Pharmacy and Therapeutics - January 2008 - (Page 54) Pharmaceutical Approval Update Mar vin M. Goldenberg, PhD, RPh, MS Nilotinib (Tasigna Capsules) Manufacturer: Novartis, Florham Park, N.J. Indications: Nilotinib is used for the second-line treatment of chronic-phase and accelerated-phase Philadelphia chromosome–positive (Ph+) chronic myelogenous leukemia (CML) in adults with disease resistant to, or with intolerance to, previous therapy that included imatinib (Gleevec, Novartis). Drug Class: Nilotinib HCl monohydrate is an orally available signal-transduction inhibitor of Bcr-Abl kinase, c-kit, and platelet-derived growth factor (PDGF), all of which play a role in cell proliferation, cell migration, and angiogenesis. Uniqueness of Drug: As a kinase inhibitor, nilotinib antagonizes Bcr-Abl kinase with a potency 20 to 50 times greater than that of imatinib. Nilotinib binds to and stabilizes the inactive conformation of the kinase domain of Abl protein. In vitro, nilotinib inhibits Bcr-Abl–mediated proliferation of murine leukemic cell lines and human cell lines derived from Ph+ CML patients. In vivo, nilotinib reduces the tumor size in a murine Bcr-Abl xenograft model. Boxed Warning: QT Prolongation and Sudden Death: Nilotinib prolongs the QT interval. Sudden deaths have occurred in patients receiving nilotinib. Nilotinib should not be used in patients with hypokalemia, hypomagnesemia, or long QT syndrome. Hypokalemia or hypomagnesemia must be corrected before patients take nilotinib, and potassium and magnesium levels should be periodically monitored. Drugs known to prolong the QT interval and strong cytochrome P450 3A4 (CYP 3A4) inhibitors should be avoided. Patients should avoid food two hours before and one hour after taking the drug. Caution must be used in patients with hepatic impairment. Electrocardiograms should be obtained to monitor the corrected QT (QTc) at baseline, seven days after initiation, and periodically thereafter, as well as after any dose adjustments. Warnings: Myelosuppression: Nilotinib can cause grade 3 and 4 thrombocytopenia, neutropenia, and anemia. Complete blood counts should be performed every two weeks for the first two months and then monthly thereafter or as clinically indicated. Myelosuppression was generally reversible and was usually managed when nilotinib was temporarily withheld or when the dose was reduced. QT Prolongation: Nilotinib can prolong cardiac ventricular repolarization, as measured by the QT interval on the surface electrocardiogram (ECG) in a concentration-dependent manner. Prolongation of the QT interval can result in a form of ventricular tachycardia (torsades de pointes), which can result in syncope, seizure, or death. The author is President of Pharmaceutical and Scientific Services at Marvin M. Goldenberg, LLC, in Westfield, New Jersey. His e-mail address is MarvinMGoldenberg@verizon.net. Nilotinib should not be used in patients with hypokalemia, hypomagnesemia, or long QT syndrome. Hypokalemia or hypomagnesemia must be corrected before nilotinib therapy begins, and potassium and magnesium levels should be monitored periodically during therapy. Drugs known to prolong the QT inter val and strong inhibitors of CYP 3A4 should be avoided. ECGs should be performed at the baseline exam, seven days after initiation of therapy, periodically as clinically indicated, and after dose adjustments. Sudden Death: In an ongoing study of 867 patients, five sudden deaths (0.6%) were reported in patients receiving nilotinib. A similar incidence was also reported in the expanded-access program. The early occurrence of some of these deaths associated with the initiation of nilotinib suggests that ventricular repolarization abnormalities might have been a contributing factor. Elevated Serum Lipase: The use of nilotinib can cause elevated levels of serum lipase. Caution is recommended in patients with a previous history of pancreatitis. Serum lipase levels should be checked periodically. Hepatotoxicity: Nilotinib may result in elevations of bilirubin, liver enzymes (AST/ALT), and alkaline phosphatase. Liver function tests should be performed periodically. Electrolyte Abnormalities: Nilotinib can cause hypophosphatemia, hypokalemia, hyperkalemia, hypocalcemia, and hyponatremia. Electrolyte abnormalities must be corrected before nilotinib therapy begins, and electrolyte levels (phosphate, potassium, calcium, and sodium) should be monitored periodically during therapy. Food Effects: Because nilotinib’s bioavailability is increased with food, the drug should not be taken with food. No food should be taken at least two hours before and at least one hour after the dose is taken. Grapefruit products and other foods that are known to inhibit CYP 3A4 should be avoided. Hepatic Impairment: Nilotinib has not been evaluated in patients with hepatic impairment. Clinical studies have excluded patients with ALT and/or AST levels above 2.5 times (or 5 times if related to disease) the upper limit of normal (ULN) and/or a total bilirubin level of more than 1.5 times the ULN. Because the metabolism of nilotinib is mainly hepatic, caution is recommended in patients with hepatic impairment. These patients should be closely monitored for prolongation of the QT interval. Pregnancy: Patients should be advised that the use of nilotinib during pregnancy may cause harm to the fetus. Women should not take this product during pregnancy unless necessary. Women of childbearing age should use effective contraceptives if they are taking nilotinib. Sexually active females taking nilotinib should use adequate contraception. Dosage and Administration: Oral doses of nilotinib should be taken twice daily approximately 12 hours apart and should 54 P&T® • January 2008 • Vol. 33 No. 1
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