxicity St John’s Wort may decrease SPRYCEL plasma concentrations unpredictably and should be avoided s Antacids. Antacids may decrease SPRYCEL drug levels. Simultaneous administration of SPRYCEL and antacids should be avoided. If antacid therapy is needed, the antacid dose should be administered at least 2 hours prior to or 2 hours after the dose of SPRYCEL s H2 antagonists/proton pump inhibitors, such as famotidine and omeprazole. Long-term suppression of gastric acid secretion by use of H2 antagonists or proton pump inhibitors is likely to reduce SPRYCEL exposure. Therefore, concomitant use of H2 antagonists or proton pump inhibitors with SPRYCEL is not recommended s Drugs that may have their plasma concentration altered by SPRYCEL are: — CYP3A4 substrates, such as simvastatin. CYP3A4 substrates with a narrow therapeutic index should be administered with caution in patients receiving SPRYCEL Adverse Reactions: The safety data reflect exposure to SPRYCEL in 258 patients with newly diagnosed chronic phase CML in a clinical study (median duration of therapy was 18 months). The majority of SPRYCEL-treated patients experienced adverse reactions at some time. Patients aged 65 years and older are more likely to experience toxicity. In the newly diagnosed chronic phase CML study, SPRYCEL was discontinued for adverse reactions in 6% of patients. s In newly diagnosed chronic phase CML patients: — The most frequently reported serious adverse reactions included pleural effusion (2%), hemorrhage (2%), congestive heart failure (1%), and pyrexia (1%) — The most frequently reported adverse reactions (reported in 10% of patients) included myelosuppression, fluid retention events (pleural effusion, superficial localized edema, generalized edema), diarrhea, headache, musculoskeletal pain, and rash — Grade 3/4 laboratory abnormalities included neutropenia (22%), thrombocytopenia (19%), anemia (11%), hypophosphatemia (5%), hypocalcemia (3%), and elevated bilirubin (1%) s Grade 3/4 elevations of transaminase or bilirubin and Grade 3/4 hypocalcemia, hypokalemia, and hypophosphatemia were reported in patients with all phases of CML — Elevations in transaminase or bilirubin were usually managed with dose reduction or interruption — Patients developing Grade 3/4 hypocalcemia during the course of SPRYCEL therapy often had recovery with oral calcium supplementation Please see brief summary of full Prescribing Information on adjacent pages. References: 1. SPRYCEL® (dasatinib) full Prescribing Information. Bristol-Myers Squibb. 2. Kantarjian H, Shah NP, Hochhaus A, et al. Dasatinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med. 2010;362:2260-2270. SPRYCEL is a registered trademark of Bristol-Myers Squibb Company. For more information online, visit www.sprycel.com. © 2011 Bristol-Myers Squibb 729US10AB13513 10/11 SPRYCEL® (dasatinib) Tablet for Oral Use Brief Summary of Prescribing Information. For complete prescribing information consult official package insert. INDICATIONS AND USAGE SPRYCEL® (dasatinib) is indicated for the treatment of adults with • newly diagnosed Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) in chronic phase. The effectiveness of SPRYCEL is based on cytogenetic response and major molecular response rates [see Clinical Studies (14.1) in Full Prescribing Information]. The trial is ongoing and further data will be required to determine long-term outcome. • chronic, accelerated, or myeloid or lymphoid blast phase Ph+ CML with resistance or intolerance to prior therapy including imatinib. • Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) with resistance or intolerance to prior therapy. CONTRAINDICATIONS: None. WARNINGS AND PRECAUTIONS Myelosuppression: Treatment with SPRYCEL is associated with severe (NCI CTC Grade 3 or 4) thrombocytopenia, neutropenia, and anemia. Their occurrence is more frequent in patients with advanced phase CML or Ph+ ALL than in chronic phase CML. In a dose-optimization study in patients with resistance or intolerance to prior imatinib therapy and chronic phase CML, Grade 3 or 4 myelosuppression was reported less frequently in patients treated with 100 mg once daily than in patients treated with other dosing regimens. Perform complete blood counts weekly for the first 2 months and then monthly thereafter, or as clinically indicated. Myelosuppression was generally reversible and usually managed by withholding SPRYCEL temporarily or dose reduction [see Dosage and Administration (2.3) in Full Prescribing Information and Adverse Reactions]. Bleeding Related Events: In addition to causing thrombocytopenia in human subjects, dasatinib caused platelet dysfunction in vitro. In all clinical studies, severe central nervous system (CNS) hemorrhages, including fatalities, occurred in 1% of patients receiving SPRYCEL. Severe gastrointestinal hemorrhage, including fatalities, occurred in 4% of patients and generally required treatment interruptions and transfusions. Other cases of severe hemorrhage occurred in 2% of patients. Most bleeding events were associated with severe thrombocytopenia. Patients were excluded from participation in initial SPRYCEL clinical studies if they took medications that inhibit platelet function or anticoagulants. In subsequent trials, the use of anticoagulants, aspirin, and non-steroidal anti-inflammatory drugs (NSAIDs) was allowed concurrently with SPRYCEL if the platelet count was >50,000–75,000 per microliter. Exercise caution if patients are required to take medications that inhibit platelet function or anticoagulants. Fluid Retention: SPRYCEL is associated with fluid retention. In clinical trials, severe fluid retention was reported in up to 10% of patients. Ascites and generalized edema were each reported in <1% of patients. Severe pulmonary edema was reported in 1% of patients. Patients who develop symptoms suggestive of pleural effusion, such as dyspnea or dry cough, should be evaluated by chest X-ray. Severe pleural effusion may require thoracentesis and oxygen therapy. Fluid retention events were typically managed by supportive care measures that include diuretics or short courses of steroids. In dose-optimization studies, fluid retention events were reported less frequently with once daily dosing than with other dosing regimens. QT Prolongation: In vitro data suggest that dasatinib has the potential to prolong cardiac ventricular repolarization (QT interval). Of the 2440 patients with CML treated with SPRYCEL in clinical studies, 15 patients (<1%) had QTc prolongation reported as an adverse reaction. Twenty-two patients (1%) experienced a QTcF >500 ms. In 865 patients with leukemia treated with SPRYCEL in five Phase 2 single-arm studies, the maximum mean changes in QTcF (90% upper bound CI) from baseline ranged from 7.0 ms to 13.4 ms. Administer SPRYCEL with caution to patients who have or may develop prolongation of QTc. These include patients with hypokalemia or hypomagnesemia, patients with congenital long QT syndrome, patients taking anti-arrhythmic medicines or other medicinal products that lead to QT prolongation, and cumulative high-dose anthracycline therapy. Correct hypokalemia or hypomagnesemia prior to SPRYCEL administration. Congestive Heart Failure, Left Ventricular Dysfunction, and Myocardial Infarction: Cardiac adverse reactions were reported in 5.8% of 258 patients taking SPRYCEL, including 1.6% of patients with cardiomyopathy, heart failure congestive, diastolic dysfunction, fatal myocardial infarction, and left ventricular dysfunction. Monitor patients for signs or symptoms consistent with cardiac dysfunction and treat appropriately. Pulmonary Arterial Hypertension: SPRYCEL may increase the risk of developing pulmonary arterial hypertension (PAH) which may occur anytime after initiation, including after more than one year of treatment. Manifestations include dyspnea, fatigue, hypoxia, and fluid retention. PAH may be reversible on discontinuation of SPRYCEL. Evaluate patients for signs and symptoms of underlying cardiopulmonary disease prior to initiating SPRYCEL and during treatment. If PAH is confirmed, SPRYCEL should be permanently discontinued. Use in Pregnancy: SPRYCEL may cause fetal harm when administered to a pregnant woman. In nonclinical studies, at plasma concentrations below those observed in humans receiving therapeutic doses of dasatinib, embryo-fetal toxicities, including skeletal malformations, were observed in rats and rabbits. There are no adequate and well-controlled studies of SPRYCEL in pregnant women. Women of childbearing potential should be advised to avoid becoming pregnant while receiving treatment with SPRYCEL [see Use in Specific Populations]. ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the labeling: • Myelosuppression [see Dosage and Administration (2.3) in Full Prescribing Information and Warnings and Precautions]. • Bleeding related events [see Warnings and Precautions]. • Fluid retention [see Warnings and Precautions]. • QT prolongation [see Warnings and Precautions]. • Congestive heart failure, left ventricular dysfunction, and myocardial infarction [see Warnings and Precautions]. • Pulmonary Arterial Hypertension [see Warnings and Precautions]. 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. The data described below reflect exposure to SPRYCEL in clinical studies including 258 patients with newly diagnosed chronic phase CML and in 2182 patients with imatinib resistant or intolerant CML or Ph+ ALL. In the newly diagnosed chronic phase CML trial, the median duration of therapy was 18 months; the median average daily dose was 99 mg. In the imatinib resistant or intolerant CML or Ph+ ALL clinical trials, patients had a minimum of 2 years follow-up (starting dosage 100 mg once daily, 140 mg once daily, 50 mg twice daily, or 70 mg twice daily). Among patients with chronic phase CML and resistance or intolerance to prior imatinib therapy, the median duration of treatment with SPRYCEL 100 mg once daily was 24 months (range 1–33 months). The median duration of treatment with SPRYCEL 140 mg once daily was 15 months (range 0.03–36 months) for accelerated phase CML, 3 months (range 0.03–29 months) for myeloid blast phase CML, and 3 months (range 0.1–10 months) for lymphoid blast CML. The majority of SPRYCEL-treated patients experienced adverse reactions at some time. In the newly diagnosed chronic phase CML trial, drug was discontinued for adverse reactions in 6% of SPRYCEL-treated patients. Among patients with resistance or intolerance to prior imatinib therapy, the rates of discontinuation for adverse reaction were 15% in chronic phase CML, 16% in accelerated phase CML, 15% in myeloid blast phase CML, 8% in lymphoid blast phase CML, and 8% in Ph+ ALL. In a dose-optimization study in patients with resistance or intolerance to prior imatinib therapy and chronic phase CML, the rate of discontinuation for adverse reaction was lower in patients treated with 100 mg once daily than in patients treated with other dosing regimens (10% and 16%, respectively). The most frequently reported adverse reactions reported in ≥10% of patients in newly diagnosed chronic phase CML included myelosuppression, fluid retention events (pleural effusion, superficial localized edema, generalized edema), diarrhea, headache, musculoskeletal pain, and rash. Pleural effusions were reported in 31 patients (see Table 1). The most frequently reported adverse reactions reported in ≥20% of patients with resistance or intolerance to prior imatinib therapy included myelosuppression, fluid retention events, diarrhea, headache, dyspnea, skin rash, fatigue, nausea, and hemorrhage. The most frequently reported serious adverse reactions in patients with newly diagnosed chronic phase CML included pleural effusion (2%), hemorrhage (2%), congestive heart failure (1%), and pyrexia (1%). The most frequently reported serious adverse reactions in patients with resistance or intolerance to prior imatinib therapy included pleural effusion (11%), gastrointestinal bleeding (4%), febrile neutropenia (4%), dyspnea (3%), pneumonia (3%), pyrexia (3%), diarrhea (3%), infection (2%), congestive heart failure/cardiac dysfunction (2%), pericardial effusion (1%), and CNS hemorrhage (1%). Chronic Myeloid Leukemia (CML): Adverse reactions (excluding laboratory abnormalities) that were reported in at least 10% of patients are shown in Table 1 for newly diagnosed patients with chronic phase CML and Table 2 for CML patients with resistance or intolerance to prior imatinib therapy. Table 1: Adverse Reactions Reported in ≥10% of Patients with Newly Diagnosed Chronic Phase CML All Grades Grade 3/4 SPRYCEL (dasatinib) Imatinib SPRYCEL Imatinib (n=258) (n=258) (n=258) (n=258) Preferred Term Percent (%) of Patients Fluid retention 23 43 1 1 Pleural effusion 12 0 <1 0 Superficial localized edema 10 36 0 <1 Generalized edema 3 7 0 0 Congestive heart failure/ 2 1 <1 <1 cardiac dysfunctiona Pericardial effusion 2 <1 <1 0 Pulmonary hypertension 1 0 0 0 Pulmonary edema <1 0 0 0 Diarrhea 18 19 <1 1 Headache 12 10 0 0 Musculoskeletal pain 12 16 0 <1 b Rash 11 17 0 1 Nausea 9 21 0 0 Fatigue 8 11 <1 0 Myalgia 6 12 0 0 Hemorrhagec 6 5 1 1 Gastrointestinal bleeding 2 <1 1 0 d Other bleeding 5 5 0 1 CNS bleeding 0 <1 0 <1 Vomiting 5 10 0 0 Muscle inflammation 4 19 0 <1 a Includes cardiac failure acute, cardiac failure congestive, cardiomyopathy, diastolic dysfunction, ejection fraction decreased, and left ventricular dysfunction. b Includes erythema, erythema multiforme, rash, rash generalized, rash macular, rash papular, rash pustular, skin exfoliation, and rash vesicular. c Adverse reaction of special interest with <10% frequency. d Includes conjunctival hemorrhage, ear hemorrhage, ecchymosis, epistaxis, eye hemorrhage, gingival bleeding, hematoma, hematuria, hemoptysis, intra-abdominal hematoma, petechiae, scleral hemorrhage, uterine hemorrhage, and vaginal hemorrhage. Table 2: Adverse Reactions Reported in ≥10% of Patients with CML Resistant or Intolerant to Prior Imatinib Therapy 100 mg Once Daily 140 mg Once Daily Myeloid Lymphoid Blast Blast Chronic Accelerated (n=74) (n=33) (n=165) (n=157) All Grade All Grade All Grade All Grade Preferred Term Grades 3/4 Grades 3/4 Grades 3/4 Grades 3/4 Percent (%) of Patients Fluid Retention 34 4 35 8 34 7 21 6 Superficial 18 0 18 1 14 0 3 0 localized edema Pleural effusion 18 2 21 7 20 7 21 6 Generalized edema 3 0 1 0 3 0 0 0 Pericardial effusion 2 1 3 1 0 0 0 0 Congestive heart failure/ 0 0 0 0 4 0 0 0 cardiac dysfunctiona Pulmonary edema 0 0 1 0 4 3 0 0 Headache 33 1 27 1 18 1 15 3 Diarrhea 27 2 31 3 20 5 18 0 Fatigue 24 2 19 2 20 1 9 3 Dyspnea 20 2 20 3 15 3 3 3 Musculoskeletal pain 19 2 11 0 8 1 0 0 Nausea 18 1 19 1 23 1 21 3 b Skin rash 17 2 15 0 16 1 21 0 Myalgia 13 0 7 1 7 1 3 0 Arthralgia 12 1 10 0 5 1 0 0 Infection (including 12 1 10 6 14 7 9 0 bacterial, viral, fungal, and non-specified) Abdominal pain 12 1 6 0 8 3 3 0 Hemorrhage 11 1 26 8 19 9 24 9 Gastrointestinal bleeding 2 1 8 6 9 7 9 3 CNS bleeding 0 0 1 1 0 0 3 3 Vomiting 7 1 11 1 12 0 15 0 Pyrexia 5 1 11 2 18 3 6 0 Febrile neutropenia 1 1 4 4 12 12 12 12 a Includes ventricular dysfunction, cardiac failure, cardiac failure congestive, cardiomyopathy, congestive cardiomyopathy, diastolic dysfunction, ejection fraction decreased, and ventricular failure. b Includes drug eruption, erythema, erythema multiforme, erythrosis, exfoliative rash, generalized erythema, genital rash, heat rash, milia, rash, rash erythematous, rash follicular, rash generalized, rash macular, rash maculopapular, rash papular, rash pruritic, rash pustular, skin exfoliation, skin irritation, urticaria vesiculosa, and rash vesicular. Laboratory Abnormalities Myelosuppression was commonly reported in all patient populations. The frequency of Grade 3 or 4 neutropenia, thrombocytopenia, and anemia was higher in patients with advanced phase CML than in chronic phase CML (Tables 3 and 4). Myelosuppression was reported in patients with normal baseline laboratory values as well as in patients with pre-existing laboratory abnormalities. In patients who experienced severe myelosuppression, recovery generally occurred following dose interruption or reduction; permanent discontinuation of treatment occurred in 2% of patients with newly diagnosed chronic phase CML and 5% of patients with resistance or intolerance to prior imatinib therapy [see Warnings and Precautions]. Grade 3 or 4 elevations of transaminase or bilirubin and Grade 3 or 4 hypocalcemia, hypokalemia, and hypophosphatemia were reported in patients with all phases of CML but were reported with an increased frequency in patients with myeloid or lymphoid blast phase CML. Elevations in transaminase or bilirubin were usually managed with dose reduction or interruption. Patients developing Grade 3 or 4 hypocalcemia during the course of SPRYCEL (dasatinib) therapy often had recovery with oral calcium supplementation. Laboratory abnormalities reported in patients with newly diagnosed chronic phase CML are shown in Table 3. There were no discontinuations of SPRYCEL therapy in this patient population due to biochemical laboratory parameters. Table 3: CTC Grade 3/4 Laboratory Abnormalities in Patients with Newly Diagnosed Chronic Phase CML SPRYCEL Imatinib (n=258) (n=258) Percent (%) of Patients Hematology Parameters Neutropenia 22 20 Thrombocytopenia 19 10 Anemia 11 7 Biochemistry Parameters Hypophosphatemia 5 24 Hypokalemia 0 2 Hypocalcemia 3 2 Elevated SGPT (ALT) <1 1 Elevated SGOT (AST) <1 1 Elevated Bilirubin 1 0 Elevated Creatinine <1 1 9 9 CTC grades: neutropenia (Grade 3 ≥0.5–<1.0 × 10 /L, Grade 4 <0.5 × 10 /L); thrombocytopenia (Grade 3 ≥25–<50 × 109/L, Grade 4 <25 × 109/L); anemia (hemoglobin Grade 3 ≥65–<80 g/L, Grade 4 <65 g/L); elevated creatinine (Grade 3 >3–6 × upper limit of normal range (ULN), Grade 4 >6 × ULN); elevated bilirubin (Grade 3 >3–10 × ULN, Grade 4 >10 × ULN); elevated SGOT or SGPT (Grade 3 >5–20 × ULN, Grade 4 >20 × ULN); hypocalcemia (Grade 3 <7.0–6.0 mg/dL, Grade 4 <6.0 mg/dL); hypophosphatemia (Grade 3 <2.0–1.0 mg/dL, Grade 4 <1.0 mg/dL); hypokalemia (Grade 3 <3.0–2.5 mmol/L, Grade 4 <2.5 mmol/L). Laboratory abnormalities reported in patients with CML resistant or intolerant to imatinib who received the recommended starting doses of SPRYCEL are shown by disease phase in Table 4. Table 4: CTC Grade 3/4 Laboratory Abnormalities in Clinical Studies of CML: Resistance or Intolerance to Prior Imatinib Therapy Chronic Phase CML Advanced Phase CML 140 mg Once Daily Accelerated Myeloid Lymphoid 100 mg Phase Blast Phase Blast Phase Once Daily (n=157) (n=74) (n=33) (n=165) Percent (%) of Patients Hematology Parameters Neutropenia 36 58 77 79 Thrombocytopenia 23 63 78 85 Anemia 13 47 74 52 Biochemistry Parameters Hypophosphatemia 10 13 12 18 Hypokalemia 2 7 11 15 Hypocalcemia <1 4 9 12 Elevated SGPT (ALT) 0 2 5 3 Elevated SGOT (AST) <1 0 4 3 Elevated Bilirubin <1 1 3 6 Elevated Creatinine 0 2 8 0 9 9 CTC grades: neutropenia (Grade 3 ≥0.5–<1.0 × 10 /L, Grade 4 <0.5 × 10 /L); thrombocytopenia (Grade 3 ≥25–<50 × 109/L, Grade 4 <25 × 109/L); anemia (hemoglobin Grade 3 ≥65–<80 g/L, Grade 4 <65 g/L); elevated creatinine (Grade 3 >3–6 × upper limit of normal range (ULN), Grade 4 >6 × ULN); elevated bilirubin (Grade 3 >3–10 × ULN, Grade 4 >10 × ULN); elevated SGOT or SGPT (Grade 3 >5–20 × ULN, Grade 4 >20 × ULN); hypocalcemia (Grade 3 <7.0–6.0 mg/dL, Grade 4 <6.0 mg/dL); hypophosphatemia (Grade 3 <2.0–1.0 mg/dL, Grade 4 <1.0 mg/dL); hypokalemia (Grade 3 <3.0–2.5 mmol/L, Grade 4 <2.5 mmol/L). Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia (Ph+ ALL) A total of 135 patients with Ph+ ALL were treated with SPRYCEL in clinical studies. The median duration of treatment was 3 months (range 0.03–31 months). The safety profile of patients with Ph+ ALL was similar to those with lymphoid blast phase CML. The most frequently reported adverse reactions included fluid retention events such as pleural effusion (24%) and superficial edema (19%), and gastrointestinal disorders such as diarrhea (31%), nausea (24%), and vomiting (16%). Hemorrhage (19%), pyrexia (17%), rash (16%), and dyspnea (16%) were also frequently reported. The most frequently reported serious adverse reactions included pleural effusion (11%), gastrointestinal bleeding (7%), febrile neutropenia (6%), infection (5%), pyrexia (4%), pneumonia (3%), diarrhea (3%), nausea (2%), vomiting (2%), and colitis (2%). Additional Data From Clinical Trials The following adverse reactions were reported in patients in the SPRYCEL clinical studies at a frequency of 1%–<10%, 0.1%–<1%, or <0.1%. These events are included on the basis of clinical relevance. Gastrointestinal Disorders: 1%–<10% – mucosal inflammation (including mucositis/stomatitis), dyspepsia, abdominal distension, constipation, gastritis, colitis (including neutropenic colitis), oral soft tissue disorder; 0.1%–<1% – ascites, dysphagia, anal fissure, upper gastrointestinal ulcer, esophagitis, pancreatitis; <0.1% – protein losing gastroenteropathy. General Disorders and Administration Site Conditions: 1%–<10% – asthenia, pain, chest pain, chills; 0.1%–<1% – malaise, temperature intolerance. Skin and Subcutaneous Tissue Disorders: 1%–<10% – pruritus, alopecia, acne, dry skin, hyperhidrosis, urticaria, dermatitis (including eczema); 0.1%–<1% – pigmentation disorder, skin ulcer, bullous conditions, photosensitivity, nail disorder, acute febrile neutrophilic dermatosis, panniculitis, palmar-plantar erythrodysesthesia syndrome. Respiratory, Thoracic, and Mediastinal Disorders: 1%–<10% – cough, lung infiltration, pneumonitis, pulmonary hypertension; 0.1%–<1% – asthma, bronchospasm; <0.1% – acute respiratory distress syndrome. Nervous System Disorders: 1%–<10% – neuropathy (including peripheral neuropathy), dizziness, dysgeusia, somnolence; 0.1%–<1% – amnesia, tremor, syncope; <0.1% – convulsion, cerebrovascular accident, transient ischemic attack, optic neuritis. Blood and Lymphatic System Disorders: 1%–<10% – pancytopenia; <0.1% – aplasia pure red cell. Musculoskeletal and Connective Tissue Disorders: 1%–<10% – muscular weakness; 0.1%–<1% – musculoskeletal stiffness, rhabdomyolysis; <0.1% – tendonitis. Investigations: 1%–<10% – weight increased, weight decreased; 0.1%–<1% – blood creatine phosphokinase increased. Infections and Infestations: 1%–<10% – pneumonia (including bacterial, viral, and fungal), upper respiratory tract infection/inflammation, herpes virus infection, enterocolitis infection; 0.1%–<1% – sepsis (including fatal outcomes). Metabolism and Nutrition Disorders: 1%–<10% – anorexia, appetite disturbances; 0.1%–<1% – hyperuricemia, hypoalbuminemia. Cardiac Disorders: 1%–<10% – arrhythmia (including tachycardia), palpitations; 0.1%–<1% – angina pectoris, cardiomegaly, pericarditis, ventricular arrhythmia (including ventricular tachycardia); <0.1% – cor pulmonale, myocarditis, acute coronary syndrome. Eye Disorders: 1%–<10% – visual disorder (including visual disturbance, vision blurred, and visual acuity reduced), dry eye; 0.1%–<1% – conjunctivitis. Vascular Disorders: 1%–<10% – flushing, hypertension; 0.1%–<1% – hypotension, thrombophlebitis; <0.1% – livedo reticularis. Psychiatric Disorders: 1%–<10% – insomnia, depression; 0.1%–<1% – anxiety, affect lability, confusional state, libido decreased. Reproductive System and Breast Disorders: 0.1%–<1% – gynecomastia, menstruation irregular. Injury, Poisoning, and Procedural Complications: 1%–<10% – contusion. Ear and Labyrinth Disorders: 1%–<10% – tinnitus; 0.1%–<1% – vertigo. Hepatobiliary Disorders: 0.1%–<1% – cholestasis, cholecystitis, hepatitis. Renal and Urinary Disorders: 0.1%–<1% – urinary frequency, renal failure, proteinuria. Neoplasms Benign, Malignant, and Unspecified: 0.1%–<1% – tumor lysis syndrome. Immune System Disorders: 0.1%–<1% – hypersensitivity (including erythema nodosum). Postmarketing Experience The following additional adverse reactions have been identified during post approval use of SPRYCEL (dasatinib). Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Cardiac disorders: atrial fibrillation/atrial flutter. Vascular disorders: thrombosis/embolism (including pulmonary embolism, deep vein thrombosis). Respiratory, thoracic, and mediastinal disorders: interstitial lung disease, pulmonary arterial hypertension. DRUG INTERACTIONS Drugs That May Increase Dasatinib Plasma Concentrations CYP3A4 Inhibitors: Dasatinib is a CYP3A4 substrate. In a study of 18 patients with solid tumors, 20-mg SPRYCEL once daily coadministered with 200 mg of ketoconazole twice daily increased the dasatinib Cmax and AUC by four- and five-fold, respectively. Concomitant use of SPRYCEL and drugs that inhibit CYP3A4 may increase exposure to dasatinib and should be avoided. In patients receiving treatment with SPRYCEL, close monitoring for toxicity and a SPRYCEL dose reduction should be considered if systemic administration of a potent CYP3A4 inhibitor cannot be avoided [see Dosage and Administration (2.1) in Full Prescribing Information]. Drugs That May Decrease Dasatinib Plasma Concentrations CYP3A4 Inducers: When a single morning dose of SPRYCEL was administered following 8 days of continuous evening administration of 600 mg of rifampin, a potent CYP3A4 inducer, the mean Cmax and AUC of dasatinib were decreased by 81% and 82%, respectively. Alternative agents with less enzyme induction potential should be considered. If SPRYCEL must be administered with a CYP3A4 inducer, a dose increase in SPRYCEL should be considered [see Dosage and Administration (2.1) in Full Prescribing Information]. Antacids: Nonclinical data demonstrate that the solubility of dasatinib is pH dependent. In a study of 24 healthy subjects, administration of 30 mL of aluminum hydroxide/magnesium hydroxide 2 hours prior to a single 50-mg dose of SPRYCEL was associated with no relevant change in dasatinib AUC; however, the dasatinib Cmax increased 26%. When 30 mL of aluminum hydroxide/magnesium hydroxide was administered to the same subjects concomitantly with a 50-mg dose of SPRYCEL, a 55% reduction in dasatinib AUC and a 58% reduction in Cmax were observed. Simultaneous administration of SPRYCEL with antacids should be avoided. If antacid therapy is needed, the antacid dose should be administered at least 2 hours prior to or 2 hours after the dose of SPRYCEL. H2 Antagonists/Proton Pump Inhibitors: Long-term suppression of gastric acid secretion by H2 antagonists or proton pump inhibitors (eg, famotidine and omeprazole) is likely to reduce dasatinib exposure. In a study of 24 healthy subjects, administration of a single 50-mg dose of SPRYCEL 10 hours following famotidine reduced the AUC and Cmax of dasatinib by 61% and 63%, respectively. In a study of 14 healthy subjects, administration of a single 100-mg dose of SPRYCEL 22 hours following a 40-mg omeprazole dose at steady state reduced the AUC and Cmax of dasatinib by 43% and 42%, respectively. The concomitant use of H2 antagonists or proton pump inhibitors with SPRYCEL is not recommended. The use of antacids (at least 2 hours prior to or 2 hours after the dose of SPRYCEL) should be considered in place of H2 antagonists or proton pump inhibitors in patients receiving SPRYCEL therapy. Drugs That May Have Their Plasma Concentration Altered By Dasatinib CYP3A4 Substrates: Single-dose data from a study of 54 healthy subjects indicate that the mean Cmax and AUC of simvastatin, a CYP3A4 substrate, were increased by 37% and 20%, respectively, when simvastatin was administered in combination with a single 100-mg dose of SPRYCEL. Therefore, CYP3A4 substrates known to have a narrow therapeutic index such as alfentanil, astemizole, terfenadine, cisapride, cyclosporine, fentanyl, pimozide, quinidine, sirolimus, tacrolimus, or ergot alkaloids (ergotamine, dihydroergotamine) should be administered with caution in patients receiving SPRYCEL. USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category D: SPRYCEL may cause fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies of SPRYCEL in pregnant women. Women of childbearing potential should be advised of the potential hazard to the fetus and to avoid becoming pregnant. If SPRYCEL is used during pregnancy, or if the patient becomes pregnant while taking SPRYCEL, the patient should be apprised of the potential hazard to the fetus. In nonclinical studies, at plasma concentrations below those observed in humans receiving therapeutic doses of dasatinib, embryo-fetal toxicities were observed in rats and rabbits. Fetal death was observed in rats. In both rats and rabbits, the lowest doses of dasatinib tested (rat: 2.5 mg/kg/day [15 mg/m2/day] and rabbit: 0.5 mg/kg/day [6 mg/m2/day]) resulted in embryo-fetal toxicities. These doses produced maternal AUCs of 105 ng•hr/mL (0.3-fold the human AUC in females at a dose of 70 mg twice daily) and 44 ng•hr/mL (0.1-fold the human AUC) in rats and rabbits, respectively. Embryo-fetal toxicities included skeletal malformations at multiple sites (scapula, humerus, femur, radius, ribs, clavicle), reduced ossification (sternum; thoracic, lumbar, and sacral vertebrae; forepaw phalanges; pelvis; and hyoid body), edema, and microhepatia. Nursing Mothers: It is unknown whether SPRYCEL is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from SPRYCEL, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use: The safety and efficacy of SPRYCEL in patients less than 18 years of age have not been established. Geriatric Use: In the newly diagnosed chronic phase CML study, 25 patients (10%) were 65 years of age and over and 7 patients (3%) were 75 years of age and over. Of the 2182 patients in clinical studies of SPRYCEL with resistance or intolerance to imatinib therapy, 547 (25%) were 65 years of age and over and 105 (5%) were 75 years of age and over. No differences in efficacy were observed between older and younger patients. Compared to patients under age 65 years, patients aged 65 years and older are more likely to experience toxicity. Hepatic Impairment: The effect of hepatic impairment on the pharmacokinetics of dasatinib was evaluated in healthy volunteers with normal liver function and patients with moderate (Child-Pugh class B) and severe (Child-Pugh class C) hepatic impairment. Compared to the healthy volunteers with normal hepatic function, the dose normalized pharmacokinetic parameters were decreased in the patients with hepatic impairment. No dosage adjustment is necessary in patients with hepatic impairment [see Clinical Pharmacology (12.3) in Full Prescribing Information]. Caution is recommended when administering SPRYCEL to patients with hepatic impairment. Renal Impairment: There are currently no clinical studies with SPRYCEL in patients with impaired renal function. Less than 4% of dasatinib and its metabolites are excreted via the kidney. OVERDOSAGE Experience with overdose of SPRYCEL in clinical studies is limited to isolated cases. Overdosage of 280 mg per day for 1 week was reported in two patients and both developed severe myelosuppression and bleeding. Since SPRYCEL is associated with severe myelosuppression [see Warnings and Precautions and Adverse Reactions], patients who ingested more than the recommended dosage should be closely monitored for myelosuppression and given appropriate supportive treatment. Acute overdose in animals was associated with cardiotoxicity. Evidence of cardiotoxicity included ventricular necrosis and valvular/ventricular/atrial hemorrhage at single doses ≥100 mg/kg (600 mg/m2) in rodents. There was a tendency for increased systolic and diastolic blood pressure in monkeys at single doses ≥10 mg/kg (120 mg/m2). Manufactured by: Bristol-Myers Squibb Company Princeton, NJ 08543 USA 1284903A0 DS-B0001A-10-11 Rev October 2011 Standard CML therapies. Are we holding them to a high enough standard? We know that current chronic myeloid leukemia (CML) treatments are efficacious. But resistance still occurs. In fact, post-imatinib studies found approximately 65% of these patients eventually discontinue use of nilotinib and dasatinib as second-line therapy.1,2 Maybe it’s time to reconsider our definition of success. Visit CMLResponseProject.com to learn more. References: 1. Le Coutre PD, Giles FJ, Pinilla-Ibarz J, et al. Nilotinib in imatinib-resistant or -intolerant patients (pts) with chronic myeloid leukemia in chronic phase (CML-CP): 48-month follow-up results of a phase 2 study. Poster presented at: 53rd ASH Annual Meeting and Exposition; December 10-13, 2011; San Diego, CA. 2. Shah NP, Cortes JE, Schiffer CA, et al. Five-year follow-up of patients with imatinibresistant or -intolerant chronic-phase chronic myeloid leukemia (CML-CP) receiving dasatinib. Poster presented at: American Society of Clinical Oncology (ASCO) Annual Meeting; June 3-7, 2011; Chicago, IL. ©2012 ARIAD Pharmaceuticals, Inc. All rights reserved. 