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Nilotinib

FDA Drug Information • Also known as: Danziten, Nilotinib, Tasigna

Brand Names
Danziten, Nilotinib, Tasigna
Dosage Form
TABLET
Product Type
DRUG FOR FURTHER PROCESSING

⚠ Boxed Warning (Black Box)

WARNING: QT PROLONGATION and SUDDEN DEATHS Nilotinib prolongs the QT interval. Prior to nilotinib administration and periodically, monitor for hypokalemia or hypomagnesemia and correct deficiencies [ see Warnings and Precautions (5.2) ] . Obtain ECGs to monitor the QTc at baseline, seven days after initiation, and periodically thereafter, and following any dose adjustments [ see Warnings and Precautions (5.2 , 5.3 , 5.7 , 5.12) ] . Sudden deaths have been reported in patients receiving nilotinib [ see Warnings and Precautions (5.3) ] . Do not administer nilotinib to patients with hypokalemia, hypomagnesemia, or long QT syndrome [ see Contraindications (4) , Warnings and Precautions (5.2) ] . Avoid use of concomitant drugs known to prolong the QT interval and strong CYP3A4 inhibitors [ see Drug Interactions (7.1 , 7.2) ] . Avoid food 2 hours before and 1 hour after taking the dose [ see Dosage and Administration (2.1) ]. WARNING: QT PROLONGATION and SUDDEN DEATHS See full prescribing information for complete boxed warning. Nilotinib prolongs the QT interval. Prior to nilotinib administration and periodically, monitor for hypokalemia or hypomagnesemia and correct deficiencies. ( 5.2 ) Obtain ECGs to monitor the QTc at baseline, seven days after initiation, and periodically thereafter, and following any dose adjustments. ( 5.2 , 5.3 , 5.7 , 5.12 ) Sudden deaths have been reported in patients receiving nilotinib. ( 5.3 ) Do not administer nilotinib to patients with hypokalemia, hypomagnesemia, or long QT syndrome. ( 4 , 5.2 ) Avoid use of concomitant drugs known to prolong the QT interval and strong CYP3A4 inhibitors. ( 7.1 , 7.2 ) Avoid food 2 hours before and 1 hour after taking the dose. ( 2.1 )

Description

11 DESCRIPTION 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

What Is Nilotinib Used For?

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

Dosage and Administration

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 ) Recommended Pediatric Dose: Newly Diagnosed Ph+ CML-CP or Ph+ CML-CP resistant or intolerant to prior TKI therapy: 230 mg/m 2 orally twice daily, rounded to the nearest 50 mg dose (to a maximum single dose of 400 mg). ( 2.1 ) See Dosage and Administration for full dosing instructions and dose-reduction instructions for toxicity. ( 2.1 ) Reduce starting dose in patients with baseline hepatic impairment. ( 2.7 ) Eligible newly diagnosed adult patients with Ph+ CML-CP who have received nilotinib capsules for a minimum of 3 years and have achieved a sustained molecular response (MR4.5) and patients with Ph+ CML-CP resistant or intolerant to imatinib who have received nilotinib capsules for at least 3 years and have achieved a sustained molecular response (MR4.5) may be considered for treatment discontinuation. ( 2.2 , 2.3 , 5.16 ) 2.1 Recommended Dosage Dose nilotinib capsules twice daily at approximately 12-hour intervals on an empty stomach. No food should be consumed for at least 2 hours before the dose is taken and for at least 1 hour after the dose is taken. Advise patients to swallow the capsules whole with water [ see Boxed Warning , Clinical Pharmacology (12.3) ]. For patients who are unable to swallow capsules, the contents of each capsule may be dispersed in 1 teaspoon of applesauce (puréed apple). The mixture should be taken immediately (within 15 minutes) and should not be stored for future use [ see Clinical Pharmacology (12.3) ]. Nilotinib capsules may be given in combination with hematopoietic growth factors, such as erythropoietin or G-CSF if clinically indicated. Nilotinib capsules may be given with hydroxyurea or anagrelide if clinically indicated. Dosage in Adult Patients with Newly Diagnosed Ph+ CML-CP The recommended dosage of nilotinib capsules are 300 mg orally twice daily. Dosage in Adult Patients with Resistant or Intolerant Ph+ CML-CP and CML-AP The recommended dosage of nilotinib capsules are 400 mg orally twice daily. Dosage in Pediatric Patients with Newly Diagnosed Ph+ CML-CP or Resistant or Intolerant Ph+ CML-CP The recommended dosage of nilotinib capsules for pediatric patients is 230 mg/m2 orally twice daily, rounded to the nearest 50 mg dose (to a maximum single dose of 400 mg) (see Table 1). If needed, attain the desired dose by combining different strengths of nilotinib capsules. Continue treatment as long as clinical benefit is observed or until unacceptable toxicity occurs. Table 1: Pediatric Dosing of Nilotinib capsules (230 mg/m 2 Twice Daily, Maximum Single Dose of 400 mg) Body surface area Single dose Total daily dose Up to 0.32 m 2 50 mg 100 mg 0.33 – 0.54 m 2 100 mg 200 mg 0.55 – 0.76 m 2 150 mg 300 mg 0.77 – 0.97 m 2 200 mg 400 mg 0.98 – 1.19 m 2 250 mg 500 mg 1.20 – 1.41 m 2 300 mg 600 mg 1.42 – 1.63 m 2 350 mg 700 mg...

