Romidepsin

Romidepsin, a histone deacetylase (HDAC) inhibitor, is a bicyclic depsipeptide. At room temperature, romidepsin is a white powder and is described chemically as (1 S ,4 S ,7 Z ,10 S ,16 E ,21 R )-7-ethylidene-4,21-bis(1-methylethyl)-2-oxa-12,13-dithia-5,8,20,23-tetraazabicyclo[8.7.6]tricos-16-ene-3,6,9,19,22-pentone. The empirical formula is C 24 H 36 N 4 O 6 S 2 . The molecular weight is 540.71 and the structural formula is: ISTODAX (romidepsin) for injection is intended for intravenous infusion only after reconstitution with the supplied diluent and after further dilution with 0.9% Sodium Chloride, USP. ISTODAX is supplied as a kit containing 2 vials. ISTODAX (romidepsin) for injection is a sterile lyophilized white powder and is supplied in a 10 mg single-dose vial containing 11 mg romidepsin, 22 mg povidone, USP, and hydrochloric acid, NF, as a pH adjuster. Diluent for ISTODAX is a sterile clear solution and is supplied in a single-dose vial containing 2.4 mL (2.2 mL deliverable volume). Diluent for ISTODAX contains 80% (v/v) propylene glycol, USP and 20% (v/v) dehydrated alcohol, USP. Chemical Structure

ISTODAX is indicated for the treatment of cutaneous T-cell lymphoma (CTCL) in adult patients who have received at least one prior systemic therapy. ISTODAX is a histone deacetylase (HDAC) inhibitor indicated for the treatment of cutaneous T-cell lymphoma (CTCL) in adult patients who have received at least one prior systemic therapy ( 1 ).

How Supplied ISTODAX is supplied as a kit including a sterile, lyophilized powder in a 10 mg single-dose vial containing 11 mg of romidepsin, 22 mg of the bulking agent, povidone, USP, and hydrochloric acid, NF, as a pH adjuster. In addition, each kit includes a single-dose sterile diluent vial containing 2.4 mL (2.2 mL deliverable volume) of 80% propylene glycol, USP, and 20% dehydrated alcohol, USP. NDC 59572-984-01: ISTODAX ® KIT containing 1 vial of romidepsin and 1 vial of diluent for romidepsin per carton. Storage and Handling ISTODAX (romidepsin) for injection is supplied as a kit containing 2 vials in a single carton. The carton must be stored at 20° to 25°C, excursions permitted between 15° to 30°C. (See USP Controlled Room Temperature.) ISTODAX is a hazardous drug. Follow applicable special handling and disposal procedures. 1