5343712 How well is your Ph+ CML patient responding to therapy? International scale (IS) RQ-PCR can tell you... RQ-PCR FACTS • RQ-PCR tests measure BCR-ABL transcripts, the key cause of Ph+ CML1 • Most sensitive test available to measure minimal residual disease, detecting 1 in 1,000,000 cells1,2 — Cytogenetic testing detects ~100-fold reductions in Ph+ CML cells, whereas RQ-PCR detects ~10,000-fold reductions in disease burden3,4 • Easy to perform blood test1 RQ-PCR can help you detect early trends in response status5 BCR-ABL/ABL % (IS) RQ-PCR testing enables you to detect trends, such as rising levels of BCR-ABL, that would not be apparent through cytogenetic testing alone.5 Rising BCRABL levels CCyR have been associated MMR with mutations and resistance, so the sooner Time you detect and confirm rising levels of BCR-ABL, the sooner you can test for mutations and evaluate adherence or tolerability issues to manage treatment accordingly.1,3 Monitoring with RQ-PCR may help indicate the durability of response1 Traditionally, complete cytogenetic response (CCyR) has been the gold standard for evaluating the potential durability of response. More recently, studies have shown that achievement of major molecular response (MMR) also correlates with durability of response.1 In fact, patients who achieve both CCyR and MMR are less likely to progress to advanced disease phases than patients who achieve CCyR alone.1 QUALITATIVE VS QUANTITATIVE PCR TESTS • Qualitative tests are diagnostic, indicating whether Ph+ CML is present1 • Quantitative tests measure the amount of disease in the peripheral blood or bone marrow1 Why it’s important to monitor with RQ-PCR tests standardized to the IS An MMR can only be defined by IS measurement, and appropriate assessment of patient response can only be performed by an IS lab. This means that only IS results can tell you if your patient has achieved MMR.6 Understanding how IS works—using international currency as an example IS normalizes the RQ-PCR results of different laboratories to a unified scale by a conversion factor.6 As illustrated below, RQ-PCR results from different laboratories are like different international currencies (ie, Lab A=US dollars and Lab B=Euros). $1000 $1 €1000 = €1 The relative reductions of $1000 and €1000 are the same—both are 3-log reductions, or 1000-fold decreases. However, the absolute value of $1 and €1 are NOT the same. Through use of a conversion factor (ie, exchange rate), the absolute value of residual BCR-ABL can be known among different labs. This means you can compare IS RQ-PCR results between labs.6 IS-standardized RQ-PCR tests provide the most consistent measure of residual BCR-ABL7 An additional benefit of IS-standardized results is that they have a lower degree of fluctuation over time compared with nonstandardized laboratory results. 0.12 This consistency 0.10 IS-standardized laboratory can help avoid Nonstandardized laboratory 0.08 overtreatment or 0.06 undertreatment of 0.04 a patient due to a 0.02 numeric fluctuation 0 8 in the test. Time BCR-ABL/ABL/Ctl (%) Real-time quantitative polymerase chain reaction (RQ-PCR) acts like an early warning system for measuring response and identifying potential relapse. This is why it is such an important tool for Philadelphia chromosome–positive chronic myeloid leukemia (Ph+ CML) response monitoring. Summary: The importance of monitoring Ph+ CML patients with IS RQ-PCR tests • RQ-PCR is the most sensitive way to monitor BCR-ABL fluctuations, which can act as an early warning signal for potential relapse5 • Monitoring for achievement of MMR in addition to CCyR may help predict response1 • IS-standardized RQ-PCR tests are the only way to know if your patient has achieved MMR and to ensure consistency of test results6 For information about a free trial of IS RQ-PCR, call 877-459-4979 and ask about GET RQ-PCR NOW. References: 1. The NCCN Chronic Myelogenous Leukemia Clinical Practice Guidelines in Oncology (Version 2.2012). © 2011 National Comprehensive Cancer Network, Inc. http://www.nccn.org. Accessed September 16, 2011. To view the most recent and complete version of the guidelines, go online to www.nccn.org. 2. Radich JP. How I monitor residual disease in chronic myeloid leukemia. Blood. 2009;114(16):3376-3381. 3. Baccarani M, Cortes J, Pane F, et al; European LeukemiaNet. Chronic myeloid leukemia: an update of concepts and management recommendations of European LeukemiaNet. J Clin Oncol. 2009;27(35):6041-6051. 4. Baccarani M, Saglio G, Goldman J, et al; European LeukemiaNet . Evolving concepts in the management of chronic myeloid leukemia: recommendations from an expert panel on behalf of the European LeukemiaNet. Blood. 2006;108(6):1809-1820. 5. Hughes T, Deininger M, Hochhaus A, et al. Monitoring CML patients responding to treatment with tyrosine kinase inhibitors: review and recommendations for harmonizing current methodology for detecting BCR-ABL transcripts and kinase domain mutations and for expressing results. Blood. 2006;108(1):28-37. 6. Branford S, Fletcher L, Cross NC, et al. Desirable performance characteristics for BCR-ABL measurement on an international reporting scale to allow consistent interpretation of individual patient response and comparison of response rates between clinical trials. Blood. 2008;112(8):3330-3338. 7. Müller MC, Cross NC, Erben P, et al. Harmonization of molecular monitoring of CML therapy in Europe. Leukemia. 2009;23(11):1957-1963. 8. Akard LP, Wang YL. Translating trial-based molecular monitoring into clinical practice: importance of international standards and practical considerations for community practitioners. Clin Lymphoma Myeloma Leuk. 2011 May 10 (Epub ahead of print). doi:10.1016/j.clml.2011.01.001. Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936-1080 ©2011 Novartis 11/11 CDE-1030011 More Choice, More Color for Blood Cell Disorders Welcome to a More Colorful World.SM Flow cytometry allows you to analyze multiple parameters simultaneously—and by adding more colors you can open up a whole new world of information and insight. BD Biosciences makes it easy for you with our ever-expanding portfolio of high-quality conjugated antibody specificities that offer a full spectrum of color choices including our new BD HorizonTM V500-C violet-laser dyes to simplify work and speed results. BD, BD Logo and all other trademarks are property of Becton, Dickinson and Company. © 2012 BD 23-13669-01 BD Biosciences reagents are part of the building blocks to support patient care for blood cell disorders. Go to bdbiosciences.com/go/color to learn more about our proven solution, try our BD FACSelectTM tools, and download a free product catalog. BD Biosciences 2350 Qume Drive San Jose, CA 95131 bdbiosciences.com ADCETRIS is the first approved CD30directed antibody-drug conjugate (ADC) Indicated for the treatment of: • Hodgkin lymphoma (HL) after failure of autologous stem cell transplant (ASCT)1 • HL in patients who are not ASCT candidates after failure of at least 2 multiagent chemotherapy regimens1 • Systemic anaplastic large cell lymphoma (sALCL) after failure of at least 1 multiagent chemotherapy regimen1 The indications for ADCETRIS are based on response rate. There are no data available demonstrating improvement in patient-reported outcomes or survival with ADCETRIS.1 A therapeutic alternative for relapsed patients 73% objective response rate (95% CI: 65%-83%) in HL1 86% objective response rate (95% CI: 77%-95%) in sALCL1 BOXED WARNING Progressive multifocal leukoencephalopathy (PML): JC virus infection resulting in PML and death can occur in patients receiving ADCETRIS.1 Contraindication Concomitant use of ADCETRIS and bleomycin is contraindicated due to pulmonary toxicity.1 Peripheral neuropathy ADCETRIS treatment causes a peripheral neuropathy that is predominantly sensory. Cases of peripheral motor neuropathy have also been reported. ADCETRIS-induced peripheral neuropathy is cumulative. Treating physicians should monitor patients for symptoms of neuropathy, such as hypoesthesia, hyperesthesia, paresthesia, discomfort, a burning sensation, neuropathic pain or weakness and institute dose modifications accordingly.1 Infusion reactions Infusion-related reactions, including anaphylaxis, have occurred with ADCETRIS. Monitor patients during infusion. If an infusion reaction occurs, the infusion should be interrupted and appropriate medical management instituted. If anaphylaxis occurs, the infusion should be immediately and permanently discontinued and appropriate medical management instituted.1 Please see Brief Summary of full Prescribing Information, including Boxed WARNING, on the last page of this ad. Please see full Prescribing Information at ADCETRIS.com. ADCETRIS is an ADC designed to target cells expressing CD301 Antibody The antibody, brentuximab, specific for CD301 Cytotoxic agent Linker A synthetic protease-cleavable linker that covalently attaches MMAE to the CD30-directed antibody and releases the agent within the target cell1 The synthetic microtubuledisrupting agent, monomethyl auristatin E (MMAE, vedotin), that induces target cell death1 CD30 is prevalent in both HL and sALCL2 • Binding of ADCETRIS to CD30 on the cell surface initiates internalization of the ADC-CD30 complex1 • Inside the cell, MMAE is released via proteolytic cleavage1 • Binding of released MMAE to tubulin disrupts the microtubule network, inducing apoptotic cell death1 Single-agent ADCETRIS was evaluated in two pivotal, phase 2, open-label, single-arm, multicenter trials: • 102 patients with HL who relapsed after ASCT1 Neutropenia Monitor complete blood counts prior to each dose of ADCETRIS and consider more frequent monitoring for patients with Grade 3 or 4 neutropenia. If Grade 3 or 4 neutropenia develops, manage by dose delays, reductions or discontinuation. Prolonged (≥1 week) severe neutropenia can occur with ADCETRIS.1 • 58 patients with relapsed sALCL1 Tumor lysis syndrome ADCETRIS 1.8 mg/kg was administered intravenously over 30 minutes every 3 weeks.1 Patients with rapidly proliferating tumor and high tumor burden are at risk of tumor lysis syndrome and these patients should be monitored closely and appropriate measures taken.1 Assessment of efficacy included objective response rate (complete remission plus partial remission) and duration of response evaluated by an independent review facility based on measures defined in the 2007 Revised Response Criteria for Malignant Lymphoma (modified).1,3 Progressive multifocal leukoencephalopathy (PML) JC virus infection resulting in PML and death has been reported in ADCETRIS-treated patients. In addition to ADCETRIS therapy, other possible contributory factors include prior therapies and underlying disease that may cause immunosuppression. Consider the diagnosis of PML in any patient presenting with new-onset signs and symptoms of central nervous system abnormalities. Evaluation of PML includes, but is not limited to, consultation with a neurologist, brain MRI, and lumbar puncture or brain biopsy. Hold ADCETRIS if PML is suspected and discontinue ADCETRIS if PML is confirmed.1 Please see Brief Summary of full Prescribing Information, including Boxed WARNING, on the last page of this ad. Please see full Prescribing Information at ADCETRIS.com. ADCETRIS induced complete and partial remissions in clinical trials1 Efficacy in relapsed patients1 Relapsed HL (N = 58) Median treatment duration: 27 weeks Median treatment duration: 24 weeks Duration of response in months Response, % (95% CI) Complete remission (CR) Partial remission (PR) Objective response rate (ORR) Relapsed sALCL (N = 102) Median (95% CI) Range 32 20.5 1.4-21.9+ (23-42) (12.0-NE*) 40 3.5 (32-49) (2.2-4.1) Median (95% CI) Range 57 13.2 0.7-15.9+ (44-70) (10.8-NE*) 1.3-18.7 73 6.7 (65-83) (4.0-14.8) Duration of response in months Response, % (95% CI) 29 2.1 (18-41) (1.3-5.7) 1.3-21.9+ 0.1-15.8+ 86 12.6 (77-95) (5.7-NE*) 0.1-15.9+ *Not estimable. +Follow-up was ongoing at the time of data submission. • ADCETRIS demonstrated efficacy in sALCL patients with poor prognosis1 – 72% of sALCL patients had anaplastic lymphoma kinase (ALK)-negative disease, which has a worse prognosis than ALK-positive disease1,4 Adverse reactions occurring in ≥20% of patients regardless of causality1 HL (N = 102) sALCL (N = 58) % of patients Adverse Reaction Neutropenia % of patients Any Grade Grade 3 Grade 4 Any Grade Grade 3 Grade 4 54 15 6 55 12 9 Peripheral sensory neuropathy 52 8 - 53 10 - Fatigue 49 3 - 41 2 2 Nausea 42 - - 38 2 - Anemia 33 8 2 52 2 - Upper respiratory tract infection 47 - - 12 - - Diarrhea 36 1 - 29 3 - Pyrexia 29 2 - 38 2 - Rash 27 - - 31 - - Thrombocytopenia 28 7 2 16 5 5 Cough 25 - - 17 - - Vomiting 22 - - 17 3 - • 21% of patients discontinued therapy due to treatment-emergent adverse reactions1 Continue treatment until a maximum of 16 cycles, disease progression or unacceptable toxicity1 Recommended dose is 1.8 mg/kg administered only as an IV infusion over 30 minutes every 3 weeks1 • Patients who have experienced a prior infusion-related reaction should be premedicated for subsequent infusions1 • Complete blood counts should be monitored prior to each dose of ADCETRIS1 Most PN was Grade 1 or 2—no Grade 4 PN events were observed1 • 54% of patients experienced peripheral neuropathy (PN) in the pivotal trials1 • Grade 3 PN (sensory) was reported by 8% and 10% of patients in the HL and sALCL trials, respectively1 – 8% discontinued due to peripheral sensory neuropathy1 • Grade 3 PN (motor) was reported by 4% and 3% of patients in the HL and sALCL trials, respectively1 – 3% discontinued due to peripheral motor neuropathy1 Monitor patients for PN and institute dose modification accordingly1 New or worsening Grade 2 or 3 Hold dose until PN improves to Grade 1 or baseline and then restart at 1.2 mg/kg Grade 4 Discontinue ADCETRIS Improvement or resolution of PN symptoms was observed in the majority of patients during follow-up1: • 49% had complete resolution • 51% had residual PN at time of last evaluation (31% partial improvement, 20% no improvement) Neutropenia should be managed by dose delay and reduction1 Grade 3 or 4 Recurrent Grade 4 despite use of growth factors Hold dose until resolution to baseline or Grade 2 or lower Consider growth factor support for subsequent cycles Discontinue or reduce dose to 1.2 mg/kg Please see Brief Summary of full Prescribing Information, including Boxed WARNING, on adjacent page. Please see full Prescribing Information at ADCETRIS.com. REFERENCES: 1. ADCETRIS [Prescribing Information]. Bothell, WA: Seattle Genetics Inc; 2012. 2. Haluska FG, Brufsky AM, Canellos GP. The cellular biology of the Reed-Sternberg cell. Blood. 1994;84(4):1005-1019. 3. Cheson BD, Pfistner B, Juweid ME, et al; International Harmonization Project on Lymphoma. Revised response criteria for malignant lymphoma. J Clin Oncol. 2007;25(5):579-586. 4. Savage KJ, Harris NL, Vose JM, et al; International Peripheral T-Cell Lymphoma Project. ALK- anaplastic large-cell lymphoma is clinically and immunophenotypically different from both ALK+ ALCL and peripheral T-cell lymphoma, not otherwise specified: report from the International Peripheral T-Cell Lymphoma Project. Blood. 2008;111(12):5496-5504. US/BV/2011/0029b 855.4SEAGEN (855.473.2436) SeaGenSecure.com Brief Summary of Prescribing Information (see Package Insert for full Prescribing Information) WARNING: PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY (PML) JC virus infection resulting in PML and death can occur in patients receiving ADCETRIS. Indications and usage ADCETRIS was studied in 58 patients with sALCL in a single arm clinical trial in which the recommended starting dose and schedule was 1.8 mg/kg intravenously every 3 weeks. Median duration of treatment was 24 weeks (range, 3 to 56 weeks). The most common adverse reactions (≥20%), regardless of causality, were neutropenia, anemia, peripheral sensory neuropathy, fatigue, nausea, pyrexia, rash, diarrhea, and pain. The most common serious adverse reactions experienced by patients with sALCL were septic shock (3%), supraventricular arrhythmia (3%), pain in extremity (3%), and urinary tract infection (3%). Drug interactions These indications are based on response rate. There are no data available demonstrating improvement in patient reported outcomes or survival with ADCETRIS. ADCETRIS (brentuximab vedotin) is indicated for treatment of patients with Hodgkin lymphoma (HL) after failure of autologous stem cell transplant (ASCT) or after failure of at least two prior multi-agent chemotherapy regimens in patients who are not ASCT candidates. ADCETRIS is indicated for treatment of patients with systemic anaplastic large cell lymphoma (sALCL) after failure of at least one prior multi-agent chemotherapy regimen. In vitro data indicate that monomethyl auristatin E (MMAE) is a substrate and an inhibitor of CYP3A4/5. Contraindications Co-administration of ADCETRIS did not affect exposure to midazolam, a CYP3A4 substrate. MMAE does not inhibit other CYP enzymes at relevant clinical concentrations. ADCETRIS is not expected to alter the exposure to drugs that are metabolized by CYP3A4 enzymes. Pulmonary toxicity: Concomitant use of ADCETRIS and bleomycin is contraindicated due to pulmonary toxicity. In a clinical trial that studied ADCETRIS with bleomycin as part of a combination regimen, the rate of non-infectious pulmonary toxicity was higher than the historical incidence reported with ABVD (adriamycin, bleomycin, vinblastine, dacarbazine). Patients typically reported cough and dyspnea. Interstitial infiltration and/or inflammation were observed on radiographs and computed tomographic imaging of the chest. Most patients responded to corticosteroids. Warnings and precautions Peripheral neuropathy ADCETRIS treatment causes a peripheral neuropathy that is predominantly sensory. Cases of peripheral motor neuropathy have also been reported. ADCETRIS-induced peripheral neuropathy is cumulative. In the HL and sALCL clinical trials, 54% of patients experienced any grade of neuropathy. Of these patients, 49% had complete resolution, 31% had partial improvement, and 20% had no improvement. Of the patients who reported neuropathy, 51% had residual neuropathy at the time of their last evaluation. Monitor patients for symptoms of neuropathy, such as