Nilotinib, an inhibitor of Bcr-Abl tyrosine kinase, is an antineoplastic agent.1, 3, 4, 5, 6, 7, 8, 9, 11, 38
Philadelphia Chromosome-Positive Chronic Myelogenous Leukemia
Nilotinib is used for the treatment of newly diagnosed Philadelphia chromosome-positive (Ph+) chronic myelogenous leukemia (CML) in adults and pediatric patients at least 1 year of age who are in the chronic phase of the disease.1, 16, 21, 22, 23 Nilotinib also is used for the treatment of Ph+ CML in adults who are in the chronic or accelerated phase of the disease after failure (secondary to resistance or intolerance) of prior therapy that included imatinib.1, 3, 4, 6, 10, 11, 20 Nilotinib is also used for Ph+ CML in pediatric patients at least 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.1, 22, 23, 24, 24 Nilotinib is designated an orphan drug by the US FDA for use in the treatment of CML.2
The tablet formulation of nilotinib (Danziten®) is only approved for use in adults with the aforementioned indications; this drug product is not labeled with pediatric information.38 The efficacy of nilotinib tablets (Danziten®) in adults was established using data from the same clinical trials that supported the approval of the original capsule formulation of nilotinib (Tasigna®).38
Newly Diagnosed Chronic Phase CML
Nilotinib is used for the treatment of newly diagnosed Ph+ CML in adults who are in the chronic phase of the disease.1, 16, 21, 38 This indication is based on major molecular and cytogenetic response rates obtained at 12 months in patients with newly diagnosed, chronic phase Ph+ CML in an from an open-label, multicenter, randomized, phase 3 study (Evaluating Nilotinib Efficacy and Safety in Clinical Trials-Newly Diagnosed Patients [ENESTnd]).1, 16, 21
In this study, 846 patients who had been diagnosed with chronic phase Ph+ CML within the previous 6 months and who had received no prior tyrosine kinase inhibitor therapy (except imatinib administered for 2 weeks or less) and no other therapies for CML (except hydroxyurea or anagrelide) for periods longer than 2 weeks were randomized to receive nilotinib 300 mg twice daily, nilotinib 400 mg twice daily, or imatinib 400 mg once daily (with the option to increase imatinib dosage to 400 mg twice daily in patients with suboptimal response or treatment failure).1, 16 The primary analysis in this study was performed when all patients had completed 12 months of therapy (or had discontinued treatment prior to that date).1, 16
Major molecular response (defined as a Bcr-Abl transcript level of 0.1% or less in peripheral blood) at 12 months of treatment was achieved in 44 or 43% of patients receiving nilotinib 300 or 400 mg twice daily, respectively, compared with 22% of patients receiving imatinib.1, 16 Complete cytogenetic response (defined as complete eradication of Ph+ metaphases in cells obtained from a bone marrow sample) was achieved at 12 months in 80 or 78% of patients receiving nilotinib 300 or 400 mg twice daily, respectively, compared with 65% of patients receiving imatinib.1, 16 The Kaplan-Meier estimate of the median time to achieve a major molecular response was 8.6 or 11 months for patients receiving nilotinib 300 or 400 mg twice daily, respectively; at the data cutoff point, the median time to achieve a major molecular response with imatinib had not yet been determined.16 Disease progression (i.e., transformation from chronic phase to accelerated or blast phase of CML) occurred by the data cutoff date in less than 1% of patients receiving nilotinib and in 4% of patients receiving imatinib.16
Among patients with a poor prognosis (based on high Sokal risk score, a CML-specific prognostic indicator based on age, spleen size, platelet count, and peripheral blast count),16, 17 major molecular response at 12 months of treatment was achieved in 41 or 32% of those receiving nilotinib 300 or 400 mg twice daily, respectively, compared with 17% of those receiving imatinib.16 Complete cytogenetic response was achieved in 74 or 63% of poor-risk patients receiving nilotinib 300 or 400 mg twice daily, respectively, compared with 49% of poor-risk patients receiving imatinib.16
Adverse dermatologic effects (i.e., rash, pruritus, alopecia), headache, and elevated transaminase and bilirubin concentrations occurred more commonly in patients receiving nilotinib, whereas adverse GI effects (i.e., nausea, diarrhea, vomiting), muscle spasm, edema, and grade 3/4 neutropenia occurred more commonly in patients receiving imatinib.1, 16
Nilotinib continued to demonstrate clinical benefit compared to imatinib in the final analysis of the ENESTnd study at 10 years' follow-up.21 The cumulative 10-year rate of major molecular response in patients receiving nilotinib 300 or 400 mg twice daily was 77.7 or 79.7%, respectively, compared to 62.5% in patients receiving imatinib.21 The cumulative rates of cardiovascular events were higher in patients receiving nilotinib 300 or 400 mg twice daily (16.5 or 23.5%, respectively) compared to those receiving imatinib (3.6%).21
Nilotinib is used for the treatment of newly diagnosed Ph+ CML in pediatric patients at least 1 year of age who are in the chronic phase of the disease.1, 22, 23
Safety and efficacy of nilotinib for this indication have been evaluated in an open-label, multicenter, phase 2 study (DIALOG) that enrolled pediatric patients at least 1 year of age with chronic phase CML who were newly diagnosed or experienced resistance or intolerance to imatinib or dasatinib therapy.1, 22 In this study, 25 pediatric patients with newly diagnosed chronic phase CML were administered nilotinib 230 mg/m2 orally twice daily.1, 22 The median age of enrolled patients was 13 years (range: 2-17 years).22 At the time of analysis, major molecular response was achieved in 60% of patients with newly diagnosed chronic phase CML by cycle 12; the median time to first major molecular response was 5.6 months and loss of MMR was confirmed in 1 patient.1 A deep molecular response (MR4.5; defined as Bcr-Abl transcripts of 0.0032% or less) was achieved in 28% of patients.1 Complete cytogenetic response was achieved in 84% of patients with newly diagnosed chronic phase CML; the median time to first major molecular response was 5.6 months and loss of complete cytogenetic response was confirmed in 1 patient.22 The estimated event-free survival rate was 91.2% in patients with newly diagnosed chronic phase CML.22
In the DIALOG study, the safety profile of nilotinib in pediatric patients was generally consistent with that seen in adults with the exception of cardiovascular adverse events.22
In a follow-up analysis of growth and safety profiles in pediatric patients with chronic phase CML enrolled in the DIALOG study, the median change in height from baseline standard deviation score was -0.54 (range: -1.6 to 0.4) after 48 cycles of nilotinib 230 mg/m2 twice daily.23 The safety profile of nilotinib remained similar to the initial analysis.23 In patients with chronic phase CML resistant or intolerant to imatinib or dasatinib, the most common grade 3 or 4 adverse events were increased serum aminotransferase or bilirubin concentrations and rash.23
