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boxed warning
WARNING: QT PROLONGATION and SUDDEN DEATHS • Nilotinib prolongs the QT interval. Prior to nilotinib administration and periodically, monitor for hypokalemia or hypomagnesemia and correct deficiencies [see Warnings and Precautions (5.2) ]. Obtain ECGs to monitor the QTc at baseline, seven days after initiation, and periodically thereafter, and following any dose adjustments [see Warnings and Precautions (5.2 , 5.3, 5.7, 5.12 )]. • Sudden deaths have been reported in patients receiving nilotinib [see Warnings and Precautions (5.3) ]. Do not administer nilotinib to patients with hypokalemia, hypomagnesemia, or long QT syndrome [see Contraindications (4) , Warnings and Precautions (5.2) ]. • Avoid use of concomitant drugs known to prolong the QT interval and strong CYP3A4 inhibitors [see Drug Interactions (7.1, 7.2) ]. • Avoid food 2 hours before and 1 hour after taking the dose [see Dosage and Administration (2.1) ]. WARNING: QT PROLONGATION and SUDDEN DEATHS See full prescribing information for complete boxed warning. • Nilotinib prolongs the QT interval. Prior to nilotinib administration and periodically, monitor for hypokalemia or hypomagnesemia and correct deficiencies ( 5.2 ). Obtain ECGs to monitor the QTc at baseline, seven days after initiation, and periodically thereafter, and following any dose adjustments. ( 5.2 , 5.3 , 5.7 , 5.12 ) • Sudden deaths have been reported in patients receiving nilotinib. ( 5.3 ) Do not administer nilotinib to patients with hypokalemia, hypomagnesemia, or long QT syndrome. ( 4 , 5.2 ) • Avoid use of concomitant drugs known to prolong the QT interval and strong CYP3A4 inhibitors. ( 7.1 , 7.2 ) • Avoid food 2 hours before and 1 hour after taking the dose. ( 2.1 )
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warnings and cautions
5 WARNINGS AND PRECAUTIONS • Myelosuppression: Monitor complete blood count (CBC) during therapy and manage by treatment interruption or dose reduction. (5.1) • Cardiac and Arterial Vascular Occlusive Events: Evaluate cardiovascular status, monitor and manage cardiovascular risk factors during nilotinib therapy. (5.4) • Pancreatitis and Elevated Serum Lipase: Monitor serum lipase; if elevations are accompanied by abdominal symptoms, interrupt doses and consider appropriate diagnostics to exclude pancreatitis. (5.5) • Hepatotoxicity: Monitor hepatic function tests monthly or as clinically indicated. (5.6) • Electrolyte Abnormalities: Nilotinib can cause hypophosphatemia, hypokalemia, hyperkalemia, hypocalcemia, and hyponatremia. Correct electrolyte abnormalities prior to initiating nilotinib and monitor periodically during therapy. (5.7) • Tumor Lysis Syndrome: Maintain adequate hydration and correct uric acid levels prior to initiating therapy with nilotinib. (5.8) • Hemorrhage: Hemorrhage from any site may occur. Advise patients to report signs and symptoms of bleeding and medically manage as needed. (5.9) • Fluid Retention: Monitor patients for unexpected rapid weight gain, swelling, and shortness of breath. Manage medically. (5.13) • 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. (5.14) • Embryo-Fetal Toxicity: Advise females of reproductive potential of potential risk to a fetus and to use effective contraception. (5.15, 8.1, 8.3) • Treatment Discontinuation: Patients must have typical BCR-ABL transcripts. An FDA-authorized test with a detection limit below MR4.5 must be used to determine eligibility for discontinuation. Patients must be frequently monitored by the FDA authorized test to detect possible loss of remission. (5.16) 5.1 Myelosuppression Treatment with nilotinib can cause Grade 3/4 thrombocytopenia, neutropenia, and anemia. Perform CBCs every 2 weeks for the first 2 months and then monthly thereafter, or as clinically indicated. Myelosuppression was generally reversible and usually managed by withholding nilotinib temporarily or dose reduction [see Dosage and Administration (2.5) ]. 5.2 QT Prolongation Nilotinib has been shown to prolong cardiac ventricular repolarization as measured by the QT i...
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adverse reactions
6 ADVERSE REACTIONS The following clinically significant adverse reactions can occur with nilotinib and are discussed in greater detail in other sections of 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 Hetero Labs Limited at 1-866-495-1995 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-moder...