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imatinib mesylate 100 mg tab generic gleevec

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Uses

Chronic Myelogenous Leukemia

Imatinib is used for the treatment of Philadelphia chromosome-positive (Ph) chronic myelogenous leukemia (CML) in adult and pediatric patients.

Adult Patients

First-line Therapy for Chronic Phase CML

Imatinib is used for the first-line treatment of Ph CML in chronic phase in adult patients. The duration of follow-up for patients receiving imatinib for this use is limited.

The indication for this use is based on the results of an open-label, multicenter, randomized phase III trial in 1,106 patients receiving either imatinib or combination therapy with interferon alfa and cytarabine for newly diagnosed chronic phase Ph CML. Single-agent therapy consisted of imatinib at an initial dose of 400 mg daily with dose escalations to 600 mg daily and then 800 mg daily as tolerated. Combination therapy consisted of interferon alfa 5 million units/m given subcutaneously daily with cytarabine 20 mg/m given subcutaneously daily for 10 days every month. Crossover therapy was allowed for treatment failure or unacceptable toxicity. The patients were mostly Caucasian (59% males and 41% females) with a median age of 51 years.

At the time of follow-up, 79% of patients initially receiving imatinib continued the assigned treatment; 7% of patients initially receiving interferon alfa and cytarabine continued the assigned treatment and the remainder either discontinued first-line therapy or crossed over to treatment with imatinib. The primary efficacy endpoint was progression-free survival, and progression was defined as death, progression to accelerated phase or blast phase CML, loss of complete hematologic response, loss of major cytogenetic response, or increasing white blood cell count in a patient with disease that did not achieve a complete hematologic response. According to intention-to-treat analysis, the estimated rate of progression-free survival at 30 months was higher in patients receiving imatinib (88%) than in those receiving interferon alfa and cytarabine (68%). The estimated rate of patients free of progression to accelerated phase CML or blast crisis at 30 months was higher in patients receiving imatinib (95%) than in those receiving interferon alfa and cytarabine (90%).

The probability of remaining free of disease progression at 30 months was associated with molecular response to treatment achieved at 12 months: 100% probability of remaining free of disease progression for patients with complete cytogenetic response and major molecular response (a reduction of at least 3 logarithms in the amount of Bcr-Abl transcripts measured by real-time quantitative reverse transcriptase polymerase chain reaction), 93% for those with complete cytogenetic response but not major molecular response, and 82% for those without complete cytogenetic response. Secondary endpoints, including complete hematologic response and major cytogenetic response, were higher in patients receiving imatinib than in those receiving interferon alfa and cytarabine. Fluid retention (including superficial edema), muscle cramps, and rash occurred more frequently in patients receiving imatinib; fatigue, pyrexia, myalgia, and depression occurred more frequently in patients receiving interferon alfa and cytarabine.

Second-line Therapy for CML

Imatinib mesylate is used for the treatment of Ph CML in patients who are in blast crisis, in the accelerated phase, or in the chronic phase of the disease after failure of interferon alfa therapy.

The current indication of imatinib is based principally on the results of 3 international, open-label, single-arm studies in more than 1000 patients with Ph CML. The first study enrolled patients in the chronic phase of CML who failed interferon alfa therapy (i.e., inadequate hematologic response following 6 months of treatment, inadequate cytogenetic response following 1 year of treatment, hematologic or cytogenetic relapse, or intolerance to interferon). The second study enrolled patients who were in the accelerated phase of CML, while the third study enrolled patients in myeloid blast crisis. Patients in the chronic phase of CML received an initial imatinib dose of 400 mg daily (increased to 600 mg daily as necessary), while those in the accelerated phase or blast crisis received either 400 or 600 mg of the drug daily. The median duration of therapy with imatinib in patients with chronic phase, accelerated phase, or blast crisis was 29, 18, or 4 months, respectively.

