Imatinib

A to Z Drug Facts

  Action Imatinib inhibits proliferation and induces apoptosis in BCR-ABL positive cell lines as well as fresh leukemic cells from Philadelphia chromosome-positive chronic myeloid leukemia (CML). Imatinib inhibits tumor growth of BCR-ABL transfected murine myeloid cells as well as BCR-ABL positive leukemia lines derived from CML patients in blast crisis. It also inhibits the receptor tyrosine kinases for platelet-derived growth factor (PDGF) and stem cell factor (SCF), c-Kit, and inhibits PDGF- and SCF-mediated cellular events. Imatinib is well absorbed after oral administration with C_max achieved within 2 to 4 hr postdose. Mean absolute bioavailability for the capsule formulation is 98%. The elimination half-lives of imatinib and its major active metabolite, the N-desmethyl derivative, were approximately 18 and 40 hr, respectively. CYP3A4 is the major enzyme responsible for metabolism of imatinib. Other cytochrome P450 enzymes, such as CYP1A2, CYP2D6, CYP2C9, and CYP2C19, play a minor role in its metabolism. Excretion is predominantly in the feces, mostly as metabolites. Clearance of imatinib in a patient 50 yr weighing 50 kg is expected to be 8 L/hr, while for a patient 50 yr weighing 100 kg, the clearance will increase to 14 L/hr.

  Indications Treatment of CML in accelerated phase, blast crisis, or interferon-refractory chronic phase, metastatic GI stromal tumors (GISTs).

  Contraindications Standard Considerations.

  Route/Dosage

CML Treatment in Accelerated Phase, Blast Crisis, or Interferon-Refractory Chronic Phase: Adults: PO Continue imatinib as long as response is favorable. Assess therapeutic response after at least 3 mo of continued therapy. Chronic Phase CML: Adults: PO 400 mg/day initially. Increase to 600 mg/day, as tolerated, in patients with disease progression, inadequate response to initial dose, or loss of previous hematologic response. CML in Accelerated Phase or Blast Crisis: Adults: PO 600 mg/day initially. Increase to 400 mg bid, as tolerated, in patients with disease progression, inadequate response to initial dose, or loss of previous hematologic response. GISTs: Adults: PO 400 or 600 mg/day. Patients with Chronic Phase CML: Adults: PO If ANC at least 1000 cells/mm³, continue at present dose. If ANC less than 1000 cells/mm³–First occurrence: Discontinue imatinib until ANC at least 1500 cells/mm³ and platelets at least 75,000 cells/mm³, then resume treatment at 400 mg/day. Second occurrence: Discontinue imatinib until ANC at least 1500 cells/mm³ and platelets at least 75,000 cells/mm³, then resume treatment at 300 mg/day. If platelet count at least 50,000 cells/mm³, continue at present dose. If platelet count less than 50,000 cells/mm³–First occurrence: Discontinue imatinib until platelets at least 75,000 cells/mm³ and ANC at least 1500 cells/mm³, then resume treatment at 400 mg/day. Second occurrence: Discontinue imatinib until platelets at least 75,000 cells/mm³ and ANC at least 1500 cells/mm³, then resume treatment at 300 mg/day. Patients with Accelerated Phase CML and Blast Crisis (if Hematologic Toxicity Occurs After at Least 1 Mo of Therapy): Adults: PO If ANC at least 500 cells/mm³, continue at present dose. If ANC less than 500 cells/mm³–Initial response: Perform marrow aspirate or biopsy. Reduce dose to 400 mg/day if neutropenia is unrelated to leukemia. Recheck counts in 2 wk. Persistent neutropenia for 2 wk: Reduce dose to 300 mg/day and recheck counts in 2 additional weeks. Persistent neutropenia for 4 wk: Perform marrow aspirate or biopsy. If neutropenia is unrelated to leukemia, discontinue imatinib until ANC at least 1000 cells/mm³ and platelets at least 20,000 cells/mm³, then resume therapy with 300 mg/day. If platelet count at least 10,000 cells/mm³, continue at present dose. If platelet count less than 10,000 cells/mm³–Initial response: Perform marrow aspirate or biopsy. Reduce dose to 400 mg/day if thrombocytopenia is unrelated to leukemia. Recheck counts in 2 wk. Persistent thrombocytopenia for 2 wk: Reduce dose to 300 mg/day and recheck counts in 2 additional weeks. Persistent thrombocytopenia for 4 wk: Perform marrow aspirate or biopsy. If thrombocytopenia is unrelated to leukemia, discontinue imatinib until platelet count at least 20,000 cells/mm³ and ANC at least 1000 cells/mm³, then resume therapy with 300 mg/day. Hepatotoxicity: Adults: PO If serum bilirubin is up to 3 times the upper limit of normal (ULN), continue at present dose. If serum bilirubin is greater than 3 times the ULN, discontinue imatinib until bilirubin is less than 1.5 times the ULN, then resume treatment at next lower dose level (reduce daily dose from 800 to 600 mg, from 600 to 400 mg, or from 400 to 300 mg, as appropriate). If serum transaminases are up to 5 times the ULN, continue at present dose. If serum transaminases are greater than 5 times the ULN, discontinue imatinib until serum transaminases are less than 2.5 times the ULN, then resume treatment at next lower dose level.

