DRUG NAME: Romidepsin

Transcription

1 DRUG NAME: Romidepsin SYNONYM(S): COMMON TRADE NAME(S): ISTODAX CLASSIFICATION: miscellaneous Special pediatric considerations are noted when applicable, otherwise adult provisions apply. MECHANISM OF ACTION: Romidepsin is a bicyclic peptide which acts as a potent and selective inhibitor of class I and II histone deacetylase (HDAC). HDAC inhibitors induce the acetylation of histones and other proteins, resulting in chromatin modification, tumour suppressor gene transcription, growth inhibition, cell cycle arrest, and apoptosis. Romidepsin is structurally unique from other HDAC inhibitors and may regulate distinct genes which may in turn lead to differences in clinical efficacy. In lymphoma cells, romidepsin has the ability to overcome the resistant effects of the prosurvival protein Bcl USES: Primary uses: Lymphoma, peripheral T-cell Lymphoma, cutaneous T-cell *Health Canada approved indication Other uses: SPECIAL PRECAUTIONS: Caution: Transient ECG changes (including T-wave and ST-segment changes) have been reported, but are not associated with functional cardiovascular changes. Clinical significance is unknown. 4 A 5 msec mean increase in QTc interval has also been reported. Use cautiously in patients with history of long QT interval, cardiovascular disease, or other risk factors for QT prolongation and correct hypokalemia and hypomagnesemia prior to and during romidepsin treatment. If possible, avoid concurrent therapy with medications which prolong QT interval and/ or strong inhibitors of CYP 3A4 which may increase exposure to romidepsin. 4,5 Tumour lysis syndrome has been reported; closely monitor patients with advanced stage disease and/ or high tumour burden. 5 S: The table includes adverse events that presented during drug treatment but may not necessarily have a causal relationship with the drug. Because clinical trials are conducted under very specific conditions, the adverse event rates observed may not reflect the rates observed in clinical practice. Adverse events are generally included if they were reported in more than 1% of patients in the product monograph or pivotal trials. When placebo-controlled trials are available, adverse events will generally be included if the incidence is >5% higher in the treatment group. blood and lymphatic system/ febrile anemia (10-37%, severe 2-6%) febrile neutropenia (3%) BC Cancer Agency Cancer Drug Manual Page 1 of 5 Romidepsin (interim monograph)

2 neutropenia cardiac gastrointestinal general disorders and administration site conditions infections and infestations investigations metabolism and nutrition leukopenia (12-30%, severe 6-12%) neutropenia (29%, severe 18%); may require dose reduction 6 thrombocytopenia (11-40%, severe 6-23%); characteristic pattern of reduction and recovery prior to next cycle 1 ; may require dose reduction 6 supraventricular arrhythmia (2%, severe 1%) tachycardia (5%) ventricular arrhythmia (3%) emetogenic potential: low 7 abdominal pain (6%) constipation (7-15%) diarrhea (8-23%, severe 1-2%) nausea (52-56%, severe 2-3%) stomatitis (7%) vomiting (19-34%, severe 1-4%) extravasation hazard: none 8-10 chills (5%) fatigue/asthenia (41-52%, severe 5-7%) peripheral edema (2%) pyrexia (17%, severe 4%) infections, all types (18%, severe 6%); can occur up to 30 days after treatment 5 pneumonia (6%) sepsis (5%) upper respiratory tract (8%) urinary tract (7%) T-wave or ST changes (6-78%); not associated with functional cardiovascular changes or symptoms QTc prolongation (3-9%) weight loss (8%) anorexia (20-26%, severe 1-2%) AST/ ALT elevations (8-12%, severe 3%) hyperbilirubinemia (3%) hyperglycemia (18%) hypermagnesemia (7%) hyperuricemia (15%, severe 4%) hypoalbuminemia (20%) hypocalcemia (42%, severe 1%) hypoglycemia (5%) BC Cancer Agency Cancer Drug Manual Page 2 of 5 Romidepsin (interim monograph)

