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U.S. Department of Health and Human Services

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Nilotinib (Tasigna)

On June 17, 2010, the U. S. Food and Drug Administration granted accelerated approval to nilotinib (Tasigna Capsules, Novartis Pharmaceuticals Corporation), an orally administered kinase inhibitor, for the treatment of adult patients with newly diagnosed Philadelphia chromosome positive chronic myeloid leukemia (Ph+ CML) in chronic phase (CP-CML).  The recommended nilotinib dose for this indication is 300 mg orally twice daily.  Tasigna was originally approved in October 2007 for the treatment of adult patients with CP-CML and accelerated phase (AP-CML) resistant or intolerant to prior therapy that included imatinib.

The efficacy and safety of nilotinib in adults with newly diagnosed CP-CML was demonstrated in a single randomized, active-control, open-label multinational clinical trial.  Eight hundred and forty six patients were randomized to imatinib 400 mg QD (n = 283), nilotinib 300 mg BID (n = 282), or nilotinib 400 mg BID (n = 281).  The primary objective was to compare the rate of major molecular response (MMR) at 12 months of nilotinib 300 mg BID and nilotinib 400 mg BID with that of imatinib 400 mg QD.  MMR was defined as a as ≤0.1% BCR-ABL/ABL % by international scale measured by RQ-PCR, which corresponds to a ≥3 log reduction of BCR-ABL transcript from standardized baseline.  The rate of complete cytogenetic response (CCyR) by month 12 was the key secondary endpoint.

The primary efficacy endpoint, MMR at 12 months, was achieved in 63 patients [22% (95% CI: 18, 28)] in the imatinib arm, 125 patients [44% (95% CI: 38, 50)] in the nilotinib 300 mg BID arm, and 120 patients [43% (95% CI: 37, 49)]

in the nilotinib 400 mg BID arm.  The differences were statistically significant (p < 0.0001) for each nilotinib arm compared to the imatinib arm.  CCyR rates by 12 months were 65% (95% CI: 59, 71) for the imatinib arm, 80% (95% CI: 75, 85) for the nilotinib 300 mg BID arm and 78% (95% CI:  73, 83) for the nilotinib 400 mg BID arm.

More than 98% of patients in all three treatment arms experienced at least one adverse drug reaction (ADR).  Overall incidences of Grade 3-4 toxicity were 46% with nilotinib 300 mg BID arm compared to 52% among patients treated with nilotinib 400 mg BID. Common ADRs reported more frequently on nilotinib treatment compared to the imatinib treatment included rash, abnormalities of liver function (AST, ALT and bilirubin), hyperglycemia, hypercholesterolemia, elevated serum lipase, and headache. The incidence and severity of myelosuppression (e.g. neutropenia, anemia, and/or thrombocytopenia) appeared similar in with both imatinib and nilotinib. The most common electrolyte imbalances in patients receiving nilotinib during were hypophosphatemia, hypokalemia, and hypocalcemia.

The safety profile of the 300 mg BID dosing regimen appeared more favorable than 400 mg BID, while the efficacy of the 300 mg BID dosing regimen appeared comparable to that of 400 mg BID. The recommended dose of nilotinib for patients with newly diagnosed CP-CML is 300 mg BID.

Full prescribing information is available at:  http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/022068s004s005lbl.pdf

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System by completing a form online at http://www.fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178) or mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).