NILODES

Nilotinib capsules contains nilotinib, which belongs to a pharmacologic class of drugs known as kinase inhibitors.

Nilotinib drug substance, in the form of monohydrochloride sesquihydrate, is a white or slightly yellowish or slightly greenish-yellow powder with the molecular formula and weight, respectively, of C 28 H 23 ClF 3 N 7 O. 1.5 H 2 O and 593 g/mol (corresponding molecular formula and weight of nilotinib base, anhydrous are C 28 H 22 F 3 N 7 O and 529 g/mol, respectively).

The solubility of nilotinib practically insoluble in water and heptane, slightly soluble in anhydrous ethanol.

Nilotinib is not optically active.

The pKa1 was determined to be 2.6 pKa2 was estimated to be 4.2.

The chemical name of nilotinib monohydrochloride sesquihydrate is 4-methyl-N-(3-(4-methyl-1H-imidazol-l-yl)-5-(trifluoromethyl)phenyl)-3-((4-(pyridin-3-yl)pyrimidin-2-yl)amino)benzamide hydrochloride sesquihydrate.

Its structure is shown below

Nilotinib capsules, for oral use, contain 50 mg, 150 mg, or 200 mg nilotinib base, anhydrous (equivalent to 56 mg, 168 mg, and 224 mg nilotinib monohydrochloride sesquihydrate respectively) with the following inactive ingredients: colloidal silicon dioxide, crospovidone, lactose monohydrate, magnesium stearate, and poloxamer 188.

The capsules contain gelatin, iron oxide (red), iron oxide (yellow) and titanium dioxide.

The imprinting ink contains black iron oxide, propylene glycol, potassium hydroxide and shellac. nilotinib-cap-structure.

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.

Adult patients with chronic phase (CP) and accelerated phase (AP) Ph+ CML resistant to or intolerant to prior therapy that included imatinib.

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. 1.1 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.

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 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). 12.2 Pharmacodynamics Based on exposure-response analyses for efficacy, a relationship between drug exposure and a greater likelihood of response was observed in clinical studies.

Based on exposure-response analyses for safety, a relationship between exposure and a greater likelihood of safety events, including a higher occurrence of total bilirubin elevations, was observed in clinical studies.

Nilotinib is associated with concentration-dependent QT prolongation.

At a dose of nilotinib 400 mg twice daily given without food in healthy subjects, the maximum mean placebo-adjusted QTcF changes were 10.4 msec (90% CI: 2.85, 18).

After a single dose of nilotinib 800 mg (two times the maximum approved recommended dosage) given with a high fat meal to healthy subjects, the maximum mean placebo-adjusted QTcF changes were) 18 msec (90% CI: 9.65, 25.8).

Peak plasma concentrations in the

QT study were 26% lower than or comparable with those observed in patients enrolled in the single-arm study. 12.3 Pharmacokinetics Steady-state nilotinib exposure was dose-dependent with less than dose-proportional increases in systemic exposure at dose levels higher than 400 mg given as once or twice daily dosing.

In adult patients with resistant or intolerant Ph+ CML given nilotinib 400 mg twice daily, the steady-state mean (% CV) C max and AUC 0-12h were 2260 ng/mL (35%) and 18000 ng∙h/mL (33%), respectively.

In adult patients with newly diagnosed

Ph+ CML given nilotinib 300 mg twice daily, the steady-state mean (% CV) C max and AUC 0-12h were 1540 ng/mL (48%) and 13337 ng∙h/mL (46%), respectively.

Steady state conditions were achieved by

Day 8.

An increase in serum exposure to nilotinib between the first dose and steady state was approximately 2-fold for daily dosing and 3.8-fold for twice daily dosing.

The average steady state nilotinib trough and peak concentrations did not change over 12 months.

Relative bioavailability of nilotinib capsule is approximately 50%, as compared to an oral drink solution (pH of 1.2 to 1.3).

Peak concentrations of nilotinib are reached 3 hours after oral administration.

Nilotinib is a substrate of

P-gp in vitro.

Median steady-state trough concentration of nilotinib was decreased by 53% in patients with total gastrectomy compared to patients who had not undergone surgeries.

Compared to the fasted state, the systemic exposure (AUC) increased by 82% when the dose was given 30 minutes after a high fat meal (meal of to 1000 calories with fat being 50% of total caloric content; approximately: 150 calories from protein, 250 calories from carbohydrates, and to 600 calories from fat).

