Imatinib Mesylate

Product: 
Imatinib Mesylate
Formalary: 
Specialty Formalary
Category: 
Oncology
Trade Name: 
Gleevec, or Glivec
Packing: 
Capsule
Potency: 
100mg
In Treatment of: 
Clinical Imatinib is used in chronic myelogenous leukemia (CML), gastrointestinal stromal tumors (GISTs) and a number of other malignancies. One study demonstrated that imatinib mesylate was effective in patients with systemic mastocytosis, including those who had the D816V mutation in c-Kit. Experience has shown, however, that imatinib is much less effective in patients with this mutation, and patients with the mutation comprise nearly 90% of cases of mastocytosis. Chronic myelogenous leukemia The U.S. Food and Drug Administration (FDA) has approved imatinib as first-line treatment for Philadelphia chromosome (Ph)-positive CML, both in adults and children. The drug is approved in multiple Ph-positive cases CML, including after stem cell transplant, in blast crisis, and newly diagnosed. Gastrointestinal stromal tumors The FDA first granted approval for advanced GIST patients in 2002. On February 1st, 2012, imatinib was approved for use after the surgical removal of KIT-positive tumors to help prevent recurrence. The drug is also approved in unresectable KIT-positive GISTs. Other approvals The FDA has approved imatinib for use in adult patients with relapsed or refractory Ph-positive ALL, myelodysplastic/ myeloproliferative diseases associated with platelet-derived growth factor receptor gene re-arrangements, aggressive systemic mastocytosis (ASM) without or an unknown D816V c-KIT mutation, hypereosinophilic syndrome (HES) and/or chronic eosinophilic leukemia (CEL) who have the FIP1L1-PDGFRα fusion kinase (CHIC2 allele deletion) or FIP1L1-PDGFRα fusion kinase negative or unknown, unresectable, recurrent and/or metastatic dermatofibrosarcoma protuberans. Plexiform neurofibromas For treatment of progressive plexiform neurofibromas associated with neurofibromatosis type I, early research has shown potential for using the c-kit tyrosine kinase blocking properties of imatinib. Experimental Imatinib may also have a role in the treatment of pulmonary hypertension. It has been shown to reduce both the smooth muscle hypertrophy and hyperplasia of the pulmonary vasculature in a variety of disease processes, including portopulmonary hypertension.[14] In systemic sclerosis, the drug has been tested for potential use in slowing down pulmonary fibrosis. In laboratory settings, imatinib is being used as an experimental agent to suppress platelet-derived growth factor (PDGF) by inhibiting its receptor (PDGF-Rβ). One of its effects is delaying atherosclerosis in mice without[15] or with diabetes. Mouse animal studies at Emory University in Atlanta have suggested that imatinib and related drugs may be useful in treating smallpox, should an outbreak ever occur. In vitro studies identified that a modified version of imatinib can bind to gamma-secretase activating protein (GSAP), which selectively increases the production and accumulation of neurotoxic beta-amyloid plaques. This suggests molecules that target at GSAP and are able to cross blood–brain barrier are potential therapeutic agents for treating Alzheimer's disease.[18] Another study suggests that imatinib may not need to cross the blood–brain barrier to be effective at treating Alzheimer's, as the research indicates the production of beta-amyloid may begin in the liver. Tests on mice indicate that imatinib is effective at reducing beta-amyloid in the brain.[19] It is not known whether reduction of beta-amyloid is a feasible way of treating Alzheimer's, as an anti-beta-amyloid vaccine has been shown to clear the brain of plaques without having any effect on Alzheimer symptoms. A formulation of imatinib with a cyclodextrin (Captisol) as a carrier to overcome the blood–brain barrier is also currently considered as an experimental drug for lowering and reversing opioid tolerance. Imatinib has shown reversal of tolerance in rats.
Adverse Effects: 
The most common side effects include weight gain, reduced number of blood cells (neutropenia, thrombocytopenia, anemia), headache, edema, nausea, rash, and musculoskeletal pain. Severe congestive cardiac failure is an uncommon but recognized side effect of imatinib and mice treated with large doses of imatinib show toxic damage to their myocardium. If imatinib is used in prepubescent children, it can delay normal growth, although a proportion will experience catch-up growth during puberty.