Discontinuation and Reinitiation of Nilotinib Therapy Following Sustained Molecular Response (MR4.5)
Based on results of an open-label, multicenter, single-arm study (Evaluating Nilotinib Efficacy and Safety in clinical Trials-freedom; ENESTfreedom), nilotinib therapy may be discontinued after a treatment duration of at least 3 years in patients with newly diagnosed Ph+ CML in the chronic phase who have achieved a sustained molecular response (MR4.5).1
In the ENESTfreedom study, 215 adults with Ph+ chronic phase CML who received nilotinib in the first-line setting for at least 2 years were enrolled to continue nilotinib therapy for an additional 52 weeks (nilotinib consolidation phase).1, 28, 29, 30 Patients enrolled in this study must have achieved MR4.5 (defined as Bcr-Abl transcripts of 0.0032% or less using the MolecularMD MRDx Bcr-Abl test) during first-line nilotinib therapy.1 Most of the patients (88.4%) entered treatment-free remission after achieving a sustained MR4.5 during the consolidation phase.1 The median age of patients who entered treatment-free remission was 55 years; 49.5% were female and 21.1% of the patients were 65 years of age or older.1
Any patient with loss of major molecular response during the treatment-free remission phase restarted nilotinib (300 mg twice daily or 400 mg once daily)within 5 weeks after the collection date of the blood sample demonstrating loss of major molecular response.1 At 24, 48, or 96 weeks, treatment-free remission was achieved in 62.1, 51.6, or 48.9% of patients, respectively,, and loss of major molecular response occurred in 35.8, 45.8, or 47.9% patients, respectively.1 The cumulative rate of major molecular response or MR4.5 regained by 24-weeks after restarting nilotinib therapy was 97.7 or 86.4%, respectively.1 At the time of the 5-year analysis, 81 of 190 patients entering the treatment-free remission phase were still in treatment-free remission and 76 patients (40.0%) were in MR4.5.30 Among 91 patients who discontinued the treatment-free remission phase due to loss of major molecular response and restarted nilotinib therapy, 98.9% of patients regained major molecular response and 92.3% patients regained MR4.5.30
Among the 190 patients in the treatment-free remission phase, 98 patients had a treatment-free survival (TFS) event (defined as discontinuation from the treatment-free remission phase due to any reason, loss of major molecular response, confirmed loss of MR4, death due to any cause, progression to accelerated or blast phase CML up to the end of treatment-free remission phase, or reinitiation of therapy due to any cause) by the 96-week cut-off date.1
A higher incidence of adverse effects were observed in patients who restarted nilotinib therapy compared with nilotinib consolidation therapy.1, 31, 32
Chronic or Accelerated Phase CML Following Prior Treatment Failure
Adults: Treatment of Chronic or Accelerated Phase CML Following Prior Treatment Failure
Nilotinib is used for the treatment of Ph+ CML in adults who are in the chronic or accelerated phase of the disease after failure (secondary to resistance or intolerance) of prior therapy that included imatinib.1, 4, 38 The indication for this use is based on overall hematologic and cytogenetic response rates.1
Safety and efficacy of nilotinib for this indication have been evaluated in one open-label, multicenter, phase 2 trial in adults with CML in the chronic or accelerated phase; patients were intolerant of or had disease that was resistant to imatinib.1, 3, 6, 10, 11, 20 In 321 patients in the chronic phase of CML, treatment with nilotinib (400 mg twice daily) resulted in a major cytogenetic response (defined as elimination or substantial reduction [to 35% or less] of Ph+ hematopoietic cells) in 51% of patients; 37% achieved a complete cytogenetic response, while 15% achieved a partial response.1 The median time to major cytogenetic response was 2.8 months (range: 1-28 months), and the duration of major cytogenetic response exceeded 18 months in 62% of those who responded.1 The estimated 24-month overall survival rate was 87%.20 In 137 patients in the accelerated phase of CML, treatment with nilotinib (400 mg twice daily) resulted in confirmed hematologic response in 39% of patients; 30% achieved a complete hematologic response, while 9% had no evidence of leukemia.1 The median time to first hematologic response was 1 month (range: 1-14 months), and the duration of hematologic response exceeded 18 months in 44% of those who responded.1 At the time of data analysis, all patients in the trial had been followed for at least 24 months or had discontinued therapy early;1, 20 the median duration of nilotinib treatment was 18.4 months for patients with CML in the chronic phase and 8.7 months for those with CML in the accelerated phase.1 At the time of data analysis, median duration of response had not been reached.1
Among patients in this study who were tested for Bcr-Abl mutations following imatinib treatment failure, 24 different Bcr-Abl mutations were detected in 42 or 54% of those with chronic or accelerated phase CML, respectively.1
Pediatric Patients: Treatment of Chronic or Accelerated Phase CML Following Prior Treatment Failure
Nilotinib is used for Ph+ CML in pediatric patients at least 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.1, 22, 23, 24
Safety and efficacy of nilotinib for this indication have been evaluated in a phase 1 multicenter, open-label, single arm study and a phase 2 multicenter, open-label, single-arm study (DIALOG).1, 22, 23, 24 In both studies, pediatric patients at least 1 year of age received nilotinib 230 mg/m2 orally twice daily.1, 22, 23, 24 Pooled results of 44 patients with previously treated chronic phase CML demonstrated a cumulative major molecular response rate of 47.7% by cycle 12; the median time to first major molecular response was 2.8 months.1 Among patients with resistant or intolerant CML, 12.1% of patients achieved a deep molecular response by cycle 66.1
In the DIALOG study, the safety profile of nilotinib in pediatric patients was generally consistent with that seen in adults; however, cardiovascular adverse events were not observed in pediatric patients.22
In a follow-up analysis of growth and safety profiles in pediatric patients with chronic phase CML enrolled in the DIALOG study, the median change in height from baseline standard deviation score was -0.54 (range: -1.6 to 0.4) after 48 cycles of nilotinib 230 mg/m2 twice daily.23 The safety profile of nilotinib remained similar to the initial analysis.23 In patients with chronic phase CML resistant or intolerant to imatinib or dasatinib, the most common grade 3 or 4 adverse events were increased serum aminotransferase or bilirubin concentrations and rash.23
Discontinuation and Reinitiation of Nilotinib Therapy Following Sustained Molecular Response (MR4.5)
