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Indications/Uses
Imatinib mesylate (Glivec) is indicated for the: Treatment of adult and pediatric patients with newly diagnosed Philadelphia chromosome positive chronic myeloid leukemia (Ph+ CML), (for pediatric use see DOSAGE & ADMINISTRATION).
Treatment of adult and pediatric patients with Ph+ CML in blast crisis, accelerated phase, or in chronic phase after failure of interferon-alpha therapy (for pediatric use see DOSAGE & ADMINISTRATION).
Treatment of adult patients with Kit+ (CD117) unresectable and/or metastatic malignant gastrointestinal stromal tumors (GIST).
100 mg: Treatment of adult and pediatric patients with newly diagnosed Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL) integrated with chemotherapy.
Treatment of adult patients with relapsed or refractory Ph+ ALL as monotherapy.
Treatment of adult patients with myelodysplastic/myeloproliferative diseases (MDS/MPD) associated with platelet-derived growth factor receptor (PDGFR) gene re-arrangements.
Treatment of adult patients with systemic mastocytosis (SM) without the D816V c-Kit mutation or with c-Kit mutational status unknown.
Treatment of adult patients with hypereosinophilic syndrome (HES) and/or chronic eosinophilic leukemia (CEL).
Adjuvant treatment of adult patients following resection of Kit+ GIST.
Treatment of adult patients with unresectable, recurrent and/or metastatic dermatofibrosarcoma protuberans (DFSP).
Treatment of adult and pediatric patients with Ph+ CML in blast crisis, accelerated phase, or in chronic phase after failure of interferon-alpha therapy (for pediatric use see DOSAGE & ADMINISTRATION).
Treatment of adult patients with Kit+ (CD117) unresectable and/or metastatic malignant gastrointestinal stromal tumors (GIST).
100 mg: Treatment of adult and pediatric patients with newly diagnosed Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL) integrated with chemotherapy.
Treatment of adult patients with relapsed or refractory Ph+ ALL as monotherapy.
Treatment of adult patients with myelodysplastic/myeloproliferative diseases (MDS/MPD) associated with platelet-derived growth factor receptor (PDGFR) gene re-arrangements.
Treatment of adult patients with systemic mastocytosis (SM) without the D816V c-Kit mutation or with c-Kit mutational status unknown.
Treatment of adult patients with hypereosinophilic syndrome (HES) and/or chronic eosinophilic leukemia (CEL).
Adjuvant treatment of adult patients following resection of Kit+ GIST.
Treatment of adult patients with unresectable, recurrent and/or metastatic dermatofibrosarcoma protuberans (DFSP).
Dosage/Direction for Use
100 mg: Therapy should be initiated by a physician experienced in the treatment of patients with hematological malignancies and malignant sarcomas, as appropriate.
400 mg: Therapy should be initiated by a physician experienced in the treatment of patients with CML or GIST, respectively.
The prescribed dose should be administered orally with a meal and a large glass of water to minimize the risk of gastrointestinal disturbances. Doses of 400 mg or 600 mg should be administered once daily, whereas a daily dose of 800 mg should be administered as 400 mg twice a day, in the morning and in the evening.
For patients unable to swallow the film-coated tablets, the tablets may be dispersed in a glass of water or apple juice. The required number of tablets should be placed in the appropriate volume of beverage (approximately 50 mL for a 100 mg tablet, and 200 mL for a 400 mg tablet) and stirred with a spoon. The suspension should be administered immediately after complete disintegration of the tablet(s).
For patients (e.g. pediatric patients) unable to swallow the capsules, their content may be diluted in a glass of still water or apple juice. Since studies in animals have shown reproductive toxicity, and the potential risk for the human fetus is unknown, women of child-bearing potential, who open capsules should be advised to handle contents with caution and avoid skin-eye contact or inhalation (see USE IN PREGNANCY & LACTATION). Hands should be washed immediately after handling open capsules.
Treatment should be continued as long as the patient continues to benefit.
Monitoring of response to imatinib mesylate (Glivec) therapy in Ph+ CML patients should be performed routinely and when therapy is modified, to identify suboptimal response, loss of response to therapy, poor patient compliance, or possible drug-drug interaction. Results of monitoring should guide appropriate CML management.
General target population: Dosage in CML: The recommended dosage of imatinib mesylate (Glivec) is 400 mg/day for adult patients in chronic phase CML and 600 mg/day for patients in accelerated phase or blast crisis.
Dose increase from 400 mg to 600 mg or 800 mg in patients with chronic phase disease, or from 600 mg to a maximum of 800 mg daily in patients in accelerated phase or blast crisis may be considered in the absence of severe adverse drug reaction and severe non-leukemia-related neutropenia or thrombocytopenia in the following circumstances: disease progression (at any time); failure to achieve a satisfactory hematological response after at least 3 months of treatment; failure to achieve a cytogenetic response after 12 months of treatment; or loss of a previously achieved hematological and/or cytogenetic response.
See section on special populations for pediatric patients as follows.
100 mg: Dosage in Ph+ ALL: The recommended dose of imatinib mesylate (Glivec) is 600 mg/day for adult patients with Ph+ ALL. See section on special populations for pediatric patients as follows.
Dosage in MDS/MPD: The recommended dose of imatinib mesylate (Glivec) is 400 mg/day for adult patients with MDS/MPD.
Dosage in SM: The recommended dose of imatinib mesylate (Glivec) is 400 mg/day for adult patients with SM without the D816V KIT mutation or mutational status unknown or not responding satisfactorily to other therapies.
For patients with SM associated with eosinophilia, a clonal hematological disease related to the fusion kinase FIP1L1-PDGFR-alpha, a starting dose of 100 mg/day is recommended. A dose increase from 100 mg to 400 mg for these patients may be considered in the absence of adverse drug reactions if assessments demonstrate an insufficient response to therapy.
Dosage in HES/CEL: The recommended dose of imatinib mesylate (Glivec) is 400 mg/day for adult patients with HES/CEL.
For HES/CEL patients with demonstrated FIP1L1-PDGFR-alpha fusion kinase, a starting dose of 100 mg/day is recommended. A dose increase from 100 mg to 400 mg for these patients may be considered in the absence of adverse drug reactions if assessments demonstrate an insufficient response to therapy.
Dosage in GIST: The recommended dose of imatinib mesylate (Glivec) is 400 mg/day for adult patients with unresectable and/or metastatic, malignant GIST.
A dose increase from 400 mg to 600 mg or 800 mg for patients may be considered in the absence of adverse drug reactions if assessments demonstrate an insufficient response to therapy.
100 mg: The recommended dose of imatinib mesylate (Glivec) is 400 mg/day for the adjuvant treatment of adult patients following resection of GIST. The recommended minimum treatment duration is 36 months.
In the adjuvant setting the optimal treatment duration with imatinib mesylate (Glivec) is not known.
Dosage in DFSP: The recommended dose of imatinib mesylate (Glivec) is 800 mg/day for adult patients with DFSP.
Dose adjustments for adverse drug reactions: Non-hematological adverse drug reactions: If a severe non-hematological adverse drug reaction develops with imatinib mesylate (Glivec) use, treatment must be withheld until the event has resolved. Thereafter, treatment can be resumed as appropriate depending on the initial severity of the event.
If elevations in bilirubin >3 x institutional upper limit of normal (IULN) or in liver transaminases >5 x IULN occur, imatinib mesylate (Glivec) should be withheld until bilirubin levels have returned to a <1.5 x IULN and transaminase levels to <2.5 x IULN. Treatment with imatinib mesylate (Glivec) may then be continued at a reduced daily dose. In adults the dose should be reduced from 400 to 300 mg, or from 600 to 400 mg, or from 800 mg to 600 mg, and in pediatric patients from 340 to 260 mg/m2/day.
Hematological adverse drug reactions: Dose reduction or treatment interruption for severe neutropenia and thrombocytopenia are recommended as indicated in the tables as follows. (See Tables 12 and 13.)
100 mg:
400 mg: Therapy should be initiated by a physician experienced in the treatment of patients with CML or GIST, respectively.
The prescribed dose should be administered orally with a meal and a large glass of water to minimize the risk of gastrointestinal disturbances. Doses of 400 mg or 600 mg should be administered once daily, whereas a daily dose of 800 mg should be administered as 400 mg twice a day, in the morning and in the evening.
For patients unable to swallow the film-coated tablets, the tablets may be dispersed in a glass of water or apple juice. The required number of tablets should be placed in the appropriate volume of beverage (approximately 50 mL for a 100 mg tablet, and 200 mL for a 400 mg tablet) and stirred with a spoon. The suspension should be administered immediately after complete disintegration of the tablet(s).