Contraindication: 
None
Special Precaution: 
Fluid Retention and Edema Imatinib Mesylate is often associated with edema and occasionally serious fluid retention. Patients should be weighed and monitored regularly for signs and symptoms of fluid retention. An unexpected rapid weight gain should be carefully investigated and appropriate treatment provided. The probability of edema was increased with higher Imatinib Mesylate dose and age > 65 years in the CML studies. Severe superficial edema was reported in 1.5% of newly diagnosed CML patients taking Imatinib Mesylate, and in 2%-6% of other adult CML patients taking Imatinib Mesylate. In addition, other severe fluid retention (e.g., pleural effusion, pericardial effusion, pulmonary edema, and ascites) reactions were reported in 1.3% of newly diagnosed CML patients taking Imatinib Mesylate, and in 2%-6% of other adult CML patients taking Imatinib Mesylate. Severe fluid retention was reported in 9% to 13.1% of patients taking Imatinib Mesylate for GIST. Hematologic Toxicity Treatment with Imatinib Mesylate is associated with anemia, neutropenia, and thrombocytopenia. Complete blood counts should be performed weekly for the first month, biweekly for the second month, and periodically thereafter as clinically indicated (for example, every 2-3 months). In CML, the occurrence of these cytopenias is dependent on the stage of disease and is more frequent in patients with accelerated phase CML or blast crisis than in patients with chronic phase CML. In pediatric CML patients the most frequent toxicities observed were Grade 3 or 4 cytopenias including neutropenia, thrombocytopenia and anemia. These generally occur within the first several months of therapy . Severe Congestive Heart Failure and Left Ventricular Dysfunction Severe congestive heart failure and left ventricular dysfunction have occasionally been reported in patients taking Imatinib Mesylate. Most of the patients with reported cardiac reactions have had other co-morbidities and risk factors, including advanced age and previous medical history of cardiac disease. In an international randomized phase 3 study in 1,106 patients with newly diagnosed Ph+ CML in chronic phase, severe cardiac failure and left ventricular dysfunction were observed in 0.7% of patients taking Imatinib Mesylate compared to 0.9% of patients taking IFN + Ara-C. Patients with cardiac disease or risk factors for cardiac failure should be monitored carefully and any patient with signs or symptoms consistent with cardiac failure should be evaluated and treated. Hepatotoxicity Hepatotoxicity, occasionally severe, may occur with Imatinib Mesylate [see ADVERSE REACTIONS]. Cases of fatal liver failure and severe liver injury requiring liver transplants have been reported with both short-term and long-term use of Imatinib Mesylate. Liver function (transaminases, bilirubin, and alkaline phosphatase) should be monitored before initiation of treatment and monthly, or as clinically indicated. Laboratory abnormalities should be managed with Imatinib Mesylate interruption and/or dose reduction. When Imatinib Mesylate is combined with chemotherapy, liver toxicity in the form of transaminase elevation and hyperbilirubinemia has been observed. Additionally, there have been reports of acute liver failure. Monitoring of hepatic function is recommended. Hemorrhage In the newly diagnosed CML trial, 1.8% of patients had Grade 3/4 hemorrhage. In the Phase 3 unresectable or metastatic GIST studies 211 patients (12.9%) reported Grade 3/4 hemorrhage at any site. In the Phase 2 unresectable or metastatic GIST study 7 patients (5%) had a total of 8 CTC Grade 3/4 hemorrhages; gastrointestinal (GI) (3 patients), intra-tumoral (3 patients) or both (1 patient). Gastrointestinal tumor sites may have been the source of GI hemorrhages. Gastrointestinal Disorders Imatinib Mesylate is sometimes associated with GI irritation. Imatinib Mesylate should be taken with food and a large glass of water to minimize this problem. There have been rare reports, including fatalities, of gastrointestinal perforation. Hypereosinophilic Cardiac Toxicity In patients with hypereosinophilic syndrome and cardiac involvement, cases of cardiogenic shock/left ventricular dysfunction have been associated with the initiation of Imatinib Mesylate therapy. The condition was reported to be reversible with the