DOSAGE FORMS & STRENGTHS SECTION.


3 DOSAGE FORMS AND STRENGTHS 100 mg film coated tablets Brownish orange, slightly biconvex, round film-coated tablets with functional scoring, engraved "IMA" over score "100" on one side, "APO" on the other side 400 mg film coated tablets Brownish orange, capsule shaped, biconvex film-coated tablets with functional scoring, engraved "IMA" score "400" on one side, "APO" on the other side Tablets (with functional scoring): 100 mg and 400 mg (3)

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.


PACKAGE LABEL.PRINCIPAL DISPLAY PANEL AvKARE NDC 42291-351-90 Imantinib Mesylate Tablets 100 mg* 90 Tablets Rx Only *Each tablet contains119.5 mg of imatinib mesylate (equivalent to 100 mg of imatinib). Store at 20 to 25C (68 to 77F); excursions permitted from 15 to 30C (59 to 86F) [See USP Controlled Room Temperature]. Protect from moisture. Dispense in a tight container [see USP]. Usual Dosage: See package insert. Keep out of the reach of children. Manufactured for: AvKARE, Inc. Pulaski, TN 38478 Mfg. Rev. 07/16 AV 08/16 (P) N3 42291 351905 AvKARE NDC 42291-352-30 Imantinib Mesylate Tablets 300 mg* 30 Tablets Rx Only *Each tablet contains478 mg of imatinib mesylate (equivalent to 400 mg of imatinib). Store at 20 to 25C (68 to 77F); excursions permitted from 15 to 30C (59 to 86F) [See USP Controlled Room Temperature]. Protect from moisture. Dispense in a tight container [see USP]. Usual Dosage: See package insert. Keep out of the reach of children. Manufactured for: AvKARE, Inc. Pulaski, TN 38478 Mfg. Rev. 07/16 AV 08/16 (P) N3 42291 352303

ADVERSE REACTIONS SECTION.