For patients (e.g. pediatric patients) unable to swallow the capsules, their content may be diluted in a glass of still water or apple juice. Since studies in animals have shown reproductive toxicity, and the potential risk for the human fetus is unknown, women of child-bearing potential, who open capsules should be advised to handle contents with caution and avoid skin-eye contact or inhalation (see USE IN PREGNANCY & LACTATION). Hands should be washed immediately after handling open capsules.
Treatment should be continued as long as the patient continues to benefit.
Monitoring of response to imatinib mesylate (Glivec) therapy in Ph+ CML patients should be performed routinely and when therapy is modified, to identify suboptimal response, loss of response to therapy, poor patient compliance, or possible drug-drug interaction. Results of monitoring should guide appropriate CML management.
General target population: Dosage in CML: The recommended dosage of imatinib mesylate (Glivec) is 400 mg/day for adult patients in chronic phase CML and 600 mg/day for patients in accelerated phase or blast crisis.
Dose increase from 400 mg to 600 mg or 800 mg in patients with chronic phase disease, or from 600 mg to a maximum of 800 mg daily in patients in accelerated phase or blast crisis may be considered in the absence of severe adverse drug reaction and severe non-leukemia-related neutropenia or thrombocytopenia in the following circumstances: disease progression (at any time); failure to achieve a satisfactory hematological response after at least 3 months of treatment; failure to achieve a cytogenetic response after 12 months of treatment; or loss of a previously achieved hematological and/or cytogenetic response.
See section on special populations for pediatric patients as follows.
100 mg: Dosage in Ph+ ALL: The recommended dose of imatinib mesylate (Glivec) is 600 mg/day for adult patients with Ph+ ALL. See section on special populations for pediatric patients as follows.
Dosage in MDS/MPD: The recommended dose of imatinib mesylate (Glivec) is 400 mg/day for adult patients with MDS/MPD.
Dosage in SM: The recommended dose of imatinib mesylate (Glivec) is 400 mg/day for adult patients with SM without the D816V KIT mutation or mutational status unknown or not responding satisfactorily to other therapies.
For patients with SM associated with eosinophilia, a clonal hematological disease related to the fusion kinase FIP1L1-PDGFR-alpha, a starting dose of 100 mg/day is recommended. A dose increase from 100 mg to 400 mg for these patients may be considered in the absence of adverse drug reactions if assessments demonstrate an insufficient response to therapy.
Dosage in HES/CEL: The recommended dose of imatinib mesylate (Glivec) is 400 mg/day for adult patients with HES/CEL.
For HES/CEL patients with demonstrated FIP1L1-PDGFR-alpha fusion kinase, a starting dose of 100 mg/day is recommended. A dose increase from 100 mg to 400 mg for these patients may be considered in the absence of adverse drug reactions if assessments demonstrate an insufficient response to therapy.
Dosage in GIST: The recommended dose of imatinib mesylate (Glivec) is 400 mg/day for adult patients with unresectable and/or metastatic, malignant GIST.
A dose increase from 400 mg to 600 mg or 800 mg for patients may be considered in the absence of adverse drug reactions if assessments demonstrate an insufficient response to therapy.
100 mg: The recommended dose of imatinib mesylate (Glivec) is 400 mg/day for the adjuvant treatment of adult patients following resection of GIST. The recommended minimum treatment duration is 36 months.
In the adjuvant setting the optimal treatment duration with imatinib mesylate (Glivec) is not known.
Dosage in DFSP: The recommended dose of imatinib mesylate (Glivec) is 800 mg/day for adult patients with DFSP.
Dose adjustments for adverse drug reactions: Non-hematological adverse drug reactions: If a severe non-hematological adverse drug reaction develops with imatinib mesylate (Glivec) use, treatment must be withheld until the event has resolved. Thereafter, treatment can be resumed as appropriate depending on the initial severity of the event.
If elevations in bilirubin >3 x institutional upper limit of normal (IULN) or in liver transaminases >5 x IULN occur, imatinib mesylate (Glivec) should be withheld until bilirubin levels have returned to a <1.5 x IULN and transaminase levels to <2.5 x IULN. Treatment with imatinib mesylate (Glivec) may then be continued at a reduced daily dose. In adults the dose should be reduced from 400 to 300 mg, or from 600 to 400 mg, or from 800 mg to 600 mg, and in pediatric patients from 340 to 260 mg/m2/day.
Hematological adverse drug reactions: Dose reduction or treatment interruption for severe neutropenia and thrombocytopenia are recommended as indicated in the tables as follows. (See Tables 12 and 13.)
100 mg:
400 mg:
Special populations: Renal insufficiency: Imatinib and its metabolites are not significantly excreted via the kidney. Patients with renal dysfunction or on dialysis could be given the minimum recommended dose of 400 mg daily as starting dose. (see PHARMACOLOGY under ACTIONS.) However, in these patients caution is recommended. The dose can be reduced if not tolerated. If tolerated, the dose can be increased for lack of efficacy (see PRECAUTIONS).
Hepatic impairment: Imatinib is mainly metabolized by the liver. Patients with mild, moderate or severe liver dysfunction should be given the minimum recommended dose of 400 mg daily. The dose can be reduced if not tolerated (see PRECAUTIONS, ADVERSE REACTIONS AND PHARMACOLOGY under ACTIONS).
100 mg: Pediatric patients (below 18 years): There is no experience with the use of imatinib mesylate (Glivec) in pediatric patients with CML below 2 years of age and with Ph+ALL below 1 year of age. There is very limited to no experience with the use of imatinib mesylate (Glivec) in pediatric patients in other indications.
Dosing in pediatric patients should be on the basis of body surface area (mg/m2). The dose of 340 mg/m2 daily is recommended for children with chronic phase and advanced phase CML and Ph+ALL (not to exceed the total dose of 600 mg daily). Treatment can be given as a once daily dose in CML and Ph+ALL. In CML, alternatively the daily dose may be split into two administrations – one in the morning and one in the evening (see PHARMACOLOGY under ACTIONS).
400 mg: Pediatric patients (below 18 years): There is no experience with the use of Imatinib in pediatric patients with CML below 2 years of age. There is very limited to no experience with the use of imatinib mesylate (Glivec) in pediatric patients in another indication.
Dosing in pediatric patients should be on the basis of body surface area (mg/m2). The dose of 340 mg/m2 daily is recommended for children with chronic phase and advanced phase CML (not to exceed the total dose of 600 mg daily). Treatment can be given as a once daily dose or alternatively the daily dose may be split into two administrations – one in the morning and one in the evening (see PHARMACOLOGY under ACTIONS).
Geriatric patients (65 years or above): No significant age related pharmacokinetic differences have been observed in adult patients in clinical trials which included over 20 % of patients age 65 and older. No specific dose recommendation is necessary in the elderly.
Hepatic impairment: Imatinib is mainly metabolized by the liver. Patients with mild, moderate or severe liver dysfunction should be given the minimum recommended dose of 400 mg daily. The dose can be reduced if not tolerated (see PRECAUTIONS, ADVERSE REACTIONS AND PHARMACOLOGY under ACTIONS).
100 mg: Pediatric patients (below 18 years): There is no experience with the use of imatinib mesylate (Glivec) in pediatric patients with CML below 2 years of age and with Ph+ALL below 1 year of age. There is very limited to no experience with the use of imatinib mesylate (Glivec) in pediatric patients in other indications.
Dosing in pediatric patients should be on the basis of body surface area (mg/m2). The dose of 340 mg/m2 daily is recommended for children with chronic phase and advanced phase CML and Ph+ALL (not to exceed the total dose of 600 mg daily). Treatment can be given as a once daily dose in CML and Ph+ALL. In CML, alternatively the daily dose may be split into two administrations – one in the morning and one in the evening (see PHARMACOLOGY under ACTIONS).
400 mg: Pediatric patients (below 18 years): There is no experience with the use of Imatinib in pediatric patients with CML below 2 years of age. There is very limited to no experience with the use of imatinib mesylate (Glivec) in pediatric patients in another indication.
Dosing in pediatric patients should be on the basis of body surface area (mg/m2). The dose of 340 mg/m2 daily is recommended for children with chronic phase and advanced phase CML (not to exceed the total dose of 600 mg daily). Treatment can be given as a once daily dose or alternatively the daily dose may be split into two administrations – one in the morning and one in the evening (see PHARMACOLOGY under ACTIONS).