Single dose administration of two 200 mg nilotinib capsules each dispersed in 1 teaspoon of applesauce and administered within 15 minutes was shown to be bioequivalent to a single dose administration of two 200 mg intact capsules.

The blood-to-serum ratio of nilotinib is 0.68.

Serum protein binding is approximately 98%.

The mean (CV%) apparent elimination half-life is estimated to be approximately 17 hours (69%) and the mean (CV%) apparent clearance approximates 29 L/h (61%).

Metabolism Nilotinib is primarily metabolized via

CYP3A4-mediated oxidation and to a minor extent by CYP2C8.

Nilotinib is the main circulating component in the serum.

None of the metabolites contribute significantly to the pharmacological activity of nilotinib.

After a single dose of radiolabeled nilotinib, more than 90% of the administered dose was eliminated within 7 days: 93% of the dose in feces.

Parent drug accounted for 69% of the dose.

Age, sex, race/ethnicity, or body weight did not significantly affect the pharmacokinetics of nilotinib.

The effect of renal impairment on nilotinib pharmacokinetics is unknown.

Following administration of the approved recommend pediatric dosage of nilotinib, steady-state exposure of nilotinib were within 2-fold to adult patients treated with 400 mg twice daily.

C min was comparable across all age groups (pediatric patients from ages to less than 18 years), diseases (patients with newly diagnosed and resistant or intolerant Ph+ CML) and studies.

Body surface area correlated with nilotinib clearance and was the primary factor responsible for the PK differences between pediatrics and adults.

Following a single dose of nilotinib 200 mg (0.5 times the maximum approved recommended dosage), the mean AUC of nilotinib increased 1.4-fold, 1.4-fold, and 1.6-fold in subjects with mild (Child-Pugh class A), moderate (Child-Pugh class B) and severe (Child-Pugh class C) hepatic impairment, respectively, compared to subjects with normal hepatic function.

Drug Interaction Studies Clinical Studies Strong

CYP3A Inhibitors: Coadministration of ketoconazole (a strong CYP3A inhibitor) 400 mg once daily for 6 days increased nilotinib AUC by approximately 3-fold.

A single concurrent intake of double-strength grapefruit juice increased the nilotinib AUC by 1.3-fold.

CYP3A Inducers: Coadministration of rifampicin (a strong CYP3A inducer) 600 mg daily for 12 days decreased nilotinib AUC by approximately 80%.

Inhibitors (PPIs): Nilotinib displays pH-dependent aqueous solubility.

Coadministration of multiple doses of esomeprazole (a PPI) at 40 mg daily decreased the nilotinib AUC by 34%.

No significant change in nilotinib pharmacokinetics was observed when a single 400 mg dose of nilotinib was administered 10 hours after and 2 hours before famotidine (an H2 blocker), or administered 2 hours after and 2 hours before an antacid (e.g., aluminum hydroxide, magnesium hydroxide, simethicone).

CYP3A Inhibitors: Following coadministration of nilotinib 400 mg twice daily with imatinib (a moderate CYP3A inhibitor) 400 mg daily or 400 mg twice daily, the AUC increased 30% to 50% for nilotinib and approximately 20% for imatinib.

CYP3A4 Substrates: Multiple doses of nilotinib increased the systemic exposure of oral midazolam (a substrate of CYP3A4) 2.6-fold.

CYP2C9 Substrates: Single-dose of nilotinib did not change the pharmacokinetics and pharmacodynamics of warfarin (a CYP2C9 substrate).

In Vitro Studies Where Drug Interaction Potential was not Further Evaluated Clinically CYP Substrates: Nilotinib is a competitive inhibitor of CYP2C8, CYP2D6, and is an inducer of CYP2B6 and CYP2C8.

Nilotinib is an inhibitor of UGT1A1 and P-gp. 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.

The following clinically significant adverse reactions can occur with nilotinib and are discussed in greater detail in other sections of labeling: Myelosuppression QT Prolongation Sudden Deaths Cardiac and Arterial Vascular Occlusive Events Pancreatitis and Elevated Serum Lipase Hepatotoxicity Electrolyte Abnormalities Hemorrhage Fluid Retention 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.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.

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%) 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 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.

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.

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%) .

Discontinuation due to adverse drug reactions was observed in 16% of CML-CP and 10% of CML-AP patients.

