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Generic Name: Imatinib Mesylate
Class: Antineoplastic Agents
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.1

Uses for Gleevec

Chronic Myelogenous Leukemia (CML)

First-line treatment of newly diagnosed Philadelphia chromosome-positive (Ph+) CML in adult and pediatric patients who are in the chronic phase of the disease (designated an orphan drug by FDA for this use);1 4 18 follow-up is limited.1

Second-line treatment of Ph+ CML in adults who are in blast crisis, in the accelerated phase, or in the chronic phase of the disease after failure of interferon alfa therapy (designated an orphan drug by FDA for this use).1 4 10

Second-line treatment of pediatric patients with Ph+ chronic phase CML whose disease has recurred after stem cell transplantation or who are resistant to interferon alfa therapy.1

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.1 a

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Acute Lymphocytic Leukemia (ALL)

Treatment of relapsed or refractory Ph+ ALL in adults (designated an orphan drug by FDA for this use).4 20 a

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).4 20 a

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).4 20 a

Ineffective for ASM with the D816V c-Kit mutation; other therapy is indicated.8 a 20

Has not been shown to be effective in patients with less aggressive forms of SM.a Therefore, 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.a

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).4 20 a

Dermatofibrosarcoma Protuberans (DFSP)

Treatment of unresectable, recurrent, and/or metastatic DFSP in adults (designated an orphan drug by FDA for this use).4 20 a

GI Stromal Tumors (GIST)

Treatment of patients with Kit (CD117)-positive unresectable and/or metastatic malignant GIST (designated an orphan drug by FDA for this use).1 4 18

Efficacy determined based on objective response rates; actual clinical benefits (e.g., decrease in disease-related symptoms, increase in survival) not adequately studied.1

Gleevec Dosage and Administration

General

  • Use under supervision of a qualified clinician experienced in the treatment of hematologic malignancies or malignant sarcomas.1

  • In patients with elevated eosinophil concentrations, consider prophylactic use of systemic corticosteroids for 1–2 weeks concomitantly with imatinib upon initiation of therapy to reduce the risk of hypereosinophilic cardiac toxicity.20 (See Cardiovascular Effects under Cautions.)

  • Therapy may be continued as long as there is no evidence of progressive disease or unacceptable toxicity.1

Administration

Oral Administration

Administer once or twice daily with a meal and a large glass (240 mL) of water to minimize gastric irritation.1 8 10

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.1

In children or adolescents, administer once daily; alternatively, administer in 2 equally divided doses in the morning and evening.1

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.1 Administer the suspension immediately after complete disintegration of the tablet(s).1 8 10

Dosage

Available as imatinib mesylate; dosage expressed in terms of imatinib.1

Pediatric Patients

CML
First-line Treatment of Ph+ CML in Chronic Phase
Oral

Children >2 years 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.1

Second-line Treatment of Ph+ CML in Chronic Phase
Oral

Children >2 years of age: 260 mg/m2 given once daily or in 2 equally divided doses (once in the morning and once in the evening).1

Adults

CML
First- or Second-line Treatment of Ph+ CML in Chronic Phase
Oral

400 mg daily.1 10 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.1 10 In the randomized trial, further dose escalation (to 800 mg daily, administered as 400 mg twice daily) was permitted.1

Second-line Treatment of Ph+ CML in Accelerated Phase or Blast Crisis
Oral

600 mg daily.1 10 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).1 10

ALL
Oral

600 mg daily.20 a

MDS/MPD
Oral

400 mg daily.20 a

ASM
Oral

ASM without D816V c-Kit mutation: 400 mg daily.20 a

ASM with unknown D816V c-Kit mutational status not responding satisfactorily to other therapies: May consider dosage of 400 mg daily.20 a