Based on results of an open-label, multicenter, single-arm study (Evaluating Nilotinib Efficacy and Safety in clinical Trials-STop; ENESTop), nilotinib therapy may be discontinued after a treatment duration of at least 3 years in patients with resistant or intolerant Ph+ CML in the chronic phase who have achieved a sustained molecular response (MR4.5).1
In the ENESTop study 163 adults with Ph+ chronic phase CML treated with a tyrosine kinase inhibitor for at least 3 years (e.g., initial therapy with imatinib for more than 4 weeks without documented MR4.5 at the time of switching therapy to nilotinib for at least 2 years) who achieved MR4.5 on nilotinib therapy (measured using the MolecularMD MRDx Bcr-Abl test) were enrolled to continue nilotinib treatment for an additional 52 weeks (nilotinib consolidation phase).1, 31, 32 Most of the patients (77.3%) entered treatment-free remission after achieving a sustained molecular response (MR4.5; defined as Bcr-Abl transcripts of 0.0032% or less) during the consolidation phase for 1 year.1 The median age of patients who entered treatment-free remission was 56 years; 55.6% were females and 27.8% of the patients were 65 years of age or older.1 The median actual dose intensity during the 52-week nilotinib consolidation phase was 771.8 mg per day.1
Nilotinib was restarted in patients with loss of major molecular response (defined as two consecutive measurements of Bcr-Abl transcript levels exceeding 0.01%) in the treatment-free remission phase.1 At 24, 48, or 96 weeks, treatment-free remission was achieved in 60.3, 57.9, or 53.2% of patients, respectively, and loss of major molecular response or confirmed loss of MR4 occurred in 38.9, 41.3, or 43.7% patients, respectively.1 The cumulative rate of MR4.0 or MR4.5 regained by 48 weeks after restarting nilotinib therapy was 92.9 or 91.1%, respectively.1 At the time of the 5-year analysis, 59 patients had discontinued from the treatment-free remission phase and restarted nilotinib therapy; 98.3, 94.9, or 93.2% of these patients regained major molecular response, MR4.0, or MR4.5, respectively1
Among the 126 patients in the treatment-free remission phase, 61 patients (48.4%) had a treatment-free survival (TFS) event (defined as discontinuation from the treatment-free remission phase due to any reason, loss of major molecular response, confirmed loss of MR4, death due to any cause, progression to accelerated or blase phase CML up to the end of treatment-free remission phase, or reinitiation of therapy due to any cause) on or before the 96-week cut-off date.1
A higher incidence of adverse effects were observed following reinitiation of nilotinib therapy compared with nilotinib during the consolidation phase.1, 31, 32
Adult Patients: Chronic Phase CML
Guidelines recommend bosutinib, dasatinib, imatinib, or nilotinib for the first-line treatment of newly diagnosed chronic phase CML; selection of the tyrosine kinase inhibitor (TKI) should be based on risk score, toxicity profile, patient's age, ability to tolerate therapy, and presence of comorbid conditions.34 All of these TKIs are appropriate first-line options for patients with chronic phase CML across all risk scores.34 In patients with an intermediate- or high-risk score, disease progression to accelerated or blast phase CML occurs more frequently; bosutinib, dasatinib, and nilotinib are associated with a reduced risk of disease progression than imatinib and are preferred for patients with an intermediate- or high-risk score.34
Nilotinib has been used in combination with chemotherapy† for first-line treatment of Ph+ acute lymphocytic leukemia (ALL)† .37 The drug also has been used in adults with ALL following failure of prior therapy†.26
Nilotinib also has been used for the treatment of malignant GI stromal tumors (GISTs)†.27
Dispensing and Administration Precautions
Nilotinib is available as capsules (Tasigna®) and tablets (Danziten®).1, 38 These formulations are available in different strengths and are approved with different indications and recommended dosages; therefore, tablets and capsules are not substitutable on a mg per mg basis.1, 38
Nilotinib capsules and tablets are administered orally twice daily (approximately 12 hours apart).1, 38 Because food increases the bioavailability of nilotinib capsules, the manufacturer states that the drug should be administered at least 1 hour before or 2 hours after any food; nilotinib tablets may be administered without regard to food.1, 38 The manufacturers state that nilotinib capsules and tablets should be swallowed whole with water.1, 38 Nilotinib tablets should not be cut, crushed, or chewed.38 If a dose of nilotinib capsules or tablets is missed, the next dose should be taken at the regularly scheduled time; the dose should not be doubled.1, 38
For patients who are unable to swallow capsules, nilotinib capsules may be opened and the contents of each capsule dispersed in one teaspoonful of applesauce; the mixture should be swallowed immediately (within 15 minutes) and not stored for later use.1 The manufacturer states that foods other than applesauce should not be used and that no more than one teaspoonful of applesauce should be mixed with the contents of each capsule.1
Nilotinib capsules and tablets may be administered in conjunction with hematopoietic growth factors (e.g., erythropoietin, filgrastim, sargramostim), if clinically indicated.1, 38 The drug also may be administered concomitantly with hydroxyurea or anagrelide, if clinically indicated.1, 38
Nilotinib capsules and tablets are stored at 20-25°C (excursions permitted between 15-30°C).1, 38
Adult Patients: Newly Diagnosed Chronic Phase CML
Tasigna®: The recommended adult dosage of nilotinib capsules for the treatment of newly diagnosed Philadelphia chromosome-positive (Ph+) CML in the chronic phase is 300 mg twice daily.1, 16 In a phase 3 clinical trial, nilotinib was administered for a median of 82.8 months.21
Danziten®: The recommended adult dosage of nilotinib tablets for the treatment of newly diagnosed Philadelphia chromosome-positive (Ph+) CML in the chronic phase is 142 mg twice daily.38
Discontinuance of therapy may be considered in patients who meet the following criteria1, 38 :
Molecular response must be measured during therapy and following discontinuation of therapy using the same FDA-authorized test.1, 38
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; Bcr-Abl transcript levels should then be monitored monthly until major molecular response is re-established and then every 12 weeks thereafter.1, 38
Adult Patients: Chronic or Accelerated Phase CML Following Prior Treatment Failure
Tasigna®: The recommended adult oral dosage of nilotinib for the treatment of Ph+ CML in the chronic or accelerated phase after failure of prior therapy that included imatinib is 400 mg twice daily.1, 3, 6 In a phase 3 clinical trial, nilotinib was administered for a median of 87.5 months.21
Danziten®: The recommended adult dosage of nilotinib tablets for the treatment of Ph+ CML in the chronic or accelerated phase after failure of prior therapy that included imatinib is 190 mg twice daily.38
