Kenyan Health Patient Information Leaflet
Kinase Inhibitor [EPC]
of: Adult and pediatric patients greater than or equal to 1 year of age with newly diagnosed Philadelphia chromosome positive chronic myeloid leukemia (Ph+ CML) in chronic phase. ( 1.1 ) Adult patients with chronic phase (CP) and accelerated phase (AP) Ph+ CML resistant to or intolerant to prior therapy that included imatinib. ( 1.2 ) Pediatric patients greater than or equal to 1 year of age with Ph+ CML-CP resistant or intolerant to prior tyrosine-kinase inhibitor (TKI) therapy. (1.3) 1.1 Adult and Pediatric Patients With Newly Diagnosed Ph+ CML-CP Nilotinib capsules are indicated for the treatment of adult and pediatric patients greater than or equal to 1 year of age with newly diagnosed Philadelphia chromosome positive chronic myeloid leukemia (Ph+ CML) in chronic phase. 1.2 Adult Patients With Resistant or Intolerant Ph+ CML-CP and CML-AP Nilotinib capsules are indicated for the treatment of adult patients with chronic phase and accelerated phase Philadelphia chromosome positive chronic myelogenous leukemia (Ph+ CML) resistant or intolerant to prior therapy that included imatinib. 1.3 Pediatric Patients With Resistant or Intolerant Ph+ CML-CP Nilotinib capsules are indicated for the treatment of pediatric patients greater than or equal to 1 year of age with chronic phase Philadelphia chromosome positive chronic myeloid leukemia (Ph+ CML) with resistance or intolerance to prior tyrosine-kinase inhibitor (TKI) therapy. Additional pediatric use information is approved for Novartis Pharmaceuticals Corporation’s TASIGNA (nilotinib) capsules. However, due to Novartis Pharmaceuticals Corporation’s marketing exclusivity rights, this drug product is not labeled with that pediatric information.
Dose: Newly diagnosed Ph+ CML-CP: 300 mg orally twice daily. Resistant or intolerant Ph+ CML-CP and CML-AP: 400 mg orally twice daily. ( 2.1 ) Recommended Pediatric Dose: Newly Diagnosed Ph+ CML-CP or Ph+ CML-CP resistant or intolerant to prior TKI therapy: 230 mg/m 2 orally twice daily, rounded to the nearest 50 mg dose (to a maximum single dose of 400 mg). ( 2.1 ) See Dosage and Administration for full dosing instructions and dose-reduction instructions for toxicity. ( 2.1 ) Reduce starting dose in patients with baseline hepatic impairment. ( 2.7 ) Eligible newly diagnosed adult patients with Ph+ CML-CP who have received nilotinib capsules for a minimum of 3 years and have achieved a sustained molecular response (MR4.5) and patients with Ph+ CML-CP resistant or intolerant to imatinib who have received nilotinib capsules for at least 3 years and have achieved a sustained molecular response (MR4.5) may be considered for treatment discontinuation. ( 2.2 , 2.3 , 5.16 ) 2.1 Recommended Dosage Dose nilotinib capsules twice daily at approximately 12-hour intervals on an empty stomach. No food should be consumed for at least 2 hours before the dose is taken and for at least 1 hour after the dose is taken. Advise patients to swallow the capsules whole with water [ see Boxed Warning , Clinical Pharmacology (12.3) ]. For patients who are unable to swallow capsules, the contents of each capsule may be dispersed in 1 teaspoon of applesauce (puréed apple). The mixture should be taken immediately (within 15 minutes) and should not be stored for future use [ see Clinical Pharmacology (12.3) ]. Nilotinib capsules may be given in combination with hematopoietic growth factors, such as erythropoietin or G-CSF if clinically indicated. Nilotinib capsules may be given with hydroxyurea or anagrelide if clinically indicated. Dosage in Adult Patients with Newly Diagnosed Ph+ CML-CP The recommended dosage of nilotinib capsules are 300 mg orally twice daily. Dosage in Adult Patients with Resistant or Intolerant Ph+ CML-CP and CML-AP The