Nilotinib (Systemic)
Brand names: Tasigna
Drug class:
Antineoplastic Agents
Usage of Nilotinib (Systemic)
Chronic Myelogenous Leukemia (CML)
Treatment of newly diagnosed Philadelphia chromosome-positive (Ph+) CML in adults and pediatric patients ≥1 year of age who are in chronic phase of the disease.
Treatment of Ph+ CML in adults who are in chronic or accelerated phase of the disease, after failure (secondary to resistance or intolerance) of prior therapy that included imatinib. Efficacy based on hematologic and cytogenetic response rates.
Treatment of Ph+ CML in pediatric patients ≥1 year of age who are in the chronic or accelerated phase of disease, after failure (secondary to resistance or intolerance) of prior tyrosine-kinase inhibitor therapy.
Designated an orphan drug by FDA for use in the treatment of CML.
Other Uses
Nilotinib has been used in combination with chemotherapy† [off-label] for first-line treatment of Ph+ acute lymphocytic leukemia (ALL)† [off-label] .
Nilotinib has been used in adults with ALL following failure of prior therapy† [off-label].
Nilotinib has been used for the treatment of malignant GI stromal tumors (GISTs)† [off-label].
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How to use Nilotinib (Systemic)
General
Pretreatment Screening
Patient Monitoring
Dispensing and Administration Precautions
Other General Considerations
Administration
Oral Administration
Administer orally twice daily (approximately 12 hours apart in the morning and evening).
Administer on an empty stomach, at least 1 hour before or 2 hours after any food.
Swallow capsules whole with water. Alternatively, patients who are unable to swallow capsules may open nilotinib capsules, disperse the contents of each capsule in one teaspoonful of applesauce, and swallow the mixture immediately (within 15 minutes). Do not store mixture for later use. Do not use foods other than applesauce. Do not mix contents of each capsule with more than one teaspoonful of applesauce.
May be administered in conjunction with hematopoietic growth factors (e.g., erythropoietin, filgrastim, sargramostim), if clinically indicated. If clinically indicated, may administer concomitantly with hydroxyurea or anagrelide.
Dosage
Pediatric Patients
CML Newly Diagnosed Chronic Phase CML Oral≥1 year of age: 230 mg/m2 (maximum dose of 400 mg) twice daily. Round dosage to nearest 50 mg dose (see Table 1). Continue therapy for the duration of clinical benefit or until unacceptable toxicity occurs.
Table 1. Nilotinib Dosing in Pediatric Patients with Chronic Phase CML1Body Surface Area
Nilotinib Dosage
≤0.32 m2
50 mg twice daily
0.33–0.54 m2
100 mg twice daily
0.55–0.76 m2
150 mg twice daily
0.77–0.97 m2
200 mg twice daily
0.98–1.19 m2
250 mg twice daily
1.2–1.41 m2
300 mg twice daily
1.42–1.63 m2
350 mg twice daily
≥1.64 m2
400 mg twice daily
Discontinuance of therapy may be considered in patients who meet the following criteria :
Measure molecular response during and following discontinuation of therapy with the same FDA-authorized test.
Patients with newly diagnosed chronic phase CML who lose major molecular response must reinitiate treatment within 4 weeks at the dosage used prior to discontinuation of therapy; monitor Bcr-Abl transcript levels monthly until major molecular response is re-established and then every 12 weeks thereafter.
Chronic or Accelerated Phase CML Following Failure of Prior Therapy Oral≥1 year of age: 230 mg/m2 (maximum dose of 400 mg) twice daily. Round dosage to nearest 50 mg dose (see Table 1). Continue therapy for the duration of clinical benefit or until unacceptable toxicity occurs.
Discontinuance of therapy may be considered in patients who meet the following criteria :
Measure molecular response during and following discontinuation of therapy with the same FDA-authorized test.
Patients with CML following failure or intolerance of prior therapy who have a confirmed loss of MR4.0 (2 consecutive measures at least 4 weeks apart) or loss of major molecular response must reinitiate treatment within 4 weeks at the dosage used prior to discontinuation of therapy; monitor Bcr-Abl transcript levels monthly until major molecular response is re-established and then every 12 weeks thereafter.
Pediatric Patients: Dosage Modification for Toxicity Prolongation of QT Interval OralIf QTc is >480 msec, withhold nilotinib. Resume treatment within 2 weeks at prior dosage if QTcF (QT interval corrected using Fridericia’s formula) returns to <450 msec and to within 20 msec of baseline. If QTcF is 450–480 msec after withholding nilotinib for 2 weeks, resume therapy at a reduced dosage of 230 mg/m2 once daily. If QTcF >480 msec following this dosage reduction, discontinue nilotinib.