Discontinuance of therapy may be considered in patients who have met the following criteria1, 38 :
Molecular response must be measured during therapy and following discontinuation of therapy using the same FDA-authorized test .1, 38
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; Bcr-Abl transcript levels should then be monitored monthly until previous major molecular response or MR4.0 is re-established and then every 12 weeks thereafter.1, 38
Pediatric Patients: Newly Diagnosed Chronic Phase CML
The recommended initial dosage of nilotinib (Tasigna®) for the treatment of newly diagnosed chronic phase CML in pediatric patients 1 year of age or older is 230 mg/m2 (maximum single dose of 400 mg) twice daily.1 The dosage should be rounded to the nearest 50 mg dose (see Table 1).1 The manufacturer recommends continuing therapy for the duration of clinical benefit or until unacceptable toxicity occurs.1
Body 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 criteria1 :
Molecular response must be measured during therapy and following discontinuation of therapy using the same FDA-authorized test.1
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; Bcr-Abl transcript levels should then be monitored monthly until major molecular response is re-established and then every 12 weeks thereafter.1
Pediatric Patients: Chronic or Accelerated Phase CML Following Prior Treatment Failure
The recommended initial dosage of nilotinib (Tasigna®) for the treatment of chronic or accelerated phase CML following prior treatment failure or intolerance in pediatric patients 1 year of age or older is 230 mg/m2 (maximum single dose of 400 mg) twice daily.1 The dosage should be rounded to the nearest 50 mg dose (see Table 1).1 The manufacturer recommends continuing therapy for the duration of clinical benefit or until unacceptable toxicity occurs.1
Discontinuance of therapy may be considered in patients who have met the following criteria1 :
Molecular response must be measured during therapy and following discontinuation of therapy using the same FDA-authorized test.1
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; Bcr-Abl transcript levels should then be monitored monthly until previous major molecular response or MR4.0 is re-established and then every 12 weeks thereafter.1
Switching Between Tablets and Capsules
Table 2 provides recommendations for switching between nilotinib tablets (Danziten®) and capsules (Tasigna®).38
Indication for Use | Nilotinib Tablet Dosage (Danziten®) | Nilotinib Capsule Dosage (Tasigna®) |
|---|---|---|
Newly diagnosed Ph+ CML in the chronic phase | 142 mg twice daily | 300 mg twice daily |
Ph+ CML in the chronic or accelerated phase after failure of prior therapy that included imatinib | 190 mg twice daily | 400 mg twice daily |
Concomitant Use with Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes
Because concomitant use of nilotinib with strong inhibitors of cytochrome P-450 (CYP) isoenzyme 3A4 may result in increased plasma concentrations of nilotinib, concomitant therapy with such drugs should be avoided.1, 38 If treatment with a strong CYP3A4 inhibitor is required, the manufacturer of nilotinib recommends that therapy with nilotinib be interrupted.1, 38
If concomitant use is required, consider reducing the nilotinib capsule dosage to 200 mg once daily in adults receiving nilotinib as first-line therapy for CML or to 300 mg once daily in adults receiving nilotinib following failure of prior therapy.1 The manufacturer states that these dosage recommendations are based on pharmacokinetic studies and that there is no clinical experience with use of these dosages in patients concomitantly receiving the nilotinib capsule with a strong CYP3A4 inhibitor.1 If concomitant use of a nilotinib tablet and strong CYP3A4 inhibitor is required, consider reducing the nilotinib tablet dosage to 95 mg once daily in adults receiving nilotinib as first-line therapy for CML or to 142 mg once daily in adults receiving nilotinib following failure of prior therapy.38
In addition, patients receiving concomitant therapy should be closely monitored for prolongation of the QT interval.1, 38 If the strong inhibitor is discontinued, the nilotinib dosage may be adjusted back to the usual indicated dosage after a suitable washout period.1, 38
Because concomitant use of nilotinib with strong CYP3A4 inducers may result in decreased plasma concentrations of nilotinib, concomitant therapy with such drugs should be avoided.1, 38
Nilotinib is associated with plasma concentration-dependent prolongation of the QT interval.1, 38 Hypomagnesemia or hypokalemia should be treated before the drug is initiated.1, 38 ECGs should be obtained to monitor the QT interval at baseline, 7 days after initiation of nilotinib, and periodically thereafter; ECGs should be repeated approximately 7 days after any dosage adjustments.1, 38
If the QT interval corrected for heart rate using Fridericia's formula (QTcF) exceeds 480 msec, nilotinib therapy should be withheld and serum potassium and magnesium concentrations and concomitant drug usage should be evaluated; if serum potassium or magnesium concentrations are below the lower limits of normal, potassium or magnesium supplementation should be administered.1, 38 When QTcF interval returns to less than 450 msec and to within 20 msec of baseline values, nilotinib therapy may be resumed within 2 weeks at the prior dosage.1, 38 If QTcF is between 450 msec and 480 msec after nilotinib has been withheld for 2 weeks, therapy with the drug may be resumed at a reduced dosage of 400 mg once daily in adults and 230 mg/m2 once daily in pediatric patients for nilotinib capsules and 190 mg once daily in adults for nilotinib tablets.1, 38 If QTcF exceeds 480 msec following this dosage reduction, nilotinib should be discontinued.1, 38
Temporary interruption or dosage reduction of nilotinib therapy is indicated in patients who develop neutropenia or thrombocytopenia that is not related to CML.1, 38 Nilotinib therapy should be withheld if absolute neutrophil counts (ANC) decrease to less than 1000/mm3 and/or platelet counts decrease to less than 50,000/mm3.1, 38 Treatment may be resumed within 2 weeks at the prior dosage when ANC exceeds 1000/mm3 and platelet counts exceed 50,000/mm3 in adults, and when ANC exceeds 1500/mm3 and platelet counts exceed 75,000/mm3 in pediatric patients.1, 38 If blood counts remain low for more than 2 weeks, nilotinib capsule dosage should be reduced to 400 mg once daily in adults and 230 mg/m2 once daily in pediatric patients and nilotinib tablet dosage should be reduced to 190 mg once daily in adults.1, 38 If toxicity recurs on a reduced dosage in pediatric patents, discontinue nilotinib therapy.1
In adults, nilotinib therapy should be withheld in patients who experience grade 3 or greater elevations of serum bilirubin and/or hepatic aminotransferase concentrations.1, 13, 38 Treatment may be resumed at a reduced capsule dosage of 400 mg once daily or a reduced tablet dosage of 190 mg once daily if the toxicity decreases in intensity to grade 1 or less.1, 38
