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Nilotinib is a brand name for Nilotinib. The medicine, its uses, side effects and dosage are the same regardless of brand.
Used for: 1 INDICATIONS AND USAGE Nilotinib capsules are a kinase inhibitor 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. ( 1.1 ) Adult patients with chronic phase (CP)…
Verbatim from this product's FDA label. Tap a section to expand.
2 DOSAGE AND ADMINISTRATION Recommended Adult 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. 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).
1 ) See Dosage and Administration for full dosing instructions and dose-reduction instructions for toxicity. 1 ) Reduce starting dose in patients with baseline hepatic impairment. 5) may be considered for treatment discontinuation. 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. 3) ]. For patients who are unable to swallow capsules, the contents of each capsule may be dispersed in 1 teaspoon of applesauce (puréed apple).
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. 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. 4) ]. gov/CompanionDiagnostics. 5 criteria, are eligible for discontinuation of nilotinib capsules.
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. gov/medwatch. 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).
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.
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.
5 WARNINGS AND PRECAUTIONS Myelosuppression : Monitor complete blood count (CBC) during therapy and manage by treatment interruption or dose reduction. 1 ) Cardiac and Arterial Vascular Occlusive Events : Evaluate cardiovascular status, monitor and manage cardiovascular risk factors during nilotinib therapy.
4 ) Pancreatitis and Elevated Serum Lipase : Monitor serum lipase; if elevations are accompanied by abdominal symptoms, interrupt doses and consider appropriate diagnostics to exclude pancreatitis. 5 ) Hepatotoxicity : Monitor hepatic function tests monthly or as clinically indicated.
6 ) Electrolyte Abnormalities : Nilotinib can cause hypophosphatemia, hypokalemia, hyperkalemia, hypocalcemia, and hyponatremia. Correct electrolyte abnormalities prior to initiating nilotinib and monitor periodically during therapy.
7 ) Tumor Lysis Syndrome : Maintain adequate hydration and correct uric acid levels prior to initiating therapy with nilotinib. 8 ) Hemorrhage : Hemorrhage from any site may occur. Advise patients to report signs and symptoms of bleeding and medically manage as needed.
9 ) Fluid Retention : Monitor patients for unexpected rapid weight gain, swelling, and shortness of breath. Manage medically. 13 ) Effects on Growth and Development in Pediatric Patients: Growth retardation has been reported in pediatric patients treated with nilotinib.
Monitor growth and development in pediatric patients. 14 ) Embryo-Fetal Toxicity : Advise females of reproductive potential of potential risk to a fetus and to use effective contraception. 3 ) Treatment Discontinuation : Patients must have typical BCR-ABL transcripts.
5 must be used to determine eligibility for discontinuation. Patients must be frequently monitored by the FDA authorized test to detect possible loss of remission. 1 Myelosuppression Treatment with nilotinib can cause Grade 3/4 thrombocytopenia, neutropenia, and anemia.
4 CONTRAINDICATIONS Nilotinib is contraindicated in patients with hypokalemia, hypomagnesemia, or long QT syndrome [ see Boxed Warning ]. Nilotinib is contraindicated in patients with hypokalemia, hypomagnesemia, or long QT syndrome.
( 4 )
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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. 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.
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.
16) ]. 1% IS] for 4 consecutive measurements. The patient can then proceed to the original monitoring schedule. 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.
16) ]. 0 is re-established and every 12 weeks thereafter. 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. 1) ]. 0 x 10 9 /L and/or platelet counts less than 50 x 10 9 /L Stop nilotinib capsules, and monitor blood counts. 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.
0 x 10 9 /L and/or platelet counts less than 50 x 10 9 /L Stop nilotinib capsules and monitor blood counts. 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. 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 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.
1) ].
Table 5:
Dosage Adjustments for Other Non-Hematologic Toxicities Degree of “other Non-hematologic toxicity” Dosage adjustment Other clinically moderate or severe non-hematologic toxicity Adult patients: 1. Withhold nilotinib capsules until toxicity has resolved.
2. Resume treatment at 400 mg once daily if previous dose was 300 mg twice daily in adult patients newly diagnosed with CML-CP or 400 mg twice daily in adult patients with resistant or intolerant CML-CP and CML-AP. 3. Discontinue treatment if the prior dose was 400 mg once daily in adult patients.
4. If clinically appropriate, consider re-escalation of the dose to 300 mg (newly diagnosed Ph+ CML-CP) or 400 mg (resistant or intolerant Ph+ CML-CP and CMLAP) twice daily. Pediatric patients: 1. Interrupt nilotinib capsules until toxicity has resolved.
