Romidepsin, a histone deacetylase (HDAC) inhibitor, is an antineoplastic agent.1, 15
Romidepsin is used for the treatment of cutaneous T-cell lymphoma (CTCL; e.g., mycosis fungoides, Sézary syndrome) in adult patients who have received at least 1 prior systemic therapy.1, 3, 4, 15 Romidepsin is designated an orphan drug by the US Food and Drug Administration (FDA) for use in this condition.2
Efficacy of romidepsin was evaluated in 2 single-arm, multicenter, phase 2 clinical studies in patients with CTCL.1, 3, 4 Study 1 included 96 patients with confirmed CTCL after failure of at least 1 prior systemic therapy.1, 4 Study 2 included 71 patients with a primary diagnosis of CTCL who had received at least 2 previous skin-directed therapies or 1 or more systemic therapies.1, 3 Patients in both studies received an initial romidepsin dosage of 14 mg/m2 by IV infusion administered over 4 hours on days 1, 8, and 15 of a 28-day cycle; patients could be treated until disease progression occurred.1, 3, 4 In both studies, objective clinical response was determined using a composite endpoint that included assessments of skin involvement, lymph node and visceral involvement, and blood involvement (i.e., measurement of abnormal circulating T-cells [Sézary cells]).1, 3, 4 A complete clinical response was defined as no evidence of disease and a partial response was characterized as 50% or greater improvement in disease.1, 3 Secondary endpoints in the 2 studies included duration of response and time to response.1, 3, 4 Similar overall objective response rates (34 and 35%) were reported in studies 1 and 2, respectively.1, 3 Complete responses occurred in 6% of romidepsin-treated patients in both studies and partial response rates were also similar in the 2 studies (28 and 30% in studies 1 and 2, respectively).1, 3 In study 1, most of the patients who presented with pruritus at baseline experienced some relief, including those with severe pruritus.4 The median time to first response was 2 months (range: 1-6 months) in both studies.1, 3 The median time to complete response was 6 months in study 1 and 4 months in study 2 (range: 2-9 months).1 The median duration of response was 15 months in study 1 and 11 months in study 2.1
Comparative studies of IV romidepsin and oral vorinostat (another HDAC inhibitor) in patients with CTCL are not yet available.1, 15 Evidence to date from noncomparative studies indicates that the drugs produce a similar overall response rate; however, vorinostat appears to have a shorter duration of response.3, 15, 16 In addition, the observed responses and duration of response of romidepsin appear to be favorable when compared with those reported following chemotherapy, oral bexarotene, or denileukin diftitox in patients with CTCL.3
Because of the risk of QT prolongation and other ECG abnormalities associated with hypomagnesemia and hypokalemia as well as with HDAC inhibitor (including romidepsin) therapy, serum concentrations of potassium and magnesium should be within the normal range prior to romidepsin administration.1, 3 (See Electrolyte Monitoring under Cautions: Warnings/Precautions.)
Prophylactic antiemetics were administered to prevent nausea in romidepsin-treated patients in clinical trials.3, 6
Romidepsin is administered by IV infusion only.1 The drug is commercially available as a kit that includes a single-use vial containing 10 mg of romidepsin and a vial containing 2 mL of diluent (composed of 80% propylene glycol and 20% dehydrated alcohol).1
Romidepsin lyophilized powder for injection must be reconstituted and further diluted prior to IV infusion.1
Based on the indicated romidepsin dosage, the appropriate number of vials labeled as containing 10 mg of romidepsin should each be reconstituted with 2 mL of the diluent provided by the manufacturer to provide a solution containing 5 mg/mL.1 Each vial should then be swirled until there are no visible particles in the resulting solution.1 The reconstituted solution is chemically stable for at least 8 hours at room temperature.1
The contents of the appropriate number of reconstituted vials should then be diluted in 500 mL of 0.9% sodium chloride injection.1 Strict aseptic technique should be observed when preparing romidepsin solutions.1 Reconstituted and diluted solutions should be inspected visually for particulate matter and discoloration whenever solution and container permit.1 Diluted romidepsin solution is compatible in polyvinyl chloride (PVC), ethylene vinyl acetate (EVA), and polyethylene (PE) infusion bags and glass bottles.1 The diluted solution is chemically stable for at least 24 hours when stored at room temperature; however, it should be administered as soon after dilution as possible.1