In pediatric patients, nilotinib capsule therapy should be withheld in patients who experience grade 2 or greater elevations of serum bilirubin and/or grade 3 or greater elevations of hepatic aminotransferase concentrations.1 Treatment may be resumed at a dosage reduced from 230 mg/m2 twice daily to 230 mg/m2 once daily if the toxicity decreases in intensity to grade 1 or less.1 If elevations in bilirubin and/or hepatic aminotransferases do not recover to grade 1 or less within 28 days, discontinue nilotinib therapy.1 If elevated bilirubin and/or hepatic aminotransferase concentrations recur on a reduced dosage of 230 mg/m2 once daily , discontinue nilotinib therapy.1
Elevated Serum Lipase and Amylase
In adults, nilotinib therapy should be withheld in patients who experience grade 3 or greater elevations of serum lipase or amylase concentrations.1, 13, 38 Treatment may be resumed at a reduced capsule dosage of 400 mg once daily or a reduced tablet dosage of 190 mg once daily if the toxicity decreases in intensity to grade 1 or less.1, 38
In pediatric patients, nilotinib capsule therapy should be withheld in patients who experience grade 3 or greater elevations of serum lipase or amylase concentrations.1 Treatment may be resumed at a dosage reduced from 230 mg/m2 twice daily to 230 mg/m2 once daily if the toxicity decreases in intensity to grade 1 or less.1 If grade 3 or greater elevations of serum lipase or amylase concentrations recur on a reduced dosage of 230 mg/m2 once daily , discontinue nilotinib therapy.1
Nilotinib therapy should be withheld in patients experiencing other clinically important moderate or severe (grade 2 or greater) nonhematologic adverse effects; once the adverse effect has resolved, nilotinib capsule treatment may be resumed at a reduced dosage of 400 mg once daily in adults and 230 mg/m2 once daily in pediatric patients.1 Nilotinib tablet treatment may be resumed at a reduced dosage of 190 mg once daily if the previous dose was 142 mg twice daily in adults newly diagnosed with chronic phase CML or 190 mg twice daily in adults with resistant or intolerant chronic or accelerated phase CML.38 If the toxicity recurs on a reduced dosage, discontinue nilotinib therapy.1, 38 If clinically appropriate, escalation of the nilotinib capsule dosage back to 300 mg twice daily (in adults receiving nilotinib as first-line therapy for CML), 400 mg twice daily (in adults receiving nilotinib following failure of prior therapy that included imatinib), or 230 mg/m2 twice daily (in pediatric patients receiving nilotinib for CML in the chronic phase that is newly diagnosed or following failure of prior therapy) should be considered.1 For nilotinib tablets, escalation of the dosage back to 142 mg twice daily (in adults as first-line therapy for CML) or 190 mg twice daily (for adults following failure of prior therapy that included imatinib) should be considered.38
If use of nilotinib is required in patients with hepatic impairment, reduction of the initial dosage is recommended.1, 38 The manufacturer states that, if possible, alternative therapy should be considered.1, 38
When nilotinib is used for the treatment of newly diagnosed, chronic phase Ph+ CML in adults with mild, moderate, or severe hepatic impairment (Child-Pugh class A, B, or C, respectively), an initial capsule dosage of 200 mg twice daily, followed by dosage escalation to 300 mg twice daily as tolerated, is recommended; for tablets, an initial dosage of 95 mg twice daily, followed by dosage escalation to 142 mg twice daily as tolerated, is recommended.1, 38
When nilotinib is used in adults for the treatment of chronic or accelerated phase Ph+ CML after failure of prior therapy that included imatinib, an initial capsule dosage of 300 mg twice daily, followed by dosage escalation to 400 mg twice daily as tolerated, is recommended for patients with mild or moderate hepatic impairment (Child-Pugh class A or B, respectively); for tablets, an initial dosage of 142 mg twice daily, followed by dosage escalation to 190 mg twice daily as tolerated, is recommended for patients with mild or moderate hepatic impairment (Child-Pugh class A or B, respectively).1, 38 When nilotinib capsules are used for this indication in adults with severe hepatic impairment (Child-Pugh class C), an initial dosage of 200 mg twice daily, followed by dosage escalation as tolerated to 300 mg twice daily and then to 400 mg twice daily, is recommended; for nilotinib tablets, an initial dosage of 95 mg twice daily, followed by dosage escalation to 142 mg twice daily and then 190 mg twice daily as tolerated, is recommended.1, 38
The manufacturer makes no specific dosage recommendations for patients with renal impairment.1, 38
The manufacturer makes no specific dosage recommendations for geriatric patients.1, 38
Because median steady-state trough concentrations of nilotinib are reduced by 53% in patients who have undergone total gastrectomy, more frequent follow-up of these patients should be considered.1 If necessary, increased dosage of nilotinib or institution of alternative therapy may be considered.1, 38
A boxed warning regarding the risk of QT prolongation is included in the prescribing information for nilotinib.1, 38 Nilotinib is associated with plasma concentration-dependent prolongation of the QT interval.1, 5, 38 In the clinical trial in patients with newly diagnosed chronic phase CML, an increase in the QT interval (corrected for heart rate using Fridericia's formula [QTcF]) of more than 60 msec from baseline was observed in one adult (0.4%) receiving nilotinib 300 mg twice daily; QTcF did not exceed 500 msec in any patient.1 In the clinical trial in adults with chronic or accelerated phase CML who received nilotinib (400 mg twice daily) after failure of prior treatment, increases in QTcF of more than 60 msec from baseline were observed in 4.1% of patients, and QTcF exceeded 500 msec in less than 1% of patients (4 patients).1 Prolongation of the QT interval can result in torsades de pointes, leading to syncope, seizure, and/or sudden death.1, 38
Nilotinib should not be used in patients with hypokalemia, hypomagnesemia, or long QT syndrome.1, 38 Because hypokalemia and hypomagnesemia may further prolong the QT interval, these electrolyte abnormalities should be corrected prior to administration of nilotinib, and these electrolytes should be monitored periodically during therapy.1, 38
Substantial prolongation of the QT interval may occur when nilotinib capsules are administered inappropriately with food or when nilotinib is used concomitantly with strong CYP3A4 inhibitors or with drugs known to prolong the QT interval; therefore, concomitant use of such drugs and administration of the capsules with food should be avoided .1, 38
ECGs should be obtained to monitor the QT interval at baseline and 7 days after initiation of the drug, and should be repeated periodically thereafter, as well as approximately 7 days after any dosage adjustments.1, 38
