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Conditional Approval Of Gleevec (Imatinib) - Novartis Pharma Canada Inc.

Date: 2001-09-01

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CONDITIONAL APPROVAL OF GLEEVEC

September 2001

Dear Health Care Professional(s),

Novartis Pharmaceuticals Canada Inc. is pleased to announce that Health Canada has granted a Notice of Compliance with Conditions (NOC-C) to Gleevec^TM (imatinib mesylate formerly known as STI571), an oral therapy for the treatment of patients with chronic myeloid leukemia (CML) in blast crisis, accelerated phase or in chronic phase after failure of interferon-alpha therapy.

Health Canada has issued a conditional marketing authorization under the Notice of Compliance with Conditions policy to reflect the promising nature of the clinical evidence and the need for confirmatory studies to verify the clinical benefit. Approval was based on hematologic and cytogenetic response rates (surrogate endpoints) that are reasonably likely to predict clinical benefit. Three separate single arm studies in approximately 1,000 patients were conducted. The long-term safety data are not available and drug interaction data are limited.

Gleevec should only be administered under the supervision of a physician experienced with the use of chemotherapy and with treatment of CML.

Patients should be advised about the conditional nature of the market authorization for Gleevec.

Gleevec is the first cancer treatment to be developed with rational drug design, based on an understanding of how cancer cells work. The drug addresses the genetic malfunction that is present in CML patients when pieces of two different chromosomes break off and reattach on the opposite chromosome forming the so-called "Philadelphia" chromosome. This chromosome translocation leads to a blood cell enzyme being "turned on" all the time. As a result, potentially life-threatening levels of both mature and immature white blood cells occur in the bone marrow and the blood. Gleevec, a specific inhibitor of the translocation-created enzyme, works by blocking the rapid growth of white blood cells.

The recommended dosage of Gleevec is 400 mg/day for patients in chronic phase CML and 600 mg/day for patients in accelerated phase or blast crisis. The prescribed dose should be administered orally, once daily with a meal and a large glass of water.

Side effects frequently reported in clinical trials include nausea, vomiting, edema (fluid retention), muscle cramps, skin rash, diarrhea, heartburn, and headache. Severe fluid retention occurred in up to two percent of patients. Patients should be weighed and monitored regularly for signs and symptoms of fluid retention. An unexpected rapid weight gain should be carefully investigated and appropriate treatment provided.

Gleevec is mainly metabolized by the CYP3A4 isoenzyme system and may interact with other drugs. In some cases, Gleevec increases blood levels of these drugs which may increase side effects. In other cases, Gleevec decreases blood levels of the drugs which may decrease effectiveness of treatment. Similarly, Gleevec blood levels may be increased or decreased by other drugs. This may increase Gleevec side effects or decrease effectiveness. Because of these potential drug-drug interactions the patient must discuss all of their medications with their doctor or pharmacist. Liver function should be monitored before initiation of treatment and monthly or as clinically needed.

Gleevec is available in capsules of 100 mg and is supplied in cartons containing 10 blister strips of 12 capsules.

Should you have medical enquiries regarding Gleevec, please contact our Medical Information department at 1-800-363-8883.

original signed by
Pier-Giorgio Fontana, PhD
Vice-President, Drug Regulatory Affairs

Beat Sümegi, MD
Vice-President, Medical

Product Monograph available to physicians and pharmacists upon request
Gleevec is a trademark of Novartis Pharmaceuticals Canada Inc.

CONDITIONAL APPROVAL OF GLEEVEC FACT SHEET

Conditional approval of Gleevec

What is Gleevec^TM?
Gleevec is a new type of cancer drug - it has been specifically developed to fight cancer by turning off an enzyme that causes cells to become cancerous and multiply.

Health Canada has issued a conditional marketing authorization under a policy called the "Notice of Compliance with Conditions". This authorization reflects the promising nature of the clinical evidence which must be confirmed and extended with further studies. Approval was based on hematologic (a measure of the number of white blood cells) and cytogenetic (a measure of the percentage of leukemic cells) response rates. Long-term safety data are not available and drug interaction data are limited.

What is Gleevec used for?
Gleevec is approved to treat a rare cancer called Chronic Myeloid Leukemia (CML). This year 3,500 Canadians will be diagnosed with leukemia of all types and approximately 500 with CML. Gleevec is used to treat people who have an advanced form of CML and have become resistant to other treatments.

Gleevec is also called STI571? What does that mean?
Gleevec was given the name STI571 when it was under early development. STI stands for Signal Transduction Inhibitor and represents the action of the drug to inhibit an enzyme called tyrosine kinase. This targeted kinase allows CML cells to grow.

