GLEEVEC
Clinical safety rating: caution
Comprehensive clinical and safety monograph for GLEEVEC (GLEEVEC).
Imatinib mesylate is a tyrosine kinase inhibitor that selectively inhibits BCR-ABL, c-KIT, PDGFR, and other kinases, blocking proliferation and inducing apoptosis in cells expressing these targets.
| Metabolism | Primarily metabolized by CYP3A4; active metabolite N-desmethyl imatinib also formed. Minor contributions from CYP1A2, CYP2D6, CYP2C9, and CYP2C19. |
| Excretion | Primarily fecal (68% of dose) as metabolites; renal excretion accounts for approximately 13% of dose (predominantly as metabolites). Unchanged imatinib in urine is <10%. |
| Half-life | Terminal elimination half-life is approximately 18 hours (range 13–20 hours) in healthy subjects; for the active N-desmethyl metabolite, half-life is about 40 hours (range 30–50 hours). Clinical context: Steady-state is achieved within 1–2 weeks; once-daily dosing maintains therapeutic concentrations. |
| Protein binding | Approximately 95% bound to plasma proteins, primarily to albumin and alpha-1-acid glycoprotein (AAG). The binding to AAG is saturable, which may affect free drug concentrations at high doses. |
| Volume of Distribution | Apparent volume of distribution (Vd/F) is approximately 6.1 L/kg (range 4.1–8.1 L/kg), indicating extensive tissue distribution. Clinical meaning: Large Vd suggests significant extravascular binding and distribution into tissues, including tumor sites. |
| Bioavailability | Absolute bioavailability of oral imatinib capsules is approximately 98% (range 80–100%). Bioavailability is not significantly affected by food (high-fat meal reduces Cmax by 11% but does not change AUC). |
| Onset of Action | Oral: Clinical response (e.g., reduction in white blood cell count in CML) may be observed within 2–4 weeks; maximal cytogenetic response typically seen after 3–6 months of continuous therapy. |
| Duration of Action | 24 hours with once-daily dosing; sustained inhibition of BCR-ABL kinase activity throughout the dosing interval. Clinical note: Continuous therapy is required to maintain response; discontinuation may lead to relapse. |
| Molecular Weight | 493.6 |
400 mg orally once daily with a meal and a large glass of water. For advanced GIST, 400 mg daily; for CML in chronic phase, 400 mg daily; for accelerated phase or blast crisis, 600 mg daily. Dose may be increased to 600 mg or 800 mg daily in patients with disease progression.
| Dosage form | TABLET |
| Renal impairment | For GFR 20-39 mL/min: reduce dose by 50%. For GFR <20 mL/min: use with caution, consider further dose reduction. Hemodialysis: administer after dialysis, start with 400 mg and adjust based on tolerability. |
| Liver impairment | Child-Pugh A: no adjustment. Child-Pugh B: reduce dose by 25%. Child-Pugh C: reduce dose by 50% or consider alternative therapy. |
| Pediatric use | For CML in children: 260 mg/m² orally once daily (maximum 400 mg). For GIST in children: not established; use adult dosing based on BSA if necessary. |
| Geriatric use | No specific dose adjustment recommended. Monitor renal function and fluid retention carefully due to increased risk of adverse effects such as edema and electrolyte imbalances. |
| 1st trimester | Avoid: associated with teratogenicity (e.g., increased risk of major congenital malformations) in animal studies and limited human data. |
| 2nd trimester | Avoid: use only if benefit outweighs risk; may cause fetal harm based on animal data. |
| 3rd trimester | Avoid: potential for third-trimester adverse effects including oligohydramnios and neonatal complications. |
Clinical note
Comprehensive clinical and safety monograph for GLEEVEC (GLEEVEC).
| Placental transfer | Known to cross the placenta; detected in fetal plasma at concentrations similar to maternal. |
| Breastfeeding | Present in human milk; potential for serious adverse reactions in nursing infants. Advise against breastfeeding during treatment and for at least 1 month after last dose. |
■ FDA Black Box Warning
No FDA black box warning.
| Serious Effects |
Hypersensitivity to imatinib or any excipient
| Precautions | Fluid retention and edema (including pleural effusion, pericardial effusion, pulmonary edema), Hepatotoxicity (elevated transaminases, bilirubin; risk of hepatic failure), Congestive heart failure and left ventricular dysfunction, Hemorrhage (especially gastrointestinal and intracranial), Bone marrow suppression (neutropenia, thrombocytopenia, anemia), Hypothyroidism in thyroidectomy patients on levothyroxine, Growth retardation in children, Fetal harm (pregnancy category D), Tumor lysis syndrome, Long QT syndrome (rare) |
| Food/Dietary | Take with food to reduce GI irritation. Avoid grapefruit products (grapefruit, grapefruit juice, Seville oranges) as they increase imatinib exposure via CYP3A4 inhibition. No specific interactions with other foods. |
Loading safety data…
| Lactation Rating |
| L5 (Contraindicated) |
| Teratogenic Risk | First trimester: Category D. Imatinib is teratogenic; case reports of spontaneous abortion, fetal anomalies including exencephaly, anencephaly, and skeletal malformations. Second and third trimesters: Limited data; potential for fetal growth restriction, oligohydramnios, and preterm delivery. Avoid use in pregnancy unless benefit outweighs risk. |
| Fetal Monitoring | Monitor complete blood counts, liver function tests (LFTs), and serum electrolytes monthly. Perform fetal ultrasound for growth and anatomy in pregnancy. Monitor for signs of fluid retention, cardiac function, and hepatic toxicity. Assess for tumor lysis syndrome in patients with high tumor burden. |
| Fertility Effects | Imatinib may impair female fertility; reversible oligomenorrhea and amenorrhea reported. In males, reduced sperm count and motility; reversible upon discontinuation. No specific data on long-term fertility outcomes. |
| Clinical Pearls | Monitor hepatic function closely; dose reduction required for moderate to severe hepatic impairment. Check CBC weekly for first month, then biweekly for second month, and periodically thereafter. Assess for fluid retention (periorbital, peripheral, pleural effusion). QT prolongation risk; obtain baseline and periodic ECG. Avoid use with strong CYP3A4 inhibitors (e.g., ketoconazole, grapefruit). |
| Patient Advice | Take with a meal and large glass of water to minimize GI irritation. · Do not crush or chew tablets; swallow whole. · Avoid grapefruit and grapefruit juice during treatment. · Report any swelling (face, hands, feet), rapid weight gain, or shortness of breath immediately. · Use effective contraception during treatment and for at least 14 days after stopping. · Do not stop taking medication without consulting your doctor. · Common side effects include fluid retention, muscle cramps, diarrhea, and fatigue. · Avoid people with infections and report any signs of infection (e.g., fever, sore throat). |