ISTODAX (Romidepsin) Must Be Fetus [See Use in Specific Populations (8.1)]

HIGHLIGHTS OF PRESCRIBING INFORMATION • Electrocardiographic (ECG) changes have been observed. Consider These highlights do not include all the information needed to use cardiovascular monitoring precautions in patients with congenital long ISTODAX safely and effectively. See full prescribing information for QT syndrome, a history of significant cardiovascular disease, and ISTODAX. patients taking medicinal products that lead to significant QT prolongation (5.3). ISTODAX® (romidepsin) for injection • Based on its mechanism of action, ISTODAX may cause fetal harm For intravenous infusion only when administered to a pregnant woman. Advise women of potential Initial US Approval: 2009 harm to the fetus (5.4, 8.1). • ISTODAX binds to estrogen receptors. Advise women of childbearing ---------------------------INDICATIONS AND USAGE---------------------------- potential that ISTODAX may reduce the effectiveness of estrogen- containing contraceptives (5.5). ISTODAX is a histone deacetylase (HDAC) inhibitor indicated for: • Treatment of cutaneous T-cell lymphoma (CTCL) in patients who have -------------------------------ADVERSE REACTIONS------------------------------ received at least one prior systemic therapy (1). The most common adverse reactions in Study 1 were nausea, fatigue, infections, vomiting, and anorexia, and in Study 2 were nausea, fatigue, -----------------------DOSAGE AND ADMINISTRATION----------------------- anemia, thrombocytopenia, ECG T-wave changes, neutropenia, and • 14 mg/m2 administered intravenously (IV) over a 4-hour period on days lymphopenia (6). 1, 8 and 15 of a 28-day cycle. Repeat cycles every 28 days provided that the patient continues to benefit from and tolerates the drug (2.1). To report SUSPECTED ADVERSE REACTIONS, contact Gloucester • Treatment discontinuation or interruption with or without dose reduction Pharmaceuticals, Inc. at 1-866-223-7145 or the FDA at 1-800-FDA-1088 to 10 mg/m2 may be needed to manage adverse drug reactions (2.2). or www.fda.gov/medwatch. -------------------------------DRUG INTERACTIONS------------------------------ ----------------------DOSAGE FORMS AND STRENGTHS--------------------- • Carefully monitor prothrombin time (PT) and International Normalized ISTODAX for injection, 10 mg, supplied with one Diluent vial containing Ratio (INR) in patients concurrently administered ISTODAX and 2 mL (deliverable volume) of solution (3) Coumadin derivatives (7.1). • Strong CYP3A4 inhibitors may increase concentrations of ISTODAX -------------------------------CONTRAINDICATIONS------------------------------ and should be avoided (7.2). None. • Potent CYP3A4 inducers may decrease concentrations of ISTODAX and should be avoided (7.2). -----------------------WARNINGS AND PRECAUTIONS----------------------- • Due to the risk of QT prolongation ensure that potassium and See 17 for PATIENT COUNSELING INFORMATION AND FDA- magnesium are within the normal range before administration of approved patient labeling. ISTODAX (5.1). • Treatment with ISTODAX has been associated with thrombocytopenia, leukopenia (neutropenia and lymphopenia), and anemia; therefore, monitor these hematological parameters during treatment with Revised: Month/2009 ISTODAX, modify the dose as necessary (5.2). _______________________________________________________________________________________________________________________________________ FULL PRESCRIBING INFORMATION CONTENTS* 8.6 Hepatic Impairment 8.7 Renal Impairment 1 INDICATIONS AND USAGE 10 OVERDOSAGE 2 DOSAGE AND ADMINISTRATION 11 DESCRIPTION 2.1 Dosing Information 2.2 Dose Modification 12 CLINICAL PHARMACOLOGY 2.3 Instructions for Preparation and Intravenous Administration 12.1 Mechanism of Action 3 DOSAGE FORMS AND STRENGTHS 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 4 CONTRAINDICATIONS 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 5 WARNINGS AND PRECAUTIONS 14 CLINICAL STUDIES 5.1 Monitoring: Laboratory Tests 14.1 Baseline Patient Characteristics 5.2 Hematologic 14.2 Clinical Results 5.3 Electrocardiographic Changes 5.4 Use in Pregnancy 15 REFERENCES 5.5 Use in Women of Childbearing Potential 16 HOW SUPPLIED/STORAGE AND HANDLING 6 ADVERSE REACTIONS How Supplied 6.1 Clinical Trials Experience Storage 7 DRUG INTERACTIONS 17 PATIENT COUNSELING INFORMATION 7.1 Coumadin or Coumadin Derivatives 17.1 Instructions 7.2 Drugs that Inhibit or Induce Cytochrome P450 3A4 Enzymes FDA-Approved Patient Labeling 7.3 Drugs that Inhibit Drug Transport Systems *Sections or subsections omitted from the Full Prescribing Information are not 8 USE IN SPECIFIC POPULATIONS listed 8.1 Pregnancy 8.3 Nursing Mothers 8.4 Pediatric Use . 