recommended dosage of nilotinib capsules are 400 mg orally twice daily. Dosage in Pediatric Patients with Newly Diagnosed Ph+ CML-CP or Resistant or Intolerant Ph+ CML-CP The recommended dosage of nilotinib capsules for pediatric patients is 230 mg/m2 orally twice daily, rounded to the nearest 50 mg dose (to a maximum single dose of 400 mg) (see Table 1). If needed, attain the desired dose by combining different strengths of nilotinib capsules. Continue treatment as long as clinical benefit is observed or until unacceptable toxicity occurs. Table 1: Pediatric Dosing of Nilotinib capsules (230 mg/m 2 Twice Daily, Maximum Single Dose of 400 mg) Body surface area Single dose Total daily dose Up to 0.32 m 2 50 mg 100 mg 0.33 – 0.54 m 2 100 mg 200 mg 0.55 – 0.76 m 2 150 mg 300 mg 0.77 – 0.97 m 2 200 mg 400 mg 0.98 – 1.19 m 2 250 mg 500 mg 1.20 – 1.41 m 2 300 mg 600 mg 1.42 – 1.63 m 2 350 mg 700 mg ≥ 1.64 m 2 400 mg 800 mg Additional pediatric use information is approved for Novartis Pharmaceuticals Corporation’s TASIGNA (nilotinib) capsules. However, due to Novartis Pharmaceuticals Corporation’s marketing exclusivity rights, this drug product is not labeled with that pediatric information. 2.2 Discontinuation of Treatment After a Sustained Molecular Response (MR4.5) on Nilotinib Capsules Patient Selection Eligibility for Discontinuation of Treatment Ph+ CML-CP patients with typical BCR-ABL transcripts, who have been taking nilotinib capsules for a minimum of 3 years and have achieved a sustained molecular response (MR4.5, corresponding to = BCR-ABL/ABL ≤ 0.0032% IS), may be eligible for treatment discontinuation [ see Clinical Studies (14.3 , 14.4) ]. Information on FDA authorized tests for the detection and quantitation of BCR-ABL transcripts to determine eligibility for treatment discontinuation is available at http://www.fda.gov/CompanionDiagnostics. Patients with typical BCR-ABL transcripts (e13a2/b2a2 or e14a2/b3a2), who achieve the sustained MR4.5 criteria, are eligible for discontinuation of nilotinib capsules. Patients must continue to be monitored for possible loss of molecular remission after treatment discontinuation. Use the same FDA-authorized test to consistently monitor molecular response levels while on and off treatment. Consider discontinuation in patients with newly diagnosed Ph+ CML-CP who have: been treated with nilotinib capsules for at least 3 years maintained a molecular response of at least MR4.0 (corresponding to = BCR-ABL/ABL ≤ 0.01% IS) for one year prior to discontinuation of therapy achieved an MR4.5 for the last assessment taken immediately prior to discontinuation of therapy been confirmed to express the typical BCR-ABL transcripts (e13a2/b2a2 or e14a2/b3a2) no history of accelerated phase or blast crisis no history of prior attempts of treatment-free remission discontinuation that resulted in relapse. Consider discontinuation in patients with Ph+ CML-CP that are resistant or intolerant to imatinib who have achieved a sustained molecular response (MR4.5) on nilotinib capsules who have: been treated with nilotinib capsules for a minimum of 3 years been treated with imatinib only prior to treatment with nilotinib capsules achieved a molecular response of MR4.5 (corresponding to = BCR-ABL/ABL ≤ 0.0032% IS) sustained an MR4.5 for a minimum of one year immediately prior to discontinuation of therapy been confirmed to express the typical BCR-ABL transcripts (e13a2/b2a2 or e14a2/b3a2) no history of accelerated phase or blast crisis no history of prior attempts of treatment-free remission discontinuation that resulted in relapse. Monitor BCR-ABL transcript levels and complete blood count (CBC) with differential in patients who have discontinued nilotinib capsules therapy monthly for one year, then every 6 weeks for the second year, and every 12 weeks thereafter [ see Warnings and Precautions (5.16) ]. Upon the loss of MR4.0 (corresponding to = BCR-ABL/ABL ≤ 0.01% IS) during the treatment-free phase, monitor BCR-ABL transcript levels every 2 weeks until BCR-ABL levels remain lower than major molecular response [(MMR), corresponding to MR3.0 or = BCR-ABL/ABL ≤ 0.1% IS] for 4 consecutive measurements. The patient can then proceed to the original monitoring schedule. 