nilotinib 95 MG Oral Tablet

INDICATIONS AND USAGE Nilotinib capsules are a kinase inhibitor indicated for the treatment of: Adult and pediatric patients greater than or equal to 1 year of age with newly diagnosed Philadelphia chromosome positive chronic myeloid leukemia (Ph+ CML) in chronic phase. ( 1.1 ) Adult patients with chronic phase (CP) and accelerated phase (AP) Ph+ CML resistant to or intolerant to prior therapy that included imatinib. ( 1.2 ) Pediatric patients greater than or equal to 1 year of age with Ph+ CML-CP resistant or intolerant to prior tyrosine-kinase inhibitor (TKI) therapy. (1.3) 1.1 Adult and Pediatric Patients With Newly Diagnosed Ph+ CML-CP Nilotinib capsules are indicated for the treatment of adult and pediatric patients greater than or equal to 1 year of age with newly diagnosed Philadelphia chromosome positive chronic myeloid leukemia (Ph+ CML) in chronic phase. 1.2 Adult Patients With Resistant or Intolerant Ph+ CML-CP and CML-AP Nilotinib capsules are indicated for the treatment of adult patients with chronic phase and accelerated phase Philadelphia chromosome positive chronic myelogenous leukemia (Ph+ CML) resistant or intolerant to prior therapy that included imatinib. 1.3 Pediatric Patients With Resistant or Intolerant Ph+ CML-CP Nilotinib capsules are indicated for the treatment of pediatric patients greater than or equal to 1 year of age with chronic phase Philadelphia chromosome positive chronic myeloid leukemia (Ph+ CML) with resistance or intolerance to prior tyrosine-kinase inhibitor (TKI) therapy. Additional pediatric use information is approved for Novartis Pharmaceuticals Corporation’s TASIGNA (nilotinib) capsules. However, due to Novartis Pharmaceuticals Corporation’s marketing exclusivity rights, this drug product is not labeled with that pediatric information.

DOSAGE AND ADMINISTRATION Recommended Adult Dose: Newly diagnosed Ph+ CML-CP: 300 mg orally twice daily. Resistant or intolerant Ph+ CML-CP and CML-AP: 400 mg orally twice daily. ( 2.1 ) Recommended Pediatric Dose: Newly Diagnosed Ph+ CML-CP or Ph+ CML-CP resistant or intolerant to prior TKI therapy: 230 mg/m 2 orally twice daily, rounded to the nearest 50 mg dose (to a maximum single dose of 400 mg). ( 2.1 ) See Dosage and Administration for full dosing instructions and dose-reduction instructions for toxicity. ( 2.1 ) Reduce starting dose in patients with baseline hepatic impairment. ( 2.7 ) Eligible newly diagnosed adult patients with Ph+ CML-CP who have received nilotinib capsules for a minimum of 3 years and have achieved a sustained molecular response (MR4.5) and patients with Ph+ CML-CP resistant or intolerant to imatinib who have received nilotinib capsules for at least 3 years and have achieved a sustained molecular response (MR4.5) may be considered for treatment discontinuation. ( 2.2 , 2.3 , 5.16 ) 2.1 Recommended Dosage Dose nilotinib capsules twice daily at approximately 12-hour intervals on an empty stomach. No food should be consumed for at least 2 hours before the dose is taken and for at least 1 hour after the dose is taken. Advise patients to swallow the capsules whole with water [ see Boxed Warning , Clinical Pharmacology (12.3) ]. For patients who are unable to swallow capsules, the contents of each capsule may be dispersed in 1 teaspoon of applesauce (puréed apple). The mixture should be taken immediately (within 15 minutes) and should not be stored for future use [ see Clinical Pharmacology (12.3) ]. Nilotinib capsules may be given in combination with hematopoietic growth factors, such as erythropoietin or G-CSF if clinically indicated. Nilotinib capsules may be given with hydroxyurea or anagrelide if clinically indicated. Dosage in Adult Patients with Newly Diagnosed Ph+ CML-CP The recommended dosage of nilotinib capsules are 300 mg orally twice daily. Dosage in Adult Patients with Resistant or Intolerant Ph+ CML-CP and CML-AP The recommended dosage of nilotinib capsules are 400 mg orally twice daily. Dosage in Pediatric Patients with Newly Diagnosed Ph+ CML-CP or Resistant or Intolerant Ph+ CML-CP The recommended dosage of nilotinib capsules for pediatric patients is 230 mg/m2 orally twice daily, rounded to the nearest 50 mg dose (to a maximum single dose of 400 mg) (see Table 1). If needed, attain the desired dose by combining different strengths of nilotinib capsules. Continue treatment as long as clinical benefit is observed or until unacceptable toxicity occurs. Table 1: Pediatric Dosing of Nilotinib capsules (230 mg/m 2 Twice Daily, Maximum Single Dose of 400 mg) Body surface area Single dose Total daily dose Up to 0.32 m 2 50 mg 100 mg 0.33 – 0.54 m 2 100 mg 200 mg 0.55 – 0.76 m 2 150 mg 300 mg 0.77 – 0.97 m 2 200 mg 400 mg 0.98 – 1.19 m 2 250 mg 500 mg 1.20 – 1.41 m 2 300 mg 600 mg 1.42 – 1.63 m 2 350 mg 700 mg ≥ 1.64 m 2 400 mg 800 mg Additional pediatric use information is approved for Novartis Pharmaceuticals Corporation’s TASIGNA (nilotinib) capsules. However, due to Novartis Pharmaceuticals Corporation’s marketing exclusivity rights, this drug product is not labeled with that pediatric information. 