hypoesthesia, hyperesthesia, paresthesia, discomfort, a burning sensation, neuropathic pain or weakness. Patients experiencing new or worsening peripheral neuropathy may require a delay, change in dose, or discontinuation of ADCETRIS. Infusion reactions Infusion-related reactions, including anaphylaxis, have occurred with ADCETRIS. Monitor patients during infusion. If anaphylaxis occurs, immediately and permanently discontinue administration of ADCETRIS and administer appropriate medical therapy. If an infusion-related reaction occurs, the infusion should be interrupted and appropriate medical management instituted. Patients who have experienced a prior infusion-related reaction should be premedicated for subsequent infusions. Premedication may include acetaminophen, an antihistamine and a corticosteroid. Neutropenia Complete blood counts should be monitored prior to each dose of ADCETRIS and more frequent monitoring should be considered for patients with Grade 3 or 4 neutropenia. Prolonged (≥1 week) severe neutropenia can occur with ADCETRIS. If Grade 3 or 4 neutropenia develops, manage by dose delays, reductions, or discontinuations. Tumor lysis syndrome Tumor lysis syndrome may occur. Patients with rapidly proliferating tumor and high tumor burden may be at increased risk of tumor lysis syndrome. Monitor closely and take appropriate measures. Progressive multifocal leukoencephalopathy JC virus infection resulting in PML and death has been reported in ADCETRIS-treated patients. In addition to ADCETRIS therapy, other possible contributory factors include prior therapies and underlying disease that may cause immunosuppression. Consider the diagnosis of PML in any patient presenting with new-onset signs and symptoms of central nervous system abnormalities. Evaluation of PML includes, but is not limited to, consultation with a neurologist, brain MRI, and lumbar puncture or brain biopsy. Hold ADCETRIS dosing for any suspected case of PML and discontinue ADCETRIS dosing if a diagnosis of PML is confirmed. Stevens-Johnson syndrome Effect of other drugs on ADCETRIS CYP3A4 Inhibitors/Inducers: MMAE is primarily metabolized by CYP3A. Co-administration of ADCETRIS with ketoconazole, a potent CYP3A4 inhibitor, increased exposure to MMAE by approximately 34%. Patients who are receiving strong CYP3A4 inhibitors concomitantly with ADCETRIS should be closely monitored for adverse reactions. Co-administration of ADCETRIS with rifampin, a potent CYP3A4 inducer, reduced exposure to MMAE by approximately 46%. Effect of ADCETRIS on other drugs Use in specific populations Pregnancy Pregnancy Category D. There are no adequate and well-controlled studies with ADCETRIS in pregnant women. However, based on its mechanism of action and findings in animals, ADCETRIS can cause fetal harm when administered to a pregnant woman. Brentuximab vedotin caused embryo-fetal toxicities in animals at maternal exposures that were similar to human exposures at the recommended doses for patients with HL and sALCL. If this drug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus. In an embryo-fetal developmental study, pregnant rats received 2 intravenous doses of 0.3, 1, 3, or 10 mg/kg brentuximab vedotin during the period of organogenesis (once each on Pregnancy Days 6 and 13). Drug-induced embryo-fetal toxicities were seen mainly in animals treated with 3 and 10 mg/kg of the drug and included increased early resorption (≥99%), post-implantation loss (≥99%), decreased numbers of live fetuses, and external malformations (i.e., umbilical hernias and malrotated hindlimbs). Systemic exposure in animals at the brentuximab vedotin dose of 3 mg/kg is approximately the same exposure in patients with HL or sALCL who received the recommended dose of 1.8 mg/kg every three weeks. Nursing mothers It is not known whether brentuximab vedotin is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from ADCETRIS a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric use The safety and effectiveness of ADCETRIS have not been established in the pediatric population. Clinical trials of ADCETRIS included only 9 pediatric patients and this number is not sufficient to determine whether they respond differently than adult patients. Geriatric use Clinical trials of ADCETRIS did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. Safety and efficacy have not been established. Renal impairment The kidney is a route of excretion for MMAE. The influence of renal impairment on the pharmacokinetics of MMAE has not been determined. Hepatic impairment The liver is a route of clearance for MMAE. The influence of hepatic impairment on the pharmacokinetics of MMAE has not been determined. Overdosage There is no known antidote for overdosage of ADCETRIS. In case of overdosage, the patient should be closely monitored for adverse reactions, particularly neutropenia, and supportive treatment should be administered. Stevens-Johnson syndrome has been reported with ADCETRIS. If Stevens-Johnson syndrome occurs, discontinue ADCETRIS and administer appropriate medical therapy. Dosage and administration Use in pregnancy The recommended dose is 1.8 mg/kg administered only as an intravenous infusion over 30 minutes every 3 weeks. The dose for patients weighing greater than 100 kg should be calculated based on a weight of 100 kg. Do not administer as an intravenous push or bolus. Continue treatment until a maximum of 16 cycles, disease progression or unacceptable toxicity. There are no adequate and well-controlled studies of ADCETRIS in pregnant women. However, based on its mechanism of action and findings in animals, ADCETRIS can cause fetal harm when administered to a pregnant woman. Brentuximab vedotin caused embryo-fetal toxicities, including significantly decreased embryo viability and fetal malformations, in animals at maternal exposures that were similar to human exposures at the recommended doses for patients with HL and sALCL. If this drug is used during pregnancy, or if the patient becomes pregnant while receiving the drug, the patient should be apprised of the potential hazard to the fetus. Adverse reactions ADCETRIS was studied as monotherapy in 160 patients in two phase 2 trials. Across both trials, the most common adverse reactions (≥10%), regardless of causality, were neutropenia, anemia, thrombocytopenia, lymphadenopathy, peripheral sensory neuropathy, peripheral motor neuropathy, headache, dizziness, fatigue, pyrexia, chills, pain, edema peripheral, upper respiratory tract infection, nausea, diarrhea, abdominal pain, vomiting, constipation, rash, pruritus, alopecia, night sweats, dry skin, cough, dyspnea, oropharyngeal pain, arthralgia, myalgia, back pain, pain in extremity, muscle spasms, insomnia, anxiety, decreased appetite and weight decreased. ADCETRIS was studied in 102 patients with HL in a single arm clinical trial in which the recommended starting dose and schedule was 1.8 mg/kg intravenously every 3 weeks. Median duration of treatment was 27 weeks (range, 3 to 56 weeks). The most common adverse reactions (≥20%), regardless of causality, were neutropenia, peripheral sensory neuropathy, fatigue, upper respiratory tract infection, nausea, diarrhea, anemia, pyrexia, thrombocytopenia, rash, abdominal pain, cough, and vomiting. The most common serious adverse reactions experienced by patients with HL include peripheral motor neuropathy (4%), abdominal pain (3%), pulmonary embolism (2%), pneumonitis (2%), pneumothorax (2%), pyelonephritis (2%), and pyrexia (2%). General dosing information Dose modification Peripheral Neuropathy: Peripheral neuropathy should be managed using a combination of dose delay and reduction to 1.2 mg/kg. For new or worsening Grade 2 or 3 neuropathy, dosing should be held until neuropathy improves to Grade 1 or baseline and then restarted at 1.2 mg/kg. For Grade 4 peripheral neuropathy, ADCETRIS should be discontinued. Neutropenia: Neutropenia should be managed by dose delays and reductions. The dose of ADCETRIS should be held for Grade 3 or 4 neutropenia until resolution to baseline or Grade 2 or lower. Growth factor support should be considered for subsequent cycles in patients who experience Grade 3 or 4 neutropenia. In patients with recurrent Grade 4 neutropenia despite the use of growth factors, discontinuation or dose reduction of ADCETRIS to 1.2 mg/kg may be considered. ADCETRIS, SeaGen Secure and their logos are trademarks and Seattle Genetics and are US registered trademarks of Seattle Genetics, Inc. © 2012 Seattle Genetics, Inc., Bothell, WA 98021 All rights reserved. Printed in USA US/BVP/2011/0150 15+ YEARS* EXPERIENCE MATTERS 3000 IU IS HERE More units. Single vial. Same 5-mL diluent.1,2 Streamline their infusion experience. The individual depicted is not a hemophilia patient. For illustrative purposes only. *BeneFIX was approved February 11, 1997.3 Indication for BeneFIX BeneFIX® Coagulation Factor IX (Recombinant) is indicated for the IX has been associated with the development of control and prevention of bleeding episodes in adult and pediatric thromboembolic complications, including patients receiving patients with hemophilia B (congenital factor IX deficiency or continuous infusion through a central venous catheter. The safety Christmas disease), including peri-operative management. and efficacy of BeneFIX administration by continuous infusion have not been established. BeneFIX is NOT indicated for the treatment of other factor deficiencies (eg, factors II, VII, VIII and X), hemophilia A patients detected in patients receiving factor IX products. If expected with inhibitors to factor VIII, reversal of coumarin-induced plasma factor IX activity levels are not attained, or if patient anticoagulation, or bleeding due to low levels of liver-dependent presents with allergic reaction, or if bleeding is not controlled coagulation factors. with an expected dose, an assay that measures factor IX inhibitor Important Safety Information for BeneFIX concentration should be performed. IX is contraindicated in patients who have manifested ! "#$%& life-threatening, immediate hypersensitivity reactions, as BeneFIX contains trace amounts. including anaphylaxis, to the product or its components, '"*+/& including hamster protein. were nausea, injection site reaction, injection site pain, headache, Should symptoms occur, treatment with the product should be discontinued, and emergency treatment should be sought. References: 1. BeneFIX®#04"6&!08:!0;;<=;;2. Lambert T, Recht M, Valentino LA, et al. Reformulated BeneFIX®: efficacy and safety in previously treated patients with moderately severe to severe haemophilia B. Haemophilia.<==?@;DE<DD<GD3.#H68JK $$K#H6 8#04"6&8N EOOPPPOQO!O !O U!UO!!O=+?=DW!;;8;WW??8<=;; Please see brief summary of full Prescribing Information for BeneFIX on reverse side. Manufactured by Wyeth Pharmaceuticals Inc. BUS424818-01 © 2012 Pfizer Inc. All rights reserved. Marketed by Pfizer Inc. Printed in USA/February 2012 Brief Summary ADVERSE REACTIONS See package insert for full Prescribing Information. For further product information and current package insert, please visit www.BeneFIX.com or call our medical communications department toll-free at 1-800-934-5556. The most serious adverse reactions are systemic hypersensitivity reactions, including bronchospastic reactions and/or hypotension and anaphylaxis and the development of high-titer inhibitors necessitating alternative treatments to factor IX replacement therapy. INDICATIONS AND USAGE The most common adverse reactions observed in clinical trials (frequency >5% of PTPs or PUPs) were headaches, dizziness, nausea, injections site reaction, injection site pain and skinrelated hypersensitivity reactions (e.g., rash, hives). Control and Prevention of Bleeding Episodes in Hemophilia B BeneFIX® Coagulation Factor IX (Recombinant) is indicated for the control and prevention of bleeding episodes in adult and pediatric patients with hemophilia B (congenital factor IX deficiency or Christmas disease). BeneFIX is NOT indicated for treatment of other factor deficiencies (e.g., factors II, VII, VIII, and X), hemophilia A patients with inhibitors to factor VIII, reversal of coumarin-induced anticoagulation, or bleeding due to low levels of liver-dependent coagulation factors. Peri-operative Management in Patients with Hemophilia B BeneFIX is indicated for peri-operative management in adult and pediatric patients with hemophilia B. CONTRAINDICATIONS 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 clinical practice. During uncontrolled open-label clinical studies with BeneFIX conducted in previously treated patients (PTPs), 113 adverse reactions with known or unknown relation to BeneFIX therapy were reported among 38.5% (25 of 65) of subjects (with some subjects reporting more than one event) who received a total of 7,573 infusions. The most frequently reported treatmentemergent adverse reactions were headache (10.8%), dizziness (7.7%), injection site reaction (7.7%), nausea (6.2%), and injection site pain (6.2%). WARNINGS AND PRECAUTIONS In the 63 previously untreated patients (PUPs), who received a total of 5,538 infusions, 10 adverse reactions were reported among 9.5% of the patients (6 out of 63) having known or unknown relationship to BeneFIX. Adverse reactions reported in ≥5% of subjects were: hives (4.8%), factor IX inhibition (3.2%), dyspnea (3.2%), injection site reaction (1.6%), chills (1.6%), and rash (1.6%). Anaphylaxis and Severe Hypersensitivity Reactions Immunogenicity Allergic type hypersensitivity reactions, including anaphylaxis, have been reported with BeneFIX and have manifested as pruritus, rash, urticaria, hives, facial swelling, dizziness, hypotension, nausea, chest discomfort, cough, dyspnea, wheezing, flushing, discomfort (generalized) and fatigue. Frequently, these events have occurred in close temporal association with the development of factor IX inhibitors. Advise patients to discontinue use of the product and contact their physician and/or seek immediate emergency care. Patients may develop hypersensitivity to hamster (CHO) protein as BeneFIX contains trace amounts. In clinical studies with 65 PTPs (defined as having more than 50 exposure days), a low-titer inhibitor was observed in one patient. The inhibitor was transient, the patient continued on study and had normal factor IX recovery pharmacokinetics at study completion (approximately 15 months after inhibitor detection). BeneFIX is contraindicated in patients who have manifested life-threatening, immediate hypersensitivity reactions, including anaphylaxis, to the product or its components, including hamster protein. Thromboembolic Complications The safety and efficacy of BeneFIX administration by continuous infusion have not been established. There have been post-marketing reports of thrombotic events in patients receiving continuous-infusion BeneFIX through a central venous catheter, including life-threatening superior vena cava (SVC) syndrome in critically ill neonates. Nephrotic Syndrome Nephrotic syndrome has been reported following immune tolerance induction with factor IX products in hemophilia B patients with factor IX inhibitors and a history of allergic reactions to factor IX. The safety and efficacy of using BeneFIX for immune tolerance induction have not been established. Neutralizing Antibodies (Immunogenicity) Patients using BeneFIX should be monitored for the development of factor IX inhibitors by appropriate clinical observations and laboratory tests. Inhibitors have been reported following administration of BeneFIX. If expected plasma factor IX activity levels are not attained, or if bleeding is not controlled with an expected dose, an assay that measures factor IX inhibitor concentration should be performed. Patients with factor IX inhibitors may be at an increased risk of anaphylaxis upon subsequent challenge with factor IX. Patients experiencing allergic reactions should be evaluated for the presence of an inhibitor. Patients should be observed closely for signs and symptoms of acute hypersensitivity reactions, particularly during the early phases of initial exposure to product. Because of the potential for allergic reactions with factor IX concentrates, the initial (approximately 10 - 20) administrations of factor IX should be performed under medical supervision where proper medical care for allergic reactions could be provided. Monitoring Laboratory Tests Patients should be monitored for factor IX activity levels by the one-stage clotting assay to confirm that adequate factor IX levels have been achieved and maintained, when clinically indicated. Patients should be monitored for the development of inhibitors if expected factor IX activity plasma levels are not attained, or if bleeding is not controlled with the recommended dose of BeneFIX. Assays used to determine if factor IX inhibitor is present should be titered in Bethesda Units (BUs). In clinical studies with pediatric PUPs, inhibitor development was observed in 2 out of 63 patients (3.2%), both were high-titer (>5 BU) inhibitors detected after 7 and 15 