Geriatric patients (65 years or above): No significant age related pharmacokinetic differences have been observed in adult patients in clinical trials which included over 20 % of patients age 65 and older. No specific dose recommendation is necessary in the elderly.
Overdosage
Experience with higher than therapeutic doses is limited. Isolated cases of imatinib mesylate (Glivec) overdosage have been reported spontaneously and in the literature. Generally the reported outcome in these cases was improvement or recovery. In the event of overdosage the patient should be observed and appropriate symptomatic treatment should be given.
Events that have been reported at different dose ranges are as follows:
Adult overdose: 1,200 to 1,600 mg (duration varying between 1 to 10 days): Nausea, vomiting, diarrhea, rash, erythema, edema, swelling, fatigue, muscle spasms, thrombocytopenia, pancytopenia, abdominal pain, headache, decreased appetite. 1,800 to 3,200 mg (as high as 3,200 mg daily for 6 days): Weakness, myalgia, increased CPK, increased bilirubin, gastrointestinal pain. 6,400 mg (single dose): One case in the literature reported one patient who experienced nausea, vomiting, abdominal pain, pyrexia, facial swelling, neutrophil count decreased, increased transaminases.
8 to 10 g (single dose): Vomiting and gastrointestinal pain have been reported.
Pediatric overdose: One 3 year-old male exposed to a single dose of 400 mg experienced vomiting, diarrhea and anorexia and another 3 year old male exposed to a single dose of 980 mg dose experienced decreased white blood cell count and diarrhea.
Events that have been reported at different dose ranges are as follows:
Adult overdose: 1,200 to 1,600 mg (duration varying between 1 to 10 days): Nausea, vomiting, diarrhea, rash, erythema, edema, swelling, fatigue, muscle spasms, thrombocytopenia, pancytopenia, abdominal pain, headache, decreased appetite. 1,800 to 3,200 mg (as high as 3,200 mg daily for 6 days): Weakness, myalgia, increased CPK, increased bilirubin, gastrointestinal pain. 6,400 mg (single dose): One case in the literature reported one patient who experienced nausea, vomiting, abdominal pain, pyrexia, facial swelling, neutrophil count decreased, increased transaminases.
8 to 10 g (single dose): Vomiting and gastrointestinal pain have been reported.
Pediatric overdose: One 3 year-old male exposed to a single dose of 400 mg experienced vomiting, diarrhea and anorexia and another 3 year old male exposed to a single dose of 980 mg dose experienced decreased white blood cell count and diarrhea.
Administration
Should be taken with food: Take w/ large amount of water.
Contraindications
Use in patients with a hypersensitivity to the active substance or to any of the excipients is contraindicated.
Special Precautions
When imatinib mesylate (Glivec) is co-administered with other medications, there is a potential for drug interactions. Caution should be used when taking imatinib mesylate (Glivec) with rifampicin or other strong CYP3A4 inducers, ketoconazole or other strong CYP3A4 inhibitors,CYP3A4 substrates with a narrow therapeutic window (e.g. cyclosporin or pimozide) or CYP2C9 substrates with a narrow therapeutic window (e.g. warfarin and other coumarin derivatives) (see INTERACTIONS).
Hypothyroidism: Clinical cases of hypothyroidism have been reported in thyroidectomy patients undergoing levothyroxine replacement during treatment with imatinib mesylate (Glivec). Thyroid-Stimulating Hormone levels should be closely monitored in such patients.
Hepatotoxicity: In patients with hepatic dysfunction (mild, moderate or severe), peripheral blood counts and liver enzymes should be carefully monitored (see DOSAGE & ADMINISTRATION, ADVERSE REACTIONS, PHARMACOLOGY under ACTIONS).
When imatinib mesylate (Glivec) is combined with high dose chemotherapy regimens, transient liver toxicity in the form of transaminase elevation and hyperbilirubinemia has been observed. Additionally, there have been uncommon reports of acute liver failure. Monitoring of hepatic function is recommended in circumstances where imatinib mesylate (Glivec) is combined with chemotherapy regimens also known to be associated with hepatic dysfunction (see ADVERSE REACTIONS).
Fluid retention: Occurrences of severe fluid retention (pleural effusion, edema, pulmonary edema, ascites, and superficial edema) have been reported in approximately 2.5% of newly diagnosed CML patients taking imatinib mesylate (Glivec). Therefore, it is recommended that patients be weighed regularly. An unexpected rapid weight gain should be carefully investigated and if necessary appropriate supportive care and therapeutic measures should be undertaken. In clinical trials, there was an increased incidence of these events in elderly patients and those with a prior history of cardiac disease.
Patients with cardiac disease or renal failure: Patients with cardiac disease, risk factors for cardiac failure or history of renal failure should be monitored carefully and any patient with signs or symptoms consistent with cardiac or renal failure should be evaluated and treated.
100 mg: In patients with hypereosinophilic syndrome (HES) with occult infiltration of HES cells within the myocardium, isolated cases of cardiogenic shock/left ventricular dysfunction have been associated with HES cell degranulation upon the initiation of imatinib mesylate (Glivec) therapy. The condition was reported to be reversible with the administration of systemic steroids, circulatory support measures and temporarily withholding imatinib mesylate (Glivec). Myelodysplastic (MDS)/myeloproliferative diseases (MPD) and systemic mastocytosis might be associated with high eosinophil levels. Performance of an echocardiogram and determination of serum troponin should therefore be considered in patients with HES/CEL, and in patients with MDS/MPD or SM associated with high eosinophil levels. If either is abnormal, the prophylactic use of systemic steroids (1 to 2 mg/kg) for one to two weeks concomitantly with imatinib mesylate (Glivec) should be considered at the initiation of therapy.
Gastrointestinal hemorrhage: In the Phase III GIST studies in patients with unresectable or metastatic malignant GIST 211 patients (12.9%) reported Grade 3/4 hemorrhage at any site. In the Phase II GIST study in patients with unresectable or metastatic malignant GIST (study B2222), eight patients (5.4%) were reported to have had gastrointestinal (GI) hemorrhage and four patients (2.7%) were reported to have had hemorrhages at the site of tumor deposits. The tumor hemorrhages have been either intra-abdominal or intra-hepatic, depending on the anatomical location of tumor lesions. GI sites of tumor may have contributed to GI bleeding in this reported patient population (see ADVERSE REACTIONS). In addition, gastric antral vascular ectasia (GAVE), a rare cause of GI hemorrhage, has been reported in post-marketing experience in patients with CML, ALL and other diseases. Patients should therefore be monitored for gastrointestinal symptoms at the start of and during therapy with imatinib mesylate (Glivec). When needed, imatinib mesylate (Glivec) discontinuation may be considered (see ADVERSE REACTIONS).
Tumor lysis syndrome: Cases of tumor lysis syndrome (TLS) have been reported in patients treated with imatinib mesylate (Glivec). Due to possible occurrence of TLS, correction of clinically significant dehydration and treatment of high uric acid levels are recommended prior to initiation of imatinib mesylate (Glivec) (see ADVERSE REACTIONS).
Hepatitis B reactivation: Reactivation of hepatitis B can occur in patients who are chronic carriers of this virus after receiving a BCR-ABL tyrosine kinase inhibitor (TKI), such as imatinib. Some cases involving drugs of the BCR-ABL TKI class resulted in acute hepatic failure or fulminant hepatitis leading to liver transplantation or a fatal outcome (see ADVERSE REACTIONS).
Patients should be tested for hepatitis B infection before initiating treatment with imatinib. Patients currently on imatinib should have baseline testing for hepatitis B infection in order to identify chronic carriers of the virus. Experts in liver disease and in the treatment of hepatitis B should be consulted before treatment is initiated in patients with positive hepatitis B serology (including those with active disease) and for patients who test positive for hepatitis B infection during treatment. Carriers of hepatitis B virus who require treatment with imatinib should be closely monitored for signs and symptoms of active hepatitis B infection throughout therapy and for several months following termination of therapy.
Laboratory tests: Hematology: Complete blood counts must be performed regularly during therapy with imatinib mesylate (Glivec). Treatment of CML patients with imatinib mesylate (Glivec) has been associated with neutropenia or thrombocytopenia. However, the occurrence of these cytopenias is dependent on the stage of the disease being treated and they were more frequent in patients with accelerated phase CML or blast crisis as compared to patients with chronic phase CML. Treatment with imatinib mesylate (Glivec) may be interrupted or the dose be reduced, as recommended in DOSAGE & ADMINISTRATION.