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.8 20 a

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.20 a

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.8 20 a

DFSP
Oral

800 mg daily.20 a

GIST
Oral

400 or 600 mg once daily.1

Dosage Modification for Toxicity

Dermatologic Toxicity

If severe dermatologic toxicity (e.g., bullous skin reactions) occurs, discontinue imatinib.1 Reinitiation of imatinib therapy has been tolerated in some patients when the drug was reinitiated at a lower dosage (with or without corticosteroids or antihistamines) following resolution or lessening of the bullous skin reaction.1

Fluid Retention/Edema

Management of edema may include diuretics, other supportive measures, and/or reduction of imatinib dosage.1 If severe fluid retention or edema develops, interrupt imatinib therapy until complete resolution occurs.1

Hepatic Toxicity

If substantial increases in bilirubin (>3 times ULN) or hepatic transaminase concentrations (>5 times ULN) occur, withhold imatinib until bilirubin or transaminase concentrations decrease to <1.5 or <2.5 times ULN, respectively.1 Resume therapy at a reduced daily dosage.1 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;1 8 pediatric patients previously receiving a dosage of 260 or 340 mg/m2 daily may resume therapy at a dosage of 200 or 260 mg/m2 daily, respectively.1

Hematologic Toxicity

Adjust dosage or interrupt therapy if severe neutropenia and/or thrombocytopenia occurs (see tables below).1

Pediatric Patients >2 Years of Age: Dosage Adjustments for Neutropenia and Thrombocytopenia

Use (Initial Dosage)

Hematologic Measurements

Comments

Newly diagnosed chronic phase Ph+ CML (initial dosage: 340 mg/m2 daily)

ANC <1000/mm3

and/or

platelets <50,000/mm3

1. Discontinue imatinib until ANC ≥1500/mm3 and platelets ≥75,000/mm31

2. Resume imatinib at previous dosage (i.e., before severe adverse reaction occurred)1

3. If recurrence of ANC <1000/mm3 and/or platelets <50,000/mm3 occurs, repeat step 1 and resume therapy at a reduced dosage of 260 mg/m21 a

Recurrent or resistant chronic phase Ph+ CML (initial dosage: 260 mg/m2 daily)

ANC <1000/mm3

and/or

platelets <50,000/mm3

1. Discontinue imatinib until ANC ≥1500/mm3 and platelets ≥75,000/mm31

2. Resume imatinib at previous dosage (i.e., before severe adverse reaction occurred)1

3. If recurrence of ANC <1000/mm3 and/or platelets <50,000/mm3 occurs, repeat step 1 and resume therapy at a reduced dosage of 200 mg/m21 a

Adults: Dosage Adjustments for Neutropenia and Thrombocytopenia

Use (Initial Dosage)

Hematologic Measurements

Comments

ASM associated with eosinophilia (initial dosage: 100 mg daily)20 a

or

HES/CEL with FIP1L1- PDGFRα fusion kinase expression (initial dosage: 100 mg daily)20 a

ANC <1000/mm3

and/or

platelets <50,000/mm3

1. Discontinue imatinib until ANC ≥1500/mm3 and platelets ≥75,000/mm320 a

2. Resume imatinib at previous dosage (i.e., before severe adverse reaction occurred)20 a

Chronic phase Ph+ CML (initial dosage: 400 mg daily)

or

MDS/MPD, ASM, or HES/CEL (initial dosage: 400 mg daily)20 a

or

GIST (initial dosage: 400 or 600 mg daily)

ANC <1000/mm3

and/or

platelets <50,000/mm3

1. Discontinue imatinib until ANC ≥1500/mm3 and platelets ≥75,000/mm31 20

2. Resume imatinib at original dosage of 400 or 600 mg once daily1

3. If recurrence of ANC <1000/mm3 and/or platelets <50,000/mm3 occurs, repeat step 1 and resume therapy at a reduced dosage (reduce from 400 mg to 300 mg or from 600 mg to 400 mg once daily)1

