Introduction

Antineoplastic agent; inhibitor of Bcr-Abl tyrosine kinase.

Uses for 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]}.

Nilotinib (Systemic) Dosage and Administration

General

Pretreatment Screening

• Complete blood cell count (CBC).

• Assess serum electrolytes; correct hypokalemia and hypomagnesemia prior to administration of nilotinib.

• Correct uric acid levels prior to initiation of therapy.

• Assess cardiovascular status and risk factors for cardiovascular events.

• Electrocardiogram (ECG) at baseline and repeated 7 days following initiation of nilotinib.

• Verify pregnancy status in females of reproductive potential.

Patient Monitoring

• Monitor CBC every 2 weeks during the first 2 months of therapy and then monthly thereafter or as clinically indicated.

• Perform ECG periodically during therapy and approximately 7 days after any dosage adjustments.

• Monitor serum electrolytes periodically during therapy.

• Assess cardiovascular status and risk factors for cardiovascular events periodically during therapy.

• Monitor for manifestations of bleeding.

• Monitor serum lipase monthly or as clinically indicated.

• Monitor liver function tests monthly or as clinically indicated.

• Monitor for signs or symptoms of fluid retention and respiratory or cardiac compromise during therapy.

• Monitor growth and development in pediatric patients.

Monitoring Following Discontinuance of Therapy

• Monitor Bcr-Abl transcript levels and CBC with differential every month for 1 year, every 6 weeks for the second year, and then every 12 weeks thereafter.

• If loss of molecular response (MR4.0; defined as Bcr-Abl of 0.01% or less) occurs during the treatment-free phase, monitor Bcr-Abl transcript levels every 2 weeks until Bcr-Abl levels remain lower than major molecular response (MR3.0; defined as Bcr-Abl 0.1% or less) for 4 consecutive measurements, then resume regular monitoring schedule.

• Consistently use the same FDA-authorized test to monitor Bcr-Abl transcript levels during therapy and following discontinuation.

Monitoring Following Reinitiation of Therapy

• In patients with newly diagnosed chronic phase CML who reinitiate nilotinib therapy due to loss of major molecular response, monitor Bcr-Abl transcript levels monthly until major molecular response is re-established and then every 12 weeks thereafter.

• In 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 who reinitiate nilotinib therapy, monitor Bcr-Abl transcript levels monthly until previous major molecular response or MR4.0 is re-established and then every 12 weeks thereafter.

Dispensing and Administration Precautions

• Based on the Institute for Safe Medication Practices (ISMP), nilotinib is a high-alert medication that has a heightened risk of causing significant patient harm when used in error.

Other General Considerations

• Maintain adequate hydration throughout therapy.

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

≥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 :

• Received ≥3 years of nilotinib therapy

• Sustained molecular response (MR4.0; defined as Bcr-Abl transcripts of ≤0.01% for 1 year)

• Achieved deep molecular response (MR4.5; defined as Bcr-Abl transcripts of ≤0.0032%) immediately prior to discontinuing therapy

• Confirmed expression of typical Bcr-Abl transcripts (e13a2/b2a2 or e14a2/b3a2)

• No history of accelerated phase or blast crisis

• No prior history of relapse following treatment-free remission

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

≥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 :

• Received ≥3 years of nilotinib therapy

• Prior therapy with imatinib only

• Achieved deep molecular response (MR4.5; defined as Bcr-Abl transcripts of ≤0.0032%)

• Sustained MR4.5 for ≥1 year immediately prior to discontinuing therapy

• Confirmed expression of typical Bcr-Abl transcripts (e13a2/b2a2 or e14a2/b3a2)

• No history of accelerated phase or blast crisis

• No prior history of relapse following treatment-free remission

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

If QT_c is >480 msec, withhold nilotinib. Resume treatment within 2 weeks at prior dosage if QT_cF (QT interval corrected using Fridericia’s formula) returns to <450 msec and to within 20 msec of baseline. If QT_cF is 450–480 msec after withholding nilotinib for 2 weeks, resume therapy at a reduced dosage of 230 mg/m² once daily. If QT_cF >480 msec following this dosage reduction, discontinue nilotinib.