Hematologic response (i.e., complete hematologic response, and, in patients in the accelerated phase or blast crisis, no evidence of leukemia or return to chronic phase of CML) occurred in 95, 71, or 31% of patients in the chronic phase, accelerated phase, or blast crisis, respectively. Complete hematologic response was achieved in approximately 95, 38, or 7% of these patients, respectively. Major cytogenetic response (i.e., complete or partial suppression of Ph cells) occurred in 60, 21, or 7% of patients in the chronic phase, accelerated phase, or blast crisis, respectively, while complete cytogenetic response (i.e., no Ph cells in metaphase) was achieved in 39, 16, or 2% of these patients, respectively. The rates of hematologic response and major cytogenetic response were higher in patients with accelerated phase CML or blast crisis who received an initial dosage of 600 mg of imatinib daily than in those who received an initial dosage of 400 mg daily.

Median time to hematologic response in patients receiving imatinib was 1 month; median duration of hematologic response is 10 months in patients in blast crisis and 29 months in those with accelerated phase CML receiving an initial dosage of imatinib 600 mg daily. About 88% of patients with late chronic phase CML, and 64% of patients with accelerated phase CML, who achieved an initial major cytogenetic response to imatinib therapy maintained that response for 2 years. About 27% of patients with blast crisis who achieved an initial hematologic response to imatinib therapy maintained that response for 2 years. In patients with late chronic phase CML receiving 2 years of imatinib therapy, estimated overall survival is 91%. In patients with accelerated CML, median survival was 21 months in patients receiving an initial imatinib dosage of 400 mg daily; median survival has not been reached in those receiving an initial imatinib dosage of 600 mg daily. In patients with blast crisis, median survival was 7 months.

Resistance to imatinib, particularly in patients with advanced-stage CML, has developed during therapy with the drug. In patients with myeloid blast crisis, development of imatinib resistance was observed as early as 42 days following initiation of therapy. Resistance to imatinib has not been evaluated in all patient groups; however, limited data from several open-label studies indicate a relapse rate of 4 or 43-80% in patients in chronic phase or blast crisis, respectively, who received the drug. Although the mechanism(s) of resistance to imatinib has not been fully determined to date, mutation and/or amplification (resulting in increased expression of Bcr-Abl tyrosine kinase) of the Bcr-Abl gene may be associated with decreased efficacy of the drug.

Pediatric Patients

First-line Therapy for Chronic Phase CML

Imatinib is used for the first-line treatment of Ph CML in chronic phase in pediatric patients. The duration of follow-up for patients receiving imatinib for this use is limited.

The indication for this use is based on the results of an open-label, uncontrolled phase II trial in 51 pediatric patients receiving imatinib 340 mg/m daily for newly diagnosed chronic phase Ph CML. After 8 weeks of imatinib therapy, complete hematologic response was observed in 78% of patients. The complete cytogenetic response rate (typically achieved between months 3 and 10) was 65%, which is comparable to the rate observed in adult patients.

Second-line Therapy for CML

Imatinib is used for the second-line treatment of Ph CML in chronic phase in pediatric patients with disease that has recurred following stem cell transplantation or is resistant to interferon alfa therapy.

The indication for this use is based on the results of 2 small uncontrolled studies in pediatric patients receiving imatinib as second-line therapy for chronic phase CML. In the first study, which involved 14 pediatric patients ranging in age from 3 to 20 years of age, a complete cytogenetic response was observed in 7 patients. In the second study, which involved 3 patients, a complete cytogenetic response was observed in 2 patients.

Gastrointestinal Stromal Tumors

Imatinib is used for the treatment of malignant gastrointestinal stromal tumors (GIST) in patients with unresectable tumor or metastatic disease that is Kit (CD117) positive. This indication is based on objective response rate; there currently are no controlled trials demonstrating a clinical benefit (e.g., lessening of disease-related symptoms, increased survival).