Adverse Hematologic Effects OralAdjust dosage if neutropenia and/or thrombocytopenia (unrelated to leukemia) occurs.
If ANC <1500/mm3 and platelet counts <50,000/mm3, withhold nilotinib. Resume treatment within 2 weeks at prior dosage if ANC >1500/mm3 and platelet counts >75,000/mm3. If blood counts remain low for >2 weeks, reduce dosage to 230 mg/m2 once daily.
If toxicity recurs on a reduced dosage, discontinue nilotinib therapy.
Other Nonhematologic Adverse Effects OralWithhold therapy in patients with grade 3 or greater lipase, amylase, or hepatic aminotransferase concentrations or grade 2 or greater bilirubin concentrations . If toxicity decreases to grade 1 or less, resume treatment at a reduced dosage of 230 mg/m2 once daily. If elevations in bilirubin and/or hepatic aminotransferases do not recover to grade 1 or less within 28 days, discontinue nilotinib therapy. If elevated lipase or amylase of grade 3 or higher or elevated bilirubin and/or hepatic aminotransferase concentrations recur on a reduced dosage of 230 mg/m2 once daily, discontinue nilotinib therapy.
Withhold therapy if other moderate or severe nonhematologic toxicities (grade 2 or higher) occur; once toxicity resolves, resume therapy, as appropriate, at a reduced dosage of 230 mg/m2 once daily. If toxicity recurs on a reduced dosage, discontinue nilotinib therapy. If clinically appropriate, consider escalation of dosage back to 230 mg/m2 twice daily.
Adults
CML Newly Diagnosed Chronic Phase CML Oral300 mg twice daily. Manufacturer recommends 200 mg once daily if concomitant use of a potent CYP3A4 inhibitor is required.
In a phase 3 clinical trial, median duration of treatment was 82.8 months.
Discontinuance of therapy may be considered in patients who meet the following criteria :
Measure molecular response during and following discontinuation of therapy with the same FDA-authorized test.
Patients with newly diagnosed chronic phase CML who lose major molecular response must reinitiate treatment within 4 weeks at the dosage used prior to discontinuation of therapy; monitor Bcr-Abl transcript levels monthly until major molecular response is re-established and then every 12 weeks thereafter.
Chronic or Accelerated Phase CML Following Failure of Prior Therapy That Included Imatinib Oral400 mg twice daily. Manufacturer recommends 300 mg once daily if concomitant use of a potent CYP3A4 inhibitor is required .
In a phase 2 clinical trial, median duration of treatment was 87.5 months.
Discontinuance of therapy may be considered in patients who meet the following criteria :
Measure molecular response during and following discontinuation of therapy with the same FDA-authorized test.
Patients with CML following failure or intolerance of prior therapy who have a confirmed loss of MR4.0 (2 consecutive measures at least 4 weeks apart) or loss of major molecular response must reinitiate treatment within 4 weeks at the dosage used prior to discontinuation of therapy; monitor Bcr-Abl transcript levels monthly until major molecular response is re-established and then every 12 weeks thereafter.
Adults: Dosage Modification for Toxicity Prolongation of QT Interval OralIf QTc is >480 msec, withhold nilotinib. Resume treatment within 2 weeks at prior dosage if QTcF (QT interval corrected using Fridericia’s formula) returns to <450 msec and to within 20 msec of baseline. If QTcF is 450–480 msec after withholding nilotinib for 2 weeks, resume therapy at a reduced dosage of 400 mg once daily. If QTcF >480 msec following this dosage reduction, discontinue nilotinib.
Adverse Hematologic Effects OralAdjust dosage if neutropenia and/or thrombocytopenia (unrelated to leukemia) occurs.
If ANC <1000/mm3 and/or platelets <50,000/mm3, withhold nilotinib. Resume treatment within 2 weeks at prior dosage if ANC >1000/mm3 and platelets >50,000/mm3. If blood counts remain low for >2 weeks, reduce dosage to 400 mg once daily.
Other Nonhematologic Adverse Effects OralWithhold therapy in patients with elevated lipase, amylase, bilirubin, and/or hepatic aminotransferase concentrations of grade 3 or higher. If toxicity decreases to grade 1 or less, resume treatment at a reduced dosage of 400 mg once daily (in adults receiving nilotinib either as first-line therapy for CML or following failure of prior therapy).