2.2 Discontinuation of Treatment After a Sustained Molecular Response (MR4.5) on Nilotinib Capsules Patient Selection Eligibility for Discontinuation of Treatment Ph+ CML-CP patients with typical BCR-ABL transcripts, who have been taking nilotinib capsules for a minimum of 3 years and have achieved a sustained molecular response (MR4.5, corresponding to = BCR-ABL/ABL ≤ 0.0032% IS), may be eligible for treatment discontinuation [ see Clinical Studies (14.3 , 14.4) ]. Information on FDA authorized tests for the detection and quantitation of BCR-ABL transcripts to determine eligibility for treatment discontinuation is available at http://www.fda.gov/CompanionDiagnostics. Patients with typical BCR-ABL transcripts (e13a2/b2a2 or e14a2/b3a2), who achieve the sustained MR4.5 criteria, are eligible for discontinuation of nilotinib capsules. Patients must continue to be monitored for possible loss of molecular remission after treatment discontinuation. Use the same FDA-authorized test to consistently monitor molecular response levels while on and off treatment. Consider discontinuation in patients with newly diagnosed Ph+ CML-CP who have: been treated with nilotinib capsules for at least 3 years maintained a molecular response of at least MR4.0 (corresponding to = BCR-ABL/ABL ≤ 0.01% IS) for one year prior to discontinuation of therapy achieved an MR4.5 for the last assessment taken immediately prior to discontinuation of therapy been confirmed to express the typical BCR-ABL transcripts (e13a2/b2a2 or e14a2/b3a2) no history of accelerated phase or blast crisis no history of prior attempts of treatment-free remission discontinuation that resulted in relapse. Consider discontinuation in patients with Ph+ CML-CP that are resistant or intolerant to imatinib who have achieved a sustained molecular response (MR4.5) on nilotinib capsules who have: been treated with nilotinib capsules for a minimum of 3 years been treated with imatinib only prior to treatment with nilotinib capsules achieved a molecular response of MR4.5 (corresponding to = BCR-ABL/ABL ≤ 0.0032% IS) sustained an MR4.5 for a minimum of one year immediately prior to discontinuation of therapy been confirmed to express the typical BCR-ABL transcripts (e13a2/b2a2 or e14a2/b3a2) no history of accelerated phase or blast crisis no history of prior attempts of treatment-free remission discontinuation that resulted in relapse. Monitor BCR-ABL transcript levels and complete blood count (CBC) with differential in patients who have discontinued nilotinib capsules therapy monthly for one year, then every 6 weeks for the second year, and every 12 weeks thereafter [ see Warnings and Precautions (5.16) ]. Upon the loss of MR4.0 (corresponding to = BCR-ABL/ABL ≤ 0.01% IS) during the treatment-free phase, monitor BCR-ABL transcript levels every 2 weeks until BCR-ABL levels remain lower than major molecular response [(MMR), corresponding to MR3.0 or = BCR-ABL/ABL ≤ 0.1% IS] for 4 consecutive measurements. The patient can then proceed to the original monitoring schedule. 2.3 Reinitiation of Treatment in Patients Who Lose Molecular Response After Discontinuation of Therapy With Nilotinib Capsules Newly diagnosed patients who lose MMR must reinitiate treatment within 4 weeks at the dose level prior to discontinuation of therapy [ see Warnings and Precautions (5.16) ]. Patients who reinitiate nilotinib capsules therapy should have their BCR-ABL transcript levels monitored monthly until major molecular response is re-established and every 12 weeks thereafter. Patients resistant or intolerant to prior treatment that included imatinib with confirmed loss of MR4.0 (2 consecutive measures separated by at least 4 weeks showing loss of MR4.0) or loss of MMR must reinitiate treatment within 4 weeks at the dose level prior to discontinuation of therapy [ see Warnings and Precautions (5.16) ]. Patients who reinitiate nilotinib capsules therapy should have their BCR-ABL transcript levels monitored monthly until previous major molecular response or MR4.0 is re-established and every 12 weeks thereafter. 2.4 Dosage Modification for QT Interval Prolongation See Table 2 for dose adjustments for QT interval prolongation [ see Warnings and Precautions (5.2) , Clinical Pharmacology (12.2) ]. Table 2: Dosage Adjustments for Adult and Pediatric Patients With QT Prolongation Degree of QTc prolongation Dosage adjustment ECGs with a QTc greater than 480 msec 1. Withhold nilotinib capsules, and perform an analysis of serum potassium and magnesium, and if below lower limit of normal, correct with supplements to within normal limits. Concomitant medication usage must be reviewed. 2. Resume within 2 weeks at prior dos