6 ADVERSE REACTIONS Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed cannot be directly compared to rates on other clinical trials and may not reflect the rates observed in clinical practice. The most frequently reported adverse reactions (30%) were edema, nausea, vomiting, muscle cramps, musculoskeletal pain, diarrhea, rash, fatigue and abdominal pain (6.1) To report SUSPECTED ADVERSE REACTIONS, contact AvKARE, Inc. at 1-855-361-3993 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Chronic Myeloid Leukemia The majority of imatinib-treated patients experienced adverse reactions at some time, most adverse reactions were of mild-to-moderate grade. Imatinib was discontinued due to drug-related adverse reactions in 2.4% of patients receiving imatinib mesylate in the randomized trial of newly diagnosed patients with Ph+ CML in chronic phase comparing imatinib mesylate versus INF+Ara-C, and in 12.5% of patients receiving imatinib mesylate in the randomized trial of newly diagnosed patients with Ph+ CML in chronic phase comparing imatinib mesylate and nilotinib. Imatinib mesylate was discontinued due to drug-related adverse reactions in 4% of patients in chronic phase after failure of interferon-alpha therapy, in 4% of patients in accelerated phase and in 5% of patients in blast crisis. The most frequently reported drug-related adverse reactions were edema, nausea and vomiting, muscle cramps, musculoskeletal pain, diarrhea and rash (Table 2 and Table 3 for newly diagnosed CML, Table 4 for other CML patients). Edema was most frequently periorbital or in lower limbs and was managed with diuretics, other supportive measures, or by reducing the dose of Imatinib [see Dosage and Administration (2.12)]. The frequency of severe superficial edema was 1.5%-6%. A variety of adverse reactions represent local or general fluid retention including pleural effusion, ascites, pulmonary edema and rapid weight gain with or without superficial edema. These reactions appear to be dose related, were more common in the blast crisis and accelerated phase studies (where the dose was 600 mg/day), and are more common in the elderly. These reactions were usually managed by interrupting imatinib mesylate treatment and using diuretics or other appropriate supportive care measures. A few of these reactions may be serious or life threatening, and one patient with blast crisis died with pleural effusion, congestive heart failure, and renal failure. Adverse reactions, regardless of relationship to study drug, that were reported in at least 10% of the imatinib mesylate treated patients are shown in Tables 2, 3, and 4. Table 2 Adverse Reactions Regardless of Relationship to Study Drug Reported in Newly Diagnosed CML Clinical Trial in the Imatinib Mesylate versus INF+Ara-C Study (10% of Imatinib Mesylate Treated Patients)(1) All Grades CTC Grades 3/4 Preferred Term Imatinib mesylate N=551 (%) IFN+Ara-C N=533 (%) Imatinib mesylate N=551 (%) IFN+Ara-C N=533 (%) Fluid Retention 61.7 11.1 2.5 0.9 - Superficial Edema 59.9 9.6 1.5 0.4 - Other Fluid Retention Reactions2 6.9 1.9 1.3 0.6 Nausea 49.5 61.5 1.3 5.1 Muscle Cramps 49.2 11.8 2.2 0.2 Musculoskeletal Pain 47.0 44.8 5.4 8.6 Diarrhea 45.4 43.3 3.3 3.2 Rash and Related Terms 40.1 26.1 2.9 2.4 Fatigue 38.8 67.0 1.8 25.1 Headache 37.0 43.3 0.5 3.8 Joint Pain 31.4 38.1 2.5 7.7 Abdominal Pain 36.5 25.9 4.2 3.9 Nasopharyngitis 30.5 8.8 0 0.4 Hemorrhage 28.9 21.2 1.8 1.7 - GI Hemorrhage 1.6 1.1 0.5 0.2 - CNS Hemorrhage 0.2 0.4 0 0.4 Myalgia 24.1 38.8 1.5 8.3 Vomiting 22.5 27.8 2.0 3.4 Dyspepsia 18.9 8.3 0 0.8 Cough 20.0 23.1 0.2 0.6 Pharyngolaryngeal Pain 18.1 11.4 0.2 0 Upper Respiratory Tract Infection 21.2 8.4 0.2 0.4 Dizziness 19.4 24.4 0.9 3.8 Pyrexia 17.8 42.6 0.9 3.0 Weight Increased 15.6 2.6 2.0 0.4 Insomnia 14.7 18.6 0 2.3 Depression 14.9 35.8 0.5 13.1 Influenza 13.8 6.2 0.2 0.2 Bone Pain 11.3 15.6 1.6 3.4 Constipation 11.4 14.4 0.7 0.2 Sinusitis 11.4 6.0 0.2 0.2 (1)All adverse reactions occurring in 10% of imatinib mesylate treated patients are listed regardless of suspected relationship to treatment. (2) Other fluid retention reactions include pleural effusion, ascites, pulmonary edema, pericardial effusion, anasarca, edema aggravated, and fluid retention not otherwise specified. Table 3: Most Frequently Reported Non-hematologic Adverse Reactions (Regardless of Relationship to Study Drug) in Patients with Newly Diagnosed Ph+ CML-CP in the Imatinib Mesylate versus Nilotinib Study (10% in Imatinib Mesylate 400 mg Once-Daily or Nilotinib 300 mg Twice-Daily Groups) 60-Month Analysisa Patients with Newly Diagnosed Ph+ CML-CP Imatinib mesylate 400 mg once-daily N=280 Nilotinib 300 mg twice-daily N=279 Imatinib mesylate 400 mg once-daily N=280 Nilotinib 300 mg twice-daily N=279 Body System and Preferred Term All Grades (%) CTC Gradesb 3/4 (%) Skin and subcutaneous tissue disorders Rash 19 38 2 3-6 x upper limit normal range [ULN], Grade 4 >6 x ULN), elevated bilirubin (Grade 3 >3-10 x ULN, Grade 4 >10 x ULN), elevated alkaline phosphatase (Grade 3 >5-20 x ULN, Grade 4 >20 x ULN), elevated SGOT or SGPT (Grade 3 >5-20 x ULN, Grade 4 >20 x ULN) Hepatotoxicity Severe elevation of transaminases or bilirubin occurred in approximately 5% of CML patients (see Tables 6 and 7) and were usually managed with dose reduction or interruption (the median duration of these episodes was approximately 1 week). Treatment was discontinued permanently because of liver laboratory abnormalities in less than 1.0% of CML patients. One patient, who was taking acetaminophen regularly for fever, died of acute liver failure. 6.2 Adverse Reactions in Pediatric Population Single agent therapy The overall safety profile of pediatric patients treated with imatinib mesylate in 93 children studied was similar to that found in studies with adult patients, except that musculoskeletal pain was less frequent (20.5%) and peripheral edema was not reported. Nausea and vomiting were the most commonly reported individual adverse reactions with an incidence similar to that seen in adult patients. Although most patients experienced adverse reactions at some time during the study, the incidence of Grade 3/4 adverse reactions was low. 6.3 Adverse Reactions in Other Subpopulations In older patients (65 years old), with the exception of edema, where it was more frequent, there was no evidence of an increase in the incidence or severity of adverse reactions. In women there was an increase in the frequency of neutropenia, as well as Grade 1/2 superficial edema, headache, nausea, rigors, vomiting, rash, and fatigue. No differences were seen that were related to race but the subsets were too small for proper evaluation. 6.4 Acute Lymphoblastic Leukemia The adverse reactions were similar for Ph+ ALL as for Ph+ CML. The most frequently reported drug-related adverse reactions reported in the Ph+ ALL studies were mild nausea and vomiting, diarrhea, myalgia, muscle cramps and rash, which were easily manageable. Superficial edema was a common finding in all studies and were described primarily as periorbital or lower limb edemas. These edemas were rarely severe and may be managed with diuretics, other supportive measures, or in some patients by reducing the dose of imatinib mesylate. 6.5 Myelodysplastic/Myeloproliferative Diseases Adverse reactions, regardless of relationship to study drug, that were reported in at least 10% of the patients treated with imatinib mesylate for MDS/MPD in the phase 2 study, are shown in Table 8. Table 8 Adverse Reactions Regardless of Relationship to Study Drug Reported (More than One Patient) in MPD Patients in the Phase 2 Study (10% All Patients) All Grades Preferred Term N=7 n (%) Nausea 4 (57.1) Diarrhea 3 (42.9) Anemia 2 (28.6) Fatigue 2 (28.6) Muscle Cramp 3 (42.9) Arthralgia 2 (28.6) Periorbital Edema 2 (28.6) 6.6 Aggressive Systemic Mastocytosis All ASM patients experienced at least one adverse reaction at some time. The most frequently reported adverse reactions were diarrhea, nausea, ascites, muscle cramps, dyspnea, fatigue, peripheral edema, anemia, pruritus, rash and lower respiratory tract infection. None of the 5 patients in the phase 2 study with ASM discontinued imatinib mesylate due to drug-related adverse reactions or abnormal laboratory values. 6.7 Hypereosinophilic Syndrome and Chronic Eosinophilic Leukemia The safety profile in the HES/CEL patient population does not appear to be different from the safety profile of imatinib mesylate observed in other hematologic malignancy populations, such as Ph+ CML. All patients experienced at least one adverse reaction, the most common being gastrointestinal, cutaneous and musculoskeletal disorders. Hematological abnormalities were also frequent, with instances of CTC Grade 3 leukopenia, neutropenia, lymphopenia, and anemia. 6.8 Dermatofibrosarcoma Protuberans Adverse reactions, regardless of relationship to study drug, that were reported in at least 10% of the 12 patients treated with imatinib mesylate for DFSP in the phase 2 study are shown in Table 9. Table 9 Adverse Reactions Regardless of Relationship to Study Drug Reported in DFSP Patients in the Phase 2 Study (10% All Patients) All Grades Preferred term N=12 n (%) Nausea 5 (41.7) Diarrhea 3 (25.0) Vomiting 3 (25.0) Periorbital Edema 4 (33.3) Face Edema 2 (16.7) Rash 3 (25.0) Fatigue 5 (41.7) Edema Peripheral 4 (33.3) Pyrexia 2 (16.7) Eye Edema 4 (33.3) Lacrimation Increased 3 (25.0) Dyspnea Exertional 2 (16.7) Anemia 3 (25.0) Rhinitis 2 (16.7) Anorexia 2 (16.7) Clinically relevant or severe laboratory abnormalities in the 12 patients treated with imatinib mesylate for DFSP in the phase 2 study are presented in Table 10. Table 10 Laboratory Abnormalities Reported in DFSP Patients in the Phase 2 Study N=12 CTC Grades1 Grade 3 Grade 4 Hematology Parameters - Anemia 17% 0% - Thrombocytopenia 17% 0% - Neutropenia 0% 8% Biochemistry Parameters - Elevated Creatinine 0% 8% 1CTC Grades: neutropenia (Grade 3 0.5-1.0 x 109/L, Grade 4 3-6 x upper limit normal range [ULN], Grade 4 >6 x ULN), 6.10 Additional Data from Multiple Clinical Trials The following adverse reactions have been reported during clinical trials of imatinib mesylate tablets. Cardiac Disorders: Estimated 1% to 10%: palpitations, pericardial effusion Estimated 0.1% to 1%: congestive cardiac failure, tachycardia, pulmonary edema Estimated 0.01% to 0.1%: arrhythmia, atrial fibrillation, cardiac arrest, myocardial infarction, angina pectoris Vascular Disorders: Estimated 1% to 10%: flushing, hemorrhage Estimated 0.1% to 1%: hypertension, hypotension, peripheral coldness, Raynauds phenomenon, hematoma, subdural hematoma Investigations : Estimated 1% to 10%: blood CPK increased, blood amylase increased Estimated 0.1% to 1%: blood LDH increased Skin and Subcutaneous Tissue Disorders : Estimated 1% to 10%: dry skin, alopecia, face edema, erythema, photosensitivity reaction, nail disorder, purpura Estimated 0.1% to 1%: exfoliative dermatitis, bullous eruption, psoriasis, rash pustular, contusion, sweating increased, urticaria, ecchymosis, increased tendency to bruise, hypotrichosis, skin hypopigmentation, skin hyperpigmentation, onychoclasis, folliculitis, petechiae, erythema multiforme Estimated 0.01% to 0.1%: vesicular rash, Stevens-Johnson syndrome, acute generalized exanthematous pustulosis, acute febrile neutrophilic dermatosis (Sweets syndrome), nail discoloration, angioneurotic edema, leucocytoclastic vasculitis Gastrointestinal Disorders: Estimated 1% to 10%: abdominal distention, gastroesophageal reflux, dry mouth, gastritis Estimated 0.1% to 1%: gastric ulcer, stomatitis, mouth ulceration, eructation, melena, esophagitis, ascites, hematemesis, chelitis, dysphagia, pancreatitis Estimated 0.01% to 0.1%: colitis, ileus, inflammatory bowel disease General Disorders and Administration Site Conditions: Estimated 1% to 10%: weakness, anasarca, chills Estimated 0.1% to 1%: malaise Blood and Lymphatic System Disorders : Estimated 1% to 10%: pancytopenia, febrile neutropenia, lymphopenia, eosinophila Estimated 0.1% to 1%: thrombocythemia, bone marrow depression, lymphadenopathy Estimated 0.01% to 0.1%: hemolytic anemia, aplastic anemia Hepatobiliary Disorders : Estimated 0.1% to 1%: hepatitis, jaundice Estimated 0.01% to 0.1%: hepatic failure and hepatic necrosis1 Immune System Disorders : Estimated 0.01% to 0.1%: angioedema Infections and Infestations: Estimated 0.1% to 1%: sepsis, herpes simplex, herpes zoster, cellulitis, urinary tract infection, gastroenteritis Estimated 0.01% to 0.1%: fungal infection Metabolism and Nutrition Disorders: Estimated 1% to 10%: weight decreased, decreased appetite Estimated 0.1% to 1%: dehydration, gout, increased appetite, hyperuricemia, hypercalcemia, hyperglycemia, hyponatremia, hyperkalemia, hypomagnesemia Musculoskeletal and Connective Tissue Disorders: Estimated 1% to 10%: joint swelling Estimated 0.1% to 1%: joint and muscle stiffness, muscular weakness, arthritis Nervous System/Psychiatric Disorders: Estimated 1% to 10%: paresthesia, hypesthesia Estimated 0.1% to 1%: syncope, peripheral neuropathy, somnolence, migraine, memory impairment, libido decreased, sciatica, restless leg syndrome, tremor Estimated 0.01% to 0.1%: increased intracranial pressure1, confusional state, convulsions, optic neuritis Renal and Urinary Disorders : Estimated 0.1% to 1%: renal failure acute, urinary frequency increased, hematuria, renal pain Reproductive System and Breast Disorders: Estimated 0.1% to 1%: breast enlargement, menorrhagia, sexual dysfunction, gynecomastia, erectile dysfunction, menstruation irregular, nipple pain, scrotal edema Respiratory, Thoracic and Mediastinal Disorders : Estimated 1% to 10%: epistaxis Estimated 0.1% to 1%: pleural effusion Estimated 0.01% to 0.1%: interstitial pneumonitis, pulmonary fibrosis, pleuritic pain, pulmonary hypertension, pulmonary hemorrhage Eye, Ear and Labyrinth Disorders : Estimated 1% to 10%: conjunctivitis, vision blurred, orbital edema, conjunctival hemorrhage, dry eye Estimated 0.1% to 1%: vertigo, tinnitus, eye irritation, eye pain, scleral hemorrhage, retinal hemorrhage, blepharitis, macular edema, hearing loss, cataract Estimated 0.01% to 0.1%: papilledema1, glaucoma 1 Including some fatalities 6.11 Postmarketing Experience The following additional adverse reactions have been identified during post approval use of imatinib mesylate tablets. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Nervous System Disorders: cerebral edema1 Eye Disorders: vitreous hemorrhage Cardiac Disorders: pericarditis, cardiac tamponade1 Vascular Disorders: thrombosis/embolism, anaphylactic shock Respiratory, Thoracic and Mediastinal Disorders: acute respiratory failure1, interstitial lung disease Gastrointestinal Disorders: ileus/intestinal obstruction, tumor hemorrhage/tumor necrosis, gastrointestinal perforation1 [see Warnings and Precautions (5.6)], diverticulitis, gastric antral vascular ectasia Skin and Subcutaneous Tissue Disorders: lichenoid keratosis, lichen planus, toxic epidermal necrolysis, palmar-plantar erythrodysesthesia syndrome, drug rash with eosinophilia and systemic symptoms (DRESS) Musculoskeletal and Connective Tissue Disorders: avascular necrosis/hip osteonecrosis, rhabdomyolysis/myopathy, growth retardation in children Reproduction Disorders: hemorrhagic corpus luteum/hemorrhagic ovarian cyst 1Including some fatalities To report SUSPECTED ADVERSE REACTIONScontact AvKARE, Inc. at 1-855-361-3993; email drugsafety@avkare.com ;or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

