Romidepsin

Pronunciation: ROE-mi-DEP-sin
Class: Histone deacetylase inhibitor

Trade Names

Istodax
- Injection, lyophilized powder for solution 10 mg

Pharmacology

Inhibits enzymatic activity of histone deacetylases (HDACs). HDACs catalyze the removal of acetyl groups from acetylated lysine residues in histones, resulting in the modulation of gene expression. HDACs also deacetylate nonhistone proteins, such as transcription factors.

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Pharmacokinetics

Absorption

C _max and AUC _0-inf were 377 ng/mL and 1,549 ng•h/mL, respectively.

Distribution

Highly protein bound in plasma (92% to 94%) with alpha-1 acid glycoprotein being the principal binding protein.

Metabolism

Extensive metabolism primarily by CYP3A4 with minor contribution from CYP3A5, CYP1A1, CYP2B6, and CYP2C19.

Elimination

Terminal half-life is approximately 3 h.

Special Populations

Renal Function Impairment

Romidepsin pharmacokinetics were not affected by mild, moderate, or severe renal impairment. The effect of ESRD on romidepsin pharmacokinetics has not been studied; use with caution.

Hepatic Function Impairment

Mild hepatic impairment had no significant influence on romidepsin pharmacokinetics. The effect of moderate and severe hepatic impairment on the pharmacokinetics of romidepsin is unknown; use with caution.

Elderly

Age did not appear to influence the pharmacokinetics of romidepsin.

Gender

Gender did not appear to influence the pharmacokinetics of romidepsin.

Race

Race (white patients compared with black patients) did not appear to influence the pharmacokinetics of romidepsin.

Indications and Usage

For treatment of cutaneous T-cell lymphoma in patients who have received at least 1 prior systemic therapy; treatment of peripheral T-cell lymphoma in patients who have received at least 1 prior therapy.

Contraindications

None well documented.

Dosage and Administration

Cutaneous T-cell Lymphoma/Peripheral T-cell Lymphoma
Adults

IV 14 mg/m ² IV over a 4-h 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 therapy.

Dosage Adjustments
Adults Nonhematologic toxicities (except alopecia) Grade 2 or 3 toxicity

Delay treatment until toxicity returns to grade 1 or less or baseline, then therapy may be restarted at 14 mg/m ² . If grade 3 toxicity recurs, treatment should be delayed until toxicity returns to grade 1 or less or baseline, then the dose should be permanently reduced to 10 mg/m ² .

Grade 4 toxicity

Delay treatment until toxicity returns to grade 1 or less or baseline, then the dose should be permanently reduced to 10 mg/m ² .

Discontinue if grade 3 or 4 toxicities recur after dose reduction.

Hematologic toxicities Grade 3 or 4 neutropenia or thrombocytopenia

Delay treatment until the specific cytopenia returns to ANC 1.5 × 10 ⁹ /L or higher and/or platelet count of 75 × 10 ⁹ /L or higher or baseline, then therapy may be restarted at 14 mg/m ² .

Grade 4 febrile (101.3°F or higher) neutropenia or thrombocytopenia that requires platelet transfusion

Delay treatment until the specific cytopenia returns to grade 1 or less or baseline, and then the dose should be permanently reduced to 10 mg/m ² .

General Advice

• Administer by IV infusion over 4 h.
• Reconstitute with 2 mL of the supplied diluent and further dilute in 500 mL of sodium chloride 0.9% injection before IV infusion.
• Diluted solution is compatible with polyvinyl chloride, ethylene vinyl acetate, and polyethylene infusion bags, as well as glass bottles.

Storage/Stability

Store between 68° and 77°F; excursions are permitted between 59° and 86°F. Reconstituted solution is stable for at least 8 h at room temperature. Diluted reconstituted solution is stable for at least 24 h at room temperature.

Drug Interactions

CYP3A4 moderate inhibitors (eg, aprepitant, diltiazem, fluconazole, grapefruit juice)

Romidepsin plasma concentrations may be elevated, increasing the pharmacologic effects and risk of adverse reactions. Coadminister with caution.

CYP3A4 strong inducers (eg, carbamazepine, dexamethasone, phenobarbital, phenytoin, rifabutin, rifampin, rifapentine)

Romidepsin plasma concentrations may be reduced, decreasing the pharmacologic effects. If possible, avoid coadministration.

CYP3A4 strong inhibitors (eg, atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole)

Romidepsin plasma concentrations may be elevated, increasing the pharmacologic effects and risk of adverse reactions. If possible, avoid coadministration.

Disulfiram, metronidazole

The diluent for romidepsin injection contains dehydrated alcohol. Therefore, the combination of romidepsin and disulfiram or metronidazole may produce acute alcohol intolerance. Avoid coadministration.