Ph+ CML: Accelerated phase and blast crisis (initial dosage: 600 mg daily)

or

Ph+ ALL (initial dosage: 600 mg daily)20 a

ANC <500/mm3

and/or

platelets <10,000/mm3

1. If cytopenia is unrelated to leukemia (as determined by marrow aspirate or biopsy), reduce dosage to 400 mg once daily1 20

2. If cytopenia persists for 2 weeks, further reduce dosage to 300 mg once daily1

3. If cytopenia persists for 4 weeks and still is unrelated to CML, withhold therapy until ANC ≥1000/mm3 and platelets ≥20,000/mm3; then reinitiate therapy at 300 mg once daily1

DFSP (initial dosage: 800 mg daily)20 a

ANC <1000/mm3

and/or

platelets <50,000/mm3

1. Discontinue imatinib until ANC ≥1500/mm3 and platelets ≥75,000/mm320 a

2. Resume imatinib at dosage of 600 mg once daily20 a

3. If recurrence of ANC <1000/mm3 and/or platelets <50,000/mm3 occurs, repeat step 1 and resume therapy at a reduced dosage of 400 mg once daily20 a

Special Populations

Hepatic Impairment

Mild to moderate hepatic impairment: Initially, up to 400 mg daily.1 In patients with conditions normally requiring initial dosages <400 mg daily (e.g., pediatric patients with small body frame, adults with ASM or HES/CEL with FIP1L1-PDGFRα fusion kinase expression), start therapy at recommended initial dosage, regardless of hepatic function.8 (See Dosage under Dosage and Administration.)

Severe hepatic impairment: Initially, up to 300 mg daily.1 In patients with conditions normally requiring initial dosages <300 mg daily (e.g., pediatric patients with small body frame, adults with ASM or HES/CEL with FIP1L1-PDGFRα fusion kinase expression), start therapy at recommended initial dosage, regardless of hepatic function.8 (See Dosage under Dosage and Administration.) In adult patients with ASM or HES/CEL with FIP1L1-PDGFRα fusion kinase expression who require dosage escalation, initially, increase dosage from 100 mg daily to 300 mg daily (rather than to 400 mg daily as usually recommended) and monitor liver function carefully; if therapeutic response is insufficient, consider increasing dosage to 400 mg daily as tolerated.8

Patients Receiving Potent CYP3A4 Inducers

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).1 (See Interactions.)

Cautions for Gleevec

Contraindications

  • Known hypersensitivity to imatinib or any ingredient in the formulation.1

Warnings/Precautions

Warnings

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm;1 teratogenicity and embryolethality demonstrated in animals.1 Avoid pregnancy during therapy.1 If used during pregnancy or if patient becomes pregnant, apprise of potential fetal hazard.1

Major Toxicities

Dermatologic Effects

Bullous skin reactions, including erythema multiforme and Stevens-Johnson syndrome, reported.1 If dermatologic toxicity occurs, discontinue imatinib.1 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.1

Fluid Retention and Edema

Risk of severe superficial edema (e.g., rapid weight gain, facial edema, anasarca),1 5 6 severe fluid retention (i.e., pleural effusion, pericardial effusion, pulmonary edema, ascites),1 8 10 cardiac tamponade, cerebral edema, increased intracranial pressure, and papilledema (including fatalities).1

The incidence of edema and fluid retention appears to be increased in CML patients in blast crisis, in patients receiving higher dosages (i.e., 600 mg daily), and in geriatric patients.1

Monitor signs (e.g., body weight) and symptoms of fluid retention regularly.1 If severe fluid retention develops, withhold imatinib therapy and provide appropriate treatment until complete resolution occurs.1

GI Effects

Nausea, vomiting, and diarrhea occur frequently.1 GI perforation, sometimes fatal, reported rarely.1

Administer with food and a large glass of water to minimize GI irritation.1

Hemorrhage

Risk of grade 3 or 4 hemorrhage, GI bleeds, and/or intratumoral bleeds.1 GI bleeds may have originated from GI tumor sites.1

