Trade Names:Tasigna- Capsules 200 mg
Binds to and stabilizes the inactive conformation of the kinase domain of Abl protein.
C max is reached 3 h after oral administration. Steady state is reached in about 8 days. Bioavailability is increased when given with a meal. Compared with fasting, the AUC is increased 82% when given 30 min after a high-fat meal.
Serum protein binding is approximately 98%.
Main metabolic pathways are oxidation and hydroxylation. The metabolites are inactive.
Elimination half-life is approximately 17 h. Approximately 93% of the administered dose is eliminated in feces within 7 days.
Has not been investigated, but a decrease in total body Cl is not anticipated.Hepatic Function Impairment
Nilotinib exposure is increased. A lower starting dose is recommended in these patients.Age, body weight, race, and gender
Pharmacokinetics are not affected.
Treatment of chronic-phase and accelerated-phase Philadelphia chromosome–positive chronic myelogenous leukemia (CML) in adult patients resistant or intolerant to prior therapy that included imatinib.
Hypokalemia; hypomagnesemia; long QT syndrome.
PO 400 mg twice daily.Dosage Adjustments for Neutropenia and ThrombocytopeniaAdults
POChronic-phase or accelerated-phase CML at 400 mg twice daily
If absolute neutrophil count (ANC) is less than 1 times 10 9 /L and/or platelet count is less than 50 times 10 9 /L, stop nilotinib and monitor blood cell counts. Resume within 2 wk at prior dosage if ANC is more than 1 times 10 9 /L and platelets are more than 50 times 10 9 /L. If blood cell counts remain low for longer than 2 wk, reduce dosage to 400 mg once daily.Dosage Adjustments for QT Interval ProlongationAdults
POECGs with QTc more than 480 msec
Withhold dose and perform an analysis of serum potassium and magnesium. If below lower limit of normal, correct with supplements to within normal limits. Review concomitant medication usage. If QTcF returns to less than 450 msec and to within 20 msec of baseline, resume treatment within 2 wk at prior dosage. If QTcF is between 450 and 480 msec after 2 wk, reduce dosage to 400 mg once daily. If, following dosage reduction to 400 mg once daily, the QTcF returns to more than 480 msec, discontinue nilotinib. An ECG should be repeated approximately 7 days after any dosage adjustment.Dosage Adjustments for Selected Nonhematologic Laboratory AbnormalitiesAdults
POElevated serum lipase or amylase of grade 3 or more
Withhold nilotinib and monitor serum lipase or amylase. Resume treatment at 400 mg once daily if serum lipase or amylase returns to grade 1 or less.Elevated bilirubin of grade 3 or more
Withhold nilotinib and monitor bilirubin. Resume treatment at 400 mg once daily if bilirubin returns to grade 1 or less.Elevated hepatic transaminases of grade 3 or more
Withhold nilotinib and monitor hepatic transaminases. Resume treatment at 400 mg once daily if hepatic transaminases return to grade 1 or less.Dosage Adjustments for Other Nonhematologic ToxicitiesAdults
PO If moderate or severe nonhematologic toxicity occurs, withhold nilotinib and resume treatment at 400 mg once daily when toxicity resolves. Consider escalation of dosage to 400 mg twice daily.Dosage Adjustments With Coadministration of Strong CYP3A4 InducersAdults
PO If a strong CYP3A4 inducer cannot be avoided, the nilotinib dosage may need to be increased, depending on patient tolerability. If the strong inducer is discontinued, reduce the nilotinib dosage to the indicated dosage.Dosage Adjustments With Coadministration of Strong CYP3A4 InhibitorsAdults
PO If a strong CYP3A4 inhibitor cannot be avoided, a dosage reduction to 400 mg once daily is predicted to adjust the AUC to the value observed without administration of an inhibitor. If the strong inhibitor is discontinued, after a washout period, adjust the nilotinib dosage upward to the indicated dosage. Closely monitor for prolongation of the QT interval.
Store at 59° to 86°F.