Tables 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 nilotinib 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 nilotinib 300 mg twice daily or imatinib 400 mg once daily groups) 60-Month Analysis a Patients With Newly Diagnosed Ph+ CML-CP Nilotinib 300 mg twice daily imatinib 400 mg once daily Nilotinib 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 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.

Table 8: Most Frequently Reported Non-Hematologic Adverse Reactions in Adult Patients With Resistant or Intolerant Ph+ CML Receiving Nilotinib 400 mg Twice Daily (regardless of relationship to study drug) (greater than or equal to 10% in any group) 24-Month Analysisa Body System and Adverse Reaction CML-CP CML-AP N = 321 N = 137 All Grades (%) CTC Grades b 3/4 (%) All Grades (%) CTC Grades b 3/4 (%) Skin and subcutaneous tissue disorders Rash 36 2 29 0 Pruritus 32 < 1 20 0 Night sweat 12 < 1 27 0 Alopecia 11 0 12 0 Gastrointestinal disorders Nausea 37 1 22 < 1 Constipation 26 < 1 19 0 Diarrhea 28 3 24 2 Vomiting 29 < 1 13 0 Abdominal pain 15 2 16 3 Abdominal pain upper 14 < 1 12 < 1 Dyspepsia 10 < 1 4 0 Nervous system disorders Headache 35 2 20 1 General disorders and administration-site conditions Fatigue 32 3 23 < 1 Pyrexia 22 < 1 28 2 Asthenia 16 0 14 1 Peripheral edema 15 < 1 12 0 Musculoskeletal and connective tissue disorders Myalgia 19 2 16 < 1 Arthralgia 26 2 16 0 Muscle spasms 13 < 1 15 0 Bone pain 14 < 1 15 2 Pain in extremity 20 2 18 1 Back pain 17 2 15 < 1 Musculoskeletal pain 11 < 1 12 1 Respiratory, thoracic, and mediastinal disorders Cough 27 < 1 18 0 Dyspnea 15 2 9 2 Oropharyngeal pain 11 0 7 0.

Infections and infestations Nasopharyngitis 24 < 1 15 0 Upper respiratory tract infection 12 0 10 0 Metabolism and nutrition disorders Decreased appetite c 15 < 1 17 < 1 Psychiatric disorders Insomnia 12 1 7 0 Vascular disorders Hypertension 10 2 11 < 1 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.

Table 9 shows the percentage of adult patients experiencing treatment-emergent Grade 3/4 laboratory abnormalities in patients who received at least one dose of nilotinib.

Table 9: Percent Incidence of Clinically Relevant Grade 3/4 Laboratory Abnormalities Patient population Newly diagnosed adult Ph+ CML-CP Resistant or intolerant adult Ph+ CML-CP CML-AP Nilotinib 300 mg twice daily N = 279 (%) imatinib 400 mg once daily N = 280 (%) Nilotinib 400 mg twice daily N = 321 (%) Nilotinib 400 mg twice daily N = 137 (%) Hematologic parameters Thrombocytopenia 10 9 30 1 42 3 Neutropenia 12 22 31 2 42 4 Anemia 4 6 11 27 Biochemistry parameters Elevated lipase 9 4 18 18 Hyperglycemia 7 < 1 12 6 Hypophosphatemia 8 10 17 15 Elevated bilirubin (total) 4 < 1 7 9 Elevated SGPT (ALT) 4 3 4 4 Hyperkalemia 2 1 6 4 Hyponatremia 1 < 1 7 7 Hypokalemia < 1 2 2 9 Elevated SGOT (AST) 1 1 3 2 Decreased albumin 0 < 1 4 3 Hypocalcemia < 1 < 1 2 5 Elevated alkaline phosphatase 0 < 1 < 1 1 Elevated creatinine 0 < 1 < 1 < 1 Abbreviations: ALT alanine aminotransferase; AST, aspartate aminotransferase; CML-AP, chronic myeloid leukemia-accelerated phase; CML-CP, chronic myeloid leukemia-chronic phase; Ph+, Philadelphia chromosome positive. NCI Common Terminology Criteria for Adverse Events, version 3.0.

Thrombocytopenia: 12% were Grade 3, 18% were Grade 4.

Neutropenia: 16% were Grade 3, 15% were Grade 4.

Thrombocytopenia: 11% were Grade 3, 32% were Grade 4.

Neutropenia: 16% were Grade 3, 26% were Grade 4.

Elevated total cholesterol (all Grades) occurred in 28% (nilotinib 300 mg twice daily) and 4% (imatinib).