Hematologic Effects

Risk of grade 3 or 4 neutropenia,1 5 8 anemia, or thrombocytopenia.1 5 8 Cytopenias reported less frequently in patients with newly diagnosed CML; higher frequency of grade 3 or 4 neutropenia and thrombocytopenia in patients with blast crisis or accelerated phase CML than in patients with chronic phase CML.1 In pediatric patients with CML, grade 3 or 4 cytopenias (neutropenia, thrombocytopenia, and anemia) usually occurred within the first several months of therapy.1

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.1 If hematologic toxicity occurs, withhold therapy.1 (See Hematologic Toxicity under Dosage and Administration.)

Hepatic Effects

Risk of grade 3 or 4 hyperbilirubinemia and elevations in alkaline phosphatase, ALT, and AST (grade 3 or 4 severity).1 10 Fatal hepatic failure occurred in at least one patient who received imatinib concomitantly with acetaminophen.1 8

Monitor liver function tests (i.e., transaminases, bilirubin, alkaline phosphatase) prior to initiation of therapy and monthly thereafter or as clinically indicated.1 If liver function test results are abnormal, withhold imatinib and/or reduce imatinib dosage.1 (See Hepatic Toxicity under Dosage and Administration.)

Cardiovascular Effects

Severe CHF and left ventricular dysfunction reported, mostly in geriatric patients or patients with a history of cardiac disease.1 17 Monitor such patients carefully; evaluate and treat any patient with manifestations of cardiac failure.1 17

In patients with HES and cardiac involvement, initiation of imatinib has been associated with cardiogenic shock or left ventricular dysfunction;20 a this condition reportedly was reversible with administration of systemic corticosteroids, circulatory support measures, and temporary discontinuance of imatinib.a 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).20 a If either is abnormal, consider prophylactic use of systemic corticosteroids for 1–2 weeks concomitantly with imatinib upon initiation of therapy.20 a

Metabolic Effects

Hypophosphatemia associated with altered bone and mineral metabolism has been reported in patients receiving imatinib for CML or GIST.1 21

General Precautions

Long-term Therapy

Consider potential toxicities suggested by animal studies, specifically, hepatic and renal toxicity and immunosuppression.1 Severe hepatic and renal toxicity observed in animals receiving imatinib for as little as 2 weeks.1 Immunosuppression reported in animals receiving imatinib for up to 39 weeks.1

Cardiomyopathy (e.g., cardiac hypertrophy and dilatation, resulting in cardiac insufficiency), chronic progressive nephropathy, and preputial gland papilloma reported in animals receiving imatinib for up to 2 years.a

Specific Populations

Pregnancy

Category D. (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Lactation

Distributed into milk in rats; drug concentration approximately threefold higher in milk than in plasma.1 Discontinue nursing because of potential risk in nursing infants.1

Pediatric Use

Safety and efficacy demonstrated only in children with newly diagnosed, recurrent, or resistant Ph+ chronic phase CML.1 The overall safety profile in 93 pediatric patients studied was similar to that in adult patients; however, musculoskeletal pain occurred less frequently in pediatric patients than in adults, and peripheral edema was not reported.1 Most frequently reported adverse effects include nausea and vomiting.1 a

No data in children <2 years of age.1

Geriatric Use

In patients with CML, no substantial differences in safety and efficacy relative to younger patients were observed, with the exception of a higher incidence of edema.1 Formal evaluation has not been performed in patients with GIST, but no obvious differences in safety and efficacy relative to younger patients observed.1

Hepatic Impairment

Increased exposure to imatinib and its major active metabolite observed in patients with severe hepatic impairment.1 Close monitoring recommended in these patients.1 (See Hepatic Impairment under Dosage and Administration.)