Withhold therapy if other moderate or severe nonhematologic toxicities occur; once toxicity resolves, resume therapy, as appropriate, at a reduced dosage of 400 mg once daily. If toxicity recurs on a reduced dosage, discontinue nilotinib therapy. If clinically appropriate, consider escalation of dosage back to 300 mg twice daily (in adults receiving nilotinib as first-line therapy for CML) or 400 mg twice daily (in those receiving nilotinib following failure of prior therapy).
Prescribing Limits
Pediatric Patients
Newly Diagnosed Chronic Phase CML Oral≥1 year of age: Maximum 400 mg per dose.
Chronic Phase CML Following Failure of Prior Therapy Oral≥1 year of age: Maximum 400 mg per dose.
Special Populations
Hepatic Impairment
If possible, consider alternative therapy. If use of nilotinib is required, consider reducing initial dosage.
Newly diagnosed chronic phase CML: In adults with mild, moderate, or severe hepatic impairment (Child-Pugh class A, B, or C), reduce initial dosage to 200 mg twice daily, followed by dosage escalation to 300 mg twice daily as tolerated.
Chronic or accelerated phase CML following failure of prior therapy: In adults with mild or moderate hepatic impairment (Child-Pugh class A or B), reduce initial dosage to 300 mg twice daily, followed by dosage escalation to 400 mg twice daily as tolerated. In adults with severe hepatic impairment (Child-Pugh class C), reduce initial dosage to 200 mg twice daily, followed by dosage escalation, as tolerated, to 300 mg twice daily and then to 400 mg twice daily.
Renal Impairment
Manufacturer makes no specific dosage recommendations.
Geriatric Patients
Manufacturer makes no specific dosage recommendations.
Total Gastrectomy
Nilotinib exposure is reduced in patients who have undergone total gastrectomy. Consider more frequent follow-up of these patients. If necessary, consider increasing nilotinib dosage or instituting alternative therapy.
Warnings
Contraindications
Warnings/Precautions
Warnings
Prolongation of QT IntervalPlasma concentration-dependent QT interval prolongation has occurred; may be associated with torsades de pointes, leading to syncope, seizure, and/or sudden death.
ECG monitoring is recommended at baseline, 7 days after initiation of drug, approximately 7 days after any dosage adjustments, and periodically during therapy to monitor for QT interval effects.
Contraindicated in patients with hypokalemia, hypomagnesemia, or long QT syndrome.
Concomitant use of potent CYP3A4 inhibitors or antiarrhythmics or other drugs that prolong QT interval may result in substantial prolongation of QT interval; avoid concomitant use of these agents.
Administration with food may result in substantial prolongation of QT interval; do not administer with food.
MortalitySudden deaths reported in patients receiving nilotinib. Possibility that ventricular repolarization abnormalities may have contributed to their occurrence.
Other Warnings and Precautions
Hematologic EffectsGrade 3 or 4 myelosuppression (neutropenia, anemia, and thrombocytopenia) reported; usually reversible by withholding or reducing the dosage.
Perform CBCs every 2 weeks during the first 2 months of therapy and monthly (or as clinically indicated) thereafter.
Cardiovascular EffectsCardiovascular effects (i.e., arterial vascular occlusive events, ischemic heart disease-related cardiac events, peripheral arterial occlusive disease, ischemic cerebrovascular events) reported.
Assess cardiovascular status and risk factors for cardiovascular events prior to starting therapy and periodically during therapy.
Pancreatitis and Elevated Serum LipaseGrade 3 or 4 elevations in serum lipase reported. Caution in patients with a previous history of pancreatitis. Monitor serum lipase monthly or as clinically indicated; interruption of therapy and/or dosage reduction may be required.
If lipase elevations are accompanied by abdominal symptoms, interrupt therapy and consider diagnostic testing to exclude pancreatitis.
Hepatic EffectsGrade 3 or 4 elevations of serum bilirubin, AST, ALT, and/or alkaline phosphatase reported. Monitor hepatic function tests monthly or as clinically indicated and following dosage adjustments; interruption of therapy and/or dosage reduction may be required.
Pharmacogenetic analysis evaluating potential association between genetic polymorphisms of uridine diphosphate-glucuronosyltransferase (UGT) 1A1 and nilotinib-associated hyperbilirubinemia found increased risk of hyperbilirubinemia with the (TA)7/(TA)7 genotype relative to the (TA)6/(TA)6 and (TA)6/(TA)7 genotypes; largest increases in bilirubin observed in patients with the (TA)7/(TA)7 genotype (UGT1A1*28).
Electrolyte AbnormalitiesGrade 3 or 4 electrolyte abnormalities (hypophosphatemia, hypokalemia, hyperkalemia, hypocalcemia, and hyponatremia) reported.