INDICATIONS & USAGE SECTION.


1 INDICATIONS AND USAGE Imatinib mesylate is a kinase inhibitor indicated for the treatment of: Newly diagnosed adult and pediatric patients with Philadelphia chromosome positive chronic myeloid leukemia (Ph+ CML) in chronic phase (1.1) Patients with Philadelphia chromosome positive chronic myeloid leukemia (Ph+ CML) in blast crisis (BC), accelerated phase (AP), or in chronic phase (CP) after failure of interferon-alpha therapy (1.2) Adult patients with relapsed or refractory Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL) (1.3) Adult patients with myelodysplastic/ myeloproliferative diseases (MDS/MPD) associated with PDGFR (platelet-derived growth factor receptor) gene re-arrangements (1.5) Adult patients with aggressive systemic mastocytosis (ASM) without the D816V c-Kit mutation or with c-Kit mutational status unknown (1.6) Adult patients with hypereosinophilic syndrome (HES) and/or chronic eosinophilic leukemia (CEL) who have the FIP1L1-PDGFR fusion kinase (mutational analysis or FISH demonstration of CHIC2 allele deletion) and for patients with HES and/or CEL who are FIP1L1-PDGFR fusion kinase negative or unknown (1.7) Adult patients with unresectable, recurrent and/or metastatic dermatofibrosarcoma protuberans (DFSP) (1.8) 1.1 Newly Diagnosed Philadelphia Positive Chronic Myeloid Leukemia (Ph+ CML) Newly diagnosed adult and pediatric patients with Philadelphia chromosome positive chronic myeloid leukemia 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. 1.5 Myelodysplastic/Myeloproliferative Diseases (MDS/MPD) Adult patients with myelodysplastic/myeloproliferative diseases associated with PDGFR (platelet-derived growth factor receptor) gene re-arrangements. 1.6 Aggressive 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-PDGFR fusion kinase (mutational analysis or FISH demonstration of CHIC2 allele deletion) and for patients with HES and/or CEL who are FIP1L1-PDGFR fusion kinase negative or unknown. 1.8 Dermatofibrosarcoma Protuberans (DFSP) Adult patients with unresectable, recurrent and/or metastatic dermatofibrosarcoma protuberans.

DOSAGE & ADMINISTRATION SECTION.


