ISTODAX® (romidepsin)

ISTODAX® (romidepsin) for injection

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ISTODAX® (romidepsin)

Romidepsin, a histone deacetylase (HDAC) inhibitor, is a bicyclic depsipeptide. At room temperature, romidepsin is a white powder and is described chemically as (1S,4S,7Z,10S,16E,21R)-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 C24H36N4O6S2. The molecular weight is 540.71

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.

Indications and usage

ISTODAX is a histone deacetylase (HDAC) inhibitor indicated for:

  • Treatment of cutaneous T-cell lymphoma (CTCL) in adult patients who have received at least one prior systemic therapy
  • Treatment of peripheral T-cell lymphoma (PTCL) in adult patients who have received at least one prior therapy. This indication is approved under accelerated approval based on response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials

Dosage and administration

  • 14 mg/m2 administered intravenously (IV) 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.
  • Discontinue or interrupt treatment (with or without dose reduction to 10 mg/m2) to manage drug toxicity
  • Reduce starting dose in patients with moderate and severe hepatic impairment

Warning and precautions

  • 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
  • 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
  • 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
  • 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
  • Embryo-fetal toxicity: Fetal harm can occur when administered to a pregnant woman. Women should be advised to avoid becoming pregnant when receiving ISTODAX

Instructions for Preparation and Intravenous Administration

ISTODAX is a cytotoxic drug. Use appropriate handling procedures. 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.

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Parenteral drug products should be inspected visually for particulate matter and discoloration before administration, whenever solution and container permit.

Mechanism of Action

Romidepsin is a histone deacetylase (HDAC) inhibitor. HDACs catalyze the removal of acetyl groups from acetylated lysine residues in histones, resulting in the modulation of gene expression. HDACs also deacetylate non-histone proteins, such as transcription factors. In vitro, romidepsin causes the accumulation of acetylated histones, and induces cell cycle arrest and apoptosis of some cancer cell lines with IC50 values in the nanomolar range. The mechanism of the antineoplastic effect of romidepsin observed in nonclinical and clinical studies has not been fully characterized.

Drug interactions

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.

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 ISTODAX 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 ISTODAX with rifampin. The use of other potent CYP3A4 inducers should be avoided when possible.

Use in specific populations

Pregnancy: Based on its mechanism of action and findings from animal studies, ISTODAX can cause embryo-fetal harm when administered to a pregnant woman.

Lactation: There are no data on the presence of ISTODAX or its metabolites in human milk, the effects on the breastfed child, or the effects on milk production. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in the breastfed child, advise lactating women not to breastfeed during treatment with ISTODAX and for at least 1 week after the last dose.

Contraception: Advise females of reproductive potential to use effective contraception during treatment with ISTODAX and for at least 1 month after the last dose. ISTODAX may reduce the effectiveness of estrogen-containing contraceptives. Therefore, alternative methods of non-estrogen containing contraception (e.g., condoms, intrauterine devices) should be used in patients receiving ISTODAX.

Advise males with female partners of reproductive potential to use effective contraception and to avoid fathering a child during treatment with ISTODAX and for at least 1 month after the last dose.

Pediatric Use: The safety and effectiveness of ISTODAX in pediatric patients has not been established.

Geriatric 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.

Overdosage

No specific information is available on the treatment of overdosage of ISTODAX.

Toxicities in a single-dose study i 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.

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 cytotoxic drug. Follow applicable special handling and disposal procedures

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