Dear Health Care Professional Letter - Authorization with conditions for Bosulif

March 07, 2014

Health Canada posts safety alerts, public health advisories, press releases and other notices from industry as a service to health professionals, consumers, and other interested parties. Although Health Canada authorizes therapeutic products, Health Canada does not endorse either the product or the company. Any questions regarding product information should be discussed with your health professional.

This is duplicated text of a letter from Pfizer Canada Inc.

Contact the company for a copy of any references, attachments or enclosures.

Authorization with conditions for Bosulif

Dear Health Care Professional(s),

Pfizer Canada Inc. is pleased to announce that Health Canada has issued a Notice of Compliance with Conditions (NOC/C) under the NOC/c policy for BOSULIF (bosutinib) 100 milligram (mg) and 500 mg tablets for the treatment of chronic, accelerated, or blast phase Philadelphia chromosome-positive (Ph+) chronic myelogenous leukemia (CML) in adult patients with resistance or intolerance to prior TKI therapy, and for whom subsequent treatment with imatinib, nilotinib and dasatinib is not clinically appropriate.

Health Canada has issued a marketing authorization with conditions under the NOC/c policy for BOSULIF to reflect the promising nature of the clinical data of BOSULIF in CML patients who do not respond to or who are intolerant of currently marketed TKIs in Canada, and in whom BOSULIF is clinically appropriate, and the need for further follow-up to verify the clinical benefit. BOSULIF possesses an acceptable safety profile based on the benefit-risk assessment. As part of its condition, Pfizer Canada Inc. has undertaken to provide Health Canada with the following:

  • final clinical study report for ongoing Study 3160A4-200-WW, a Phase 1/2, open-label, single-arm, safety and efficacy study of bosutinib with continuous daily dosing in previously treated patients with Ph+ CML, and
  • analysis of safety data [including electrocardiograph (ECG) and multigated acquisition scan (MUGA) analyses] from Study 3160A4-3000-WW, a Phase 3, randomized, open-label study of bosutinib versus imatinib in newly diagnosed Ph+ chronic phase (CP) CML patients.

Indications and Clinical Use

BOSULIF (bosutinib) has been issued marketing authorization with conditions for the treatment of chronic, accelerated, or blast phase Philadelphia chromosome-positive (Ph+) CML in adult patients with resistance or intolerance to prior TKI therapy, and for whom subsequent treatment with imatinib, nilotinib and dasatinib is not clinically appropriate.

Marketing authorization with conditions is based on cytogenetic and hematologic response rates observed in a single-arm, Phase 1/2 study. Overall survival benefit has not been demonstrated.

Patients should be advised about the conditional nature of the marketing authorization for this indication.

Action and Clinical Pharmacology

BOSULIF belongs to a pharmacologic class of drugs known as tyrosine kinase inhibitors. BOSULIF inhibits the activity of the oncogenic Bcr-Abl kinase that promotes CML, and Src-family kinases such as Src, Lyn and Hck, which participate in Bcr-Abl signaling. Modeling studies indicate that BOSULIF binds the kinase domain of Bcr-Abl. BOSULIF also inhibits other kinases such as EPH, TEC and STE20 kinases. BOSULIF minimally inhibits platelet derived growth factor (PDGF) receptor and c-Kit (protein-tyrosine kinase Kit).

BOSULIF exhibits potent anti-leukemic activity in imatinib-sensitive and resistant BCR-ABL-dependent leukemia cells. In in vitro studies, BOSULIF inhibits proliferation and survival of established CML cell lines, Ph+ ALL cell lines, and patient-derived primary primitive CML cells. BOSULIF inhibited 16 of 18 imatinib-resistant forms of Bcr-Abl expressed in murine myeloid cell lines, except T315I. Bosutinib treatment reduced the size of CML tumors growing in nude mice and inhibited growth of murine myeloid tumors expressing imatinib-resistant forms of Bcr-Abl. BOSULIF also inhibits receptor tyrosine kinases c-Fms, EphA and B receptors, Trk-family kinases, Axl-family kinases, Tec-family kinases, some members of the ErbB-family, the non-receptor tyrosine kinase Csk, serine/threonine kinases of the Ste20-family and two calmodulin-dependent protein kinases.

Contraindications

BOSULIF is not to be used in patients who are hypersensitive to this drug or to any ingredient in the formulation or component of the container. Cases of Grade 3 or 4 drug hypersensitivity were reported in patients treated with BOSULIF. Two cases (less than 0.2%) of Grade 4 drug-related anaphylactic shock were reported in patients treated with BOSULIF. For a complete listing of ingredients, please refer to the BOSULIF Product Monograph, Dosage Forms, Composition and Packaging section.

BOSULIF is not to be used:

  • by patients with a known history of long QT syndrome or with a persistent QT interval of >480 milliseconds (ms) (see Adverse Reactions);
  • in patients with uncorrected hypokalemia or hypomagnesemia (see Adverse Reactions);
  • by hepatically impaired patients. Higher risk of QT prolongation has been seen in patients with declining hepatic function (see Action and Clinical Pharmacology, Warnings and Precautions, Special Populations, and Other Considerations).

Serious Warnings and Precautions

The following list is a summary of the most serious warnings and precautions. For a complete list and further details for those on this list, please refer to the BOSULIF Product Monograph.

