Romidepsin Drug Information

Romidepsin injection is indicated for the treatment of cutaneous T-cell lymphoma (CTCL) in adult patients who have received at least one prior systemic therapy. Romidepsin injection 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.

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 romidepsin in four clinical trials involving 363 patients with T-cell lymphoma, including 185 patients with CTCL. Romidepsin 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 romidepsin, 21% were exposed for 6 months or longer and 13% were exposed for greater than one year.

Cutaneous T-Cell Lymphoma The safety of romidepsin 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 month 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 36 83 68 Nausea 57 3 71 5 Asthenia/Fatigue 54 8 64 12 Infections 47 11 45 27 Vomiting 35 1 (< 1) 43 8 Anorexia 23 1 (< 1) 45 3 Hypomagnesemia 22 1 (< 1) 23 0 Diarrhea 20 1 (< 1) 22 1 Pyrexia 20 4 19 1 Anemia 19 3 60 13 Thrombocytopenia 17 0 54 12 Dysgeusia 15 0 33 0 Constipation 12 2 32 1 Neutropenia 11 4 47 22 Hypotension 7 3 19 3 Pruritus 7 0 26 5 Hypokalemia 6 0 17 2 Dermatitis/Exfoliative dermatitis 4 1 (< 1) 22 7 Hypocalcemia 4 0 43 5 Leukopenia 4 0 38 18 Lymphopenia 4 0 47 31 Alanine aminotransferase increased 3 0 18 2 Aspartate aminotransferase increased 3 0 23 3 Hypoalbuminemia 3 1 (< 1) 40 3 Electrocardiogram ST-T wave changes 2 0 52 0 Hyperglycemia 2 2 42 1 Hyponatremia 1 (< 1) 1 (< 1) 17 2 Hypermagnesemia 0 0 22 7 Hypophosphatemia 0 0 22 8 Hyperuricemia 0 0 27 7 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 romidepsin as a single agent in 178 patients with peripheral T-cell lymphoma, for which romidepsin 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.

Warfarin or Coumarin Derivatives Prolongation of PT and elevation of

INR were observed in a patient receiving romidepsin concomitantly with warfarin. Monitor PT and INR more frequently in patients concurrently receiving romidepsin injection and warfarin .

Drugs That Inhibit

CYP3A4 Enzymes Strong CYP3A4 inhibitors increase concentrations of romidepsin . Monitor for toxicity related to increased romidepsin exposure and follow the dose modifications for toxicity when romidepsin injection is initially co-administered with strong CYP3A4 inhibitors.

Drugs That Induce

CYP3A4 Enzymes Rifampin (a potent CYP3A4 inducer) increased the concentrations of romidepsin . Avoid co-administration of romidepsin injection with rifampin. The use of other potent CYP3A4 inducers should be avoided when possible.

Pregnancy Risk Summary Based on its mechanism of action and findings from animal studies, romidepsin injection can cause embryo-fetal harm when administered to a pregnant woman . There are no available data on romidepsin 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 romidepsin 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% to 4% and 15% to 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.

Pediatric Use The safety and effectiveness of romidepsin injection in pediatric patients have not been established.

No specific information is available on the treatment of overdosage of romidepsin. 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 romidepsin and it is not known if romidepsin is dialyzable.