The indication for this use is based on the results of an open-label, multinational study in 147 patients receiving either imatinib 400 mg daily or imatinib 600 mg daily for up to 36 months for unresectable or metastatic malignant GIST. The objective response rate was 67% with a complete response in one patient and partial responses in 98 patients. The median time to response was 12 weeks. The study was not designed with adequate power to detect a statistically significant difference in response rates between the dose groups.

Other Uses

Imatinib is used as a single agent for the treatment of relapsed or refractory Ph acute lymphocytic leukemia (ALL), myelodysplastic syndrome (MDS) or myeloproliferative disease (MPD) associated with gene rearrangements of platelet-derived growth factor receptor (PDGFR), aggressive systemic mastocytosis (ASM), hypereosinophilic syndrome (HES) or chronic eosinophilic leukemia (CEL), and dermatofibrosarcoma protuberans (DFSP).

Dosage and Administration

General

Imatinib mesylate should be used under the supervision of a qualified clinician experienced in the treatment of hematologic malignancies or malignant sarcomas as indicated.

In patients with elevated eosinophil concentrations, consider concomitant administration of prophylactic therapy with systemic corticosteroids (1-2 mg/kg) for 1-2 weeks upon initiation of imatinib therapy to reduce the risk of hypereosinophilic cardiac toxicity.(See Major Toxicities: Adverse Cardiovascular Effects and see General Precautions: Cardiovascular Toxicity.)

Imatinib mesylate is administered orally. In adults, imatinib doses of 400 or 600 mg should be administered once daily; an imatinib dosage of 800 mg daily should be administered as 400 mg twice daily using the 400-mg tablet to reduce exposure to iron. In children or adolescents, imatinib may be given as a once-daily dose or, alternatively, the daily dose may be divided equally in the morning and the evening.

Imatinib mesylate should be given with a meal and a large glass (240 mL) of water to minimize gastric irritation. Alternatively, for patients unable to swallow the tablets, the film-coated tablets may be dispersed in a glass of water or apple juice. The required number of tablets should be dispersed in 50 mL of beverage for each 100-mg tablet or 200 mL of beverage for each 400-mg tablet. The suspension should be administered immediately after complete disintegration of the tablet(s).

The manufacturer states that imatinib therapy may be continued as indicated in the absence of progressive disease or unacceptable toxicity.

Dosage of imatinib mesylate is expressed in terms of imatinib.

Chronic Myelogenous Leukemia

Adult Patients

The recommended initial adult dosage of imatinib for the first-line treatment of Ph chronic phase CML is 400 mg daily. Dose escalations to 600 mg daily, and then to 800 mg daily (administered as 400 mg twice daily), were permitted in patients receiving imatinib in the randomized trial.

The recommended adult dosage of imatinib for the second-line treatment of Ph chronic phase CML is 400 mg daily; the recommended adult dosage for the second-line treatment of patients in accelerated phase or blast crisis is 600 mg daily. If there is inadequate hematologic response after at least 3 months of therapy, failure to achieve a cytogenetic response after 6-12 months of therapy, loss of a previously achieved hematologic or cytogenetic response, or evidence of disease progression, the manufacturer states that, in the absence of severe adverse drug or hematologic effects, adult dosage of imatinib may be increased to 600 mg daily in adults with chronic phase CML or to 800 mg daily (administered as 400 mg twice daily) in those with accelerated phase CML or blast crisis.

Pediatric Patients

The recommended pediatric dosage of imatinib for the first-line treatment of Ph chronic phase CML is 340 mg/m daily, and the daily dose should not exceed 600 mg.

The recommended pediatric dosage of imatinib for the second-line treatment of Ph chronic phase CML that has recurred following stem cell transplantation or is resistant to interferon alfa therapy is 260 mg/m daily.

Acute Lymphocytic Leukemia

For the treatment of relapsed or refractory Ph ALL, the recommended adult dosage of imatinib is 600 mg daily.

Myelodysplastic Syndrome/Myeloproliferative Diseases

For the treatment of myelodysplastic syndrome or myeloproliferative disease associated with gene rearrangements of PDGFR, the recommended adult dosage of imatinib is 400 mg daily.

