PRINCIPAL DISPLAY PANEL – 400 mg

NDC 72819-186-03

Imatinib Mesylate
Tablets
400 mg*

Rx only 30 Tablets

*Each tablet contains: 400 mg of imatinib free base

Usual Dosage: See Prescribing Information

Storage condition: Store at 20°C to 25°C (68°F to
77°F); excursions permitted 15°C to 30°C (59°F to
86°F) [See USP Controlled Room Temperature].

Protect from moisture.

Dispense in a tight container, USP.

Keep this and all drugs out of the reach of children.

34120051404A

CL-186-03-00

Distributed by: Archis Pharma LLC
15 Corporate Place South, Suite 108
Piscataway, NJ 08854,
U.S.A.

Made in China

1** INDICATIONS AND USAGE**

1.1** Newly Diagnosed Philadelphia Positive Chronic Myeloid Leukemia (Ph+

CML)**

Newly diagnosed adult and pediatric patients with Philadelphia chromosome positive chronic myeloid leukemia (Ph+ CML) in chronic phase.

1.2** Ph+ CML in Blast Crisis (BC), Accelerated Phase (AP) or Chronic

Phase (CP) After Interferon-alpha (IFN) Therapy**

Patients with Philadelphia chromosome positive chronic myeloid leukemia in blast crisis, accelerated phase, or in chronic phase after failure of interferon-alpha therapy.

1.3** Adult Patients With Ph+ Acute Lymphoblastic Leukemia (ALL)**

Adult patients with relapsed or refractory Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL).

1.4** Pediatric Patients With Ph+ Acute Lymphoblastic Leukemia (ALL)**

Pediatric patients with newly diagnosed Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL) in combination with chemotherapy.

1.5Myelodysplastic/Myeloproliferative Diseases (MDS/MPD)

Adult patients with myelodysplastic/myeloproliferative diseases associated with platelet-derived growth factor receptor (PDGFR) gene re-arrangements.

1.6Aggressive Systemic Mastocytosis (ASM)

Adult patients with aggressive systemic mastocytosis without the D816V c-Kit mutation or with c-Kit mutational status unknown.

1.7** Hypereosinophilic Syndrome (HES) and/or Chronic Eosinophilic

Leukemia (CEL)**

Adult patients with hypereosinophilic syndrome and/or chronic eosinophilic leukemia who have the FIP1L1-PDGFRα fusion kinase (mutational analysis or fluorescence in situ hybridization [FISH] demonstration of CHIC2 allele deletion) and for patients with HES and/or CEL who are FIP1L1-PDGFRα fusion kinase negative or unknown.

1.8 Dermatofibrosarcoma Protuberans (DFSP)

Adult patients with unresectable, recurrent and/or metastatic dermatofibrosarcoma protuberans.

1.9** Kit+ Gastrointestinal Stromal Tumors (GIST**)

Patients with Kit (CD117) positive unresectable and/or metastatic malignant gastrointestinal stromal tumors.

1.10Adjuvant Treatment of GIST

Adjuvant treatment of adult patients following complete gross resection of Kit (CD117) positive GIST.

5** WARNINGS AND PRECAUTIONS**

5.1** Fluid Retention and Edema**

Imatinib mesylate tablets are often associated with edema and occasionally serious fluid retention [See Adverse Reactions (6.1)] . Weigh and monitor patients regularly for signs and symptoms of fluid retention. Investigate unexpected rapid weight gain carefully and provide appropriate treatment. The probability of edema was increased with higher imatinib mesylate tablets dose and age greater than 65 years in the CML studies. Severe superficial edema was reported in 1.5% of newly diagnosed CML patients taking imatinib mesylate tablets, and in 2%-6% of other adult CML patients taking imatinib mesylate tablets. 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 tablets, and in 2%-6% of other adult CML patients taking imatinib mesylate tablets. Severe fluid retention was reported in 9% to 13.1% of patients taking imatinib mesylate tablets for GIST [See Adverse Reactions (6.1)] . In a randomized trial in patients with newly diagnosed Ph+ CML in chronic phase comparing imatinib mesylate tablets and nilotinib, severe (Grade 3 or 4) fluid retention occurred in 2.5% of patients receiving imatinib mesylate tablets and in 3.9% of patients receiving nilotinib 300 mg twice daily. Effusions (including pleural effusion, pericardial effusion, ascites) or pulmonary edema were observed in 2.1% (none were Grade 3 or 4) of patients in the imatinib mesylate tablets arm and 2.2% (0.7% Grade 3 or 4) of patients in the nilotinib 300 mg twice daily arm.

