Nilotinib

Tasigna is 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 and CML-AP resistant or intolerant to prior tyrosine-kinase inhibitor (TKI) therapy. ( 1.3 )

1.1 Adult and Pediatric Patients With Newly Diagnosed Ph+ CML-CP Tasigna is 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 Tasigna 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.

1.3 Pediatric Patients With Resistant or Intolerant Ph+ CML-CP and CML-AP Tasigna is indicated for the treatment of pediatric patients greater than or equal to 1 year of age with chronic phase and accelerated phase Philadelphia chromosome positive chronic myeloid leukemia (Ph+ CML) with resistance or intolerance to prior tyrosine-kinase inhibitor (TKI) therapy.

Capsules: 50 mg red opaque cap and light-yellow opaque body hard gelatin capsules with black radial imprint “NVR/ABL.” 150 mg red opaque hard gelatin capsules with black axial imprint “NVR/BCR.” 200 mg light-yellow opaque hard gelatin capsules with a red axial imprint “NVR/TKI.” Capsules: 50 mg, 150 mg, and 200 mg ( 3 )

Tasigna is contraindicated in patients with hypokalemia, hypomagnesemia, or long QT syndrome [see Boxed Warning]. Tasigna is contraindicated in patients with hypokalemia, hypomagnesemia, or long QT syndrome. ( 4 )

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 Tasigna 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: Tasigna can cause hypophosphatemia, hypokalemia, hyperkalemia, hypocalcemia, and hyponatremia. Correct electrolyte abnormalities prior to initiating Tasigna and monitor periodically during therapy. ( 5.7 ) Tumor Lysis Syndrome: Maintain adequate hydration and correct uric acid levels prior to initiating therapy with Tasigna. ( 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 Tasigna. 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 Tasigna 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 Tasigna temporarily or dose reduction [see Dosage and Administration (2.5)] . 5.2 QT Prolongation Tasigna 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 Tasigna, and periodically as clinically indicated and following dose adjustments [see Dosage and Administration (2.4), Warnings and Precautions (5.12)] . Tasigna should not be used in patients who have hypokalemia, hypomagnesemia, or long QT syndrome. Before initiating Tasigna and periodically, test electrolyte, calcium, and magnesium blood levels. Hypokalemia or hypomagnesemia must be corrected prior to initiating Tasigna and these electrolytes should be monitored periodically during therapy [see Warnings and Precautions (5.12)] . Significant prolongation of the QT interval may occur when Tasigna 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 Tasigna in clinical studies of 5661 patients. The relative early occurrence of some of these deaths relative to the initiation of Tasigna 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 Tasigna 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 Tasigna 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 Tasigna 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 Tasigna 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 Tasigna 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 Tasigna therapy according to standard guidelines [see Dosage and Administration (2.4)] .

5.5 Pancreatitis and Elevated Serum Lipase Tasigna 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 Tasigna may result in hepatotoxicity as measured by elevations in bilirubin, aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase. Grade 3-4 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 Tasigna can cause hypophosphatemia, hypokalemia, hyperkalemia, hypocalcemia, and hyponatremia. Correct electrolyte abnormalities prior to initiating Tasigna and during therapy. Monitor these electrolytes periodically during therapy [see Warnings and Precautions (5. 1 2 )].

5.8 Tumor Lysis Syndrome Tumor lysis syndrome (TLS) cases have been reported in Tasigna 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 Tasigna.

5.9 Hemorrhage Serious hemorrhagic events, including fatal events, have occurred in patients with CML treated with Tasigna. In a randomized trial in patients with newly diagnosed Ph+ CML in chronic phase comparing Tasigna and imatinib, Grade 3 or 4 hemorrhage occurred in 1.1% of patients in the Tasigna 300 mg twice daily arm, in 1.8% of patients in the Tasigna 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 Tasigna 300 mg twice daily and 400 mg twice daily arms and in 1.4% of patients in the imatinib arm, respectively. […]

