Imatinib (Monograph)
Brand name: Gleevec
Drug class: Antineoplastic Agents
- Kinase Inhibitors
- Receptor Tyrosine Kinase Inhibitors
- Tyrosine Kinase Inhibitors
VA class: AN900
Chemical name: 4-[(4-methyl-1-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]aminophenyl]-benzamide methanesulfonate salt
CAS number: 152459-95-5
Introduction
Antineoplastic agent; an inhibitor of Bcr-Abl tyrosine kinase.
Uses for Imatinib
Chronic Myelogenous Leukemia (CML)
First-line treatment of newly diagnosed Philadelphia chromosome-positive (Ph+) CML in adults and pediatric patients who are in the chronic phase of the disease (designated an orphan drug by FDA for this use).
Second-line treatment of Ph+ CML in adults who are in blast crisis, accelerated phase, or chronic phase of the disease after failure of interferon alfa therapy (designated an orphan drug by FDA for this use).
Second-line treatment of pediatric patients with Ph+ chronic phase CML whose disease recurred after stem cell transplantation and in those with disease resistant to interferon alfa therapy.
Efficacy in pediatric patients determined based on overall hematologic and/or cytogenetic response rates; actual clinical benefits (e.g., decrease in disease-related symptoms, increase in survival) not adequately studied.
Acute Lymphocytic Leukemia (ALL)
Treatment of relapsed or refractory Ph+ ALL in adults (designated an orphan drug by FDA for this use).
Used in combination with chemotherapy for the treatment of pediatric patients ≥1 year of age with newly diagnosed Ph+ ALL.
Designated an orphan drug by FDA for use in this condition.
Myelodysplastic Syndrome (MDS) or Myeloproliferative Disease (MPD)
Treatment of MDS or MPD associated with gene rearrangements of platelet-derived growth factor receptor (PDGFR) in adults (designated an orphan drug by FDA for this use).
Systemic Mastocytosis (SM)
Treatment of aggressive systemic mastocytosis (ASM) in adults who lack the D816V c-Kit mutation or in whom c-Kit mutational status is unknown (designated an orphan drug by FDA for this use).
Ineffective for ASM with the D816V c-Kit mutation; other therapy is indicated.
Has not been shown to be effective in patients with less aggressive forms of SM. Imatinib is not recommended for use in patients with cutaneous mastocytosis, indolent SM (smoldering SM or isolated bone marrow mastocytosis), SM with an associated clonal hematologic non-mast cell lineage disease, mast cell leukemia, mast cell sarcoma, or extracutaneous mastocytoma.
Hypereosinophilic Syndrome (HES) or Chronic Eosinophilic Leukemia (CEL)
Treatment of HES and/or CEL in adults who have the FIP1L1-PDGFRα fusion kinase (mutational analysis or FISH demonstration of CHIC2 allele deletion), patients who are negative for FIP1L1-PDGFRα fusion kinase, or patients in whom expression of FIP1L1-PDGFRα fusion kinase is unknown (designated an orphan drug by FDA for this use).
Dermatofibrosarcoma Protuberans
Treatment of unresectable, recurrent, and/or metastatic dermatofibrosarcoma protuberans in adults (designated an orphan drug by FDA for this use).
GI Stromal Tumors (GIST)
Treatment of patients with c-Kit (CD117)-positive unresectable and/or metastatic malignant GIST (designated an orphan drug by FDA for this use).
Adjuvant treatment of c-Kit (CD117) positive GIST of patients following complete gross resection.
Other Uses
Has been evaluated for the treatment of bone cancer† [off-label], desmoid tumors† [off-label], AIDS-related Kaposi sarcoma† [off-label], melanoma† [off-label], pigmented villonodular synovitis/tenosynovial giant cell tumor† [off-label].
Imatinib Dosage and Administration
General
Pretreatment Screening
-
Complete blood cell count (CBC).
-
Baseline liver and renal function.