5.2Hematologic Toxicity

Treatment with imatinib mesylate tablets is associated with anemia, neutropenia, and thrombocytopenia. Perform complete blood counts weekly for the first month, biweekly for the second month, and periodically thereafter as clinically indicated (for example, every 2 to 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 [See Dosage and Administration (2.14)] .

5.3** Congestive Heart Failure and Left Ventricular Dysfunction**

Congestive heart failure and left ventricular dysfunction have been reported in patients taking imatinib mesylate tablets. Cardiac adverse reactions were more frequent in patients with advanced age or co-morbidities, including previous medical history of cardiac disease. In an international randomized Phase 3 study in 1106 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 tablets compared to 0.9% of patients taking IFN + Ara-C. In another randomized trial with newly diagnosed Ph+ CML patients in chronic phase that compared imatinib mesylate tablets and nilotinib, cardiac failure was observed in 1.1% of patients in the imatinib mesylate tablets arm and 2.2% of patients in the nilotinib 300 mg twice daily arm and severe (Grade 3 or 4) cardiac failure occurred in 0.7% of patients in each group. Carefully monitor patients with cardiac disease or risk factors for cardiac or history of renal failure. Evaluate and treat any patient with signs or symptoms consistent with cardiac or renal failure.

5.4Hepatotoxicity

Hepatotoxicity, occasionally severe, may occur with imatinib mesylate tablets [See Adverse Reactions (6.1)] . 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 tablets. Monitor liver function (transaminases, bilirubin, and alkaline phosphatase) before initiation of treatment and monthly, or as clinically indicated. Manage laboratory abnormalities with imatinib mesylate tablets interruption and/or dose reduction [See Dosage and Administration (2.13)] . When imatinib mesylate tablets are 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.

5.5** Hemorrhage**

In a trial of imatinib mesylate tablets versus IFN+Ara-C in patients with the newly diagnosed CML, 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. In a randomized trial in patients with newly diagnosed Ph+ CML in chronic phase comparing imatinib mesylate tablets and nilotinib, GI hemorrhage occurred in 1.4% of patients in the imatinib mesylate tablets arm, and in 2.9% of patients in the nilotinib 300 mg twice daily arm. None of these events were Grade 3 or 4 in the imatinib mesylate tablets arm; 0.7% were Grade 3 or 4 in the nilotinib 300 mg twice daily arm. In addition, gastric antral vascular ectasia has been reported in postmarketing experience.

5.6Gastrointestinal Disorders

Imatinib mesylate tablets are sometimes associated with GI irritation. Imatinib mesylate tablets should be taken with food and a large glass of water to minimize this problem. There have been rare reports, including fatalities, of GI perforation.

5.7** Hypereosinophilic Cardiac Toxicity**

In patients with hypereosinophilic syndrome with occult infiltration of HES cells within the myocardium, cases of cardiogenic shock/left ventricular dysfunction have been associated with HES cell degranulation upon the initiation of imatinib mesylate tablets therapy. The condition was reported to be reversible with the administration of systemic steroids, circulatory support measures and temporarily withholding imatinib mesylate tablets.