WARNINGS AND PRECAUTIONS Myelosuppression : Monitor complete blood count (CBC) during therapy and manage by treatment interruption or dose reduction. ( 5.1 ) Cardiac and Arterial Vascular Occlusive Events : Evaluate cardiovascular status, monitor and manage cardiovascular risk factors during nilotinib therapy. ( 5.4 ) Pancreatitis and Elevated Serum Lipase : Monitor serum lipase; if elevations are accompanied by abdominal symptoms, interrupt doses and consider appropriate diagnostics to exclude pancreatitis. ( 5.5 ) Hepatotoxicity : Monitor hepatic function tests monthly or as clinically indicated. ( 5.6 ) Electrolyte Abnormalities : Nilotinib can cause hypophosphatemia, hypokalemia, hyperkalemia, hypocalcemia, and hyponatremia. Correct electrolyte abnormalities prior to initiating nilotinib and monitor periodically during therapy. ( 5.7 ) Tumor Lysis Syndrome : Maintain adequate hydration and correct uric acid levels prior to initiating therapy with nilotinib. ( 5.8 ) Hemorrhage : Hemorrhage from any site may occur. Advise patients to report signs and symptoms of bleeding and medically manage as needed. ( 5.9 ) Fluid Retention : Monitor patients for unexpected rapid weight gain, swelling, and shortness of breath. Manage medically. ( 5.13 ) Effects on Growth and Development in Pediatric Patients: Growth retardation has been reported in pediatric patients treated with nilotinib. Monitor growth and development in pediatric patients. ( 5.14 ) Embryo-Fetal Toxicity : Advise females of reproductive potential of potential risk to a fetus and to use effective contraception. ( 5.15 , 8.1 , 8.3 ) Treatment Discontinuation : Patients must have typical BCR-ABL transcripts. An FDA-authorized test with a detection limit below MR4.5 must be used to determine eligibility for discontinuation. Patients must be frequently monitored by the FDA authorized test to detect possible loss of remission. ( 5.16 ) 5.1 Myelosuppression Treatment with nilotinib can cause Grade 3/4 thrombocytopenia, neutropenia, and anemia. Perform CBCs every 2 weeks for the first 2 months and then monthly thereafter, or as clinically indicated. Myelosuppression was generally reversible and usually managed by withholding nilotinib temporarily or dose reduction [ see Dosage and Administration (2.5) ]. 5.2 QT Prolongation Nilotinib has been shown to prolong cardiac ventricular repolarization as measured by the QT interval on the surface electrocardiogram (ECG) in a concentration-dependent manner [ see Adverse Reactions (6.1) , Clinical Pharmacology (12.2) ]. Prolongation of the QT interval can result in a type of ventricular tachycardia called torsade de pointes, which may result in syncope, seizure, and/or death. Electrocardiograms should be performed at baseline, 7 days after initiation of nilotinib, and periodically as clinically indicated and following dose adjustments [ see Dosage and Administration (2.4) , Warnings and Precautions (5.12) ]. Nilotinib should not be used in patients who have hypokalemia, hypomagnesemia, or long QT syndrome. Before initiating nilotinib and periodically, test electrolyte, calcium, and magnesium blood levels. Hypokalemia or hypomagnesemia must be corrected prior to initiating nilotinib and these electrolytes should be monitored periodically during therapy [ see Warnings and Precautions (5.12) ]. Significant prolongation of the QT interval may occur when nilotinib is inappropriately taken with food and/or strong CYP3A4 inhibitors and/or medicinal products with a known potential to prolong QT. Therefore, coadministration with food must be avoided and concomitant use with strong CYP3A4 inhibitors and/or medicinal products with a known potential to prolong QT should be avoided [ see Dosage and Administration (2.1) , Drug Interactions (7.1 , 7.2) ]. The presence of hypokalemia and hypomagnesemia may further prolong the QT interval [ see Warnings and Precautions (5.7 , 5.12) ]. 5.3 Sudden Deaths Sudden deaths have been reported in 0.3% of patients with CML treated with nilotinib in clinical studies of 5661 patients. The relative early occurrence of some of these deaths relative to the initiation of nilotinib suggests the possibility that ventricular repolarization abnormalities may have contributed to their occurrence. 