P-glycoprotein efflux transport inhibitors (eg, cyclosporine, ranolazine)

Romidepsin plasma concentrations may be elevated, increasing the pharmacologic effects and risk of adverse reactions. Coadminister with caution.

QT interval prolonging drugs (eg, antiarrhythmic agents [eg, amiodarone, propafenone], drugs that lead to important QT prolongation [eg, nilotinib, toremifene])

Because of the risk of QT prolongation, consider appropriate CV monitoring, such as monitoring electrolytes and ECG at baseline and periodically during treatment.

St. John's wort

Romidepsin plasma concentrations may be reduced, decreasing the pharmacologic effects. If possible, avoid coadministration.

Warfarin

Coadministration may result in PT prolongation and elevated INR. Monitor PT and INR in a patient receiving romidepsin and warfarin concurrently. Adjust the warfarin dose as needed.

Adverse Reactions

Cardiovascular

ECG ST-T wave changes (63%); hypotension (23%); tachycardia (10%); supraventricular arrhythmia (6%); deep vein thrombosis, syncope, ventricular arrhythmia (4%).

CNS

Asthenia/fatigue (77%); headache (34%).

Dermatologic

Pruritus (31%); dermatitis/exfoliative dermatitis (27%); cellulitis (4%).

GI

Nausea (86%); anorexia (54%); vomiting (52%); constipation, dysgeusia (40%); diarrhea (36%); weight decreased (15%); abdominal pain (14%); stomatitis (10%).

Hematologic

Anemia, thrombocytopenia (72%); neutropenia (66%); lymphopenia (57%); leukopenia (55%); febrile neutropenia, packed RBC transfusion, platelet transfusion (4%).

Hepatic

Increased AST (28%); increased ALT (22%); hyperbilirubinemia (6%).

Metabolic

Hypocalcemia (52%); hyperglycemia (51%); hypoalbuminemia (48%); hyperuricemia (33%); hypomagnesemia (28%); hypermagnesemia, hypophosphatemia (27%); hypokalemia, hyponatremia (20%); edema (5%).

Respiratory

Cough, dyspnea (21%); hypoxia (6%); pneumonia (5%); pneumonitis (4%); pulmonary embolism (2%).

Miscellaneous

Infections (54%); pyrexia (47%); chills (17%); peripheral edema (10%); dehydration (9%); central line infection (6%); sepsis (5%); catheter-related infection, hypersensitivity (4%); chest pain (2%).

Precautions

Monitor Potassium and magnesium should be within the normal range before administration. Monitor electrolytes and ECGs at baseline and periodically during treatment in patients with congenital long QT syndrome or a history of CV disease, and in patients taking antiarrhythmic medications or medications that can lead to QT prolongation. Monitor hematologic parameters during treatment. Closely monitor patients with advanced stage disease and/or high tumor burden; take appropriate precautions and institute treatment as appropriate.

Pregnancy

Category D . May cause fetal harm. Competition between romidepsin and beta-estradiol could cause pregnancy loss. Effectiveness of estrogen-containing contraceptives may be decreased.

Lactation

Undetermined.

Children

Safety and efficacy not established.

Elderly

Greater sensitivity of some older patients cannot be ruled out.

Renal Function

Treat patients with ESRD with caution.

Hepatic Function

Treat patients with moderate and severe hepatic impairment with caution.

CV effects

ECG changes, including T-wave and ST-segment changes, have been reported. QT prolongation may occur.

Hematologic effects

May cause thrombocytopenia, leukopenia (neutropenia and lymphopenia), and anemia.

Infection

Serious and sometimes fatal infections, including pneumonia and sepsis, have been reported.

Tumor lysis syndrome

Reported to occur in 1% of patients with tumor-stage cutaneous T-cell lymphoma and in 2% of patients with stage 3/4 peripheral T-cell lymphoma.

Overdosage

Symptoms

No data available.

Patient Information

• Advise patient, family, or caregiver that medication will be prepared and administered by health care provider in a health care setting.
• Advise patients that nausea and vomiting are common during treatment and to report these symptoms so that appropriate treatment can be instituted.
• Advise patient, family, or caregiver to report any of the following to health care provider: abnormal heartbeat, chest pain, or any unusual bleeding.
• Inform patients that treatment can cause low blood cell counts and that frequent monitoring of hematologic parameters is required.
• Inform patients that infections may occur during treatment and to report fever; cough; shortness of breath, with or without chest pain; burning on urination; flu-like symptoms; muscle aches; or worsening of skin problems to their health care provider.
• Advise women of childbearing potential that romidepsin may reduce the effectiveness of estrogen-containing contraceptives.

Copyright © 2009 Wolters Kluwer Health.