-
Consider performing an echocardiogram and determining serum troponin concentrations in patients with hypereosinophilic syndrome (HES) and/or chronic eosinophilic leukemia (CEL), and in patients with myelodysplastic/myeloproliferative diseases or aggressive systemic mastocytosis associated with high eosinophil levels. If results of the echocardiogram or serum troponin concentrations are abnormal, consider prophylactic use of systemic corticosteroids.
-
Verify pregnancy status in females of reproductive potential.
Patient Monitoring
-
Monitor for signs or symptoms of fluid retention (e.g., weight gain) regularly during therapy.
-
Monitor CBC weekly for the first month of therapy, every other week during the second month, and periodically (e.g., every 2–3 months) thereafter as clinically indicated.
-
Carefully monitor patients with cardiac disease or risk factors for cardiac disease for signs and symptoms of cardiac toxicity or renal failure.
-
Carefully monitor patients with a history of renal failure for signs and symptoms of cardiac toxicity or renal failure.
-
Monitor liver function monthly or as clinically indicated during therapy.
-
Monitor renal function during therapy.
-
Monitor serum TSH concentrations in patients receiving levothyroxine replacement therapy following thyroidectomy.
-
In pediatric patients, monitor bone growth and development.
-
Monitor patients with high tumor burden or those with a high proliferative rate for tumor lysis syndrome.
Premedication and Prophylaxis
-
In patients with HES and/or CEL, myelodysplastic/myeloproliferative diseases, or aggressive systemic mastocytosis associated with high eosinophil levels, and an abnormal echocardiogram or serum troponin concentrations, consider prophylaxis with systemic corticosteroids (1–2 mg/kg) for 1–2 weeks concomitantly with imatinib therapy at the time of initiation of therapy to reduce risk of hypereosinophilic cardiac toxicity.
Dispensing and Administration Precautions
- Handling and Disposal
-
Consult specialized references for procedures for proper handling (e.g., use of gloves) and disposal of antineoplastics.
-
Avoid direct contact of crushed tablets with the skin or mucous membranes. If such contact occurs, wash affected area thoroughly according to specialized references for procedures for proper handling of antineoplastics.
Administration
Oral Administration
Administer orally once or twice daily with a meal and a large glass of water to minimize gastric irritation.
In adults, administer doses of 400 or 600 mg once daily; dosages of 800 mg should be administered as 400 mg twice daily using the 400-mg tablet to reduce exposure to iron.
In children or adolescents, administer once daily; alternatively, administer in 2 equally divided doses in the morning and evening.
For patients unable to swallow the film-coated tablets, place required number of tablets in the appropriate volume (approximately 50 mL for a 100-mg tablet and 200 mL for a 400-mg tablet) of water or apple juice; stir with a spoon. Administer the suspension immediately after complete disintegration of the tablet(s).
If a dose of imatinib is missed, take the prescribed dose at the next scheduled time; do not administer an additional dose to replace the missed dose.
Dosage
Available as imatinib mesylate; dosage expressed in terms of imatinib.
Pediatric Patients
CML
First-line Treatment of Ph+ CML in Chronic Phase
Oral≥1 year of age: 340 mg/m2 given once daily or in 2 equally divided doses (once in the morning and once in the evening), not to exceed 600 mg daily.
ALL
Newly Diagnosed Ph+ ALL in Combination with Chemotherapy
Oral≥1 year of age: 340 mg/m2 given once daily or in 2 equally divided doses (once in the morning and once in the evening), not to exceed 600 mg daily.
Adults
CML
First- or Second-line Treatment of Ph+ CML in Chronic Phase
Oral400 mg daily.
If there is evidence of disease progression (at any time), inadequate hematologic response after at least 3 months of therapy, inadequate cytogenetic response after 6–12 months of therapy, or loss of a previously achieved hematologic or cytogenetic response, may increase dosage (in the absence of severe adverse drug or hematologic effects) to 600 mg daily.