The following clinically significant adverse reactions can occur with Tasigna 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 and pediatric patients were 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 Novartis Pharmaceuticals Corporation at 1-888-669-6682 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 Tasigna 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 Tasigna 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 Tasigna 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%) and have been of mild-to-moderate severity, manageable and generally did not require dose reduction. 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 dose intensity for patients with CML-CP and CML-AP is 789 mg/day (range, 151 to 1110) and 780 mg/day (range, 150 to 1149), respectively, and corresponded to the planned 400 mg twice daily dosing. 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 commonly reported non-hematologic adverse drug reactions (greater than or equal to 10%) were rash, pruritus and fatigue. The common serious adverse drug reactions (greater than or equal to 1% and less than 10%) were thrombocytopenia, neutropenia, febrile neutropenia, pneumonia, leukopenia, intracranial hemorrhage, elevated lipase, and pyrexia. Sudden deaths and QT prolongation were reported. The maximum mean QTcF change from baseline at steady-state was 10 msec. Increase in QTcF greater than 60 msec from baseline was observed in 4.1% of the patients and QTcF of greater than 500 msec was observed in 4 patients (less than 1%) [see Boxed Warning, Warnings and Precautions (5.2, 5.3), Clinical Pharmacology (12.2)] . Discontinuation due to adverse drug reactions was observed in 16% of CML-CP and 10% of CML-AP patients. Most Frequently Reported Adverse Reactions Tables 7 and 8 show the percentage of adult patients experiencing non-hematologic adverse reactions (excluding laboratory abnormalities) regardless of relationship to study drug. Adverse reactions reported in greater than 10% of adult patients who received at least 1 dose of Tasigna are listed. Table 7: Most Frequently Reported Non-Hematologic Adverse Reactions (Regardless of Relationship to Study Drug) in Adult Patients With Newly Diagnosed Ph+ CML-CP (greater than or equal to 10% in Tasigna 300 mg twice daily or imatinib 400 mg once daily groups) 60-Month Analysis a Abbreviations: CML-CP, chronic myeloid leukemia-chronic phase; Ph+, Philadelphia chromosome positive. a Excluding laboratory abnormalities. b NCI Common Terminology Criteria (CTC) for Adverse Events, version 3.0. Patients With Newly Diagnosed Ph+ CML-CP Tasigna 300 mg twice daily imatinib 400 mg once daily Tasigna 300 mg twice daily imatinib 400 mg once daily N = 279 N = 280 N = 279 N = 280 Body System and Adverse Reaction All Grades (%) CTC Grades b 3/ 4 (%) Skin and subcutaneous tissue disorders Rash 38 19 < 1 2 Pruritus 21 7 < 1 0 Alopecia 13 7 0 0 Dry skin 12 6 0 0 Gastrointestinal disorders Nausea 22 41 2 2 Constipation 20 8 < 1 0 Diarrhea 19 46 1 4 Vomiting 15 27 < 1 < 1 Abdominal pain upper 18 14 1 < 1 Abdominal pain 15 12 2 0 Dyspepsia 10 12 0 0 Nervous system disorders Headache 32 23 3 < 1 Dizziness 12 11 < 1 < 1 General disorders and administration-site conditions Fatigue 23 20 1 1 Pyrexia 14 13 < 1 0 Asthenia 14 12 < 1 0 Peripheral edema 9 20 < 1 0 Face edema < 1 14 0 < 1 Musculoskeletal and connective tissue disorders Myalgia 19 19 < 1 < 1 Arthralgia 22 17 < 1 < 1 Muscle spasms 12 34 0 1 Pain in extremity 15 16 < 1 < 1 Back pain 19 17 1 1 Respiratory, thoracic, and mediastinal disorders Cough 17 13 0 0 Oropharyngeal pain 12 6 0 0 Dyspnea 11 6 2 < 1 Infections and infestations Nasopharyngitis 27 21 0 0 Upper respiratory tract infection 17 14 < 1 0 Influenza 13 9 0 0 Gastroenteritis 7 10 0 < 1 Eye disorders Eyelid edema 1 19 0 < 1 Periorbital edema < 1 15 0 0 Psychiatric disorders Insomnia 11 9 0 0 Vascular disorder Hypertension 10 4 1 < 1 Table 8: Most Frequently Reported Non-Hematologic Adverse Reactions in Adult Patients With Resistant or Intolerant Ph+ CML Receiving Tasigna 400 mg Twice Daily (regardless of relationship to study drug) (greater than or equal to 10% in any group) 24-Month Analysis a Abbreviations: CML-AP, chronic myeloid leukemia-accelerated phase; CML-CP, chronic myeloid leukemia-chronic phase; Ph+, Philadelphia chromosome positive. a Excluding laboratory abnormalities. b NCI Common Terminology Criteria for Adverse Events, version 3.0. c Also includes preferred term anorexia. […]

5.8 Tumor Lysis Syndrome Tumor lysis syndrome (TLS) cases have been reported in Tasigna 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 Tasigna.