Liver Function: Liver function (transaminases, bilirubin, alkaline phosphatase) should be monitored regularly in patients receiving imatinib mesylate (Glivec). As recommended in DOSAGE & ADMINISTRATION, non-hematological adverse drug reactions, these laboratory abnormalities should be managed with interruption and/or dose reduction of the treatment with imatinib mesylate (Glivec).
Renal Function: Imatinib mesylate (Glivec) and its metabolites are not excreted via the kidney to a significant extent. Creatinine clearance (CrCL) is known to decrease with age, and age did not significantly affect imatinib mesylate (Glivec) kinetics. In patients with impaired renal function, imatinib mesylate plasma exposure seems to be higher than that in patients with normal renal function, probably due to an elevated plasma level of alpha-acid glycoprotein (AGP), an imatinib mesylate-binding protein, in these patients. There is no correlation between imatinib mesylate exposure and the degree of renal impairment, as classified by the measurement of creatinine clearance (CrCL), between patients with mild (CrCL: 40 to 59 mL/min) and severe (CrCL: <20 mL/min) renal impairment. However, as recommended in DOSAGE & ADMINISTRATION, the starting dose of imatinib mesylate (Glivec) can be reduced if not tolerated.
Long-term treatment with imatinib may be associated with a clinically significant decline in renal function. Renal function should, therefore, be evaluated prior to the start of imatinib therapy and closely monitored during therapy, with particular attention to those patients exhibiting risk factors for renal dysfunction. If renal dysfunction is observed, appropriate management and treatment should be initiated in accordance with standard treatment guidelines.
Use in Children: There have been case reports of growth retardation occurring in children and pre-adolescents receiving imatinib mesylate (Glivec). The long term effects of prolonged treatment with imatinib mesylate (Glivec) on growth in pediatric patients are unknown. Therefore, close monitoring of growth in children under imatinib mesylate (Glivec) treatment is recommended (see ADVERSE REACTIONS).
Driving and using machines: Reports of motor vehicle accidents have been received in patients receiving imatinib mesylate (Glivec). While most of these reports are not suspected to be caused by imatinib mesylate (Glivec), patients should be advised that they may experience undesirable effects such as dizziness, blurred vision or somnolence during treatment with imatinib mesylate (Glivec). Therefore, caution should be recommended when driving a car or operating machinery.
Hypothyroidism: Clinical cases of hypothyroidism have been reported in thyroidectomy patients undergoing levothyroxine replacement during treatment with imatinib mesylate (Glivec). Thyroid-Stimulating Hormone levels should be closely monitored in such patients.
Hepatotoxicity: In patients with hepatic dysfunction (mild, moderate or severe), peripheral blood counts and liver enzymes should be carefully monitored (see DOSAGE & ADMINISTRATION, ADVERSE REACTIONS, PHARMACOLOGY under ACTIONS).
When imatinib mesylate (Glivec) is combined with high dose chemotherapy regimens, transient liver toxicity in the form of transaminase elevation and hyperbilirubinemia has been observed. Additionally, there have been uncommon reports of acute liver failure. Monitoring of hepatic function is recommended in circumstances where imatinib mesylate (Glivec) is combined with chemotherapy regimens also known to be associated with hepatic dysfunction (see ADVERSE REACTIONS).
Fluid retention: Occurrences of severe fluid retention (pleural effusion, edema, pulmonary edema, ascites, and superficial edema) have been reported in approximately 2.5% of newly diagnosed CML patients taking imatinib mesylate (Glivec). Therefore, it is recommended that patients be weighed regularly. An unexpected rapid weight gain should be carefully investigated and if necessary appropriate supportive care and therapeutic measures should be undertaken. In clinical trials, there was an increased incidence of these events in elderly patients and those with a prior history of cardiac disease.
Patients with cardiac disease or renal failure: Patients with cardiac disease, risk factors for cardiac failure or history of renal failure should be monitored carefully and any patient with signs or symptoms consistent with cardiac or renal failure should be evaluated and treated.
100 mg: In patients with hypereosinophilic syndrome (HES) with occult infiltration of HES cells within the myocardium, isolated cases of cardiogenic shock/left ventricular dysfunction have been associated with HES cell degranulation upon the initiation of imatinib mesylate (Glivec) therapy. The condition was reported to be reversible with the administration of systemic steroids, circulatory support measures and temporarily withholding imatinib mesylate (Glivec). Myelodysplastic (MDS)/myeloproliferative diseases (MPD) and systemic mastocytosis might be associated with high eosinophil levels. Performance of an echocardiogram and determination of serum troponin should therefore be considered in patients with HES/CEL, and in patients with MDS/MPD or SM associated with high eosinophil levels. If either is abnormal, the prophylactic use of systemic steroids (1 to 2 mg/kg) for one to two weeks concomitantly with imatinib mesylate (Glivec) should be considered at the initiation of therapy.
Gastrointestinal hemorrhage: In the Phase III GIST studies in patients with unresectable or metastatic malignant GIST 211 patients (12.9%) reported Grade 3/4 hemorrhage at any site. In the Phase II GIST study in patients with unresectable or metastatic malignant GIST (study B2222), eight patients (5.4%) were reported to have had gastrointestinal (GI) hemorrhage and four patients (2.7%) were reported to have had hemorrhages at the site of tumor deposits. The tumor hemorrhages have been either intra-abdominal or intra-hepatic, depending on the anatomical location of tumor lesions. GI sites of tumor may have contributed to GI bleeding in this reported patient population (see ADVERSE REACTIONS). In addition, gastric antral vascular ectasia (GAVE), a rare cause of GI hemorrhage, has been reported in post-marketing experience in patients with CML, ALL and other diseases. Patients should therefore be monitored for gastrointestinal symptoms at the start of and during therapy with imatinib mesylate (Glivec). When needed, imatinib mesylate (Glivec) discontinuation may be considered (see ADVERSE REACTIONS).
Tumor lysis syndrome: Cases of tumor lysis syndrome (TLS) have been reported in patients treated with imatinib mesylate (Glivec). Due to possible occurrence of TLS, correction of clinically significant dehydration and treatment of high uric acid levels are recommended prior to initiation of imatinib mesylate (Glivec) (see ADVERSE REACTIONS).
Hepatitis B reactivation: Reactivation of hepatitis B can occur in patients who are chronic carriers of this virus after receiving a BCR-ABL tyrosine kinase inhibitor (TKI), such as imatinib. Some cases involving drugs of the BCR-ABL TKI class resulted in acute hepatic failure or fulminant hepatitis leading to liver transplantation or a fatal outcome (see ADVERSE REACTIONS).
Patients should be tested for hepatitis B infection before initiating treatment with imatinib. Patients currently on imatinib should have baseline testing for hepatitis B infection in order to identify chronic carriers of the virus. Experts in liver disease and in the treatment of hepatitis B should be consulted before treatment is initiated in patients with positive hepatitis B serology (including those with active disease) and for patients who test positive for hepatitis B infection during treatment. Carriers of hepatitis B virus who require treatment with imatinib should be closely monitored for signs and symptoms of active hepatitis B infection throughout therapy and for several months following termination of therapy.
Laboratory tests: Hematology: Complete blood counts must be performed regularly during therapy with imatinib mesylate (Glivec). Treatment of CML patients with imatinib mesylate (Glivec) has been associated with neutropenia or thrombocytopenia. However, the occurrence of these cytopenias is dependent on the stage of the disease being treated and they were more frequent in patients with accelerated phase CML or blast crisis as compared to patients with chronic phase CML. Treatment with imatinib mesylate (Glivec) may be interrupted or the dose be reduced, as recommended in DOSAGE & ADMINISTRATION.
Liver Function: Liver function (transaminases, bilirubin, alkaline phosphatase) should be monitored regularly in patients receiving imatinib mesylate (Glivec). As recommended in DOSAGE & ADMINISTRATION, non-hematological adverse drug reactions, these laboratory abnormalities should be managed with interruption and/or dose reduction of the treatment with imatinib mesylate (Glivec).
Renal Function: Imatinib mesylate (Glivec) and its metabolites are not excreted via the kidney to a significant extent. Creatinine clearance (CrCL) is known to decrease with age, and age did not significantly affect imatinib mesylate (Glivec) kinetics. In patients with impaired renal function, imatinib mesylate plasma exposure seems to be higher than that in patients with normal renal function, probably due to an elevated plasma level of alpha-acid glycoprotein (AGP), an imatinib mesylate-binding protein, in these patients. There is no correlation between imatinib mesylate exposure and the degree of renal impairment, as classified by the measurement of creatinine clearance (CrCL), between patients with mild (CrCL: 40 to 59 mL/min) and severe (CrCL: <20 mL/min) renal impairment. However, as recommended in DOSAGE & ADMINISTRATION, the starting dose of imatinib mesylate (Glivec) can be reduced if not tolerated.