Second-line Treatment of Ph+ CML in Accelerated Phase or Blast Crisis
Oral600 mg daily.
If there is evidence of disease progression (at any time), inadequate hematologic response after at least 3 months of therapy, inadequate cytogenetic response after 6–12 months of therapy, or loss of a previously achieved hematologic or cytogenetic response, may increase dosage (in the absence of severe adverse drug or hematologic effects) to 800 mg daily (administered as 400 mg twice daily).
ALL
Oral
600 mg daily.
MDS/MPD
Oral
400 mg daily.
ASM
Oral
ASM without D816V c-Kit mutation: 400 mg daily.
ASM with unknown D816V c-Kit mutational status not responding satisfactorily to other therapies: May consider dosage of 400 mg daily.
ASM (without D816V c-Kit mutation or with unknown D816V c-Kit mutational status) that is associated with eosinophilia (a clonal hematologic disease related to the FIP1L1-PDGFRα fusion kinase): Initially, 100 mg daily; if therapeutic response is insufficient, may increase dosage to 400 mg daily as tolerated.
HES/CEL
Oral
HES/CEL with FIP1L1-PDGFRα fusion kinase expression: Initially, 100 mg daily; if therapeutic response is insufficient, may increase dosage to 400 mg daily as tolerated.
HES/CEL in patients without FIP1L1-PDGFRα fusion kinase expression or in patients in whom expression of FIP1L1-PDGFRα fusion kinase is unknown: 400 mg daily.
Dermatofibrosarcoma Protuberans
Oral
800 mg daily.
GIST
Advanced GIST
Oral400 mg daily; may increase to 800 mg daily, as tolerated, if disease progression occurs.
Adjuvant Therapy
Oral400 mg daily.
Dosage Modification for Toxicity
Hepatic Toxicity
If substantial increases in bilirubin (>3 times ULN) or hepatic aminotransferase concentrations (>5 times ULN) occur, withhold imatinib until bilirubin or aminotransferase concentrations decrease to <1.5 or <2.5 times ULN, respectively. Resume therapy at a reduced daily dosage. Adults previously receiving a dosage of 400, 600, or 800 mg daily may resume therapy at a dosage of 300, 400, or 600 mg daily, respectively; pediatric patients previously receiving a dosage of 340 mg/m2 daily may resume therapy at a dosage of 260 mg/m2 daily.
Hematologic Toxicity
Adjust dosage or interrupt therapy if severe neutropenia and/or thrombocytopenia occurs (see tables below).
Use |
Absolute Neutrophil Count (ANC) and/or Platelet Count |
Dosage Modification |
---|---|---|
Newly diagnosed chronic phase CML (initial starting dosage = 340 mg/m2) |
ANC <1000/mm3 and/or platelets <50,000/mm3 |
First occurrence: Withhold therapy until ANC ≥1500/mm3 and platelet count ≥75,000/mm3, then resume at same dosage |
Second occurrence: Withhold therapy until ANC ≥1500/mm3 and platelet count ≥75,000/mm3, then resume at a reduced dosage of 260 mg/m2 |
Use (Initial Dosage) |
Hematologic Measurements |
Dosage Modification |
---|---|---|
Aggressive systemic mastocytosis (initial starting dosage = 400 mg daily) |
ANC <1000/mm3 and/or platelets <50,000/mm3 |
First occurrence: Withhold therapy until ANC ≥1500/mm3 and platelet count ≥75,000/mm3, then resume at original starting dosage (400 mg daily) |
Second occurrence: Withhold therapy until ANC ≥1500/mm3 and/or platelet count ≥75,000/mm3, then resume at a reduced dosage of 300 mg daily |
||
Aggressive systemic mastocytosis associated with eosinophilia (initial starting dosage = 100 mg daily) |
ANC <1000/mm3 and/or platelets <50,000/mm3 |