2 DOSAGE AND ADMINISTRATION 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 (imatinib as free base) should be administered once-daily, whereas a dose of 800 mg (imatinib as free base) should be administered as 400 mg (imatinib as free base) twice a day. In children, imatinib mesylate tablet treatment can be given as a once-daily dose in CML. Alternatively, in children with CML 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 tablet treatment in children under 1 year 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 (imatinib as free base) and above, dosing should be accomplished using the 400 mg (imatinib as free base) tablet to reduce exposure to iron. Treatment may be continued as long as there is no evidence of progressive disease or unacceptable toxicity. Adults with Ph+ CML CP (2.1): 400 mg/day Adults with Ph+ CML AP or BC (2.1): 600 mg/day Pediatrics with Ph+ CML CP (2.2): 340 mg/m2/day Adults with Ph+ ALL (2.3): 600 mg/day Adults with MDS/MPD (2.5): 400 mg/day Adults with ASM (2.6): 100 mg/day or 400 mg/day Adults with HES/CEL (2.7): 100 mg/day or 400 mg/day Adults with DFSP (2.8): 800 mg/day Patients with mild to moderate hepatic impairment (2.11): 400 mg/day Patients with severe hepatic impairment (2.11): 300 mg/day All doses of imatinib mesylate tablets should be taken with a meal and a large glass of water. Doses of 400 mg or 600 mg (imatinib as free base) should be administered once-daily, whereas a dose of 800 mg (imatinib as free base) should be administered as 400 mg (imatinib as free base) twice a day. Imatinib mesylate tablets can be dissolved in water or apple juice for patients having difficulty swallowing. Daily dosing of 800 mg (imatinib as free base) and above should be accomplished using the 400 mg tablet (imatinib as free base) to reduce exposure to iron. 2.1 Adult Patients with Ph+ CML CP, AP, and BC The recommended dose of imatinib mesylate tablets is 400 mg/day (imatinib as free base) for adult patients in chronic phase CML and 600 mg/day (imatinib as free base) for adult patients in accelerated phase or blast crisis. In CML, a dose increase from 400 mg to 600 mg (imatinib as free base) in adult patients with chronic phase disease, or from 600 mg to 800 mg (imatinib as free base) (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. 2.2 Pediatric Patients with Ph+ CML CP The recommended dose of imatinib mesylate tablets for children with newly diagnosed Ph+ CML is 340 mg/m2/day (imatinib as free base) (not to exceed 600 mg). 2.3 Adults Patients with Ph+ ALL The recommended dose of imatinib mesylate tablets is 600 mg/day (imatinib as free base) for adult patients with relapsed/refractory Ph+ ALL. </text </section </component 2.5 MDS/MPD The recommended dose of imatinib mesylate tablets is 400 mg/day (imatinib as free base) for adult patients with MDS/MPD. 2.6 ASM The recommended dose of imatinib mesylate tablets is 400 mg/day (imatinib as free base) 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 (imatinib as free base) 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-PDGFR, a starting dose of 100 mg/day (imatinib as free base) is recommended. Dose increase from 100 mg to 400 mg (imatinib as free base) for these patients may be considered in the absence of adverse drug reactions if assessments demonstrate an insufficient response to therapy. 2.7 HES/CEL The recommended dose of imatinib mesylate tablets is 400 mg/day (imatinib as free base) for adult patients with HES/CEL. For HES/CEL patients with demonstrated FIP1L1-PDGFR fusion kinase, a starting dose of 100 mg/day (imatinib as free base) is recommended. Dose increase from 100 mg to 400 mg (imatinib as free base) for these patients may be considered in the absence of adverse drug reactions if assessments demonstrate an insufficient response to therapy. 2.8 DFSP The recommended dose of imatinib mesylate tablets is 800 mg/day (imatinib as free base) for adult patients with DFSP. 2.11 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 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 (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 (imatinib as free base) 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 (imatinib as free base) 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)]. 2.12 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 (imatinib as free base)). In children, daily doses can be reduced under the same circumstances from 340 mg/m2/day to 260 mg/m2/day (imatinib as free base). 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. 2.13 Dose 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 ASM associated with eosinophilia (starting dose 100 mg) ANC < 1.0 x 109/L and/or platelets < 50 x 109/L 1. Stop imatinib mesylate until ANC 1.5 x 109/L and platelets 75 x 109/L. 2. Resume treatment with imatinib mesylate at previous dose (i.e. dose before severe adverse reaction). HES/CEL with FIP1L1-PDGFR fusion kinase (starting dose 100 mg) ANC < 1.0 x 109/L and/or platelets < 50 x 109/L 1. Stop imatinib mesylate until ANC 1.5 x 109/L and platelets 75 x 109/L. 2. Resume treatment with imatinib mesylate at previous dose (i.e. dose before severe adverse reaction). Chronic Phase CML (starting dose 400 mg) ANC <1.0 x 109/L and/or platelets <50 x 109/L 1. Stop imatinib mesylate until ANC 1.5 x 109/L and platelets 75 x 109/L MDS/MPD, ASM and HES/CEL (starting dose 400 mg) 2. Resume treatment with imatinib mesylate at the original starting dose of 400 mg 3. If recurrence of ANC <1.0 x 109/L and/or platelets <50 x 109/L, repeat step 1 and resume imatinib mesylate at a reduced dose of 300 mg Ph+ CML : Accelerated Phase and Blast Crisis (starting dose 600 mg) ANC <0.5 x 109/L and/or platelets <10 x 109/L 1. Check if cytopenia is related to leukemia (marrow aspirate or biopsy) 2. If cytopenia is unrelated to leukemia, reduce dose of imatinib mesylate to 400 mg Ph+ ALL (starting dose 600 mg) 3. If cytopenia persists 2 weeks, reduce further to 300 mg 4. If cytopenia persists 4 weeks and is still unrelated to leukemia, stop imatinib mesylate until ANC 1 x 109/L and platelets 20 x 109/L and then resume treatment at 300 mg DFSP(starting dose 800 mg) ANC < 1.0 x 109/L and/or platelets < 50 x 109/L 1. Stop imatinib mesylate until ANC 1.5 x 109/L and platelets 75 x 109/L. 2. Resume treatment with imatinib mesylate at 600 mg 3. In the event of recurrence of ANC < 1.0 x 109/L and/or platelets < 50 x 109/L, repeat step 1 and resume imatinib mesylate at reduced dose of 400 mg. Pediatric newly diagnosed chronic phase CML (starting dose 340 mg/m2) ANC < 1.0 x 109/L and/or platelets < 50 x 109/L 1. Stop imatinib mesylate until ANC 1.5 x 109/L and platelets 75 x 109/L. 2. Resume treatment with imatinib mesylate at previous dose (i.e., dose before severe adverse reaction) 3. In the event of recurrence of ANC < 1.0 x 109/L and/or platelets < 50 x 109/L, repeat step 1 and resume imatinib mesylate at reduced dose of 260 mg/m2

HOW SUPPLIED SECTION.


16 HOW SUPPLIED/STORAGE AND HANDLING Each imatinib mesylate film-coated tablet contains 100 mg or 400 mg of imatinib free base. 100 mg Tablets Brownish orange, slightly biconvex, round film-coated tablets with functional scoring, engraved "IMA" over score "100" on one side, "APO" on the other side Bottles of 90 tablets...... NDC 42291-351-90 400 mg Tablets Brownish orange, capsule shaped, biconvex film-coated tablets with functional scoring, engraved "IMA" score "400" on one side, "APO" on the other side Bottles of 30 tablets...... NDC 42291-352-30 Storage and Handling Store at 20 to 25C (68 to 77F); excursions permitted to 15 to 30C (59 to 86F) [see USP Controlled Room Temperature]. Protect from moisture. Dispense in a tight container, USP. Imatinib mesylate is an antineoplastic product. Follow special handling and disposal procedures.1 Imatinib mesylate tablets should not be crushed. Direct contact of crushed tablets with the skin or mucous membranes should be avoided. If such contact occurs, wash thoroughly as outlined in the references. Personnel should avoid exposure to crushed tablets.