Elevated triglycerides (all Grades) occurred in 12% and 8% of patients in the nilotinib and imatinib arms, respectively.

Hyperglycemia (all Grades) occurred in 50% and 31% of patients in the nilotinib and imatinib arms, respectively.

Most common biochemistry laboratory abnormalities (all Grades) were alanine aminotransferase increased (72%), blood bilirubin increased (59%), aspartate aminotransferase increased (47%), lipase increased (28%), blood glucose increased (50%), blood cholesterol increased (28%), and blood triglyceride increased (12%).

Ph+ CML-CP Who Have Achieved a Sustained Molecular Response (MR4.5) In eligible patients who discontinued nilotinib therapy after attaining a sustained molecular response (MR4.5), musculoskeletal symptoms (e.g., myalgia, pain in extremity, arthralgia, bone pain, spinal pain, or musculoskeletal pain), were reported more frequently than before treatment discontinuation in the first year, as noted in Table 10.

The rate of new musculoskeletal symptoms generally decreased in the second year after treatment discontinuation.

In the newly diagnosed population in whom musculoskeletal symptoms occurred at any time duri.

Overdose with nilotinib has been reported, where an unspecified number of nilotinib capsules were ingested in combination with alcohol and other drugs.

Events included neutropenia, vomiting, and drowsiness.

In the event of overdose, observe the patient and provide appropriate supportive treatment.

Nilotinib is contraindicated in patients with hypokalemia, hypomagnesemia, or long QT syndrome.

Newly diagnosed

Ph+ CML-CP: 300 mg orally twice daily.

Resistant or intolerant

Ph+ CML-CP and CML-AP: 400 mg orally twice daily.

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).

See Dosage and

Administration for full dosing instructions and dose-reduction instructions for toxicity.

Reduce starting dose in patients with baseline hepatic impairment.

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. 2.1 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.

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.

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) .

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.

Information on

FDA authorized tests for the detection and quantitation of BCR-ABL transcripts to determine eligibility for treatment discontinuation is available at 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.

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.

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.

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.

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 for dose adjustments for QT interval prolongation.

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 dose if QTcF returns to less than 450 msec and to within 20 msec of baseline. 3.

If QTcF is between 450 msec and 480 msec after 2 weeks, reduce the dose to 400 mg once daily in adults and 230 mg/m 2 once daily in pediatric patients. 4.

Discontinue nilotinib capsules if, following dose-reduction to 400 mg once daily in adults and 230 mg/m 2 once daily in pediatric patients, QTcF returns to greater than 480 msec. 5.

An ECG should be repeated approximately 7 days after any dose adjustment.

ECG, electrocardiogram. 2.5 Dosage Modifications for Myelosuppression Withhold or reduce nilotinib capsules dosage for hematological toxicities (neutropenia, thrombocytopenia) that are not related to underlying leukemia (Table 3) .

Table 3: Dosage Adjustments for Neutropenia and Thrombocytopenia Diagnosis Degree of myelosuppression Dosage adjustment Adult patients with: Newly diagnosed Ph+ CML in chronic phase at 300 mg twice daily Resistant or intolerant Ph+ CML in chronic phase or accelerated phase at 400 mg twice daily ANC less than 1.0 x 10 9 /L and/or platelet counts less than 50 x 10 9 /L Stop nilotinib capsules, and monitor blood counts.

Resume within 2 weeks at prior dose if ANC greater than 1.0 x 10 9 /L and platelets greater than 50 x 10 9 /L. If blood counts remain low for greater than 2 weeks, reduce the dose to 400 mg once daily.

Pediatric patients with

Newly diagnosed Ph+ CML in chronic phase at 230 mg/m 2 twice daily Resistant or intolerant Ph+ CML in chronic phase at 230 mg/m 2 twice daily ANC less than 1.0 x 10 9 /L and/or platelet counts less than 50 x 10 9 /L Stop nilotinib capsules and monitor blood counts.

Resume within 2 weeks at prior dose if ANC greater than 1.5 x 10 9 /L and/or platelets greater than 75 x 10 9 /L. If blood counts remain low for greater than 2 weeks, a dose reduction to 230 mg/m 2 once daily may be required.

If event occurs after dose reduction, consider discontinuing treatment.

ANC, absolute neutrophil count; Ph+ CML, Philadelphia chromosome positive chronic myeloid leukemia. 2.6 Dosage Modifications for Selected Non-Hematologic Laboratory Abnormalities and Other Toxicities See Table for dosage adjustments for elevations of lipase, amylase, bilirubin, and/or hepatic transaminases.

