Nilotinib

1 INDICATIONS AND USAGE Nilotinib Capsules is a kinase inhibitor indicated for the treatment of: Adult patients 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 ) 1.1 Adult Patients With Newly Diagnosed Ph+ CML-CP Nilotinib Capsules is indicated for the treatment of adult patients with newly diagnosed Philadelphia chromosome positive chronic myeloid leukemia (Ph+ CML) in chronic phase. 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. 1.2 Adult Patients With Resistant or Intolerant Ph+ CML-CP and CML-AP Nilotinib Capsules is 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. 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 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 ) 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 Dosage in Adult Patients with Newly Diagnosed Ph+ CML-CP The recommended dosage of Nilotinib Capsules is 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 is 400 mg orally twice daily . Additional Administration Instructions 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 and not open the capsules [see Boxed Warning, Clinical Pharmacology ( 12.3 )] . If a dose of Nilotinib Capsules is missed, the patient should take the next scheduled dose at its regular time. The patient should not take two doses at the same time. Optional Concomitant Therapy 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. 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 sustai…

5 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 Capsules 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 Capsules can cause hypophosphatemia, hypokalemia, hyperkalemia, hypocalcemia, and hyponatremia. Correct electrolyte abnormalities prior to initiating Nilotinib Capsules and monitor periodically during therapy. ( 5.7 ) Tumor Lysis Syndrome: Maintain adequate hydration and correct uric acid levels prior to initiating therapy with Nilotinib Capsules. ( 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 : Can cause fetal harm. 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 Capsules 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 Capsules 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 Capsules, and periodically as clinically indicated and following dose adjustments [see Dosage and Administration ( 2.4 ), Warnings and Precautions ( 5.12 )]. Nilotinib Capsules should not be used in patients who have hypokalemia, hypomagnesemia, or long QT syndrome. Before initiating Nilotinib Capsules and periodically, test electrolyte, calcium, and magnesium blood levels. Hypokalemia or hypomagnesemia must be corrected prior to initiating Nilotinib Capsules 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 Capsules is inappropriately taken with food and/or strong CYP3A4 inhibitors and/or medicinal products with a known potential to prolong QT. Therefore, avoid coadministration with food and concomitant Nilotinib Capsules 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…

4 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 )

7 DRUG INTERACTIONS Strong CYP3A Inhibitors : Avoid concomitant use with Nilotinib Capsules or reduce Nilotinib Capsules dose if concomitant use cannot be avoided. ( 7.1 ) Strong CYP3A Inducers: Avoid concomitant use with Nilotinib Capsules. ( 7.1 ) Proton Pump Inhibitors: Use short-acting antacids or H2 blockers as an alternative to proton pump inhibitors. ( 7.1 ) 7.1 Effect of Other Drugs on Nilotinib Capsules Strong CYP3A Inhibitors Avoid concomitant use of strong CYP3A inhibitors with Nilotinib Capsules. If concomitant use cannot be avoided, reduce Nilotinib Capsules dose [see Dosage and Administration (2.8)]. Nilotinib is a CYP3A substrate [see Clinical Pharmacology (12.3)]. Concomitant use with a strong CYP3A inhibitor increases nilotinib exposure [see Clinical Pharmacology (12.3)], which may increase the risk of Nilotinib Capsules adverse reactions. Strong CYP3A Inducers Avoid concomitant use of strong CYP3A inducers with Nilotinib Capsules. Nilotinib is a CYP3A substrate [see Clinical Pharmacology (12.3)]. Concomitant use with a strong CYP3A inducer decreases nilotinib exposure [see Clinical Pharmacology (12.3)], which may reduce Nilotinib Capsules efficacy. Proton Pump Inhibitors Avoid concomitant use of proton pump inhibitors (PPI) with Nilotinib Capsules. As an alternative to PPIs, use H2 blockers approximately 10 hours before or approximately 2 hours after the dose of Nilotinib Capsules, or use antacids approximately 2 hours before or approximately 2 hours after the dose of Nilotinib Capsules. Nilotinib displays pH-dependent aqueous solubility [see Description (11)]. Concomitant use with a PPI decreases nilotinib concentrations [see Clinical Pharmacology (12.3)], which may reduce Nilotinib Capsules efficacy. 7.2 Drugs That Prolong the QT Interval Avoid coadministration of Nilotinib Capsules with agents that may prolong the QT interval, such as anti-arrhythmic drugs [see Boxed Warning , Dosage and Administration ( 2.4 ), Warnings and Precautions ( 5.2 ), Drug Interactions ( 7.1 ), Clinical Pharmacology ( 12.2 )] . Nilotinib is associated with a clinically significant concentration-dependent QT prolongation [see Clinical Pharmacology (12.2)].