administration of systemic steroids, circulatory support measures and temporarily withholding Imatinib Mesylate. Myelodysplastic/myeloproliferative disease and systemic mastocytosis may 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 ASM associated with high eosinophil levels. If either is abnormal, the prophylactic use of systemic steroids (1-2 mg/kg) for one to two weeks concomitantly with Imatinib Mesylate should be considered at the initiation of therapy. Dermatologic Toxicities Bullous dermatologic reactions, including erythema multiforme and Stevens-Johnson syndrome, have been reported with use of Imatinib Mesylate. In some cases of bullous dermatologic reactions, including erythema multiforme and Stevens-Johnson syndrome reported during postmarketing surveillance, a recurrent dermatologic reaction was observed upon re-challenge. Several foreign post-marketing reports have described cases in which patients tolerated the reintroduction of Imatinib Mesylate therapy after resolution or improvement of the bullous reaction. In these instances, Imatinib Mesylate was resumed at a dose lower than that at which the reaction occurred and some patients also received concomitant treatment with corticosteroids or antihistamines. Hypothyroidism Clinical cases of hypothyroidism have been reported in thyroidectomy patients undergoing levothyroxine replacement during treatment with Imatinib Mesylate. TSH levels should be closely monitored in such patients. Toxicities from Long-Term Use It is important to consider potential toxicities suggested by animal studies, specifically, liver, kidney and cardiac toxicity and immunosuppression. Severe liver toxicity was observed in dogs treated for 2 weeks, with elevated liver enzymes, hepatocellular necrosis, bile duct necrosis, and bile duct hyperplasia. Renal toxicity was observed in monkeys treated for 2 weeks, with focal mineralization and dilation of the renal tubules and tubular nephrosis. Increased BUN and creatinine were observed in several of these animals. An increased rate of opportunistic infections was observed with chronic imatinib treatment in laboratory animal studies. In a 39-week monkey study, treatment with imatinib resulted in worsening of normally suppressed malarial infections in these animals. Lymphopenia was observed in animals (as in humans). Additional long-term toxicities were identified in a 2-year rat study. Histopathological examination of the treated rats that died on study revealed cardiomyopathy (both sexes), chronic progressive nephropathy (females) and preputial gland papilloma as principal causes of death or reasons for sacrifice. Non-neoplastic lesions seen in this 2-year study which were 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. Use in Pregnancy Pregnancy Category D Women of childbearing potential should be advised to avoid becoming pregnant while taking Imatinib Mesylate. Sexually active female patients taking Imatinib Mesylate should use adequate contraception. Imatinib mesylate was teratogenic in rats when administered during organogenesis at doses approximately equal to the maximum human dose of 800 mg/day based on body surface area.. Significant post-implantation loss was seen in female rats administered imatinib mesylate at doses approximately one-half the maximum human dose of 800 mg/day based on body surface area. Children and Adolescents Growth retardation has been reported in children and pre-adolescents receiving Imatinib Mesylate. The long term effects of prolonged treatment with Imatinib Mesylate on growth in children are unknown. Therefore, close monitoring of growth in children under Imatinib Mesylate treatment is recommended. [see Postmarketing Experience] Tumor Lysis Syndrome Cases of Tumor Lysis Syndrome (TLS), including fatal cases, have been reported in patients with CML, GIST, ALL and eosinophilic leukemia receiving Imatinib Mesylate. The patients at risk of TLS are those with tumors having a high proliferative rate or high tumor burden prior to treatment. These patients should be monitored closely and appropriate precautions taken. Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment of Fertility 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. Target organs for neoplastic changes were the kidneys (renal tubule and renal pelvis), urinary bladder, urethra, preputial and clitoral gland, small intestine, parathyroid glands, adrenal glands and non-glandular stomach. Neoplastic lesions were not seen at: 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 tubule adenoma/carcinoma, renal pelvis transitional cell neoplasms, the urinary bladder and urethra transitional cell papillomas, 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. Positive genotoxic effects were obtained for imatinib in an in vitro mammalian cell assay (Chinese hamster ovary) for clastogenicity (chromosome aberrations) in the presence of metabolic activation. Two intermediates of the manufacturing process, which are also present in the final product, are positive for mutagenesis in the Ames assay. One of these intermediates was also positive in the mouse lymphoma assay. Imatinib was not genotoxic when tested in an in vitro bacterial cell assay (Ames test), an in vitro mammalian cell assay (mouse lymphoma) and an in vivo rat micronucleus assay. In a study of fertility, male rats were dosed for 70 days prior to mating and female rats were dosed 14 days prior to mating and through to gestational Day 6. Testicular and epididymal weights and percent motile sperm were decreased at 60 mg/kg, approximately three-fourths the maximum clinical dose of 800 mg/day based on body surface area. This was not seen at doses ≤ 20 mg/kg (one-fourth the maximum human dose of 800 mg). The fertility of male and female rats was not affected. In a pre- and post-natal development study in female rats dosed with imatinib mesylate at 45 mg/kg (approximately one-half the maximum human dose of 800 mg/day, based on body surface area) from gestational Day 6 until the end of lactation, red vaginal discharge was noted on either gestational Day 14 or 15. In the first generation offspring at this same dose level, mean body weights were reduced from birth until terminal sacrifice. First generation offspring 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. 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 Mesylate. Human studies on male patients receiving Imatinib Mesylate and its affect on male fertility and spermatogenesis have not been performed. Male patients concerned about their fertility on Imatinib Mesylate treatment should consult with their physician. Use In Specific Populations Pregnancy Pregnancy Category D Imatinib Mesylate can cause fetal harm when administered to a pregnant woman. Imatinib mesylate was teratogenic in rats when administered during organogenesis at doses ≥ 100 mg/kg (approximately equal to the maximum human dose of 800 mg/day based on body surface area). Teratogenic effects included exencephaly or encephalocele, absent/reduced frontal and absent parietal bones. Female rats administered doses ≥ 45 mg/kg (approximately one-half the maximum human dose of 800 mg/day based on body surface area) also experienced significant post-implantation loss as evidenced by either early fetal resorption or stillbirths, nonviable pups and early pup mortality between postpartum Days 0 and 4. At doses higher than 100 mg/kg, total fetal loss was noted in all animals. Fetal loss was not seen at doses ≤ 30 mg/kg (one-third the maximum human dose of 800 mg). There are no adequate and well-controlled studies with Imatinib Mesylate in pregnant women. Women should be advised not to become pregnant when taking Imatinib Mesylate. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Nursing Mothers Imatinib and its active metabolite are excreted into human milk. Based on data from three breastfeeding women taking Imatinib Mesylate, the milk:plasma ratio is about 0.5 for imatinib and about 0.9 for the active metabolite. Considering the combined concentration of imatinib and active metabolite, a breastfed infant could receive up to 10 % of the maternal therapeutic dose based on body weight. Because of the potential for serious adverse reactions in nursing infants from Imatinib Mesylate, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use Imatinib Mesylate safety and efficacy have been demonstrated in children with newly diagnosed Ph+ chronic phase CML. There are no data in children under 2 years of age. As in adult patients, imatinib was rapidly absorbed after oral administration in pediatric patients, with a Cmax of 2-4 hours. Apparent oral clearance was similar to adult values (11.0 L/hr/m² in children vs. 10.0 L/hr/m² in adults), as was the half-life (14.8 hours in