Aggressive Systemic Mastocytosis

For the treatment of aggressive systemic mastocytosis (ASM) without the D816V c-Kit mutation, the recommended adult dosage of imatinib is 400 mg daily. For ASM with unknown status of the D816V c-Kit mutation that is not responding satisfactorily to other therapies, treatment with an adult imatinib dosage of 400 mg daily may be considered. For ASM without the D816V c-Kit mutation or of unknown D816V c-Kit mutational status that is associated with eosinophilia (a clonal hematologic disease related to the FIP1L1-PDGFRα fusion kinase), the recommended initial adult dosage of imatinib is 100 mg daily; if therapeutic response is insufficient, dose escalation from 100 mg to 400 mg may be attempted as tolerated. For ASM with the D816V c-Kit mutation, imatinib is ineffective and other therapy is indicated.

Hypereosinophilic Syndrome/Chronic Eosinophilic Leukemia

For the treatment of hypereosinophilic syndrome (HES) or chronic eosinophilic leukemia (CEL) in patients without FIP1L1-PDGFRα fusion kinase expression or in patients in whom expression of FIP1L1-PDGFRα fusion kinase is unknown, the recommended adult dosage of imatinib is 400 mg daily. For HES or CEL with FIP1L1-PDGFRα fusion kinase expression, the recommended initial adult dosage of imatinib is 100 mg daily; if therapeutic response is insufficient, dose escalation from 100 to 400 mg may be attempted as tolerated.

Dermatofibrosarcoma Protuberans

For unresectable, recurrent, and/or metastatic dermatofibrosarcoma protuberans, the recommended adult dosage of imatinib is 800 mg daily.

Gastrointestinal Stromal Tumors

For the treatment of unresectable and/or metastatic malignant GIST, the recommended adult dosage of imatinib is 400 or 600 mg daily.

Dosage Modification for Toxicity

Dermatologic Toxicity

Imatinib therapy should be discontinued in patients experiencing severe dermatologic toxicity, such as bullous skin reactions.(See Dermatologic Effects in Cautions: Major Toxicities.) In some patients, imatinib therapy was reinitiated at a lower dosage following resolution or lessening of the bullous skin reaction.

Fluid Retention/Edema

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

Hepatic Toxicity

In patients who exhibit substantial increases in bilirubin (more than 3 times the upper limit of normal) or hepatic transaminase concentrations (more than 5 times the upper limit of normal), the manufacturer recommends that therapy with imatinib be withheld until bilirubin concentrations decrease to less than 1.5 times the upper limit of normal or transaminase concentrations decrease to less than 2.5 times the upper limit of normal. Imatinib therapy may then be resumed at a reduced daily dosage (e.g., in adults, 400 mg to 300 mg, 600 mg to 400 mg, or 800 mg to 600 mg). In pediatric patients showing hepatic toxicity, daily imatinib doses can be reduced from 340 to 260 mg/m daily or from 260 to 200 mg/m daily.

Hematologic Toxicity

In adult patients with chronic phase Ph+ CML, myelodysplastic syndrome/myeloproliferative disease, aggressive systemic mastocytosis, or hypereosinophilic syndrome/chronic eosinophilic leukemia receiving an initial imatinib dosage of 400 mg daily who experience a first occurrence of neutropenia (i.e., absolute neutrophil counts [ANC] less than 1000/mm) or thrombocytopenia (i.e., platelet counts less than 50,000/mm), the manufacturer recommends that subsequent doses of the drug be withheld until ANC reaches or exceeds 1500/mm and platelet counts reach or exceed 75,000/mm. Imatinib therapy may then be resumed at the original starting dosage (400 mg daily). Following a recurrence of neutropenia or thrombocytopenia, imatinib therapy should be withheld until neutrophil and platelet counts return to acceptable levels (ANC of 1500/mm or greater and platelet count of 75,000/mm or greater), then reinitiated at a reduced dosage of 300 mg daily.