Withhold therapy until ANC ≥1500/mm3 and platelet count ≥75,000/mm3, resume at same dosage |
Hypereosinophilic syndrome/chronic eosinophilic leukemia without FIP1L1-PDGFRα fusion kinase expression or unknown FIP1L1-PDGFRα status (initial starting dosage = 400 mg) |
ANC <1000/mm3 and/or platelets <50,000/mm3 |
First occurrence: Withhold therapy until ANC ≥1500/mm3 and platelet count ≥75,000/mm3, then resume at original starting dosage (400 mg daily) |
Second occurrence: Withhold therapy until ANC ≥1500/mm3 and/or platelet count ≥75,000/mm3, then resume at a reduced dosage of 300 mg daily |
||
Hypereosinophilic syndrome/chronic eosinophilic leukemia with FIP1L1-PDGFRα fusion kinase (initial starting dosage = 100 mg daily) |
ANC <1000/mm3 and/or platelets <50,000/mm3 |
Withhold therapy until ANC ≥1500/mm3 and platelet count ≥75,000/mm3, resume at same dosage |
Chronic phase CML (initial starting dosage = 400 mg daily) |
ANC <1000/mm3 and/or platelets <50,000/mm3 |
First occurrence: Withhold therapy until ANC ≥1500/mm3 and platelet count ≥75,000/mm3, then resume at original starting dosage (400 mg daily) |
Second occurrence: Withhold therapy until ANC ≥1500/mm3 and/or platelet count ≥75,000/mm3, then resume at a reduced dosage of 300 mg daily |
||
Myelodysplastic Syndrome/Myeloproliferative Diseases (initial starting dosage = 400 mg daily) |
ANC <1000/mm3 and/or platelets <50,000/mm3 |
First occurrence: Withhold therapy until ANC ≥1500/mm3 and platelet count ≥75,000/mm3, then resume at original starting dosage (400 mg daily) |
Second occurrence: Withhold therapy until ANC ≥1500/mm3 and/or platelet count ≥75,000/mm3, then resume at a reduced dosage of 300 mg daily |
||
GIST (initial starting dosage = 400 mg daily) |
ANC <1000/mm3 and/or platelets <50,000/mm3 |
First occurrence: Withhold therapy until ANC ≥1500/mm3 and platelet count ≥75,000/mm3, then resume at original starting dosage (400 mg daily) |
Second occurrence: Withhold therapy until ANC ≥1500/mm3 and/or platelet count ≥75,000/mm3, then resume at a reduced dosage of 300 mg daily |
||
Ph+ CML in accelerated phase or blast crisis (initial starting dosage = 600 mg daily) |
ANC <500/mm3 and/or platelets <10,000/mm3 and unrelated to CML |
Reduce dosage to 400 mg daily |
If cytopenia persists for 2 weeks, further reduce dosage to 300 mg daily |
||
If cytopenia persists for 4 weeks, withhold subsequent doses until ANC≥1000/mm3 and platelet counts ≥20,000/mm3, then resume therapy at a reduced dosage of 300 mg daily |
||
Ph+ ALL (initial starting dosage = 600 mg daily) |
ANC <500/mm3 and/or platelets <10,000/mm3 and unrelated to ALL |
Reduce dosage to 400 mg daily |
If cytopenia persists for 2 weeks, reduce dosage further to 300 mg daily |
||
If cytopenia persists for 4 weeks, withhold subsequent doses until ANC≥1000/mm3 and platelet counts ≥20,000/mm3, then resume therapy at a reduced dosage of 300 mg daily |
||
Dermatofibrosarcoma Protuberans (initial starting dosage = 800 mg daily) |
ANC <1000/mm3 and/or platelets <50,000/mm3 |
First occurrence: Withhold therapy until ANC ≥1500/mm3 and platelet count ≥75,000/mm3, then resume therapy at a reduced dosage of 600 mg |
Second occurrence: Withhold therapy until ANC ≥1500/mm3 and platelet count ≥75,000/mm3, then resume at a reduced dosage of 400 mg daily |
Nonhematologic Toxicity
If severe nonhematologic toxicity (e.g., severe fluid retention) develops, withhold therapy until the toxicity resolves, then resume therapy as appropriate.
