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FDA unclear on link between Novartis' MS drug Gilenya, patient deaths

Monday, May 14 2012 | Comments
Evidence Grade 0 What's This?
The Food and Drug Administration said it could not definitively conclude that Novartis Pharmaceutical Corp.'s multiple sclerosis (MS) treatment Gilenya (fingolimod) was connected with the deaths of any patients who took the drug.

The agency issued a statement after completing its review of a report of a patient who died last December within 24 hours after taking the first dose of Gilenya.

The cause of death could not be determined based on information that was available when Novartis first reported the case in April. At the time, Novartis said the patient had developed progressive multifocal leukoencephalopathy (PML), adding that the patient had undergone approximately 3.5 years of treatment with Biogen Idec Inc. and Elan Pharmaceuticals Inc.'s Tysabri (natalizumab) before initiating treatment with Gilenya and had tested positive for the John Cunningham virus (JCV) antibody. Long-term use of Tysabri (i.e., for more than two years) is a recognized risk factor for PML, as is JCV-positive antibody status.

The FDA also described the patient as having extensive brainstem MS lesions, noting that such lesions have been associated with sudden death. Further, the patient had been taking two blood pressure drugs, and the FDA said the role of those drugs in the death is unknown.

The agency re-evaluated trial data related to the effects of Gilenya on heart rate and blood pressure, including data from trials that were ongoing when the drug was approved. It also recently evaluated postmarketing data for Gilenya, including reports of patients who died from cardiovascular events or unknown causes. "For each of these deaths, Gilenya's contribution to the death was unclear," the FDA remarked.

Although the FDA said it could not definitively conclude that Gilenya was tied to any of the deaths, the regulatory agency said it remains concerned about the cardiovascular effects of Gilenya after the first dose.

"In light of the findings of the clinical trial data and postmarketing data, including all reported deaths of cardiovascular or unknown origin, [the] FDA has revised the Gilenya drug label with specific recommendations for monitoring patients and with new contraindications for use of Gilenya in certain patients," the agency wrote in a statement.

The FDA had already updated Gilenya's label in April to advise that Gilenya is contraindicated in patients with a history or presence of certain cardiac conditions, including myocardial infarction or stroke in the previous six months, second- and third-degree atrioventricular block and other serious cardiac rhythm disturbances, and in patients treated with certain antiarrhythmic drugs.

The label also indicates that all patients who start treatment with Gilenya have an electrocardiogram (ECG) before receiving the first dose of the drug and after the six-hour first-dose observation period, in addition to hourly measurement of blood pressure and heart rate. The label further provides specific initiation guidance for patients to better aid health care providers.

The FDA is now also recommending that the time of cardiovascular monitoring be extended beyond six hours in patients who are at higher risk for or who may not tolerate bradycardia. Extended monitoring should include continuous ECG monitoring that continues overnight, the agency added.

Gilenya was approved in September 2010, making it the first oral MS treatment to gain FDA approval. Gilenya is indicated for the first-line treatment of patients with relapsing forms of MS to reduce relapses and delay disability progression.

The FDA approved Gilenya with a risk evaluation and mitigation strategy, and Novartis is required to conduct a postmarketing safety study, which the firm noted would last five years. When the drug was approved, the FDA said upon initiation of treatment with Gilenya, patients should be monitored for a decrease in heart rate, and Novartis said this adverse effect would generally be most pronounced during the first six hours after the initial dose and that the heart rate should return to normal after the first month of treatment.

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