Adverse Hematologic Effects

Adjust 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

Withhold 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

300 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 :

• Received ≥3 years of nilotinib therapy

• Sustained molecular response (MR4.0; defined as Bcr-Abl transcripts of ≤0.01% for 1 year)

• Achieved deep molecular response (MR4.5; defined as Bcr-Abl transcripts of ≤0.0032%) immediately prior to discontinuing therapy

• Confirmed expression of typical Bcr-Abl transcripts (e13a2/b2a2 or e14a2/b3a2)

• No history of accelerated phase or blast crisis

• No prior history of relapse following treatment-free remission

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

400 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 :

• Received ≥3 years of nilotinib therapy

• Prior therapy with imatinib only

• Achieved deep molecular response (MR4.5; defined as Bcr-Abl transcripts of ≤0.0032%)

• Sustained MR4.5 for ≥1 year immediately prior to discontinuing therapy

• Confirmed expression of typical Bcr-Abl transcripts (e13a2/b2a2 or e14a2/b3a2)

• No history of accelerated phase or blast crisis

• No prior history of relapse following treatment-free remission

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

If QT_c is >480 msec, withhold nilotinib. Resume treatment within 2 weeks at prior dosage if QT_cF (QT interval corrected using Fridericia’s formula) returns to <450 msec and to within 20 msec of baseline. If QT_cF is 450–480 msec after withholding nilotinib for 2 weeks, resume therapy at a reduced dosage of 400 mg once daily. If QT_cF >480 msec following this dosage reduction, discontinue nilotinib.

Adverse Hematologic Effects

Adjust 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

Withhold 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.

Contraindications

• Hypokalemia, hypomagnesemia, or long QT syndrome.

Warnings/Precautions

Warnings

Prolongation of QT Interval

Plasma 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.

Mortality

Sudden deaths reported in patients receiving nilotinib. Possibility that ventricular repolarization abnormalities may have contributed to their occurrence.

Other Warnings and Precautions

Hematologic Effects

Grade 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 Effects

Cardiovascular 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 Lipase

Grade 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 Effects

Grade 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 Abnormalities

Grade 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 Syndrome

May 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.

Hemorrhage

Severe hemorrhage, sometimes fatal, reported.

Monitor for manifestations of hemorrhage. If hemorrhagic event occurs, provide appropriate treatment.

Lactose Intolerance

Contains 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 Edema

Fluid 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 Patients

Nilotinib 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 Mortality

May 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

Pregnancy

May cause fetal harm.

If used during pregnancy or if patient becomes pregnant, apprise of potential fetal hazard.

Lactation

Distributed 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 Use

Safety 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 Use

In 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 Impairment

Increased 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 Impairment

Not studied in patients with renal impairment; however, renal impairment not expected to decrease nilotinib clearance.

Pharmacogenomics

Nilotinib 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).

General

Pretreatment Screening

• Complete blood cell count (CBC).

• Assess serum electrolytes; correct hypokalemia and hypomagnesemia prior to administration of nilotinib.

• Correct uric acid levels prior to initiation of therapy.

• Assess cardiovascular status and risk factors for cardiovascular events.

• Electrocardiogram (ECG) at baseline and repeated 7 days following initiation of nilotinib.

• Verify pregnancy status in females of reproductive potential.

Patient Monitoring

• Monitor CBC every 2 weeks during the first 2 months of therapy and then monthly thereafter or as clinically indicated.

• Perform ECG periodically during therapy and approximately 7 days after any dosage adjustments.

• Monitor serum electrolytes periodically during therapy.

• Assess cardiovascular status and risk factors for cardiovascular events periodically during therapy.

• Monitor for manifestations of bleeding.

• Monitor serum lipase monthly or as clinically indicated.

• Monitor liver function tests monthly or as clinically indicated.

• Monitor for signs or symptoms of fluid retention and respiratory or cardiac compromise during therapy.

• Monitor growth and development in pediatric patients.

Monitoring Following Discontinuance of Therapy

• Monitor Bcr-Abl transcript levels and CBC with differential every month for 1 year, every 6 weeks for the second year, and then every 12 weeks thereafter.

