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

Medically reviewed by Drugs.com on Mar 15, 2024. Written by ASHP.

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

Oral

400 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

Oral

600 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

Oral

400 mg daily; may increase to 800 mg daily, as tolerated, if disease progression occurs.

Adjuvant Therapy

Oral

400 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).

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 (Cl_cr 40–59 mL/minute): Do not exceed 600 mg daily.

Moderate renal impairment (Cl_cr 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

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

Reload page with references included

Frequently asked questions

• What to avoid when taking Gleevec?
• How does Gleevec (imatinib) work?
• Is there a generic for Gleevec?
• Can I take Gleevec while pregnant?

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