2. Resume treatment at 230 mg/m 2 once daily if previous dose was 230 mg/m 2 twice daily; discontinue treatment if prior dose was 230 mg/m 2 once daily. 3. If clinically appropriate, consider re-escalation of the dose to 230 mg/m 2 twice daily.
Abbreviations:
CML-AP, chronic myeloid leukemia-accelerated phase; CML-CP, chronic myeloid leukemia-chronic phase; Ph+, Philadelphia chromosome positive. 7 Dosage Modification for Hepatic Impairment If possible, consider alternative therapies. 7) ]: Table 6: Dose Adjustments for Adult Patients With Hepatic Impairment Diagnosis Degree of hepatic impairment Dosage adjustment Newly diagnosed Ph+ CML in chronic phase Mild (Child-Pugh A), Moderate (Child-Pugh B), or Severe (Child-Pugh C) Reduce dosage to 200 mg twice daily.
Increase dosage to 300 mg twice daily based on tolerability. Resistant or intolerant Ph+ CML in chronic phase or accelerated phase Mild or Moderate Reduce dosage to 300 mg twice daily. Increase dosage to 400 mg twice daily based on tolerability.
Severe Reduce dosage to 200 mg twice daily. Increase dosage to 300 mg twice daily and then to 400 mg twice daily based on tolerability. 8 Dosage Modification With Concomitant Strong CYP3A4 Inhibitors Avoid the concomitant use of strong CYP3A4 inhibitors.
Should treatment with any of these agents be required, interrupt therapy with nilotinib capsules. If patients must be coadministered a strong CYP3A4 inhibitor, reduce dosage to 300 mg once daily in patients with resistant or intolerant Ph+ CML or to 200 mg once daily in patients with newly diagnosed Ph+ CML-CP.
However, there are no clinical data with this dose adjustment in patients receiving strong CYP3A4 inhibitors. If the strong inhibitor is discontinued, allow a washout period before adjusting nilotinib capsules dose upward to the indicated dose.
3) ].
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. 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. 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. 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.
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%).
, 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 imatinib in whom musculoskeletal events occurred at any time during the TFR phase, 32/57 (56%) had not resolved by the data cut-off date.
The rate of musculoskeletal symptoms decreased in patients who entered the nilotinib treatment reinitiation (NTRI) phase, at 11/88 (13%) in the newly diagnosed population and 14/56 (25%) in the population previously treated with imatinib.
Other adverse reactions observed in the nilotinib re-treatment phase were similar to those observed during nilotinib use in patients with newly diagnosed Ph+ CML-CP and resistant or intolerant Ph+ CML-CP and CML-AP.
Table 10:
Musculoskeletal Symptoms Occurring Upon Treatment Discontinuation in the Context of Treatment-Free Remission (TFR) Entire TFR period in all TFR patients By time interval, in subset of patients in TFR greater than 48 weeks Ph+ CMLCP patients N Median follow-up in TFR Patients with musculoskeletal symptoms N Year prior to nilotinib discontinuation 1 st year after nilotinib discontinuation 2 nd year after nilotinib discontinuation All Grades Grade 3/4 All Grades Grade 3/4 All Grades Grade 3/4 All Grades Grade 3/4 Newly Diagnosed 190 76 weeks 28% 1% 100 17% 0% 34% 2% 9% 0% Previously treated with imatinib 126 99 weeks 45% 2% 73 14% 0% 48% 3% 15% 1% Abbreviations: CML-CP, chronic myeloid leukemia-chronic phase; Ph+, Philadelphia chromosome positive ;TFR, treatment-free remission.
Additional Data From Clinical Trials The following adverse drug reactions were reported in adult patients in the nilotinib clinical studies at the recommended doses. 1% and less than 1%), and unknown frequency (single events). For laboratory abnormalities, very common events (greater than or equal to 10%), which were not included in Tables 7 and 8, are also reported.
These adverse reactions are included based on clinical relevance and ranked in order of decreasing seriousness within each category, obtained from 2 clinical studies: 1. Adult patients with newly diagnosed Ph+ CML-CP 60 month analysis and, 2.
Adult patients with resistant or intolerant Ph+ CML-CP and CMP-AP 24 months’ analysis.
Infections and Infestations:
Common: folliculitis. Uncommon: pneumonia, bronchitis, urinary tract infection, candidiasis (including oral candidiasis). Unknown frequency: hepatitis B reactivation, sepsis, subcutaneous abscess, anal abscess, furuncle, tinea pedis.