Myelodysplastic/myeloproliferative disease and systemic mastocytosis may be associated with high eosinophil levels. Consider performing an echocardiogram and determining serum troponin in patients with HES/CEL, and in patients with MDS/MPD or ASM associated with high eosinophil levels. If either is abnormal, consider prophylactic use of systemic steroids (1-2 mg/kg) for one to two weeks concomitantly with imatinib mesylate tablets at the initiation of therapy.

5.8Dermatologic Toxicities

Bullous dermatologic reactions, including erythema multiforme and Stevens- Johnson syndrome, have been reported with use of imatinib mesylate tablets. 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 rechallenge. Several foreign postmarketing reports have described cases in which patients tolerated the reintroduction of imatinib mesylate tablets therapy after resolution or improvement of the bullous reaction. In these instances, imatinib mesylate tablets were resumed at a dose lower than that at which the reaction occurred and some patients also received concomitant treatment with corticosteroids or antihistamines.

5.9** Hypothyroidism**

Clinical cases of hypothyroidism have been reported in thyroidectomy patients undergoing levothyroxine replacement during treatment with imatinib mesylate tablets. Monitor TSH levels in such patients.

5.10** Embryo-Fetal Toxicity**

Imatinib mesylate tablets can cause fetal harm when administered to a pregnant woman. 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 (BSA). 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 BSA. Advise sexually active female patients of reproductive potential to use effective contraception (methods that result in less than 1% pregnancy rates) when using imatinib mesylate tablets and for 14 days after stopping imatinib mesylate tablets. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to a fetus [See Use in Specific Populations (8.1)] .

5.11Growth Retardation in Children and Adolescents

Growth retardation has been reported in children and pre-adolescents receiving imatinib mesylate tablets. The long-term effects of prolonged treatment with imatinib mesylate tablets on growth in children are unknown. Therefore, monitor growth in children under imatinib mesylate tablets treatment [See Adverse Reactions (6.1)].

5.12** 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 tablets. The patients at risk of TLS are those with tumors having a high proliferative rate or high tumor burden prior to treatment. Monitor these patients closely and take appropriate precautions. Due to possible occurrence of TLS, correct clinically significant dehydration and treat high uric acid levels prior to initiation of imatinib mesylate tablets.

5.13** Impairments Related to Driving and Using Machinery**

Motor vehicle accidents have been reported in patients receiving imatinib mesylate tablets. Advise patients that they may experience side effects, such as dizziness, blurred vision, or somnolence during treatment with imatinib mesylate tablets. Recommend caution when driving a car or operating machinery.

5.14** Renal Toxicity**

A decline in renal function may occur in patients receiving imatinib mesylate tablets. Median estimated glomerular filtration rate (eGFR) values in patients on imatinib mesylate tablets 400 mg daily for newly-diagnosed CML (four randomized trials) and malignant GIST (one single-arm trial) declined from a baseline value of 85 mL/min/1.73 m 2 (N = 1190) to 75 mL/min/1.73 m 2 at 12 months (N = 1082) and 69 mL/min/1.73 m 2 at 60 months (N = 549). Evaluate renal function prior to initiating imatinib mesylate tablets and monitor during therapy, with attention to risk factors for renal dysfunction, such as preexisting renal impairment, diabetes mellitus, hypertension, and congestive heart failure.

8** USE IN SPECIFIC POPULATIONS**

8.1** Pregnancy**

Risk Summary

Imatinib mesylate tablets can cause fetal harm when administered to a pregnant woman based on human and animal data. There are no clinical studies regarding use of imatinib mesylate tablets in pregnant women. There have been postmarket reports of spontaneous abortions and congenital anomalies from women who have been exposed to imatinib mesylate tablets during pregnancy. Reproductive studies in rats have demonstrated that imatinib mesylate induced teratogenicity and 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 BSA. Advise women to avoid pregnancy when taking imatinib mesylate tablets. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus.

The background risk of major birth defects and miscarriage for the indicated population is not known; however, in the U.S. general population, the estimated background risk of major birth defects of clinically recognized pregnancies is 2% to 4% and of miscarriage is 15% to 20%.