What is Leukemia?
Leukemia is a type of cancer in which the bone marrow produces an excessive number of abnormal (leukemic) white blood cells. These abnormal cells suppress the production of normal white blood cells, which act to protect the body against infection.

What are the symptoms of CML?
In the early stage, patients may only be diagnosed through routine blood tests that show an increase in white blood cells. In later stages, patients experience infections, bleeding, fever, chills, sweats, weakness, fatigue and headaches.

What are the phases of CML?
CML worsens as it progresses from the chronic phase to the accelerated phase and the final phase called the blast crisis. The three phases are characterized by steadily increasing numbers of abnormal cells within the bone marrow and by spread of abnormal cells to sites outside of the bone marrow.

The three phases are:

• Chronic phase: This phase may last for about 4 to 5 years. Initially, patients in this phase usually have minor symptoms and their cancer is usually detected by routine blood tests. Most patients receive interferon therapy alone or with other drugs. Patients can also be treated with bone marrow transplants.
• Accelerated phase: This phase may last from 6 to 18 months. The white blood cell count increases and the disease is harder to control with conventional treatments.
• Myeloid blast crisis: This phase is the final phase of the disease and may last about 3 to 6 months.

How does Gleevec work?
Gleevec's action is different from other cancer drugs in that it specifically targets an enzyme that allows CML cells to grow.

What are the advantages of Gleevec treatment over other cancer therapies?
One advantage of Gleevec is that it can be given by mouth instead of by injection. A second advantage is that CML seems to respond relatively quickly (within one to three months) to the drug. This response can be measured by tests that show that the blood count returns to a normal range or tests that measure cancer cells in the bone marrow. It is hoped that Gleevec has fewer serious side effects than other cancer drugs.

What are the side effects of Gleevec and how serious are they?
Commonly reported side effects include nausea, vomiting, muscle and joint pains, skin rash, diarrhea, heartburn, headache, and water retention (edema.) Although some of the serious side effects occur less frequently, severe side effects include severe water retention (edema), liver toxicity, the potential for bleeding (hemorrhage) especially in the elderly and weight gain.

What do patients need to know about using Gleevec?
If patients experience swelling or weight gain from water retention, they should inform their doctor as soon as possible and should be closely monitored. Because Gleevec interacts with many other medications, including over-the-counter medications (medications that can be purchased without a prescription), patients should inform their doctors as to all medications that they are taking.

What other treatments have been used to treat CML?
Several drugs have been used to treat CML including cancer drugs such as busulfan, hydroxyurea, and cytosine arabinoside (ara-C). Current therapy for the chronic phase of CML generally includes interferon with or without other drugs. Bone marrow transplant may be an option for some patients.

Who can be treated with Gleevec?
Patients who are diagnosed with CML in the three phases of disease are eligible for treatment. Patients with accelerated phase and blast crisis of CML can receive Gleevec immediately. Patients with chronic phase of CML can receive Gleevec if they have not responded adequately or have experienced intolerable side-effects to interferon therapy.

The diagnosis of CML is established by blood and bone marrow examination and by physical examination to detect possible involvement of the liver and spleen. When the bone marrow is examined, special tests are performed to demonstrate the presence of the Philadelphia chromosome (the specific marker of CML)

How is Gleevec taken?
Dosage and administration recommendations: Gleevec should only be administered under the supervision of a physician experienced with the use of chemotherapy and with treatment of CML.

Gleevec should be taken with food and a large glass of water to minimize the risk of stomach and gastrointestinal irritation.

The recommended dosage of Gleevec is 400 mg per day for patients in chronic phase CML and 600 mg per day for patients in accelerated phase or blast crisis. The prescribed dose should be administered orally, once daily with a meal and a large glass of water.

Treatment should be continued as long as the patient continues to benefit.

Can Gleevec be taken with other drugs?
Gleevec interacts with many other drugs. In some cases, Gleevec increases blood levels of these drugs which may increase side effects. In other cases, Gleevec decreases blood levels of the drugs which may decrease effectiveness of treatment. Similarly, Gleevec blood levels may be increased or decreased by other drugs. This might increase Gleevec side effects or decrease effectiveness. Because of these potential drug-drug interactions the patient must discuss all of their medications with their doctor or pharmacist.

Medical Enquiries:

Should you have medical enquiries regarding Gleevec, please contact our Medical Information department at 1-800-363-8883.

Gleevec is a trademark of Novartis Pharmaceuticals Canada Inc.