DESCRIPTION SECTION.


11 DESCRIPTION Imatinib is a small molecule kinase inhibitor. Imatinib mesylate film-coated tablets contain imatinib mesylate equivalent to 100 mg or 400 mg of imatinib free base. Imatinib mesylate is designated chemically as 4-[(4-Methyl-1-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-phenyl]benzamide methanesulfonate and its structural formula is: Imatinib mesylate is a white to off-white crystalline powder. Its molecular formula is C29H31N7O CH4SO3 and its molecular weight is 589.7. Imatinib mesylate is freely soluble in water and freely to sparingly soluble in methanol. Inactive Ingredients: colloidal silicon dioxide (NF); crospovidone (NF); and magnesium stearate (NF). Tablet coating: hypromellose (USP); hydroxypropyl cellulose, red ferric oxide (NF); yellow ferric oxide (NF); and polyethylene glycol (NF).

OVERDOSAGE SECTION.


10 OVERDOSAGE Experience with doses greater than 800 mg is limited. Isolated cases of imatinib mesylate overdose have been reported. In the event of overdosage, the patient should be observed and appropriate supportive treatment given. 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, increase transaminases. 8 to 10 g (single dose): Vomiting and gastrointestinal pain have been reported. A patient with myeloid blast crisis experienced Grade 1 elevations of serum creatinine, Grade 2 ascites and elevated liver transaminase levels, and Grade 3 elevations of bilirubin after inadvertently taking 1,200 mg of imatinib mesylate (imatinib as free base) daily for 6 days. Therapy was temporarily interrupted and complete reversal of all abnormalities occurred within 1 week. Treatment was resumed at a dose of 400 mg daily (imatinib as free base) without recurrence of adverse reactions. Another patient developed severe muscle cramps after taking 1,600 mg of imatinib mesylate (imatinib as free base) daily for 6 days. Complete resolution of muscle cramps occurred following interruption of therapy and treatment was subsequently resumed. Another patient that was prescribed 400 mg daily (imatinib as free base), took 800 mg of imatinib mesylate (imatinib as free base) on Day 1 and 1,200 mg (imatinib as free base) on Day 2. Therapy was interrupted, no adverse reactions occurred and the patient resumed therapy. 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 experienced decreased white blood cell count and diarrhea.

WARNINGS AND PRECAUTIONS SECTION.


5 WARNINGS AND PRECAUTIONS Edema and severe fluid retention have occurred. Weigh patients regularly and manage unexpected rapid weight gain by drug interruption and diuretics (5.1, 6.1) Cytopenias, particularly anemia, neutropenia, and thrombocytopenia, have occurred. Manage with dose reduction or dose interruption and in rare cases discontinuation of treatment. Perform complete blood counts weekly for the first month, biweekly for the second month, and periodically thereafter (5.2) Severe congestive heart failure and left ventricular dysfunction have been reported, particularly in patients with comorbidities and risk factors. Patients with cardiac disease or risk factors for cardiac failure should be monitored and treated (5.3) Severe hepatotoxicity including fatalities may occur. Assess liver function before initiation of treatment and monthly thereafter or as clinically indicated. Monitor liver function when combined with chemotherapy known to be associated with liver dysfunction (5.4) Gastrointestinal perforations, some fatal, have been reported (5.6) Cardiogenic shock/left ventricular dysfunction has been associated with the initiation of imatinib mesylate in patients with conditions associated with high eosinophil levels (e.g., HES, MDS/MPD and ASM) (5.7) Bullous dermatologic reactions (e.g., erythema multiforme and Stevens-Johnson syndrome) have been reported with the use of imatinib mesylate (5.8) Hypothyroidism has been reported in thyroidectomy patients undergoing levothyroxine replacement. Closely monitor TSH levels in such patients (5.9) Fetal harm can occur when administered to a pregnant woman. Women should be apprised of the potential harm to the fetus (5.10, 8.1) Growth retardation occurring in children and pre-adolescents receiving imatinib mesylate has been reported. Close monitoring of growth in children under imatinib mesylate treatment is recommended (5.11, 6.11) Tumor lysis syndrome. Close monitoring is recommended (5.12) Reports of motor vehicle accidents have been received in patients receiving imatinib mesylate. Caution patients about driving a car or operating machinery (5.13) 5.1 Fluid Retention and Edema Imatinib mesylate is often associated with edema and occasionally serious fluid retention [ see Adverse Reactions (6.1) ] . 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% to 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% to 6% of other adult CML patients taking imatinib mesylate. In a randomized trial in patients with newly diagnosed Ph+CML in chronic phase comparing imatinib mesylate and nilotinib, severe (Grade 3 or 4) fluid retention occurred in 2.5% of patients receiving imatinib mesylate and in 3.9% of patients receiving nilotinib 300 mg bid. 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 arm and 2.2% (0.7% Grade 3 or 4) of patients in the nilotinib 300 mg bid arm. 5.2 Hematologic Toxicity Treatment with imatinib mesylate tablets 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 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 (2.12)]. 5.3 Congestive Heart Failure and Left Ventricular Dysfunction Congestive heart failure and left ventricular dysfunction have 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. In another randomized trial with newly diagnosed Ph+ CML patients in chronic phase that compared imatinib mesylate and nilotinib, cardiac failure was observed in 1.1% of patient in the imatinib mesylate arm and 2.2% of patients in the nilotinib 300 mg bid arm and severe (Grade 3 or 4) cardiac failure occurred in 0.7% of patients in each group. Patients with cardiac disease or risk factors for cardiac 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. 5.4 Hepatotoxicity Hepatotoxicity, occasionally severe, may occur with imatinib mesylate [ 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. 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 [ see Dosage and Administration (2.12) ] . 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. 5.5 Hemorrhage In a trial of imatinib mesylate versus IFN+Ara-C in patients with the newly diagnosed CML, 1.8% of patients had Grade 3/4 hemorrhage. In a randomized trial in patients with newly diagnosed Ph+ CML in chronic phase comparing imatinib mesylate and nilotinib, GI hemorrhage occurred in 1.4% of patients in the imatinib mesylate arm, and in 2.9% of patients in the nilotinib 300 mg bid arm. None of these events were Grade 3 or 4 in the imatinib mesylate arm; 0.7% were Grade 3 or 4 in the nilotinib 300 mg bid arm. In addition, gastric antral vascular ectasia has been reported in postmarketing experience. 5.6 Gastrointestinal Disorders Imatinib mesylate is 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 gastrointestinal 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 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 to 2 mg/kg) for one to two weeks concomitantly with imatinib mesylate should be considered at the initiation of therapy. 5.8 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 rechallenge. Several foreign postmarketing 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. 5.9 Hypothyroidism Clinical cases of hypothyroidism have been reported in thyroidectomy patients undergoing levothyroxine replacement during treatment with imatinib mesylate tablets. TSH levels should be closely monitored in such patients. 5.10 Embryo-fetal Toxicity Imatinib mesylate 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. 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. Sexually active female patients of reproductive potential taking imatinib mesylate should use highly effective contraception. 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 a fetus [ see Use in Specific Populations (8.1) ]. 5.11 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 on growth in children are unknown. Therefore, close monitoring of growth in children under imatinib mesylate treatment is recommended [ see Adverse Reactions (6.11) ]. 5.12 Tumor Lysis Syndrome Cases of Tumor Lysis Syndrome (TLS), including fatal cases, have been reported in patients with CML, 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. These patients should be monitored closely and appropriate precautions taken. 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. 5.13 Driving and Using Machinery Reports of motor vehicle accidents have been received in patients receiving imatinib mesylate tablets. While most of these reports are not suspected to be caused by imatinib mesylate, patients should be advised that they may experience undesirable effects such as dizziness, blurred vision or somnolence during treatment with imatinib mesylate. Therefore, caution should be recommended when driving a car or operating machinery.