Concomitant Use of Drugs Affecting Hepatic Microsomal Enzymes
Increase imatinib dosage by at least 50% and carefully monitor clinical response in patients receiving concomitant therapy with imatinib and potent CYP3A4 inducers (e.g., phenytoin, rifampin).
Special Populations
Hepatic Impairment
Mild to moderate hepatic impairment: No dosage adjustment necessary.
Severe hepatic impairment: Reduce dosage by 25%.
Renal Impairment
Mild renal impairment (Clcr 40–59 mL/minute): Do not exceed 600 mg daily.
Moderate renal impairment (Clcr 20–39 mL/minute): Decrease initial dosage by 50%; increase subsequent dosage as tolerated up to a maximum dosage of 400 mg.
Severe renal impairment: Use with caution.
Geriatric Patients
Manufacturer makes no specific dosage recommendations.
Cautions for Imatinib
Contraindications
-
None.
Warnings/Precautions
Fluid Retention and Edema
Risk of severe superficial edema, severe fluid retention (i.e., pleural effusion, pericardial effusion, pulmonary edema, ascites).
The incidence of edema and fluid retention appears to be increased in patients receiving higher dosages and in geriatric patients.
Monitor signs (e.g., body weight) and symptoms of fluid retention regularly. If severe fluid retention develops, withhold imatinib therapy and provide appropriate treatment until complete resolution occurs.
Hematologic Effects
Risk of neutropenia, anemia, or thrombocytopenia. In pediatric patients with CML, grade 3 or 4 cytopenias (neutropenia, thrombocytopenia, and anemia) were the most common toxicities.
Monitor CBCs weekly during the first month of therapy, every other week during the second month, and periodically (e.g., every 2–3 months) thereafter as clinically indicated.
Cardiovascular Effects
Severe CHF and left ventricular dysfunction reported, mostly in geriatric patients or patients with a history of cardiac disease. Monitor such patients carefully; evaluate and treat any patient with manifestations of cardiac or renal failure.
In patients with HES and cardiac involvement, initiation of imatinib has been associated with cardiogenic shock or left ventricular dysfunction; this condition reportedly was reversible with administration of systemic corticosteroids, circulatory support measures, and temporary discontinuance of imatinib.
Consider performing echocardiogram and determining serum troponin concentration in patients with elevated eosinophil concentrations (including patients with HES/CEL or patients with MDS/MPD or ASM associated with high eosinophil concentrations). If echocardiogram or serum troponin concentration is abnormal, consider prophylactic use of systemic corticosteroids for 1–2 weeks concomitantly with imatinib upon initiation of therapy.
Hepatic Effects
Risk of grade 3 or 4 hyperbilirubinemia and elevations in alkaline phosphatase, ALT, and AST (grade 3 or 4 severity). Fatal hepatic failure has been reported following short- and long-term use.
Monitor liver function tests (i.e., transaminases, bilirubin, alkaline phosphatase) prior to initiation of therapy and monthly thereafter or as clinically indicated. If liver function test results are abnormal, withhold imatinib and/or reduce imatinib dosage. (See Hepatic Toxicity under Dosage and Administration.)
Hemorrhage
Risk of grade 3 or 4 hemorrhage, GI bleeds, and/or intratumoral bleeds. GI bleeds may have originated from GI tumor sites.
GI Effects
GI perforation, sometimes fatal, reported rarely.
Administer with food and a large glass of water to minimize GI irritation.
Dermatologic Effects
Bullous skin reactions, including erythema multiforme and Stevens-Johnson syndrome, reported. Some cases have recurred upon rechallenge of imatinib therapy. If dermatologic toxicity occurs, discontinue imatinib. Has been reinitiated in some patients at a reduced dosage (with or without concomitant corticosteroids or antihistamines) following resolution or lessening of the bullous skin reaction.