Correct electrolyte abnormalities prior to administration of nilotinib; monitor electrolytes periodically during therapy.
Tumor Lysis SyndromeMay increase risk of tumor lysis syndrome, primarily in patients with advanced disease who are resistant to or intolerant of imatinib therapy.
Correct uric acid levels prior to starting therapy and monitor electrolytes periodically thereafter. Maintain adequate hydration during therapy.
HemorrhageSevere hemorrhage, sometimes fatal, reported.
Monitor for manifestations of hemorrhage. If hemorrhagic event occurs, provide appropriate treatment.
Lactose IntoleranceContains lactose monohydrate; not recommended in patients with rare hereditary problems of galactose intolerance, severe lactase deficiency with severe intolerance to lactose-containing products, or glucose-galactose malabsorption.
Fluid Retention or EdemaFluid retention reported. Effusions (including pleural effusion, pericardial effusion, ascites) or pulmonary edema reported.
Monitor for signs and symptoms of fluid retention (e.g., unexpected rapid weight gain, swelling) and respiratory or cardiac compromise (e.g. shortness of breath) during therapy.
Effects on Growth and Development of Pediatric PatientsNilotinib has been associated with adverse reactions related to bone growth and development. Growth retardation reported in 3 patients.
Monitor growth and development during therapy in pediatric patients.
Fetal/Neonatal Morbidity and MortalityMay cause fetal harm; maternal and embryofetal toxicity demonstrated in animals.
Avoid pregnancy during therapy. Verify pregnancy status in females of reproductive potential prior to starting nilotinib therapy and advise such patients to use effective contraception during therapy with nilotinib and for ≥14 days after the last dose. If used during pregnancy or if patient becomes pregnant, apprise of potential fetal hazard.
Specific Populations
PregnancyMay cause fetal harm.
If used during pregnancy or if patient becomes pregnant, apprise of potential fetal hazard.
LactationDistributed into milk in rats; not known whether nilotinib is distributed into human milk. Discontinue breast-feeding during therapy and for ≥14 days after the last dose.
Pediatric UseSafety and efficacy of nilotinib have been evaluated in pediatric patients ≥1 year of age with Ph+ CML in the chronic phase that is newly diagnosed or failed prior therapy. No data in pediatric patients <2 years of age.
The frequency, type, and severity of adverse effects in pediatric population are generally consistent with those observed in adults; however, grade 3 or 4 hyperbilirubinemia and elevations in serum aminotransferase concentrations occurred more frequently in pediatric patients than in adults. Adverse effects on growth and development in pediatric patients with Ph+ chronic phase CML receiving nilotinib has been reported. Monitor growth and development in pediatric patients.
Geriatric UseIn newly diagnosed chronic-phase CML patients, no difference in major molecular response rates between patients ≥65 years of age and younger adults.
In chronic-phase CML patients receiving nilotinib after failure of prior therapy that included imatinib, no difference in major cytogenetic response rates between patients ≥65 years of age and younger adults.
In accelerated-phase CML patients receiving nilotinib after failure of prior therapy that included imatinib, hematologic response rate was 29% in patients ≥65 years of age compared with 44% in patients <65 years of age.
No major differences in safety relative to younger adults.
Hepatic ImpairmentIncreased nilotinib exposure in patients with hepatic impairment. If possible, consider alternative therapy. If nilotinib therapy is required, reduce initial dosage and closely monitor QT interval.
Renal ImpairmentNot studied in patients with renal impairment; however, renal impairment not expected to decrease nilotinib clearance.
PharmacogenomicsNilotinib can increase serum bilirubin concentrations. A statistically significant increase in the risk of hyperbilirubinemia in patients with uridine diphosphate-glucuronosyltransferase (UGT) 1A1 (TA)7/(TA)7 genotype relative to the (TA)6/(TA)6 and (TA)6/(TA)7 genotypes. The largest increases in bilirubin were observed in patients with the (TA)7/(TA)7 genotype (UGT1A1*28).
Common Adverse Effects
Adverse nonhematologic effects reported in 20% or more of adult and pediatric patients receiving nilotinib include nausea, rash, headache, fatigue, pruritus, vomiting, diarrhea, cough, constipation, arthralgia, nasopharyngitis, pyrexia, and night sweats.
Adverse hematologic effects include thrombocytopenia, neutropenia, and anemia.
In patients who discontinued nilotinib after attaining a sustained molecular response, musculoskeletal symptoms were reported more frequently the first year of the treatment-free phase (34% in newly diagnosed CML and 48% in previously treated CML) compared to during nilotinib therapy, but decreased in the second year (9% in newly diagnosed CML and 15% in previously treated CML).
Among patients who entered the nilotinib treatment reinitiation phase, musculoskeletal symptoms decreased in those with newly diagnosed or previously treated CML (12.5 or 25%, respectively).
What other drugs will affect Nilotinib (Systemic)
Metabolized principally by CYP3A4.
Inhibits CYP2C8, CYP2D6, and UGT1A1; induces CYP2B6, and CYP2C8. Potential pharmacokinetic interactions with drugs metabolized by these isoenzymes.
Substrate and inhibitor of efflux transporter P-gp (ABCB1).
Drugs and Foods Affecting Hepatic Microsomal Enzymes
Potent CYP3A4 inhibitors: Potential pharmacokinetic interaction (increased serum nilotinib concentrations). Avoid concomitant use; interrupt nilotinib therapy if use of a potent CYP3A4 inhibitor is required. If interruption is not possible, consider reduced nilotinib dosage (200 mg once daily as first-line therapy for CML in adults or 300 mg once daily in adults with previously treated CML) and closely monitor for QT interval prolongation. Recommended dosage adjustment based on pharmacokinetic studies, not on clinical experience. If the CYP3A4 inhibitor is discontinued, increase nilotinib dosage to usual indicated dosage after a suitable washout period.
Potent CYP3A4 inducers: Potential pharmacokinetic interaction (decreased plasma nilotinib concentrations). Avoid concomitant use.
Drugs Metabolized by Hepatic Microsomal Enzymes
Substrates of CYP3A4, CYP2C8, CYP2D6: Potential pharmacokinetic interaction (increased plasma substrate concentrations).
Substrates of CYP2B6 and CYP2C8: Potential pharmacokinetic interaction (decreased plasma substrate concentrations).
Drugs Metabolized by Uridine Diphosphate-glucuronosyltransferase (UGT)
Substrates of UGT1A1: Potential pharmacokinetic interaction (increased concentrations of drugs metabolized by this enzyme).
Substrates or Inhibitors of P-Glycoprotein Transport Systems (P-gp)
Substrates of P-gp: Potential pharmacokinetic interaction (increased plasma substrate concentrations).
P-gp inhibitors: Potential pharmacokinetic interaction (increased plasma nilotinib concentrations).
Drugs that Prolong QT Interval
Potential pharmacologic interactions (additive effect on QT interval prolongation). Avoid concomitant use of nilotinib with drugs known to prolong the QT interval. If use of such drugs is required, interrupt nilotinib therapy. If interruption is not possible, closely monitor patients for QT interval prolongation.
Specific Drugs and Foods
Drug or Food
Interaction
Comments
Antacids
Possible decreased nilotinib bioavailability secondary to decreased solubility at higher pH
Administer nilotinib 2 hours before or 2 hours after an antacid
Antifungals, azoles (ketoconazole)
Possible increased plasma nilotinib concentrations
Ketoconazole: Increased nilotinib AUC approximately threefold
Avoid concomitant use; interrupt nilotinib therapy if use of antifungal with potent CYP3A4 inhibitory activity is required
If interruption is not possible in adults, consider reduced nilotinib dosage (200 mg once daily as first-line therapy for CML or 300 mg once daily following failure of prior CML therapy that included imatinib) and closely monitor for QT interval prolongation
If antifungal is discontinued, increase nilotinib dosage to usual indicated dosage after a suitable washout period
Antimycobacterials (rifampin)
Possible decreased plasma nilotinib concentrations
Rifampin: Decreased nilotinib AUC approximately 80%
Avoid concomitant use
Grapefruit
Possible increased plasma nilotinib concentrations
Double-strength grapefruit increased nilotinib AUC by 1.3-fold
Avoid grapefruit products
Histamine H2-receptor antagonists
Possible decreased nilotinib bioavailability secondary to decreased solubility at higher pH
Administer nilotinib 2 hours before or 10 hours after a histamine H2-receptor antagonist
Imatinib
Increase in nilotinib and imatinib exposure
Increased nilotinib AUC by 30–50%
Increased imatinib AUC by 20%
Midazolam
Increased midazolam AUC by 2.6-fold
Proton-pump inhibitors
Decreased nilotinib bioavailability and exposure secondary to decreased solubility at higher pH
Esomeprazole: Decreased nilotinib AUC by 34%
Avoid concomitant use; select alternative drug such as histamine H2-receptor antagonists or antacids
St. John’s wort (Hypericum perforatum)
Possible decreased nilotinib concentrations
Avoid concomitant use
Warfarin
In healthy individuals, single nilotinib dose did not alter warfarin pharmacokinetics or pharmacodynamics
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