2.3 Reinitiation of Treatment in Patients Who Lose Molecular Response After Discontinuation of Therapy With Nilotinib Capsules Newly diagnosed patients who lose MMR must reinitiate treatment within 4 weeks at the dose level prior to discontinuation of therapy [ see Warnings and Precautions (5.16) ]. Patients who reinitiate nilotinib capsules therapy should have their BCR-ABL transcript levels monitored monthly until major molecular response is re-established and every 12 weeks thereafter. Patients resistant or intolerant to prior treatment that included imatinib with confirmed loss of MR4.0 (2 consecutive measures separated by at least 4 weeks showing loss of MR4.0) or loss of MMR must reinitiate treatment within 4 weeks at the dose level prior to discontinuation of therapy [ see Warnings and Precautions (5.16) ]. Patients who reinitiate nilotinib capsules therapy should have their BCR-ABL transcript levels monitored monthly until previous major molecular response or MR4.0 is re-established and every 12 weeks thereafter. 2.4 Dosage Modification for QT Interval Prolongation See Table 2 for dose adjustments for QT interval prolongation [ see Warnings and Precautions (5.2) , Clinical Pharmacology (12.2) ]. Table 2: Dosage Adjustments for Adult and Pediatric Patients With QT Prolongation Degree of QTc prolongation Dosage adjustment ECGs with a QTc greater than 480 msec 1. Withhold nilotinib capsules, and perform an analysis of serum potassium and magnesium, and if below lower limit of normal, correct with supplements to within normal limits. Concomitant medication usage must be reviewed. 2. Resume within 2 weeks at prior dose if QTcF returns to less than 450 msec and to within 20 msec of baseline. 3. If QTcF is between 450 msec and 480 msec after 2 weeks, reduce the dose to 400 mg once daily in adults and 230 mg/m 2 once daily in pediatric patients. 4. Discontinue nilotinib capsules if, following dose-reduction to 400 mg once daily in adults and 230 mg/m 2 once daily in pediatric patients, QTcF returns to greater than 480 msec. 5. An ECG should be repeated approximately 7 days after any dose adjustment. Abbreviation: ECG, electrocardiogram. 2.5 Dosage Modifications for Myelosuppression Withhold or reduce nilotinib capsules dosage for hematological toxicities (neutropenia, thrombocytopenia) that are not related to underlying leukemia (Table 3) [ see Warnings and Precautions (5.1) ]. Table 3: Dosage Adjustments for Neutropenia and Thrombocytopenia Diagnosis Degree of myelosuppression Dosage adjustment Adult patients with: Newly diagnosed Ph+ CML in chronic phase at 300 mg twice daily Resistant or intolerant Ph+ CML in chronic phase or accelerated phase at 400 mg twice daily ANC less than 1.0 x 10 9 /L and/or platelet counts less than 50 x 10 9 /L Stop nilotinib capsules, and monitor blood counts. Resume within 2 weeks at prior dose if ANC greater than 1.0 x 10 9 /L and platelets greater than 50 x 10 9 /L. If blood counts remain low for greater than 2 weeks, reduce the dose to 400 mg once daily. Pediatric patients with: Newly diagnosed Ph+ CML in chronic phase at 230 mg/m 2 twice daily Resistant or intolerant Ph+ CML in chronic phase at 230 mg/m 2 twice daily ANC less than 1.0 x 10 9 /L and/or platelet counts less than 50 x 10 9 /L Stop nilotinib capsules and monitor blood counts. Resume within 2 weeks at prior dose if ANC greater than 1.5 x 10 9 /L and/or platelets greater than 75 x 10 9 /L. If blood counts remain low for greater than 2 weeks, a dose reduction to 230 mg/m 2 once daily may be required. If event occurs after dose reduction, consider discontinuing treatment. Abbreviations: ANC, absolute neutrophil count; Ph+ CML, Philadelphia chromosome positive chronic myeloid leukemia. 