• 14 mg/m 2 administered intravenously over a 4-hour period on days 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 ). • Discontinue or interrupt treatment (with or without dose reduction to 10 mg/m 2 ) to manage drug toxicity ( 2.2 ). • Reduce starting dose in patients with moderate and severe hepatic impairment ( 2.3 ). 2.1 Dosage Information The recommended dosage of romidepsin is 14 mg/m 2 administered intravenously over a 4-hour period on days 1, 8, and 15 of a 28-day cycle. Cycles should be repeated every 28 days provided that the patient continues to benefit from and tolerates the drug. 2.2 Dosage Modification Nonhematologic toxicities except alopecia • Grade 2 or 3 toxicity: Treatment with romidepsin should be delayed until toxicity returns to Grade 0-1 or baseline, then therapy may be restarted at 14 mg/m 2 . If Grade 3 toxicity recurs, treatment with romidepsin should be delayed until toxicity returns to Grade 0-1 or baseline and the dose should be permanently reduced to 10 mg/m 2 . • Grade 4 toxicity: Treatment with romidepsin should be delayed until toxicity returns to Grade 0-1 or baseline, then the dose should be permanently reduced to 10 mg/m 2 . • Romidepsin should be discontinued if Grade 3 or 4 toxicities recur after dose reduction. Hematologic toxicities • Grade 3 or 4 neutropenia or thrombocytopenia: Treatment with romidepsin should be delayed until the specific cytopenia returns to ANC greater than or equal to 1.5×10 9 /L and platelet count greater than or equal to 75×10 9 /L or baseline, then therapy may be restarted at 14 mg/m 2 . • Grade 4 febrile (greater than or equal to 38.5ºC) neutropenia or thrombocytopenia that requires platelet transfusion: Treatment with romidepsin should be delayed until the specific cytopenia returns to less than or equal to Grade 1 or baseline, and then the dose should be permanently reduced to 10 mg/m 2 . 2.3 Dosage in Patients with Hepatic Impairment For patients with moderate or severe hepatic impairment, reduce the starting dose of ISTODAX as shown in Table 1 and monitor for toxicities more frequently. Dosage adjustment is not required for patients with mild hepatic impairment. Table 1: Recommendations for Starting Dose in Patients with Moderate and Severe Hepatic Impairment Hepatic Impairment Bilirubin Levels ISTODAX Dose ULN=Upper limit of normal. Moderate greater than 1.5 × ULN to less than or equal to 3 × ULN 7 mg/m 2 Severe greater than 3 × ULN 5 mg/m 2 2.4 Instructions for Preparation and Intravenous Administration ISTODAX is a hazardous drug. Use appropriate handling procedures. 1 ISTODAX must be reconstituted with the supplied diluent and further diluted with 0.9% Sodium Chloride Injection, USP, before intravenous infusion. ISTODAX and diluent vials contain an overfill to ensure the recommended volume can be withdrawn at a concentration of 5 mg/mL. • Each 10 mg single-dose vial of ISTODAX must be reconstituted with 2.2 mL of the supplied diluent. • With a suitable syringe, aseptically withdraw 2.2 mL from the supplied diluent vial, and slowly inject it into the ISTODAX (romidepsin) for injection vial. Swirl the contents of the vial until there are no visible particles in the resulting solution. The reconstituted solution will contain ISTODAX 5 mg/mL. The reconstituted ISTODAX vial will contain 2 mL of deliverable volume of drug product. The reconstituted ISTODAX solution is chemically stable for up to 8 hours at room temperature. • Extract the appropriate amount of ISTODAX from the vials to deliver the desired dose, using proper aseptic technique. Before intravenous infusion, further dilute ISTODAX in 500 mL 0.9% Sodium Chloride Injection, USP. • Infuse over 4 hours. The diluted solution is compatible with polyvinyl chloride (PVC), ethylene vinyl acetate (EVA), polyethylene (PE) infusion bags as well as glass bottles, and is chemically stable for up to 24 hours when stored at room temperature. However, it should be administered as soon after dilution as possible. Parenteral drug products should be inspected visually for particulate matter and discoloration before administration, whenever solution and container permit.

None. None ( 4 ).