A boxed warning regarding the risk of sudden death is included in the prescribing information for nilotinib.1, 38 Sudden death has been reported in 0.3% of patients with CML who received nilotinib in clinical trials.1, 38 The early occurrence of some of these deaths relative to the initiation of nilotinib suggests the possibility that ventricular repolarization abnormalities may have contributed to their occurrence.1, 38
Other Warnings and Precautions
Substitution with Other Nilotinib Products and Risk of Medication Errors
Nilotinib is available in varying formulations (i.e., tablets and capsules), strengths, and recommended dosages; nilotinib products are not substitutable on a mg per mg basis.1, 38 Clinicians may need to perform a dose conversion when switching patients between nilotinib products.38 Substitution of nilotinib tablets for another nilotinib product to achieve the same daily nilotinib dosage on a mg per mg basis may result in a clinically significant increase in nilotinib exposure and risk of associated adverse effects or a decrease in exposure resulting in reduced efficacy.38 Clinicians should confirm that the intended nilotinib product is being prescribed and dispensed.38
In the clinical trial evaluating nilotinib 400 mg twice daily after failure of prior therapy, grade 3/4 neutropenia, thrombocytopenia, and anemia occurred in 31, 30, and 11%, respectively, of adults in the chronic phase of CML and in 42, 42, and 27%, respectively, of patients in the accelerated phase of CML.1 In the clinical trial in patients with newly diagnosed chronic phase CML, grade 3/4 neutropenia, thrombocytopenia, and anemia occurred in 12, 10, and 4%, respectively, of adults receiving nilotinib 300 mg twice daily.1 The manufacturer states that myelosuppression generally was reversible and usually was managed by withholding nilotinib or reducing the dosage.1, 38 Complete blood cell counts should be monitored every 2 weeks during the first 2 months of therapy and monthly (or as clinically indicated) thereafter.1, 38 If hematologic toxicity occurs, interruption of nilotinib therapy and/or dosage reduction may be necessary.1, 38
In clinical trials, cardiovascular effects (i.e., arterial vascular occlusive events, ischemic heart disease-related cardiac events, peripheral arterial occlusive disease, ischemic cerebrovascular events) occurred in 9 or 15% of adults receiving nilotinib 300 or 400 mg twice daily, respectively, for a median of 60 months.1 Assess cardiovascular status and risk factors for cardiovascular events during therapy and actively manage according to standard guidelines.1, 38
Pancreatitis and Elevated Serum Lipase
In clinical trials, grade 3/4 elevations in serum lipase occurred in 9% of adults with newly diagnosed chronic phase CML who received nilotinib 300 mg twice daily and in 18% of adults with chronic or accelerated phase CML who received nilotinib 400 mg twice daily after failure of prior therapy.1 Caution is recommended in patients with a previous history of pancreatitis.1, 38 Serum lipase should be monitored monthly or as clinically indicated, and interruption of therapy and/or dosage reduction may be necessary in some patients.1, 38 If lipase elevations are accompanied by abdominal symptoms, nilotinib therapy should be interrupted and diagnostic testing to exclude pancreatitis considered.1, 38
In clinical trials, grade 3/4 elevations in hepatic enzymes (AST/ALT and/or alkaline phosphatase) and/or bilirubin occurred in up to 4% of adults with newly diagnosed chronic phase CML who received nilotinib 300 mg twice daily and in up to 9% of adults with chronic or accelerated phase CML who received nilotinib 400 mg twice daily after failure of prior therapy.1 Hepatic function tests should be monitored monthly or as clinically indicated and following dosage adjustments, and interruption of therapy and/or dosage reduction may be necessary in some patients.1, 38
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 exists.1, 38 The largest increases in bilirubin were observed in patients with the (TA)7/(TA)7 genotype (UGT1A1*28).1, 38
Electrolyte abnormalities (hypophosphatemia, hypokalemia, hyperkalemia, hypocalcemia, and hyponatremia) of grade 3 or 4 in severity occurred in up to 8% of adults with newly diagnosed chronic phase CML who received nilotinib 300 mg twice daily and in up to 17% of adults with chronic or accelerated phase CML who received nilotinib 400 mg twice daily after failure of prior therapy.1 Electrolyte abnormalities must be corrected prior to initiation of nilotinib therapy, and these electrolytes should be monitored periodically during therapy.1, 38
Nilotinib may increase the risk of tumor lysis syndrome, primarily in patients with advanced disease who are resistant to or intolerant of imatinib therapy.1, 38 Uric acid levels should be corrected prior to starting therapy and electrolytes should be monitored periodically thereafter.1, 38 Adequate hydration should be maintained throughout therapy.1, 38
Severe hemorrhage, sometimes fatal, has occurred in patients receiving nilotinib.1, 38 In a clinical trial of patients with newly diagnosed chronic phase CML, hemorrhage of grade 3 or 4 severity was reported in 1.1% of adults who received nilotinib 300 mg twice daily and 1.8% of adults with who received nilotinib 400 mg twice daily.1 GI hemorrhage was reported in 2.9% and 5.1% of adults who received nilotinib 300 or 400 mg twice daily, respectively.1 Monitor patients for manifestations of hemorrhage.1, 38 If a hemorrhagic event occurs, provide appropriate treatment.1, 38
Since nilotinib capsules contain lactose, use of the drug in patients with rare hereditary problems of galactose intolerance, severe lactase deficiency with severe intolerance to lactose-containing products, or glucose-galactose malabsorption is not recommended.1
In a clinical trial of patients with newly diagnosed chronic phase CML, fluid retention of grade 3 or 4 severity was reported in 3.9 or 2.9% of adults receiving nilotinib 300 or 400 mg twice daily, respectively.1 Effusions (including pleural effusion, pericardial effusion, ascites) or pulmonary edema were observed in 2.2 or 1.1% of adults receiving nilotinib 300 or 400 mg twice daily, respectively.1
Monitor patients 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.1, 38
Effects on Growth and Development of Pediatric Patients
Nilotinib has been associated with adverse reactions related to bone growth and development.1, 38 In a clinical trial of 58 pediatric patients with chronic phase CML (median exposure of 56.7 months), 8 patients experienced growth deceleration.1 Growth deceleration was more pronounced in children <12 years of age at baseline.1, 38 Growth retardation was reported in 3 patients.1
Monitor growth and development during therapy in pediatric patients.1, 38
Fetal/Neonatal Morbidity and Mortality
Nilotinib may cause fetal harm; maternal and embryofetal toxicity have been demonstrated in animals.1, 38 No adequate and well-controlled studies have been conducted to date in humans.1, 38