Renal Impairment

Safety and efficacy not established; use with caution.1 8

Common Adverse Effects

In patients with CML,1 nausea,1 8 10 vomiting,1 8 10 diarrhea,1 8 10 edema,1 8 10 muscle cramps,1 10 musculoskeletal pain,1 rash.1

In patients with ALL,a adverse effects similar to those reported in patients with CML (e.g., mild nausea,a vomiting,a diarrhea,a myalgia,a muscle cramps,a rash).a

In patients with MDS/MPD, nausea,a diarrhea,a muscle cramp,a anemia,a fatigue,a arthralgia,a periorbital edema.a

In patients with ASM, diarrhea,a nausea,a ascites,a muscle cramps,a dyspnea,a fatigue,a peripheral edema,a anemia,a pruritus,a rash,a lower respiratory tract infection.a

In patients with HES/CEL, adverse effects similar to those reported in patients with other hematologic malignancies (e.g., GI/cutaneous/musculoskeletal disorders).a

In patients with DFSP, nausea,a fatigue,a periorbital edema,a peripheral edema,a ocular edema,a diarrhea,a vomiting,a rash,a increased lacrimation,a anemia,a facial edema,a pyrexia,a exertional dyspnea,a rhinitis,a anorexia.a

In patients with GIST,1 edema,1 8 10 nausea,1 8 10 diarrhea,1 8 10 abdominal pain,1 muscle cramps,1 10 fatigue,1 rash.1 5 6 8 10

Other adverse effects occurring in ≥10% of patients: GI/CNS/tumor hemorrhage,1 headache,1 dyspepsia,1 8 joint pain,1 weight increase,1 cough,1 flatulence,1 constipation,1 nasopharyngitis,1 pharyngolaryngeal pain,1 night sweats,1 pruritus,1 hypokalemia,1 pneumonia,1 upper respiratory tract infection,1 dizziness,1 insomnia,1 depression,1 rigors,1 back pain,1 asthenia,1 influenza,1 taste disturbance,1 anxiety,1 liver toxicity,1 chest pain,1 sinusitis,1 loose stools.1

The incidence of neutropenia and grade 1 or 2 superficial edema, headache, nausea, rigors, vomiting, rash, and fatigue appears to be higher in women than in men.1

Interactions for Gleevec

Metabolized principally by CYP3A4 and to a lesser degree by CYP1A2, CYP2D6, CYP2C9, and CYP2C19.1

Appears to inhibit CYP3A4, CYP2C9, and CYP2D6.1

Drugs Affecting Hepatic Microsomal Enzymes

Inhibitors of CYP3A4: Potential pharmacokinetic interaction (decreased imatinib metabolism and increased plasma imatinib concentrations).1 10

Inducers of CYP3A4: Potential pharmacokinetic interaction (increased imatinib metabolism and decreased plasma imatinib concentrations).1 10

Drugs Metabolized by Hepatic Microsomal Enzymes

Potential pharmacokinetic interaction (increased plasma concentrations of substrates of CYP3A4, CYP2C9, and CYP2D6).1

Specific Drugs

Drug

Interaction

Comments

Acetaminophen

Possible increased serum acetaminophen concentrations1 8

Fatal hepatic failure reported in at least one patient 1 8

Use concomitantly with caution1 8

Antifungals, azoles (itraconazole, ketoconazole)

Decreased imatinib metabolism and increased plasma imatinib concentrations1

Benzodiazepines (i.e., triazolo)

Increased benzodiazepine concentrations1

Calcium channel blockers (i.e., dihydropyridines)

Increased calcium channel blocker concentrations1

Carbamazepine

Increased imatinib metabolism and decreased plasma imatinib concentrations1 10

Consider choosing other agents with less enzyme induction potential1

Cyclosporine

Increased cyclosporine concentrations1

Use with caution since cyclosporine has a narrow therapeutic window1

Dexamethasone

Increased imatinib metabolism and decreased plasma imatinib concentrations1 10

Consider choosing other agents with less enzyme induction potential1

HMG-CoA reductase inhibitors (statins) (simvastatin)

Increased statin concentrations1

Macrolide antibiotics (clarithromycin, erythromycin)