exposure days, respectively. Both patients were withdrawn from the study. DRUG INTERACTIONS—None known. USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C—Animal reproduction and lactation studies have not been conducted with BeneFIX. It is not known whether BeneFIX can affect reproductive capacity or cause fetal harm when given to pregnant women. BeneFIX should be administered to pregnant women only if needed. Labor and Delivery There is no information available on the effect of factor IX replacement therapy on labor and delivery. Use only if needed. Nursing Mothers It is not known whether this drug is excreted into human milk. Because many drugs are excreted into human milk, caution should be exercised if BeneFIX is administered to nursing mothers. Use only if needed. Pediatric Use Safety, efficacy, and pharmacokinetics of BeneFIX have been evaluated in previously treated (PTP) and previously untreated pediatric patients (PUP). On average, lower recovery has been observed in pediatric patients (<15 years). A dose adjustment may be needed. Geriatric Use Clinical studies of BeneFIX did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Dose selection for an elderly patient should be individualized. STORAGE AND HANDLING Product kit as packaged for sale: BeneFIX can be stored at room temperature or under refrigeration, at a temperature of 2 to 30°C (36 to 86°F). Do not use BeneFIX after the expiration date on the label. Do not freeze to prevent damage to the diluent syringe. Product after reconstitution: The product does not contain a preservative and should be used within 3 hours. This brief summary is based on the BeneFIX® Coagulation Factor IX (Recombinant) Prescribing Information LAB-0464-8.0, revised 11/2011. Manufactured by Wyeth Pharmaceuticals Inc. BUS420430-01 © 2011 Pfizer Inc. All rights reserved. Marketed by Pfizer Inc. Printed in USA/November 2011 ® makes all the difference With CancerCare, the difference comes from: • Professional oncology social workers • Free counseling • Education and practical help • Up-to-date information • CancerCare for Kids® For needs that go beyond medical care, refer your patients and their loved ones to CancerCare. CancerCare’s free services help people cope with the emotional and practical concerns arising from a cancer diagnosis and are integral to the standard of care for all cancer patients, as recommended by the Institute of Medicine. Help and Hope 1-800-813-HOPE (4673) www.cancercare.org WARNINGS AND PRECAUTIONS: ! " " ! ! ! # " $% ! ! ! " ! " ! &# # '" '() " # # " " * ! "+ # " , "+ * " # " " '() " ' " " ! ! " - . # " / " ! " - # # " #" - ! " " " ! " " ! 0 ! ." (" ADVERSE REACTIONS: ) $/1 # 234 " ! $ 56$6 714 7%4 664 /!" 84 94 1 51: 1:4 134 $94 784 /!" 6;4 & 6:4 #" ;4 94! ! # # $ 56$6 1 51:- $ 73 6;4 & ! " 9 34 , !- 1 66 7$4 & ! " 8 6:4 , ! # " ! $ 56$6 3;4 /!" 334 164 #" $;4 $94 & $34 1 51: /!" ::4 :34 :74 994 974 334 & 1:4 & 134 #" 1%4 1%4 $94- ) $/1 # 234 " ! 6 56%7 ! 664 /!" 84 7 58$ $:4 ! $$4 7:4 774 694 /!" 614 614 6%4 #" 6%4 /&!# 84 " 84 84 94 94 94! ! # # 6 56%7 7 58$ 8 84 6 79 $64 7 &" ! # " ! 6 56%7 394 /!" 3$4 ! 194 #" $14 & 7$4 7 58$ 894 /!" ::4 :74 934 '() , # " 9$4 3:4 3:4 ! 314 & 314 #" 374 374 " 364 184 194 " 1%4 $;4DRUG INTERACTIONS: 0 (<.$1- # " (<.$1 (<.$1 ! ( & ! (<.$1 .," .," =(=6 . ! . >0 ? >? ! ## USE IN SPECIFIC POPULATIONS: = " & ! ! # " ! ! " " " ! " . # / ," ! " #$% "&# # #% ' ISTODAX® is a registered trademark of Celgene Corporation. ©2011 Celgene Corporation 10/11 IST11038 INDICATIONS s4REATMENTOFPERIPHERAL4CELLLYMPHOMA04#,INPATIENTS WHOHAVERECEIVEDATLEASTONEPRIORTHERAPY s4REATMENTOFCUTANEOUS4CELLLYMPHOMA#4#,INPATIENTS WHOHAVERECEIVEDATLEASTONEPRIORSYSTEMICTHERAPY 4HESEINDICATIONSAREBASEDONRESPONSERATE#LINICALBENElT SUCHASIMPROVEMENTINOVERALLSURVIVALHASNOTBEENDEMONSTRATED RECHARGE THE POSSIBILITIES www.istodax.com Please see Important Safety Information on adjacent page. Please see Brief Summary of full Prescribing Information on following pages. Only ISTODAX® (romidepsin) for injection For intravenous infusion only The following is a brief summary only; see full prescribing information for complete product information. 1 INDICATIONS AND USAGE ISTODAX is indicated for: M+D73F?7@FA85GF3@7AGE+57>>>K?B:A?3+#;@B3F;7@FEI:A:3H7 D757;H763F>73EFA@7BD;ADEKEF7?;5F:7D3BK M+D73F?7@FA8B7D;B:7D3>+57>>>K?B:A?3'+#;@B3F;7@FEI:A:3H7 D757;H763F>73EFA@7BD;ADF:7D3BK +:7E7;@6;53F;A@E3D743E76A@D7EBA@E7D3F7>;@;53>47@78;FEG5:3E ;?BDAH7?7@F;@AH7D3>>EGDH;H3>:3E@AF477@67?A@EFD3F76 2 DOSAGE AND ADMINISTRATION 2.1 Dosing Information +:7D75A??7@6766AE7A8DA?;67BE;@;E?9?2 36?;@;EF7D76 ;@FD3H7@AGE>KAH7D3:AGDB7D;A6A@63KE3@6A8363K 5K5>7 K5>7EE:AG>647D7B73F767H7DK63KEBDAH;676F:3FF:7B3F;7@F 5A@F;@G7EFA47@78;F8DA?3@6FA>7D3F7EF:76DG9 2.2 Dose Modification %A@:7?3FA>A9;5FAJ;5;F;7E7J57BF3>AB75;3 MD367ADFAJ;5;FK+D73F?7@FI;F:DA?;67BE;@E:AG>64767>3K76 G@F;>FAJ;5;FKD7FGD@EFA≤D367AD43E7>;@7F:7@F:7D3BK?3K47 D7EF3DF763F?9?2 8D367FAJ;5;FKD75GDEFD73F?7@FI;F: DA?;67BE;@E:AG>64767>3K76G@F;>FAJ;5;FKD7FGD@EFA≤D367AD 43E7>;@73@6F:76AE7E:AG>647B7D?3@7@F>KD76G576FA ?9?2 MD367FAJ;5;FK+D73F?7@FI;F:DA?;67BE;@E:AG>64767>3K76G@F;> FAJ;5;FKD7FGD@EFA≤D367AD43E7>;@7F:7@F:76AE7E:AG>647 B7D?3@7@F>KD76G576FA ?9?2 M)A?;67BE;@E:AG>6476;E5A@F;@G76;8D367ADFAJ;5;F;7ED75GD38F7D 6AE7D76G5F;A@ 7?3FA>A9;5FAJ;5;F;7E MD367AD@7GFDAB7@;3ADF:DA?4A5KFAB7@;3+D73F?7@FI;F: DA?;67BE;@E:AG>64767>3K76G@F;>F:7EB75;8;55KFAB7@;3D7FGD@EFA %≥P 9#3@6ADB>3F7>7F5AG@F≥P 9#AD43E7>;@7F:7@ F:7D3BK?3K47D7EF3DF763F?9?2 MD367874D;>7≥N@7GFDAB7@;3ADF:DA?4A5KFAB7@;3F:3F D7CG;D7EB>3F7>7FFD3@E8GE;A@+D73F?7@FI;F:DA?;67BE;@E:AG>647 67>3K76G@F;>F:7EB75;8;55KFAB7@;3D7FGD@EFA≤D367AD43E7>;@7 3@6F:7@F:76AE7E:AG>647B7D?3@7@F>KD76G576FA ?9?2 2.3 Instructions for Preparation and Intravenous Administration *+&/E:AG>647:3@6>76;@3?3@@7D5A@E;EF7@FI;F:D75A??7@676 E387BDA576GD7E8AD:3@6>;@95KFAFAJ;56DG9E 5 WARNINGS AND PRECAUTIONS 5.1 Hematologic +D73F?7@FI;F: *+&/53@53GE7F:DA?4A5KFAB7@;3>7G=AB7@;3 @7GFDAB7@;33@6>K?B:AB7@;33@63@7?;3F:7D78AD7F:7E7:7?3FA>A9;53> B3D3?7F7DEE:AG>647?A@;FAD766GD;@9FD73F?7@FI;F: *+&/3@6F:7 6AE7E:AG>647?A6;8;763E@757EE3DK1*77AE3973@66?;@;EFD3F;A@ 3@66H7DE7)735F;A@E2 5.2 Infection *7D;AGE3@6EA?7F;?7E83F3>;@875F;A@E;@5>G6;@9B@7G?A@;33@6E7BE;E :3H7477@D7BADF76;@5>;@;53>FD;3>EI;F: *+&/+:7E753@A55GD 6GD;@9FD73F?7@F3@6I;F:;@ 63KE38F7DFD73F?7@F3@6F:7D;E=A8>;87 F:D73F7@;@9;@875F;A@E?3K47:;9:7D;@B3F;7@FEI;F:3:;EFADKA87JF7@E;H7 AD;@F7@E;H75:7?AF:7D3BK1*776H7DE7)735F;A@E2 5.3 Electrocardiographic Changes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umor Lysis Syndrome +G?AD>KE;EEK@6DA?7+#*:3E477@D7BADF76FAA55GD;@A8B3F;7@FE I;F:FG?ADEF397+#3@6A8B3F;7@FEI;F:*F397 -'+#'3F;7@FE I;F:36H3@576EF3976;E73E73@6AD:;9:FG?AD4GD67@E:AG>6475>AE7>K ?A@;FAD763BBDABD;3F7BD753GF;A@EE:AG>647F3=7@3@6FD73F?7@FE:AG>6 47;@EF;FGF763E3BBDABD;3F7 5.5 Use in Pregnancy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linical Trials Experience 753GE75>;@;53>FD;3>E3D75A@6G5F76G@67DI;67>KH3DK;@95A@6;F;A@E 36H7DE7D735F;A@D3F7EA4E7DH76;@F:75>;@;53>FD;3>EA836DG953@@AF47 6;D75F>K5A?B3D76FAD3F7E;@F:75>;@;53>FD;3>EA83@AF:7D6DG93@6?3K @AFD78>75FF:7D3F7EA4E7DH76;@BD35F;57 Cutaneous T-Cell Lymphoma +:7E387FKA8 *+&/I3E7H3>G3F76;@B3F;7@FEI;F:+#;@ E;@9>73D?5>;@;53>EFG6;7E;@I:;5:B3F;7@FED757;H763EF3DF;@96AE7A8 ?9?2+:7?73@6GD3F;A@A8FD73F?7@F;@F:7E7EFG6;7EI3E ?A@F:ED3@97FA?A@F:E A??A@6H7DE7)735F;A@E +34>7EG??3D;L7EF:7?AEF8D7CG7@F36H7DE7D735F;A@E D793D6>7EEA853GE3>;FKGE;@9F:7%3F;A@3>3@57D @EF;FGF7A??A@ +7D?;@A>A9KD;F7D;38AD6H7DE7H7@FE% +-7DE;A@ G7 FA?7F:A6A>A9;53>6;887D7@57E47FI77@F:7EFG6;7EF:763F33D7 BD7E7@F76E7B3D3F7>K8AD*FG6K3@6*FG6K6H7DE7D735F;A@E3D7 D3@=764KF:7;D;@5;67@57;@*FG6K#34AD3FADK34@AD?3>;F;7E5A??A@>K D7BADF76 3E36H7DE7D735F;A@E3D7;@5>G676;@+34>7 Table 1. Adverse Reactions Occurring in >20% of Patients in Either CTCL Study (N=185) Study 1 Study 2 (n=102) (n=83) Grade 3 Grade 3 Adverse Reactions n (%) All or 4 All or 4 @K36H7DE7D735F;A@ %3GE73 EF:7@;33F;9G7 @875F;A@E -A?;F;@9 @AD7J;3 KBA?39@7E7?;3 ;3DD:73 'KD7J;3 @7?;3 +:DA?4A5KFAB7@;3 KE97GE;3 A@EF;B3F;A@ %7GFDAB7@;3 KBAF7@E;A@ 'DGD;FGE KBA=3>7?;3 7D?3F;F;EJ8A>;3F;H7 67D?3F;F;E KBA53>57?;3 #7G=AB7@;3 #K?B:AB7@;3 >3@;@73?;@AFD3@E87D3E7 ;@5D73E76 EB3DF3F73?;@AFD3@E87D3E7 ;@5D73E76 KBA3>4G?;@7?;3 >75FDA53D6;A9D3? *++I3H75:3@97E KB7D9>K57?;3 KBA@3FD7?;3 KB7D?39@7E7?;3 KBAB:AEB:3F7?;3 KB7DGD;57?;3 Serious Adverse Reactions Infections were the most common type of SAE reported in both studies with 8 patients (8%) in Study 1 and 26 patients (31%) in Study 2 experiencing a serious infection. Serious adverse reactions reported in > 2% of patients in Study 1 were sepsis and pyrexia (3%). In Study 2, serious adverse reactions in > 2% of patients were fatigue (7%), supraventricular arrhythmia, central line infection, neutropenia (6%), hypotension, hyperuricemia, edema (5%), ventricular arrhythmia, thrombocytopenia, nausea, leukopenia, dehydration, pyrexia, aspartate aminotransferase increased, sepsis, catheter related infection, hypophosphatemia and dyspnea (4%). Most deaths were due to disease progression. In Study 1, there were two deaths due to cardiopulmonary failure and acute renal failure. In Study 2, there were six deaths due to infection (4), myocardial ischemia, and acute respiratory distress syndrome. Discontinuations Discontinuation due to an adverse event occurred in 21% of patients in Study 1 and 11% in Study 2. Discontinuations occurring in at least 2% of patients in either study included infection, fatigue, dyspnea, QT prolongation, and hypomagnesmia. Peripheral T-Cell Lymphoma The safety of ISTODAX was evaluated in 178 patients with PTCL in a sponsor-conducted pivotal study (Study 3) and a secondary NCI-sponsored study (Study 4) in which patients received a starting dose of 14 mg/m2. The mean duration of treatment and number of cycles in these studies were 5.6 months and 6 cycles. Common Adverse Reactions Table 2 summarizes the most frequent adverse reactions (≥ 10%) regardless of causality, using the NCI-CTCAE, Version 3.0. The AE data are presented separately for Study 3 and Study 4. Laboratory abnormalities commonly reported (≥ 10%) as adverse reactions are included in Table 2. Table 2. Adverse Reactions Occurring in ≥10% of Patients with PTCL in Study 3 and Corresponding Incidence in Study 4 (N=178) Study 3 Study 4 (N=131) (N=47) Grade 3 Grade 3 Adverse Reactions n (%) All or 4 All or 4 Any adverse reactions 127 (97) 86 (66) 47 (100) 40 (85) Gastrointestinal disorders Nausea 77 (59) 3 (2) 35 (75) 3 (6) Vomiting 51 (39) 6 (5) 19 (40) 4 (9) Diarrhea 47 (36) 3 (2) 17 (36) 1 (2) Constipation 39 (30) 1 (<1) 19 (40) 1 (2) Abdominal pain 18 (14) 3 (2) 6 (13) 1 (2) Stomatitis 13 (10) 0 3 (6) 0 General disorders and administration site conditions Asthenia/Fatigue 72 (55) 11 (8) 36 (77) 9 (19) Pyrexia 46 (35) 7 (5) 22 (47) 8 (17) Chills 14 (11) 1 (<1) 8 (17) 0 Edema peripheral 13 (10) 1 (<1) 3 (6) 0 Blood and lymphatic system disorders Thrombocytopenia 53 (41) 32 (24) 34 (72) 17 (36) Neutropenia 39 (30) 26 (20) 31 (66) 22 (47) Anemia 32 (24) 14 (11) 29 (62) 13 (28) Leukopenia 16 (12) 8 (6) 26 (55) 21 (45) Metabolism and nutrition disorders Anorexia 37 (28) 2 (2) 21 (45) 1 (2) Hypokalemia 14 (11) 3 (2) 8 (17) 1 (2) Nervous system disorders Dysgeusia 27 (21) 0 13 (28) 0 Headache 19 (15) 0 16 (34) 1 (2) Respiratory, thoracic and mediastinal disorders Cough 23 (18) 0 10 (21) 0 Dyspnea 17 (13) 3 (2) 10 (21) 2 (4) Investigations Weight decreased 13 (10) 0 7 (15) 0 Cardiac disorders Tachycardia 13 (10) 0 0 0 Serious Adverse Reactions Infections were the most common type of SAE reported. In Study 3, 25 patients (19%) experienced a serious infection, including 6 patients (5%) with serious treatment-related infections. In Study 4, 11 patients (23%) experienced a serious infection, including 8 patients (17%) with serious treatment-related infections. Serious adverse reactions reported in ≥ 2% of patients in Study 3 were pyrexia (7%), pneumonia, sepsis, vomiting (5%), cellulitis, deep vein thrombosis, (4%), febrile neutropenia, abdominal pain (3%), chest pain, neutropenia, pulmonary embolism, dyspnea, and dehydration (2%). In Study 4, serious adverse reactions in ≥ 2 of patients were pyrexia (17%), aspartate aminotransferase increased, hypotension (13%), anemia, thrombocytopenia, alanine aminotransferase increased (11%), infection, dehydration, dyspnea (9%), lymphopenia, neutropenia, hyperbilirubinemia, hypocalcemia, hypoxia (6%), febrile neutropenia, leukopenia, ventricular arrhythmia, vomiting, hypersensitivity, catheter related infection, hyperuricemia, hypoalbuminemia, syncope, pneumonitis, packed red blood cell transfusion, and platelet transfusion (4%). Deaths due to all causes within 30 days of the last dose of ISTODAX occurred in 7% of patients in Study 3 and 17% of patients in Study 4. In Study 3, there were 5 deaths unrelated to disease progression that were due to infections, including multi-organ failure/sepsis, pneumonia, septic shock, candida sepsis, and sepsis/cardiogenic shock. In Study 4, there were 3 deaths unrelated to disease progression that were due to sepsis, aspartate aminotransferase elevation in the setting of Epstein Barr virus reactivation, and death of unknown cause. Discontinuations Discontinuation due to an adverse event occurred in 19% of patients in Study 3 and in 28% of patients in Study 4. In Study 3, thrombocytopenia and pneumonia were the only events leading to treatment discontinuation in at least 2% of patients. In Study 4, events leading to treatment discontinuation in ≥ 2 patients were thrombocytopenia (11%), anemia, infection, and alanine aminotransferase increased (4%). 6.2 Postmarketing Experience No additional safety signals have been observed from postmarketing experience. 7 DRUG INTERACTIONS 7.1 Coumadin or Coumadin Derivatives Prolongation of PT and elevation of INR were observed in a patient receiving ISTODAX concomitantly with warfarin. Although the interaction potential between ISTODAX and Coumadin or Coumadin derivatives has not been formally studied, physicians should carefully monitor PT and INR in patients concurrently administered ISTODAX and Coumadin or Coumadin derivatives [See Clinical Pharmacology (12.3)]. 7.2 Drugs that Inhibit or Induce Cytochrome P450 3A4 Enzymes Romidepsin is metabolized by CYP3A4. Although there are no formal drug interaction studies for ISTODAX, strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole) may increase concentrations of romidepsin. Therefore, co-administration with strong CYP3A4 inhibitors should be avoided if possible. Caution should be exercised with concomitant use of moderate CYP3A4 inhibitors. Co-administration of potent CYP3A4 inducers (e.g., dexamethasone, carbamazepine, phenytoin, rifampin, rifabutin, rifapentine, phenobarbital) may decrease concentrations of romidepsin and should be avoided if possible. Patients should also refrain from taking St. John’s Wort. 7.3 Drugs that Inhibit Drug Transport Systems Romidepsin is a substrate of the efflux transporter P-glycoprotein (P-gp, ABCB1). If ISTODAX is administered with drugs that inhibit P-gp, increased concentrations of romidepsin are likely, and caution should be exercised. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category D [See Warnings and Precautions (5.5)]. There are no adequate and well-controlled studies of ISTODAX in pregnant women. However, based on its mechanism of action and findings in animals, ISTODAX may cause fetal harm when administered to a pregnant woman. In an animal reproductive study, romidepsin was embryocidal and resulted in adverse effects on the developing fetus at exposures below those in patients at the recommended dose. If this drug is used during pregnancy, or if the patient becomes pregnant while taking ISTODAX, the patient should be apprised of the potential hazard to the fetus. Romidepsin was administered intravenously to rats during the period of organogenesis at doses of 0.1, 0.2, or 0.5 mg/kg/day. Substantial resorption or post-implantation loss was observed at the high-dose of 0.5 mg/kg/day, a maternally toxic dose. Adverse embryo-fetal effects were noted at romidepsin doses of ≥0.1 mg/kg/day, with systemic exposures (AUC) ≥0.2% of the human exposure at the recommended dose of 14 mg/m2/week. Drug-related fetal effects consisted of folded retina, rotated limbs, and incomplete sternal ossification. 8.3 Nursing Mothers It is not known whether romidepsin is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from ISTODAX, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. 8.4 Pediatric Use The safety and effectiveness of ISTODAX in pediatric patients has not been established. 8.5 Geriatric Use Of the approximately 300 patients with CTCL or PTCL in trials, about 25% were > 65 years old. No overall differences in safety or effectiveness were observed between these subjects and younger subjects; however, greater sensitivity of some older individuals cannot be ruled out. 8.6 Hepatic Impairment No dedicated hepatic impairment study for ISTODAX has been conducted. Mild hepatic impairment does not alter pharmacokinetics of romidepsin based on a population pharmacokinetic analysis. Patients with moderate and severe hepatic impairment should be treated with caution [See Clinical Pharmacology (12.3)]. 