2.6 Dosage Modifications for Selected Non-Hematologic Laboratory Abnormalities and Other Toxicities See Table 4 for dosage adjustments for elevations of lipase, amylase, bilirubin, and/or hepatic transaminases [ see Warnings and Precautions (5.5 , 5.6) , Adverse Reactions (6.1) ]. Table 4: Dosage Adjustments for Selected Non-Hematologic Laboratory Abnormalities Degree of non-hematologic laboratory abnormality Dosage adjustment Elevated serum lipase or amylase greater than or equal to Grade 3 Adult patients: 1. Withhold nilotinib capsules, and monitor serum lipase or amylase. 2. Resume treatment at 400 mg once daily if serum lipase or amylase returns to less than or equal to Grade 1. Pediatric patients: Interrupt nilotinib capsules until the event returns to less than or equal to Grade 1. Resume treatment at 230 mg/m 2 once daily if prior dose was 230 mg/m 2 twice daily; discontinue treatment if prior dose was 230 mg/m 2 once daily. Elevated bilirubin greater than or equal to Grade 3 in adult patients and greater than or equal to Grade 2 in pediatric patients Adult patients: 1. Withhold nilotinib capsules, and monitor bilirubin. 2. Resume treatment at 400 mg once daily if bilirubin returns to less than or equal to Grade 1. Pediatric patients: 1. Interrupt nilotinib capsules until the event returns to less than or equal to Grade 1. 2. Resume treatment at 230 mg/m 2 once daily if prior dose was 230 mg/m 2 twice daily; discontinue treatment if prior dose was 230 mg/m 2 once daily, and recovery to less than or equal to Grade 1 takes longer than 28 days. Elevated hepatic transaminases greater than or equal to Grade 3 Adult patients: 1. Withhold nilotinib capsules, and monitor hepatic transaminases. 2. Resume treatment at 400 mg once daily if hepatic transaminases returns to less than or equal to Grade 1. Pediatric patients: 1. Interrupt nilotinib capsules until the event returns to less than or…
labeling: Myelosuppression [ see Warnings and Precautions (5.1) ] QT Prolongation [ see Boxed Warning , Warnings and Precautions (5.2) ] Sudden Deaths [ see Boxed Warning , Warnings and Precautions (5.3) ] Cardiac and Arterial Vascular Occlusive Events [ see Warnings and Precautions (5.4) ] Pancreatitis and Elevated Serum Lipase [ see Warnings and Precautions (5.5) ] Hepatotoxicity [ see Warnings and Precautions (5.6) ] Electrolyte Abnormalities [ see Boxed Warning , Warnings and Precautions (5.7) ] Hemorrhage [ see Warnings and Precautions (5.9) ] Fluid Retention [ see Warnings and Precautions (5.13) ] The most commonly reported non-hematologic adverse reactions (≥ 20%) in adult and pediatric patients were nausea, rash, headache, fatigue, pruritus, vomiting, diarrhea, cough, constipation, arthralgia, nasopharyngitis, pyrexia, and night sweats. Hematologic adverse drug reactions include myelosuppression: thrombocytopenia, neutropenia, and anemia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Novadoz Pharmaceuticals LLC at 1-855-668-2369 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. In Adult Patients With Newly Diagnosed Ph+ CML-CP The data below reflect exposure to nilotinib from a randomized trial in patients with newly diagnosed Ph+ CML in chronic phase treated at the recommended dose of 300 mg twice daily (n = 279). The median time on treatment in the nilotinib 300 mg twice daily group was 61 months (range, 0.1 to 71 months). The median actual dose intensity was 593 mg/day in the nilotinib 300 mg twice daily group. The