8.1 Pregnancy Risk Summary Based on findings from animal studies and the mechanism of action, Nilotinib Capsules can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology ( 12.1 )] . There are no available data in pregnant women to inform the drug-associated risk. In animal reproduction studies, administration of nilotinib to pregnant rats and rabbits during organogenesis caused adverse developmental outcomes, including embryo-fetal lethality, fetal effects, and fetal variations in rats and rabbits at maternal exposures (AUC) approximately 2 and 0.5 times, respectively, the exposures in patients at the recommended dose ( see Data ). Advise pregnant women of the potential risk to a fetus. The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies are 2% to 4% and 15% to 20%, respectively. Data Animal Data In embryo-fetal development studies in rats and rabbits, pregnant animals received oral doses of nilotinib up to 100 mg/kg/day and 300 mg/kg/day, respectively, during the period of organogenesis. In rats, oral administration of nilotinib produced embryo-lethality/fetal effects at doses ≥ 30 mg/kg/day. At ≥ 30 mg/kg/day, skeletal variations of incomplete ossification of the frontals and misshapen sternebra were noted, and there was an increased incidence of small renal papilla and fetal edema. At 100 mg/kg/day, nilotinib was associated with maternal toxicity (decreased gestation weight, gravid uterine weight, net weight gain, and food consumption) and resulted in a single incidence of cleft palate and two incidences of pale skin were noted in the fetuses. A single incidence of dilated ureters was noted in a fetus also displaying small renal papilla at 100 mg/kg/day. Additional variations of forepaw and hindpaw phalanx unossified, fused sternebra, bipartite sternebra ossification, and incomplete ossification of the cervical vertebra were noted at 100 mg/kg/day. In rabbits, oral administration of nilotinib resulted in the early sacrifice of two females, maternal toxicity and increased resorption of fetuses at 300 mg/kg/day. Fetal skeletal variations (incomplete ossification of the hyoid, bent hyoid, supernumerary short detached ribs and the presence of additional ossification sites near the nasals, frontals and in the sternebral column) were also increased at this dose in the presence of maternal toxicity. Slight maternal toxicity was evident at 100 mg/kg/day but there were no reproductive or embryo-fetal effects at this dose. At 30 mg/kg/day in rats and 300 mg/kg/day in rabbits, the maternal systemic exposure (AUC) were 72700 ng*hr/mL and 17100 ng*hr/mL, respectively, representing approximately 2 and 0.5 times the exposure in humans at the highest recommended dose 400 mg twice daily. When pregnant rats were dosed with nilotinib during organogenesis and through lactation, the adverse effects included a longer gestational period, lower pup body weights until weaning and decreased fertility indices in the pups when they reached maturity, all at a maternal dose of 60 mg/kg (i.e., 360 mg/m 2 , approximately 0.7 times the clinical dose of 400 mg twice daily based on body surface area) . At doses up to 20 mg/kg (i.e., 120 mg/m 2 , approximately 0.25 times the clinical dose of 400 mg twice daily based on body surface area) no adverse effects were seen in the maternal animals or the pups.