  Interactions

Acetaminophen (eg, Tylenol)

Increased risk of hepatotoxicity. Drugs that induce CYP3A4 (eg, aminoglutethimide, barbiturates, carbamazepine, dexamethasone, griseofulvin, modafinil, nafcillin, phenytoin, primidone, rifabutin, rifampin, St. John's wort): Decreased imatinib concentrations and antineoplastic efficacy. Drugs that inhibit CYP3A4 (eg, clarithromycin, diltiazem, erythromycin, itraconazole, ketoconazole, verapamil): Increased imatinib concentrations and toxicity. Drugs that are metabolized by CYP2C9 (eg, fluvastatin, glimepiride, glipizide, glyburide, phenytoin, warfarin, some NSAIDs): Imatinib may reduce metabolism, resulting in increased concentrations and toxicity. Drugs that are metabolized by CYP2D6 (eg, propafenone, tricyclic antidepressants, some beta-adrenergic blockers, some SSRIs): Imatinib may reduce metabolism, resulting in increased concentrations and toxicity. Drugs that are metabolized by CYP3A4 (eg, atorvastatin, triazolobenzodiazepines): Imatinib may reduce metabolism, resulting in increased concentrations and toxicity.

  Lab Test Interferences None well documented.

  Adverse Reactions

CARDIOVASCULAR: Fluid retention in up to 70% of patients, including superficial edema, pleural effusion. Severe edema in 1% to 5% of patients. CNS: Headache, fatigue, and pyrexia (less than 40% incidence for each); weakness reported. DERMATOLOGIC: Skin rash in up to 40% of patients; night sweats and pruritus. GI: Moderate potential for nausea and vomiting; diarrhea and abdominal pain common; dyspepsia, anorexia, and constipation reported. Elevated LFTs (up to 3.5%), which resolve within 1 wk of dose reduction or discontinuation. GU: Fetal malformations and reduced fertility in rats. HEMATOLOGIC: Neutropenia, thrombocytopenia, and anemia common, with white count recovery in 2 to 3 wk and platelet recovery in 3 to 4 wk. Hemorrhage common (35% incidence in blast crisis, 48% in accelerated phase, and 13% in chronic phase), although severe hemorrhage only. METABOLIC: Hypokalemia. MUSCULOSKELETAL: Muscle cramps or pain common; arthralgia, myalgia. RESPIRATORY: Cough, dyspnea, nasopharyngitis.

  Precautions

Pregnancy: Category D. Lactation: Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants, advise women against breastfeeding while taking imatinib. Children: The safety and efficacy of imatinib in pediatric patients is not established. Elderly: The efficacy of imatinib was similar in older and younger patients. Dosage Adjustment for Hepatic Dysfuntion: Consider dosage reduction in patients with hepatic impairment at baseline. Dosage Adjustment for Toxicity: Consider dosage reduction or temporary discontinuation for severe edema. GI Irritation: Take with food and a large glass of water to minimize this problem. Resistance: Resistance to imatinib has developed during continued therapy, usually in advanced-stage CML. In patients with blast crisis, resistance has occurred as soon as 42 days after starting therapy. Fluid Retention: Risk of severe edema increases with imatinib dose and in patients greater than 65 yr. Edema may manifest as rapid weight gain and should be managed promptly, with dose reduction, interruption of therapy, diuretics, or supportive care, as indicated.

  Administration/Storage

• Store at room temperature in tightly sealed container.
• Administer orally. Give with food and at least 240 mL water to reduce gastric irritation.
• Follow procedures for proper handling and disposal of anticancer drugs. Wear gloves and avoid skin exposure and inhalation of fumes.

  Assessment/Interventions

• Monitor CBC, differential, and platelet count at baseline, once weekly for the first month, every other week for the second month, and at least q 2 to 3 mo thereafter.
• Monitor LFTs at baseline and at least once monthly during therapy.
• Monitor fluid status and weight at baseline and periodically during therapy.

  Patient/Family Education

• Explain name, dose, action, and potential side effects of drug.
• Review dosing schedule with patient.
• Advise patient that dose may be changed based upon results of lab tests.
• Advise patient to take prescribed dose with food and large glass of water to minimize GI irritation.
• Advise patient that if a dose is missed, take it as soon as possible, but if close to the next dose, do not double the dose to catch up and take the next dose as scheduled.
• Advise patient to immediately report any of the following to the health care provider: rash; swelling of the feet, ankles, legs, or around the eyes; rapid weight gain; bloating; shortness of breath or difficulty breathing; fever, chills, or other signs of infection; sore throat; persistent nausea, vomiting, or appetite loss; unusual bruising or bleeding.
• Advise patient that drug may cause dizziness and to use caution while driving or performing other tasks requiring mental alertness.
• Caution women of childbearing potential to avoid becoming pregnant while being treated.
• Instruct women of childbearing potential to notify health care provider if becoming pregnant, planning on becoming pregnant, or breastfeeding.
• Instruct patient not to take any prescription or otc medications or dietary supplements unless advised by the health care provider.
• Advise patient that frequent follow-up examinations and lab tests will be required to monitor therapy and to keep appointments.

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Copyright © 2003 Facts and Comparisons
David S. Tatro
A to Z Drug Facts