Data

Animal 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 BSA), 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 BSA, 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 BSA) included an increased number 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 no-observed-effect level (NOEL) for both maternal animals and the F1 generation was 15 mg/kg/day.

8.2** Lactation**

Risk Summary

Imatinib and its active metabolite are excreted into human milk. Because of the potential for serious adverse reactions in breastfed infants from imatinib mesylate tablets, advise a lactating woman not to breastfeed during treatment and for 1 month after the last dose.

Human Data

Based on data from 3 breastfeeding women taking imatinib mesylate tablets, 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.

8.3Females and Males of Reproductive Potential

Pregnancy Testing

Human postmarketing reports and animal studies have shown imatinib mesylate tablets to be harmful to the developing fetus. Test pregnancy status in females with reproductive potential prior to the initiation of treatment with imatinib mesylate tablets.

Contraception

Females

Advise female patients of reproductive potential to use effective contraception (methods that result in less than 1% pregnancy rates) when using imatinib mesylate tablets during treatment and for fourteen days after stopping treatment with imatinib mesylate tablets [See Use in Specific Populations (8.1)] .

Infertility

The risk of infertility in females or males of reproductive potential has not been studied in humans. In a rat study, the fertility in males and females was not affected [See Nonclinical Toxicology (13)] .

8.4Pediatric Use

The safety and effectiveness of imatinib mesylate tablets have been demonstrated in pediatric patients with newly diagnosed Ph+ chronic phase CML and Ph+ ALL [See Clinical Studies (14.2, 14.4)]. There are no data in children under 1 year of age.

8.5** 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. The frequency of edema was higher in patients older than 65 years as compared to younger patients; no other difference in the safety profile was observed [See Warnings and Precautions (5.1)] . The efficacy of imatinib mesylate tablets 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 tablets was similar in patients older than 65 years and younger patients.

8.6** Hepatic Impairment**

The effect of hepatic impairment on the pharmacokinetics of both imatinib and its major metabolite, CGP74588, was assessed in 84 patients with cancer with varying degrees of hepatic impairment at imatinib doses ranging from 100 mg to 800 mg.

Mild and moderate hepatic impairment do not influence exposure to imatinib and CGP74588. In patients with severe hepatic impairment, the imatinib C max and area under curve (AUC) increased by 63% and 45% and the CGP74588 C max and AUC increased by 56% and 55%, relative to patients with normal hepatic function [See Clinical Pharmacology (12.3)] . Reduce the dose by 25% for patients with severe hepatic impairment [See Dosage and Administration (2.12)] .

Table 16: Liver Function Classification

Abbreviation: SGOT, serum glutamic-oxaloacetic transaminase is now referred to as aspartate aminotransferase (AST); ULN, upper limit of normal for the institution.
Liver Function Test	Normal**** (n = 14)	Mild**** (n = 30)	Moderate**** (n = 20)	Severe**** (n = 20)
Total Bilirubin	less than or equal to ULN	greater than 1.0–1.5 times the ULN	greater than 1.5–3 times the ULN	greater than 3–10 times the ULN
SGOT	less than or equal to ULN	greater than ULN (can be normal if Total Bilirubin is greater than ULN)	Any	Any

8.7** Renal Impairment**

The effect of renal impairment on the pharmacokinetics of imatinib was assessed in 59 patients with cancer and varying degrees of renal impairment 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. There are not sufficient data in patients with severe renal impairment [See Clinical Pharmacology (12.3)] . Dose reductions are necessary for patients with moderate and severe renal impairment [See Dosage and Administration (2.12)] .

Table 17: Renal Function Classification

Abbreviation: CrCL, creatinine clearance.
Renal Dysfunction	Renal Function Tests
Mild	CrCL = 40-59 mL/min
Moderate	CrCL = 20-39 mL/min
Severe	CrCL = less than 20 mL/min

15** REFERENCES**

OSHA Hazardous Drugs. OSHA. [Accessed on 20-September- 2013, from http://www.osha.gov/SLTC/hazardousdrugs/index.html]

2** DOSAGE AND ADMINISTRATION**

2.1** Drug Administration**

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.