Hypothyroidism
Hypothyroidism reported in imatinib-treated patients receiving levothyroxine replacement therapy following thyroidectomy; monitor serum TSH concentrations in such patients.
Fetal/Neonatal Morbidity and Mortality
May cause fetal harm; teratogenicity and embryolethality demonstrated in animals. Avoid pregnancy during therapy. Verify pregnancy status of females of reproductive potential and advise such patients to use an effective contraceptive method during therapy and for 14 days after the last dose. If used during pregnancy or if patient becomes pregnant, apprise of potential fetal hazard.
Effects on Growth of Pediatric Patients
May be associated with adverse reactions related to growth in children or pre-adolescents receiving the drug. Long-term effects on growth in children is unknown; monitor growth during therapy in pediatric patients.
Tumor Lysis Syndrome
Tumor lysis syndrome, sometimes fatal, reported in patients with CML, GIST, ALL, and eosinophilic leukemia. Increased risk in patients with high tumor burden or high proliferative rate; monitor such patients and take appropriate precautions (e.g, adequate hydration, correct uric acid levels).
Impaired Driving/Machinery Operation
Motor vehicle accidents reported in patients receiving imatinib. Dizziness, blurred vision, or somnolence may occur. Advise patients to use caution when driving or operating machinery.
Renal Toxicity
Reduced renal function reported. Monitor renal function prior to initiation of and during imatinib therapy, with close attention to patients with risk factors for renal dysfunction (e.g., preexisting renal impairment, diabetes mellitus, hypertension, congestive heart failure).
Specific Populations
Pregnancy
May cause fetal harm.
Lactation
Imatinib and its metabolites distribute into human milk. Discontinue breast-feeding during therapy and for 1 month after last dose.
Pediatric Use
Safety and efficacy demonstrated only in children with newly diagnosed Ph+ chronic phase CML and Ph+ ALL.
No data in children <1 years of age.
May be associated with adverse reactions related to growth in children or pre-adolescents receiving the drug. Long-term effects on growth in children is unknown; monitor growth during therapy in pediatric patients.
Geriatric Use
In patients with CML or GIST, no substantial differences in safety and efficacy relative to younger patients were observed, with the exception of a higher incidence of edema.
Hepatic Impairment
Increased exposure to imatinib and its major active metabolite observed in patients with severe hepatic impairment; reduce imatinib dosage by 25%. Close monitoring recommended in these patients.
Renal Impairment
Increased exposure to imatinib in mild and moderate renal impairment; dosage adjustment may be necessary. Safety and efficacy not established in severe renal impairment; use with caution.
Common Adverse Effects
Adverse effects reported in ≥30% of patients were edema, nausea, vomiting, muscle cramps, musculoskeletal pain, diarrhea, rash, fatigue, and abdominal pain.
Drug Interactions
Metabolized principally by CYP3A4 and to a lesser degree by CYP1A2, CYP2D6, CYP2C9, and CYP2C19.
Potent competitive inhibitor of CYP3A4/5, CYP2C9, and CYP2D6.
Drugs Affecting Hepatic Microsomal Enzymes
Inhibitors of CYP3A4: Potential pharmacokinetic interaction (increased plasma imatinib concentrations).
Inducers of CYP3A4: Potential pharmacokinetic interaction (decreased plasma imatinib concentrations). Increase imatinib dosage by ≥50% when coadministered with a potent CYP3A4 inducer.
Drugs Metabolized by Hepatic Microsomal Enzymes
Potential pharmacokinetic interaction (increased plasma concentrations of substrates of CYP3A4, CYP2C9, and CYP2D6).