DRUG INTERACTIONS SECTION.


7 DRUG INTERACTIONS CYP3A4 inducers may decrease imatinib mesylate Cmax and AUC (2.11, 7.1) CYP3A4 inhibitors may increase imatinib mesylate Cmax and AUC (7.2) Imatinib mesylate is an inhibitor of CYP3A4 and CYP2D6 which may increase the Cmax and AUC of other drugs (7.3, 7.4) Patients who require anticoagulation should receive low-molecular weight or standard heparin and not warfarin (7.3) 7.1 Agents Inducing CYP3A Metabolism Pretreatment of healthy volunteers with multiple doses of rifampin followed by a single dose of imatinib mesylate, increased imatinib mesylate oral-dose clearance by 3.8-fold, which significantly (p400 mg/day or the chronic use of concomitant acetaminophen and imatinib mesylate.

NONCLINICAL TOXICOLOGY SECTION.


13 NONCLINICAL TOXICOLOGY 13.1 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 post-natal 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. 13.2 Animal Toxicology and/or Pharmacology 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 SPECIFIC POPULATIONS SECTION.


8 USE IN SPECIFIC POPULATIONS There is no experience in children less than 1 year of age (8.4) Pregnancy: Sexually active female patients should use highly effective contraception during treatment (5.10) 8.1 Pregnancy Pregnancy Category D [see Warnings and Precautions (5.10)]. Risk Summary Imatinib mesylate can cause fetal harm when administered to a pregnant woman. There have been post-market reports of spontaneous abortions and infant congenital anomalies from women who have taken imatinib mesylate. Imatinib was teratogenic in animals. 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. Animal Data Imatinib mesylate was teratogenic in rats when administered orally 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 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). 8.3 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. 8.4 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 1 year of age. As in adult patients, imatinib was rapidly absorbed after oral administration in pediatric patients, with a Cmax of 2 to 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. Based on pooled population pharmacokinetic analysis in pediatric patients with hematological disorders (CML or other hematological disorders treated with imatinib), clearance of imatinib increases with increasing body surface area (BSA). After correcting for the BSA effect, other demographics such as age, body weight and body mass index did not have clinically significant effects on the exposure of imatinib. The analysis confirmed that exposure of imatinib in pediatric patients receiving 260 mg/m2 once-daily (not exceeding 400 mg once-daily) or 340 mg/m2 once-daily (not exceeding 600 mg once-daily) were similar to those in adult patients who received imatinib 400 mg or 600 mg once-daily. 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. 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 [see Warnings and Precautions (5.1)]. The efficacy of imatinib mesylate was similar in older 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 cancer patients with varying degrees of hepatic impairment (Table 11) at imatinib doses ranging from 100 mg to 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 [see Dosage and Administration (2.11)]. Table 11 Liver Function Classification Liver Function Test Normal (n=14) Mild (n=30) Moderate (n=20) Severe (n=20) Total Bilirubin ULN >1.0-1.5 x ULN >1.5-3 x ULN >3-10 x ULN SGOT ULN > ULN (can be normal if Total Bilirubin is >ULN) Any Any ULN=upper limit of normal for the institution 8.7 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 12) 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 (2.11)]. Table 12 Renal Function Classification Renal Dysfunction Renal Function Tests Mild CrCL=40-59 mL/min Moderate CrCL=20-39 mL/min Severe CrCL=<20 mL/min CrCL = Creatinine Clearance

RECENT MAJOR CHANGES SECTION.


Warnings and Precautions (5) 1/2015

REFERENCES SECTION.


15 REFERENCES 1. OSHA Hazardous Drugs. OSHA. [Accessed on 20-September- 2013, from http://www.osha.gov/SLTC/hazardousdrugs/index.html]

INFORMATION FOR PATIENTS SECTION.


17 PATIENT COUNSELING INFORMATION Dosing and Administration Advise patients to take imatinib mesylate tablets exactly as prescribed, not to change their dose or to stop taking imatinib mesylate unless they are told to do so by their doctor. If the patient missed a dose of imatinib mesylate tablets, the patient should take the next scheduled dose at its regular time. The patient should not take two doses at the same time. Advise patients to take imatinib mesylate tablets with a meal and a large glass of water. Pregnancy and Breastfeeding Advise patients to inform their doctor if they are or think they may be pregnant. Advise women of reproductive potential to avoid becoming pregnant while taking imatinib mesylate tablets. Sexually active female patients taking imatinib mesylate tablets should use highly effective contraception. Avoid breastfeeding while taking imatinib mesylate tablets. Adverse Reactions Advise patients to tell their doctor if they experience side effects during imatinib mesylate therapy including fever, shortness of breath, blood in their stools, jaundice, sudden weight gain, symptoms of cardiac failure, or if they have a history of cardiac disease or risk factors for cardiac failure. Drug Interactions Imatinib mesylate tablets and certain other medicines such as warfarin, erythromycin, and phenytoin, including over-the-counter medications such as herbal products, can interact with each other. Advise patients to tell their doctor if they are taking or plan to take iron supplements. Avoid grapefruit juice and other foods known to inhibit CYP3A4 while taking imatinib mesylate tablets. Pediatric Advise patients that 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. Driving and Using Machines Advise patients that they may experience undesirable effects such as dizziness, blurred vision or somnolence during treatment with imatinib mesylate. Therefore, caution patients about driving a car or operating machinery. Manufactured for: AvKARE, Inc. Pulaski, TN 38478 Mfg. Rev. 07/16 AV 08/16 (P)

CLINICAL STUDIES SECTION.