• Myelosuppression: ISTODAX can cause thrombocytopenia, leukopenia (neutropenia and lymphopenia), and anemia; monitor blood counts during treatment with ISTODAX; interrupt and/or modify the dose as necessary ( 5.1 ). • Infections: Fatal and serious infections. Reactivation of DNA viruses (Epstein Barr and hepatitis B). Consider monitoring and prophylaxis in patients with evidence of prior hepatitis B ( 5.2 ). • Electrocardiographic (ECG) changes: Consider cardiovascular monitoring in patients with congenital long QT syndrome, a history of significant cardiovascular disease, and patients taking medicinal products that lead to significant QT prolongation. Ensure that potassium and magnesium are within the normal range before administration of ISTODAX ( 5.3 ). • Tumor lysis syndrome: Patients with advanced stage disease and/or high tumor burden are at greater risk and should be closely monitored and appropriate precautions taken ( 5.4 ). • Embryo-fetal toxicity: Can cause fetal harm. Advise females of reproductive potential and males with female partners of reproductive potential of potential risk to a fetus and to use effective contraception ( 5.5 , 8.1 , 8.3 ). 5.1 Myelosuppression Treatment with ISTODAX can cause thrombocytopenia, leukopenia (neutropenia and lymphopenia), and anemia. Monitor blood counts regularly during treatment with ISTODAX and modify the dose as necessary [see Dosage and Administration (2.2) and Adverse Reactions (6.1) ]. 5.2 Infections Fatal and serious infections have been reported in clinical trials of ISTODAX, including pneumonia, sepsis, and viral reactivation, including reactivation of Epstein Barr and hepatitis B viruses. These infections can occur during and following treatment. The risk of life-threatening infections may be greater in patients with a history of prior treatment with monoclonal antibodies directed against lymphocyte antigens and in patients with disease involvement of the bone marrow [see Adverse Reactions (6.1) ] . Reactivation of hepatitis B virus infection was reported in 1% of patients in clinical trials. In patients with evidence of prior hepatitis B infection, consider monitoring for reactivation, and consider antiviral prophylaxis. Reactivation of Epstein Barr viral infection leading to liver failure has occurred in recipients of ISTODAX including after ganciclovir prophylaxis. 5.3 Electrocardiographic Changes Several treatment-emergent morphological changes in ECGs (including T-wave and ST-segment changes) have been reported in clinical studies. The clinical significance of these changes is unknown [see Adverse Reactions (6.1) ]. In patients with congenital long QT syndrome, patients with a history of significant cardiovascular disease, and patients taking anti-arrhythmic medicines or medicinal products that lead to significant QT prolongation, consider cardiovascular monitoring of ECGs at baseline and periodically during treatment. Confirm that potassium and magnesium levels are within normal range before administration of ISTODAX [see Adverse Reactions (6.1) ] . 5.4 Tumor Lysis Syndrome Tumor lysis syndrome (TLS) has been reported to occur in recipients of ISTODAX, including in 1% of patients with tumor stage CTCL. Patients with advanced stage disease and/or high tumor burden are at greater risk, should be closely monitored, and managed as appropriate. 5.5 Embryo-Fetal Toxicity Based on its mechanism of action and findings from animal studies, ISTODAX can cause fetal harm when administered to a pregnant woman. In an animal reproductive study, romidepsin was embryocidal and caused adverse developmental outcomes at exposures below those in patients at the recommended dose of 14 mg/m 2 . Advise females of reproductive potential to use effective contraception during treatment and for 1 month after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment and for 1 month after the last dose [see Use in Specific Populations (8.1 , 8.3) and Clinical Pharmacology (12.1) ] .

Advise the patient to read the FDA-approved patient labeling ( Patient Information ). Low Blood Counts Advise patients 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) ]. Infections Advise patients that infections may occur during treatment with ISTODAX. Advise patients to report fever, cough, shortness of breath with or without chest pain, burning on urination, flu-like symptoms, muscle aches, or worsening skin problems. Advise patients to report any previous history of hepatitis B before starting romidepsin [see Warnings and Precautions (5.2) ]. Tumor Lysis Syndrome Advise patients of the risk of tumor lysis syndrome (especially those with advanced stage disease and/or high tumor burden) to maintain high fluid intake for at least 72 hours after each dose [see Warnings and Precautions (5.4) ]. Nausea and Vomiting Advise patients that nausea and vomiting are common following treatment with ISTODAX. Prophylactic antiemetics are recommended for all patients. Advise patients to report these symptoms so that appropriate treatment can be instituted [see Adverse Reactions (6.1) ]. Embryo-Fetal Toxicity Advise patients that ISTODAX can cause fetal harm when administered during pregnancy [see Warnings and Precautions (5.5) and Use in Specific Populations (8.1) ]. Contraception Advise females of reproductive potential to use effective contraception during treatment with ISTODAX and for 1 month after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with ISTODAX and for 1 month after the last dose [ Use in Specific Populations (8.3) ]. Lactation Advise lactating women not to breastfeed during treatment with ISTODAX and for 1 week after the last dose [see Use in Specific Populations (8.2) ]. Infertility Advise females and males of reproductive potential that ISTODAX may cause infertility [see Nonclinical Toxicology (13.1) ]. Marketed by: Bristol-Myers Squibb Company Princeton, NJ 08543 USA ISTODAX ® is a trademark of Celgene Corporation, a Bristol-Myers Squibb company. ISTBAXPI.011/PPI.011