children vs. 17.1 hours in adults). Dosing in children at both 260 mg/m² and 340 mg/m² achieved an AUC similar to the 400 mg dose in adults. The comparison of AUC on Day 8 vs. Day 1 at 260 mg/m² and 340 mg/m² dose levels revealed a 1.5- and 2.2-fold drug accumulation, respectively, after repeated once-daily dosing. Mean imatinib AUC did not increase proportionally with increasing dose. Geriatric Use In the CML clinical studies, approximately 20% of patients were older than 65 years. In the study of patients with newly diagnosed CML, 6% of patients were older than 65 years. No difference was observed in the safety profile in patients older than 65 years as compared to younger patients, with the exception of a higher frequency of edema..the efficacy of Imatinib Mesylate was similar in older and younger patients. In the unresectable or metastatic GIST study, 16% of patients were older than 65 years. No obvious differences in the safety or efficacy profile were noted in patients older than 65 years as compared to younger patients, but the small number of patients does not allow a formal analysis. In the adjuvant GIST study, 221 patients (31%) were older than 65 years. No difference was observed in the safety profile in patients older than 65 years as compared to younger patients, with the exception of a higher frequency of edema. The efficacy of Imatinib Mesylate was similar in patients older than 65 years and younger patients. Hepatic Impairment The effect of hepatic impairment on the pharmacokinetics of both imatinib and its major metabolite, CGP74588, was assessed in 84 cancer patients with varying degrees of hepatic impairment (Table 12) at imatinib doses ranging from 100-800 mg. Exposure to both imatinib and CGP74588 was comparable between each of the mildly and moderately hepatically-impaired groups and the normal group. Patients with severe hepatic impairment tend to have higher exposure to both imatinib and its metabolite than patients with normal hepatic function. At steady state, the mean Cmax/dose and AUC/dose for imatinib increased by about 63% and 45%, respectively, in patients with severe hepatic impairment compared to patients with normal hepatic function. The mean Cmax/dose and AUC/dose for CGP74588 increased by about 56% and 55%, respectively, in patients with severe hepatic impairment compared to patients with normal hepatic function. Renal Impairment The effect of renal impairment on the pharmacokinetics of imatinib was assessed in 59 cancer patients with varying degrees of renal impairment (Table 13) at single and steady state imatinib doses ranging from 100 to 800 mg/day. The mean exposure to imatinib (dose normalized AUC) in patients with mild and moderate renal impairment increased 1.5- to 2-fold compared to patients with normal renal function. The AUCs did not increase for doses greater than 600 mg in patients with mild renal impairment. The AUCs did not increase for doses greater than 400 mg in patients with moderate renal impairment. Two patients with severe renal impairment were dosed with 100 mg/day and their exposures were similar to those seen in patients with normal renal function receiving 400 mg/day. Dose reductions are necessary for patients with moderate and severe renal impairment [See DOSAGE AND ADMINISTRATION]. Table 13 Renal Function Classification.
Interaction: 
Since imatinib is mainly metabolised via the liver enzyme CYP3A4, substances influencing the activity of this enzyme change the plasma concentration of the drug. An example of a drug that increases imatinib activity and therefore side effects by blocking CYP3A4 is ketoconazole. The same could be true of itraconazole, clarithromycin, grapefruit juice, among others. Conversely, CYP3A4 inductors like rifampicin and St. John's Wort reduce the drug's activity, risking therapy failure. Imatinib also acts as an inhibitor of CYP3A4, 2C9 and 2D6, increasing the plasma concentrations of a number of other drugs like simvastatin, ciclosporin, pimozide, warfarin, metoprolol, and possibly paracetamol. The drug also reduces plasma levels of levothyroxin via an unknown mechanism. As with other immunosuppressants, application of live vaccines is contraindicated because the microorganisms in the vaccine could multiply and infect the patient. Inactivated and toxoid vaccines do not hold this risk, but may not be effective under imatinib therapy.