Long-term treatment with imatinib may be associated with a clinically significant decline in renal function. Renal function should, therefore, be evaluated prior to the start of imatinib therapy and closely monitored during therapy, with particular attention to those patients exhibiting risk factors for renal dysfunction. If renal dysfunction is observed, appropriate management and treatment should be initiated in accordance with standard treatment guidelines.
Use in Children: There have been case reports of growth retardation occurring in children and pre-adolescents receiving imatinib mesylate (Glivec). The long term effects of prolonged treatment with imatinib mesylate (Glivec) on growth in pediatric patients are unknown. Therefore, close monitoring of growth in children under imatinib mesylate (Glivec) treatment is recommended (see ADVERSE REACTIONS).
Driving and using machines: Reports of motor vehicle accidents have been received in patients receiving imatinib mesylate (Glivec). While most of these reports are not suspected to be caused by imatinib mesylate (Glivec), patients should be advised that they may experience undesirable effects such as dizziness, blurred vision or somnolence during treatment with imatinib mesylate (Glivec). Therefore, caution should be recommended when driving a car or operating machinery.
Use In Pregnancy & Lactation
Since studies in animals have shown reproductive toxicity, and the potential risk for the human fetus is unknown, women of child-bearing potential, who open capsules should be advised to handle contents with caution and avoid skin-eye contact or inhalation (see section PREGNANCY, LACTATION, FEMALES AND MALES OF REPRODUCTIVE POTENTIAL as follows). Hands should be washed immediately after handling open capsules.
Pregnancy: Risk Summary: Imatinib can cause fetal harm when administered to a pregnant woman based on findings from animal reproduction studies. There are no clinical trials on the use of imatinib mesylate (Glivec) in pregnant women. There have been post-marketing reports of spontaneous abortions and infant congenital anomalies from women who have taken imatinib mesylate (Glivec). Reproductive studies in rats have demonstrated that imatinib mesylate induced teratogenicity (increased incidence of congenital abnormalities) following prenatal exposure to imatinib mesylate at doses equal to the highest recommended human dose of 800 mg/day based on body surface area. Imatinib mesylate (Glivec) should be used during pregnancy only if the expected benefit outweighs the potential risk to the fetus. If it is used during pregnancy, the patient must be informed of the potential risk to the fetus.
Data: In embryo-fetal development studies in rats and rabbits, pregnant animals received oral doses of imatinib mesylate up to 100 mg/kg/day and 60 mg/kg/day, respectively, during the period of organogenesis.
In rats, imatinib mesylate was teratogenic at 100 mg/kg/day (approximately equal to the maximum human dose of 800 mg/day based on body surface area), the number of fetuses with encephalocoele and exencephaly was higher than historical control values and these findings were associated with missing or underdeveloped cranial bones. Lower mean fetal body weights were associated with retarded skeletal ossifications.
In rabbits, at doses 1.5 times higher than the maximum human dose of 800 mg/day based on body surface area, no effects on the reproductive parameters with respect to implantation sites, number of live fetuses, sex ratio or fetal weight were observed. The examinations of the fetuses did not reveal any drug related morphological changes.
In a pre- and postnatal development study in rats, pregnant rats received oral doses of imatinib mesylate during gestation (organogenesis) and lactation up to 45 mg/kg/day. Five animals developed a red vaginal discharge in the 45 mg/kg/day group on Days 14 or 15 of gestation, the significance of which is unknown since all females produced viable litters and none had increased post-implantation loss. Other maternal effects noted only at the dose of 45 mg/kg/day (approximately one-half the maximum human dose of 800 mg/day based on body surface area) included increased numbers of stillborn pups and pups dying between postpartum Days 0 and 4. In the F1 offspring at this same dose level, mean body weights were reduced from birth until terminal sacrifice and the number of litters achieving criterion for preputial separation was slightly decreased. There were no other significant effects in developmental parameters or behavioral testing. F1 fertility was not affected but reproductive effects were noted at 45 mg/kg/day including an increased number of resorptions and a decreased number of viable fetuses. The NOEL for both maternal animals and the F1 generation was 15 mg/kg/day.
Lactation: Risk summary: Both imatinib and its active metabolite can be transferred into human milk. The effects of low-dose exposure of the infant to imatinib are unknown, because of the potential for serious adverse drug reactions in the breastfed child, breastfeeding is not recommended during treatment and for at least 15 days after stopping treatment with Imatinib.
Human Data: The milk plasma ratio was determined to be 0.5 for imatinib mesylate and 0.9 for the metabolite, suggesting greater distribution of the metabolite into the milk. Considering the combined concentration of imatinib and of the metabolite and the maximum daily milk intake by infants the total exposure would be expected to be approximately~10% of a therapeutic dose. Females and males of reproductive potential: Females: Females of reproductive potential should be advised to use effective contraception (methods that result in less than 1 % pregnancy rates) when using imatinib mesylate (Glivec) during treatment and for at least 15 days after stopping treatment with imatinib mesylate (Glivec).
Infertility: Human studies on male patients receiving imatinib mesylate (Glivec) and its effect on male fertility and spermatogenesis have not been performed. Male patients concerned about their fertility on imatinib mesylate (Glivec) treatment should consult with their physician. Fertility was not affected in the preclinical fertility and early embryonic development study although lower testes and epididymal weights as well as a reduced number of motile sperm were observed in the high dose males rats. In the preclinical pre- and postnatal study in rats, fertility in the first generation offspring was also not affected by Imatinib.
Pregnancy: Risk Summary: Imatinib can cause fetal harm when administered to a pregnant woman based on findings from animal reproduction studies. There are no clinical trials on the use of imatinib mesylate (Glivec) in pregnant women. There have been post-marketing reports of spontaneous abortions and infant congenital anomalies from women who have taken imatinib mesylate (Glivec). Reproductive studies in rats have demonstrated that imatinib mesylate induced teratogenicity (increased incidence of congenital abnormalities) following prenatal exposure to imatinib mesylate at doses equal to the highest recommended human dose of 800 mg/day based on body surface area. Imatinib mesylate (Glivec) should be used during pregnancy only if the expected benefit outweighs the potential risk to the fetus. If it is used during pregnancy, the patient must be informed of the potential risk to the fetus.
Data: In embryo-fetal development studies in rats and rabbits, pregnant animals received oral doses of imatinib mesylate up to 100 mg/kg/day and 60 mg/kg/day, respectively, during the period of organogenesis.
In rats, imatinib mesylate was teratogenic at 100 mg/kg/day (approximately equal to the maximum human dose of 800 mg/day based on body surface area), the number of fetuses with encephalocoele and exencephaly was higher than historical control values and these findings were associated with missing or underdeveloped cranial bones. Lower mean fetal body weights were associated with retarded skeletal ossifications.
In rabbits, at doses 1.5 times higher than the maximum human dose of 800 mg/day based on body surface area, no effects on the reproductive parameters with respect to implantation sites, number of live fetuses, sex ratio or fetal weight were observed. The examinations of the fetuses did not reveal any drug related morphological changes.
In a pre- and postnatal development study in rats, pregnant rats received oral doses of imatinib mesylate during gestation (organogenesis) and lactation up to 45 mg/kg/day. Five animals developed a red vaginal discharge in the 45 mg/kg/day group on Days 14 or 15 of gestation, the significance of which is unknown since all females produced viable litters and none had increased post-implantation loss. Other maternal effects noted only at the dose of 45 mg/kg/day (approximately one-half the maximum human dose of 800 mg/day based on body surface area) included increased numbers of stillborn pups and pups dying between postpartum Days 0 and 4. In the F1 offspring at this same dose level, mean body weights were reduced from birth until terminal sacrifice and the number of litters achieving criterion for preputial separation was slightly decreased. There were no other significant effects in developmental parameters or behavioral testing. F1 fertility was not affected but reproductive effects were noted at 45 mg/kg/day including an increased number of resorptions and a decreased number of viable fetuses. The NOEL for both maternal animals and the F1 generation was 15 mg/kg/day.
Lactation: Risk summary: Both imatinib and its active metabolite can be transferred into human milk. The effects of low-dose exposure of the infant to imatinib are unknown, because of the potential for serious adverse drug reactions in the breastfed child, breastfeeding is not recommended during treatment and for at least 15 days after stopping treatment with Imatinib.
