CAVHANZA

1 INDICATIONS AND USAGE CAVHANZA 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 CAVHANZA is indicated for the treatment of adult patients 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 CAVHANZA 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

1.1 Adult Patients with Newly Diagnosed Ph+ CML-CP CAVHANZA is indicated for the treatment of adult patients 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 CAVHANZA 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 To avoid medication errors and overdosage or underdosage, note that CAVHANZA may have different strengths and dosages than other nilotinib products and may not be substitutable with other nilotinib products on a milligram per milligram basis. ( 2.1 ) Recommended Adult Dose: Newly diagnosed Ph+ CML-CP: 120 mg orally twice daily. Resistant or intolerant Ph+ CML-CP and CML-AP: 160 mg orally twice daily. ( 2.2 ) See Dosage and Administration for full administration instructions, dosing instructions, and dose-reduction instructions for toxicity. ( 2.4 , 2.5 , 2.6 , 2.7 , 2.8 , 2.9 ) Reduce starting dose in patients with baseline hepatic impairment. ( 2.8 ) Eligible newly diagnosed adult patients with Ph+ CML-CP who have received CAVHANZA 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 CAVHANZA for at least 3 years and have achieved a sustained molecular response (MR4.5) may be considered for treatment discontinuation. ( 2.3 , 2.4 , 5.16 ) 2.1 Important Use and Administration Instructions Nilotinib is available in different formulations, dosage forms, and strengths that are approved with different indications and recommended dosages. CAVHANZA may not be substitutable with other nilotinib products, including other nilotinib tablets, on a milligram per milligram basis; to avoid medication errors, including overdosage or underdosage, when using CAVHANZA ensure that the recommended dosage of CAVHANZA (not the recommended dosage of other nilotinib products) is prescribed [see Dosage and Administration ( 2.2 ) and Warnings and Precautions ( 5.1 )]. When switching between CAVHANZA (nilotinib) orally disintegrating tablets and Tasigna (nilotinib) capsules, use the dosage conversion table [see Dosage and Administration ( 2.2 )]. 2.2 Recommended Dosage and Administration Dosage in Adult Patients with Newly Diagnosed Ph+ CML-CP The recommended dosage of CAVHANZA is 120 mg orally twice daily at approximately 12-hour intervals with or without food [see Clinical Pharmacology ( 12.3 )]. Dosage in Adult Patients with Resistant or Intolerant Ph+ CML-CP and CML-AP The recommended dosage of CAVHANZA is 160 mg orally twice daily at approximately 12-hour intervals with or without food [see Clinical Pharmacology ( 12.3 )]. Additional Administration Instructions Use dry hands when opening the bottle and handling tablets. Place the tablet(s) on top of the tongue and allow to disintegrate, then swallow with saliva. Administration with liquid is not necessary. CAVHANZA may also be chewed prior to swallowing with saliva or swallowed intact with water. CAVHANZA should not be crushed prior to administration. If a dose of CAVHANZA 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. Switching Instructions Use Table 1 when switching between CAVHANZA and Tasigna based on dosage equivalence. Table 1: Recommendations for Switching Between CAVHANZA and Tasigna Approved Indications CAVHANZA dosage Tasigna dosage Newly diagnosed Ph+ CML-CP 120 mg orally twice daily 300 mg orally twice daily Resistant or intolerant Ph+ CML-CP and CML-AP 160 mg orally twice daily 400 mg orally twice daily Optional Concomitant Therapy CAVHANZA may be given in combination with hematopoietic growth factors, such as erythropoietin or G-CSF if clinically indicated. CAVHANZA 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, the drug product is not labeled with that pediatric information. 2.3 Discontinuation of Treatment After a Sustained Molecular Response (MR4.5) on CAVHANZA Patient Selection Eligibility for Discontinuation of Treatment Ph+ CML-CP …

3 DOSAGE FORMS AND STRENGTHS Orally disintegrating tablets: 60 mg strength: white to tan, round, debossed on one side with “15” over “5” 80 mg strength: white to tan, round, debossed on one side with “15” over “7” Orally disintegrating tablets: 60 mg and 80 mg ( 3 )

4 CONTRAINDICATIONS CAVHANZA is contraindicated in patients with hypokalemia, hypomagnesemia, or long QT syndrome [see Boxed Warning and Warnings and Precautions ( 5.3 )] . CAVHANZA is contraindicated in patients with hypokalemia, hypomagnesemia, or long QT syndrome. ( 4 )