Side Effects (Adverse Reactions)

6 ADVERSE REACTIONS The following clinically significant adverse reactions can occur with nilotinib 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 Novadoz Pharmaceuticals LLC at 1-855-668-2369 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%) 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...

Drug Interactions

7 DRUG INTERACTIONS Strong CYP3A Inhibitors : Avoid concomitant use with nilotinib, or reduce nilotinib dose if coadministration cannot be avoided. ( 7.1 ) Strong CYP3A Inducers : Avoid concomitant use with nilotinib. ( 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 Strong CYP3A Inhibitors Concomitant use with a strong CYP3A inhibitor increased nilotinib concentrations compared to nilotinib alone [ see Clinical Pharmacology (12.3) ] , which may increase the risk of nilotinib toxicities. Avoid concomitant use of strong CYP3A inhibitors with nilotinib. If patients must be coadministered a strong CYP3A4 inhibitor, reduce nilotinib dose [ see Dosage and Administration (2.8) ] . Strong CYP3A Inducers Concomitant use with a strong CYP3A inducer decreased nilotinib concentrations compared to nilotinib alone [ see Clinical Pharmacology (12.3) ] , which may reduce nilotinib efficacy. Avoid concomitant use of strong CYP3A inducers with nilotinib. Proton Pump Inhibitors Concomitant use with a proton pump inhibitor (PPI) decreased nilotinib concentrations compared to nilotinib alone [ see Clinical Pharmacology (12.3) ] , which may reduce nilotinib efficacy. Avoid concomitant use of PPI with nilotinib. As an alternative to PPIs, use H2 blockers approximately 10 hours before or approximately 2 hours after the dose of nilotinib, or use antacids approximately 2 hours before or approximately 2 hours after the dose of nilotinib. 7.2 Drugs That Prolong the QT Interval Avoid coadministration of nilotinib 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) ].

Contraindications

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

Pregnancy and Breastfeeding

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

Overdosage

10 OVERDOSAGE 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.

How Supplied

16 HOW SUPPLIED/STORAGE AND HANDLING 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) [see USP Controlled Room Temperature].

About This Information

This drug information is sourced from FDA-approved labeling via the openFDA database. It is intended for educational and reference purposes only. This is not medical advice. Always consult your healthcare provider before making decisions about medication. Drug information may be updated by the FDA; check with your pharmacist for the most current information.

What are side effects?

Side effects are unwanted reactions that can occur when taking a medication. They range from mild (headache, nausea) to severe (allergic reactions, organ damage). Not everyone experiences side effects, and severity varies. Report any concerning side effects to your doctor.

What are drug interactions?

Drug interactions occur when a medication is affected by another drug, food, or supplement. Interactions can make medications less effective or cause dangerous side effects. Always tell your doctor about all medications and supplements you take.