  • Drug interactions with inhibitors or inducers of CYP3A4. The concomitant use of BOSULIF with potent or moderate CYP3A4 inhibitors or inducers should be avoided (see Warnings and Precautions, Drug-Drug Interactions and Dosage and Administration)
  • Gastrointestinal toxicity, including diarrhea (see Warnings and Precautions and Adverse Reactions)
  • Hepatic toxicity, including Hy's Law case (see Warnings and Precautions and Adverse Reactions)
  • Cardiac failure, including fatal outcomes (see Warnings and Precautions and Adverse Reactions)
  • Fluid retention (including pleural effusion, pulmonary edema and pericardial effusion (see Warnings and Precautions and Adverse Reactions)
  • Hemorrhage (see Warnings and Precautions and Adverse Reactions)
  • QT interval prolongation (see Warnings and Precautions and Adverse Reactions)

Other important warnings and precautions are as follows:

  • Secondary malignancies have been reported in humans in clinical trials with BOSULIF (see Adverse Reactions)
  • Cardiac-related toxicity (including atrial fibrillation, tachycardia, coronary artery disease/stenosis)
  • ECG results for Phase 1/2 and Phase 3 safety population
  • Hepatically impaired patients are at higher risk of developing QT interval prolongation
  • Myelosuppression
  • Hemorrhage
  • Pancreatic: Elevated serum lipase/amylase and pancreatitis
  • Infections
  • Immunotoxicity
  • Hypersensitivity
  • Sexual function/reproduction (male and female)
  • Tumor lysis syndrome
  • Bone density/musculoskeletal
  • Respiratory

BOSULIF should only be prescribed by a qualified healthcare professional who is experienced in the use of antineoplastic therapy and in the treatment of chronic myeloid leukemia.

Adverse Reactions

Treatment-related adverse drug reactions of any toxicity grade reported at a Very Common frequency (³10%) in patientswere thrombocytopenia , neutropenia, anemia, diarrhea, nausea, vomiting, abdominal pain, abdominal pain upper, fatigue, alanine-aminotransferase increased, aspartate-aminotransferase increased, headache, rash and pruritus.

For further details, please refer to the BOSULIF Product Monograph.

Special Populations

  • Renal impairment
  • Hepatic impairment
  • Sensitivity/Intolerance
  • Coagulation dysfunction/platelet disorders
  • Pancreatic (serum lipase/pancreatitis)

Drug Interactions

In vitro studies indicated that Bosutinib is metabolized by CYP3A4. No metabolism of bosutinib was observed with CYPs 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, or 3A5. Flavin-containing monooxygenase enzymes (FMO1, FMO3, and FMO5) are capable of metabolizing bosutinib to its N-oxide metabolite. Potent and moderate CYP3A inhibitors increase BOSULIF exposure. Avoid concomitant use of these inhibitors. Potent and moderate CYP3A inducers decrease BOSULIF exposure. Avoid concomitant use of these inducers.

Caution should be used when administering BOSULIF concomitantly with proton pump inhibitors (PPIs). Short-acting antacids should be considered as an alternative to PPIs and administration times of BOSULIF and antacids should be separated [for example (e.g.) take BOSULIF in the morning, and antacids in the evening] whenever possible.

Concomitant use of BOSULIF with another QT/QTc-prolonging drug is discouraged. The BOSULIF Product Monograph includes lists of drugs that have been associated with QT/QTc interval prolongation and/or torsade de pointes, and drugs that can disrupt electrolyte levels. These lists are not comprehensive. Current information sources should be consulted for newly approved drugs that prolong the QT/QTc interval, inhibit metabolizing enzymes and/or transporters, or cause electrolyte disturbances, as well as for older drugs for which these effects have recently been established.

For further details, please refer to the BOSULIF Product Monograph.

Dosage and Administration

The recommended dose and schedule of BOSULIF is 500 mg orally once daily, swallowed whole, with a meal. Do not take with grapefruit products and star fruit, pomegranate, Seville oranges and other similar fruits that are known to inhibit CYP3A4. Tablets should not be crushed or cut, and should not be dissolved in a liquid (see Drug-Drug Interactions).

In the Phase 1/2 clinical trial, treatment with BOSULIF continued until disease progression or until it was no longer tolerated by the patient.

In the Phase 1/2 clinical trial, dose escalation to 600 mg once daily with food was allowed only in patients who failed to reach complete hematological response (CHR) by week 8 or a complete cytogenetic response (CCyR) by week 12, at the recommended starting dosage, and who did not have Grade 3 or higher adverse reactions.Dose escalations are expected to result in greater toxicity.

For the complete prescribing information and information available for the patients/caregivers, please consult the BOSULIF Product Monograph. The Product Monograph can be found at: www.pfizer.ca or requested by contacting Pfizer Canada at 1-800-463-6001.

Access to BOSULIF

Pfizer will introduce the FIRST RESOURCE Program shortly, which is designed to provide reimbursement assistance to patients prescribed BOSULIF for a limited time for the indication in the Product Monograph. This will be a service offered at no cost to the patient and will be fully confidential. For more information please call toll free 1-888-96-FIRST (1-888-963-4778).

Should you have medical enquiries regarding BOSULIF, please contact our Medical Information Department at 1-800-463-6001.

Original Signed by

Vratislav Hadrava, MD, PhD
Vice-President and Medical Director

*TM Pfizer Inc.
Pfizer Canada Inc., Licensee

Pfizer Canada Inc.
17300 Trans Canada Highway
Kirkland, Quebec
H9J 2M5

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

The Adverse Reaction Reporting Form and the Adverse Reaction Guidelines can be found on the Health Canada website or in  The Canadian Compendium of Pharmaceuticals and Specialties.

For other inquiries related to this communication, please contact Health Canada at:
Bureau of Metabolism, Oncology and Reproductive Sciences (BMORS) 
E-mail: bmors_enquiries@hc-sc.gc.ca
Telephone: 613-941-3171
Fax: 613-941-1365

Report a problem or mistake on this page
Please select all that apply:

Thank you for your help!

You will not receive a reply. For enquiries, contact us.

Date modified: