February 01, 2006
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Potential drug interactions with imatinib therapy identified

Long-term imatinib treatment for CML must be carefully measured.

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The FDA first approved imatinib (Gleevec, Novartis), a protein-tyrosine kinase inhibitor, in 2001 under the accelerated approval program for use in adult patients with chronic myelogenous leukemia (CML) resistant to interferon therapy. This indication applies to all three stages of CML: myeloid blast crisis, accelerated phase and chronic phase.

It is also indicated for treatment of adult patients with newly diagnosed CML in the chronic phase. In the pediatric population, imatinib is approved for use in CML patients with interferon-resistant disease or recurrent disease following hematopoietic stem cell transplant (HSCT).

Standard of care

According to the clinical practice guidelines by the National Comprehensive Cancer Network (NCCN), imatinib therapy has become the standard of care for CML patients who are not considered adequate transplant candidates.

As such, the implications of chronic imatinib therapy, specifically possible drug interactions, need to be evaluated in this patient population.

Imatinib works by inhibiting the BCR-ABL tyrosine kinase that is synthesized by the Philadelphia chromosome abnormality found in CML. As a result, it inhibits further tumor growth by suppressing proliferation and inducing apoptosis in BCR-ABL–positive cells.

Initially, imatinib is dosed at 400 mg orally per day. Doses may be increased to 600-800 mg/day if the patient is not responding or is in blast crisis.

Generally, imatinib is well tolerated, even in older patients. The most common adverse effects include edema, muscle cramps, nausea, vomiting and diarrhea. Imatinib is metabolized in the liver by the cytochrome P450 (CYP450) enzyme family with CYP3A4 as the primary metabolizer.

There are several other isozymes, including CYP1A2, CYP2D6, CYP2C9 and CYP2C19, that are involved in imatinib’s metabolism to a lesser extent. As a result, inhibitors, inducers and substrates of CYP3A4 have a potential for drug-drug interactions with imatinib. The charts list potential drug interactions and the recommended clinical management.

Several of these drug interactions may be commonly encountered in this patient population. Because of previous chemotherapy or immunosuppressant therapy following stem cell transplant, CML patients may be immunocompromised.

As a result, therapy with azole antifungals may be necessary. Careful monitoring of possible adverse effects due to increased imatinib plasma concentrations is recommended. Therapy with non-azole antifungals may be optimal for use in imatinib patients.

Warfarin also interacts with imatinib. Initial coadministration with these agents requires vigilant monitoring of anticoagulation parameters and for signs and symptoms of bleeding. It may be necessary to switch to heparin or low-molecular weight heparin products.

Imatinib and acetaminophen is another probable drug interaction worth noting. Imatinib may increase the plasma levels of acetaminophen when administered together; it has been shown that imatinib inhibits glucuronidation of acetaminophen in vitro.

Moreover, imatinib clinical trials reported elevated bilirubin and/or liver transaminases in 3% to 6% of study patients. As such, concomitant use with acetaminophen may increase a patient’s risk for liver toxicity.

A recent case report was published describing a woman who had been taking imatinib for the last year. Over a two-day period, she consumed a large amount of alcohol and approximately 4 grams of acetaminophen. Elevated transaminases and a liver biopsy revealed severe hepatitis. Imatinib was discontinued, and the patient’s laboratory values normalized after about 90 days.

Thus, the use of acetaminophen should be limited in patients taking imatinib. The NCCN clinical practice guidelines recommend that clinicians should limit acetaminophen to no more than 1,300 mg/day in patients taking imatinib.

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Conclusions

Imatinib is effective in the treatment of patients with CML and has become the standard of care in those patients not eligible for HSCT. Although long-term effectiveness is unknown, early literature looks promising in terms of improving overall survival for the patient.

Because treatment with imatinib is long-term, implications for chronic therapy need to be considered. Unfortunately, there are numerous drug interactions associated with imatinib. As a result, thorough evaluation of a patient’s medication therapy is important to ensure safe use of imatinib as a chronic medication.


For more information:
  • Ayoub WS, Geller SA, Tran T, et al. Imatinib (Gleevec)-induced hepatotoxicity. J Clin Gastroenterol. 2005;39:75-77.
  • National Comprehensive Cancer Network. Clinical practice guidelines: chronic myelogenous leukemia, version 1.2006. Available at: www.nccn.org/professionals/physician_gls/PDF/cml.pdf. Accessed January 6, 2006.
About the author:
  • Cathryn A. Jennissen, PharmD, is a pharmacy practice resident at the University of Minnesota Medical Center, Fairview in Minneapolis.