14 CLINICAL STUDIES 14.1 Chronic Myeloid Leukemia Chronic Phase, Newly Diagnosed: An open-label, multicenter, international randomized Phase 3 study (imatinib mesylate versus INF+Ara-C) has been conducted in patients with newly diagnosed Philadelphia chromosome positive (Ph+) chronic myeloid leukemia (CML) in chronic phase. This study compared treatment with either single-agent imatinib mesylate or a combination of interferon-alpha (IFN) plus cytarabine (Ara-C). Patients were allowed to cross over to the alternative treatment arm if they failed to show a complete hematologic response (CHR) at 6 months, a major cytogenetic response (MCyR) at 12 months, or if they lost a CHR or MCyR. Patients with increasing WBC or severe intolerance to treatment were also allowed to cross over to the alternative treatment arm with the permission of the study monitoring committee (SMC). In the imatinib mesylate arm, patients were treated initially with 400 mg daily. Dose escalations were allowed from 400 mg daily to 600 mg daily, then from 600 mg daily to 800 mg daily. In the IFN arm, patients were treated with a target dose of IFN of 5 MIU/m2/day subcutaneously in combination with subcutaneous Ara-C 20 mg/m2/day for 10 days/month. A total of 1,106 patients were randomized from 177 centers in 16 countries, 553 to each arm. Baseline characteristics were well balanced between the two arms. Median age was 51 years (range 18 to 70 years), with 21.9% of patients 60 years of age. There were 59% males and 41% females; 89.9% Caucasian and 4.7% black patients. At the cut-off for this analysis (7 years after last patient had been recruited), the median duration of first-line treatment was 82 and 8 months in the imatinib mesylate and IFN arm, respectively. The median duration of second-line treatment with imatinib mesylate was 64 months. Sixty percent of patients randomized to imatinib mesylate are still receiving first-line treatment. In these patients, the average dose of imatinib mesylate was 403 mg 57 mg. Overall, in patients receiving first line imatinib mesylate, the average daily dose delivered was 406 mg 76 mg. Due to discontinuations and cross-overs, only 2% of patients randomized to IFN were still on first-line treatment. In the IFN arm, withdrawal of consent (14%) was the most frequent reason for discontinuation of first-line therapy, and the most frequent reason for cross over to the imatinib mesylate arm was severe intolerance to treatment (26%) and progression (14%). The primary efficacy endpoint of the study was progression-free survival (PFS). Progression was defined as any of the following events: progression to accelerated phase or blast crisis (AP/BC), death, loss of CHR or MCyR, or in patients not achieving a CHR an increasing WBC despite appropriate therapeutic management. The protocol specified that the progression analysis would compare the intent to treat (ITT) population: patients randomized to receive imatinib mesylate were compared with patients randomized to receive IFN. Patients that crossed over prior to progression were not censored at the time of cross-over, and events that occurred in these patients following cross-over were attributed to the original randomized treatment. The estimated rate of progression-free survival at 84 months in the ITT population was 81.2% [95% CI: 78, 85] in the imatinib mesylate arm and 60.6% [56, 65] in the IFN arm (p18 years old. Patients were treated at doses of 260 mg/m2/day (n=3), 340 mg/m2/day (n=4), 440 mg/m2/day (n=5) and 570 mg/m2/day (n=2). In the 13 patients for whom cytogenetic data are available, 4 achieved a major cytogenetic response, 7 achieved a complete cytogenetic response, and 2 had a minimal cytogenetic response. In a second study, 2 of 3 patients with Ph+ chronic phase CML resistant to interferon-alpha therapy achieved a complete cytogenetic response at doses of 242 and 257 mg/m2/day. 14.3 Acute Lymphoblastic Leukemia A total of 48 Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL) patients with relapsed/refractory disease were studied, 43 of whom received the recommended imatinib mesylate dose of 600 mg/day. In addition 2 patients with relapsed/refractory Ph+ ALL received imatinib mesylate 600 mg/day in a phase 1 study. Confirmed and unconfirmed hematologic and cytogenetic response rates for the 43 relapsed/refractory Ph+ALL phase 2 study patients and for the 2 phase 1 patients are shown in Table 16. The median duration of hematologic response was 3.4 months and the median duration of MCyR was 2.3 months. Table 16 Effect of Imatinib Mesylate on Relapsed/Refractory Ph+ ALL. Phase 2 Study (N=43) n % Phase 1 Study (N=2) n % CHR 8 (19) 2 (100) NEL 5 (12) RTC/PHR 11 (26) MCyR 15 (35) CCyR 9 (21) PCyR 6 (14) </text </section </component 14.5 Myelodysplastic/Myeloproliferative Diseases An open-label, multicenter, phase 2 clinical trial was conducted testing imatinib mesylate in diverse populations of patients suffering from life-threatening diseases associated with Abl, Kit or PDGFR protein tyrosine kinases. This study included 7 patients with MDS/MPD. These patients were treated with imatinib mesylate 400 mg daily (imatinib as free base). The ages of the enrolled patients ranged from 20 to 86 years. A further 24 patients with MDS/MPD aged 2 to 79 years were reported in 12 published case reports and a clinical study. These patients also received imatinib mesylate at a dose of 400 mg (imatinib as free base) daily with the exception of three patients who received lower doses. Of the total population of 31 patients treated for MDS/MPD, 14 (45%) achieved a complete hematological response and 12 (39%) a major cytogenetic response (including 10 with a complete cytogenetic response). Sixteen patients had a translocation, involving chromosome 5q33 or 4q12, resulting in a PDGFR gene re-arrangement. All of these patients responded hematologically (13 completely). Cytogenetic response was evaluated in 12 out of 14 patients, all of whom responded (10 patients completely). Only 1 (7%) out of the 14 patients without a translocation associated with PDGFR gene re-arrangement achieved a complete hematological response and none achieved a major cytogenetic response. A further patient with a PDGFR gene re-arrangement in molecular relapse after bone marrow transplant responded molecularly. Median duration of therapy was 12.9 months (0.8-26.7) in the 7 patients treated within the phase 2 study and ranged between 1 week and more than 18 months in responding patients in the published literature. Results are provided in Table 17. Response durations of phase 2 study patients ranged from 141+ days to 457+ days. Table 17 Response in MDS/MPD Number of patients N Complete Hematologic Response n (%) Major Cytogenetic Response n ( % ) Overall Population 31 14 (45) 12 (39) Chromosome 5 Translocation 14 11 (79) 11 (79) Chromosome 4 Translocation 2 2 (100) 1 (50) Others / no Translocation 14 1 (7) 0 Molecular Relapse 1 NE1 NE1 1NE: Not Evaluable 14.6 Aggressive Systemic Mastocytosis One open-label, multicenter, phase 2 study was conducted testing imatinib mesylate in diverse populations of patients with life-threatening diseases associated with Abl, Kit or PDGFR protein tyrosine kinases. This study included 5 patients with aggressive systemic mastocytosis (ASM) treated with 100 mg to 400 mg of imatinib mesylate (imatinib as free base) daily. These 5 patients ranged from 49 to 74 years of age. In addition to these 5 patients, 10 published case reports and case series describe the use of imatinib mesylate in 23 additional patients with ASM aged 26 to 85 years who also received 100 mg to 400 mg of imatinib mesylate (imatinib as free base) daily. Cytogenetic abnormalities were evaluated in 20 of the 28 ASM patients treated with imatinib mesylate from the published reports and in the phase 2 study. Seven of these 20 patients had the FIP1L1-PDGFR fusion kinase (or CHIC2 deletion). Patients with this cytogenetic abnormality were predominantly males and had eosinophilia associated with their systemic mast cell disease. Two patients had a Kit mutation in the juxtamembrane region (one Phe522Cys and one K509I) and four patients had a D816V c-Kit mutation (not considered sensitive to imatinib mesylate), one with concomitant CML. Of the 28 patients treated for ASM, 8 (29%) achieved a complete hematologic response and 9 (32%) a partial hematologic response (61% overall response rate). Median duration of imatinib mesylate therapy for the 5 ASM patients in the phase 2 study was 13 months (range 1.4 to 22.3 months) and between 1 month and more than 30 months in the responding patients described in the published medical literature. A summary of the response rates to imatinib mesylate in ASM is provided in Table 18. Response durations of literature patients ranged from 1+ to 30+ months. Table 18 Response in ASM Cytogenetic Abnormality Number of Patients N Complete Hematologic Response n (%) Partial Hematologic Response n (%) FIP1L1-PDGFR Fusion Kinase (or CHIC2 Deletion) 7 7 (100) 0% Juxtamembrane Mutation 2 0 2 (100%) Unknown or No Cytogenetic Abnormality Detected 15 0 7 (44%) D816V Mutation 4 1* (25) 0% Total 28 8 (29) 9 (32%) *Patient had concomitant CML and ASM Imatinib mesylate has not been shown to be effective in patients with less aggressive forms of systemic mastocytosis (SM). Imatinib mesylate is therefore not recommended for use in patients with cutaneous mastocytosis, indolent systemic mastocytosis (smoldering SM or isolated bone marrow mastocytosis), SM with an associated clonal hematological non-mast cell lineage disease, mast cell leukemia, mast cell sarcoma or extracutaneous mastocytoma. Patients that harbor the D816V mutation of c-Kit are not sensitive to imatinib mesylate and should not receive imatinib mesylate. 14.7 Hypereosinophilic Syndrome/Chronic Eosinophilic Leukemia One open-label, multicenter, phase 2 study was conducted testing imatinib mesylate in diverse populations of patients with life-threatening diseases associated with Abl, Kit or PDGFR protein tyrosine kinases. This study included 14 patients with Hypereosinophilic Syndrome/Chronic Eosinophilic Leukemia (HES/CEL). HES patients were treated with 100 mg to 1000 mg of imatinib mesylate daily. The ages of these patients ranged from 16 to 64 years. A further 162 patients with HES/CEL aged 11 to 78 years were reported in 35 published case reports and case series. These patients received imatinib mesylate at doses of 75 mg to 800 mg (imatinib as free base) daily. Hematologic response rates are summarized in Table 19. Response durations for literature patients ranged from 6+ weeks to 44 months. Table 19 Response in HES/CEL Cytogenetic Abnormality Number o f Patients N Complete Hematological Response n (%) Partial Hematological Response n (%) Positive FIP1L1-PDGFR Fusion Kinase 61 61 (100) 0% Negative FIP1L1-PDGFR Fusion Kinase 56 12 (21) 9 (16%) Unknown Cytogenetic Abnormality 59 34 (58) 7 (12%) Total 176 107 (61) 23 (13%) 14.8 Dermatofibrosarcoma Protuberans Dermatofibrosarcoma Protuberans (DFSP) is a cutaneous soft tissue sarcoma. It is characterized by a translocation of chromosomes 17 and 22 that results in the fusion of the collagen type 1 alpha 1 gene and the PDGF B gene. An open-label, multicenter, phase 2 study was conducted testing imatinib mesylate in a diverse population of patients with life-threatening diseases associated with Abl, Kit or PDGFR protein tyrosine kinases. This study included 12 patients with DFSP who were treated with imatinib mesylate 800 mg daily (imatinib as free base) (age range 23 to 75 years). DFSP was metastatic, locally recurrent following initial surgical resection and not considered amenable to further surgery at the time of study entry. A further 6 DFSP patients treated with imatinib mesylate are reported in 5 published case reports, their ages ranging from 18 months to 49 years. The total population treated for DFSP therefore comprises 18 patients, 8 of them with metastatic disease. The adult patients reported in the published literature were treated with either 400 mg (4 cases) or 800 mg (1 case) imatinib mesylate (imatinib as free base) daily. A single pediatric patient received 400 mg/m2/daily, subsequently increased to 520 mg/m2/daily. Ten patients had the PDGF B gene rearrangement, 5 had no available cytogenetics and 3 had complex cytogenetic abnormalities. Responses to treatment are described in Table 20. Table 20 Response in DFSP Number of Patients ( n=18) % Complete Response 7 39 Partial Response * 8 44 Total Responders 15 83 * 5 patients made disease free by surgery Twelve of these 18 patients either achieved a complete response (7 patients) or were made disease free by surgery after a partial response (5 patients, including one child) for a total complete response rate of 67%. A further 3 patients achieved a partial response, for an overall response rate of 83%. Of the 8 patients with metastatic disease, five responded (62%), three of them completely (37%). For the 10 study patients with the PDGF B gene rearrangement there were 4 complete and 6 partial responses. The median duration of response in the phase 2 study was 6.2 months, with a maximum duration of 24.3 months, while in the published literature it ranged between 4 weeks and more than 20 months.