Dosages: 
Therapy should be initiated by a physician experienced in the treatment of patients with hematological malignancies or malignant sarcomas, as appropriate. The prescribed dose should be administered orally, with a meal and a large glass of water. Doses of 400 mg or 600 mg should be administered once daily, whereas a dose of 800 mg should be administered as 400 mg twice a day. In children, Imatinib Mesylate treatment can be given as a once-daily dose or alternatively the daily dose may be split into two - once in the morning and once in the evening. There is no experience with Imatinib Mesylate treatment in children under 2 years of age. 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 daily dosing of 800 mg and above, dosing should be accomplished using the 400 mg tablet to reduce exposure to iron. Treatment may be continued as long as there is no evidence of progressive disease or unacceptable toxicity. Adult Patients with Ph+ CML CP, AP and BC The recommended dose of Imatinib Mesylate is 400 mg/day for adult patients in chronic phase CML and 600 mg/day for adult patients in accelerated phase or blast crisis. In CML, a dose increase from 400 mg to 600 mg in adult patients with chronic phase disease, or from 600 mg to 800 mg (given as 400 mg twice daily) in adult 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 hematologic response after at least 3 months of treatment, failure to achieve a cytogenetic response after 6-12 months of treatment, or loss of a previously achieved hematologic or cytogenetic response. Pediatric Patients with Ph+ CML CP The recommended dose of Imatinib Mesylate for children with newly diagnosed Ph+ CML is 340 mg/m²/day (not to exceed 600 mg). Ph+ ALL The recommended dose of Imatinib Mesylate is 600 mg/day for adult patients with relapsed/refractory Ph+ ALL. MDS/MPD The recommended dose of Imatinib Mesylate is 400 mg/day for adult patients with MDS/MPD. ASM The recommended dose of Imatinib Mesylate is 400 mg/day for adult patients with ASM without the D816V c-Kit mutation. If c-Kit mutational status is not known or unavailable, treatment with Imatinib Mesylate 400 mg/day may be considered for patients with ASM not responding satisfactorily to other therapies. For patients with ASM associated with eosinophilia, a clonal hematological disease related to the fusion kinase FIP1L1-PDGFRα, a starting dose of 100 mg/day is recommended. 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. HES/CEL The recommended dose of Imatinib Mesylate is 400 mg/day for adult patients with HES/CEL. For HES/CEL patients with demonstrated FIP1L1-PDGFRα fusion kinase, a starting dose of 100 mg/day is recommended. 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. DFSP The recommended dose of Imatinib Mesylate is 800 mg/day for adult patients with DFSP. GIST The recommended dose of Imatinib Mesylate is 400 mg/day for adult patients with unresectable and/or metastatic, malignant GIST. A dose increase up to 800 mg daily (given as 400 mg twice daily) may be considered, as clinically indicated, in patients showing clear signs or symptoms of disease progression at a lower dose and in the absence of severe adverse drug reactions. The recommended dose of Imatinib Mesylate is 400 mg/day for the adjuvant treatment of adult patients following complete gross resection of GIST. In the clinical study, Imatinib Mesylate was administered for one year. The optimal treatment duration with Imatinib Mesylate is not known. Dose Modification Guidelines Concomitant Strong CYP3A4 inducers: The use of concomitant strong CYP3A4 inducers should be avoided (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifampacin, phenobarbital). If patients must be co-administered a strong CYP3A4 inducer, based on pharmacokinetic studies, the dosage of Imatinib Mesylate should be increased by at least 50%, and clinical response should be carefully monitored [see DRUG INTERACTIONS]. Hepatic Impairment Patients with mild and moderate hepatic impairment do not require a dose adjustment and should be treated per the recommended dose. A 25% decrease in the recommended dose should be used for patients with severe hepatic impairment [see Use in Specific Populations]. Renal Impairment Patients with moderate renal impairment (CrCL = 20-39 mL/min) should receive a 50% decrease in the recommended starting dose and future doses can be increased as tolerated. Doses greater than 600 mg are not recommended in patients with mild renal impairment (CrCL = 40-59 mL/min). For patients with moderate renal impairment doses greater than 400 mg are not recommended. Imatinib should be used with caution in patients with severe renal impairment. A dose of 100 mg/day was tolerated in two patients with severe renal impairment. [See Use In Specific Populations] Dose Adjustment for Hepatotoxicity and Non-Hematologic Adverse Reactions If elevations in bilirubin > 3 x institutional upper limit of normal (IULN) or in liver transaminases > 5 x IULN occur, Imatinib Mesylate should be withheld until bilirubin levels have returned to a < 1.5 x IULN and transaminase levels to < 2.5 x IULN. In adults, treatment with Imatinib Mesylate may then be continued at a reduced daily dose (i.e., 400 mg to 300 mg, 600 mg to 400 mg or 800 mg to 600 mg). In children, daily doses can be reduced under the same circumstances from 340 mg/m²/day to 260 mg/m²/day. If a severe non-hematologic adverse reaction develops (such as severe hepatotoxicity or severe fluid retention), Imatinib Mesylate should be withheld until the event has resolved. Thereafter, treatment can be resumed as appropriate depending on the initial severity of the event.

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