Romidepsin

Romidepsin
Adult Indications & Dosage
Pediatric Indications & Dosage
Contraindications
Warnings & Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Administration & Monitoring
Overdosage
Pharmacology
Clinical Studies
How Supplied
Images
Patient Counseling Information
Precautions with Alcohol
Brand Names
Look-Alike Names

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ammu Susheela, M.D. [2]

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Overview

Romidepsin is a histone deacetylase inhibitor that is FDA approved for the treatment of cutaneous T-cell lymphoma (CTCL), peripheral T-cell lymphoma (PTCL). Common adverse reactions include EKG ST segment changes, anemia, neutropenia, infectious disease, cutaneous T-cell lymphoma, lymphocytopenia.

Adult Indications and Dosage

FDA-Labeled Indications and Dosage (Adult)

• Romidepsin is indicated for:

• Treatment of cutaneous T-cell lymphoma (CTCL) in patients who have received at least one prior systemic therapy.
• Treatment of peripheral T-cell lymphoma (PTCL) in patients who have received at least one prior therapy.
• These indications are based on response rate. Clinical benefit such as improvement in overall survival has not been demonstrated.

Dosing Information

• 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. Cycles should be repeated every 28 days provided that the patient continues to benefit from and tolerates the drug.

Dose Modification

• Nonhematologic toxicities except alopecia
• Grade 2 or 3 toxicity: Treatment with romidepsin should be delayed until toxicity returns to ≤ Grade 1 or baseline, then therapy may be restarted at 14 mg/m2. If Grade 3 toxicity recurs, treatment with romidepsin should be delayed until toxicity returns to ≤ Grade 1 or baseline and the dose should be permanently reduced to 10 mg/m2.
• Grade 4 toxicity

• Treatment with romidepsin should be delayed until toxicity returns to ≤ Grade 1 or baseline, then the dose should be permanently reduced to 10 mg/m2.

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 ≥1.5×109/L and platelet count ≥75×109/L or baseline, then therapy may be restarted at 14 mg/m2.
• Grade 4 febrile (≥ 38.5ºC) neutropenia or thrombocytopenia that requires platelet transfusion: Treatment with romidepsin should be delayed until the specific cytopenia returns to ≤ Grade 1 or baseline, and then the dose should be permanently reduced to 10 mg/m2.

Instructions for Preparation and Intravenous Administration

• Romidepsin is a cytotoxic drug. Use appropriate handling procedures.
• Romidepsin must be reconstituted with the supplied diluent and further diluted with 0.9% Sodium Chloride Injection, USP before intravenous infusion.
• Each 10 mg single-use vial of Romidepsin must be reconstituted with 2 mL of the supplied diluent. With a suitable syringe, aseptically withdraw 2 mL from the supplied diluent vial, and slowly inject it into the 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 Romidepsin 5 mg/mL. The reconstituted Romidepsin solution is chemically stable for up to 8 hours at room temperature.
• Extract the appropriate amount of Romidepsin from the vials to deliver the desired dose, using proper aseptic technique. Before intravenous infusion, further dilute Romidepsin 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.

Off-Label Use and Dosage (Adult)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Romidepsin in adult patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Romidepsin in adult patients.

Pediatric Indications and Dosage

FDA-Labeled Indications and Dosage (Pediatric)

There is limited information regarding Romidepsin FDA-Labeled Indications and Dosage (Pediatric) in the drug label.

Off-Label Use and Dosage (Pediatric)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Romidepsin in pediatric patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Romidepsin in pediatric patients.

Contraindications

There is limited information regarding Romidepsin Contraindications in the drug label.

Warnings

Myelosuppression

• Treatment with Romidepsin can cause thrombocytopenia, leukopenia (neutropenia and lymphopenia), and anemia. Monitor blood counts regularly during treatment with Romidepsin, and modify the dose as necessary.

Infections

• Fatal and serious infections, including pneumonia, sepsis, and viral reactivation, including Epstein Barr and hepatitis B viruses, have been reported in clinical trials with Romidepsin. These can occur during treatment and within 30 days after 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.
• Reactivation of hepatitis B virus infection has occurred in 1% of PTCL patients in clinical trials in Western populations. 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 a trial of patients with relapsed or refractory extranodal NK/T-cell lymphoma. In one case, ganciclovir prophylaxis failed to prevent Epstein Barr viral reactivation.