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.

2.2** Adult Patients With Ph+ CML CP, AP, or BC**

The recommended dose of imatinib mesylate tablets 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 to 12 months of treatment, or loss of a previously achieved hematologic or cytogenetic response.

2.3Pediatric Patients With Ph+ CML CP

The recommended dose of imatinib mesylate tablets for children with newly diagnosed Ph+ CML is 340 mg/m 2/day (not to exceed 600 mg). Imatinib mesylate tablets treatment can be given as a once daily dose or the daily dose may be split into two–one portion dosed in the morning and one portion in the evening. There is no experience with imatinib mesylate tablets treatment in children under 1 year of age.

2.4Adult Patients With Ph+ ALL

The recommended dose of imatinib mesylate tablets is 600 mg/day for adult patients with relapsed/refractory Ph+ ALL.

2.5Pediatric Patients With Ph+ ALL

The recommended dose of imatinib mesylate tablets to be given in combination with chemotherapy to children with newly diagnosed Ph+ ALL is 340 mg/m 2/day (not to exceed 600 mg). Imatinib mesylate tablets treatment can be given as a once daily dose.

2.6Adult Patients With MDS/MPD

Determine PDGFRb gene rearrangements status prior to initiating treatment.

The recommended dose of imatinib mesylate tablets is 400 mg/day for adult patients with MDS/MPD.

2.7** Adult Patients With ASM**

Determine D816V c-Kit mutation status prior to initiating treatment.

The recommended dose of imatinib mesylate tablets 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 tablets 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.

2.8Adult Patients With HES/CEL

The recommended dose of imatinib mesylate tablets 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.

2.9Adult Patients With DFSP

The recommended dose of imatinib mesylate tablets is 800 mg/day for adult patients with DFSP.

2.10Adult Patients With Metastatic and/or Unresectable GIST

The recommended dose of imatinib mesylate tablets 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.

2.11** Adult Patients With Adjuvant GIST**

The recommended dose of imatinib mesylate tablets is 400 mg/day for the adjuvant treatment of adult patients following complete gross resection of GIST. In clinical trials, one year of imatinib mesylate tablets and three years of imatinib mesylate tablets were studied. In the patient population defined in Study 2, three years of imatinib mesylate tablets is recommended [See Clinical Studies (14.8)] . The optimal treatment duration with imatinib mesylate tablets is not known.

2.12Dose 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 coadministered a strong CYP3A4 inducer, based on pharmacokinetic studies, the dosage of imatinib mesylate tablets should be increased by at least 50%, and clinical response should be carefully monitored [See Drug Interactions (7.1)].

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 (8.6)] .

Renal Impairment: Patients with moderate renal impairment (creatinine clearance [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 Warnings and Precautions (5.3), Use in Specific Populations (8.7)].

2.13** Dose Adjustment for Hepatotoxicity and Non-Hematologic Adverse

Reactions**

If elevations in bilirubin greater than 3 times the institutional upper limit of normal (IULN) or in liver transaminases greater than 5 times the IULN occur, imatinib mesylate tablets should be withheld until bilirubin levels have returned to a less than 1.5 times the IULN and transaminase levels to less than 2.5 times the IULN. In adults, treatment with imatinib mesylate tablets 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/m 2/day to 260 mg/m 2/day.

If a severe non-hematologic adverse reaction develops (such as severe hepatotoxicity or severe fluid retention), imatinib mesylate tablets should be withheld until the event has resolved. Thereafter, treatment can be resumed as appropriate depending on the initial severity of the event.

2.14Dose Adjustment for Hematologic Adverse Reactions

Dose reduction or treatment interruptions for severe neutropenia and thrombocytopenia are recommended as indicated in Table 1.