In adult patients with aggressive systemic mastocytosis associated with eosinophilia, or hypereosinophilic syndrome/chronic eosinophilic leukemia with FIP1L1-PDGFRα fusion kinase expression receiving an initial imatinib dosage of 100 mg daily who experience neutropenia (i.e., ANC less than 1000/mm) or thrombocytopenia (i.e., platelet counts less than 50,000/mm), the manufacturer recommends that subsequent doses of the drug be withheld until ANC reaches or exceeds 1500/mm and platelet counts reach or exceed 75,000/mm. Imatinib therapy may then be resumed at the same dosage.

In adult patients with accelerated phase or blast crisis Ph+ CML or Ph+ ALL receiving an initial imatinib dosage of 600 mg daily who experience severe neutropenia (i.e., ANC less than 500/mm) or thrombocytopenia (i.e., platelet counts less than 10,000/mm) that is unrelated to the disease, the manufacturer recommends that dosage of imatinib be reduced to 400 mg daily. If cytopenia persists for 2 weeks, the dosage of imatinib should be reduced further to 300 mg daily. If cytopenia persists for 4 weeks, the manufacturer recommends that subsequent doses of the drug be withheld until ANC reaches or exceeds 1000/mm and platelet counts reach or exceed 20,000/mm; imatinib therapy may then be reinitiated at a reduced dosage of 300 mg daily.

In pediatric patients with newly diagnosed chronic phase Ph+ CML receiving an initial imatinib dosage of 340 mg/m daily who experience a first occurrence of neutropenia (i.e., ANC less than 1000/mm) or thrombocytopenia (i.e., platelet counts less than 50,000/mm), the manufacturer recommends that subsequent doses of the drug be withheld until ANC reaches or exceeds 1500/mm and platelet counts reach or exceed 75,000/mm. Imatinib therapy may then be resumed at the same dosage. Following a recurrence of neutropenia or thrombocytopenia, imatinib therapy should be withheld until neutrophil and platelet counts return to acceptable levels (ANC of 1500/mm or greater and platelet count of 75,000/mm or greater), then reinitiated at a reduced dosage of 260 mg/m daily.

In pediatric patients with recurrent or resistant chronic phase Ph+ CML receiving an initial imatinib dosage of 260 mg/m daily who experience a first occurrence of neutropenia (i.e., ANC less than 1000/mm) or thrombocytopenia (i.e., platelet counts less than 50,000/mm), the manufacturer recommends that subsequent doses of the drug be withheld until ANC reaches or exceeds 1500/mm and platelet counts reach or exceed 75,000/mm. Imatinib therapy may then be resumed at the same dosage. Following a recurrence of neutropenia or thrombocytopenia, imatinib therapy should be withheld until neutrophil and platelet counts return to acceptable levels (ANC of 1500/mm or greater and platelet count of 75,000/mm or greater), then reinitiated at a reduced dosage of 200 mg/m daily.

In adult patients with dermatofibrosarcoma protuberans receiving an initial imatinib dosage of 800 mg daily who experience a first occurrence of neutropenia (i.e., ANC less than 1000/mm) or thrombocytopenia (i.e., platelet counts less than 50,000/mm), the manufacturer recommends that subsequent doses of the drug be withheld until ANC reaches or exceeds 1500/mm and platelet counts reach or exceed 75,000/mm. Imatinib therapy may then be reinitiated at a reduced dosage of 600 mg daily. Following a recurrence of neutropenia or thrombocytopenia, imatinib therapy should be withheld until neutrophil and platelet counts return to acceptable levels (ANC of 1500/mm or greater and platelet count of 75,000/mm or greater), then reinitiated at a reduced dosage of 400 mg daily.