• Carefully monitor prothrombin time (PT) and International Normalized Ratio (INR) in patients concurrently administered ISTODAX and warfarin or coumarin derivatives ( 7.1 ). • Monitor for toxicities related to increased romidepsin exposure when co-administering romidepsin with strong CYP3A4 inhibitors ( 7.2 ). • Avoid use with rifampin and strong CYP3A4 inducers ( 7.3 ). 7.1 Warfarin or Coumarin Derivatives Prolongation of PT and elevation of INR were observed in a patient receiving ISTODAX concomitantly with warfarin. Monitor PT and INR more frequently in patients concurrently receiving ISTODAX and warfarin [see Clinical Pharmacology (12.3) ]. 7.2 Drugs That Inhibit CYP3A4 Enzymes Strong CYP3A4 inhibitors increase concentrations of romidepsin [see Clinical Pharmacology (12.3) ]. Monitor for toxicity related to increased romidepsin exposure and follow the dose modifications for toxicity [see Dosage and Administration (2.2) ] when ISTODAX is initially co-administered with strong CYP3A4 inhibitors. 7.3 Drugs That Induce CYP3A4 Enzymes Rifampin (a potent CYP3A4 inducer) increased the concentrations of romidepsin [see Clinical Pharmacology (12.3) ] . Avoid co-administration of ISTODAX with rifampin. The use of other potent CYP3A4 inducers should be avoided when possible.

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/m 2 in males and females, respectively). These doses were up to 1.3-fold the recommended human dose, based on body surface area. Based on nonclinical 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/m 2 /dose) following the clinical dosing schedule. This dose resulted in AUC 0-∞ values that were approximately 2% the exposure level in patients receiving the recommended dose of 14 mg/m 2 /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/m 2 /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/m 2 /dose) following the clinical dosing schedule. This dose resulted in AUC 0-∞ values that were 0.3% of those in patients receiving the recommended dose of 14 mg/m 2 /dose. Maturation arrest of ovarian follicles and decreased weight of ovaries were observed in a separate study in rats after 4 weeks of daily drug administration at 0.1 mg/kg/day (0.6 mg/m 2 /day). This dose is approximately 30% the estimated human daily dose based on body surface area.

Risk Summary Based on its mechanism of action and findings from animal studies, ISTODAX can cause embryo-fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1) ] . There are no available data on ISTODAX use in pregnant women to inform a drug associated risk of major birth defects and miscarriage. In an animal reproductive study, romidepsin was embryocidal and caused adverse developmental outcomes including embryo-fetal toxicity and malformations at exposures below those in patients at the recommended dose (see Data ). Advise pregnant women of the potential risk to a fetus and to avoid becoming pregnant while receiving ISTODAX and for at least 1 month after the last dose. The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Data Animal Data Romidepsin was administered intravenously to pregnant rats during the period of organogenesis at doses of 0.1, 0.2, or 0.5 mg/kg/day. Substantial resorption or postimplantation 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/m 2 /week. Drug-related fetal effects consisted of reduced fetal body weights, folded retina, rotated limbs, and incomplete sternal ossification.

The safety and effectiveness of ISTODAX in pediatric patients have not been established.

Of the 186 patients with CTCL who received ISTODAX in clinical studies, 51 (28%) were 65 years of age and older, while 16 (9%) were 75 years of age. No overall differences in safety or effectiveness were observed between patients 65 years or age and over and younger patients; however, greater sensitivity of some older individuals cannot be ruled out.

