Class: Tyrosine kinase inhibitor
- Capsules, oral 150 mg
- Capsules, oral 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 approximately 8 days. Bioavailability is increased when given with a meal. Compared with fasting, the AUC is increased by 82% when given 30 min after a high-fat meal.
Serum protein binding is approximately 98%.
The 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.
Special PopulationsRenal Function Impairment
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.Total gastrectomy
Median steady-state trough concentrations are decreased by 53%.
Indications and Usage
Treatment of chronic-phase and accelerated-phase Philadelphia chromosome–positive chronic myelogenous leukemia (CML) in adults resistant or intolerant to prior therapy that included imatinib; for the treatment of adults with newly diagnosed Philadelphia chromosome–positive CML in chronic phase.
Hypokalemia; hypomagnesemia; long QT syndrome.
Dosage and AdministrationAdults
PO 400 mg twice daily for resistant or intolerant CML; 300 mg twice daily for newly diagnosed CML.Dosage Adjustments for Neutropenia and Thrombocytopenia
Adults Resistant or intolerant chronic-phase or accelerated-phase CML at 400 mg twice daily or newly diagnosed CML in chronic phase at 300 mg twice daily
PO If absolute neutrophil count (ANC) is less than 1 × 10 9 /L and/or platelet count is less than 50 × 10 9 /L, stop nilotinib and monitor CBC. Resume within 2 wk at prior dosage if ANC is more than 1 × 10 9 /L and platelets are more than 50 × 10 9 /L. If ANC and/or platelet count remains low for longer than 2 wk, reduce dosage to 400 mg once daily.Dosage Adjustments for QT Interval Prolongation
Adults ECGs with QTc more than 480 msec
PO 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 Abnormalities
Adults Elevated serum lipase, amylase, bilirubin, or hepatic transaminases of grade 3 or more
PO Withhold nilotinib and monitor serum level of affected laboratory parameter. Resume treatment at 400 mg once daily if serum level returns to grade 1 or less.Dosage Adjustments for Other Nonhematologic Toxicities
PO If other 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 (resistant or intolerant CML chronic or accelerated phase) or to 300 mg twice daily (newly diagnosed CML).Dosage Adjustments With Coadministration of Strong CYP3A4 Inhibitors
PO If a strong CYP3A4 inhibitor cannot be avoided, reduce dosage to 300 mg once daily in patients with resistant or intolerant CML or to 200 mg once daily in patients with newly diagnosed CML chronic phase. If the strong inhibitor is discontinued, a washout period should be allowed before the nilotinib dose is adjusted upward to the indicated dose. Closely monitor for prolongation of the QT interval.Hepatic Function Impairment
PO For patients with newly diagnosed CML in chronic phase, 200 mg twice daily initially, followed by dose escalation to 300 mg twice daily based on tolerability. For patients with resistant or intolerant CML, 300 mg twice daily (mild or moderate hepatic impairment) or 200 mg twice daily (severe hepatic impairment) initially, followed by a dose escalation to 400 mg twice daily (mild or moderate hepatic impairment) or a sequential dose escalation to 300 mg twice daily and then 400 mg twice daily (severe hepatic impairment) based on tolerability.
- For oral use only. Capsules should be swallowed whole with water only.
- Do not administer with food. Food should not be consumed for at least 2 h before or at least 1 h after a dose is taken.
- Administer twice daily at approximately 12-h intervals.
- May be given in combination with hematopoietic growth factors, such as erythropoietin or granulocyte colony-stimulating factor, or with hydroxyurea or anagrelide if clinically indicated.
- For patients who are unable to swallow capsules, the contents of each capsule may be dispersed in 1 tsp of applesauce (pureed apple). The mixture should be taken immediately (within 15 min) and should not be stored for future use.
Store between 59° and 86°F.