Decreased imatinib metabolism and increased plasma imatinib concentrations1

Phenobarbital

Increased imatinib metabolism and decreased plasma imatinib concentrations1 10

Consider choosing other agents with less enzyme induction potential1

Phenytoin

Increased imatinib metabolism and decreased plasma imatinib concentrations1 10

Increase imatinib dosage by at least 50% and monitor clinical response carefully; alternatively, consider choosing other agents with less enzyme induction potential1

Pimozide

Increased pimozide concentrations1

Use with caution since pimozide has a narrow therapeutic window1

Rifampin

Increased imatinib metabolism and decreased peak plasma concentration and AUC of imatinib1 10

Increase imatinib dosage by at least 50% and carefully monitor clinical response; alternatively, consider choosing other agents with less enzyme induction potential1

St. John’s wort

Increased imatinib metabolism and decreased plasma imatinib concentrations1 10

Consider choosing other agents with less enzyme induction potential1

Warfarin

Potential pharmacokinetic and pharmacologic interaction (enhanced anticoagulant effect)1

Patients requiring anticoagulation therapy should receive heparin or low molecular weight heparin1

Gleevec Pharmacokinetics

The pharmacokinetics of imatinib are similar in CML and GIST patients.1

Absorption

Bioavailability

Well absorbed following oral administration.1 Mean absolute bioavailability is 98%.1

Following oral administration, peak plasma concentrations are attained within 2–4 hours in adult and pediatric patients.1 When dosed once daily, accumulation is 1.5–2.5-fold at steady state.1

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.1 Mean imatinib AUC increases proportionally with dose in adults but not in pediatric patients.1

Special Populations

In patients with severe hepatic impairment, increased peak plasma concentration and AUC of imatinib and its major active metabolite have been observed.1 (See Hepatic Impairment under Dosage and Administration.)

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.1

Distribution

Extent

Distributed into milk in animals; not known whether the drug or its metabolites are distributed into human milk.1

Plasma Protein Binding

Approximately 95% (mainly albumin and α1-acid glycoprotein).1 Plasma protein binding of major active metabolite is similar to that of the parent drug.1

Elimination

Metabolism

Metabolized in the liver, principally by CYP3A4 and to a lesser degree by CYP1A2, CYP2D6, CYP2C9, and CYP2C19.1 The major active metabolite is the N-desmethyl derivative, which has an in vitro potency similar to the parent drug.1

Elimination Route

Predominantly in feces, mostly as metabolites.1 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), the remainder being metabolites.1

Apparent oral clearance appears to be similar in adults and pediatric patients.1

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.1

Special Populations

Clearance appears to increase with increasing body weight; no initial dosage adjustment necessary but close monitoring of treatment-related toxicity recommended.1

Stability

Storage

Oral

Tablets

Tight container at 25°C (may be exposed to 15–30°C).1 Protect from moisture.1

Actions

  • Competitively inhibits Bcr-Abl tyrosine kinase,5 the constitutive abnormal tyrosine kinase created by the Philadelphia chromosome abnormality in CML.11

  • Inhibits proliferation and induces apoptosis of Bcr-Abl-positive cell lines as well as fresh leukemic cells from Ph+ CML.1 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.1

  • 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.1 8 Inhibits proliferation and induces apoptosis of GIST cells (which express an activating c-kit mutation) in vitro.1

Advice to Patients

  • Risk of severe fluid retention, cytopenia, hepatotoxicity, and adverse dermatologic or cardiovascular effects.1

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed; necessity of advising women to avoid pregnancy and nursing during therapy.1 Advise pregnant women of risk to the fetus.1

  • Importance of informing clinicians of existing or contemplated therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses (e.g., cardiac disease).1

  • Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Imatinib Mesylate

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets, film-coated

100 mg (of imatinib)

Gleevec (scored)

Novartis

400 mg (of imatinib)

Gleevec (scored)

Novartis

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 09/2014. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Gleevec 100MG Tablets (NOVARTIS): 30/$1,640.92 or 90/$4,887.85

Gleevec 400MG Tablets (NOVARTIS): 30/$5,963.04 or 60/$11,753.26

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions August 13, 2014. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. Novartis Pharmaceuticals Corporation. Gleevec (imatinib mesylate) tablets prescribing information. East Hanover, NJ; 2006 Sep.