Concentrations of drugs that are substrates for these enzymes may be reduced; administer with caution.CYP2C8, CYP2C9, CYP2D6, CYP3A4, and UGT1A1 substrates
Concentrations of drugs that are substrates for these enzymes may be elevated; administer with caution. Avoid warfarin because it is a substrate for CYP2C9 and CYP3A4.Food
The bioavailability of nilotinib is increased with food ingestion. Compared with the fasted state, AUC increased 82% when the dose was given 30 min after a high-fat meal. Nilotinib should not be taken with food. No food should be ingested at least 2 h before and at least 1 h after the dose is taken.Grapefruit juice
Because nilotinib concentrations may be elevated, avoid grapefruit juice.Nevirapine
Nilotinib plasma concentrations and pharmacologic effects may be reduced by nevirapine. Avoid coadministration of nilotinib and nevirapine. If concomitant use cannot be avoided, monitor the response of the patient and adjust the nilotinib dose as needed.P-glycoprotein inhibitors (eg, ranolazine)
Nilotinib concentrations may be increased. Use with caution. Monitor the response of the patient and adjust the nilotinib dose as needed.P-glycoprotein substrates
Concentrations of drugs that are a substrate for P-glycoprotein may be increased by nilotinib. Use with caution. Monitor the response of the patient and adjust the dose of these agents as needed.QT interval–prolonging drugs (eg, antiarrhythmic agents [eg, amiodarone, disopyramide, procainamide, quinidine, sotalol], bepridil, chloroquine, clarithromycin, halofantrine, haloperidol, methadone, moxifloxacin, paliperidone, perflutren, pimozide, tetrabenazine, tricyclic antidepressants [eg, doxepin])
Because of the risk of QT interval prolongation, concomitant use of nilotinib with QT interval–prolonging drugs should be avoided. If treatment with of any of these agents is required, interrupt nilotinib treatment. If withholding nilotinib treatment is not possible, closely monitor for QT interval prolongation.St. John's wort
Because nilotinib concentrations may be reduced, avoid St. John's wort.Strong CYP3A4 inducers (eg, carbamazepine, dexamethasone, phenobarbital, phenytoin, rifabutin, rifampin, rifapentine)
Nilotinib concentrations may be reduced, leading to subtherapeutic levels. Avoid coadministration.Strong CYP3A4 inhibitors (eg, atazanavir, clarithromycin, delavirdine, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, trazodone, voriconazole)
Nilotinib concentrations may be elevated, increasing the risk of toxicity.
None well documented.
Flushing, hypertension, palpitations, prolonged QT (1% to 10%); atrial fibrillation, bradycardia, cardiac failure, cardiac murmur, cardiomegaly, coronary artery disease, hemorrhagic shock, hypertensive crisis, MI, pericardial effusion, pericarditis, thrombosis, ventricular dysfunction.
Headache (31%); fatigue (28%); pyrexia (24%); asthenia (14%); dizziness, insomnia, paresthesia, vertigo (1% to 10%); intracranial hemorrhage.
Rash (33%); pruritus (29%); alopecia, dry skin, eczema, erythema, hyperhidrosis, night sweats, urticaria (1% to 10%); erythema nodosum, exfoliative rash.
Nausea (31%); diarrhea (22%); constipation, vomiting (21%); abdominal pain (13%); abdominal discomfort, anorexia, dyspepsia, flatulence (1% to 10%); GI hemorrhage, GI ulcer perforation, hematemesis, retroperitoneal hemorrhage.
Hematuria, renal failure.
Neutropenia, thrombocytopenia (37%); anemia (23%); febrile neutropenia, pancytopenia (1% to 10%); leukocytosis, thrombocytosis.
Hepatitis, hepatomegaly, hepatotoxicity, jaundice.
Elevated lipase (17%); hyperglycemia (11%); elevated bilirubin, hypophosphatemia (10%); hypokalemia (5%); elevated ALT, hyperkalemia, hypocalcemia (4%); elevated alkaline phosphatase, hyponatremia (3%); hypomagnesemia, increased blood amylase, increased blood creatine phosphokinase, increased GGT (1% to 10%); decreased albumin, elevated AST (1%).
Arthralgia (18%); pain in extremities (16%); muscle spasm, myalgia (14%); bone pain (13%); back pain (12%); musculoskeletal chest pain, musculoskeletal pain (1% to 10%).
Cough (17%); dyspnea (11%); dysphonia exertional, dyspnea (1% to 10%); interstitial lung disease, plural effusion, pulmonary edema.
Peripheral edema (11%); sepsis.
QT interval prolongation and sudden deaths have been reported. Do not use nilotinib in patients with hypokalemia, hypomagnesemia, or long QT syndrome. Correct hypokalemia and hypomagnesemia prior to starting therapy. A dose reduction is recommended in patients with hepatic impairment.
Monitor QTc at baseline, 7 days after starting treatment, and periodically thereafter, as well as following dosage adjustments. Periodically monitor for hypokalemia and hypomagnesemia. Perform CBC every 2 wk during the first 2 mo of treatment and then monthly thereafter, or as clinically indicated. Periodically monitor serum calcium, magnesium, sodium, phosphate, and potassium. Check hepatic function tests and serum lipase monthly or as clinically indicated. Closely monitor for QT interval prolongation.
Category D .
Safety and efficacy not established.
Use with caution in patients with relevant cardiac disorders.
Because the capsules contain lactose, nilotinib therapy is not recommended in patients with hereditary problems of galactose intolerance, severe lactase deficiency, or glucose-galactose malabsorption.
Elevations in AST/ALT, bilirubin, and alkaline phosphatase may occur.
Grade 3/4 thrombocytopenia, neutropenia, and anemia can occur.
Hyperkalemia, hypokalemia, hypocalcemia, hyponatremia, and hypophosphatemia may occur.
Elevation may occur; use with caution in patients with a history of pancreatitis.
No cases of overdose have been reported.
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