most common (greater than 10%) non-hematologic adverse drug reactions were rash, pruritus, headache, nausea, fatigue, alopecia, myalgia, and upper abdominal pain. Constipation, diarrhea, dry skin, muscle spasms, arthralgia, abdominal pain, peripheral edema, vomiting, and asthenia were observed less commonly (less than or equal to 10% and greater than 5%) and have been of mild-to-moderate severity, manageable and generally did not require dose reduction. Increase in QTcF greater than 60 msec from baseline was observed in 1 patient (0.4%) in the 300 mg twice daily treatment group. No patient had an absolute QTcF of greater than 500 msec while on study drug. The most common hematologic adverse drug reactions (all Grades) were myelosuppression, including: thrombocytopenia (18%), neutropenia (15%), and anemia (8%). See Table 9 for Grade 3/4 laboratory abnormalities. Discontinuation due to adverse reactions, regardless of relationship to study drug, was observed in 10% of patients. In Adult Patients With Resistant or Intolerant Ph+ CML-CP and CML-AP In the single-arm, open-label multicenter clinical trial, a total of 458 patients with Ph+ CML-CP and CML-AP resistant to or intolerant to at least one prior therapy, including imatinib were treated (CML-CP = 321; CML-AP = 137) at the recommended dose of 400 mg twice daily. The median duration of exposure in days for CML-CP and CML-AP patients is 561 (range, 1 to 1096) and 264 (range, 2 to 1160), respectively. The median dose intensity for patients with CML-CP and CML-AP is 789 mg/day (range, 151 to 1110) and 780 mg/day (range, 150 to 1149), respectively, and corresponded to the planned 400 mg twice daily dosing. The median cumulative duration in days of dose interruptions for the CML-CP patients was 20 (range, 1 to 345), and the median duration in days of dose interruptions for the CML-AP patients was 23 (range, 1 to 234). In patients with CML-CP, the most commonly reported non-hematologic adverse drug reactions (greater than or equal to 10%) were rash, pruritus, nausea, fatigue, headache, constipation, diarrhea, vomiting, and myalgia. The common serious drug-related adverse reactions (greater than or equal to 1% and less than 10%) were thrombocytopenia, neutropenia, and anemia. In patients with CML-AP, the most commonly reported non-hematologic adverse drug reactions (greater than or equal to 10%) were rash, pruritus and fatigue. The common serious adverse drug reactions (greater than or equal to 1% and less than 10%) were thrombocytopenia, neutropenia, febrile neutropenia, pneumonia, leukopenia, intracranial hemorrhage, elevated lipase, and pyrexia. Sudden deaths and QT prolongation were reported. The maximum mean QTcF change from baseline at steady-state was 10 msec. Increase in QTcF greater than 60 msec from baseline was observed in 4.1% of the patients and QTcF of greater than 500 msec was observed in 4 patients (less than 1%) [ see Boxed Warning , Warnings and Precautions (5.2 , 5.3) , Clinical Pharmacology (12.2) ]. Discontinuation due to adverse drug reactions was observed in 16% of CML-CP and 10% of CML-AP patients. Most Frequently Reported Adverse Reactions Tables 7 and 8 show the percentage of adult patients experiencing non-hematologic adverse reactions (excluding laboratory abnormalities) regardless of relationship to study drug. Adverse reactions reported in greater than 10% of adult patients who received at least 1 dose of nilotinib are listed. Table 7: Most Frequently Reported Non-Hematologic Adverse Reactions (Regardless of Relationship to Study Drug) in Adult Patients With Newly Diagnosed Ph+ CML-CP (greater than or equal to 10% in nilotinib 300 mg twice daily or imatinib 400 mg once daily groups) 60-Month Analysis a Patients With Newly Diagnosed Ph+ CML-CP Nilotinib 300 mg twice daily imatinib 400 mg