Avoid pregnancy during therapy.1, 38 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 at least 14 days after the last dose.1, 38 If used during pregnancy or if the patient becomes pregnant while receiving nilotinib, the patient should be apprised of the potential fetal hazard.1, 38
If used during pregnancy or if the patient becomes pregnant while receiving nilotinib, the patient should be apprised of the potential fetal hazard.1, 38
Nilotinib is distributed into milk in rats.1, 38 It is not known whether the drug is distributed into milk in humans.1, 38 Because of the potential for serious adverse effects from nilotinib in breast-fed infants, the manufacturer states that females should not breast-feed during nilotinib therapy and for at least 14 days after the last dose.1, 38
Females and Males of Reproductive Potential
Nilotinib is associated with fetal harm; females of reproductive potential should have a pregnancy test prior to therapy initiation.1, 38
Females of reproductive potential should use effective contraception during treatment and for 14 days after the final dose.1, 38 The risk of infertility in females or males of reproductive potential administered nilotinib has not been studied.1, 38
Safety and efficacy of nilotinib capsules have been evaluated in pediatric patients at least 1 year of age with chronic phase Ph+ CML that is newly diagnosed or progressed during prior therapy.1 There are no data in pediatric patients under 2 years of age.1
Use of nilotinib capsules in pediatric patients 1 to <2 years of age with newly diagnosed or resistant or intolerant Ph+ CML in chronic phase is supported by efficacy in pediatric patients 2-6 years of age for these indications.1 Use of nilotinib capsules in pediatric patients 1 year of age or greater with resistant or intolerant Ph+ CML in accelerated phase is based on evidence from a study in adults with safety data from 2 pediatric studies.1
The frequency, type, and severity of adverse effects in the 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.1, 38 Adverse effects on growth and development in pediatric patients with Ph+ chronic phase CML receiving nilotinib have been reported.1, 38 Monitor growth and development in pediatric patients.1, 38
The tablet formulation of nilotinib (Danziten®) is only approved for use in adults with the aforementioned indications; this drug product is not labeled with pediatric information.38
In the clinical trial evaluating nilotinib in patients with newly diagnosed, chronic phase Ph+ CML, approximately 12% of patients were 65 years of age or older.1, 38 No differences in major molecular response rates were observed between geriatric patients 65 years of age or older and younger adults.1, 38
In the clinical trial evaluating nilotinib in patients with chronic or accelerated phase CML following failure of prior therapy, approximately 30% of patients were 65 years of age or older.1, 38 In patients in the chronic phase of CML, no difference was found in major cytogenetic response rates in patients 65 years of age and older relative to younger adults.1, 38 In patients in the accelerated phase of CML, the hematologic response rate was 29% in those 65 years of age and older compared with 44% in those younger than 65 years of age.1, 38
No major differences in safety were observed in patients 65 years of age and older compared with younger adults.1, 38
Nilotinib exposure is increased in patients with hepatic impairment.1, 38 Following administration of a single 200-mg dose of the drug in individuals with mild (Child-Pugh class A), moderate (Child-Pugh class B), or severe (Child-Pugh class C) hepatic impairment, area under the concentration-time curve (AUC) was increased by 1.4-, 1.4-, or 1.6-fold, respectively, compared with values observed in individuals with normal hepatic function.1 The manufacturer recommends that alternative therapy be considered, if possible, in patients with hepatic impairment.1, 38 If nilotinib therapy is required in patients with hepatic impairment, reduction of the initial dosage and close monitoring of the QT interval are recommended.1, 38
Nilotinib has not been studied in patients with renal impairment; however, since nilotinib and its metabolites are not renally excreted, a decrease in total body clearance is not anticipated in patients with renal impairment.1
Because median steady-state trough concentrations of nilotinib are reduced by 53% in patients who have undergone total gastrectomy, more frequent follow-up of these patients should be considered.1 If necessary, increased dosage of nilotinib or institution of alternative therapy may be considered.1, 38
Nilotinib can increase serum bilirubin concentrations.1, 38 A statistically significant increase in the risk of hyperbilirubinemia in patients with uridine diphosphate-glucuronosyltransferase (UGT) 1A1 (TA)7/(TA)7 genotype relative to (TA)6/(TA)6 and (TA)6/(TA)7 genotypes has been observed.1, 38 The largest increases in bilirubin were observed in patients with the (TA)7/(TA)7 genotype (UGT1A1*28).1, 38
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.1, 38
Adverse hematologic effects include thrombocytopenia, neutropenia, and anemia.1, 38
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).1
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).1
Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes
Drugs Metabolized by Hepatic Microsomal Enzymes
In vitro studies indicate that nilotinib is a competitive inhibitor of cytochrome P-450 (CYP) isoenzymes 2C8, and 2D6 and has the potential to increase concentrations of drugs metabolized by these enzymes.1, 38 Concomitant administration of nilotinib with midazolam (a CYP3A4 substrate) increased midazolam exposure by 2.6-fold.1 Administration of a single dose of nilotinib did not alter the pharmacokinetics or pharmacodynamics of warfarin (a CYP2C9 substrate).1
In vitro studies also suggest that nilotinib may induce CYP isoenzymes 2B6 and 2C8, and thereby has the potential to decrease concentrations of drugs that are metabolized by these enzymes.1, 38
Plasma concentrations of nilotinib may be increased during concomitant use with strong CYP3A4 inhibitors (e.g., ketoconazole); avoid concomitant use.1, 38 In healthy individuals receiving ketoconazole (400 mg once daily for 6 days), systemic exposure (as measured by the area under the concentration-time curve [AUC]) to nilotinib increased approximately threefold.1 If therapy with a strong CYP3A4 inhibitor is required, therapy with nilotinib should be interrupted; however, if concomitant use is required, consider reducing the dosage of nilotinib.1, 38 If the CYP3A4 inhibitor is discontinued, increase nilotinib dosage to usual indicated dosage after a suitable washout period.1, 38 In addition, patients should be closely monitored for prolongation of the QT interval.1, 38
Decreased nilotinib plasma concentrations may occur during concomitant use with strong CYP3A4 inducers (e.g., rifampin, St. John's wort [ Hypericum perforatum ]).1, 38 In individuals receiving rifampin (600 mg once daily for 12 days), a CYP3A4 inducer, systemic exposure (as measured by AUC) to nilotinib was decreased by approximately 80%.1 Concomitant use of nilotinib with strong CYP3A4 inducers should be avoided.1, 38