Human Data: The milk plasma ratio was determined to be 0.5 for imatinib mesylate and 0.9 for the metabolite, suggesting greater distribution of the metabolite into the milk. Considering the combined concentration of imatinib and of the metabolite and the maximum daily milk intake by infants the total exposure would be expected to be approximately~10% of a therapeutic dose. Females and males of reproductive potential: Females: Females of reproductive potential should be advised to use effective contraception (methods that result in less than 1 % pregnancy rates) when using imatinib mesylate (Glivec) during treatment and for at least 15 days after stopping treatment with imatinib mesylate (Glivec).
Infertility: Human studies on male patients receiving imatinib mesylate (Glivec) and its effect on male fertility and spermatogenesis have not been performed. Male patients concerned about their fertility on imatinib mesylate (Glivec) treatment should consult with their physician. Fertility was not affected in the preclinical fertility and early embryonic development study although lower testes and epididymal weights as well as a reduced number of motile sperm were observed in the high dose males rats. In the preclinical pre- and postnatal study in rats, fertility in the first generation offspring was also not affected by Imatinib.
Adverse Reactions
Summary of the safety profile: The overall safety profile of imatinib mesylate (Glivec) in human clinical use has been well-characterized through more than 12 years of imatinib mesylate (Glivec) experience. During clinical development, the majority of patients experienced adverse events at some point in time. The most frequently reported ADRs (>10%) were neutropenia, thrombocytopenia, anemia, headache, dyspepsia, edema, weight increased, nausea, vomiting, muscle cramps, musculoskeletal pain, diarrhea, rash, fatigue, and abdominal pain. Events were of mild to moderate grade, and only 2 to 5% of patients permanently discontinued therapy due to drug-related events.
100 mg: The safety profile of imatinib mesylate (Glivec) in adult and pediatric patients with Ph+ Leukemias is similar.
The differences in the safety profile between Ph+ leukemias and solid tumors are a higher incidence and severity of myelosuppression in Ph+ leukemias, and GI and intra-tumoral hemorrhages in GIST patients and are probably due to disease-related factors. Myelosuppression, GI adverse events, edema, and rashes are common between these two patient populations. Other GI conditions, such as gastrointestinal obstruction, perforation and ulceration, appear to be more indication-specific. Other prominent adverse events that have been observed after exposure to imatinib mesylate (Glivec), and which may be causally related, include hepatotoxicity, acute renal failure, hypophosphatemia, severe respiratory adverse reactions, and tumor lysis syndrome and growth retardation in children.
Depending on severity of events, dose adjustment may be required. In very few cases will the medication have to be discontinued based on ADRs.
100 mg: The safety profile of imatinib mesylate (Glivec) in adult and pediatric patients with Ph+ Leukemias is similar.
The differences in the safety profile between Ph+ leukemias and solid tumors are a higher incidence and severity of myelosuppression in Ph+ leukemias, and GI and intra-tumoral hemorrhages in GIST patients and are probably due to disease-related factors. Myelosuppression, GI adverse events, edema, and rashes are common between these two patient populations. Other GI conditions, such as gastrointestinal obstruction, perforation and ulceration, appear to be more indication-specific. Other prominent adverse events that have been observed after exposure to imatinib mesylate (Glivec), and which may be causally related, include hepatotoxicity, acute renal failure, hypophosphatemia, severe respiratory adverse reactions, and tumor lysis syndrome and growth retardation in children.
Depending on severity of events, dose adjustment may be required. In very few cases will the medication have to be discontinued based on ADRs.
Drug Interactions
Observed interactions resulting in a concomitant use not recommended: Drugs that may decrease imatinib plasma concentrations: Substances that are inducers of CYP3A4 activity (e.g. dexamethasone, phenytoin, carbamazepine, rifampicin, phenobarbital or hypericum perforatum, also known as St. John's Wort) may significantly reduce exposure to imatinib mesylate (Glivec). Pretreatment of 14 healthy volunteers with multiple doses of rifampicin, 600 mg daily for 8 days, followed by a single 400 mg dose of imatinib mesylate (Glivec), increased imatinib mesylate (Glivec) oral-dose clearance by 3.8 fold (90% confidence interval = 3.5 to 4.3 fold), which represents mean decreases Cmax, AUC(0-24) and AUC(0-∞) by 54%, 68% and 74%, of the respective values without rifampicin treatment. Similar results were observed in patients with malignant gliomas treated with imatinib mesylate (Glivec) while taking enzyme-inducing anti-epileptic drugs (EIAEDs) such as carbamazepine, oxcarbazepine, phenytoin, fosphenytoin, phenobarbital, and primidone. The plasma AUC for imatinib decreased by 73% compared to patients not on EIAEDs. In two published studies, concomitant administration of imatinib mesylate (Glivec) and a product containing St. John's wort led to a 30 to 32% reduction in the AUC of imatinib mesylate (Glivec). In patients where rifampicin or other CYP3A4 inducers are indicated, alternative therapeutic agents with less enzyme induction potential should be considered.
Other interactions that may affect exposure to imatinib mesylate (Glivec) or other drugs: Drugs that may increase imatinib mesylate plasma concentrations: Substances that inhibit the cytochrome P450 isoenzyme CYP3A4 activity (e.g. ketoconazole, itraconazole, erythromycin, clarithromycin) could decrease metabolism and increase imatinib mesylate concentrations. There was a significant increase in exposure to imatinib mesylate (the mean Cmax and AUC of imatinib mesylate rose by 26% and 40%, respectively) in healthy subjects when it was co-administered with a single dose of ketoconazole (a CYP3A4 inhibitor). Caution should be taken when administering imatinib mesylate (Glivec) with inhibitors of the CYP3A4 family.
Drugs that may have their plasma concentration altered by imatinib mesylate (Glivec): Imatinib mesylate (Glivec) increases the mean Cmax and AUC of simvastatin (CYP3A4 substrate) 2 and 3.5 fold, respectively, indicating an inhibition of the CYP3A4 by imatinib mesylate (Glivec). Therefore, caution is recommended when administering imatinib mesylate (Glivec) with CYP3A4 substrates with a narrow therapeutic window (e.g. cyclosporin or pimozide). Imatinib mesylate (Glivec) may increase plasma concentration of other CYP3A4 metabolized drugs (e.g. triazolo-benzodiazepines, dihydropyridine calcium channel blockers, certain HMG-CoA reductase inhibitors, i.e. statins, etc.).
Imatinib mesylate (Glivec) also inhibits CYP2C9 and CYP2C19 activity in vitro. PT prolongation was observed following co-administration with warfarin. When giving coumarins, short-term PT monitoring is therefore necessary at the start and end of Imatinib mesylate (Glivec) therapy and when altering the dosage. Alternatively, the use of low-molecular weight heparin should be considered.
In vitro, Imatinib mesylate (Glivec) inhibits the cytochrome P450 isoenzyme CYP2D6 activity at concentrations similar to those that affect CYP3A4 activity. Imatinib mesylate (Glivec) at 400 mg twice daily had a weak inhibitory effect on CYP2D6-mediated metoprolol metabolism, with metoprolol Cmax and AUC being increased by approximately 23%. Co-administration of imatinib mesylate (Glivec) with CYP2D6 substrates, such as metoprolol, does not seem to be a risk factor for drug-drug interactions and dose adjustment may not be necessary.
In vitro, imatinib mesylate (Glivec) inhibits the acetaminophen O-glucuronidate pathway (Ki 58.5 microM).
Co-administration of imatinib mesylate (Glivec) (400 mg/day for eight days) with acetaminophen/paracetamol (1000 mg single dose on day eight) in patients with CML did not result in any changes in the pharmacokinetics of acetaminophen/paracetamol.
Imatinib mesylate (Glivec) pharmacokinetics was not altered in the presence of single-dose acetaminophen/ paracetamol.
There is no PK or safety data on the concomitant use of imatinib mesylate (Glivec) at doses >400 mg/day or the chronic use of concomitant acetaminophen/paracetamol and imatinib mesylate (Glivec).
Other interactions that may affect exposure to imatinib mesylate (Glivec) or other drugs: Drugs that may increase imatinib mesylate plasma concentrations: Substances that inhibit the cytochrome P450 isoenzyme CYP3A4 activity (e.g. ketoconazole, itraconazole, erythromycin, clarithromycin) could decrease metabolism and increase imatinib mesylate concentrations. There was a significant increase in exposure to imatinib mesylate (the mean Cmax and AUC of imatinib mesylate rose by 26% and 40%, respectively) in healthy subjects when it was co-administered with a single dose of ketoconazole (a CYP3A4 inhibitor). Caution should be taken when administering imatinib mesylate (Glivec) with inhibitors of the CYP3A4 family.