The following adverse reactions are described in more detail in other sections of the prescribing information. • Myelosuppression [see Warnings and Precautions (5.1) ] • Infections [see Warnings and Precautions (5.2) ] • Electrocardiographic Changes [see Warnings and Precautions (5.3) ] • Tumor Lysis Syndrome [see Warnings and Precautions (5.4) ] The most common adverse reactions (≥30%), excluding laboratory abnormalities, are nausea, fatigue, infections, vomiting, anorexia, electrocardiogram ST-T wave changes, dysgeusia, constipation and pruritis. Grade 3‐4 laboratory abnormalities (≥10%) include lymphopenia, neutropenia, anemia and thrombocytopenia ( 6 ). To report SUSPECTED ADVERSE REACTIONS, contact Bristol-Myers Squibb at 1-800-721-5072 or the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data in the WARNINGS AND PRECAUTIONS reflect exposure to ISTODAX in four clinical trials involving 363 patients with T-cell lymphoma, including 185 patients with CTCL. ISTODAX was administered as a single agent at a dosage of 14 mg/m 2 on days 1, 8, and 15 of a 28-day cycle. Among 363 patients who received ISTODAX, 21% were exposed for 6 months or longer and 13% were exposed for greater than one year. Cutaneous T-Cell Lymphoma The safety of ISTODAX was evaluated in 185 patients with CTCL in 2 single arm clinical studies in which patients received a dosage of 14 mg/m 2 on days 1, 8, and 15 of a 28-day cycle. Treatment continued as long as the patient benefitted from and tolerated the drug. The mean duration of treatment in these studies was 5.6 months (range: <1 to 83.4 months). Common Adverse Reactions Table 2 summarizes the most frequent adverse reactions (>20%) regardless of causality using the National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE, Version 3.0). Due to methodological differences between the studies, the AE data are presented separately for Study 1 and Study 2. Adverse reactions are ranked by their incidence in Study 1. Laboratory abnormalities commonly reported (>20%) as adverse reactions are included in Table 2. Table 2. Adverse Reactions Occurring in >20% of Patients in Either CTCL Study (N=185) Adverse Reactions n (%) Study 1 (n=102) Study 2 (n=83) All grades Grade 3 or 4 All grades Grade 3 or 4 Any adverse reactions 99 (97) 36 (35) 83 (100) 68 (82) Nausea 57 (56) 3 (3) 71 (86) 5 (6) Asthenia/Fatigue 54 (53) 8 (8) 64 (77) 12 (14) Infections 47 (46) 11 (11) 45 (54) 27 (33) Vomiting 35 (34) 1 (<1) 43 (52) 8 (10) Anorexia 23 (23) 1 (<1) 45 (54) 3 (4) Hypomagnesemia 22 (22) 1 (<1) 23 (28) 0 Diarrhea 20 (20) 1 (<1) 22 (27) 1 (1) Pyrexia 20 (20) 4 (4) 19 (23) 1 (1) Anemia 19 (19) 3 (3) 60 (72) 13 (16) Thrombocytopenia 17 (17) 0 54 (65) 12 (14) Dysgeusia 15 (15) 0 33 (40) 0 Constipation 12 (12) 2 (2) 32 (39) 1 (1) Neutropenia 11 (11) 4 (4) 47 (57) 22 (27) Hypotension 7 (7) 3 (3) 19 (23) 3 (4) Pruritus 7 (7) 0 26 (31) 5 (6) Hypokalemia 6 (6) 0 17 (20) 2 (2) Dermatitis/Exfoliative dermatitis 4 (4) 1 (<1) 22 (27) 7 (8) Hypocalcemia 4 (4) 0 43 (52) 5 (6) Leukopenia 4 (4) 0 38 (46) 18 (22) Lymphopenia 4 (4) 0 47 (57) 31 (37) Alanine aminotransferase increased 3 (3) 0 18 (22) 2 (2) Aspartate aminotransferase increased 3 (3) 0 23 (28) 3 (4) Hypoalbuminemia 3 (3) 1 (<1) 40 (48) 3 (4) Electrocardiogram ST-T wave changes 2 (2) 0 52 (63) 0 Hyperglycemia 2 (2) 2 (2) 42 (51) 1 (1) Hyponatremia 1 (<1) 1 (<1) 17 (20) 2 (2) Hypermagnesemia 0 0 22 (27) 7 (8) Hypophosphatemia 0 0 22 (27) 8 (10) Hyperuricemia 0 0 27 (33) 7 (8) 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%). There were eight deaths not due to disease progression. In Study 1, there were two deaths: one due to cardiopulmonary failure and one due to acute renal failure. There were six deaths in Study 2: four due to infection and one each due to 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 hypomagnesemia. Other Clinical Trials Experience The following common adverse reactions have been reported following administration of ISTODAX as a single agent in 178 patients with peripheral T-cell lymphoma, for which ISTODAX is not indicated or recommended. The most common adverse reactions (≥30%) included nausea (63%), fatigue (61%), thrombocytopenia (49%), vomiting (39%), neutropenia (39%), pyrexia (38%), diarrhea (36%) and anemia (35%). Other common (≥10%) clinically significant adverse reactions included dysgeusia (22%), headache (20%), cough (19%), dyspnea (15%), abdominal pain (13%) and stomatitis (10%). Grade 3 and higher adverse reactions in ≥10% were hematologic toxicities (including thrombocytopenia, neutropenia, leukopenia and anemia) and fatigue.

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 heartbeat, 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.