TASIGNA® (nilotinib) capsules

TASIGNA® (nilotinib) capsules

TASIGNA® (nilotinib) capsules

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

Nilotinib drug substance, in the form of monohydrochloride monohydrate, is a white to slightly yellowish to slightly greenish yellow powder with the molecular formula and weight, respectively, of C28H22F3N7O•HCl • H2O and 584 g/mol (corresponding molecular formula and weight of nilotinib base, anhydrous are C28H22F3N7O and 529 g/mol, respectively). The solubility of nilotinib in aqueous solutions decreases with increasing pH. Nilotinib is not optically active. The pKa1 was determined to be 2.1; pKa2 was estimated to be 5.4.

The chemical name of nilotinib monohydrochloride monohydrate is 4-methyl-N-[3-(4-methyl-1H-imidazol-1­yl)-5-(trifluoromethyl)phenyl]-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-benzamide, monohydrochloride, monohydrate.

Tasigna (nilotinib) capsules, for oral use, contain 50 mg, 150 mg, or 200 mg nilotinib base, anhydrous (equivalent to 55 mg, 166 mg, and 221 mg nilotinib monohydrochloride monohydrate 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), iron oxide (black), and titanium dioxide.

INDICATIONS AND USAGE

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.

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.

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.

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).

DOSAGE AND ADMINISTRATION

Dose Tasigna 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

Tasigna may be given in combination with hematopoietic growth factors, such as erythropoietin or G-CSF if clinically indicated. Tasigna may be given with hydroxyurea or anagrelide if clinically indicated.

Dosage in Adult Patients with Newly Diagnosed Ph+ CML-CP: The recommended dosage of Tasigna is 300 mg orally twice daily.

Dosage in Adult Patients with Resistant or Intolerant Ph+ CML-CP and CML-AP: The recommended dosage of Tasigna is 400 mg orally twice daily.

Dosage in Pediatric Patients with Newly Diagnosed Ph+ CML-CP or Resistant or Intolerant Ph+ CML-CP and CML-AP:  The recommended dosage of Tasigna 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 Tasigna capsules. Continue treatment as long as clinical benefit is observed or until unacceptable toxicity occurs.

Table 1: Pediatric Dosing of Tasigna (230 mg/m2 twice daily, maximum single dose of 400 mg)

Body Surface AreaSingle DoseTotal Daily Dose
Up to 0.32 m250 mg100 mg
0.33–0.54 m2100 mg200 mg
0.55–0.76 m2150 mg300 mg
0.77–0.97 m2200 mg400 mg
0.98–1.19 m2250 mg500 mg
1.20–1.41 m2300 mg600 mg
1.42–1.63 m2350 mg700 mg
≥ 1.64 m2400 mg800 mg

CONTRAINDICATIONS

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

 WARNINGS AND PRECAUTIONS

  • Myelosuppression: Monitor complete blood count (CBC) during therapy and manage by treatment interruption or dose reduction.
  • Cardiac and Arterial Vascular Occlusive Events: Evaluate cardiovascular status, monitor and manage cardiovascular risk factors during Tasigna therapy.
  • Pancreatitis and Elevated Serum Lipase: Monitor serum lipase; if elevations are accompanied by abdominal symptoms, interrupt doses and consider appropriate diagnostics to exclude pancreatitis.
  • Hepatotoxicity: Monitor hepatic function tests monthly or as clinically indicated.
  • Electrolyte Abnormalities: Tasigna can cause hypophosphatemia, hypokalemia, hyperkalemia, hypocalcemia, and hyponatremia. Correct electrolyte abnormalities prior to initiating Tasigna and monitor periodically during therapy.
  • Tumor Lysis Syndrome: Maintain adequate hydration and correct uric acid levels prior to initiating therapy with Tasigna.
  • Hemorrhage: Hemorrhage from any site may occur. Advise patients to report signs and symptoms of bleeding and medically manage as needed.
  • Fluid Retention: Monitor patients for unexpected rapid weight gain, swelling, and shortness of breath. Manage medically.
  • 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.
  • Embryo-Fetal Toxicity: Advise females of reproductive potential of potential risk to a fetus and to use effective contraception.
  • 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.
  • 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. 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.
  • 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.

DRUG INTERACTIONS

Strong CYP3A Inhibitors: Concomitant use with a strong CYP3A inhibitor increased nilotinib concentrations compared to Tasigna alone, 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.

Strong CYP3A Inducers: Concomitant use with a strong CYP3A inducer decreased nilotinib concentrations compared to Tasigna alone, 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, 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.

Drugs That Prolong the QT Interval: Avoid coadministration of Tasigna with agents that may prolong the QT interval, such as anti-arrhythmic drugs.

USE IN SPECIFIC POPULATIONS

Pregnancy: Based on findings from animal studies and the mechanism of action, Tasigna can cause fetal harm when administered to a pregnant woman. There are no available data in pregnant women to inform the drug-associated risk.

Lactation: 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.

OVERDOSAGE

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

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