Drugs that may have their plasma concentration altered by imatinib mesylate (Glivec): Imatinib mesylate (Glivec) increases the mean Cmax and AUC of simvastatin (CYP3A4 substrate) 2 and 3.5 fold, respectively, indicating an inhibition of the CYP3A4 by imatinib mesylate (Glivec). Therefore, caution is recommended when administering imatinib mesylate (Glivec) with CYP3A4 substrates with a narrow therapeutic window (e.g. cyclosporin or pimozide). Imatinib mesylate (Glivec) may increase plasma concentration of other CYP3A4 metabolized drugs (e.g. triazolo-benzodiazepines, dihydropyridine calcium channel blockers, certain HMG-CoA reductase inhibitors, i.e. statins, etc.).
Imatinib mesylate (Glivec) also inhibits CYP2C9 and CYP2C19 activity in vitro. PT prolongation was observed following co-administration with warfarin. When giving coumarins, short-term PT monitoring is therefore necessary at the start and end of Imatinib mesylate (Glivec) therapy and when altering the dosage. Alternatively, the use of low-molecular weight heparin should be considered.
In vitro, Imatinib mesylate (Glivec) inhibits the cytochrome P450 isoenzyme CYP2D6 activity at concentrations similar to those that affect CYP3A4 activity. Imatinib mesylate (Glivec) at 400 mg twice daily had a weak inhibitory effect on CYP2D6-mediated metoprolol metabolism, with metoprolol Cmax and AUC being increased by approximately 23%. Co-administration of imatinib mesylate (Glivec) with CYP2D6 substrates, such as metoprolol, does not seem to be a risk factor for drug-drug interactions and dose adjustment may not be necessary.
In vitro, imatinib mesylate (Glivec) inhibits the acetaminophen O-glucuronidate pathway (Ki 58.5 microM).
Co-administration of imatinib mesylate (Glivec) (400 mg/day for eight days) with acetaminophen/paracetamol (1000 mg single dose on day eight) in patients with CML did not result in any changes in the pharmacokinetics of acetaminophen/paracetamol.
Imatinib mesylate (Glivec) pharmacokinetics was not altered in the presence of single-dose acetaminophen/ paracetamol.
There is no PK or safety data on the concomitant use of imatinib mesylate (Glivec) at doses >400 mg/day or the chronic use of concomitant acetaminophen/paracetamol and imatinib mesylate (Glivec).
Caution For Usage
Incompatibilities: Not applicable.
Instructions for Use and Handling: No special requirements.
Instructions for Use and Handling: No special requirements.
Storage
Protect from moisture.
100 mg: Store at temperatures not exceeding 30°C.
100 mg: Store at temperatures not exceeding 30°C.
Action
Pharmacology: Mechanism of action (MOA): Imatinib is a small molecule protein-tyrosine kinase inhibitor that potently inhibits the activity of the (BCR-ABL) tyrosine kinase (TK), as well as several receptor TKs: KIT, the receptor for stem cell factor (SCF) coded for by the KIT proto-oncogene, the discoidin domain receptors (DDR1 and DDR2), the colony stimulating factor receptor (CSF-1R) and the platelet-derived growth factor receptors alpha and beta (PDGFR-alpha and PDGFR-beta). Imatinib can also inhibit cellular events mediated by activation of these receptor kinases.
Pharmacodynamics: Imatinib is a protein-tyrosine kinase inhibitor, which potently inhibits the breakpoint cluster region-Abelson (BCR-ABL) tyrosine kinase at the in vitro, cellular, in vivo levels. The compound selectively inhibits proliferation and induces apoptosis in BCR-ABL positive cell lines as well as fresh leukemic cells from Philadelphia chromosome positive CML and acute lymphoblastic leukemia (ALL) patients. In colony transformation assays using ex vivo peripheral blood and bone marrow samples, imatinib shows selective inhibition of BCR-ABL positive colonies from CML patients.
In vivo, the compound shows anti-tumor activity as a single agent in animal models using BCR-ABL positive tumor cells.
Imatinib is also an inhibitor of the receptor tyrosine kinases for platelet-derived growth factor (PDGF) and stem cell factor (SCF), KIT, and inhibits PDGF- and SCF-mediated cellular events. In vitro, imatinib inhibits proliferation and induces apoptosis in gastrointestinal stromal tumor (GIST) cells, which express an activating KIT mutation.
100 mg: Constitutive activation of the PDGFR or the ABL protein tyrosine kinases as a consequence of fusion to diverse partner proteins or constitutive production of PDGF have been implicated in the pathogenesis of MDS/MPD, HES/CEL and DFSP. In addition, constitutive activation of KIT or the PDGFR has been implicated in the pathogenesis of SM. Imatinib inhibits signaling and proliferation of cells driven by dysregulated PDGFR, KIT and ABL kinase activity.
Clinical studies in CML: The effectiveness of imatinib mesylate (Glivec) is based on overall hematological and cytogenetic response rates and progression free survival.
Pharmacodynamics: Imatinib is a protein-tyrosine kinase inhibitor, which potently inhibits the breakpoint cluster region-Abelson (BCR-ABL) tyrosine kinase at the in vitro, cellular, in vivo levels. The compound selectively inhibits proliferation and induces apoptosis in BCR-ABL positive cell lines as well as fresh leukemic cells from Philadelphia chromosome positive CML and acute lymphoblastic leukemia (ALL) patients. In colony transformation assays using ex vivo peripheral blood and bone marrow samples, imatinib shows selective inhibition of BCR-ABL positive colonies from CML patients.
In vivo, the compound shows anti-tumor activity as a single agent in animal models using BCR-ABL positive tumor cells.
Imatinib is also an inhibitor of the receptor tyrosine kinases for platelet-derived growth factor (PDGF) and stem cell factor (SCF), KIT, and inhibits PDGF- and SCF-mediated cellular events. In vitro, imatinib inhibits proliferation and induces apoptosis in gastrointestinal stromal tumor (GIST) cells, which express an activating KIT mutation.
100 mg: Constitutive activation of the PDGFR or the ABL protein tyrosine kinases as a consequence of fusion to diverse partner proteins or constitutive production of PDGF have been implicated in the pathogenesis of MDS/MPD, HES/CEL and DFSP. In addition, constitutive activation of KIT or the PDGFR has been implicated in the pathogenesis of SM. Imatinib inhibits signaling and proliferation of cells driven by dysregulated PDGFR, KIT and ABL kinase activity.
Clinical studies in CML: The effectiveness of imatinib mesylate (Glivec) is based on overall hematological and cytogenetic response rates and progression free survival.
Pharmacokinetics: The pharmacokinetics of imatinib mesylate (Glivec) have been evaluated over a dosage range of 25 to 1,000 mg. Plasma pharmacokinetic profiles were analyzed on day 1 and on either day 7 or day 28, by which time plasma concentrations had reached steady state.
Absorption: Mean absolute bioavailability for the capsule formulation imatinib is 98%. The coefficient of variation for plasma imatinib AUC is in the range of 40% to 60% after an oral dose. When given with a high fat meal, the rate of absorption of imatinib was minimally reduced (11% decrease in Cmax and prolongation of tmax by 1.5 h), with a small reduction in AUC (7.4%) compared to fasting conditions.
Distribution: At clinically relevant concentrations of imatinib, binding to plasma proteins was approximately 95% on the basis of in vitro experiments, mostly to albumin and alpha-acid-glycoprotein, with little binding to lipoprotein.
Biotransformation/metabolism: The main circulating metabolite in humans is the N-demethylated piperazine derivative (CGP71588), which shows similar in vitro potency as the parent compound. The plasma AUC for this metabolite was found to be only 16% of the AUC for imatinib. The plasma protein binding of the N-demethylated metabolite is similar to that of the parent compound.
Elimination: Based on the recovery of compound(s) after an oral 14C-labelled dose of imatinib, approximately 81% of the dose was eliminated within 7 days in feces (68% of dose) and urine (13% of dose). Unchanged imatinib accounted for 25% of the dose (5% urine, 20% feces), the remainder being metabolites.
The mean apparent elimination half-life estimated from the single dose PK study was 13.5 hours. The half-life of all 14C-labelled components in plasma was from 41-72 hours.