8.5 Geriatric Use __________________________________________________________________________________________ 2 FULL PRESCRIBING INFORMATION agent, povidone, USP. In addition, each kit includes 1 sterile vial containing 1 INDICATIONS AND USAGE 2 mL (deliverable volume) of the Diluent composed of 80% propylene glycol, ISTODAX is indicated for treatment of cutaneous T-cell lymphoma (CTCL) USP, and 20% dehydrated alcohol, USP. in patients who have received at least one prior systemic therapy. 4 CONTRAINDICATIONS 2 DOSAGE AND ADMINISTRATION None. 2.1 Dosing Information 5 WARNINGS AND PRECAUTIONS The recommended dose of romidepsin is 14 mg/m2 administered intravenously over a 4-hour period on days 1, 8 and 15 of a 28-day cycle. 5.1 Monitoring: Laboratory Tests Cycles should be repeated every 28 days provided that the patient continues to Due to the risk of QT prolongation, potassium and magnesium should be benefit from and tolerates the therapy. within the normal range before administration of ISTODAX [See Warnings and Precautions (5.3) and Adverse Reactions (6)]. 2.2 Dose Modification 5.2 Hematologic Nonhematologic toxicities except alopecia Treatment with ISTODAX can cause thrombocytopenia, leukopenia • Grade 2 or 3 toxicity: Treatment with romidepsin should be delayed (neutropenia and lymphopenia), and anemia; therefore, these hematological until toxicity returns to ≤Grade 1 or baseline, then therapy may be parameters should be monitored during treatment with ISTODAX, and the restarted at 14 mg/m2. If Grade 3 toxicity recurs, treatment with dose should be modified, as necessary [See Dosage and Administration (2.2) romidepsin should be delayed until toxicity returns to ≤Grade 1 or and Adverse Reactions (6)]. baseline and the dose should be permanently reduced to 10 mg/m2. Grade 4 toxicity: Treatment with romidepsin should be delayed until • 5.3 Electrocardiographic Changes toxicity returns to ≤Grade 1 or baseline, then the dose should be permanently reduced to 10 mg/m2. Several treatment-emergent morphological changes in ECGs (including • Romidepsin should be discontinued if Grade 3 or 4 toxicities recur after T-wave and ST-segment changes) have been reported in clinical studies. The dose reduction. clinical significance of these changes is unknown [See Adverse Reactions (6)]. Hematologic toxicities In patients with congenital long QT syndrome, patients with a history of • Grade 3 or 4 neutropenia or thrombocytopenia: Treatment with significant cardiovascular disease, and patients taking anti-arrhythmic romidepsin should be delayed until the specific cytopenia returns to medicines or medicinal products that lead to significant QT prolongation, ANC ≥1.5×109/L and/or platelet count ≥75×109/L or baseline, then appropriate cardiovascular monitoring precautions should be considered, such therapy may be restarted at 14 mg/m2. as the monitoring of electrolytes and ECGs at baseline and periodically during • Grade 4 febrile (≥38.5ºC) neutropenia or thrombocytopenia that requires treatment. platelet transfusion: Treatment with romidepsin should be delayed until the specific cytopenia returns to ≤Grade 1 or baseline, and then the dose 5.4 Use in Pregnancy 2 should be permanently reduced to 10 mg/m . There are no adequate and well-controlled studies of ISTODAX in pregnant women. However, based on its mechanism of action, ISTODAX may cause 2.3 Instructions for Preparation and Intravenous Administration fetal harm when administered to a pregnant woman. A study in rats did not ISTODAX should be handled in a manner consistent with recommended safe expose pregnant animals to enough romidepsin to fully evaluate adverse procedures for handling cytotoxic drugs. outcomes. ISTODAX must be reconstituted with the supplied diluent and further diluted If this drug is used during pregnancy, or if the patient becomes pregnant while with 0.9% Sodium Chloride Injection, USP before intravenous infusion. taking ISTODAX, the patient should be apprised of the potential hazard to the • Each 10 mg single-use vial of ISTODAX (romidepsin) must be fetus [See Use in Specific Populations (8.1)]. reconstituted with 2 mL of the supplied Diluent. With a suitable syringe, aseptically withdraw 2 mL from the supplied Diluent vial, and 5.5 Use in Women of Childbearing Potential slowly inject it into the ISTODAX (romidepsin) for injection vial. Swirl Advise women of childbearing potential that ISTODAX may reduce the the contents of the vial until there are no visible particles in the resulting effectiveness of estrogen-containing contraceptives. An in vitro binding assay solution. The reconstituted solution will contain ISTODAX 5 mg/mL. determined that romidepsin competes with β-estradiol for binding to estrogen The reconstituted ISTODAX solution is chemically stable for at least receptors [See Nonclinical Toxicology (13.1)]. 8 hours at room temperature. • Extract the appropriate amount

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