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.

Dosage in Patients with Hepatic Impairment

For patients with moderate or severe hepatic impairment, reduce the starting dose of romidepsin injection 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

Instructions for Preparation and Intravenous Administration

Romidepsin injection is a hazardous drug. Follow applicable special handling and disposal procedures. 1 Romidepsin injection must be diluted with 0.9% Sodium Chloride Injection, USP before intravenous infusion. Extract the appropriate amount of romidepsin injection from the vial to deliver the desired dose, using proper aseptic technique.

Before intravenous infusion, dilute romidepsin injection in 500 mL 0.9% Sodium Chloride Injection, USP. Infuse over 4 hours. Discard unused portion.

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.

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. 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. Serious adverse reactions reported in > 2% of patients in Study 1 were sepsis and pyrexia (3%).

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 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. 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 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.

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.