12.5 Pharmacogenomics Nilotinib can increase bilirubin levels. The (TA)7/(TA)7 genotype of UGT1A1 was associated with a statistically significant increase in the risk of hyperbilirubinemia relative to the (TA)6/(TA)6 and (TA)6/(TA)7 genotypes. However, the largest increases in bilirubin were observed in the (TA)7/(TA)7 genotype (UGT1A1*28) patients [see Warnings and Precautions ( 5.6 )].

6 ADVERSE REACTIONS The following clinically significant adverse reactions can occur with Nilotinib Capsules and are discussed in greater detail in other sections of labeling: • Myelosuppression [see Warnings and Precautions ( 5.1 )] • QT Prolongation [see Boxed Warning, Warnings and Precautions ( 5.2 )] • Sudden Deaths [see Boxed Warning, Warnings and Precautions ( 5.3 )] • Cardiac and Arterial Vascular Occlusive Events [see Warnings and Precautions ( 5.4 )] • Pancreatitis and Elevated Serum Lipase [see Warnings and Precautions ( 5.5 )] • Hepatotoxicity [see Warnings and Precautions ( 5.6 )] • Electrolyte Abnormalities [see Boxed Warning, Warnings and Precautions ( 5.7 )] • Hemorrhage [see Warnings and Precautions ( 5.9 )] • Fluid Retention [see Warnings and Precautions ( 5.13 )] The most commonly reported non-hematologic adverse reactions (≥ 20%) in adult patients are nausea, rash, headache, fatigue, pruritus, vomiting, diarrhea, cough, constipation, arthralgia, nasopharyngitis, pyrexia, and night sweats. Hematologic adverse drug reactions include myelosuppression: thrombocytopenia, neutropenia, and anemia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Cipla Ltd. at 1-866-604-3268 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. In Adult Patients With Newly Diagnosed Ph+ CML-CP The data below reflect exposure to nilotinib from a randomized trial in patients with newly diagnosed Ph+ CML in chronic phase treated at the recommended dose of 300 mg twice daily (n = 279). The median time on treatment in the nilotinib 300 mg twice daily group was 61 months (range, 0.1 to 71 months). The median actual dose intensity was 593 mg/day in the nilotinib 300 mg twice daily group. The most common (greater than 10%) non-hematologic adverse drug reactions were rash, pruritus, headache, nausea, fatigue, alopecia, myalgia, and upper abdominal pain. Constipation, diarrhea, dry skin, muscle spasms, arthralgia, abdominal pain, peripheral edema, vomiting, and asthenia were observed less commonly (less than or equal to 10% and greater than 5%). Increase in QTcF greater than 60 msec from baseline was observed in 1 patient (0.4%) in the 300 mg twice daily treatment group . No patient had an absolute QTcF of greater than 500 msec while on study drug. The most common hematologic adverse drug reactions (all Grades) were myelosuppression, including: thrombocytopenia (18%), neutropenia (15%), and anemia (8%) . See Table 9 for Grade 3/4 laboratory abnormalities. Discontinuation due to adverse reactions, regardless of relationship to study drug, was observed in 10% of patients. In Adult Patients With Resistant or Intolerant Ph+ CML-CP and CML-AP In the single-arm, open-label multicenter clinical trial, a total of 458 patients with Ph+ CML-CP and CML-AP resistant to or intolerant to at least one prior therapy, including imatinib were treated (CML-CP = 321; CML-AP = 137) at the recommended dose of 400 mg twice daily. The median duration of exposure in days for CML-CP and CML-AP patients is 561 (range, 1 to 1096) and 264 (range, 2 to 1160), respectively. The median cumulative duration in days of dose interruptions for the CML-CP patients was 20 (range, 1 to 345), and the median duration in days of dose interruptions for the CML-AP patients was 23 (range, 1 to 234). In patients with CML-CP, the most commonly reported non-hematologic adverse drug reactions (greater than or equal to 10%) were rash, pruritus, nausea, fatigue, headache, constipation, diarrhea, vomiting, and myalgia. The common serious drug-related adverse reactions (greater than or equal to 1% and less than 10%) were thrombocytopenia, neutropenia, and anemia. In patients with CML-AP, the most commonl…