2. Druker BJ, Lydon NB. Lessons learned from the development of an Abl tyrosine kinase inhibitor for chronic myelogenous leukemia. J Clin Investig. 2000; 105:3-7. [PubMed 10619854]

3. McGuire TR, Kazakoff PW. Chronic leukemias. In: DiPiro JT, Talbert RL, Yee GC et al., eds. Pharmacotherapy: a pathophysiologic approach. 4th ed. Stamford: Appleton and Lange; 1999:2169-80.

4. Food and Drug Administration. List of orphan designations and approvals. From FDA web site.

5. Druker BJ, Talpaz M, Resta DJ et al. Efficacy and safety of a specific inhibitor of the Bcr-Abl tyrosine kinase in chronic myeloid leukemia. N Engl J Med. 2001; 344:1031-7. [IDIS 461596] [PubMed 11287972]

6. Druker BJ, Sawyers CL, Kantarjian H et al. Activity of a specific inhibitor of the Bcr-Abl tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome. N Engl J Med. 2001; 344:1038-42. [IDIS 461597] [PubMed 11287973]

7. Joensuu H, Roberts PJ, Sarlomo-Rikala M. Effect of the tyrosine kinase inhibitor STI571 in a patient with a metastatic gastrointestinal stromal tumor. N Engl J Med. 2001; 344:1052-6. [IDIS 461598] [PubMed 11287975]

8. Novartis, East Hanover, NJ: Personal communication.

9. Blanke CD, von Mehren M, Joensuu H et al. Evaluation of the safety and efficacy of an oral molecularly-targeted therapy, STI-571, in patients (pts) with unresectable or metastatic gastrointestinal stromal tumors (GISTS) expressing C-KIT. From ASCO website.

10. Anon. Gleevec (STI-571) for chronic myeloid leukemia. Med Lett Drugs Ther. 2001; 43:49-50. [PubMed 11402258]

11. Weisberg E, Griffin J. Mechanisms of resistance imatinib (STI-571) in preclinical models and in leukemia patients. Drug Resistance Updates. 2001; 4:22-8. [PubMed 11512149]

12. Mohammed M, Shin S, Deng S et al. Bcr/Abl gene amplification: a possible mechanism of drug resistance in patients treated with an ABL-specific kinase inhibitor. Blood. 2000; 96:344a.

13. Talpaz M, Donato NJ, Wu JY et al. Characterization of the clinical response to STI-571: biochemical evaluation of responsive and resistant advanced stage chronic myelogenous leukemia patients. Blood. 2000;96:735a.

14. Gorre ME, Mohammed M, Ellwood K et al. Clinical resistance to STI-571 cancer therapy caused by Bcr-Abl gene mutation or amplication. Sciencexpress. 2001;10:1126. Abstract.

15. Food and Drug Administration. MedWatch—Safety-related drug labeling changes: Gleevec (imatinib) [May 2003]. From FDA web site.

16. O’Brien SG, Guilhot F, Larson RA et al. Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med. 2003; 348:994-1004.

17. Hohneker J. Dear healthcare provider letter re: severe congestive heart failure and left ventricular dysfunction in Gleevec treated patients. East Hanover, NJ: Novartis Pharmaceuticals; 2006 Oct 19.

18. Anon. Drugs of choice for cancer. Treat Guidel Med Lett. 2003; 1:41-52.

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a. Novartis Pharmaceuticals Corporation. Gleevec (imatinib mesylate) tablets prescribing information. East Hanover, NJ; 2006 Nov.

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