Neoplasms Benign, Malignant, and Unspecified:
Common: skin papilloma. Unknown frequency: oral papilloma, paraproteinemia.
Blood and Lymphatic System Disorders:
Common: leukopenia, eosinophilia, febrile neutropenia, pancytopenia, lymphopenia. Unknown frequency: thrombocythemia, leukocytosis.
Immune System Disorders:
Unknown frequency: hypersensitivity.
Endocrine Disorders:
Uncommon: hyperthyroidism, hypothyroidism. Unknown frequency: hyperparathyroidism secondary, thyroiditis.
Metabolism and Nutrition Disorders:
Very Common: hypophosphatemia. Common: electrolyte imbalance (including hypomagnesemia, hyperkalemia, hypokalemia, hyponatremia, hypocalcemia, hypercalcemia, hyperphosphatemia), diabetes mellitus, hyperglycemia, hypercholesterolemia, hyperlipidemia, hypertriglyceridemia.
Uncommon: gout, dehydration, increased appetite. Unknown frequency: hyperuricemia, hypoglycemia.
Psychiatric Disorders:
Common: depression, anxiety. Unknown frequency: disorientation, confusional state, amnesia, dysphoria.
Nervous System Disorders:
Common: peripheral neuropathy, hypoesthesia, paresthesia. Uncommon: intracranial hemorrhage, ischemic stroke, transient ischemic attack, cerebral infarction, migraine, loss of consciousness (including syncope), tremor, disturbance in attention, hyperesthesia, facial paralysis.
Unknown frequency: basilar artery stenosis, brain edema, optic neuritis, lethargy, dysesthesia, restless legs syndrome.
Eye Disorders:
Common: eye hemorrhage, eye pruritus, conjunctivitis, dry eye (including xerophthalmia). Uncommon: vision impairment, vision blurred, visual acuity reduced, photopsia, hyperemia (scleral, conjunctival, ocular), eye irritation, conjunctival hemorrhage.
Unknown frequency: papilledema, diplopia, photophobia, eye swelling, blepharitis, eye pain, chorioretinopathy, conjunctivitis allergic, ocular surface disease.
Ear and Labyrinth Disorders:
Common: vertigo. Unknown frequency: hearing impaired, ear pain, tinnitus.
Cardiac Disorders:
Common: angina pectoris, arrhythmia (including atrioventricular block, cardiac flutter, extrasystoles, atrial fibrillation, tachycardia, bradycardia), palpitations, electrocardiogram QT prolonged. Uncommon: cardiac failure, myocardial infarction, coronary artery disease, cardiac murmur, coronary artery stenosis, myocardial ischemia, pericardial effusion, cyanosis.
Unknown frequency: ventricular dysfunction, pericarditis, ejection fraction decrease.
Vascular Disorders:
Common: flushing. Uncommon: hypertensive crisis, peripheral arterial occlusive disease, intermittent claudication, arterial stenosis limb, hematoma, arteriosclerosis. Unknown frequency: shock hemorrhagic, hypotension, thrombosis, peripheral artery stenosis.
Respiratory, Thoracic and Mediastinal Disorders:
Common: dyspnea exertional, epistaxis, dysphonia. Uncommon: pulmonary edema, pleural effusion, interstitial lung disease, pleuritic pain, pleurisy, pharyngolaryngeal pain, throat irritation. Unknown frequency: pulmonary hypertension, wheezing.
Gastrointestinal Disorders:
Common: pancreatitis, abdominal discomfort, abdominal distension, dysgeusia, flatulence. Uncommon: gastrointestinal hemorrhage, melena, mouth ulceration, gastroesophageal reflux, stomatitis, esophageal pain, dry mouth, gastritis, sensitivity of teeth.
Unknown frequency: gastrointestinal ulcer perforation, retroperitoneal hemorrhage, hematemesis, gastric ulcer, esophagitis ulcerative, subileus, enterocolitis, hemorrhoids, hiatus hernia, rectal hemorrhage, gingivitis.
Hepatobiliary Disorders:
Very common: hyperbilirubinemia. Common: hepatic function abnormal. Uncommon: hepatotoxicity, toxic hepatitis, jaundice. Unknown frequency: cholestasis, hepatomegaly.
Skin and Subcutaneous Tissue Disorders:
Common: eczema, urticaria, erythema, hyperhidrosis, contusion, acne, dermatitis (including allergic, exfoliative and acneiform). Uncommon: exfoliative rash, drug eruption, pain of skin, ecchymosis. Unknown frequency: psoriasis, erythema multiforme, erythema nodosum, skin ulcer, palmar-plantar erythrodysesthesia syndrome, petechiae, photosensitivity, blister, dermal cyst, sebaceous hyperplasia, skin atrophy, skin discoloration, skin exfoliation, skin hyperpigmentation, skin hypertrophy, hyperkeratosis.