7 DRUG INTERACTIONS Strong CYP3A Inhibitors: Avoid concomitant use with Tasigna, or reduce Tasigna dose if coadministration cannot be avoided. ( 7.1 ) Strong CYP3A Inducers: Avoid concomitant use with Tasigna. ( 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 Tasigna Strong CYP3A Inhibitors Concomitant use with a strong CYP3A inhibitor increased nilotinib concentrations compared to Tasigna alone [see Clinical Pharmacology (12.3)] , which may increase the risk of Tasigna toxicities. Avoid concomitant use of strong CYP3A inhibitors with Tasigna. If patients must be coadministered a strong CYP3A4 inhibitor, reduce Tasigna dose [see Dosage and Administration (2.8)] . Strong CYP3A Inducers Concomitant use with a strong CYP3A inducer decreased nilotinib concentrations compared to Tasigna alone [see Clinical Pharmacology (12.3)] , which may reduce Tasigna efficacy. Avoid concomitant use of strong CYP3A inducers with Tasigna. Proton Pump Inhibitors Concomitant use with a proton pump inhibitor (PPI) decreased nilotinib concentrations compared to Tasigna alone [see Clinical Pharmacology (12.3)] , which may reduce Tasigna efficacy. Avoid concomitant use of PPI with Tasigna. As an alternative to PPIs, use H2 blockers approximately 10 hours before or approximately 2 hours after the dose of Tasigna, or use antacids approximately 2 hours before or approximately 2 hours after the dose of Tasigna.

7.2 Drugs That Prolong the QT Interval Avoid coadministration of Tasigna 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)] .

Lactation: Advise women not to breastfeed. ( 8.2 )

8.1 Pregnancy Risk Summary Based on findings from animal studies and the mechanism of action, Tasigna 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.

8.2 Lactation Risk Summary There are no data on the presence of nilotinib or its metabolites in human milk or its effects on a breastfed child or on milk production. However, nilotinib is present in the milk of lactating rats. Because of the potential for serious adverse reactions in a breastfed child, advise women not to breastfeed during treatment with Tasigna and for 14 days after the last dose. Animal Data After a single 20 mg/kg of [ 14 C] nilotinib dose to lactating rats, the transfer of parent drug and its metabolites into milk was observed. The overall milk-to-plasma exposure ratio of total radioactivity was approximately 2, based on the AUC 0-24h or AUC 0-INF values. No rat metabolites of nilotinib were detected that were unique to milk.

8.3 Females and Males of Reproductive Potential Based on animal studies, Tasigna can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)] . Pregnancy Testing Females of reproductive potential should have a pregnancy test prior to starting treatment with Tasigna. Contraception Females Advise females of reproductive potential to use effective contraception during treatment with Tasigna and for 14 days after the last dose. Infertility The risk of infertility in females or males of reproductive potential has not been studied in humans. In studies in rats and rabbits, the fertility in males and females was not affected [see Nonclinical Toxicology (13.1)] .

8.4 Pediatric Use The safety and effectiveness of Tasigna have been established in pediatric patients greater than or equal to 1 year of age with newly diagnosed and resistant or intolerant Ph+ CML in chronic phase [see Clinical Studies (14.5)] . There are no data for pediatric patients under 2 years of age. Use of Tasigna in pediatric patients 1 year to less than 2 years of age with newly diagnosed or resistant or intolerant Ph+ CML in chronic phase is supported by efficacy in pediatric patients 2 to 6 years of age for these indications. The safety and effectiveness of Tasigna have been established in pediatric patients greater than or equal to 1 year of age with resistant or intolerant Ph+ CML in accelerated phase based on evidence of effectiveness from an adequate and well-controlled single-arm study in adults [see Clinical Studies (14.2)] with safety data from two pediatric studies as described in the next paragraph. Use of Tasigna in pediatric patients 1 to less than 18 years of age is supported by evidence from two clinical trials [see Clinical Studies (14.5)] . The 25 patients with newly diagnosed Ph+ CML-CP were in the following age groups: 6 children (age 2 to less than 12 years) and 19 adolescents (age 12 to less than 18 years). The 44 patients with resistant or intolerant Ph+ CML-CP included 18 children (age 2 to less than 12 years) and 26 adolescents (age 12 to less than 18 years). All pediatric patients received Tasigna treatment at a dose of 230 mg/m 2 twice daily, rounded to the nearest 50 mg dose (to a maximum single dose of 400 mg). No differences in efficacy or safety were observed between the different age subgroups in the two trials. The frequency, type, and severity of adverse reactions observed were generally consistent with those observed in adults, with the exception of the laboratory abnormalities of hyperbilirubinemia (Grade 3/4: 16%) and transaminase elevation (AST Grade 3/4: 2.9%, ALT Grade 3/4: 10%), which were reported at a higher frequency in pediatric patients than in adults [see Adverse Reactions (6.1)] . For pediatric growth and development, growth retardation has been reported in pediatric patients with Ph+ CML-CP treated with Tasigna [see Warnings and Precautions (5.14), Adverse Reactions (6.1)] . The safety and effectiveness of Tasigna in pediatric patients below the age of 1 year with newly diagnosed, or resistant or intolerant Ph+ CML in chronic phase and accelerated phase, have not been established.

8.5 Geriatric Use In the clinical trials of Tasigna (patients with newly diagnosed Ph+ CML-CP and resistant or intolerant Ph+ CML-CP and CML-AP), approximately 12% and 30% of patients were 65 years or over, respectively. […]

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 IC50 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).