Istodax - Dear Health Care Professional Letter (Celgene Inc.)

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This is duplicated text from a letter from Celgene Inc.
Contact the company for a copy of any references, attachments or enclosures.

 

Authorization with conditions of PrISTODAX®, lyophilized powder for injection, 10 milligram/vial, for the treatment of patients with relapsed/refractory peripheral t-cell lymphoma (PTCL) who are not eligible for transplant and have received at least one prior systemic therapy.

September 26, 2013

Dear Health Care Professional(s),

Celgene Inc. is pleased to announce that Health Canada has issued a Notice of Compliance with Conditions under the Notice of Compliance with Conditions (NOC/c) policy for ISTODAX® (romidepsin), lyophilized powder for injection, 10 milligram/vial, for the treatment of patients with relapsed/refractory peripheral T-cell lymphoma (PTCL) who are not eligible for transplant and have received at least one prior systemic therapy.

Health Canada has issued a marketing authorization with conditions under the NOC/c policy for ISTODAX® to reflect the promising nature of the clinical data of ISTODAX® in patients with this serious disease and the need for a confirmatory study to verify the clinical benefit. Products authorized under Health Canada's NOC/c policy are of high quality and possess an acceptable safety profile based on the benefit/risk assessment. As part of its condition Celgene Inc. has undertaken to provide Health Canada with results from a blinded, controlled trial of previously untreated PTCL patients randomized to treatment with cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) or to romidepsin plus CHOP.

Authorization with conditions for ISTODAX® was based on the efficacy and safety results obtained from a phase II, open-label, multicentre, single arm, international clinical study in 131 patients with PTCL who had failed at least one prior therapy.

In the pivotal clinical trial, the complete response rate was 15% and overall response rate was 25%. Stable disease was reported as best response in 25% of patients. Median time to objective response was 1.8 months (approximately 2 cycles) for the 34 patients who achieved complete response, complete response unconfirmed or partial response and was 3.7 months (approximately 4 cycles) for patients with complete response. The median duration of response was 17 months.

Indications and Clinical Use

ISTODAX® (romidepsin) has been issued market authorization with conditions for the treatment of patients with relapsed/refractory peripheral T-cell lymphoma (PTCL) who are not eligible for transplant and have received at least one prior systemic therapy. Approval is based on response rates demonstrated in a single-arm trial. Improvement in overall survival has not been demonstrated with ISTODAX®.

Patients should be advised about the conditional market authorization for this indication.

Action and Clinical Pharmacology

Romidepsin is a histone deacetylase (HDAC) inhibitors. 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. The mechanism of the antineoplastic effect of romidepsin observed in nonclinical and clinical studies has not been fully characterized.

Serious Warning and Precautions

ISTODAX® should be administered under the supervision of a physician experienced with the use of chemotherapy and with treatment of peripheral T-cell lymphoma.

The following list is a summary of the most serious warnings and precautions. For further details see the ISTODAX® Product Monograph.

  • Pancytopenia
  • QT interval prolongation
  • Fatal infections
  • Tumor lysis syndrome
  • Potential fetal harm

ISTODAX® has not been studied in patients with hepatic or renal impairment.

Adverse Reactions

The most common adverse events reported were functional gastrointestinal disorders (82%), including reports of nausea with or without vomiting (64%), diarrhea (36%) and constipation (30%); hematological disorders (57%), including thrombocytopenia (41%), neutropenia (30%), and anemia (24%); asthenic conditions (55%), including reports of fatigue (41%) and asthenia (16%); infections (55%); pyrexia (35%); anorexia (28%); and dysgeusia (21%).

Sixty patients (46%) required at least 1 dose to be held and 14 (11%) required at least 1 dose reduction for the management of an adverse event. Doses were most commonly held for the management of thrombocytopenia (22 patients; 17%) and neutropenia (14 patients; 11%).

Adverse events leading to discontinuation were reported in 25 (19%) of the 131 patients. The most common events leading to discontinuation were thrombocytopenia and pneumonia (each 3 patients, 2%) and fatigue, sepsis, and dyspnea (each 2 patients, 2%).

Infections were the most common type of serious adverse event reported, with 25 patients (19%) experiencing a serious infection. Serious adverse reactions reported in = 2% of patients were pyrexia (7%), pneumonia, sepsis, vomiting (5%), cellulitis, deep vein thrombosis (4%), febrile neutropenia, abdominal pain (3%), chest pain, neutropenia, pulmonary embolism, dyspnea, and dehydration (2%).

Deaths within 30 days of the last dose occurred in 8 patients (6%), most frequently due to disease progression. There were 5 deaths due to infections in the setting of disease progression concurrent with multi-organ failure/sepsis, pneumonia, septic shock, candida sepsis, and sepsis/cardiogenic shock.

Drug Interactions

Romidepsin is metabolized by CYP3A4. Potential interactions may occur with drugs/foods/herbs that are inhibitors or inducers of this enzyme.

Strong CYP3A4 inhibitors increase concentrations of romidepsin. In a pharmacokinetic drug interaction trial the strong CYP3A4 inhibitor ketoconazole increased romidepsin (AUC8) by approximately 25%. Monitor for toxicity related to increased romidepsin exposure when romidepsin is co-administered with strong CYP3A4 inhibitors.

Avoid co-administration of ISTODAX® 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 AUC8 and Cmax, respectively. Typically, co-administration of CYP3A4 inducers decrease concentrations of drugs metabolized by CYP3A4. Avoid the concomitant administration of ISTODAX® with strong CYP3A4 inducers.

Caution should be observed if ISTODAX® is administered with drugs that cause QTc prolongation. Avoid when possible the concomitant use of drugs that can disrupt electrolyte levels during treatment with ISTODAX®.

For further information on drug interactions see the ISTODAX® Product Monograph.

Dosage and Administration

The recommended dose 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 therapy.

For information on dose adjustments, see the ISTODAX® Product Monograph.

For the complete prescribing information and information available for the patients/caregivers please consult the ISTODAX® Product Monograph. The Product Monograph can be found at  www.celgene.com/Canada  or by request by contacting Celgene Inc at 1-888-712-2353.

Celgene Inc.
6755 Mississauga Rd, Suite 600
Mississauga, Ontario, L5N 7Y2    

Reporting Suspected Side Effects
Canada Vigilance Program
Marketed Health Products Directorate
Health Products and Food Branch
Health Canada
Tunney's Pasture
Address Locator: 0701C
Ottawa, Ontario
K1A 0K9
Telephone: 613-957-0337 or Fax: 613-957-0335
To report an Adverse Reaction, consumers and health professionals may call toll free:
Telephone: 1-866-234-2345
Fax: 1-866-678-6789
Email: CanadaVigilance@hc-sc.gc.ca

For other inquiries related to this communication, please contact Health Canada at:
Bureau of Metabolism, Oncology and Reproductive Sciences
Therapeutic Products Directorate
Email: BMORS_Enquiries@hc-sc.gc.ca
Telephone: 613-941-3171
Fax: 613-941-1365   

Should you have any questions or require further information regarding ISTODAX®, please contact Celgene Medical Information at 1-888-712-2353.

Dianne Azzarello
Senior Director, Pharmacovigilance & Regulatory Affairs

® ISTODAX is a registered trademark of Celgene Corporation

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