In adult patients with GIST receiving an initial imatinib dosage of 400 or 600 mg daily who experience a first occurrence of neutropenia (i.e., ANC less than 1000/mm) or thrombocytopenia (i.e., platelet counts less than 50,000/mm), the manufacturer recommends that subsequent doses of the drug be withheld until ANC reaches or exceeds 1500/mm and platelet counts reach or exceed 75,000/mm. Imatinib therapy may then be resumed at the original starting dosage (400 or 600 mg daily). Following a recurrence of neutropenia or thrombocytopenia, imatinib therapy should be withheld until neutrophil and platelet counts return to acceptable levels (ANC of 1500/mm or greater and platelet count of 75,000/mm or greater), then reinitiated at a reduced dosage: 300 mg daily if the starting dose was 400 mg, or 400 mg daily if the starting dose was 600 mg.

Special Populations

Hepatic Impairment

Patients with mild to moderate hepatic impairment should receive an initial imatinib dosage of 400 mg daily. In patients with conditions normally requiring initial dosages less than 400 mg daily (e.g., pediatric patients with small body frame, adults with ASM or HES/CEL with FIP1L1-PDGFRα fusion kinase expression), therapy should be initiated at the recommended initial dosage, regardless of hepatic function.

Patients with severe hepatic impairment should receive an initial imatinib dosage of 300 mg daily. In patients with conditions normally requiring initial dosages less than 300 mg daily (e.g., pediatric patients with small body frame, adults with ASM or HES/CEL with FIP1L1-PDGFRα fusion kinase expression), therapy should be initiated at the recommended initial dosage, regardless of hepatic function. In patients with ASM or HES/CEL with FIP1L1-PDGFRα fusion kinase expression and severe hepatic impairment who require dosage escalation, dosage may be initially increased from 100 mg daily to 300 mg daily (rather than to 400 mg daily as usually recommended); liver function should be monitored carefully. If therapeutic response is insufficient in such patients, increasing the dosage to 400 mg daily as tolerated may be considered.

Cautions

Contraindications

Known hypersensitivity to imatinib or any ingredient in the formulation.

Warnings/Precautions

Warnings

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm; teratogenicity and embryolethality demonstrated in animals. No adequate and well-controlled studies to date in humans. Pregnancy should be avoided during therapy. If used during pregnancy, apprise of potential fetal hazard.

Major Toxicities

Cardiovascular Effects

Severe congestive heart failure and left ventricular dysfunction have been reported during imatinib therapy, 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 failure.

In patients with hypereosinophilic syndrome and cardiac involvement, cardiogenic shock and left ventricular dysfunction has been associated with the initiation of imatinib therapy. In patients with this condition, withhold imatinib therapy and administer systemic corticosteroid therapy and supportive measures.

Dermatologic Effects

Bullous skin reactions, including erythema multiforme and Stevens-Johnson syndrome, have been reported in patients receiving imatinib. If dermatologic toxicity occurs, discontinue imatinib therapy.(See Dosage Modification for Toxicity, in Dosage and Administration.) Following resolution or lessening of the bullous skin reaction, imatinib therapy was reinitiated in some patients at a reduced dosage with or without concomitant administration of corticosteroids or antihistamines.

Fluid Retention/Edema

Fluid retention/edema occurred in about 60-80% of patients receiving imatinib for CML or GIST. Severe fluid retention (i.e., pleural effusion, pericardial effusion, pulmonary edema, ascites) or severe superficial edema (i.e., rapid weight gain, anasarca), occurred in 1-12% of patients receiving imatinib for CML or GIST in clinical studies. Other types of fluid retention and edema events, sometimes fatal, have occurred in patients receiving imatinib, including cardiac tamponade, cerebral edema, increased intracranial pressure, and papilledema. At least one patient with blast crisis who received imatinib in clinical studies died as a result of pleural effusion, congestive heart failure, and renal failure. In patients with CML, the incidence of these adverse effects appears to be increased in patients in blast crisis, in those receiving higher dosages (i.e., 600 mg daily), and in geriatric patients. Monitor signs (e.g., body weight) and symptoms of fluid retention regularly during imatinib therapy. If severe fluid retention develops, withhold imatinib therapy and provide appropriate treatment until complete resolution occurs.