Musculoskeletal and Connective Tissue Disorders:
Common: bone pain, musculoskeletal chest pain, musculoskeletal pain, back pain, neck pain, flank pain, muscular weakness. Uncommon: musculoskeletal stiffness, joint swelling. Unknown frequency: arthritis.
Renal and Urinary Disorders:
Common: pollakiuria. Uncommon: dysuria, micturition urgency, nocturia. Unknown frequency: renal failure, hematuria, urinary incontinence, chromaturia.
Reproductive System and Breast Disorders:
Uncommon: breast pain, gynecomastia, erectile dysfunction. Unknown frequency: breast induration, menorrhagia, nipple swelling.
General Disorders and Administration Site Conditions:
Common: pyrexia, chest pain (including non-cardiac chest pain), pain, chest discomfort, malaise. Uncommon: gravitational edema, influenza-like illness, chills, feeling body temperature change (including feeling hot, feeling cold). Unknown frequency: localized edema.
Investigations:
Very Common: alanine aminotransferase increased, aspartate aminotransferase increased, lipase increased, lipoprotein cholesterol (including very low density and high density) increased, total cholesterol increased, blood triglycerides increased.
Common: hemoglobin decreased, blood amylase increased, gamma¬-glutamyltransferase increased, blood creatinine phosphokinase increased, blood alkaline phosphatase increased, weight decreased, weight increased, globulins decreased. Uncommon: blood lactate dehydrogenase increased, blood urea increased.
Unknown frequency: troponin increased, blood bilirubin unconjugated increased, insulin C-peptide decreased, blood parathyroid hormone increased. 5 )]. 5 months). 1%). Thirty-nine patients (57%) had relative dose intensity superior to 90%.
In pediatric patients with Ph+ CML-CP, the most common (greater than 20%) non-hematologic adverse reactions were hyperbilirubinemia, headache, alanine aminotransferase increased, rash, pyrexia, nausea, aspartate aminotransferase increased, pain in extremity, upper respiratory tract infection, vomiting, diarrhea, and nasopharyngitis.
The most common (greater than 5%) Grade 3/4 non-hematologic adverse reactions were hyperbilirubinemia, rash, alanine aminotransferase increased, and neutropenia. 9%, ALT Grade 3/4: 10%), were reported at a higher frequency than in adult patients.
The most common hematological laboratory abnormalities (greater than or equal to 30% of patients, of all Grades) were decreases in total white blood cells (54%), platelet count (44%), absolute neutrophils (44%), hemoglobin (38%), and absolute lymphocytes (36%).
Discontinuation of study treatment due to adverse reactions occurred in 15 patients (22%). The most frequent adverse reactions leading to discontinuation were hyperbilirubinemia (9%) and rash (6%). Increase in QTcF greater than 30 msec from baseline was observed in 19 patients (28%).
No patient had an absolute QTcF of greater than 500 msec or QTcF increase of greater than 60 msec from baseline. 7 months, adverse reactions associated with growth and deceleration of growth in regard to height were reported in 3 patients (5%).
The adverse reactions include growth retardation in 2 adolescent patients and growth hormone deficiency with short stature in the remaining patient (age category: child). Of the 58 pediatric patients, five (9%) crossed two main percentile lines from baseline and three (5%) crossed three main percentile lines from baseline (percentile lines: 5th, 10th, 25th, 50th, 75th, 90th, and 95th).
14 )]. 2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of nilotinib. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Blood and Lymphatic System Disorders : thrombotic microangiopathy Nervous System Disorders : facial paralysis Musculoskeletal and Connective Tissue Disorders : osteonecrosis
Perform CBCs every 2 weeks for the first 2 months and then monthly thereafter, or as clinically indicated. 5) ]. 2) ]. Prolongation of the QT interval can result in a type of ventricular tachycardia called torsade de pointes, which may result in syncope, seizure, and/or death.
12) ]. Nilotinib should not be used in patients who have hypokalemia, hypomagnesemia, or long QT syndrome. Before initiating nilotinib and periodically, test electrolyte, calcium, and magnesium blood levels. 12) ]. Significant prolongation of the QT interval may occur when nilotinib is inappropriately taken with food and/or strong CYP3A4 inhibitors and/or medicinal products with a known potential to prolong QT.