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.
• 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 Romidepsin.

Tumor Lysis Syndrome

• Tumor lysis syndrome (TLS) has been reported to occur in 1% of patients with tumor stage CTCL and 2% of patients with Stage III/IV PTCL. Patients with advanced stage disease and/or high tumor burden may be at greater risk, should be closely monitored, and managed as appropriate.

Use in Pregnancy

• There are no adequate and well-controlled studies of Romidepsin in pregnant women. However, based on its mechanism of action and findings in animals, Romidepsin 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 of 14 mg/m2/week. If this drug is used during pregnancy, or if the patient becomes pregnant while taking Romidepsin, the patient should be apprised of the potential hazard to the fetus.

Adverse Reactions

Clinical Trials Experience

• Myelosuppression
• Infection
• Electrocardiographic Changes
• Tumor Lysis Syndrome

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.

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 starting dose of 14 mg/m2. The mean duration of treatment in these studies was 5.6 months (range: <1 to 83.4 months).

Common Adverse Reactions

• Table 1 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 1.

This image is provided by the National Library of Medicine.

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 hypomagnesemia.

Peripheral T-Cell Lymphoma

• The safety of Romidepsin 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 were 5.6 months and 6 cycles in Study 3 and 9.6 months and 8 cycles in Study 4.

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.

This image is provided by the National Library of Medicine.

Serious Adverse Reactions

• Infections were the most common type of SAE reported. In Study 3, 26 patients (20%) 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(8%), 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 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%).
• Reactivation of hepatitis B virus infection has occurred in 1% of patients with PTCL patients in clinical trials in Western population enrolled in Study 3 and Study 4.
• Deaths due to all causes within 30 days of the last dose of Romidepsin 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%).

Postmarketing Experience

• No additional safety signals have been observed from postmarketing experience.

Drug Interactions

Warfarin or Coumarin Derivatives

• Prolongation of PT and elevation of INR were observed in a patient receiving Romidepsin concomitantly with warfarin. Although the interaction potential between Romidepsin and warfarin has not been formally studied, monitor PT and INR more frequently in patients concurrently receiving Romidepsin and warfarin.

Drugs That Inhibit Cytochrome P450 3A4 Enzymes

• Romidepsin is metabolized by CYP3A4. Strong CYP3A4 inhibitors increase concentrations of romidepsin. In a pharmacokinetic drug interaction trial the strong CYP3A4 inhibitor ketoconazole increased romidepsin (AUC0-∞) by approximately 25%.
• Monitor for toxicity related to increased romidepsin exposure and follow the dose modifications for toxicity when romidepsin is initially co-administered with strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole).

Drugs That Induce Cytochrome P450 3A4 Enzymes

• Avoid co-administration of Romidepsin with rifampin.
• In a pharmacokinetic drug interaction trial with co-administered rifampin (a strong CYP3A4 inducer), romidepsin exposure was increased by approximately 80% and 60% for AUC0-∞ and Cmax, respectively. Typically, co-administration of CYP3A4 inducers decrease concentrations of drugs metabolized by CYP3A4. The increase in exposure seen after co-administration with rifampin is likely due to rifampin’s inhibition of an undetermined hepatic uptake process that is predominantly responsible for the disposition of Romidepsin.
• It is unknown if other potent CYP3A4 inducers (e.g., dexamethasone, carbamazepine, phenytoin, rifabutin, rifapentine, phenobarbital, St. John’s Wort) would alter the exposure of Romidepsin. Therefore, the use of other potent CYP3A4 inducers should be avoided when possible.

Drugs That Inhibit Drug Transport Systems

• Romidepsin is a substrate of the efflux transporter P-glycoprotein (P-gp, ABCB1). If Romidepsin is administered with drugs that inhibit P-gp, increased concentrations of romidepsin are likely, and caution should be exercised.

Use in Specific Populations

Pregnancy

Pregnancy Category (FDA): D

• There are no adequate and well-controlled studies of Romidepsin in pregnant women. However, based on its mechanism of action and findings in animals, Romidepsin 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 Romidepsin, 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.

Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Romidepsin in women who are pregnant.

Labor and Delivery

There is no FDA guidance on use of Romidepsin during labor and delivery.

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 Romidepsin, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

The safety and effectiveness of Romidepsin in pediatric patients has not been established.

Geriatic 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.

Gender

There is no FDA guidance on the use of Romidepsin with respect to specific gender populations.

Race

There is no FDA guidance on the use of Romidepsin with respect to specific racial populations.

Renal Impairment

• No dedicated renal impairment study for Romidepsin 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.

Hepatic Impairment

• No dedicated hepatic impairment study for Romidepsin 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.

Females of Reproductive Potential and Males

There is no FDA guidance on the use of Romidepsin in women of reproductive potentials and males.

Immunocompromised Patients

There is no FDA guidance one the use of Romidepsin in patients who are immunocompromised.

Administration and Monitoring

Administration

• Intravenous

Monitoring

• Monitor blood counts regularly during treatment with Romidepsin, and modify the dose as necessary.
• 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.
• Carefully monitor prothrombin time (PT) and International Normalized Ratio (INR) in patients concurrently administered Romidepsin and warfarin or coumarin derivatives.

IV Compatibility

There is limited information regarding the compatibility of Romidepsin and IV administrations.

Overdosage

• 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.

Pharmacology

There is limited information regarding Romidepsin Pharmacology in the drug label.

Mechanism of Action

• 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.

Structure

There is limited information regarding Romidepsin Structure in the drug label.

Pharmacodynamics

Cardiac Electrophysiology

• The effect of romidepsin on the heart-rate corrected QTc/QTcF was evaluated in 26 subjects with advanced malignancies given romidepsin at doses of 14 mg/m2 as a 4-hour intravenous infusion, and at doses of 8, 10 or 12 mg/m2 as a 1–hour infusion. Patients received premedications with antiemetics. No large changes in the mean QTc interval (> 20 milliseconds) from baseline based on Fridericia correction method were detected in the trial. Small increase in mean QT interval (< 10 milliseconds) and mean QT interval increase between 10 to 20 milliseconds cannot be excluded because of the limitations in the trial design.
• Romidepsin was associated with a delayed concentration-dependent increase in heart rate in patients with advanced cancer with a maximum mean increase in heart rate of 20 beats per minute occurring at the 6 hour time point after start of romidepsin infusion for patients receiving 14 mg/m2 as a 4-hour infusion.

Pharmacokinetics

Absorption

• Romidepsin exhibited linear pharmacokinetics across doses ranging from 1.0 to 24.9 mg/m2 when administered intravenously over 4 hours in patients with advanced cancers.
• In patients with T-cell lymphomas who received 14 mg/m2 of romidepsin intravenously over a 4-hour period on days 1, 8, and 15 of a 28-day cycle, geometric mean values of the maximum plasma concentration (Cmax) and the area under the plasma concentration versus time curve (AUC0-inf) were 377 ng/mL and 1549 ng*hr/mL, respectively.

Distribution

• Romidepsin is highly protein bound in plasma (92% to 94%) over the concentration range of 50 ng/mL to 1000 ng/mL with α1-acid-glycoprotein (AAG) being the principal binding protein. Romidepsin is a substrate of the efflux transporter P-glycoprotein (P-gp, ABCB1).
• In vitro, romidepsin accumulates into human hepatocytes via an unknown active uptake process. Romidepsin is not a substrate of the following uptake transporters: BCRP, BSEP, MRP2, OAT1, OAT3, OATP1B1, OATP1B3, or OCT2. In addition, romidepsin is not an inhibitor of BCRP, MRP2, MDR1 or OAT3. Although romidepsin did not inhibit OAT1, OCT2, and OATP1B3 at concentrations seen clinically (1 μmol/L), modest inhibition was observed at 10 µmol/L. Romidepsin was found to be an inhibitor of BSEP and OATP1B1.