CLINICAL PHARMACOLOGY SECTION.


12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Imatinib mesylate is a protein-tyrosine kinase inhibitor that inhibits the BCR-ABL tyrosine kinase, the constitutive abnormal tyrosine kinase created by the Philadelphia chromosome abnormality in CML. Imatinib inhibits proliferation and induces apoptosis in BCR-ABL positive cell lines as well as fresh leukemic cells from Philadelphia chromosome positive chronic myeloid leukemia. Imatinib inhibits colony formation in assays using ex vivo peripheral blood and bone marrow samples from CML patients. In vivo, imatinib inhibits tumor growth of BCR-ABL transfected murine myeloid cells as well as BCR-ABL positive leukemia lines derived from CML patients in blast crisis. Imatinib is also an inhibitor of the receptor tyrosine kinases for platelet-derived growth factor (PDGF) and stem cell factor (SCF), c-kit, and inhibits PDGF- and SCF-mediated cellular events. 12.3 Pharmacokinetics The pharmacokinetics of imatinib mesylate have been evaluated in studies in healthy subjects and in population pharmacokinetic studies in over 900 patients. Imatinib is well absorbed after oral administration with Cmax achieved within 2 to 4 hours post-dose. Mean absolute bioavailability is 98%. Following oral administration in healthy volunteers, the elimination half-lives of imatinib and its major active metabolite, the N-demethyl derivative (CGP74588), are approximately 18 and 40 hours, respectively. Mean imatinib AUC increases proportionally with increasing doses ranging from 25 mg to 1,000 mg. There is no significant change in the pharmacokinetics of imatinib on repeated dosing, and accumulation is 1.5- to 2.5-fold at steady state when imatinib mesylate is dosed once daily. At clinically relevant concentrations of imatinib, binding to plasma proteins in in vitro experiments is approximately 95%, mostly to albumin and 1-acid glycoprotein. CYP3A4 is the major enzyme responsible for metabolism of imatinib. Other cytochrome P450 enzymes, such as CYP1A2, CYP2D6, CYP2C9, and CYP2C19, play a minor role in its metabolism. The main circulating active metabolite in humans is the N-demethylated piperazine derivative, formed predominantly by CYP3A4. It shows in vitro potency similar to the parent imatinib. The plasma AUC for this metabolite is about 15% of the AUC for imatinib. The plasma protein binding of N-demethylated metabolite CGP74588 is similar to that of the parent compound. Human liver microsome studies demonstrated that imatinib mesylate is a potent competitive inhibitor of CYP2C9, CYP2D6, and CYP3A4/5 with Ki values of 27, 7.5, and 8 microM, respectively. Imatinib elimination is predominately in the feces, mostly as metabolites. Based on the recovery of compound(s) after an oral 14C-labeled 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. Typically, clearance of imatinib in a 50-year-old patient weighing 50 kg is expected to be 8 L/h, while for a 50-year-old patient weighing 100 kg the clearance will increase to 14 L/h. The inter-patient variability of 40% in clearance does not warrant initial dose adjustment based on body weight and/or age but indicates the need for close monitoring for treatment-related toxicity.

CONTRAINDICATIONS SECTION.


4 CONTRAINDICATIONS None None (4)