The recommended adult IV dosage of romidepsin for the treatment of cutaneous T-cell lymphoma (CTCL) in patients who have received at least 1 prior systemic therapy is 14 mg/m2 administered by IV infusion over 4 hours on days 1, 8, and 15 of a 28-day cycle.1, 4 Cycles should be repeated every 28 days as long as the patient derives benefit and tolerates therapy.1 In clinical trials, treatment generally was continued until evidence of disease progression was observed.1, 3, 4 Although therapy was continued for up to 83 months in clinical trials, the optimal duration of romidepsin treatment has not been clearly established.1, 3, 4
Dosage Modification for Non-hematologic Toxicity (Except Alopecia)
In patients experiencing grade 2 or 3 toxicity, romidepsin therapy should be delayed until toxicity returns to grade 1 (or less) or to baseline.1 Then therapy may be restarted at 14 mg/m2.1 If grade 3 toxicity recurs, therapy should be delayed until toxicity returns to grade 1 (or less) or baseline and the dosage should be permanently reduced to 10 mg/m2.1
In patients experiencing grade 4 toxicity, romidepsin therapy should be delayed until toxicity returns to grade 1 (or less) or to baseline and the dosage should be permanently reduced to 10 mg/m2.1
Romidepsin should be discontinued if grade 3 or 4 toxicities recur after dosage reduction.1
Dosage Modification for Hematologic Toxicity
In patients experiencing grade 3 or 4 neutropenia or thrombocytopenia, romidepsin treatment should be delayed until the specific cytopenia returns to an absolute neutrophil count (ANC) of 1500 cells/mm3 (or greater) and/or a platelet count of 75,000 cells/mm3 (or greater) or to baseline, then treatment may be restarted at 14 mg/m2.1
In patients experiencing grade 4 febrile neutropenia (a temperature of 38.5°C or higher) or thrombocytopenia requiring a platelet transfusion, romidepsin treatment should be delayed until the specific cytopenia returns to grade 1 (or less) or to baseline, and the dosage should be permanently reduced to 10 mg/m2.1
No special population dosage recommendations at this time.1
The manufacturer states that there are no known contraindications to the use of romidepsin.1
Patients with cutaneous T-cell lymphoma (CTCL) are at risk of hypomagnesemia.3, 9 Because of the risk of QT prolongation and other ECG abnormalities associated with hypomagnesemia and hypokalemia as well as with histone deacetylase inhibitor (including romidepsin) therapy, the manufacturer states that serum concentrations of potassium and magnesium should be within the normal range prior to administration of romidepsin.1, 3 Clinicians should also consider electrolyte and ECG monitoring at baseline and periodically during romidepsin therapy in patients at high risk for QT-interval prolongation (see ECG Changes under Cautions: Warnings/Precautions).1 In one clinical trial, electrolyte supplementation was provided prior to romidepsin therapy to achieve serum potassium and magnesium concentrations of greater than 4 and 0.85 mmol/L, respectively.3
Risk of thrombocytopenia, leukopenia (neutropenia and lymphopenia), and anemia.1 These hematologic parameters should be monitored during therapy and the dosage of romidepsin should be adjusted if necessary.1 (See Dosage Modification for Hematologic Toxicity under Dosage and Administration: Dosage.)
Treatment-related ECG changes, including T-wave and ST-segment changes, have been reported with romidepsin.1, 6, 7 The drug also may prolong the QT interval; however, further studies are needed.1, 3, 6, 7, 15 The clinical importance of these ECG changes is unknown.1 In cardiac monitoring studies in patients in a phase 2 study, transient ECG abnormalities (including T-wave flattening and ST-segment depression) were observed in more than half of the ECGs obtained post-treatment; however, these changes were not associated with myocardial damage or impaired cardiac function.6
The manufacturer recommends that appropriate cardiovascular monitoring precautions, such as monitoring electrolytes and ECGs at baseline and periodically during therapy, be considered in patients with congenital long QT syndrome, those with a history of substantial cardiovascular disease, and those taking antiarrhythmic drugs or other agents that can cause clinically important QT-interval prolongation.1 (See Electrolyte Monitoring under Cautions: Warnings/Precautions and also see Drug Interactions: Drugs that Prolong QT Interval.)
Fetal/Neonatal Morbidity and Mortality
May cause fetal harm;1 a study in rats did not expose pregnant animals to enough romidepsin to fully evaluate possible adverse outcomes.1 If used during pregnancy or if patient becomes pregnant while receiving the drug, apprise of potential fetal hazard.1
Interactions with Estrogen-containing Contraceptives
An in vitro binding assay demonstrated that romidepsin competes with β-estradiol for binding to estrogen receptors.1, 15 Therefore, the drug potentially may reduce the effectiveness of estrogen-containing contraceptives (e.g., oral contraceptives, patches, implants, IUDs), possibly resulting in pregnancy.1, 15
Category D.1 (See Users Guide and also see Fetal/Neonatal Morbidity and Mortality under Cautions: Warnings/Precautions.)
