Imatinib - Drug Monograph

Introduction

Imatinib mesylate is a revolutionary targeted therapy that represents a paradigm shift in cancer treatment. As a first-generation tyrosine kinase inhibitor, it was the first molecularly targeted drug approved for chronic myeloid leukemia (CML) and has dramatically improved outcomes for patients with this previously fatal disease. Imatinib specifically inhibits abnormal tyrosine kinase proteins that drive certain cancers, offering a more precise approach to treatment with fewer side effects than conventional chemotherapy.

Mechanism of Action

Imatinib is a selective inhibitor of multiple tyrosine kinases, most notably the BCR-ABL fusion protein, which is the pathogenic driver in chronic myeloid leukemia. It competitively inhibits the ATP-binding site of the kinase, preventing phosphorylation of downstream substrates and interrupting the signal transduction pathways that promote leukemogenesis. Imatinib also inhibits platelet-derived growth factor receptors (PDGFR-α and PDGFR-β), stem cell factor receptor (c-KIT), and other oncogenic kinases. This targeted approach specifically blocks the proliferation and induces apoptosis in BCR-ABL-positive cell lines while sparing normal cells.

Indications

• Chronic myeloid leukemia (CML): Philadelphia chromosome-positive (Ph+) in chronic phase, accelerated phase, or blast crisis
• Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL)
• Myelodysplastic/myeloproliferative diseases (MDS/MPD) associated with PDGFR gene rearrangements
• Aggressive systemic mastocytosis (ASM) without the D816V c-KIT mutation or with unknown c-KIT status
• Hypereosinophilic syndrome (HES) and/or chronic eosinophilic leukemia (CEL)
• Dermatofibrosarcoma protuberans (DFSP)
• Kit (CD117)-positive gastrointestinal stromal tumors (GIST)

Dosage and Administration

• CML chronic phase: 400 mg orally once daily
• CML accelerated phase or blast crisis: 600 mg orally once daily
• Ph+ ALL: 600 mg orally once daily
• GIST: 400 mg orally once daily (may be increased to 800 mg daily in divided doses for advanced disease)

• Take with a meal and large glass of water to minimize gastrointestinal irritation
• Tablets should be swallowed whole
• For patients unable to swallow tablets, tablets may be dispersed in water or apple juice

• Hepatic impairment: Reduce dose by 25%
• Renal impairment (CrCl <30 mL/min): Reduce dose by 50%
• Elderly: No specific dose adjustment required
• Pediatrics: Safety and efficacy established for children ≥2 years

Pharmacokinetics

• Absorption: Well absorbed orally with absolute bioavailability of 98%; peak plasma concentrations reached within 2-4 hours
• Distribution: Volume of distribution 295 L; 95% protein-bound, primarily to albumin and α1-acid glycoprotein
• Metabolism: Primarily hepatic via CYP3A4 and CYP3A5; also metabolized by CYP1A2, CYP2D6, CYP2C9, and CYP2C19
• Elimination: Elimination half-life approximately 18 hours; excreted predominantly in feces (68%) with 13% renal excretion

Contraindications

• Hypersensitivity to imatinib or any component of the formulation
• Pregnancy (unless potential benefit justifies potential risk to fetus)

Warnings and Precautions

• Hematologic toxicity: Severe neutropenia, thrombocytopenia, and anemia may occur; monitor blood counts regularly
• Hepatotoxicity: Severe hepatic toxicity, including cases of fatal acute liver failure, has been reported; monitor liver function
• Fluid retention: May cause severe fluid retention (pleural effusion, pericardial effusion, pulmonary edema, ascites); weigh patients regularly
• Cardiac toxicity: Congestive heart failure and left ventricular dysfunction have been reported
• Gastrointestinal toxicity: Severe gastrointestinal irritation, perforation, and hemorrhage may occur
• Dermatologic reactions: Severe bullous dermatologic reactions, including erythema multiforme and Stevens-Johnson syndrome
• Thyroid dysfunction: Hypothyroidism has been reported in patients taking concomitant levothyroxine
• Growth retardation: In children and adolescents, long-term therapy may cause growth retardation

Drug Interactions

• Strong CYP3A4 inducers (rifampin, phenytoin, carbamazepine, St. John's wort): May decrease imatinib concentrations; avoid concurrent use or increase imatinib dose
• Strong CYP3A4 inhibitors (ketoconazole, itraconazole, clarithromycin, ritonavir): May increase imatinib concentrations; monitor for toxicity
• Warfarin: Imatinib may affect metabolism; use low molecular weight heparin instead
• Simvastatin: Increased risk of rhabdomyolysis; consider alternative statin
• P-gp substrates: Imatinib may increase concentrations of digoxin, cyclosporine, and other P-gp substrates

Adverse Effects

• Nausea, vomiting, diarrhea
• Muscle cramps, musculoskeletal pain
• Fatigue, headache
• Peripheral edema
• Rash
• Neutropenia, thrombocytopenia

• Abdominal pain, dyspepsia
• Weight increase
• Insomnia, dizziness
• Conjunctivitis, lacrimation increased
• Cough, dyspnea
• Hepatitis, elevated liver enzymes

• Severe fluid retention (pleural effusion, pericardial effusion)
• Congestive heart failure
• Severe hepatotoxicity
• Gastrointestinal perforation
• Severe dermatologic reactions
• Tumor lysis syndrome (particularly in patients with high tumor burden)

Monitoring Parameters

• Complete blood count: Weekly for first month, biweekly for second month, then periodically
• Liver function tests: Baseline and monthly or as clinically indicated
• Weight: Regularly to monitor for fluid retention
• ECG and cardiac function: In patients with cardiac risk factors or symptoms
• Electrolytes: Particularly potassium and magnesium (may cause hypokalemia, hypomagnesemia)
• Response monitoring: Cytogenetic and molecular monitoring (BCR-ABL transcript levels) in CML patients
• Growth and development: In pediatric patients

Patient Education

• Take with food and a large glass of water to reduce stomach upset
• Do not crush or break tablets
• Report any signs of fluid retention (swelling, weight gain, shortness of breath)
• Report unusual bleeding or bruising, fever, or signs of infection
• Use effective contraception during treatment and for at least 15 days after discontinuation
• Inform all healthcare providers about imatinib therapy, including dentists
• Many drug interactions possible; discuss all medications (including over-the-counter and herbal products) with healthcare provider
• Regular blood tests are necessary to monitor safety and effectiveness
• Do not stop taking medication without consulting your healthcare provider

References

1. Druker BJ, et al. Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med. 2001;344(14):1031-1037. 2. Deininger M, et al. The development of imatinib as a therapeutic agent for chronic myeloid leukemia. Blood. 2005;105(7):2640-2653. 3. Gleevec® (imatinib mesylate) [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2021. 4. Hochhaus A, et al. Long-term outcomes of imatinib treatment for chronic myeloid leukemia. N Engl J Med. 2017;376(10):917-927. 5. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Chronic Myeloid Leukemia. Version 2.2023. 6. O'Brien SG, et al. Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med. 2003;348(11):994-1004.