• If loss of molecular response (MR4.0; defined as Bcr-Abl of 0.01% or less) occurs during the treatment-free phase, monitor Bcr-Abl transcript levels every 2 weeks until Bcr-Abl levels remain lower than major molecular response (MR3.0; defined as Bcr-Abl 0.1% or less) for 4 consecutive measurements, then resume regular monitoring schedule.

• Consistently use the same FDA-authorized test to monitor Bcr-Abl transcript levels during therapy and following discontinuation.

Monitoring Following Reinitiation of Therapy

• In patients with newly diagnosed chronic phase CML who reinitiate nilotinib therapy due to loss of major molecular response, monitor Bcr-Abl transcript levels monthly until major molecular response is re-established and then every 12 weeks thereafter.

• In 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 who reinitiate nilotinib therapy, monitor Bcr-Abl transcript levels monthly until previous major molecular response or MR4.0 is re-established and then every 12 weeks thereafter.

Dispensing and Administration Precautions

• Based on the Institute for Safe Medication Practices (ISMP), nilotinib is a high-alert medication that has a heightened risk of causing significant patient harm when used in error.

Other General Considerations

• Maintain adequate hydration throughout therapy.

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

≥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 :

• Received ≥3 years of nilotinib therapy

• Sustained molecular response (MR4.0; defined as Bcr-Abl transcripts of ≤0.01% for 1 year)

• Achieved deep molecular response (MR4.5; defined as Bcr-Abl transcripts of ≤0.0032%) immediately prior to discontinuing therapy

• Confirmed expression of typical Bcr-Abl transcripts (e13a2/b2a2 or e14a2/b3a2)

• No history of accelerated phase or blast crisis

• No prior history of relapse following treatment-free remission

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

≥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 :

• Received ≥3 years of nilotinib therapy

• Prior therapy with imatinib only

• Achieved deep molecular response (MR4.5; defined as Bcr-Abl transcripts of ≤0.0032%)

• Sustained MR4.5 for ≥1 year immediately prior to discontinuing therapy

• Confirmed expression of typical Bcr-Abl transcripts (e13a2/b2a2 or e14a2/b3a2)

• No history of accelerated phase or blast crisis

• No prior history of relapse following treatment-free remission

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

If QT_c is >480 msec, withhold nilotinib. Resume treatment within 2 weeks at prior dosage if QT_cF (QT interval corrected using Fridericia’s formula) returns to <450 msec and to within 20 msec of baseline. If QT_cF is 450–480 msec after withholding nilotinib for 2 weeks, resume therapy at a reduced dosage of 230 mg/m² once daily. If QT_cF >480 msec following this dosage reduction, discontinue nilotinib.

Adverse Hematologic Effects

Adjust 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

Withhold 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

300 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 :

• Received ≥3 years of nilotinib therapy

• Sustained molecular response (MR4.0; defined as Bcr-Abl transcripts of ≤0.01% for 1 year)

• Achieved deep molecular response (MR4.5; defined as Bcr-Abl transcripts of ≤0.0032%) immediately prior to discontinuing therapy

• Confirmed expression of typical Bcr-Abl transcripts (e13a2/b2a2 or e14a2/b3a2)

• No history of accelerated phase or blast crisis

• No prior history of relapse following treatment-free remission

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

400 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 :

• Received ≥3 years of nilotinib therapy

• Prior therapy with imatinib only

• Achieved deep molecular response (MR4.5; defined as Bcr-Abl transcripts of ≤0.0032%)

• Sustained MR4.5 for ≥1 year immediately prior to discontinuing therapy

• Confirmed expression of typical Bcr-Abl transcripts (e13a2/b2a2 or e14a2/b3a2)

• No history of accelerated phase or blast crisis

• No prior history of relapse following treatment-free remission

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

If QT_c is >480 msec, withhold nilotinib. Resume treatment within 2 weeks at prior dosage if QT_cF (QT interval corrected using Fridericia’s formula) returns to <450 msec and to within 20 msec of baseline. If QT_cF is 450–480 msec after withholding nilotinib for 2 weeks, resume therapy at a reduced dosage of 400 mg once daily. If QT_cF >480 msec following this dosage reduction, discontinue nilotinib.

Adverse Hematologic Effects

Adjust 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

Withhold 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.

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