What You Need to Know About Gleevec (Imatinib)

A cancer drug on WHO's list of essential medicines

Gleevec (imatinib)

Courtesy of Novartis

Gleevec (imatinib mesylate) is a targeted medication approved for use by the U.S. Food and Drug Administration (FDA) for the treatment of chronic myeloid leukemia and other cancers and blood-related disorders. Targeted therapy is the term used to describe a newer form of cancer treatment in which drugs are more precise in their ability to identify and destroy cancer cells.

Indications

Gleevec was first granted FDA approval in 2001 for use in treating chronic myeloid leukemia (CML) in people with the so-called Philadelphia chromosome. The drug can be used for people newly diagnosed with CML, who have undergone a stem cell transplant to treat CML, or are experiencing a life-threatening emergency known as a blast crisis.

So profound has Gleevec been on the treatment of CML that it is credited in part with increasing the five-year survival rate from 31 percent in the 1990s to 68 percent by 2013, according to the American Cancer Society.

In addition to treating Philadelphia-positive (Ph+) CML, Gleevec has since received FDA approval for use in treating:

In April 2013, Gleevec was approved for use in children with Ph+ acute lymphoblastic leukemia. That same year, Gleevec was added to the World Health Organization (WHO) List of Essential Medicines, a compendium of the most effective and safe drugs needed in a health care system.

In some countries outside of the United States, the drug is known by the trade name Glivec.

Drug Development

Gleevec is a product of rational drug design, a structured process in which medicines are designed based on a known biologic target.

With regards to Gleevec, the process began with the discovery of the Philadelphia chromosome in the 1950s by scientists Peter Nowell and David Hungerford. After spotting the same atypical chromosome in two different people with CML, the pair expanded their investigation and soon realized that nearly all cancer cells from people with CML carried the same chromosomal mutation, which they dubbed "Philadelphia" after the city in which it was discovered.

In the early 1980s, scientists from the National Cancer Institute were able to pinpoint the actual genes involved in the chromosomal mutation. This, in turn, led investigators at the University of California Los Angeles (UCLA) to unravel how the Philadelphia chromosome causes disease.

In their research, the UCLA scientists discovered that the mutation triggers the production of an abnormal form of a protein known as tyrosine kinase. Under normal circumstances, tyrosine kinase functions as a signaling molecule, activating when cells need to divide and shutting down when the division is complete. The type produced by the Philadelphia chromosome does not shut down as it is supposed to, leading to the overproduction and accumulation of immature white blood cells—the very hallmarks of CML.

The discovery led to the exploration and eventual development of kinase inhibitors, a class of drugs able to identify and block specific kinase proteins. In 1998, scientists at Ciba-Geigy (now Novartis) began human trials to investigate an inhibitor known as STI-571 (later imatinib) which was able to target the specific tyrosine kinase protein generated by the Philadelphia chromosome.

The success of that initial trial led to the fast-track approval of imatinib in 2001. Since then, the inhibitory action of imatinib has proven effective in treating other diseases, both cancerous and non-cancerous, by effectively "turning off" tyrosine kinase when it is unable to turn itself off.

Formulations

Gleevec is an oral drug available in a 100 milligram (mg) and 400 mg formulation. The 100-mg pill is orange and film-coated, embossed on one side with "NVR" and on the other with "SA."

Most 400-mg tablets are orange and film-coated, embossed on one side with "SL" and the number "400" on the other. Others are simply embossed with "gleevec" on one side.

Pills and tablets are both scored so that the dose can be divided in half and packaged in a 30 count blister pack.

Dosages

The Gleevec dosage varies with the condition being treated and the age and weight of the user. Additional tests may be performed to establish the stage and genetic characteristics of the disease. The information can be used to confirm whether you are a candidate for treatment or to determine the appropriate dose for treatment.

Recommended Adult Dosages

  • Ph+ chronic myeloid leukemia: 600 mg per day
  • Ph+ chronic myeloid leukemia during a blast crisis: 400 mg twice daily
  • Ph+ acute lymphoblastic leukemia: 600 mg per day
  • Chronic eosinophilic leukemia: 100 mg to 400 mg per day
  • Myelodysplastic syndrome: 400 mg per day
  • Myeloproliferative neoplasm: 400 mg per day
  • Gastrointestinal stromal tumors: 400 mg per day
  • Systemic mastocytosis: 100 mg to 400 mg per day
  • Hypereosinophilic syndrome: 100 mg to 400 mg per day
  • Dermatofibrocarcoma protuberans: 400 mg twice day

Pediatric dosages are calculated by multiplying the base dose (350 mg) by the child's body surface area measured in square meters (m2). Based on this formula, doctors can increase the dosage as the child grows (up to but never beyond the recommended adult dose).

Recommended Pediatric Dosages

  • Ph+ chronic myeloid leukemia: 350 mg per m2 per day
  • Ph+ acute lymphoblastic leukemia: 350 mg per m2 per day

Gleevec should be taken with a meal and a large glass of water to minimize stomach upset and nausea.

For children or adults unable swallow pills, the drug can be crushed and dissolved in water or apple juice (roughly ½ cup of liquid to a 100 mg of Gleevec, or 1 cup of liquid to 400 mg of Gleevec).

Side Effects

Generally speaking, targeted therapies have fewer and less severe side effects than traditional chemotherapy drugs. This is because the earlier-generation medications are inherently cytotoxic (toxic to cells) and will attack any cell that is fast replicating. While most cancers multiply rapidly, there are a number of normal cells that do as well. These include hair, skin, bone marrow, and the lining of the digestive tract.

Because Gleevec works by targeting specific kinase molecules, there is less "collateral damage" and fewer high-grade side effects. 

