International Approvals: Tasigna, Eraxis, INOmax

Yael Waknine

December 10, 2007

December 10, 2007 — The European Commission has approved nilotinib capsules for the treatment of chronic- and accelerated-phase Philadelphia chromosome-positive chronic myeloid leukemia in adults resistant or intolerant of prior therapy including imatinib; Health Canada has approved anidulafungin intravenous infusion for the treatment of invasive candidiasis/candidemia in adult non-neutropenic patients; and Australia's Therapeutic Goods Administration has approved nitric oxide for inhalation with ventilatory support for the treatment of term and near-term newborns with hypoxic respiratory failure .

Nilotinib ( Tasigna ) for Imatinib-Refractory Chronic Myeloid Leukemia in EU

On November 28, the European Commission (EC) approved nilotinib 200-mg capsules ( Tasigna, Novartis AG), allowing their twice-daily use for the treatment of chronic-phase (CP) and accelerated-phase (AP) Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) in adult patients whose disease is resistant to or intolerant of previous therapy that included imatinib ( Gleevec/ Glivec, Novartis) therapy.

Although both drugs target the Bcr-Abl protein that is created by the Ph chromosome abnormality in CML, nilotinib is a more selective and potent second-generation product.

"The approval of Tasigna gives us the opportunity to help more CML patients and, with Glivec as our first-line agent, provide comprehensive treatment options for prescribers," says David Epstein, president and CEO of Novartis Oncology, in a news release.

The EC's decision was based on data from a phase 3 open-label multicenter study in which 232 patients with CML-CP and 105 patients with CML-AP whose disease was refractory to or intolerant of imatinib were treated for a median of 8.7 and 5.6 months, respectively.

Results showed that 49% of patients with CML-CP and 27% of those with CML-AP achieved major cytogenetic response (reduction or elimination of Ph chromosome). The complete hematologic response rates (ie, normalization of white blood cell counts) were 70% and 42%, respectively.

Serious (grade 3/4) adverse events related to nilotinib therapy in the trial were primarily hematologic and included thrombocytopenia and neutropenia. Elevations in bilirubin, liver function tests, lipase enzymes, and blood glucose levels were mostly transient and rarely led to discontinuation.

The most frequent nonhematologic adverse events were mild to moderate rash, pruritus, nausea, fatigue, headache, constipation, and diarrhea.

The recommended dose of nilotinib is 400 mg taken at 12-hour intervals. Because food increases bioavailability of nilotinib, doses should be taken on an empty stomach 2 hours before or 1 hour after meals. Dose adjustments may be required for patients with myelosuppression, other laboratory abnormalities, and those who develop a prolonged QT interval.

Because of the risk for QT interval prolongation, an electrocardiogram should be performed at baseline, 7 days after initiation of therapy, and after dose adjustments. Hypokalemia and hypomagnesemia should be corrected before treatment; drugs known to prolong the interval and cytochrome P450 isoenzyme 3A4 inhibitors should be avoided.

Nilotinib previously was approved by the Swiss Agency for Therapeutic Products and the US Food and Drug Administration (FDA) in July and October 2007, respectively. According to the news release, the FDA approval was based on data from the same study that was analyzed by different methods, including shorter duration of follow-up.

Anidulafungin Infusion ( Eraxis ) for Life-Threatening Fungal Infections in Canada

On November 14, Health Canada approved anidulafungin intravenous (IV) infusion ( Eraxis, Pfizer Canada, Inc) for the treatment of invasive candidiasis/candidemia in adult non-neutropenic patients.

"Invasive candidiasis is a leading cause of death from hospital-acquired-infections in Canada, with crude mortality rates ranging between 38% and 46%," according to a company news release. Critically ill patients, those suffering from cancer, or those having undergone an organ transplant are at the greatest risk for invasive infection, the company said.

The approval was based in part on data from a double-blind, double-dummy, randomized phase 3 study (n = 245) showing that IV anidulafungin was more effective than fluconazole for successfully treating candidemia and other forms of Candida infections by the end of therapy (median duration, 14 vs 11 days; 75.6% vs 60.2%). Also, success rates remained higher in the anidulafungin group at 2- and 6-week follow-ups (64.6% vs 49.2% and 55.9% vs 44.1%, respectively).

In the study, anidulafungin and fluconazole therapy were similarly well-tolerated, with comparable rates for adverse events. Adverse events most commonly reported in the anidulafungin group included hypokalemia, diarrhea, and increased alanine aminotransferase levels.

The recommended regimen for anidulafungin in the treatment of candidemia and other Candida infections is a 200-mg loading dose on day 1, followed by a 100-mg daily dose thereafter. Therapy duration should be based on clinical response; in general, antifungals should be continued for at least 14 days after the last positive culture. No dose adjustments are required based on hepatic/renal insufficiency, age, gender, weight, ethnicity, or HIV status.

Anidulafungin previously was approved by the US Food and Drug Administration in February 2006.

Nitric Oxide for Inhalation ( INOmax) for Newborn Hypoxic Respiratory Failure in Australia

On October 27, Australia's Therapeutic Goods Administration approved nitric oxide for inhalation ( INOmax, INO Therapeutics, LLC, a subsidiary of Ikaria Holdings, Inc) in conjunction with ventilatory support and other appropriate agents for the treatment of term and near-term (>34 weeks) neonates with hypoxic respiratory failure associated with clinical or echocardiographic evidence of pulmonary hypertension. Distribution is expected beginning in January 2008 via an alliance with BOC Medical.

According to a company news release, use of nitric oxide has been shown to reduce the need for extracorporeal membrane oxygenation. However, it should not be used in infants who are dependant on right-to-left blood shunting. Because methoglobinemia is a dose-dependant adverse event associated with treatment, methemoglobin, nitric oxide, and the fraction of inspired oxygen should be monitored during treatment.

The product has not been approved by the US Food and Drug Administration.

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