Hematologic Effects

Cytopenias, including neutropenia, thrombocytopenia, and anemia, occurred in patients receiving imatinib for CML or GIST. For patients with CML, the frequency of cytopenias was dependent on the stage of disease. Cytopenias were less frequent in patients with newly diagnosed CML; the frequency of grade 3 or 4 neutropenia and thrombocytopenia was between 2-fold and 3-fold higher in patients with blast crisis or accelerated phase CML than in those with chronic phase CML. In pediatric patients receiving imatinib for CML, grade 3 or 4 cytopenias (neutropenia, thrombocytopenia, and anemia) occurred, usually within the first several months of therapy. Monitor complete blood cell counts (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. If hematologic toxicity occurs, withhold imatinib.(See Dosage Modification for Toxicity, in Dosage and Administration.)

Hepatic Effects

In patients receiving imatinib as first-line therapy for CML, grade 3 or 4 hyperbilirubinemia occurred in about 1%, and grade 3 or 4 elevations in ALT or AST in about 3-4%, of patients. In patients receiving imatinib as second-line therapy for CML, grade 3 or 4 hyperbilirubinemia occurred in up to 4% of patients, and elevations in alkaline phosphatase, ALT, and AST (grade 3 or 4 severity) occurred in up to 5% of patients. Fatal hepatic failure occurred in at least one patient who received imatinib concomitantly with acetaminophen.(See Drug Interactions: Acetaminophen.) In patients receiving imatinib for GIST, grade 3 or 4 elevations in ALT, AST, and bilirubin occurred in about 7, 5, and 3% of patients, respectively. 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 elevated, withhold imatinib.(See Dosage Modification for Toxicity, in Dosage and Administration.)

GI Effects

Nausea, vomiting, and diarrhea occur frequently in patients receiving imatinib. Gastrointestinal perforation, sometimes fatal, has occurred rarely in patients receiving imatinib.

Hemorrhage

Grade 3 or 4 hemorrhage has occurred in about 1% of patients receiving imatinib for first-line treatment of CML and 5% of those receiving the drug for GIST. In patients with GIST, hemorrhagic events included GI bleeds, intratumoral bleeds, or both; GI tumor sites may have been the source of GI bleeds.

Metabolic Effects

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

General Precautions

Cardiovascular Toxicity

Patients with cardiac disease or increased risk for cardiac failure should be monitored carefully for manifestations of cardiac failure during imatinib therapy.

Patients with elevated eosinophil concentrations are at increased risk for hypereosinophilic cardiac toxicity associated with imatinib. Patients with myelodysplastic syndrome (MDS)/myeloproliferative disease (MPD) or aggressive systemic mastocytosis (ASM) should be tested for elevated eosinophil concentrations. Perform an echocardiogram and measure serum troponin concentrations in patients with elevated eosinophil concentrations, including patients with hypereosinophilic syndrome/chronic eosinophilic leukemia or patients with MDS/MPD or ASM associated with high eosinophil concentrations. If the results of the echocardiogram or serum troponin concentrations are abnormal, consider the use of prophylactic therapy with systemic corticosteroids upon initiation of imatinib therapy.(See Dosage and Administration: General.)

GI Toxicity

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

Long-term Therapy

Long-term safety data not available in humans. Severe hepatic and renal toxicity observed in animals receiving imatinib for as little as 2 weeks. Immunosuppression also reported in animals receiving imatinib for up to 39 weeks.

Specific Populations

Pregnancy

Category D. (See Warnings: Fetal/Neonatal Morbidity and Mortality.)

Lactation

Imatinib and/or its metabolites are distributed into milk in rats; discontinue nursing because of potential risk in nursing infants.

