Dear Health Care Professional Letter: ^PrGLEEVEC^®

2006-05-17

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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 approves 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 Novartis Pharmaceuticals Canada Inc. Contact the company for a copy of any references, attachments or enclosures.

May 17, 2007

Dear Health Care Professional:

Novartis Pharmaceuticals Canada Inc. is pleased to announce that Health Canada has granted a Notice of Compliance with Conditions (NOC/c) for GLEEVEC^® (imatinib mesylate) 100 mg and 400 mg tablets, an oral therapy indicated for use in treatment of pediatric patients with newly diagnosed, Philadelphia-chromosome-positive, chronic myeloid leukemia in chronic phase.

Health Canada has issued a marketing authorization with conditions under the Notice of Compliance with Conditions policy for GLEEVEC^® (imatinib mesylate) 100 mg and 400 mg tablets based on the promising nature of the clinical efficacy and safety of GLEEVEC^® in pediatric patients with this serious disease, and the need for further follow up to verify the clinical benefit.

This NOC/c is based on hematologic and cytogenetic response rates from Study 2108, an open-label, multicenter, single arm Phase II Study, conducted in 51 newly-diagnosed and untreated pediatric CML patients in chronic phase. Study 2108 is a bridging study to a prior adult trial for the same indication. There are no controlled trials that demonstrate clinical benefit in pediatric patients.

Patients were treated with GLEEVEC^® 340 mg/m2/day on a continuous daily dosing schedule. GLEEVEC^® treatment induced a Complete Hematologic Response (CHR) of 78% after 8 weeks of therapy. Those patients for whom cytogenetics was evaluable (33/51) developed a complete cytogenetic response (CCyR) of 65% which is comparable to the results observed in adults. Additionally, partial cytogenetic response (PCyR) was observed in 16% adding up to a Major Cytogenetic Response (MCyR) rate of 81%. The majority of patients who achieved a CCyR developed that response between months 3 and 10 with a median time to response based on the Kaplan-Meier estimate of 5.6 months.

Indications and Clinical Use

GLEEVEC^® (imatinib mesylate) is indicated for use in the treatment of pediatric patients with newlydiagnosed, Philadelphia chromosome-positive, chronic myeloid leukemia (CML) in chronic phase.

Conditional approval was based on hematologic and cytogenetic response rates (surrogate endpoints) that are reasonably likely to predict clinical benefit. There are no controlled trials that demonstrate clinical benefit in pediatric patients.

Patients should be advised about the conditional nature of the market authorization for GLEEVEC^® in this indication.

Other Uses of GLEEVEC^®

GLEEVEC^® has been issued marketing authorization with conditions, pending the results of studies to verify its clinical benefit for the following indications:

1. The treatment of adult patients with newly-diagnosed, Philadelphia chromosome-positive, chronic myeloid leukemia (CML) in chronic phase.
2. The treatment of adult patients with unresectable and/or metastatic malignant gastrointestinal
   stromal tumours (GIST).

GLEEVEC^®has been issued non-conditional approval for the following indications:

1. The treatment of adult patients with Philadelphia chromosome-positive CML in blast crisis, accelerated phase or chronic phase (after failure of interferon-alpha therapy).
2. The use as a single agent for induction phase therapy in adult patients with newly-diagnosed
   Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL).
3. The treatment of adult patients with relapsed or refractory Ph+ ALL as monotherapy.

Warnings and Precautions

Based on the GLEEVEC^® integrated safety database, the following is a summary of the most serious warnings and precautions. For a complete list and further details refer to the GLEEVEC^® Product Monograph.

• Severe congestive heart failure (CHF) and reduction of left ventricular ejection fraction (LVEF)
  have been observed.
• Severe hemorrhages may occur.
• Fluid retention may occur.

Pediatrics:

There is no experience with the use of GLEEVEC^® in pediatric patients with CML under 2 years of age. There is very limited experience with the use of GLEEVEC^® in children under 3 years of age in other indications.

Hematologic Toxicity:

In pediatric CML patients the most frequent toxicities observed were Grade 3 or 4 cytopenias involving neutropenia, thrombocytopenia and anemia. These generally occur within the first several months of therapy.

Adverse Reactions

GLEEVEC^® was generally well tolerated with chronic oral daily dosing in patients with CML including pediatric patients.

The overall safety profile of GLEEVEC^® treatment in 93 pediatric patients was similar to that observed in studies with adult patients. Nausea, vomiting were the most commonly reported individual adverse events with an incidence similar to that seen in adult patients. Although most patients experienced adverse events at some time during the studies, the incidence of Grade 3/4 adverse events was low.

Significantly higher frequencies of hypocalcemia (23.5 vs. 1.1%), hyperglycemia (19.6 vs. 2.9%), hypoglycaemia (21.6 vs. 1.5%), hypophosphatemia (19.6 vs. 3.3%) hypoalbuminemia (13.7 vs. 0.2%) and hyponatremia (13.7 vs. 0.2%) were observed in pediatric patients compared to adult patients.

Drug Interactions

CYP3A4 inhibitors (e.g. ketoconazole, erythromycin, clarithromycin, itraconazole, grapefruit juice), when used concomitantly with GLEEVEC^®, may increase the serum concentration of imatinib. CYP3A4 inducers (e.g. dexamethasone, phenytoin, carbamazepine, rifampicin, Phenobarbital or St. John's Wort), when used concomitantly with GLEEVEC^®, may significantly reduce exposure to imatinib. In patients in whom rifampin or other CYP3A4 inducers are indicated, alternate therapeutic agents with less enzyme induction potential should be considered.

Certain drugs may have their plasma concentration altered by GLEEVEC^®. For a further information on drug interaction details refer to the GLEEVEC^® Product Monograph.

Dosage and Administration

The recommended dosage of GLEEVEC^® for pediatric patients with newly diagnosed Ph+ CML is 340 mg/m2/day (rounded to the nearest 100 mg, i.e. not to exceed 600 mg), administered orally.

Dosing Considerations

The prescribed dose should be administered during a meal and with a large glass of water.

Dosing in pediatric patients should be on the basis of body surface area (mg/m²). Treatment can be given as a once daily dose or alternatively the daily dose may be split into two administrations - one in the morning and one in the evening.

For patients unable to swallow the film-coated tablets, the tablets may be dispersed in a glass of water or apple juice. The required number of tablets should be placed in the appropriate volume of beverage (approximately 50 mL for a 100 mg tablet, and 200 mL for a 400 mg tablet) and stirred with a spoon.
The suspension should be administered immediately after complete disintegration of the tablet(s). Traces of the disintegrated tablet left in the glass after drinking should also be consumed. Treatment should be continued as long as the patient continues to benefit.

Should you have medical enquiries regarding GLEEVEC^®, kindly contact our Medical Information Department at 1-800-363-8883.

Original signed by

Pier-Giorgio Fontana, PhD
Vice-President
Regulatory Affairs

Jean-Marie Leclerc, M.D. FRCP(C)
Chief Scientific Officer and
Senior Vice-President Clinical
and Regulatory Affairs

^PrGLEEVEC^® is a registered trademark.