8.7 Renal Impairment No dedicated renal impairment study for ISTODAX has been conducted. Based upon the population pharmacokinetic analysis, renal impairment is not expected to significantly influence drug exposure. The effect of end-stage renal disease on romidepsin pharmacokinetics has not been studied. Thus, patients with end-stage renal disease should be treated with caution [See Clinical Pharmacology (12.3)]. 10 OVERDOSAGE No specific information is available on the treatment of overdosage of ISTODAX. Toxicities in a single-dose study in rats or dogs, at intravenous romidepsin doses up to 2.2 fold the recommended human dose based on the body surface area, included irregular respiration, irregular heart beat, staggering gait, tremor, and tonic convulsions. In the event of an overdose, it is reasonable to employ the usual supportive measures, e.g., clinical monitoring and supportive therapy, if required. There is no known antidote for ISTODAX and it is not known if ISTODAX is dialyzable. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity studies have not been performed with romidepsin. Romidepsin was not mutagenic in vitro in the bacterial reverse mutation assay (Ames test) or the mouse lymphoma assay. Romidepsin was not clastogenic in an in vivo rat bone marrow micronucleus assay when tested to the maximum tolerated dose (MTD) of 1 mg/kg in males and 3 mg/kg in females (6 and 18 mg/m2 in males and females, respectively). These doses were up to 1.3-fold the recommended human dose, based on body surface area. Based on non-clinical findings, male and female fertility may be compromised by treatment with ISTODAX. In a 26-week toxicology study, romidepsin administration resulted in testicular degeneration in rats at 0.33 mg/kg/dose (2 mg/m2/dose) following the clinical dosing schedule. This dose resulted in AUC0-inf. values that were approximately 2% the exposure level in patients receiving the recommended dose of 14 mg/m2/dose. A similar effect was seen in mice after 4 weeks of drug administration at higher doses. Seminal vesicle and prostate organ weights were decreased in a separate study in rats after 4 weeks of daily drug administration at 0.1 mg/kg/day (0.6 mg/m2/day), approximately 30% the estimated human daily dose based on body surface area. Romidepsin showed high affinity for binding to estrogen receptors in pharmacology studies. In a 26-week toxicology study in rats, atrophy was seen in the ovary, uterus, vagina and mammary gland of females administered doses as low as 0.1 mg/kg/dose (0.6 mg/m2/dose) following the clinical dosing schedule. This dose resulted in AUC0-inf. values that were 0.3% of those in patients receiving the recommended dose of 14 mg/m2/dose. Maturation arrest of ovarian follicles and decreased weight of ovaries were observed in a separate study in rats after four weeks of daily drug administration at 0.1 mg/kg/day (0.6 mg/m2/day). This dose is approximately 30% the estimated human daily dose based on body surface area. 16 HOW SUPPLIED/STORAGE AND HANDLING Keep out of reach of children. Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published1-4 [See References (15)]. 17 PATIENT COUNSELING INFORMATION See FDA-approved patient labeling. 17.1 Instructions M%3GE733@6-A?;F;@9 Nausea and vomiting are common following treatment with ISTODAX. Prophylactic antiemetics are recommended to be used in all patients. Advise patients to report these symptoms so that appropriate treatment can be instituted [See Adverse Reactions (6)]. M#AI>AA6AG@FE Patients should be informed that treatment with ISTODAX can cause low blood counts and that frequent monitoring of hematologic parameters is required. Patients should be instructed to report fever or other signs of infection, significant fatigue, shortness of breath, or bleeding [See Warnings and Precautions (5.1)]. M @875F;A@E Patients should be informed that infections may occur during treatment with ISTODAX. Patients should be instructed to report fever, cough, shortness of breath with or without chest pain, burning on urination, flu-like symptoms, muscle aches, or worsening skin problems [See Warnings and Precautions (5.2)]. M+G?AD#KE;E*K@6DA?7 Patients at risk of tumor lysis syndrome (i.e, those with advanced stage disease and/or high tumor burden) should be monitored closely for TLS and appropriate measures taken if symptoms are observed [See Warnings and Precautions (5.4)]. M,E7;@'D79@3@5K If pregnancy occurs during treatment with ISTODAX, female patients should be advised to seek immediate medical advice and counseling. [See Warnings and Precautions (5.5)]. M'3F;7@FEE:AG>647;@EFDG5F76FAD736F:7B3F;7@F;@E7DF53D78G>>K Manufactured for: Celgene Corporation Summit, NJ 07901 Manufactured by: 7@-7@G7#34AD3FAD;7E @5 Bedford, OH 44146 ISTODAX® is a registered trademark of Celgene Corporation U.S. Patents: 4,977,138; 7,608,280; 7,611,724 *+-' '' Author guide Blood, the Journal of the American Society of Hematology, published online and in print, provides an international forum for the publication of original articles describing basic laboratory, translational, and clinical investigations in hematology. Acceptance of manuscripts is based on the originality and importance of the observations or investigations, the quality of the work and validity of the evidence, the clarity of presentation, and the relevance to our readership and field. Membership in the American Society of Hematology is not required for submission. All articles are expected to be concise, well organized and clearly written. Authors submit a manuscript with the understanding that the manuscript (or its essential substance) has not been published other than as an abstract in any language or format and is not currently submitted elsewhere for print or electronic publication. Blood receives over 5,000 online submissions per year and accepts about 25% of them after a thorough and impartial peer review. Accepted papers are published ahead of print as First Edition papers. The average time to first decision is 21.3 days. The average time from acceptance to publication is 7 weeks. Non-English-speaking authors are encouraged to visit the Authors Guide online at http:// bloodjournal.hematologylibrary.org/authors/authorguide.dtl to view links to professional editing services that may help improve the presentation of the paper. 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The American Society of Hematology supports free access to Blood on the broadest possible basis, although ASH and Blood cannot adopt or support a publishing model that is not economically sustainable over a long horizon. Blood maintains a 12-month access embargo to non-subscribers while offering an inexpensive pay-per-view option; however, online content older than 12 months is free to all. Also, significant sections of each new issue are immediately free-to-all online, including abstracts and tables of contents, Inside Blood commentaries, How I Treat articles, and 5 clinically relevant research articles or Review Articles per issue selected by the Editor-in-Chief. In addition, Blood ensures that patients looking for pertinent information can access any article without charge by contacting the Journal. Any author (including, but not limited to, those supported by the Howard Hughes Medical Institute or Wellcome Trust) wishing immediate public access for their accepted paper may pay an additional Public Access manuscript fee of $2,000. Upon receipt of payment, Blood will also deposit on behalf of the author the final edition of the published paper into PubMed Central. This fee does not apply to research funded by the National Institutes of Health. BLOOD, 8 MARCH 2012 䡠 VOLUME 119, NUMBER 10 NOW ENROLLING Study Description A multicenter, randomized, double-blind, placebo-controlled clinical trial of deferasirox in patients with myelodysplastic syndromes (MDS) (low/intermediate-1 risk) and transfusional iron overload (Clinical Trial Protocol CICL670A2302). The purpose of this study is to demonstrate in low/intermediate-1 risk MDS patients, treated as per standard practice, the clinical superiority of deferasirox to placebo, while rigorously monitoring relevant clinical parameters (cardiac and liver function, and transformation to acute leukemia [AML]) potentially affected by iron overload complications. Study Design Primary Endpoint* Deferasirox Screening 5y Placebo Expected end of study 5andomization (2:1=Deferasirox/Placebo) The following dosing schedule is to be followed: Ȼ 10 mg/kg/day (once daily) for 2 weeks, followed by 20 mg/kg/day (once daily) Ȼ After 3 months, the dose can be adjusted by 5 mg/kg/day or 10 mg/kg/day up to 40 mg/kg/day based on serum ferritin response Two interim analyses for safety and efÀcacy are planned when approximately 50 and 75 of the reTuired number of events (244) have been observed. Composite primary endpoint (event-free survival): Ȼ Death Ȼ 1onfatal event: 1. Echocardiographic evidence of worsening cardiac function 2. Hospitalization for congestive heart failure 3. Liver function impairment 4. Liver cirrhosis 5. Progression to AML Eligibility† Inclusion criteria: Ȼ Male or female patients, 1 years of age Ȼ Patient must weigh between 35 kg to 135 kg Ȼ Patients with low or intermediate risk MDS, as determined by IPSS score Ȼ )erritin ! 1000 mcg/L and 3500 mcg/L at screening Ȼ History of transfusion of 15 P5%C to 75 P5%C units Ȼ Anticipated to be transfused with units of P5%Cs annually during the study Endpoint details are deÀned in the protocol. † 2ther protocol-deÀned inclusion/exclusion criteria may apply. Exclusion criteria: Ȼ More than 6 months of cumulative iron chelation therapy (such as daily deferasirox or deferiprone or 5 ×/week deferoxamine) Ȼ More than 3 years since patient began receiving regular transfusions (2 units per weeks or 4 units received in a 3-month period) Ȼ Creatinine clearance 40 mL/min Ȼ Serum creatinine ! 1.2 × 8L1 at screening Ȼ SigniÀcant proteinuria Ȼ EC2* performance status ! 2 Ȼ L9E) 50 by echocardiography Ȼ History of hospitalization for congestive heart failure Ȼ Systemic diseases which would prevent study treatment (eg, uncontrolled hypertension, cardiovascular, renal, hepatic, metabolic, etc) Ȼ Evidence of active hepatitis % or hepatitis C Ȼ History of HI9-positive test result Ȼ ALT or AST ! 2.5 × 8L1 at screening Ȼ Total bilirubin ! 8L1 at screening Ȼ Diagnosis of liver cirrhosis For more information Ȼ Call 1ovartis 2ncology at 1-00-340-643 Ȼ Contact your local 1ovartis Medical Science Liaison (MSL) Ȼ ClinicalTrials.gov identiÀer: 1CT0040602 Novartis Pharmaceuticals Corporation East Hanover, 1- 0736-100 2012 1ovartis 1/12 I2E-103651 Indications and usage Soliris is a complement inhibitor indicated for: • The treatment of patients with paroxysmal nocturnal hemoglobinuria (PNH) to reduce hemolysis • The treatment of patients with atypical hemolytic uremic syndrome (aHUS) to inhibit complement-mediated thrombotic microangiopathy The effectiveness of Soliris in aHUS is based on the effects on thrombotic microangiopathy (TMA) and renal function. Prospective clinical trials in additional patients are ongoing to confirm the benefit of Soliris in patients with aHUS. Limitation of Use Soliris is not indicated for the treatment of patients with Shiga toxin E. coli related hemolytic uremic syndrome (STEC-HUS). ® ( e c u l i z u m a b ) ® ( e c u l i z u m a b ) Concentrated solution for intravenous infusion Brief summary—please see full prescribing information IMPORTANT SAFETY INFORMATION WARNING: SERIOUS MENINGOCOCCAL INFECTIONS See full prescribing information for complete boxed warning Life-threatening and fatal meningococcal infections have occurred in patients treated with Soliris. Meningococcal infection may become rapidly life-threatening or fatal if not recognized and treated early. t$PNQMZXJUIUIFNPTUDVSSFOU"EWJTPSZ$PNNJUUFFPO*NNVOJ[BUJPO 1SBDUJDFT"$*1 SFDPNNFOEBUJPOTGPSNFOJOHPDPDDBMWBDDJOBUJPOJO patients with complement deficiencies. t*NNVOJ[FQBUJFOUTXJUIBNFOJOHPDPDDBMWBDDJOFBUMFBTUXFFLTQSJPS UPBENJOJTUFSJOHUIFmSTUEPTFPG4PMJSJTVOMFTTUIFSJTLTPGEFMBZJOH 4PMJSJTUIFSBQZPVUXFJHIUIFSJTLTPGEFWFMPQJOHBNFOJOHPDPDDBM infection. (See Serious Meningococcal Infections for additional HVJEBODFPOUIFNBOBHFNFOUPGUIFSJTLPGNFOJOHPDPDDBMJOGFDUJPO t.POJUPSQBUJFOUTGPSFBSMZTJHOTPGNFOJOHPDPDDBMJOGFDUJPOTBOE evaluate immediately if infection is suspected. 4PMJSJTJTBWBJMBCMFPOMZUISPVHIBSFTUSJDUFEQSPHSBNVOEFSB3JTL &WBMVBUJPOBOE.JUJHBUJPO4USBUFHZ3&.4 6OEFSUIF4PMJSJT3&.4 prescribers must enroll in the program. Enrollment in the Soliris REMS program and additional information are available by telephone: 40-*3*4 INDICATIONS AND USAGE Paroxysmal Nocturnal Hemoglobinuria (PNH) Soliris is indicated for the treatment of patients with paroxysmal nocturnal IFNPHMPCJOVSJB1/) UPSFEVDFIFNPMZTJT Atypical Hemolytic Uremic Syndrome (aHUS) Soliris is indicated for the treatment of patients with atypical hemolytic uremic TZOESPNFB)64 UPJOIJCJUDPNQMFNFOUNFEJBUFEUISPNCPUJDNJDSPBOHJPQBUIZ 5IF FGGFDUJWFOFTT PG 4PMJSJT JO B)64 JT CBTFE PO UIF FGGFDUT PO UISPNCPUJD NJDSPBOHJPQBUIZ5." BOESFOBMGVODUJPO1SPTQFDUJWFDMJOJDBMUSJBMTJOBEEJUJPOBM QBUJFOUTBSFPOHPJOHUPDPOmSNUIFCFOFmUPG4PMJSJTJOQBUJFOUTXJUIB)64 -JNJUBUJPOPG6TF: Soliris is not indicated for the treatment of patients with Shiga toxin E. coliSFMBUFEIFNPMZUJDVSFNJDTZOESPNF45&$)64 CONTRAINDICATIONS Soliris is contraindicated in: t 1BUJFOUTXJUIVOSFTPMWFETFSJPVTNeisseria meningitidis infection t 1BUJFOUT XIP BSF OPU DVSSFOUMZ WBDDJOBUFE BHBJOTU Neisseria meningitidis, VOMFTTUIFSJTLTPGEFMBZJOH4PMJSJTUSFBUNFOUPVUXFJHIUIFSJTLTPGEFWFMPQJOHB meningococcal infection [see Warnings and Precautions]. WARNINGS AND PRECAUTIONS Serious Meningococcal Infections The use of Soliris increases a patient’s susceptibility to serious meningococcal JOGFDUJPOT TFQUJDFNJB BOEPS NFOJOHJUJT -JGFUISFBUFOJOH BOE GBUBM meningococcal infections have occurred in patients treated with Soliris. "ENJOJTUFSBQPMZWBMFOUNFOJOHPDPDDBMWBDDJOFBDDPSEJOHUPUIFNPTUDVSSFOU "EWJTPSZ$PNNJUUFFPO*NNVOJ[BUJPO1SBDUJDFT"$*1 SFDPNNFOEBUJPOTGPS patients with complement deficiencies. Revaccinate patients in accordance XJUI"$*1SFDPNNFOEBUJPOTDPOTJEFSJOHUIFEVSBUJPOPG4PMJSJTUIFSBQZ 7BDDJOBUFQBUJFOUTXJUIPVUBIJTUPSZPGNFOJOHPDPDDBMWBDDJOBUJPOBUMFBTU XFFLT QSJPS UP SFDFJWJOH UIF mSTU EPTF PG 4PMJSJT *G VSHFOU 4PMJSJT UIFSBQZ JT indicated in an unvaccinated patient, administer the meningococcal vaccine BTTPPOBTQPTTJCMF*ODMJOJDBMTUVEJFTQBUJFOUTXJUIB)64XFSFUSFBUFE XJUI4PMJSJTMFTTUIBOXFFLTBGUFSNFOJOHPDPDDBMWBDDJOBUJPOBOEPGUIFTF QBUJFOUT SFDFJWFE BOUJCJPUJDT GPS QSPQIZMBYJT PG NFOJOHPDPDDBM JOGFDUJPO VOUJMBUMFBTUXFFLTBGUFSNFOJOHPDPDDBMWBDDJOBUJPO5IFCFOFmUTBOESJTLT of antibiotic prophylaxis for prevention of meningococcal infections in patients receiving Soliris have not been established. 7BDDJOBUJPO SFEVDFT CVU EPFT OPU FMJNJOBUF UIF SJTL PG NFOJOHPDPDDBM JOGFDUJPOT *O DMJOJDBM TUVEJFT PVU PG 1/) QBUJFOUT EFWFMPQFE TFSJPVT meningococcal infections while receiving treatment with Soliris; both had been vaccinated [see Adverse Reactions>*ODMJOJDBMTUVEJFTBNPOHOPO1/) QBUJFOUTNFOJOHPDPDDBMNFOJOHJUJTPDDVSSFEJOPOFVOWBDDJOBUFEQBUJFOU*O BEEJUJPOBQSFWJPVTMZWBDDJOBUFEQBUJFOUXJUIB)64EFWFMPQFENFOJOHPDPDDBM sepsis during the post-study follow-up period [see Adverse Reactions]. $MPTFMZ NPOJUPS QBUJFOUT GPS FBSMZ TJHOT BOE TZNQUPNT PG NFOJOHPDPDDBM infection and evaluate patients immediately if an infection is suspected. Meningococcal infection may become rapidly life-threatening or fatal if not recognized and treated early. Discontinue Soliris in patients who are undergoing treatment for serious meningococcal infections. QBSBNFUFST NBZ JEFOUJGZ B 5." DPNQMJDBUJPO PDDVSSFODF PG UXP PS SFQFBUFE NFBTVSFNFOUPGBOZPOFPGUIFGPMMPXJOHBEFDSFBTFJOQMBUFMFUDPVOUCZPS NPSFDPNQBSFEUPCBTFMJOFPSUIFQFBLQMBUFMFUDPVOUEVSJOH4PMJSJTUSFBUNFOUBO JODSFBTFJOTFSVNDSFBUJOJOFCZPSNPSFDPNQBSFEUPCBTFMJOFPSOBEJSEVSJOH 4PMJSJTUSFBUNFOUPSBOJODSFBTFJOTFSVN-%)CZPSNPSFPWFSCBTFMJOFPSOBEJS during Soliris treatment. *G5."DPNQMJDBUJPOTPDDVSBGUFS4PMJSJTEJTDPOUJOVBUJPODPOTJEFSSFJOTUJUVUJPOPG Soliris treatment, plasma therapy [plasmapheresis, plasma exchange, or fresh GSP[FOQMBTNBJOGVTJPO1&1* >PSBQQSPQSJBUFPSHBOTQFDJmDTVQQPSUJWFNFBTVSFT TABLE 1 (CONT.): ADVERSE REACTIONS OCCURRING IN AT LEAST 15% OF PATIENTS LESS THAN 18 YEARS OF AGE ENROLLED IN aHUS STUDY 3 MedDRA Number (%) of Patients ver. 11.0 < 2 yrs 2 to < 12 yrs 12 to<18 yrs Total (n=5) (n=10) (n=4) (n=19) Respiratory, Thoracic and Mediastinal Disorders $PVHI Thrombosis Prevention and Management The effect of withdrawal of anticoagulant therapy during Soliris treatment has not /BTBMDPOHFTUJPO been established. Therefore, treatment with Soliris should not alter anticoagulant $BSEJBD%JTPSEFST management. 5BDIZDBSEJB a. Laboratory Monitoring includes the preferred terms upper respiratory tract infection and nasopharyngitis. PNH: Serum LDH levels increase during hemolysis and may assist in monitoring 4PMJSJT FGGFDUT JODMVEJOH UIF SFTQPOTF UP EJTDPOUJOVBUJPO PG UIFSBQZ *O DMJOJDBM Immunogenicity studies, six patients achieved a reduction in serum LDH levels only after a decrease in "TXJUIBMMQSPUFJOTUIFSFJTBQPUFOUJBMGPSJNNVOPHFOJDJUZ5IFJNNVOPHFOJDJUZPG UIF4PMJSJTEPTJOHJOUFSWBMGSPNUPEBZT"MMPUIFSQBUJFOUTBDIJFWFEBSFEVDUJPO Soliris has been evaluated using two different immunoassays for the detection of JOTFSVN-%)MFWFMTXJUIUIFEBZEPTJOHJOUFSWBM<TFFClinical Pharmacology and BOUJFDVMJ[VNBCBOUJCPEJFTBEJSFDUFO[ZNFMJOLFEJNNVOPTPSCFOUBTTBZ&-*4" using the Fab fragment of eculizumab as target was used for the PNH indication; Clinical Studies]. B)64 &BSMZ TJHOT PG UISPNCPUJD NJDSPBOHJPQBUIZ 5." JODMVEF B EFDSFBTF JO BOE BO FMFDUSPDIFNJMVNJOFTDFODF &$- CSJEHJOH BTTBZ VTJOH UIF FDVMJ[VNBC platelet count, and increases in serum LDH and creatinine levels. Follow patients for XIPMFNPMFDVMBSBTUBSHFUXBTVTFEGPSUIFB)64JOEJDBUJPO-PXUJUFSTPGBOUJCPEJFT TJHOTPG5."CZNPOJUPSJOHTFSJBMQMBUFMFUDPVOUTTFSVN-%)BOEDSFBUJOJOFEVSJOH UP4PMJSJTXFSFEFUFDUFEJO PGBMM1/)QBUJFOUTUSFBUFEXJUI4PMJSJTCZ UIF&-*4"BTTBZ*OQBUJFOUTXJUIB)64USFBUFEXJUI4PMJSJTBOUJCPEJFTUP4PMJSJT Soliris therapy and following discontinuation of Soliris. XFSFEFUFDUFEJO CZUIF&$-BTTBZ"O&$-CBTFEOFVUSBMJ[JOH)")" BTTBZ XJUI B MPX TFOTJUJWJUZ PG NDHN- XBT QFSGPSNFE UP EFUFDU OFVUSBMJ[JOH Infusion Reactions "TXJUIBMMQSPUFJOQSPEVDUTBENJOJTUSBUJPOPG4PMJSJTNBZSFTVMUJOJOGVTJPOSFBDUJPOT BOUJCPEJFT GPS UIF QBUJFOUT XJUI B)64 /P OFVUSBMJ[JOH BDUJWJUZ UP 4PMJSJT XBT JODMVEJOH BOBQIZMBYJT PS PUIFS IZQFSTFOTJUJWJUZ SFBDUJPOT *O DMJOJDBM USJBMT OP EFUFDUFE JO QBUJFOUT XJUI B)64 USFBUFE XJUI 4PMJSJT /P BQQBSFOU DPSSFMBUJPO PG patients experienced an infusion reaction which required discontinuation of Soliris. antibody development to clinical response was observed in both indications. The *OUFSSVQU4PMJSJTJOGVTJPOBOEJOTUJUVUFBQQSPQSJBUFTVQQPSUJWFNFBTVSFTJGTJHOTPG immunogenicity data reflect the percentage of patients whose test results were DPOTJEFSFEQPTJUJWFGPSBOUJCPEJFTUP4PMJSJTJOBO&-*4"CBTFEBTTBZBOEPSBO&$- cardiovascular instability or respiratory compromise occur. based assay are highly dependent on the sensitivity and specificity of the assay ADVERSE REACTIONS VTFE"EEJUJPOBMMZUIFPCTFSWFEJODJEFODFPGBOUJCPEZQPTJUJWJUZJOUIFBTTBZNBZCF Clinical Trial Experience influenced by several factors including sample handling, timing of sample collection, Meningococcal infections are the most important adverse reactions experienced concomitant medications and underlying disease. For these reasons, comparison CZ QBUJFOUT SFDFJWJOH 4PMJSJT *O 1/) DMJOJDBM TUVEJFT UXP QBUJFOUT FYQFSJFODFE of the incidence of antibodies to Soliris with the incidence of antibodies to other meningococcal sepsis. Both patients had previously received a meningococcal products may be misleading. WBDDJOF*ODMJOJDBMTUVEJFTBNPOHQBUJFOUTXJUIPVU1/)NFOJOHPDPDDBMNFOJOHJUJT occurred in one unvaccinated patient. Meningococcal sepsis occurred in one Postmarketing Experience QSFWJPVTMZWBDDJOBUFEQBUJFOUFOSPMMFEJOUIFSFUSPTQFDUJWFB)64TUVEZEVSJOHUIF $BTFTPGTFSJPVTPSGBUBMNFOJOHPDPDDBMJOGFDUJPOTIBWFCFFOSFQPSUFE post-study follow-up period [see Warnings and Precautions]. USE IN SPECIFIC POPULATIONS PNH 5IF EBUB EFTDSJCFE CFMPX SFnFDU FYQPTVSF UP 4PMJSJT JO BEVMU QBUJFOUT XJUI1/)BHFPGXIPNXFSFGFNBMF"MMIBETJHOTPSTZNQUPNTPG Pregnancy intravascular hemolysis. Soliris was studied in a placebo-controlled clinical study (in 1SFHOBODZ$BUFHPSZ$ XIJDIQBUJFOUTSFDFJWFE4PMJSJTBOEQMBDFCP BTJOHMFBSNDMJOJDBMTUVEZBOE There are no adequate and well-controlled studies of Soliris in pregnant women. BMPOHUFSNFYUFOTJPOTUVEZQBUJFOUTXFSFFYQPTFEGPSHSFBUFSUIBOPOFZFBS"MM 4PMJSJTBSFDPNCJOBOU*H(NPMFDVMFIVNBOJ[FEBOUJ$BOUJCPEZ JTFYQFDUFEUP DSPTTUIFQMBDFOUB"OJNBMTUVEJFTVTJOHBNPVTFBOBMPHVFPGUIF4PMJSJTNPMFDVMF patients received the recommended Soliris dose regimen. Because clinical trials are conducted under widely varying conditions, adverse NVSJOFBOUJ$BOUJCPEZ TIPXFEJODSFBTFESBUFTPGEFWFMPQNFOUBMBCOPSNBMJUJFT reaction rates observed in the clinical trials of a drug cannot be directly compared BOEBOJODSFBTFESBUFPGEFBEBOENPSJCVOEPGGTQSJOHBUEPTFTUJNFTUIFIVNBO to rates in the clinical trials of another drug and may not reflect the rates observed dose. Soliris should be used during pregnancy only if the potential benefit justifies UIFQPUFOUJBMSJTLUPUIFGFUVT in practice. The most frequently reported adverse reactions in the PNH randomized trial "OJNBM SFQSPEVDUJPO TUVEJFT XFSF DPOEVDUFE JO NJDF VTJOH EPTFT PG B NVSJOF öPWFSBMMBOEHSFBUFSUIBOQMBDFCP BSFIFBEBDIFOBTPQIBSZOHJUJTCBDLQBJO BOUJ$BOUJCPEZUIBUBQQSPYJNBUFEUJNFTMPXEPTF BOEUJNFTIJHIEPTF the recommended human Soliris dose, based on a body weight comparison. When and nausea. animal exposure to the antibody occurred in the time period from before mating until *OUIFQMBDFCPDPOUSPMMFEDMJOJDBMTUVEZTFSJPVTBEWFSTFSFBDUJPOTPDDVSSFEBNPOH early gestation, no decrease in fertility or reproductive performance was observed. QBUJFOUT SFDFJWJOH 4PMJSJT BOE QBUJFOUT SFDFJWJOH QMBDFCP 5IF When maternal exposure to the antibody occurred during organogenesis, two cases serious reactions included infections and progression of PNH. No deaths occurred PG SFUJOBM EZTQMBTJB BOE POF DBTF PG VNCJMJDBM IFSOJB XFSF PCTFSWFE BNPOH in the study and no patients receiving Soliris experienced a thrombotic event; one offspring born to mothers exposed to the higher antibody dose; however, the exposure thrombotic event occurred in a patient receiving placebo. did not increase fetal loss or neonatal death. When maternal exposure to the antibody "NPOHQBUJFOUTXJUI1/)USFBUFEXJUI4PMJSJTJOUIFTJOHMFBSNDMJOJDBMTUVEZ occurred in the time period from implantation through weaning, a higher number of or the follow-up study, the adverse reactions were similar to those reported in the NBMFPGGTQSJOHCFDBNFNPSJCVOEPSEJFEDPOUSPMTMPXEPTFHSPVQIJHI QMBDFCPDPOUSPMMFEDMJOJDBMTUVEZ4FSJPVTBEWFSTFSFBDUJPOTPDDVSSFEBNPOHPG EPTFHSPVQ 4VSWJWJOHPGGTQSJOHIBEOPSNBMEFWFMPQNFOUBOESFQSPEVDUJWFGVODUJPO the patients in these studies. The most common serious adverse reactions were: viral Nursing Mothers JOGFDUJPO IFBEBDIF BOFNJB BOEQZSFYJB B)64 5IF TBGFUZ PG 4PMJSJT UIFSBQZ JO QBUJFOUT XJUI B)64 XBT FWBMVBUFE JO UXP *U JT OPU LOPXO XIFUIFS 4PMJSJT JT FYDSFUFE JOUP IVNBO NJML *H( JT FYDSFUFE JO QSPTQFDUJWFTJOHMFBSNTUVEJFTB)644UVEJFTBOE BOEPOFSFUSPTQFDUJWFTUVEZ IVNBONJMLTPJUJTFYQFDUFEUIBU4PMJSJTXJMMCFQSFTFOUJOIVNBONJML)PXFWFS B)644UVEZ 5IFEBUBEFTDSJCFECFMPXXFSFEFSJWFEGSPNBEVMUBOEBEPMFTDFOU QVCMJTIFEEBUBTVHHFTUUIBUBOUJCPEJFTJOIVNBONJMLEPOPUFOUFSUIFOFPOBUBM QBUJFOUTXJUIB)64FOSPMMFEJOB)644UVEZBOEB)644UVEZ"MMQBUJFOUTSFDFJWFE BOEJOGBOUDJSDVMBUJPOJOTVCTUBOUJBMBNPVOUT$BVUJPOTIPVMECFFYFSDJTFEXIFO UIFSFDPNNFOEFEEPTBHFPG4PMJSJT.FEJBOFYQPTVSFXBTXFFLTSBOHFXFFLT 4PMJSJTJTBENJOJTUFSFEUPBOVSTJOHXPNBO5IFVOLOPXOSJTLTUPUIFJOGBOUGSPN gastrointestinal or limited systemic exposure to Soliris should be weighed against Because clinical trials are conducted under widely varying conditions, adverse UIFLOPXOCFOFmUTPGIVNBONJMLGFFEJOH 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 Pediatric Use in practice. The safety and effectiveness of Soliris for the treatment of PNH in pediatric patients 5IFNPTUGSFRVFOUMZSFQPSUFEBEWFSTFSFBDUJPOTJOB)64TJOHMFBSNQSPTQFDUJWFUSJBMT below the age of 18 years have not been established. öDPNCJOFEQFSQBUJFOUJODJEFODF BSFIZQFSUFOTJPOVQQFSSFTQJSBUPSZUSBDU Three clinical studies assessing the safety and effectiveness of Soliris for the infection, diarrhea, headache, anemia, vomiting, nausea, urinary tract infection, USFBUNFOUPGB)64JODMVEFEBUPUBMPGQFEJBUSJDQBUJFOUTBHFTNPOUITUP BOEMFVLPQFOJB ZFBST 5IFTBGFUZBOEFGGFDUJWFOFTTPG4PMJSJTGPSUIFUSFBUNFOUPGB)64BQQFBS *OB)644UVEJFTBOEDPNCJOFE PGQBUJFOUTFYQFSJFODFEBTFSJPVT similar in pediatric and adult patients [see Dosage and Administration, Adverse BEWFSTFFWFOU4"& 5IFNPTUDPNNPOMZSFQPSUFE4"&TXFSFIZQFSUFOTJPO Reactions, and Clinical Studies]. BOEJOGFDUJPOT 0OFQBUJFOUEJTDPOUJOVFE4PMJSJTEVFUPBEWFSTFFWFOUTEFFNFE "ENJOJTUFSWBDDJOBUJPOTGPSUIFQSFWFOUJPOPGJOGFDUJPOEVFUPNeisseria meningitidis, unrelated to Soliris. Streptococcus pneumoniae and Haemophilus influenzaUZQFC)JC BDDPSEJOHUP"$*1 "OBMZTJTPGSFUSPTQFDUJWFMZDPMMFDUFEBEWFSTFFWFOUEBUBGSPNQFEJBUSJDBOEBEVMU guidelines [see Warnings and Precautions]. QBUJFOUTFOSPMMFEJOB)644UVEZ/ SFWFBMFEBTBGFUZQSPmMFUIBUXBTTJNJMBS UPUIBUXIJDIXBTPCTFSWFEJOUIFUXPQSPTQFDUJWFTUVEJFTB)644UVEZJODMVEFE Geriatric Use pediatric patients less than 18 years of age. Overall, the safety of Soliris in pediatric 4JYUFFOQBUJFOUTZFBSTPGBHFPSPMEFSXJUI1/)BOEXJUIB)64 XFSFUSFBUFE QBUJFOUTXJUIB)64FOSPMMFEJO4UVEZBQQFBSFETJNJMBSUPUIBUPCTFSWFEJOBEVMU XJUI4PMJSJT"MUIPVHIUIFSFXFSFOPBQQBSFOUBHFSFMBUFEEJGGFSFODFTPCTFSWFEJO QBUJFOUT5IFNPTUDPNNPOö BEWFSTFFWFOUTPDDVSSJOHJOQFEJBUSJDQBUJFOUT UIFTFTUVEJFTUIFOVNCFSPGQBUJFOUTBHFEBOEPWFSJTOPUTVGmDJFOUUPEFUFSNJOF whether they respond differently from younger patients. are presented in Table 1. Soliris REMS #FDBVTFPGUIFSJTLPGNFOJOHPDPDDBMJOGFDUJPOT4PMJSJTJTBWBJMBCMFPOMZUISPVHIB SFTUSJDUFEQSPHSBNVOEFSB3JTL&WBMVBUJPOBOE.JUJHBUJPO4USBUFHZ3&.4 6OEFS the Soliris REMS, prescribers must enroll in the program. 1SFTDSJCFST NVTU DPVOTFM QBUJFOUT BCPVU UIF SJTL PG NFOJOHPDPDDBM JOGFDUJPO provide the patients with the REMS educational materials, and ensure patients are vaccinated with a meningococcal vaccine. Enrollment in the Soliris REMS program and additional information are available by Table 1: Adverse Reactions Occurring in at Least 15% of Patients Less UFMFQIPOF40-*3*4 than 18 Years of Age Enrolled in aHUS Study 3 Other Infections Number (%) of Patients 4PMJSJT CMPDLT UFSNJOBM DPNQMFNFOU BDUJWBUJPO UIFSFGPSF QBUJFOUT NBZ IBWF MedDRA < 2 yrs 2 to < 12 yrs 12 to<18 yrs Total increased susceptibility to infections, especially with encapsulated bacteria. ver. 11.0 (n=5) (n=10) (n=4) (n=19) $IJMESFOUSFBUFEXJUI4PMJSJTNBZCFBUJODSFBTFESJTLPGEFWFMPQJOHTFSJPVTJOGFDUJPOT due to Streptococcus pneumoniae and Haemophilus influenzaUZQFC)JC "ENJOJTUFS General Disorders vaccinations for the prevention of Streptococcus pneumoniae and Haemophilus and Administration influenzaUZQFC)JC JOGFDUJPOTBDDPSEJOHUP"$*1HVJEFMJOFT6TFDBVUJPOXIFO Site Conditions administering Soliris to patients with any systemic infection. 1ZSFYJB Monitoring After Soliris Discontinuation Gastrointestinal Treatment Discontinuation for PNH: Monitor patients after discontinuing Soliris for at Disorders MFBTUXFFLTUPEFUFDUIFNPMZTJT 5SFBUNFOU%JTDPOUJOVBUJPOGPSB)64"GUFSEJTDPOUJOVJOH4PMJSJTNPOJUPSQBUJFOUT %JBSSIFB XJUI B)64 GPS TJHOT BOE TZNQUPNT PG UISPNCPUJD NJDSPBOHJPQBUIZ 5." 7PNJUJOH DPNQMJDBUJPOTGPSBUMFBTUXFFLT*OB)64DMJOJDBMTUVEJFTQBUJFOUTJOUIF Infections and QSPTQFDUJWF TUVEJFT EJTDPOUJOVFE 4PMJSJT USFBUNFOU 5." DPNQMJDBUJPOT PDDVSSFE GPMMPXJOHBNJTTFEEPTFJOQBUJFOUTBOE4PMJSJTXBTSFJOJUJBUFEJOPGUIFTFQBUJFOUT Infestations $MJOJDBMTJHOTBOETZNQUPNTPG5."JODMVEFDIBOHFTJONFOUBMTUBUVTTFJ[VSFT 6QQFSSFTQJSBUPSZ BOHJOB EZTQOFB PS UISPNCPTJT *O BEEJUJPO UIF GPMMPXJOH DIBOHFT JO MBCPSBUPSZ tract infectiona HOW SUPPLIED/STORAGE AND HANDLING 4PMJSJTFDVMJ[VNBC JTTVQQMJFEBTNHTJOHMFVTFWJBMTDPOUBJOJOHN-PG mg/mL sterile, preservative-free Soliris solution per vial. Soliris vials must be stored in the original carton until time of use under refrigerated DPOEJUJPOTBU$' BOEQSPUFDUFEGSPNMJHIU%POPUVTFCFZPOEUIF expiration date stamped on the carton. Refer to Dosage and Administration (2) for information on the stability and storage of diluted solutions of Soliris. DO NOT FREEZE. DO NOT SHAKE. /%$4JOHMFVOJUNHDBSUPO$POUBJOTPOF N-WJBMPG4PMJSJT NHN- .BOVGBDUVSFECZ"MFYJPO1IBSNBDFVUJDBMT*OD ,OPUUFS%SJWF$IFTIJSF$564" Soliris® is a registered trademark of Alexion Pharmaceuticals, Inc. Copyright © 2011, Alexion Pharmaceuticals, Inc. All rights reserved. SOL 1175 How do you get double the exposure for the same price? Your classified advertisement in Blood gives you more exposure than you think. When you place a print advertisement, you will also receive a free 30-day* posting on the American Society of Hematology’s online Job Bank. This employment resource is located at www.hematology.org and is free for all job seekers. For more information on submitting a classified ad in Blood, contact Valerie Marvin at [email protected] or at 201-767-4170. *Your 30-day online posting will start when your print advertisement first appears in Blood. DACOGEN® (decitabine) for INJECTION Brief Summary of Prescribing Information Before prescribing, please see the full Prescribing Information for DACOGEN. INDICATIONS AND USAGE Dacogen is indicated for treatment of patients with myelodysplastic syndromes (MDS) including previously treated and untreated, de novo and secondary MDS of all French-American-British subtypes (refractory anemia, refractory anemia with ringed sideroblasts, refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, and chronic myelomonocytic leukemia) and intermediate-1, intermediate-2, and high-risk International Prognostic Scoring System groups. WARNINGS AND PRECAUTIONS Neutropenia and Thrombocytopenia Treatment with Dacogen is associated with neutropenia and thrombocytopenia. Complete blood and platelet counts should be performed as needed to monitor response and toxicity, but at a minimum, prior to each dosing cycle. After administration of the recommended dosage for the first cycle, treatment for subsequent cycles should be adjusted [see Dosage and Administration]. Clinicians should consider the need for early institution of growth factors and/or antimicrobial agents for the prevention or treatment of infections in patients with MDS. Myelosuppression and worsening neutropenia may occur more frequently in the first or second treatment cycles, and may not necessarily indicate progression of underlying MDS. Use in Pregnancy Dacogen can cause fetal harm when administered to a pregnant woman. Based on its mechanism of action, Dacogen is expected to result in adverse reproductive effects. In preclinical studies in mice and rats, decitabine was teratogenic, fetotoxic, and embryotoxic. There are no adequate and wellcontrolled studies of Dacogen in pregnant women. If this drug is used during pregnancy, or if a patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant while taking Dacogen [see Use in Specific Populations] Use in Women of Childbearing Potential Women of childbearing potential should be advised to avoid becoming pregnant while receiving Dacogen and for 1 month following completion of treatment. Women of childbearing potential should be counseled to use effective contraception during this time [Use in Specific Populations]. Based on its mechanism of action, Dacogen can cause fetal harm if used during pregnancy. Use in Men Men should be advised not to father a child while receiving treatment with Dacogen, and for 2 months following completion of treatment [see Nonclinical Toxicology]. Men with female partners of childbearing potential should use effective contraception during this time. Based on its mechanism of action, Dacogen alters DNA synthesis and can cause fetal harm. 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. Most Commonly Occurring Adverse Reactions: neutropenia, thrombocytopenia, anemia, fatigue, pyrexia, nausea, cough, petechiae, constipation, diarrhea, and hyperglycemia. The following Adverse Events were Reported in ≥ 5% of Patients in the Dacogen Group and at a Rate Greater than Supportive Care in the Phase 3 MDS Trial for Dacogen [N = 83 (%)] and Supportive Care [N = 81 (%)], respectively: Blood and lymphatic system disorders—Neutropenia 75(90), 58(72); Thrombocytopenia 74(89), 64 (79); Anemia NOS 68 (82), 60 (74); Febrile neutropenia 24 (29), 5 (6); Leukopenia NOS 23 (28),11 (14); Lymphadenopathy 10(12), 6 (7) Thrombocythemia 4(5),1(1); Cardiac disorders—Pulmonary edema NOS 5(6),0(0); Eye disorders—Vision blurred 5(6),0(0); Gastrointestinal disorders— Nausea 35(42),13(16); Constipation 29(35),11(14); Diarrhea NOS 28(34),13(16) ; Vomiting NOS 21(25), 7(9); Abdominal pain NOS 12(14), 5(6); Oral mucosal petechiae 11(13), 4(5); Stomatitis 10(12), 5(6); Dyspepsia 10(12), 1(1); Ascites 8(10), 2(2); Gingival bleeding 7(8), 5(6); Hemorrhoids 7(8), 3(4); Loose stools 6(7), 3(4); Tongue ulceration 6(7), 2(2); Dysphagia 5(6), 2(2); Oral soft tissue disorder NOS 5(6), 1(1); Lip ulceration 4(5), 3(4); Abdominal distension 4(5), 1(1); Abdominal pain upper 4(5), 1(1); Gastro-esophageal reflux disease 4(5), 0(0); Glossodynia 4(5), 0(0); General disorders and administrative site disorders—Pyrexia 44(53), 23(28); Edema peripheral 21(25), 13(16); Rigors 18(22), 14(17); Edema NOS 15(18), 5(6); Pain NOS 11(13), 5(6); Lethargy 10(12), 3(4); Tenderness NOS 9(11), 0(0); Fall 7(8), 3(4); Chest discomfort 6(7), 3(4); Intermittent pyrexia 5(6), 3(4); Malaise 4(5), 1(1); Crepitations NOS 4(5), 1(1); Catheter site erythema 4(5), 1(1); Catheter site pain 4(5), 0(0); Injection site swelling 4(5), 0(0); Hepatobiliary Disorders— Hyperbilirubinemia 12(14), 4(5); Infections and Infestations—Pneumonia NOS 18(22), 11(14); Cellulitis 10(12), 6(7); Candidal infection NOS 8(10), 1(1); Catheter related infection 7(8), 0(0); Urinary tract infection NOS 6(7), 1(1); Staphylococcal infection 6(7), 0(0); Oral candidiasis 5(6), 2(2); Sinusitis NOS 4(5), 2(2); Bacteremia 4(5), 0(0); Injury, poisoning and procedural complications—Transfusion reaction 6(7), 3(4); Abrasion NOS 4(5), 1(1); Investigations—Cardiac murmur NOS 13(16), 9(11); Blood alkaline phosphatase NOS increased 9(11), 7(9); Aspartate aminotransferase increased 8(10), 7(9); Blood urea increased 8(10), 1(1); Blood lactate dehydrogenase increased 7(8), 5(6); Blood albumin decreased 6(7), 0(0); Blood bicarbonate increased 5(6), 1(1); Blood chloride decreased 5(6), 1(1); Protein total decreased 4(5), 3(4); Blood bicarbonate decreased 4(5), 1(1); Blood bilirubin decreased 4(5), 1(1); Metabolism and nutrition disorders—Hyperglycemia NOS 27(33), 16(20); Hypoalbuminemia 20(24), 14(17); Hypomagnesemia 20(24), 6(7); Hypokalemia 18(22), 10(12); Hyponatremia 16(19), 13(16); Appetite decreased NOS 13(16), 12(15); Anorexia 13(16), 8(10); Hyperkalemia 11(13), 3(4); Dehydration 5(6), 4(5); Musculoskeletal and connective tissue disorders—Arthralgia 17(20), 8(10); Pain in limb 16(19), 8(10); Back pain 14(17); 5(6); Chest wall pain 6(7), 1(1); Musculoskeletal discomfort 5(6), 0(0); Myalgia 4(5), 1(1); Nervous system disorders—Headache 23(28), 11(14); Dizziness 15(18), 10(12); Hypoesthesia 9(11), 1(1); Psychiatric disorders—Insomnia 23(28), 11(14); Confusional state 10(12), 3(4); Anxiety 9(11), 8(10); Renal and urinary disorders—Dysuria 5(6), 3(4); Urinary frequency 4(5), 1(1); Respiratory, thoracic and Mediastinal disorders—Cough 33(40), 25(31); Pharyngitis 13(16), 6(7); Crackles lung 12(14), 1(1); Breath sounds decreased 8(10), 7(9); Hypoxia 8(10), 4(5); Rales 7(8), 2(2); Postnasal drip 4(5), 2(2); Skin and subcutaneous tissue disorders—Ecchymosis 18(22), 12(15); Rash NOS 16(19), 7(9); Erythema 12(14), 5(6); Skin lesion NOS 9(11), 3(4); Pruritis 9(11), 2(2); Alopecia 7(8), 1(1); Urticaria NOS 5(6), 1(1); Swelling face 5(6), 0(0); Vascular disorders—Petechiae 32(39), 13(16); Pallor 19(23), 10(12); Hypotension NOS 5(6), 4(5); Hematoma NOS 4(5), 3(4). Discussion of Clinically Important Adverse Reactions In the controlled trial using Dacogen dosed at 15 mg/m2, administered by continuous intravenous infusion over 3 hours repeated every 8 hours for 3 days, the highest incidence of Grade 3 or Grade 4 adverse events in the Dacogen arm were neutropenia (87%), thrombocytopenia (85%), febrile neutropenia (23%) and leucopenia (22%). Bone marrow suppression was the most frequent cause of dose reduction, delay and discontinuation. Six patients had fatal events associated with their underlying disease and myelosuppression (anemia, neutropenia, and thrombocytopenia) that were considered at least possibly related to drug treatment [See Warnings and Precautions]. Of the 83 Dacogen-treated patients, 8 permanently discontinued therapy for adverse events; compared to 1 of 81 patients in the supportive care arm. In a single-arm study (N=99) Dacogen was dosed at 20 mg/m2 intravenous, infused over one hour daily for 5 consecutive days of a 4 week cycle. The information below presents all adverse events regardless of causality occurring in at least 5% of patients. The following Adverse Events were Reported in ≥ 5% of Patients in a Single-arm Study* for Dacogen [N = 99 (%)]: Blood and lymphatic system disorders—Anemia 31(31%); Febrile neutropenia 20(20%); Leukopenia 6(6%); Neutropenia 38, (38%); Pancytopenia 5 (5%); Thrombocythemia 5 (5%); Thrombocytopenia 27 (27%); Cardiac disorders—Cardiac failure congestive 5 (5%); Tachycardia 8 (8%); Ear and labyrinth disorders—Ear pain 6 (6%); Gastrointestinal disorders—Abdominal pain 14 (14%); Abdominal pain upper 6 (6%); Constipation 30 (30%); Diarrhea 28 (28%); Dyspepsia 10 (10%); Dysphagia 5 (5%); Gastro-esophageal reflux disease 5 (5%); Nausea 40 (40%); Oral pain 5 (5%); Stomatitis 11 (11%); Toothache 6 (6%); Vomiting 16 (16%); General disorders and administration site conditions—Asthenia 15 (15%); Chest pain 6 (6%); Chills 16 (16%); Fatigue 46 (46%); Mucosal inflammation 9 (9%); Edema 5 (5%); Edema peripheral 27 (27%); Pain 5 (5%); Pyrexia 36 (36%); Infections and infestations—Cellulitis 9 (9%); Oral candidiasis 6 (6%); Pneumonia 20 (20%); Sinusitis 6 (6%); Staphylococcal bacteremia 8 (8%); Tooth abscess 5 (5%); Upper respiratory tract infection 10 (10%); Urinary tract infection 7 (7%); Injury, poisoning and procedural complications—Contusion 9 (9%); Investigations—Blood bilirubin increased 6 (6%); Breath sounds abnormal 5 (5%); Weight decreased 9 (9%); Metabolism and nutrition disorders—Anorexia 23 (23%); Decreased appetite 8 (8%); Dehydration 8 (8%); Hyperglycemia 6 (6%); Hypokalemia 12 (12%); Hypomagnesemia 5 (5%); Musculoskeletal and connective tissue disorders—Arthralgia 17 (17%); Back pain 18 (18%); Bone pain 6 (6%); Muscle spasms 7 (7%); Muscular weakness 5 (5%); Musculoskeletal pain 5 (5%); Myalgia 9 (9%); Pain in extremity 18 (18%); Nervous system disorders—Dizziness 21 (21%); Headache 23 (23%); Psychiatric disorders—Anxiety 9 (9%); Confusional state 8 (8%); Depression 9 (9%); Insomnia 14 (14%); Respiratory, thoracic and mediastinal disorders—Cough 27 (27%); Dyspnea 29 (29%); Epistaxis 13 (13%); Pharyngolaryngeal pain 8 (8%); Pleural effusion 5 (5%); Sinus congestion 5 (5%); Skin and subcutaneous tissue disorders—Dry skin 8 (8%); Ecchymosis 9 (9%); Erythema 5 (5%); Night sweats 5 (5%); Petechiae 12 (12%); Pruritus 9 (9%) ; Rash 11 (11%) ; Skin lesion 5 (5%) ; Vascular disorders—Hypertension 6 (6%); Hypotension 11 (11%). *In this single arm study, investigators reported adverse events based on clinical signs and symptoms rather than predefined laboratory abnormalities. Thus not all laboratory abnormalities were recorded as adverse events. Discussion of Clinically Important Adverse Reactions In the single-arm study (N=99) when Dacogen was dosed at 20 mg/m2 intravenous, infused over one hour daily for 5 consecutive days, the highest incidence of Grade 3 or Grade 4 adverse events were neutropenia (37%), thrombocytopenia (24%) and anemia (22%). Seventy-eight percent of patients had dose delays, the median duration of this delay was 7 days and the largest percentage of delays were due to hematologic toxicities. Hematologic toxicities and infections were the most frequent causes of dose delays and discontinuation. Eight patients had fatal events due to infection and/or bleeding (seven of which occurred in the clinical setting of myelosuppression) that were considered at least possibly related to drug treatment. Nineteen of 99 patients permanently discontinued therapy for adverse events. No overall difference in safety was detected between patients >65 years of age and younger patients in these myelodysplasia trials. No significant gender differences in safety or efficacy were detected. Patients with renal or hepatic dysfunction were not studied. Insufficient numbers of non-white patients were available to draw conclusions in these clinical trials. Serious Adverse Events that occurred in patients receiving Dacogen regardless of causality, not previously reported above include: Blood and Lymphatic System Disorders—myelosuppression,splenomegaly; Cardiac Disorders—myocardial infarction, cardio-respiratory arrest, cardiomyopathy, atrial fibrillation, supraventricular tachycardia; Gastrointestinal Disorders—gingival pain, upper gastrointestinal Hemorrhage; General Disorders and Administrative Site Conditions—chest pain, catheter site hemorrhage; Hepatobiliary Disorders—cholecystitis; Infections and Infestations—fungal infection, sepsis, bronchopulmonary aspergillosis, peridiverticular abscess, respiratory tract infection, pseudomonal lung infection, Mycobacterium avium complex infection; Injury, Poisoning and Procedural Complications—post procedural pain, post procedural hemorrhage; Nervous System Disorders—intracranial hemorrhage; Psychiatric Disorders—mental status changes; Renal and Urinary Disorders—renal failure, urethral hemorrhage; Respiratory, Thoracic and Mediastinal Disorders—hemoptysis, lung infiltration, pulmonary embolism, respiratory arrest, pulmonary mass; Allergic Reaction—Hypersensitivity (anaphylactic reaction) to Dacogen has been reported in a Phase 2 trial. Post-marketing Experience The following adverse reactions have been identified during postapproval use of Dacogen. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Cases of Sweet’s Syndrome (acute febrile neutrophilic dermatosis) have been reported. DRUG INTERACTIONS Drug interaction studies with decitabine have not been conducted. In vitro studies in human liver microsomes suggest that decitabine is unlikely to inhibit or induce cytochrome P450 enzymes. In vitro metabolism studies have suggested that decitabine is not a substrate for human liver cytochrome P450 enzymes. As plasma protein binding of decitabine is negligible (<1%), interactions due to displacement of more highly protein bound drugs from plasma proteins are not expected. USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category D [see Warnings and Precautions] Dacogen can cause fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies of Dacogen in pregnant women. The developmental toxicity of decitabine was examined in mice exposed to single IP (intraperitoneal) injections (0, 0.9 and 3.0 mg/m2, approximately 2% and 7% of the recommended daily clinical dose, respectively) over gestation days 8, 9, 10 or 11. No maternal toxicity was observed but reduced fetal survival was observed after treatment at 3 mg/m2 and decreased fetal weight was observed at both dose levels. The 3 mg/m2 dose elicited characteristic fetal defects for each treatment day, including supernumerary ribs (both dose levels), fused vertebrae and ribs, cleft palate, vertebral defects, hind-limb defects and digital defects of fore- and hind-limbs. In rats given a single IP injection of 2.4, 3.6 or 6 mg/m2 (approximately 5, 8, or 13% the daily recommended clinical dose, respectively) on gestation days 9-12, no maternal toxicity was observed. No live fetuses were seen at any dose when decitabine was injected on gestation day 9. A significant decrease in fetal survival and reduced fetal weight at doses greater than 3.6 mg/m2 was seen when decitabine was given on gestation day 10. Increased incidences of vertebral and rib anomalies were seen at all dose levels, and induction of exophthalmia, exencephaly, and cleft palate were observed at 6.0 mg/m2. Increased incidence of foredigit defects was seen in fetuses at doses greater than 3.6 mg/m2. Reduced size and ossification of long bones of the fore-limb and hindlimb were noted at 6.0 mg/m2. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of child bearing potential should be advised to avoid becoming pregnant while taking Dacogen. Nursing Mothers It is not known whether decitabine or its metabolites are excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions from Dacogen in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use The safety and effectiveness of Dacogen in pediatric patients have not been established. Geriatric Use Of the total number of patients exposed to Dacogen in the controlled clinical trial, 61 of 83 patients were age 65 and over, while 21 of 83 patients were age 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Renal Impairment There are no data on the use of Dacogen in patients with renal dysfunction; therefore, Dacogen should be used with caution in these patients. Hepatic Impairment There are no data on the use of Dacogen in patients with hepatic dysfunction; therefore, Dacogen should be used with caution in these patients. OVERDOSAGE There is no known antidote for overdosage with Dacogen. Higher doses are associated with increased myelosuppression including prolonged neutropenia and thrombocytopenia. Standard supportive measures should be taken in the event of an overdose. DOSAGE AND ADMINISTRATION [See section 2 of full Prescribing Information for complete information on Dosage and Administration for DACOGEN] Complete blood counts and platelet counts should be performed as needed to monitor response and toxicity, but at a minimum, prior to each cycle. Liver chemistries and serum creatinine should be obtained prior to initiation of treatment. Treatment Regimen – Option 1 Patients may be premedicated with standard anti-emetic therapy. If hematologic recovery (ANC ≥ 1,000/μL and platelets ≥50,000/μL) from a previous Dacogen treatment cycle requires more than 6 weeks, then the next cycle of Dacogen therapy should be delayed and dosing temporarily reduced. Treatment Regimen – Option 2 Patients may be premedicated with standard anti-emetic therapy. If myelosuppression is present, subsequent treatment cycles of Dacogen should be delayed until there is hematologic recovery (ANC ≥ 1,000/μL platelets ≥ 50,000/μL ). Patients with Non-hematologic Toxicity Following the first cycle of Dacogen treatment, if any of the following non-hematologic toxicities are present, Dacogen treatment should not be restarted until the toxicity is resolved: 1) serum creatinine ≥ 2 mg/dL; 2) SGPT, total bilirubin ≥ 2 times ULN; 3) and active or uncontrolled infection. Instructions for Intravenous Administration Dacogen is a cytotoxic drug and caution should be exercised when handling and preparing Dacogen. Procedures for proper handling and disposal of antineoplastic drugs should be applied. Unless used within 15 minutes of reconstitution, the diluted solution must be prepared using cold (2°C–8°C) infusion fluids and stored at 2°C–8°C (36°F–46°F) for up to a maximum of 7 hours until administration. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use if there is evidence of particulate matter or discoloration. NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis and Impairment of Fertility Carcinogenicity studies with decitabine have not been conducted. The mutagenic potential of decitabine was tested in several in vitro and in vivo systems. Decitabine increased mutation frequency in L5178Y mouse lymphoma cells, and mutations were produced in an Escherichia coli lac-I transgene in colonic DNA of decitabine-treated mice. Decitabine caused chromosomal rearrangements in larvae of fruit flies. The effect of decitabine on postnatal development and reproductive capacity was evaluated in mice administered a single 3 mg/m2 IP injection (approximately 7% the recommended daily clinical dose) on day 10 of gestation. Body weights of males and females exposed in utero to decitabine were significantly reduced relative to controls at all postnatal time points. No consistent effect on fertility was seen when female mice exposed in utero were mated to untreated males. Untreated females mated to males exposed in utero showed decreased fertility at 3 and 5 months of age (36% and 0% pregnancy rate, respectively). In male mice given IP injections of 0.15, 0.3 or 0.45 mg/m2 decitabine (approximately 0.3% to 1% the recommended clinical dose) 3 times a week for 7 weeks, decitabine did not affect survival, body weight gain or hematological measures (hemoglobin and WBC counts). Testes weights were reduced, abnormal histology was observed and significant decreases in sperm number were found at doses ≥ 0.3 mg/m2. In females mated to males dosed with ≥ 0.3 mg/m2 decitabine, pregnancy rate was reduced and preimplantation loss was significantly increased. Instructions for Patients Women of childbearing potential should be advised to avoid becoming pregnant while receiving treatment with Dacogen and for 1 month afterwards, and to use effective contraception during this time, [See Warnings and Precautions]. Men should be advised not to father a child while receiving treatment with Dacogen, and for 2 months afterwards. During these times, men with female partners of childbearing potential should use effective contraception [See Warnings and Precautions and Nonclinical Toxicology]. Patients should be advised to monitor and report any symptoms of neutropenia, thrombocytopenia, or fever to their physician as soon as possible [See Warnings and Precautions]. Prescribing information as of March 2010. Manufactured by Pharmachemie B.V. Haarlem, the Netherlands DACOGEN® is a registered trademark of SuperGen, Inc., Dublin, CA,U.S.A. used under license. Distributed and marketed by Eisai Inc. © 2010 Eisai Inc. All rights reserved. Printed in USA. DAC345 +' .0!L 'L.+'L!+#0/ /0+ .P- . ?-L -.#0/% -./0 & 2 ,) $ $ -"1% &Q $(7$& #P % ) 2 ? 1 ; ,* %? $(7$& #P 9 ) < ) 2 9 1 B ,* 8) ) ($ $$ ) ) 2 $$$ 2 ; 1 ', $ $ * ( ) ; #$ 2 #2$ , ) - ( $ 2 ) 2 ( #2$1 DACOGEN is indicated for the treatment of patients with MDS including those who are: De novo !" #$% #$& '() * # ( ( $ ( Important Safety Information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lease see the accompanying brief summary of full Prescribing Information on the following page. Reference: 1. -( " 2 #6 2 ( 2$1 Dacogen® is a registered trademark of SuperGen, Inc., Dublin, CA, USA, used under license. Distributed and marketed by Eisai Inc. © 2011 Eisai Inc. All rights reserved. Printed in USA. DAC399 3/11