Plasma pharmacokinetics: Following oral administration in healthy volunteers, the t½ was approximately 18 h, suggesting that once-daily dosing is appropriate. The increase in mean AUC with increasing dose was linear and dose proportional in the range of 25 to 1,000 mg imatinib after oral administration. There was no change in the kinetics of imatinib on repeated dosing, and accumulation was 1.5 to 2.5 fold at steady state when dosed once daily.
Special populations: Based on population pharmacokinetic analysis, there was a small effect of age on the volume of distribution (12% increase in patients >65 years old). This change is not thought to be clinically significant. The effect of body weight on the clearance of imatinib is such that for a patient weighing 50 kg the mean clearance is expected to be 8.5 L/h, while for a patient weighing 100 kg the clearance will rise to 11.8 L/h. These changes are not considered sufficient to warrant dose adjustment based on kg bodyweight. There is no effect of gender on the kinetics of imatinib.
Absorption: Mean absolute bioavailability for the capsule formulation imatinib is 98%. The coefficient of variation for plasma imatinib AUC is in the range of 40% to 60% after an oral dose. When given with a high fat meal, the rate of absorption of imatinib was minimally reduced (11% decrease in Cmax and prolongation of tmax by 1.5 h), with a small reduction in AUC (7.4%) compared to fasting conditions.
Distribution: At clinically relevant concentrations of imatinib, binding to plasma proteins was approximately 95% on the basis of in vitro experiments, mostly to albumin and alpha-acid-glycoprotein, with little binding to lipoprotein.
Biotransformation/metabolism: The main circulating metabolite in humans is the N-demethylated piperazine derivative (CGP71588), which shows similar in vitro potency as the parent compound. The plasma AUC for this metabolite was found to be only 16% of the AUC for imatinib. The plasma protein binding of the N-demethylated metabolite is similar to that of the parent compound.
Elimination: Based on the recovery of compound(s) after an oral 14C-labelled dose of imatinib, approximately 81% of the dose was eliminated within 7 days in feces (68% of dose) and urine (13% of dose). Unchanged imatinib accounted for 25% of the dose (5% urine, 20% feces), the remainder being metabolites.
The mean apparent elimination half-life estimated from the single dose PK study was 13.5 hours. The half-life of all 14C-labelled components in plasma was from 41-72 hours.
Plasma pharmacokinetics: Following oral administration in healthy volunteers, the t½ was approximately 18 h, suggesting that once-daily dosing is appropriate. The increase in mean AUC with increasing dose was linear and dose proportional in the range of 25 to 1,000 mg imatinib after oral administration. There was no change in the kinetics of imatinib on repeated dosing, and accumulation was 1.5 to 2.5 fold at steady state when dosed once daily.
Special populations: Based on population pharmacokinetic analysis, there was a small effect of age on the volume of distribution (12% increase in patients >65 years old). This change is not thought to be clinically significant. The effect of body weight on the clearance of imatinib is such that for a patient weighing 50 kg the mean clearance is expected to be 8.5 L/h, while for a patient weighing 100 kg the clearance will rise to 11.8 L/h. These changes are not considered sufficient to warrant dose adjustment based on kg bodyweight. There is no effect of gender on the kinetics of imatinib.
Toxicology: Non-Clinical Safety Data: Imatinib has been evaluated in safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenicity, and juvenile toxicity studies. Target organs associated with the pharmacological action of imatinib include bone marrow, peripheral blood, lymphoid tissues, gonads and gastrointestinal tract. Other target organs include the liver and the kidney.
No new target organs were identified in the rat juvenile development toxicology study (day 10 to 70 post-partum). In the juvenile toxicology study, transitory effects upon growth and delay in vaginal opening and preputial separation were observed at approximately 0.3 to 2 times the average pediatric exposure at the highest recommended dose of 340 mg/m2. Also, mortality was observed in juvenile animals (around weaning phase) at approximately 2-times the average pediatric exposure at the highest recommended dose of 340 mg/m2.
In the 2 year rat carcinogenicity study administration of imatinib at 15, 30 and 60 mg/kg/day resulted in a statistically significant reduction in the longevity of males at 60 mg/kg/day and females at ≥30 mg/kg/day. Histopathological examination of decedents revealed cardiomyopathy (both sexes), chronic progressive nephropathy (females) and preputial gland papilloma as principal causes of death or reasons for sacrifice. Target organs for neoplastic changes were the kidneys, urinary bladder, urethra, preputial and clitoral gland, small intestine, parathyroid glands, adrenal glands and non-glandular stomach. The no observed effect levels (NOEL) for the various target organs with neoplastic lesions were established as follows: 30 mg/kg/day for the kidneys, urinary bladder, urethra, small intestine, parathyroid glands, adrenal glands and non-glandular stomach, and 15 mg/kg/day for the preputial and clitoral gland.
The papilloma/carcinoma of the preputial/clitoral gland were noted at 30 and 60 mg/kg/day, representing approximately 0.5 to 4 or 0.3 to 2.4 times the human daily exposure (based on AUC) at 400 mg/day or 800 mg/day, respectively, and 0.4 to 3.0 times the daily exposure in children (based on AUC) at 340 mg/m2. The renal adenoma/carcinoma, the urinary bladder and urethra papilloma, the small intestine adenocarcinomas, the parathyroid glands adenomas, the benign and malignant medullary tumors of the adrenal glands and the non-glandular stomach papillomas/carcinomas were noted at 60 mg/kg/day.
The relevance of these findings in the rat carcinogenicity study for humans is not known. An analysis of the safety data from clinical trials and spontaneous adverse event reports did not provide evidence of an increase in overall incidence of malignancies in patients treated with imatinib mesylate (Glivec) compared to that of the general population.
Non-neoplastic lesions not identified in earlier preclinical studies were the cardiovascular system, pancreas, endocrine organs and teeth. The most important changes included cardiac hypertrophy and dilatation, leading to signs of cardiac insufficiency in some animals.
No new target organs were identified in the rat juvenile development toxicology study (day 10 to 70 post-partum). In the juvenile toxicology study, transitory effects upon growth and delay in vaginal opening and preputial separation were observed at approximately 0.3 to 2 times the average pediatric exposure at the highest recommended dose of 340 mg/m2. Also, mortality was observed in juvenile animals (around weaning phase) at approximately 2-times the average pediatric exposure at the highest recommended dose of 340 mg/m2.
In the 2 year rat carcinogenicity study administration of imatinib at 15, 30 and 60 mg/kg/day resulted in a statistically significant reduction in the longevity of males at 60 mg/kg/day and females at ≥30 mg/kg/day. Histopathological examination of decedents revealed cardiomyopathy (both sexes), chronic progressive nephropathy (females) and preputial gland papilloma as principal causes of death or reasons for sacrifice. Target organs for neoplastic changes were the kidneys, urinary bladder, urethra, preputial and clitoral gland, small intestine, parathyroid glands, adrenal glands and non-glandular stomach. The no observed effect levels (NOEL) for the various target organs with neoplastic lesions were established as follows: 30 mg/kg/day for the kidneys, urinary bladder, urethra, small intestine, parathyroid glands, adrenal glands and non-glandular stomach, and 15 mg/kg/day for the preputial and clitoral gland.
The papilloma/carcinoma of the preputial/clitoral gland were noted at 30 and 60 mg/kg/day, representing approximately 0.5 to 4 or 0.3 to 2.4 times the human daily exposure (based on AUC) at 400 mg/day or 800 mg/day, respectively, and 0.4 to 3.0 times the daily exposure in children (based on AUC) at 340 mg/m2. The renal adenoma/carcinoma, the urinary bladder and urethra papilloma, the small intestine adenocarcinomas, the parathyroid glands adenomas, the benign and malignant medullary tumors of the adrenal glands and the non-glandular stomach papillomas/carcinomas were noted at 60 mg/kg/day.
The relevance of these findings in the rat carcinogenicity study for humans is not known. An analysis of the safety data from clinical trials and spontaneous adverse event reports did not provide evidence of an increase in overall incidence of malignancies in patients treated with imatinib mesylate (Glivec) compared to that of the general population.
Non-neoplastic lesions not identified in earlier preclinical studies were the cardiovascular system, pancreas, endocrine organs and teeth. The most important changes included cardiac hypertrophy and dilatation, leading to signs of cardiac insufficiency in some animals.
MedsGo Class
Targeted Cancer Therapy
Features
Dosage
100 mg
Ingredients
- Imatinib
Packaging
Film-Coated Tablet 1's
Generic Name
Imatinib Mesylate Beta Crystals
Registration Number
DRP-8528
Classification
Prescription Drug (RX)
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