Specific Drugs and Foods
Drug or Food |
Interaction |
Comments |
---|---|---|
Acetaminophen |
Possible increased serum acetaminophen concentrations Imatinib inhibits the acetaminophen O-glucuronidate pathway; however, concomitant administration of acetaminophen (single-dose) and imatinib (400 mg daily for 8 days) did not change acetaminophen pharmacokinetics Fatal hepatic failure reported in at least one patient No data on concomitant long-term use |
Use concomitantly with caution |
Alfentanil |
Increased alfentanil concentrations |
Use with caution since alfentanil has a narrow therapeutic window |
Antifungals, azoles (itraconazole, ketoconazole, voriconazole) |
Decreased imatinib metabolism and increased plasma imatinib concentrations |
Use concomitantly with caution |
Antiepileptic drugs (carbamazepine, fosphenytoin, oxcarbamazepine, phenobarbital, phenytoin, primidone) |
Decreased plasma imatinib concentrations |
Consider alternative agents with less enzyme induction potential |
Benzodiazepines (i.e., triazolo) |
Increased benzodiazepine concentrations |
|
Calcium channel blockers (i.e., dihydropyridines) |
Increased calcium channel blocker concentrations |
|
Dexamethasone |
Increased imatinib metabolism and decreased plasma imatinib concentrations |
Consider choosing other agents with less enzyme induction potential |
Ergot alkaloids (dihydroergotamine, ergotamine) |
Increased ergot alkaloid concentrations |
Use with caution since ergot alkaloids have a narrow therapeutic window |
Grapefruit juice |
Increased plasma imatinib concentrations |
Avoid concomitant use |
HMG-CoA reductase inhibitors (statins) (simvastatin) |
Increased statin concentrations |
|
Immunosuppressants (cyclosporine, sirolimus, tacrolimus) |
Increased immunosuppressant concentrations |
Use with caution since immunosuppressants have a narrow therapeutic window |
Macrolide antibiotics (clarithromycin) |
Decreased imatinib metabolism and increased plasma imatinib concentrations |
Use concomitantly with caution |
Metoprolol |
Imatinib increased systemic exposure of metoprolol by approximately 23% |
No dosage adjustment necessary |
Nefazodone |
Decreased imatinib metabolism and increased plasma imatinib concentrations |
Use concomitantly with caution |
Pimozide |
Increased pimozide concentrations |
Use with caution since pimozide has a narrow therapeutic window |
Protease inhibitors (atazanavir, indinavir, nelfinavir, ritonavir, saquinavir) |
Decreased imatinib metabolism and increased plasma imatinib concentrations |
Use concomitantly with caution |
Quinidine |
Increased quinidine concentrations |
Use with caution since quinidine has a narrow therapeutic window |
Rifabutin |
Decreased imatinib concentrations |
Consider alternative agents with less enzyme induction potential |
Rifampin |
Increased imatinib metabolism and decreased peak plasma concentration and AUC of imatinib |
Increase imatinib dosage by at least 50% and carefully monitor clinical response; alternatively, consider choosing other agents with less enzyme induction potential |
St. John’s wort |
Increased imatinib metabolism and decreased plasma imatinib concentrations |
Consider choosing other agents with less enzyme induction potential |
Warfarin |
Potential pharmacokinetic and pharmacologic interaction (enhanced anticoagulant effect) |
Patients requiring anticoagulation therapy should receive heparin or low molecular weight heparin |
Imatinib Pharmacokinetics
The pharmacokinetics of imatinib are similar in CML and GIST patients.
Absorption
Bioavailability
Well absorbed following oral administration. Mean absolute bioavailability is 98%.
Following oral administration, peak plasma concentrations are attained within 2–4 hours in adult and pediatric patients. Following administration of once daily dosing, accumulation is 1.5–2.5-fold at steady state.
Administration of 260 mg/m2 or 340 mg/m2 in pediatric patients achieved an AUC similar to that attained with a 400-mg dose in adults. Mean imatinib AUC increases proportionally with dose in adults but not in pediatric patients.
Special Populations
In patients with severe hepatic impairment, increased peak plasma concentration and AUC of imatinib and its major active metabolite have been observed.