Not known whether romidepsin is distributed into human milk.1 Because of the potential for serious adverse reactions to romidepsin in nursing infants, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman.
Safety and efficacy not established in children younger than 18 years of age.1
In a limited number of pediatric patients from 2-21 years of age, the pharmacokinetics of romidepsin were found to be similar to those reported in adults in a phase I trial.14
Of the 167 patients with CTCL in clinical trials, 23% were older than 65 years of age.1 Although no overall differences in safety or efficacy were observed between geriatric and younger individuals, the possibility of greater sensitivity in some geriatric patients cannot be ruled out.1
Romidepsin has not been systematically studied in patients with hepatic impairment.1 Data from a population pharmacokinetic analysis indicate that mild hepatic impairment does not substantially affect the pharmacokinetics of the drug.1 Because the effects of moderate and severe hepatic impairment on the pharmacokinetics of romidepsin are unknown, the manufacturer recommends that the drug be used with caution in patients with moderate or severe hepatic impairment.1
Romidepsin has not been formally studied in patients with renal impairment.1 Data from a population pharmacokinetic analysis indicate that the pharmacokinetics of romidepsin are not substantially affected by mild (creatinine clearance of 50-80 mL/minute), moderate (creatinine clearance of 30-50 mL/minute), or severe renal impairment (creatinine clearance of less than 30 mL/minute). 1
The effect of end-stage renal disease on the pharmacokinetics of romidepsin has not been studied.1 The manufacturer therefore recommends that the drug be used with caution in patients with end-stage renal disease.1
Adverse events reported in 10% or more of patients receiving romidepsin include nausea,1, 3, 4 asthenia/fatigue,1, 3, 4 infections,1, 3 vomiting,1, 3, 4 anorexia,1, 3, 4 hypomagnesemia,1, 3, 4 diarrhea,1 pyrexia,1, 4 anemia,1, 3 thrombocytopenia,1, 3 dysgeusia,1, 3 constipation,1 neutropenia,1, 3 hypotension,1 pruritus,1, 4 hypokalemia,1 dermatitis/exfoliative dermatitis,1 hypocalcemia,1, 3 leukopenia, 1, 3 lymphopenia,1, 3 elevated transaminase concentrations,1, 3 hypoalbuminemia,1, 3 ECG changes (ST-T wave changes), 1 hyperglycemia,1, 3 hyponatremia,1 hypermagnesemia,1 hypophosphatemia,1 and hyperuricemia.1, 3
Romidepsin is metabolized principally by cytochrome P-450 (CYP) isoenzyme 3A4 and, to a lesser extent, by CYP3A5, CYP1A1, CYP2B6, and CYP2C19.1, 15, 22 The drug also is a substrate of P-glycoprotein.1, 10, 11, 15
Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes
Inhibitors of Cytochrome P-450 (CYP) 3A4 Isoenzyme
Pharmacokinetic interaction (increased plasma romidepsin concentrations) may occur during concomitant administration of potent CYP3A4 inhibitors (e.g., amprenavir [no longer commercially available in the US], atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole); concomitant use of romidepsin with these drugs should be avoided, if possible.1, 15 Caution should be used when administering romidepsin concomitantly with moderate CYP3A4 inhibitors.1
Pharmacokinetic interaction (decreased plasma romidepsin concentrations) may occur during concurrent administration of potent CYP3A4 inducers (e.g., carbamazepine, dexamethasone, phenobarbital, phenytoin, rifabutin, rifampin, rifapentine).1, 15 Concomitant use of romidepsin with such drugs should be avoided, if possible.1
Use of St. John's wort ( Hypericum perforatum ) also should be avoided during romidepsin therapy.1
Drugs Affecting P-glycoprotein Transport
Romidepsin is a substrate of P-glycoprotein.1 If romidepsin is concurrently administered with drugs that inhibit P-glycoprotein (e.g., erythromycin), increased plasma concentrations of romidepsin are likely and caution should be exercised.1, 15
Drugs that Prolong QT Interval
Potential pharmacologic interaction (additive effect on QT-interval prolongation); concomitant use of other drugs known to prolong the corrected QT (QTc) interval, including class IA antiarrhythmics (e.g., quinidine, procainamide), class III antiarrhythmics (e.g., amiodarone, sotalol), some antipsychotic agents (e.g., chlorpromazine, thioridazine, haloperidol, asenapine, olanzapine, pimozide, paliperidone, quetiapine, ziprasidone), some antibiotics (e.g., gatifloxacin, moxifloxacin), and tetrabenazine should be avoided.1, 17, 18, 19, 20 (See ECG Changes under Cautions: Warnings/Precautions.)