Pediatric Use

Safety and efficacy of imatinib in children younger than 2 years of age have not been established. Imatinib has been used in a small number of pediatric patients for first-line or second-line treatment of CML. The duration of follow-up for patients receiving imatinib for newly diagnosed chronic phase CML is limited. Studies to date suggest that the safety and efficacy of imatinib are similar in children and adults, except musculoskeletal pain was less frequent and peripheral edema was not reported. Nausea and vomiting and myalgias were the most frequent adverse effects in children receiving imatinib.

Geriatric Use

With the exception of a higher incidence of edema (see Major Toxicities: Fluid Retention/Edema under Warnings/Precautions, in Cautions), no substantial differences in safety and efficacy relative to younger adults were observed.

Hepatic Impairment

Imatinib is metabolized extensively in the liver, and increased exposure to the drug and its major active metabolite is observed in patients with severe hepatic impairment. Close monitoring is recommended in these patients.(See Major Toxicities: Hepatic Effects, under Warnings/Precautions in Cautions.)

Renal Impairment

Safety and efficacy not established; use with caution.

Common Adverse Effects

The most common adverse effects associated with imatinib therapy are fluid retention/edema, nausea and vomiting, muscle cramps, musculoskeletal pain, diarrhea, and rash. Other adverse effects occurring in 10% or more of patients receiving imatinib for CML or GIST include fatigue, asthenia, headache, dizziness, insomnia, depression, anxiety, joint pain, arthralgia, myalgia, back pain, abdominal pain, flatulence, dyspepsia, loose stools, anorexia, constipation, taste disturbance, nasopharyngitis, cough, pharyngolaryngeal pain, pharyngitis, sinusitis, upper respiratory tract infection, pneumonia, influenza, dyspnea, hemorrhage (including GI and CNS hemorrhage), pyrexia, increased weight, night sweats, rigors, hepatic toxicity, hypokalemia, pruritus, chest pain, and increased lacrimation.

Drug Interactions

Drugs Affecting Hepatic Microsomal Enzymes

Cytochrome P-450 (CYP) isoenzyme 3A4 (CYP3A4) inhibitors (e.g., clarithromycin, erythromycin, itraconazole, ketoconazole): Potential pharmacokinetic interaction causing increased serum imatinib concentrations.

CYP3A4 inducers (e.g., carbamazepine, dexamethasone, phenobarbital, phenytoin, rifampin, St. John's wort): Potential pharmacokinetic interaction causing substantially decreased serum imatinib concentrations; alternative agents with less enzyme induction potential should be considered. For patients receiving a potent CYP3A4 inducer, such as rifampin or phenytoin, imatinib dosage should be increased by at least 50%, and clinical response should be monitored carefully.

CYP3A4 Substrates

Imatinib appears to inhibit CYP3A4. Potential pharmacokinetic interaction (increased plasma CYP3A4-substrate concentrations) when imatinib is used with CYP3A4 substrates (e.g., cyclosporine, pimozide, triazolo-benzodiazepines, dihydropyridine calcium-channel blockers, certain HMG-CoA reductase inhibitors).

Warfarin

Imatinib appears to inhibit CYP2C9 and CYP3A4. Potential pharmacokinetic and pharmacologic interaction (enhanced anticoagulant effect). Patients requiring anticoagulation therapy should receive heparin or low molecular weight heparin.

CYP2D6 Substrates

Imatinib appears to inhibit CYP2D6. Potential pharmacokinetic interaction (increased CYP2D6 substrate plasma concentrations).

Acetaminophen

Potential pharmacokinetic interaction (increased serum acetaminophen concentrations); caution is recommended.(See Major Toxicities: Hepatic Effects.)

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. When dosed once daily, accumulation is 1.5-2.5-fold at steady state.

Administration of 260 mg/m or 340 mg/m 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.

Distribution

Extent

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

Plasma Protein Binding

Approximately 95% (mainly albumin and α1-acid glycoprotein).

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 and plasma protein binding 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), the remainder being metabolites.

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

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

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

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