2) ]. 12) ]. 3% of patients with CML treated with nilotinib in clinical studies of 5661 patients. The relative 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) ]. 2% in the imatinib arm. 7% in the imatinib arm). If acute signs or symptoms of cardiovascular events occur, advise patients to seek immediate medical attention. 4) ]. 1) ]. Patients with a previous history of pancreatitis may be at greater risk of elevated serum lipase.
6) ]. Test serum lipase levels monthly or as clinically indicated. 6 Hepatotoxicity Nilotinib may result in hepatotoxicity as measured by elevations in bilirubin, aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase.
Grade 3 to 4 elevations of bilirubin, AST, and ALT were reported at a higher frequency in pediatric than in adult patients. 12) ] and following dose adjustments. 6) ]. 7 Electrolyte Abnormalities The use of nilotinib can cause hypophosphatemia, hypokalemia, hyperkalemia, hypocalcemia, and hyponatremia.
Correct electrolyte abnormalities prior to initiating nilotinib and during therapy. 12) ]. 8 Tumor Lysis Syndrome Tumor lysis syndrome (TLS) cases have been reported in nilotinib treated patients with resistant or intolerant CML. Malignant disease progression, high white blood cell (WBC) counts and/or dehydration were present in the majority of these cases.
Due to potential for TLS, maintain adequate hydration and correct uric acid levels prior to initiating therapy with nilotinib. 9 Hemorrhage Serious hemorrhagic events, including fatal events, have occurred in patients with CML treated with nilotinib.
4% of patients in the imatinib arm. 4% of patients in the imatinib arm, respectively. 4% of patients in the nilotinib 300 mg twice daily and 400 mg twice daily arms, respectively, and in no patients in the imatinib arm. Monitor for signs and symptoms of bleeding and medically manage as needed.
10 Total Gastrectomy Since the exposure of nilotinib is reduced in patients with total gastrectomy, perform more frequent monitoring of these patients. 3) ]. 11 Lactose Since the capsules contain lactose, nilotinib is not recommended for patients with rare hereditary problems of galactose intolerance, severe lactase deficiency with a severe degree of intolerance to lactose-containing products, or of glucose-galactose malabsorption.
12 Monitoring Laboratory Tests Complete blood counts should be performed every 2 weeks for the first 2 months and then monthly thereafter. Perform chemistry panels, including electrolytes, calcium, magnesium, liver enzymes, lipid profile, and glucose prior to therapy and periodically.
2) ]. Monitor lipid profiles and glucose periodically during the first year of nilotinib therapy and at least yearly during chronic therapy. 1) ]. Assess glucose levels before initiating treatment with nilotinib and monitor during treatment as clinically indicated.
If test results warrant therapy, physicians should follow their local standards of practice and treatment guidelines. 5% of patients receiving imatinib. 1% of patients receiving imatinib. 4% of patients receiving nilotinib 300 mg twice daily and 400 mg twice daily, respectively, and in no patients receiving imatinib.
Similar events were also observed in postmarketing reports. , shortness of breath) during nilotinib treatment; evaluate etiology and treat patients accordingly. 14 Effects on Growth and Development in Pediatric Patients Growth retardation has been reported in pediatric patients with Ph+ CML in chronic phase treated with nilotinib.
7 months, growth deceleration (crossing at least two main height percentile lines from baseline) was observed in eight patients: five (9%) crossed two main percentile lines from baseline and three (5%) crossed three main percentile lines from baseline (percentile lines: 5th, 10th, 25th, 50th, 75th, 90th, and 95th).
Growth deceleration was more pronounced in children who were less than age 12 at baseline. Adverse reactions associated with growth retardation were reported in 3 patients (5%). Monitor growth and development in pediatric patients receiving nilotinib treatment.
15 Embryo-Fetal Toxicity Based on findings from animal studies and its mechanism of action, nilotinib can cause fetal harm when administered to a pregnant woman. 5 times, respectively, the AUC in patients receiving the recommended dose.
Advise pregnant women of the potential risk to a fetus. 1) ]. 0032% IS). 2) ]. 1% IS]. 01% IS). For patients who fail to achieve MMR after three months of treatment reinitiation, BCR-ABL kinase domain mutation testing should be performed.
Monitoring of BCR-ABL Transcript Levels in Patients Who Have Reinitiated Therapy After Loss of Molecular Response Monitor CBC and BCR-ABL transcripts in patients who reinitiate treatment with nilotinib due to loss of molecular response quantitation every 4 weeks until a major molecular response is re-established, then every 12 weeks.