Metabolism

• Romidepsin undergoes extensive metabolism in vitro primarily by CYP3A4 with minor contribution from CYP3A5, CYP1A1, CYP2B6, and CYP2C19. At therapeutic concentrations, romidepsin did not competitively inhibit CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, or CYP3A4 in vitro.
• At therapeutic concentrations, romidepsin did not cause notable induction of CYP1A2, CYP2B6 and CYP3A4 in vitro. Therefore, pharmacokinetic drug-drug interactions are unlikely to occur due to CYP450 induction or inhibition by romidepsin when co-administered with CYP450 substrates.

Excretion

• Following 4-hour intravenous administration of romidepsin at 14 mg/m2 on days 1, 8, and 15 of a 28-day cycle in patients with T-cell lymphomas, the terminal half-life (t½) was approximately 3 hours. No accumulation of plasma concentration of romidepsin was observed after repeated dosing.

Drug Interactions

• Ketoconazole

• A drug interaction clinical trial with the strong CYP3A4 inhibitor, ketoconazole, was conducted in patients with advanced cancer. Following co-administration of 8 mg/m2 Romidepsin (4-hour infusion) with ketoconazole, the overall romidepsin exposure was increased by approximately 25% and 10% for AUC0-∞ and Cmax, respectively, compared to romidepsin alone, and the difference in AUC0-∞ between the 2 treatments was statistically significant. Co-administration of ketoconazole slightly decreased the romidepsin clearance and volume of distribution, but did not have a statistically significant effect on peak exposure (Cmax).

• Rifampin

• A drug interaction clinical trial with the strong CYP3A4 inducer, rifampin, was conducted in patients with advanced cancer. Following co-administration of 14 mg/m2 Romidepsin (4-hour infusion) with rifampin, the overall romidepsin exposure was unexpectedly increased by approximately 80% and 60% for AUC0-∞ and Cmax, respectively, compared to romidepsin alone, and the difference between the 2 treatments was statistically significant. Co-administration of rifampin decreased the romidepsin clearance and volume of distribution by 44% and 52%, respectively. The increase in exposure seen after co-administration with rifampin is likely due to rifampin's inhibition of an undetermined hepatic uptake process that is predominant for the disposition of Romidepsin.

Use in Specific Populations

Effect of Age, Gender or Race

• The population pharmacokinetic analysis of romidepsin showed that age, gender, or race (white vs. black) did not appear to influence the pharmacokinetics of romidepsin.

Effect of Hepatic Impairment

• No dedicated hepatic impairment study has been conducted for Romidepsin. The population pharmacokinetic analysis indicates that mild hepatic impairment [total bilirubin (TB) ≤upper limit of normal (ULN) and aspartate aminotransferase (AST) >ULN; or TB >1.0x - 1.5x ULN and any AST] had no significant influence on romidepsin pharmacokinetics. As the effect of moderate (TB >1.5x - 3x ULN and any AST) and severe (TB >3x ULN and any AST) hepatic impairment on the pharmacokinetics of romidepsin is unknown, patients with moderate and severe hepatic impairment should be treated with caution.

Effect of Renal Impairment

• No dedicated renal impairment study has been conducted for Romidepsin. The population pharmacokinetic analysis showed that romidepsin pharmacokinetics were not affected by mild (estimated creatinine clearance 50 - 80 mL/min), moderate (estimated creatinine clearance 30 - 50 mL/min), or severe (estimated creatinine clearance <30 mL/min) renal impairment. Nonetheless, 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.

Nonclinical Toxicology

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 nonclinical findings, male and female fertility may be compromised by treatment with Romidepsin. 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 4 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.

Clinical Studies

Cutaneous T-Cell Lymphoma

• Romidepsin was evaluated in 2 multicenter, single-arm clinical studies in patients with CTCL. Overall, 167 patients with CTCL were treated in the US, Europe, and Australia. Study 1 included 96 patients with confirmed CTCL after failure of at least 1 prior systemic therapy. Study 2 included 71 patients with a primary diagnosis of CTCL who received at least 2 prior skin directed therapies or one or more systemic therapies. Patients were treated with Romidepsin at a starting dose of 14 mg/m2 infused over 4 hours on days 1, 8, and 15 every 28 days.
• In both studies, patients could be treated until disease progression at the discretion of the investigator and local regulators. Objective disease response was evaluated according to a composite endpoint that included assessments of skin involvement, lymph node and visceral involvement, and abnormal circulating T-cells ("Sézary cells").
• The primary efficacy endpoint for both studies was overall objective disease response rate (ORR) based on the investigator assessments, and defined as the proportion of patients with confirmed complete response (CR) or partial response (PR). CR was defined as no evidence of disease and PR as ≥ 50% improvement in disease. Secondary endpoints in both studies included duration of response and time to response.