Certain type 3 serotonin (5-HT3) receptor antagonists used as antiemetic agents (e.g., dolasetron, ondansetron, palonosetron) are associated with QT-interval prolongation.6 If a 5-HT3 receptor antagonist is necessary in a patient receiving romidepsin, granisetron, which has not been associated with QT-interval prolongation, is recommended by some clinicians.6
Prolongation of prothrombin time (PT) and elevation in international normalized ratio (INR) have been reported in patients receiving romidepsin concomitantly with coumarin-derivative anticoagulants.1, 14 Although the interaction potential between romidepsin and coumarin-derivative anticoagulants has not been systematically evaluated, the manufacturer recommends careful monitoring of PT and INR during concurrent administration.1
Estrogen-containing Contraceptives
An in vitro binding assay demonstrated that romidepsin competes with β-estradiol for binding to estrogen receptors.1, 15 Therefore, the drug potentially may reduce the effectiveness of estrogen-containing contraceptives (e.g., birth control pills, patches, implants, IUDs), possibly resulting in pregnancy.1, 15
Romidepsin, a histone deacetylase (HDAC) inhibitor, is an antineoplastic agent.1, 10, 11 The drug is a bicyclic depsipeptide isolated from Chromobacterium violaceum .1, 10, 11 The precise mechanism of the antineoplastic effect of romidepsin has not been fully characterized.1 However, HDACs catalyze the removal of acetyl groups from acetylated lysine residues in histones, resulting in the modulation of gene expression.1, 11 HDACs also deacetylate non-histone proteins, such as transcription factors.1, 11, 13 In vitro, romidepsin restores the acetylation of histones, resulting in the accumulation of acetylated histones, and induces cell cycle arrest and apoptosis in some cancer cell lines with IC50 (concentration of the drug required to inhibit cell growth by 50%) values in the nanomolar range.1, 11
Romidepsin is extensively metabolized, principally by the cytochrome P-450 (CYP) isoenzyme CYP3A4 and, to a lesser extent, by CYP3A5, CYP1A1, CYP2B6, and CYP2C19.1, 15, 22 Following 4-hour IV administration on days 1, 8, and 15 of a 28-day cycle in patients with T-cell lymphomas, the terminal elimination half-life of romidepsin was approximately 3 hours.1, 4, 22 No accumulation of romidepsin was observed following repeated dosing.1 The exact route of elimination and the metabolic fate of romidepsin in humans are not known.23
Importance of instructing patients to read the patient information carefully before starting romidepsin therapy and before each treatment.1
Importance of instructing patients to report excessive nausea or vomiting.1
Risk of low blood cell counts.1 Importance of informing patient that regular blood tests will be performed during therapy and of notifying a clinician immediately if unusual bleeding or bruising, tiredness, pallor, shortness of breath, infection, fever, cough, flu-like symptoms, burning on urination, muscle aches, and/or worsening of skin problems occurs.1
Risk of ECG changes; importance of informing patient that an ECG test may be performed as needed to check for possible changes.1 Importance of notifying clinician immediately if abnormal heartbeat, chest pain, or shortness of breath occurs. 1
Importance of informing women of childbearing potential that romidepsin may reduce the effectiveness of estrogen-containing contraceptives (e.g., birth control pills, patches, implants, IUDs).1, 15
Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1 Advise pregnant women of risk to the fetus.1
Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription (e.g., anticoagulants, estrogen-containing contraceptives) and OTC drugs and herbal supplements, as well as any concomitant illnesses.1
Importance of informing patients of other important precautionary information.1 (See Cautions.)
Additional Information
Overview® (see Users Guide). For additional information on this drug until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity. For further information on the handling of antineoplastic agents, see the ASHP Guidelines on Handling Hazardous Drugs at [Web].
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
AHFS® Drug Information. © Copyright, 1959-2026, Selected Revisions December 1, 2010. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.
1. Celgene Corporation. Istodax® (romidepsin) for injection prescribing information. Summit, NJ; 2009 Nov.
2. Food and Drug Administration. Orphan designation pursuant to Section 526 of the Federal Food and Cosmetic Act as amended by the Orphan Drug Act. (P.L. 97-414). Rockville, MD. From FDA website; accessed 2010 Jul 1. [Web]
3. Piekarz RL, Frye R, Turner M et al. Phase II multi-institutional trial of the histone deacetylase inhibitor romidepsin as monotherapy for patients with cutaneous T-cell lymphoma. J Clin Oncol . 2009; 27:5410-7. [PubMedCentral][PubMed 19826128]
4. Kim Y, Whittaker S, Demierre MF et al. Clinically significant responses achieved with romidepsin in treatment-refractory cutaneous T-cell lymphoma: final results from a phase 2B international, multicenter, registration study. Blood. 2008; 112: Abstr. No. 263. Presented at the 50th Annual ASH Meeting. San Francisco, CA: 2008 Dec 6-9.