once daily Nilotinib 300 mg twice daily imatinib 400 mg once daily N = 279 N = 280 N = 279 N = 280 Body System and Adverse Reaction All Grades (%) CTC Grades b 3/4 (%) Skin and subcutaneous tissue disorders Rash 38 19 < 1 2 Pruritus 21 7 < 1 0 Alopecia 13 7 0 0 Dry skin 12 6 0 0 Gastrointestinal disorders Nausea 22 41 2 2 Constipation 20 8 < 1 0 Diarrhea 19 46 1 4 Vomiting 15 27 < 1 < 1 Abdominal pain upper 18 14 1 < 1 Abdominal pain 15 12 2 0 Dyspepsia 10 12 0 0 Nervous system disorders Headache 32 23 3 < 1 Dizziness 12 11 < 1 < 1 General disorders and administration-site conditions Fatigue 23 20 1 1 Pyrexia 14 13 < 1 0 Asthenia 14 12 < 1 0 Peripheral edema 9 20 < 1 0 Face edema < 1 14 0 < 1 Musculoskeletal and connective tissue disorders Myalgia 19 19 < 1 < 1 Arthralgia 22 17 < 1 < 1 Muscle spasms 12 34 0 1 Pain in extremity 15 16 < 1 < 1 Back pain 19 17 1 1 Respiratory, thoracic, and mediastinal disorders Cough 17 13 0 0 Oropharyngeal pain 12 6 0 0 Dyspnea 11 6 2 < 1 Infections and infestations Nasopharyngitis 27 21 0 0 Upper respiratory tract infection 17 14 < 1 0 Influenza 13 9 0 0 Gastroenteritis 7 10 0 < 1 Eye disorders Eyelid edema 1 19 0 < 1 Periorbital edema < 1 15 0 0 Psychiatric disorders Insomnia 11 9 0 0 Vascular disorder Hypertension 10 4 1 < 1 Abbreviations: CML-CP, chronic myeloid leukemia-chronic phase; Ph+, Philadelphia chromosome positive. a Excluding laboratory abnormalities. b NCI Common Terminology Criteria (CTC) for Adverse Events, version 3.0. Table 8: Most Frequently Reported Non-Hematologic Adverse Reactions in Adult Patients With Resistant or Intolerant Ph+ CML Receiving Nilotinib 400 mg Twice Daily (regardless of relationship to study drug) (greater than or equal to 10% in any group) 24-Month Analysisa Body System and Adverse Reaction CML-CP CML-AP N = 321 N = 137 All Grades (%) CTC Grades b 3/4 (%) All Grades (%) CTC Grades b 3/4 (%) Skin and subcutaneous tissue disorders Rash 36 2 29 0 Pruritus 32 < 1 20 0 Night sweat 12 < 1 27 0 Alopecia 11 0 12 0 Gastrointestinal disorders Nausea 37 1 22 < 1 Constipation 26 < 1 19 0 Diarrhea 28 3 24 2 Vomiting 29 < 1 13 0 Abdominal pain 15 2 16 3 Abdominal pain upper 14 < 1 12 < 1 Dyspepsia 10 < 1 4 0 Nervous system disorders Headache 35 2 20 1 General disorders and administration-site conditions Fatigue 32 3 23 < 1 Pyrexia 22 < 1 28 2 Asthenia 16 0 14 1 Peripheral edema 15 < 1 12 0 Musculoskeletal and connective tissue disorders Myalgia 19 2 16 < 1 Arthralgia 26 2 16 0 Muscle spasms 13 < 1 15 0 Bone pain 14 < 1 15 2 Pain in extremity 20 2 18 1 Back pain 17 2 15 < 1 Musculoskeletal pain 11 < 1 12 1 Respiratory, thoracic, and mediastinal disorders Cough 27 < 1 18 0 Dyspnea 15 2 9 2 Oropharyngeal pain 11 0 7 0 Infections and infestations Nasopharyngitis 24 < 1 15 0 Upper respiratory tract infection 12 0 10 0 Metabolism and nutrition disorders Decreased appetite c 15 < 1 17 < 1 Psychiatric disorders Insomnia 12 1 7 0 Vascular disorders Hypertension 10 2 11 < 1 Abbreviations: CML-AP, chronic myeloid leukemia-accelerated phase; CML-CP, chronic myeloid leukemia-chronic phase; Ph+, Philadelphia chromosome positive. a Excluding laboratory abnormalities. b NCI Common Terminology Criteria for Adverse Events, version 3.0. c Also includes preferred term anorexia. Laboratory Abnormalities Table 9 shows the percentage of adult patients experiencing treatment-emergent Grade 3/4 laboratory abnormalities in patients who received at least one dose of nilotinib. Table 9: Percent Incidence of Clinically Relevant Grade 3/4* Laboratory Abnormalities Patient population Newly diagnosed adult Ph+ CML-CP Resistant or intolerant adult Ph+ CML-CP CML-AP Nilotinib 300 mg twice daily N = 279 (%) imatinib 400 mg once daily N = 280 (%) Nilotinib 400 mg twice daily N = 321 (%) Nilotinib 400 mg twice daily N = 137 (%) Hematologic