Table 4: Dosage Adjustments for Selected Non-Hematologic Laboratory Abnormalities Degree of non-hematologic laboratory abnormality Dosage adjustment Elevated serum lipase or amylase greater than or equal to Grade 3 Adult patients: 1.

Withhold nilotinib capsules, and monitor serum lipase or amylase. 2.

Resume treatment at 400 mg once daily if serum lipase or amylase returns to less than or equal to Grade 1.

Pediatric patients

Interrupt nilotinib capsules until the event returns to less than or equal to Grade 1.

Resume treatment at 230 mg/m 2 once daily if prior dose was 230 mg/m 2 twice daily; discontinue treatment if prior dose was 230 mg/m 2 once daily.

Elevated bilirubin greater than or equal to Grade in adult patients and greater than or equal to Grade in pediatric patients Adult patients: 1.

Withhold nilotinib capsules, and monitor bilirubin. 2.

Resume treatment at 400 mg once daily if bilirubin returns to less than or equal to Grade 1.

Pediatric patients: 1.

Interrupt nilotinib capsules until the event returns to less than or equal to Grade 1. 2.

Resume treatment at 230 mg/m 2 once daily if prior dose was 230 mg/m 2 twice daily; discontinue treatment if prior dose was 230 mg/m 2 once daily, and recovery to less than or equal to Grade 1 takes longer than 28 days.

Elevated hepatic transaminases greater than or equal to Grade 3 Adult patients: 1.

Withhold nilotinib capsules, and monitor hepatic transaminases. 2.

Resume treatment at 400 mg once daily if hepatic transaminases returns to less than or equal to Grade 1.

Interrupt nilotinib capsules until the event.

Nilotinib 50 mg capsules are light yellow opaque colour body and red opaque colour cap imprinted with “MN5” with black ink.

Nilotinib 150 mg capsules are red opaque colour body and red opaque colour cap imprinted with“MN4” with black ink.

Nilotinib 200 mg capsules are light yellow opaque colour body and light yellow opaque colour cap imprinted with “MN3” with black ink.

Nilotinib 50 mg capsules are supplied in bottles and nilotinib 150 mg and 200 mg capsules are supplied in blister packs. 50 mg Bottle of 120 capsules.NDC 72205-237-92 150 mg Carton of 4 blister packs of (4x28) .NDC 72205-238-64 Blisters of 28 capsules.NDC 72205-238-63 200 mg Carton of 4 blister packs of (4x28) .NDC 72205-239-64 Blisters of 28 capsules.NDC 72205-239-63 Nilotinib capsules should be stored at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C (59°F and 86°F) .

Based on findings from animal studies and the mechanism of action, nilotinib can cause fetal harm when administered to a pregnant woman.

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 and 0.5 times, respectively, the exposures in patients at the recommended dose.

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.

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 nghr/mL and 17100 nghr/mL, respectively, representing approximately 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.

The safety and effectiveness of nilotinib 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.

There are no data for pediatric patients under 2 years of age.

Use of nilotinib 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 to 6 years of age for these indications.

Use of nilotinib in pediatric patients to less than 18 years of age is supported by evidence from two clinical trials.

The 25 patients with newly diagnosed Ph+ CML-CP were in the following age groups: 6 children (age to less than 12 years) and 19 adolescents (age to less than 18 years).

The 44 patients with resistant or intolerant Ph+ CML-CP included 18 children (age to less than 12 years) and 26 adolescents (age to less than 18 years).

All pediatric patients received nilotinib 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.

For pediatric growth and development, growth retardation has been reported in pediatric patients with Ph+ CML-CP treated with nilotinib.

The safety and effectiveness of nilotinib 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.

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.

In the clinical trials of nilotinib (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.

Patients with newly diagnosed

Ph+ CML-CP: There was no difference in major molecular response between patients aged less than 65 years and those greater than or equal to 65 years.

Patients with resistant or intolerant CML-CP

There was no difference in major cytogenetic response rate between patients aged less than 65 years and those greater than or equal to 65 years.

Patients with resistant or intolerant CML-AP

The hematologic response rate was 44% in patients less than 65 years of age and 29% in patients greater than or equal to 65 years.

No major differences for safety were observed in patients greater than or equal to 65 years of age as compared to patients less than 65 years.