3 hypokalemia (5-9%, severe 1-2%) hypomagnesemia (15%) hyponatremia (8%) hypophosphatemia (8%, severe 4%) tumour lysis syndrome (1-2%, severe 2%) nervous system dysgeusia, ageusia (11-21%) headache (7-14%) respiratory, thoracic and mediastinal cough (2%) dyspnea (5%, severe 1%) vascular hypotension (3%) Adapted from standard reference 2,3,11 unless specified otherwise. INTERACTIONS: AGENT EFFECT MECHANISM MANAGEMENT ketoconazole 9 rifampin 9 warfarin 9 increased romidepsin AUC by 25% increased romidepsin AUC by 80% and Cmax by 60% prolongation of PT and elevation of INR CYP 3A4 inhibition by ketoconazole possibly by inhibition of an undetermined hepatic uptake process by rifampin not formally studied monitor for increased toxicity from romidepsin; may require dose modification of romidepsin avoid concurrent therapy monitor PT and INR and adjust warfarin dose as needed Romidepsin is a substrate of CYP 3A4. Avoid co-administration with strong CYP 3A4 inhibitors or inducers. 1,6 Romidepsin is a substrate of p-glycoprotein. Clinical significance is unknown. 1,9 Romidepsin binds to estrogen receptors and may reduce the effectiveness of estrogen-containing contraceptives. 1 Romidepsin causes a mean 5 msec increase in the QTc interval, which is considered clinically insignificant; however coadministration with other QT prolonging drugs should be avoided if possible. 1,4 SUPPLY AND STORAGE: Injection: Celgene Corporation supplies romidepsin as 10 mg single-use vials of sterile lyophilized powder. Vials contain povidone as a bulking agent. Use supplied diluent (propylene glycol and dehydrated alcohol) for reconstitution. Store at room temperature. 12 For basic information on the current brand used at the BC Cancer Agency, see Chemotherapy Preparation and Stability Chart in Appendix. BC Cancer Agency Cancer Drug Manual Page 3 of 5 Romidepsin (interim monograph)

4 SOLUTION PREPARATION AND COMPATIBILITY: For basic information on the current brand used at the BC Cancer Agency, see Chemotherapy Preparation and Stability Chart in Appendix. Additional information: Reconstituted solution will be slightly viscous. The full 2 ml volume may not be recovered from the drug vial. 10 Compatibility: consult detailed reference PARENTERAL ADMINISTRATION: BCCA administration guideline noted in bold, italics Subcutaneous Intramuscular Direct intravenous Intermittent infusion over 4 hours 2,3,6,11 Continuous infusion Intraperitoneal Intrapleural Intrathecal Intra-arterial Intravesical DOSAGE GUIDELINES: Refer to protocol by which patient is being treated. Numerous dosing schedules exist and depend on disease, response and concomitant therapy. Guidelines for dosing also include consideration of absolute neutrophil count (ANC). Dosage may be reduced, delayed or discontinued in patients with bone marrow depression due to cytotoxic/radiation therapy or with other toxicities. Adults: Cycle Length: Intravenous: 4 weeks 2,3,5,6,11 : BCCA usual dose noted in bold, italics 14 mg/m 2 (range mg/m 2 ) IV for one dose on days 1, 8, and 15 (total dose per cycle 42 mg/m 2 [range mg/m 2 ]) REFERENCES: 1. McGraw AL. Romidepsin for the treatment of T-cell lymphomas. Am J Health-Syst Pharm 2013;70(13): Coiffier B, Pro B, Prince HM, et al. Results from a pivotal, open-label, phase II study of romidepsin in relapsed or refractory peripheral T-cell lymphoma after prior systemic therapy. J of Clin Oncol 2012;30(6): Whittaker SJ, Demierre M, Kim EJ, et al. Final results from a multicenter, international, pivotal study of romidepsin in refractory cutaneous T-cell lymphoma. J Clin Oncol 2010;28(29): Celgene Inc Medical Information. Cardiac adverse reactions and ISTODAX (romidepsin) for Injection. Mississauga, Ontario; v2.1can; 8 February Celgene Inc Medical Information. Dosing, dose modification, monitoring and ISTODAX (romidepsin) for Injection. Mississauga, Ontario; v3.2can; 13 September Celgene Inc Medical Information. Peripheral T-cell lymphoma and ISTODAX (romidepsin) for Injection. Mississauga, Ontario; v5.1can; 22 February BC Cancer Agency Cancer Drug Manual Page 4 of 5 Romidepsin (interim monograph)

5 7. BC Cancer Agency. (SCNAUSEA) Guidelines for Prevention and Treatment of Chemotherapy-induced Nausea and Vomiting in Adults. Vancouver, British Columbia: BC Cancer Agency; 1 Mar BC Cancer Agency Provincial Systemic Therapy Program. Provincial Systemic Therapy Program Policy III-20: Prevention and Management of Extravasation of Chemotherapy. Vancouver, British Columbia: BC Cancer Agency; 1 June Celgene Corporation. ISTODAX prescribing information. Summit, New Jersey USA; June Celgene Inc Medical Information. Preparation and administration of ISTODAX (romidepsin) for Injection. Mississauga, Ontario; v5.2can; 13 September Piekarz RL, Frye R, Turner M, et al. Phase II multi-iinstitutional trial of the histone deacetylase inhibitor romidepsin as monotherapy for patients with cutaneous T-cell lymphoma. J Clin Oncol 2009;27(32): Celgene Inc Medical Information. Compatibility and stability of ISTODAX (romidepsin) for Injection with intravenous solutions. Mississauga, Ontario; v2.2can; 13 September BC Cancer Agency Cancer Drug Manual Page 5 of 5 Romidepsin (interim monograph)