5. Kim Y, Demierre MF, Kim EJ et al. Clinically significant responses achieved with romidepsin in 37 patients with cutaneous T-cell lymphoma (CTCL) with blood involvement. Blood. 2009; 114: Abstr. No. 2683. Presented at the 51st Annual ASH Meeting. New Orleans, LA: 2009 Dec 5-8.
6. Piekarz RL, Frye AR, Wright JJ et al. Cardiac studies in patients treated with depsipeptide, FK228, in a phase II trial for T-cell lymphoma. Clin Cancer Res . 2006; 12:3762-73. [PubMed 16778104]
7. Cabell C, Bates S, Piekarz R et al. Systematic assessment of potential cardiac effects of the novel histone deacetylase (HDAC) inhibitor romidepsin. Blood. 2009; Abstr. No. 3709. Presented at the 51st Annual ASH Meeting. New Orleans, LA: 2009 Dec 5-8.
8. Food and Drug Administration, Center for Drug Evaluation and Research (CDER). Guidance for Industry. E14 Clinical Evaluation of QT/QTc interval prolongation and proarrhythmic potential for non-antiarrhythmic drugs. 2005 Oct. Accessed at FDA website. [Web]
9. Morgan M, Maloney D, Duvic M. Hypomagnesemia and hypocalcemia in mycosis fungoides: a retrospective case series. Leuk Lymphoma . 2002; 43:1297-302. [PubMed 12152999]
10. Lech-Maranda E, Robak E, Korycka A et al. Depsipeptide (FK228) as a novel histone deacetylase inhibitor: mechanism of action and anticancer activity. Mini Rev Med Chem . 2007; 7:1062-9. [PubMed 17979809]
11. Konstantinopoulos PA, Vandoros GP, Papavassiliou AG. FK228 (depsipeptide): a HDAC inhibitor with pleiotropic antitumor activities. Cancer Chemother Pharmacol . 2006; 58:711-5. [PubMed 16435156]
12. Blagosklonny MV, Robey R, Sackett DL et al. Histone deacetylase inhibitors all induce p21 but differentially cause tubulin acetylation, mitotic arrest, and cytotoxicity. Mol Cancer Ther . 2002; 1:937-41. [PubMed 12481415]
13. Lane AA, Chabner BA. Histone deacetylase inhibitors in cancer therapy. J Clin Oncol . 2009; 27:5459-68. [PubMed 19826124]
14. Fouladi M, Furman WL, Chin T et al. Phase I study of depsipeptide in pediatric patients with refractory solid tumors: a Children's Oncology Group report. J Clin Oncol . 2006; 24:3678-85. [PubMed 16877737]
15. Anon. Romidepsin (Istodax) for cutaneous T-cell lymphoma. Med Lett Drugs Ther . 2010; 52:42-3. [PubMed 20508581]
16. Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.. Zolinza® (vorinostat) capsules prescribing information. Whitehouse Station, NJ; 2010 Feb.
17. Schering-Plough. Saphris® (asenapine maleate) sublingual tablets prescribing information. Kenilworth, NJ; 2010 Jun.
18. Ortho-McNeil-Janssen Pharmaceuticals. Invega® (paliperidone) extended-release tablets prescribing information. Titusville, NJ; 2010 Jan.
19. Stöllberger C, Huber JO, Finsterer J. Antipsychotic drugs and QT prolongation. Int Clin Psychopharmacol . 2005; 20:243-51. [PubMed 16096514]
20. Lundbeck Inc. Xenazine® (tetrabenazine) tablets prescribing information. Deerfield, IL; 2009 Sep.
21. Klimek VM, Fircanis S, Maslak P et al. Tolerability, pharmacodynamics, and pharmacokinetic studies of depsipepide (Romidepsin) in patients with acute myelogenous leukemia or advanced myelodysplastic syndromes. Clin Cancer Res . 2008; 14:826-32. [PubMed 18245545]
22. Woo S, Gardner ER, Chen X et al. Population pharmacokinetics of romidepsin in patients with cutaneous T-cell lymphomas and relapsed peripheral T-cell lymphoma. Clin Cancer Res . 2009; 15:1496-503. [PubMedCentral][PubMed 19228751]
23. Celgene Corporation. Summit, NJ: Personal communication.