5.4 Cardiac and Arterial Vascular Occlusive Events Cardiovascular events, including arterial vascular occlusive events, were reported in a randomized, clinical trial in newly diagnosed CML patients and observed in the postmarketing reports of patients receiving nilotinib therapy [ see Adverse Reactions (6.1) ]. With a median time on therapy of 60 months in the clinical trial, cardiovascular events, including arterial vascular occlusive events, occurred in 9% and 15% of patients in the nilotinib 300 and 400 mg twice daily arms, respectively, and in 3.2% in the imatinib arm. These included cases of cardiovascular events, including ischemic heart disease-related cardiac events (5% and 9% in the nilotinib 300 mg and 400 mg twice daily arms, respectively, and 2.5% in the imatinib arm), peripheral arterial occlusive disease (3.6% and 2.9% in the nilotinib 300 mg and 400 mg twice daily arms, respectively, and 0% in the imatinib arm), and ischemic cerebrovascular events (1.4% and 3.2% in the nilotinib 300 mg and 400 mg twice daily arms, respectively, and 0.7% in the imatinib arm). If acute signs or symptoms of cardiovascular events occur, advise patients to seek immediate medical attention. The cardiovascular status of patients should be evaluated and cardiovascular risk factors should be monitored and actively managed during nilotinib therapy according to standard guidelines [ see Dosage and Administration (2.4) ]. 5.5 Pancreatitis and Elevated Serum Lipase Nilotinib can cause increases in serum lipase [ see Adverse Reactions (6.1) ]. Patients with a previous history of pancreatitis may be at greater risk of elevated serum lipase. If lipase elevations are accompanied by abdominal symptoms, interrupt dosing and consider appropriate diagnostics to exclude pancreatitis [ see Dosage and Administration (2.6) ]. Test serum lipase levels monthly or as clinically indicated. 5.6 Hepatotoxicity Nilotinib may result in hepatotoxicity as measured by elevations in bilirubin, aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase. Grade 3 to 4 elevations of bilirubin, AST, and ALT were reported at a higher frequency in pediatric than in adult patients. Monitor hepatic function tests monthly or as clinically indicated [ see Warnings and Precautions (5.12) ] and following dose adjustments. [ see Dosage and Administration (2.6) ]. 5.7 Electrolyte Abnormalities The use of nilotinib can cause hypophosphatemia, hypokalemia, hyperkalemia, hypocalcemia, and hyponatremia. Correct electrolyte abnormalities prior to initiating nilotinib and during therapy. Monitor these electrolytes periodically during therapy [ see Warnings and Precautions (5.12) ]. 5.8 Tumor Lysis Syndrome Tumor lysis syndrome (TLS) cases have been reported in nilotinib treated patients with resistant or intolerant CML. Malignant disease progression, high white blood cell (WBC) counts and/or dehydration were present in the majority of these cases. Due to potential for TLS, maintain adequate hydration and correct uric acid levels prior to initiating therapy with nilotinib. 5.9 Hemorrhage Serious hemorrhagic events, including fatal events, have occurred in patients with CML treated with nilotinib. In a randomized trial in patients with newly diagnosed Ph+ CML in chronic phase comparing nilotinib and imatinib, Grade 3 or 4 hemorrhage occurred in 1.1% of patients in the nilotinib 300 mg twice daily arm, in 1.8% of patients in the nilotinib 400 mg twice daily arm, and 0.4% of patients in the imatinib arm. GI hemorrhage occurred in 2.9% and 5% of patients in the nilotinib 300 mg twice daily and 400 mg twice daily arms and in 1.4% of patients in the imatinib arm, respectively. Grade 3 or

CONTRAINDICATIONS Nilotinib Capsules is contraindicated in patients with hypokalemia, hypomagnesemia, or long QT syndrome [see Boxed Warning and Warnings and Precautions (5.2)]. Nilotinib Capsules is contraindicated in patients with, • hypokalemia ( 4 ) • hypomagnesemia ( 4 ) • long QT syndrome ( 4 )

Mechanism of Action Nilotinib is an inhibitor of the BCR-ABL kinase. Nilotinib binds to and stabilizes the inactive conformation of the kinase domain of ABL protein. In vitro , nilotinib inhibited BCR-ABL mediated proliferation of murine leukemic cell lines and human cell lines derived from patients with Ph+ CML. Under the conditions of the assays, nilotinib was able to overcome imatinib resistance resulting from BCR-ABL kinase mutations, in 32 out of 33 mutations tested. Nilotinib inhibited the autophosphorylation of the following kinases at IC 50 values as indicated: BCR-ABL (20 to 60 nM), PDGFR (69 nM), c-KIT (210 nM), CSF-1R (125 to 250 nM), and DDR1 (3.7 nM).