parameters Thrombocytopenia 10 9 30 1 42 3 Neutropenia 12 22 31 2 42 4 Anemia 4 6 11 27 Biochemistry parameters Elevated lipase 9 4 18 18 Hyperglycemia 7 < 1 12 6 Hypophosphatemia 8 10 17 15 Elevated bilirubin (total) 4 < 1 7 9 Elevated SGPT (ALT) 4 3 4 4 Hyperkalemia 2 1 6 4 Hyponatremia 1 < 1 7 7 Hypokalemia < 1 2 2 9 Elevated SGOT (AST) 1 1 3 2 Decreased albumin 0 < 1 4 3 Hypocalcemia < 1 < 1 2 5 Elevated alkaline phosphatase 0 < 1 < 1 1 Elevated creatinine 0 < 1 < 1 < 1 Abbreviations: ALT alanine aminotransferase; AST, aspartate aminotransferase; CML-AP, chronic myeloid leukemia-accelerated phase; CML-CP, chronic myeloid leukemia-chronic phase; Ph+, Philadelphia chromosome positive. *NCI Common Terminology Criteria for Adverse Events, version 3.0. 1 CML-CP: Thrombocytopenia: 12% were Grade 3, 18% were Grade 4. 2 CML-CP: Neutropenia: 16% were Grade 3, 15% were Grade 4. 3 CML-AP: Thrombocytopenia: 11% were Grade 3, 32% were Grade 4. 4 CML-AP: Neutropenia: 16% were Grade 3, 26% were Grade 4. Elevated total cholesterol (all Grades) occurred in 28% (nilotinib 300 mg twice daily) and 4% (imatinib). Elevated triglycerides (all Grades) occurred in 12% and 8% of patients in the nilotinib and imatinib arms, respectively. Hyperglycemia (all Grades) occurred in 50% and 31% of patients in the nilotinib and imatinib arms, respectively. Most common biochemistry laboratory abnormalities (all Grades) were alanine aminotransferase increased (72%), blood bilirubin increased (59%), aspartate aminotransferase increased (47%), lipase increased (28%), blood glucose increased (50%), blood cholesterol increased (28%), and blood triglyceride increased (12%). Treatment Discontinuation in Patients With Ph+ CML-CP Who Have Achieved a Sustained Molecular Response (MR4.5) In eligible patients who discontinued nilotinib therapy after attaining a sustained molecular response (MR4.5), musculoskeletal symptoms (e.g., myalgia, pain in extremity, arthralgia, bone pain, spinal pain, or musculoskeletal pain), were reported more frequently than before treatment discontinuation in the first year, as noted in Table 10. The rate of new musculoskeletal symptoms generally decreased in the second year after treatment discontinuation. In the newly diagnosed population in whom musculoskeletal symptoms occurred at any time during the TFR phase, 23/53 (43%) had not resolved by the TFR end date or data cut-off date. In the population previously treated with…
16 HOW SUPPLIED/STORAGE AND HANDLING Nilotinib 50 mg capsules are light yellow opaque colour body and red opaque colour cap imprinted with “MN5” with black ink. Nilotinib 150 mg capsules are red opaque colour body and red opaque colour cap imprinted with“MN4” with black ink. Nilotinib 200 mg capsules are light yellow opaque colour body and light yellow opaque colour cap imprinted with “MN3” with black ink. Nilotinib 50 mg capsules are supplied in bottles and nilotinib 150 mg and 200 mg capsules are supplied in blister packs. 50 mg Bottle of 120 capsules...................................................................................................NDC 72205-237-92 150 mg Carton of 4 blister packs of (4x28) ...............................................................................NDC 72205-238-64 Blisters of 28 capsules .................................................................................................NDC 72205-238-63 200 mg Carton of 4 blister packs of (4x28) ...............................................................................NDC 72205-239-64 Blisters of 28 capsules .................................................................................................NDC 72205-239-63 Nilotinib capsules should be stored at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C (59°F and 86°F) [see USP Controlled Room Temperature].