In patients with mild or moderate hepatic impairment, exposure to imatinib and its major active metabolite was comparable to that in patients with normal hepatic function.
Distribution
Extent
Distributed into human milk.
Plasma Protein Binding
Approximately 95% (mainly albumin and α1-acid glycoprotein). Plasma protein binding of major active metabolite is similar to that of the parent drug.
Elimination
Metabolism
Metabolized in the liver, principally by CYP3A4 and to a lesser degree by CYP1A2, CYP2D6, CYP2C9, and CYP2C19. The major active metabolite is the N-desmethyl derivative, which has an in vitro potency similar to the parent drug.
Elimination Route
Predominantly in feces, mostly as metabolites. Following oral administration of a single radiolabeled dose of imatinib, approximately 81% of the dose was eliminated within 7 days (68% of the dose in feces and 13% of the dose in urine); unchanged drug accounted for 25% of the dose (20% in feces, 5% in urine) with the remainder being metabolites.
Apparent oral clearance appears to be similar in adults and pediatric patients.
Half-life
Approximately 18 hours for imatinib and 40 hours for its major active metabolite in adults; the elimination half-lives in pediatric patients appear to be similar to those in adults.
Special Populations
Clearance appears to increase with increasing body weight.
Stability
Storage
Oral
Tablets
Tight container at 20–25°C (excursions permitted between 15–30°C). Protect from moisture.
Actions
-
Competitively inhibits Bcr-Abl tyrosine kinase, the constitutive abnormal tyrosine kinase created by the Philadelphia chromosome abnormality in CML.
-
Inhibits proliferation and induces apoptosis of Bcr-Abl-positive cell lines as well as fresh leukemic cells from Ph+ CML. 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 in vivo.
-
Inhibits receptor tyrosine kinases for platelet-derived growth factor (PDGF) and stem cell factor (SCF), c-Kit, and inhibits PDGF-mediated and SCF-mediated cellular events. Inhibits proliferation and induces apoptosis of GIST cells (which express an activating c-Kit mutation) in vitro.
Advice to Patients
-
Advise patients to take imatinib exactly as prescribed with a full glass of water. If a dose is missed, take the next dose at its regular time; do not take 2 doses at the same time.
-
Advise patients of the possibility of fluid retention/edema and the importance of informing their clinician if rapid weight gain occurs.
-
Advise patients that hepatic toxicity may occur and the importance of contacting their clinician if signs of liver dysfunction (e.g., jaundice, anorexia, bleeding, bruising) occur.
-
Advise women to inform their clinician if they are or plan to become pregnant or plan to breastfeed. Advise women to avoid becoming pregnant while taking imatinib; advise women to use highly effective contraception while taking imatinib and for 2 weeks after stopping treatment.
-
Advise patients to inform their clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary and herbal supplements, as well as any concomitant illnesses. Avoid grapefruit juice. Advise patients to inform their clinician if they plan to take iron supplements.
-
Advise patients that growth should be monitored in pediatric patients receiving imatinib.
-
Advise patients that blurred vision, dizziness, or somnolence may occur while receiving imatinib and caution is advised while driving or operating machinery.
-
Importance of advising women to avoid breast-feeding while receiving imatinib and for 1 month after discontinuance of therapy.
-
Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements (e.g., St. John’s wort), as well as any concomitant illnesses.
-
Importance of informing patients of other important precautionary information.
Preparations
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
Routes |
Dosage Forms |
Strengths |
Brand Names |
Manufacturer |
---|---|---|---|---|
Oral |
Tablets, film-coated |
100 mg (of imatinib)* |
Gleevec |
Novartis |
Imatinib Tablets |
||||
400 mg (of imatinib)* |
Gleevec |
Novartis |
||
Imatinib Tablets |
AHFS DI Essentials™. © Copyright 2024, Selected Revisions March 25, 2022. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.
† Off-label: Use is not currently included in the labeling approved by the US Food and Drug Administration.
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