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FDA Approval for Nilotinib

Brand name(s) Tasigna™

Approved for newly diagnosed patients with chronic myelogenous leukemia (CML)

Full prescribing information is available, including clinical trial information, safety, dosing, drug-drug interactions and contraindications.

 On June 17, 2010, the U. S. Food and Drug Administration (FDA) granted accelerated approval to nilotinib (Tasigna®  Capsules, made by the 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 randomly assigned to receive imatinib 400 mg once daily (n = 283), nilotinib 300 mg twice a day (n = 282), or nilotinib 400 mg twice a day (n = 281). The primary objective was to compare the rate of major molecular response (MMR) at 12 months of each nilotinib dose with that of imatinib 400 mg QD. MMR was defined as BCR-ABL transcript level of < 0.1 percent in peripheral blood by international scale measured by RQ-PCR, which corresponds to a ≥3 log reduction of BCR-ABL transcripts from the 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 percent (95 percent CI: 18, 28)] treated with imatinib, 125 patients [44 percent (95 percent CI: 38, 50)] treated with the lower dose of nilotinib, and 120 patients [43 percent (95 percent CI: 37, 49)] treated with the higher dose of nilotinib. The differences were statistically significant for both groups of nilotinib-treated patients compared with imatinib-treated patients (p< .001). CCyR rates by 12 months were 65 percent (95 percent CI: 59, 71) for patients treated with imatinib, 80 percent (95 percent CI: 75, 85) for patients treated with the lower dose of  nilotinib  and 78 percent (95 percent CI:  73, 83) for patients who received the higher dose of nilotinib.

More than 98 percent of patients in all three treatment groups experienced at least one adverse drug reaction (ADR). Overall incidences of Grade 3-4 toxicity were 46 percent in patients treated with nilotinib 300 mg twice-daily compared to 52 percent of patients treated with nilotinib 400 mg twice-daily. 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 twice-daily dosing regimen appeared more favorable than that of the 400 mg twice-daily regimen, while the efficacy appeared comparable. The recommended dose of nilotinib for patients with newly diagnosed CP-CML is 300 mg twice a day.

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Approved forpreviously treated patients with chronic myelogenous leukemia (CML)

On October 29, 2007, the FDA granted accelerated approval to nilotinib (Tasigna® Capsules, made by Novartis Pharmaceuticals Corp.) for use in the treatment of chronic phase (CP) and accelerated phase (AP) Philadelphia chromosome positive (Ph+) chronic myelogenous leukemia (CML) in adult patients resistant or intolerant to prior therapy that included imatinib.

The effectiveness of nilotinib is based on hematologic (blood-related) and cytogenetic (chromosome-related) response rates. There are no controlled trials demonstrating a clinical benefit, such as improvement in disease-related symptoms or increased survival. Submission of further follow-up data from an ongoing study is required to convert this accelerated approval to regular approval.

Efficacy was demonstrated in one ongoing non-randomized multicenter study. Patients were treated with nilotinib at a starting dose of 400 mg twice daily. At the time of data cut-off, 232 CML-CP patients and 105 CML-AP patients were considered evaluable for efficacy. Prior treatment included imatinib (100 percent), hydroxyurea (85 percent), interferon (62 percent) and bone marrow transplantation (8 percent). Imatinib was discontinued in 73 percent of patients because of resistance; 27 percent discontinued imatinib because of drug intolerance. The highest prior maximum imatinib dose was > 600 mg/day in 77 percent of patients.

The efficacy endpoint for CML-CP was unconfirmed major cytogenetic response, defined as elimination or substantial diminution (by at least 65 percent) of Ph+ metaphases in the bone marrow. The major cytogenetic response rate in CP patients was 40 percent (95 percent CI: 33 percent, 46 percent).

The efficacy endpoint for CML-AP was hematologic responses. Hematologic response was defined as either a complete hematologic response or no evidence of leukemia. The hematologic response rate in AP patients was 26 percent (95 percent CI: 18 percent, 35 percent). The median duration of response has not been reached for CML-CP and CML-AP. At the time of data cutoff, 59 percent of CML-CP patients and 63 percent of CML-AP patients had a response duration of at least six months.

The safety population included 318 patients with CML-CP and 120 patients with CML-AP. In CML-CP patients, the most commonly reported drug-related adverse reactions (>10 percent) were rash, pruritis, nausea, fatigue, headache, constipation, diarrhea, and vomiting. The common serious drug-related adverse reactions were thrombocytopenia and neutropenia.

In CML-AP patients, the most commonly reported drug-related adverse reactions (>10 percent) were rash, pruritus, and constipation. The common serious drug-related adverse reactions were thrombocytopenia, neutropenia, pneumonia, febrile neutropenia, leukopenia, intracranial hemorrhage, elevated lipase, and pyrexia.

Nilotinib prolongs the QT interval and sudden deaths have been reported; this risk is described in a boxed warning in the labeling. Nilotinib should not be used in patients with hypokalemia, hypomagnesemia, or long QT syndrome. Drugs known to prolong the QT interval and strong CYP3A4 inhibitors should be avoided. Patients should avoid food two hours before and one hour after taking a dose. ECG’s should be obtained to monitor the QTc at baseline, seven days after initiation, and periodically thereafter, as well as following dose adjustments.

This summary was provided by Richard Pazdur, M.D., director of the FDA's Division of Oncology Drug Products.

The FDA is the division of the U.S. Department of Health and Human Services charged with ensuring the safety and effectiveness of new drugs and other products. (See "Learn How Drugs and Devices Get Approved.") The FDA's mission is to promote and protect the public health by helping safe and effective products to reach the market in a timely way, and monitoring products for continued safety after they are in use.

  • Updated: July 3, 2013