Drug InteractionsCYP2B6, CYP2C8, and CYP2C9 substrates
Concentrations of drugs that are substrates for these enzymes may be reduced; administer with caution and monitor the clinical response of the patient. Adjust the dose of these agents as needed.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. Advise patients not to take nilotinib with food. Instruct patients not to ingest food at least 2 hours before and at least 1 hour after the dose is taken.Gastric pH–altering agents (eg, antacids [eg, aluminum hydroxide], H 2 blockers [eg, cimetidine], proton pump inhibitors [eg, esomeprazole])
Drugs that increase gastric pH may decrease nilotinib solubility and reduce its bioavailability. Increasing the dose of nilotinib is not likely to compensate for the decrease in exposure. Separation of the nilotinib dose when proton pump inhibitors are administered may not eliminate the interaction. Therefore, use with caution and closely monitor the patient. If an antacid or H 2 blocker is coadministered with nilotinib, separate the administration times by at least several hours.Grapefruit products
Because nilotinib concentrations may be elevated, avoid grapefruit products.Imatinib
Coadministration of nilotinib 400 mg twice daily and imatinib 400 mg daily twice daily increased the nilotinib AUC by 30% to 50% and the imatinib AUC by 20%. Monitor the clinical response of the patient.Nevirapine
Nilotinib plasma concentrations and pharmacologic effects may be reduced by nevirapine. Avoid coadministration.P-glycoprotein inhibitors/substrates (eg, ranolazine)
Nilotinib concentrations may be increased. Concentrations of drugs that are a substrate for P-glycoprotein may be increased by nilotinib. Coadminister with caution. Monitor the response of the patient and adjust the nilotinib dose as needed.QT interval–prolonging drugs (eg, antiarrhythmic agents [eg, amiodarone, disopyramide, dronedarone, procainamide, quinidine, sotalol], bepridil, chloroquine, clarithromycin, dofetilide, halofantrine, haloperidol, iloperidone, lithium, maprotiline, methadone, moxifloxacin, paliperidone, perflutren, pimozide, tacrolimus, tetrabenazine, tricyclic antidepressants [eg, doxepin])
Because of the risk of QT interval prolongation, avoid concomitant use of nilotinib with QT interval–prolonging drugs. 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.Strong CYP3A4 inducers (eg, carbamazepine, dexamethasone, phenobarbital, phenytoin, rifabutin, rifampin, rifapentine, St. John's wort)
Nilotinib concentrations may be reduced, leading to subtherapeutic levels. Avoid coadministration.Strong CYP3A4 inhibitors (eg, atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole)
Nilotinib concentrations may be elevated, increasing the risk of toxicity. Avoid concomitant use. If coadministration of any of these agents is required, interrupt nilotinib treatment. If patients must be coadministered a strong CYP3A4 inhibitor, reduce the dosage of nilotinib to 300 mg once daily in patients with resistant or intolerant Philadelphia chromosome–positive CML or to 200 mg once daily in patients with newly diagnosed Philadelphia chromosome–positive CML in chronic phase. If the strong inhibitor is discontinued, a washout period should occur before the nilotinib dose is adjusted upward. If a strong CYP3A4 inhibitor is coadministered, closely monitor for QT interval prolongation.
Hypertension (11%); angina pectoris, arrhythmia (including atrial fibrillation, AV block, bradycardia, cardiac flutter, extrasystoles), ECG prolonged QT, flushing, palpitations (1% to 10%); cardiac failure, cardiac murmur, coronary artery disease, cyanosis, hematoma, hypertensive crisis, pericardial effusion (up to 1%).
Headache (35%); fatigue (32%); asthenia (16%); insomnia (12%); depression, dizziness, hypoesthesia, paresthesia, vertigo (1% to 10%); anxiety, disturbance in attention, hyperesthesia, intracranial hemorrhage, loss of consciousness (syncope), malaise, migraine, tremor (up to 1%).
Rash (36%); pruritus (32%); night sweats (27%); alopecia (12%); acne, contusion, dermatitis, dry skin, eczema, erythema, folliculitis, hyperhidrosis, skin papilloma, urticaria (1% to 10%); drug eruption, ecchymosis, exfoliative rash, pain of skin, swelling of the face (up to 1%).
Nasopharyngitis (24%); oropharyngeal pain (11%); conjunctivitis, dry eye, eye hemorrhage, eye pruritus, periorbital edema (1% to 10%); eyelid edema (1%); eye irritation, photopsia, vision blurred, vision impairment, visual acuity reduced (up to 1%).
Hyperthyroidism, hypothyroidism (up to 1%).
Nausea (37%); vomiting (29%); diarrhea (28%); constipation (26%); dyspepsia (10%); abdominal pain (16%); abdominal pain upper, anorexia (15%); abdominal discomfort, abdominal distension, flatulence, pancreatitis (1% to 10%); dry mouth, dysgeusia, esophageal pain, gastroenteritis, GERD, GI hemorrhage, melena, mouth ulceration, stomatitis (up to 1%).
Pollakiuria (1% to 10%); breast pain, dysuria, erectile dysfunction, gynecomastia, micturition urgency, nocturia, UTI (up to 1%).
Neutropenia, thrombocytopenia (42%); anemia (27%); febrile neutropenia, lymphopenia, pancytopenia (1% to 10%).
Hepatic function abnormal (1% to 10%); hepatitis, jaundice (up to 1%).