6 ADVERSE REACTIONS The following clinically significant adverse reactions can occur with CAVHANZA and are discussed in greater detail in other sections of labeling: Myelosuppression [see Warnings and Precautions ( 5.2 )] QT Prolongation [see Boxed Warning , Warnings and Precautions ( 5.3 )] Sudden Deaths [see Boxed Warning , Warnings and Precautions ( 5.4 )] Cardiac and Arterial Vascular Occlusive Events [see Warnings and Precautions ( 5.5 )] Pancreatitis and Elevated Serum Lipase [see Warnings and Precautions ( 5.6 )] Hepatotoxicity [see Warnings and Precautions ( 5.7 )] Electrolyte Abnormalities [see Boxed Warning , Warnings and Precautions ( 5.8 )] Hemorrhage [see Warnings and Precautions ( 5.10 )] Fluid Retention [see Warnings and Precautions ( 5.13 )] The most commonly reported non-hematologic adverse reactions (≥ 20%) in 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 Cycle Pharmaceuticals Ltd at 1-800-841-0898 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. The safety of CAVHANZA (nilotinib) orally disintegrating tablets has been established from adequate and well-controlled studies of Tasigna ® (nilotinib) capsules, which has different recommended dosages than CAVHANZA, in adult patients with newly diagnosed Philadelphia chromosome positive chronic myeloid leukemia (Ph+ CML) in chronic phase (CP) and adult patients with CP and accelerated phase (AP) Ph+ CML resistant to or intolerant to prior therapy that included imatinib [see Clinical Studies ( 14 )] . Below is a display of the adverse reactions of Tasigna ® (nilotinib) capsules in these adequate and well-controlled studies. 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 equivalent recommended dosage of 120 mg of CAVHANZA twice daily (n = 279). The median time on treatment at the equivalent recommended dosage of 120 mg of CAVHANZA twice daily group was 61 months (range, 0.1 to 71 months). 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%) at the equivalent recommended dosage of 120 mg of CAVHANZA 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 10 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 equivalent recommended dosage of 160 mg of CAVHANZA twice daily. The median duration of exposure in days for CML-CP and CML-AP patients is 561 (range, 1 to 1096) and …

7 DRUG INTERACTIONS Strong CYP3A Inhibitors: Avoid concomitant use with CAVHANZA or reduce CAVHANZA dose if concomitant use cannot be avoided. ( 7.1 ) Strong CYP3A Inducers: Avoid concomitant use with CAVHANZA. ( 7.1 ) 7.1 Effect of Other Drugs on CAVHANZA Strong CYP3A Inhibitors Avoid concomitant use of strong CYP3A inhibitors with CAVHANZA. If concomitant use cannot be avoided, reduce CAVHANZA dose [see Dosage and Administration ( 2.9 )] . 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 CAVHANZA adverse reactions. Strong CYP3A Inducers Avoid concomitant use of strong CYP3A inducers with CAVHANZA. 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 CAVHANZA efficacy. 7.2 Drugs That Prolong the QT Interval Avoid coadministration of CAVHANZA with agents that may prolong the QT interval, such as anti-arrhythmic drugs [see Boxed Warning , Dosage and Administration ( 2.5 ), Warnings and Precautions ( 5.3 ), 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 USE IN SPECIFIC POPULATIONS Lactation : Advise women not to breastfeed. ( 8.2 ) 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. 8.1 Pregnancy Risk Summary Based on findings from animal studies and the mechanism of action, CAVHANZA 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%-4% and 15%-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 (equivalent to 160 mg twice daily of CAVHANZA). 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 [equivalent to 160 mg of CAVHANZA] 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 eff …

12.1 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).

11 DESCRIPTION CAVHANZA orally disintegrating tablets contain nilotinib, a kinase inhibitor. The chemical name of nilotinib is 4-methyl-N-[3-(4-methyl-1H-imidazol-1- yl)-5-(trifluoromethyl)phenyl]-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-benzamide. The molecular formula is C28H22F3N7O and molecular weight is 529.5 g/mol. The solubility of nilotinib in aqueous solutions decreases with increasing pH. The pKa1 was determined to be 2.6; pKa2 was determined to be 4.2. Nilotinib has the following structure: CAVHANZA (nilotinib) orally disintegrating tablets, contain 60 mg or 80 mg nilotinib with the following inactive ingredients: butylated hydroxytoluene, colloidal silicon dioxide, crospovidone, hypromellose acetate succinate, magnesium stearate, mannitol, microcrystalline cellulose, and starch. structure

10 OVERDOSAGE Overdose with nilotinib has been reported, where an unspecified number of nilotinib 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.

16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied CAVHANZA (nilotinib) orally disintegrating tablets are available in bottles containing desiccant with a child-resistant closure as described in Table 16. Table 16: CAVHANZA Trade Presentations NDC Number Strength Description Tablets per Bottle 70709-191-12 60 mg white to tan tablets debossed on one side with “15” over “5” 112 70709-192-12 80 mg white to tan tablets debossed on one side with “15” over “7” 112 Storage and Handling CAVHANZA (nilotinib) orally disintegrating tablets 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) [see USP Controlled Room Temperature]. Store and dispense to patient in original container only. Replace cap securely each time after opening. Do not discard desiccants.