Drugs Affecting Gastric Acidity
Drugs that increase the pH of the upper GI tract may decrease the solubility of nilotinib and reduce its bioavailability.1, 18 In healthy individuals, concomitant oral administration of the proton-pump inhibitor esomeprazole (40 mg once daily for 6 days) with nilotinib (a single 400-mg dose given concomitantly with the sixth dose of esomeprazole) resulted in a 34% reduction in the AUC of nilotinib.1, 18 Concomitant use of nilotinib with proton-pump inhibitors should be avoided; alternative drugs should be selected (histamine H2-receptor antagonists or antacids).1, 38
The effects of histamine H2-receptor antagonists and antacids on the pharmacokinetics of nilotinib have not been established to date.1 If use of a histamine H2-receptor antagonist is necessary, the manufacturer recommends administering a histamine H2-receptor antagonist approximately 10 hours before or 2 hours after the dose of nilotinib.1, 38 If use of an antacid is necessary, the manufacturer recommends administering antacids approximately 2 hours before or 2 hours after nilotinib.1, 38
Drugs Metabolized by Uridine Diphosphate-glucuronosyltransferase
In vitro studies indicate that nilotinib is a competitive inhibitor of uridine diphosphate-glucuronosyltransferase (UGT) 1A1, potentially increasing the concentrations of drugs metabolized by this enzyme.1, 38
Substrates or Inhibitors of P-Glycoprotein Transport Systems
Nilotinib inhibits the efflux transporter P-glycoprotein (P-gp, ABCB1).1, 38
Nilotinib also is a P-gp substrate.1
Drugs that Prolong the QT Interval
The administration of nilotinib with drugs that prolong the QT interval should be avoided.1, 38 If therapy with any of these drugs is required, therapy with nilotinib should be interrupted.1, 38 If interruption of treatment with nilotinib is not possible, patients who require treatment with a drug that prolongs the QT interval should be closely monitored for prolongation of the QT interval.1, 38
Grapefruit products and other foods known to inhibit CYP3A4 should be avoided.1, 38 Concomitant administration of nilotinib with double-strength grapefruit juice increased nilotinib AUC by 1.3-fold.1, 38
In a phase 1 clinical trial, administration of nilotinib (400 mg twice daily) in conjunction with imatinib (400 mg once or twice daily) resulted in a 30-50% increase in nilotinib AUC and an increase of approximately 20% in imatinib AUC.1
Nilotinib, an inhibitor of Bcr-Abl tyrosine kinase, is an antineoplastic agent.1, 3, 4, 5, 6, 7, 8, 9, 11, 38 Chronic myelogenous leukemia (CML) is a clonal myeloproliferative disorder characterized by the expansion of hematopoietic cells carrying the Philadelphia chromosome (Ph), resulting from a reciprocal translocation of the long arms of chromosomes 9 and 22.3, 8 A novel fusion gene is formed, Bcr-Abl, which encodes a constitutively active, cytoplasmic form of protein tyrosine kinase.3, 8 The unregulated activity of the Abl tyrosine kinase in Bcr-Abl is the cause of CML.5, 14 Nilotinib is an orally active aminopyrimidine-derivative tyrosine kinase inhibitor that functions through competitive inhibition at the ATP-binding site of Bcr-Abl, leading to the inhibition of tyrosine phosphorylation of proteins that are involved in the intracellular signal transduction that Bcr-Abl mediates.4, 5
Clinical resistance to imatinib in CML has been attributed to several mechanisms, but point mutations in the Bcr-Abl kinase domain appear to the most common, occurring in 30-90% of patients who develop resistance.15 The ability of nilotinib to overcome imatinib resistance resulting from Bcr-Abl kinase domain mutations has been demonstrated in vitro.1 In preclinical studies in cell-line models, nilotinib inhibited most (32 of 33) imatinib-resistant Bcr-Abl kinase domain mutant forms.1, 5
Nilotinib is extensively metabolized by the cytochrome P-450 (CYP) microsomal enzyme system, principally by the isoenzyme 3A4.1, 38 Nilotinib is the principal circulating component in serum, and none of the metabolites substantially contribute to the pharmacologic activity of the drug.1 Following oral administration of a single radiolabeled dose of nilotinib, 93% of the radioactivity was recovered in feces within 7 days; unchanged drug accounted for 69% of the dose recovered in feces.1, 38 Nilotinib is 98% protein bound.1, 38 The mean plasma half-life of nilotinib capsules is 17 hours and 14 hours for nilotinib tablets.1, 38 Relative bioavailability of nilotinib capsule is approximately 50%, as compared to an oral drink solution.1 Following administration of nilotinib, peak plasma concentrations are reached in approximately 3 hours.1, 38 Food increases the bioavailability of nilotinib capsules.1 When the nilotinib capsule was administered 30 minutes after a high-fat meal, systemic exposure (as measured by the area under the concentration-time curve [AUC]) was increased by 82% relative to administration in the fasted state.1 However, single-dose administration of two intact 200-mg nilotinib capsules was bioequivalent to single-dose administration of two 200-mg capsules when the contents of each capsule were dispersed in a teaspoonful of applesauce and ingested within 15 minutes following dispersal.1 No clinically significant differences in exposure were seen following administration of nilotinib tablets with a high- or low-fat meal compared to fasted healthy patients.38 Steady-state exposure of nilotinib capsule is dose dependent; at dosages exceeding 400 mg once daily, the increase in exposure is less than proportional to the increase in dose.1 Steady-state exposure at a capsule dosage of 400 mg twice daily is 13% higher than exposure at a capsule dosage of 300 mg twice daily.1
Additional Information
The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care. For further information on the handling of antineoplastic agents, see the ASHP Guidelines on Handling Hazardous Drugs at [Web].
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Capsules | 50 mg* | ||
Nilotinib Capsules | ||||
150 mg* | Tasigna® | Novartis | ||
Nilotinib Capsules | ||||
200 mg* | Tasigna® | Novartis | ||
Nilotinib Capsules | ||||
Tablets | 71 mg | Danziten® | ||
95 mg | Danziten® |
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
1. Novartis Pharmaceuticals Corporation. Tasigna® (nilotinib) capsules prescribing information. East Hanover, NJ; 2024 Feb. [Web]
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27. Reichardt P, Blay JY, Gelderblom H et al. Phase III study of nilotinib versus best supportive care with or without a TKI in patients with gastrointestinal stromal tumors resistant to or intolerant of imatinib and sunitinib. Ann Oncol . 2012; 23:1680-7. [PubMed 22357255]
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38. Azurity Pharmaceuticals, Inc. Danziten® (nilotinib) tablets prescribing information. Woburn, MA; 2024 Nov.