Table 1: Dose Adjustments for Neutropenia and Thrombocytopenia

Abbreviations: ANC, absolute neutrophil count; ASM, aggressive systemic mastocytosis; CEL, chronic eosinophilic leukemia; CML, chronic myeloid leukemia; DFSP, dermatofibrosarcoma protuberans; HES, hypereosinophilic syndrome; MDS/MPD, myelodysplastic/myeloproliferative diseases; PDGFR, platelet-derived growth factor receptor; Ph+ CML, Philadelphia chromosome positive chronic myeloid leukemia; Ph+ ALL, Philadelphia chromosome positive acute lymphoblastic leukemia.
ASM associated with eosinophilia (starting dose 100 mg)	ANC less than 1.0 x 10 9/L and/or platelets less than 50 x 10 9/L	Stop imatinib mesylate tablets until ANC greater than or equal to 1.5 x 10 9/L and platelets greater than or equal to 75 x 10 9/L Resume treatment with imatinib mesylate tablets at previous dose (i.e., dose before severe adverse reaction)
HES/CEL with FIP1L1-PDGFRα fusion kinase (starting dose 100 mg)	ANC less than 1.0 x 10 9/L and/or platelets less than 50 x 10 9/L	Stop imatinib mesylate tablets until ANC greater than or equal to 1.5 x 10 9/L and platelets greater than or equal to 75 x 10 9/L Resume treatment with imatinib mesylate tablets at previous dose (i.e., dose before severe adverse reaction)
Chronic Phase CML (starting dose 400 mg) MDS/MPD, ASM and HES/CEL (starting dose 400 mg) GIST (starting dose 400 mg)	ANC less than 1.0 x 10 9/L and/or platelets less than 50 x 10 9/L	Stop imatinib mesylate tablets until ANC greater than or equal to 1.5 x 10 9/L and platelets greater than or equal to 75 x 10 9/L Resume treatment with imatinib mesylate tablets at the original starting dose of 400 mg If recurrence of ANC less than 1.0 x 10 9/L and/or platelets less than 50 x 10 9/L, repeat step 1 and resume imatinib mesylate tablets at a reduced dose of 300 mg
Ph+ CML: Accelerated Phase and Blast Crisis (starting dose 600 mg) Ph+ ALL (starting dose 600 mg)	ANC less than 0.5 x 10 9/L and/or platelets less than 10 x 10 9/L	Check if cytopenia is related to leukemia (marrow aspirate or biopsy) If cytopenia is unrelated to leukemia, reduce dose of imatinib mesylate tablets to 400 mg If cytopenia persists 2 weeks, reduce further to 300 mg If cytopenia persists 4 weeks and is still unrelated to leukemia, stop imatinib mesylate tablets until ANC greater than or equal to 1 x 10 9/L and platelets greater than or equal to 20 x 10 9/L and then resume treatment at 300 mg
DFSP (starting dose 800 mg)	ANC less than 1.0 x 10 9/L and/or platelets less than 50 x 10 9/L	Stop imatinib mesylate tablets until ANC greater than or equal to 1.5 x 10 9/L and platelets greater than or equal to 75 x 10 9/L Resume treatment with imatinib mesylate tablets at 600 mg In the event of recurrence of ANC less than 1.0 x 10 9/L and/or platelets less than 50 x 10 9/L, repeat step 1 and resume imatinib mesylate tablets at reduced dose of 400 mg
Pediatric newly diagnosed chronic phase CML (starting dose 340 mg/m 2)	ANC less than 1.0 x 10 9/L and/or platelets less than 50 x 10 9/L	Stop imatinib mesylate tablets until ANC greater than or equal to 1.5 x 10 9/L and platelets greater than or equal to 75 x 10 9/L Resume treatment with imatinib mesylate tablets at previous dose (i.e., dose before severe adverse reaction) In the event of recurrence of ANC less than 1.0 x 10 9/L and/or platelets less than 50 x 10 9/L, repeat step 1 and resume imatinib mesylate tablets at reduced dose of 260 mg/m 2