Elevated lipase (18%); elevated bilirubin (9%); hyponatremia (7%); decreased albumin, elevated ALT, (4%); elevated AST (3%); increased blood amylase, increased blood creatine phosphokinase, increased GGT (1% to 10%); elevated alkaline phosphatase (1%); decreased hemoglobin , increased LDH, increased urea (up to 1%); increased WBC (postmarketing).
Hypophosphatemia (17%); hyperglycemia (12%); diabetes mellitus, electrolyte imbalance (including hypercalcemia, hyperkalemia, hyperphosphatemia, hypocalcemia, hypokalemia, hypomagnesemia, hyponatremia), hypercholesterolemia, hyperlipidemia, weight decreased, weight increased (1% to 10%); decreased or increased appetite, dehydration (up to 1%).
Arthralgia (26%); pain in extremities (20%); myalgia (19%); back pain (17%); bone pain, muscle spasm (15%); musculoskeletal pain (12%); flank pain, musculoskeletal chest pain (1% to 10%); joint swelling, muscular weakness, musculoskeletal stiffness (up to 1%).
Cough (27%); dyspnea (15%); upper respiratory tract infection (13%); dysphonia, dyspnea exertional, epistaxis (1% to 10%); interstitial lung disease, pharyngitis, pharyngolaryngeal pain, pleural effusion, pleurisy, pleuritic pain, pneumonia, pulmonary edema, sinusitis, throat irritation (up to 1%).
Pyrexia (28%); peripheral edema (15%); chest discomfort, chest pain, pain (including neck pain and back pain) (1% to 10%); candidiasis, chills, face edema, gravitational edema, herpes virus infection, influenza-like illness (up to 1%); malignant disease progression, tumor lysis syndrome (postmarketing).
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 and monitor serum levels periodically. Avoid drugs known to prolong the QT interval and strong CYP3A4 inhibitors. Patients should avoid food 2 h before and 1 h after taking a dose. A dose reduction is recommended in patients with hepatic impairment. Obtain ECGs at baseline, 7 days after initiation, and periodically thereafter, as well as following any dose adjustments.
Obtain ECGs at baseline, 7 days after starting treatment, and periodically thereafter, as well as following dosage adjustments. Periodically monitor chemistry panels, lipid profiles, and electrolytes (eg, calcium, magnesium, phosphate, potassium, sodium). Perform CBC every 2 wk during the first 2 mo of treatment and then monthly thereafter, or as clinically indicated. Check hepatic function tests and serum lipase monthly or as clinically indicated. Closely monitor for QT interval prolongation.
Category D . May cause fetal harm.
Safety and efficacy not established.
If possible, consider alternative therapies. A lower starting dose is recommended in patients with hepatic impairment.
Use with caution in patients with relevant cardiac disorders.
Elevations in AST/ALT, bilirubin, and alkaline phosphatase may occur.
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.
Grade 3/4 thrombocytopenia, neutropenia, and anemia can occur.
Hyperkalemia, hypocalcemia, hypokalemia, hyponatremia, and hypophosphatemia may occur.
Elevation may occur; use with caution in patients with a history of pancreatitis.
The exposure of nilotinib is reduced in patients with total gastrectomy. Consider more frequent follow-up of these patients. Consider dose increase or alternative therapy in patients with total gastrectomy.
Drowsiness, neutropenia, vomiting.
- Advise patients to read the Medication Guide before starting therapy and with each refill.
- Advise patients to take nilotinib on an empty stomach with water. Instruct patients not to consume food for at least 2 h before or at least 1 h after a dose is taken.
- Advise patients to take medication twice daily at approximately 12-h intervals.
- Advise patient to avoid grapefruit, grapefruit juice, and any supplement containing grapefruit extract.
- Advise patients not to take a makeup dose if a dose is missed, but to resume taking the next prescribed daily dose.
- Advise patients who are unable to swallow the capsules that the content of each capsule may be dispersed in 5 mL of applesauce and that the mixture should be swallowed immediately (within 15 minutes).
- Inform patients that nilotinib and certain other medicines, including nonprescription medications or herbal supplements (such as St. John's wort), can interact with each other.
- Advise patients that the use of nilotinib during pregnancy may cause harm to the fetus and advise them not to take nilotinib during pregnancy unless necessary. Instruct women of childbearing potential to use effective contraceptives if taking nilotinib. Advise sexually active women taking nilotinib to use adequate contraception.
- Advise patients to continue taking nilotinib every day for as long as their health care provider tells them. This is a long-term treatment; advise patients not to change the dose or stop taking nilotinib without first consulting with their health care provider.
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