Baseline Patient Characteristics

• Demographic and disease characteristics of the patients in Study 1 and Study 2 are provided in Table 3.

This image is provided by the National Library of Medicine.

Peripheral T-Cell Lymphoma

• Romidepsin was evaluated in a multicenter, single-arm, international clinical study in patients with PTCL who had failed at least 1 prior systemic therapy (Study 3). Patients in US, Europe, and Australia were treated with Romidepsin at a dose of 14 mg/m2 infused over 4 hours on days 1, 8, and 15 every 28 days. Of the 131 patients treated, 130 patients had histological confirmation by independent central review and were evaluable for efficacy (HC Population). Six cycles of treatment were planned; patients who developed progressive disease (PD), significant toxicity, or who met another criterion for study termination were to discontinue treatment. Responding patients had the option of continuing treatment beyond 6 cycles at the discretion of the patient and Investigator until study withdrawal criteria were met.
• Primary assessment of efficacy was based on rate of complete response (CR + CRu) as determined by an Independent Review Committee (IRC) using the International Workshop Response Criteria (IWC). Secondary measures of efficacy included IRC assessment of duration of response and objective disease response (ORR, CR + CRu + PR).

Baseline Patient Characteristics

• Demographic and disease characteristics of the PTCL patients are provided in Table 5.

This image is provided by the National Library of Medicine.

• All patients in both studies had received prior systemic therapy for PTCL. In Study 4, a greater percentage of patients had extensive prior radiation and chemotherapy. Twenty-one patients (16%) in Study 3 and 18 patients (38%) in Study 4 had received prior autologous stem cell transplant and 31 (24%) and 19 (40%) patients, respectively, had received prior radiation therapy.

Clinical Results

• Efficacy outcomes for PTCL patients as determined by the IRC are provided in Table 6 for Study 3. The complete response rate was 15% and overall response rate was 26%. Similar complete response rates were observed by the IRC across the 3 major PTCL subtypes (NOS, AITL, and ALK-1 negative ALCL). Median time to objective response was 1.8 months (~2 cycles) for the 34 patients who achieved CR, CRu, or PR and median time to CR was 3.5 months (~4 cycles) for the 20 patients with complete response. The responses in 12 of the 20 patients achieving CR and CRu were known to exceed 11.6 months; the follow-up on the remaining 8 patients was discontinued prior to 8.5 months.

This image is provided by the National Library of Medicine.

• In a second single-arm clinical study in patients with PTCL who had failed prior therapy (Study 4), patients were treated with Romidepsin at a starting dose of 14 mg/m2 infused over 4 hours on days 1, 8, and 15 every 28 days. Patients could be treated until disease progression at the discretion of the patient and the Investigator. The percentage of patients achieving CR + CRu in Study 4 was similar to that in Study 3.

How Supplied

• Romidepsin is supplied as a kit including a sterile, lyophilized powder in a single-use vial containing 10 mg of romidepsin and 20 mg of the bulking agent, povidone, USP. In addition, each kit includes one sterile diluent vial containing 2 mL (deliverable volume) of 80% propylene glycol, USP, and 20% dehydrated alcohol, USP.
• NDC 59572-983-01: Romidepsin® KIT containing 1 vial of romidepsin, 10 mg and 1 vial of diluent for romidepsin, 2 mL per carton.

Storage

• 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.
• 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.

Images

Drug Images

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Package and Label Display Panel

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Patient Counseling Information

There is limited information regarding Romidepsin Patient Counseling Information in the drug label.

Precautions with Alcohol

Alcohol-Romidepsin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

Brand Names

• Romidepsin ®

Look-Alike Drug Names

There is limited information regarding Romidepsin Look-Alike Drug Names in the drug label.

Drug Shortage Status

Price

References

The contents of this FDA label are provided by the National Library of Medicine.

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