With that being said, Gleevec is known to cause an array of common side effects. Among those affecting 15 percent or more of users:

  • Fluid retention (62 percent)
  • Nausea (50 percent)
  • Muscle cramps (49 percent)
  • Musculoskeletal pain (47 percent)
  • Diarrhea (45 percent)
  • Rash (40 percent)
  • Fatigue (39 percent)
  • Headache (37 percent)
  • Abdominal pain (36 percent)
  • Joint pain (31 percent)
  • Cold-like symptoms (31 percent)
  • Unusual bleeding (29 percent)
  • Muscle aches (24 percent)
  • Vomiting (23 percent)
  • Upper respiratory tract infection (21 percent)
  • Cough (20 percent)
  • Upset stomach (19 percent)
  • Dizziness (19 percent)
  • Fever (18 percent)
  • Weight increase (16 percent)
  • Depression (15 percent)
  • Insomnia (15 percent)

The majority of side effects are mild to moderate and rarely result in treatment termination. Serious side effects are uncommon, affecting fewer than 3 percent of users. The only exceptions are musculoskeletal pain (5.4 percent), abdominal pain (4.2 percent), and diarrhea (3.3 percent).

Other than intolerance to the drug itself, there are no contraindications to Gleevec use

Drug Interactions

Certain types of medication can interact with Gleevec. In some cases, they may increase the concentration of Gleevec in the blood and, with it, the risk of side effects. Other may decrease the blood concentration and reduce the efficacy of the drug.

The interactions are primarily associated with an enzyme known as CYP3A4 which the body uses to oxidize drugs so that they can be removed from the body. CYP3A4 plays a vital role by ensuring that Gleevec remains within the expected range in the blood. If another drug inhibits or increases CYP3A4 activity, those concentrations can be thrown off, sometimes significantly.

To compensate for this, Gleevec doses may need to be adjusted. Alternately, the offending drug can be stopped, substituted, or reduced.

The drug or substances that can potentially interact with Gleevec include:

  • Anti-arrhythmia drugs like quinidine
  • Anti-epilepsy drugs like carbamazepine, oxcarbazepine, phenytoin, fosphenytoin, phenobarbital, and primidone
  • Antifungal drugs like ketoconazole, itraconazole, and voriconazole
  • Anti-hypertensive medications like amlodipine and nifedipine
  • Antipsychotic drugs like pimozide
  • Atypical antidepressants like nefazodone
  • Grapefruit juice
  • HIV drugs like atazanavir, indinavir, nelfinavir, ritonavir, and saquinavir
  • Immune-suppressive drugs like cyclosporine, sirolimus, and tacrolimus
  • Macrolide antibiotics like clarithromycin and telithromycin
  • Migraine medications like diergotamine and ergotamine
  • Opioid analgesics like alfentanil and fentanyl
  • Rifampin-based drugs used to treat tuberculosis
  • St. John's Wort
  • Triazolo-benzodiazepine tranquilizers like clonazepam and triazolam

Precautions and Considerations

Gleevec is metabolized in the liver and may cause liver toxicity in some people. In rare cases, severe liver damage and fatal liver failure may occur. The risk is increased if Gleevec is combined with chemotherapy. While Gleevec is not contraindicated for use in people with liver disease, every effort should be made to monitor liver function in anyone on Gleevec whether there is a pre-existing liver condition or not.

Similarly, while not contraindicated in pregnancy, animal studies have shown that Gleevec has a potential for fetal birth defects and may increase the risk of miscarriage. If you are pregnant, speak with your oncologist to weigh the benefits and risks of treatment. Women in their child-bearing years should use effective contraception while on Gleevec and for 14 days following the termination of treatment.

People with kidney disease or impaired kidney function need to be monitored closely while on Gleevec. When first starting treatment, only 50 percent of the recommended dose should be given and only increased once kidney function tests show no signs of further deterioration. People with mild kidney impairment should be given no more than 600 mg daily, while those with moderate impairment should be limited to no more than 400 mg daily.

Congestive heart failure is a rare complication of Gleevec use, but one that was identified in 1.1 percent of clinical trial participants. The risk appears to be greatest in older people who have underlying risk factors for heart disease and/or a history of kidney failure. Anemia and other cellular blood imbalances can occur, the conditions of which may be normalized by temporarily stopping treatment or reducing the Gleevec dose.

Cost

The average wholesale price (AWP) of Gleevec is just over $100 for a 100-mg pill and $400 for a 400-mg tablet. In 2016, the first generic version of Gleevec was approved and was distributed at more-or-less the same AWP.

Co-Pay Assistance

If your health insurer includes Gleevec in its drug formulary, you may be eligible for co-payment assistance to reduce out-of-pocket expenses. There are several co-pay assistance programs offered by manufacturers which either cover the total cost of your co-pay or reduce your co-pay share to $10 per month for a 30-day supply.

Eligibility is restricted to U.S. residents with health insurance whose annual family income is at or below 500 percent of the federal poverty limit (FPL). In 2018, that translated to an eligible annual income of:

  • $60,700 or less for individuals
  • $82,000 or less for a family of two
  • $103,900 or less for a family of three

You can apply directly to Novartis at 866-453-3832 or Sun Pharmaceutical at 844-502-5950.

Patient Assistance Programs

If you don't have health insurance or are underinsured, you may be able to obtain Gleevec free of charge through the Novartis Patient Assistance Foundation (NPAF). To be eligible for assistance, you must be a U.S. residence, have limited or no prescription drug coverage, and have an annual income at or less than:

  • $75,000 for one person
  • $100,000 for a family of two
  • $125,000 for a family of three
  • $150,000 for a family of four

For families larger than four, add $25,000 for each family member. You can download the application and complete it with your treating doctor. For further assistance or information, contact NPAF at 800-277-2254.

Was this page helpful?
Article Sources