July 21st, 2011
FDA and EMA Issue Updates on Dronedarone, Varenicline, and Pioglitazone
Larry Husten, PHD
The FDA has issued an update on dronedarone (Multaq, Sanofi Aventis), and the European Medicines Agency (EMA) has updated its reviews of dronedarone and 2 other drugs that also have been the subject of recent controversies: pioglitazone (Actos and other names, Takeda) and varenicline (Champix, Pfizer).
The FDA and dronedarone: The FDA issued a safety communication about dronedarone and an increased risk for death and serious CV events. The agency said it was reviewing data from the PALLAS (Permanent Atrial fibriLLAtion outcome Study using Dronedarone on top of standard therapy) trial, which Sanofi announced on July 7 had been prematurely stopped. The PALLAS trial was testing the effect of dronedarone in patients with permanent AF, which is not an indication for dronedarone currently. According to the FDA:
A critical question is whether and how the unfavorable results of the PALLAS study, obtained in patients with permanent atrial fibrillation, apply to patients who use Multaq for the approved indications (non-permanent atrial fibrillation, also known as paroxysmal or persistent atrial fibrillation).
The FDA did not recommend that patients stop taking dronedarone but did recommend that they “should talk to their healthcare professional about whether they should continue to take Multaq for non-permanent atrial fibrillation.”
Dronedarone was the subject of a safety warning earlier this year based on reports of rare but severe cases of liver injury.
Here is the table of events released by the FDA (click to enlarge):
Separately, the EMA issued 3 separate updates about dronedarone, varenicline, and pioglitazone.
Dronedarone: The EMA said it was reviewing the benefits and risk of dronedarone based on the PALLAS data, and that the new data “could have an impact on the use of the medicine in its approved indication.” The EMA advised prescribers “to monitor patients regularly in order to ensure that they remain within the authorized indication and do not progress to permanent atrial fibrillation.”
The EMA noted that the Committee for Medicinal Products for Human Use (CHMP), which had already initiated a review of dronedarone based on the reports of severe liver injury, would extend its review of the drug until September 2011, when it will issue a final assessment.
Varenicline: The EMA confirmed the “positive benefit-risk balance” of varenicline, saying that its “benefits as a smoking-cessation medicine outweigh a slight reported increase in cardiovascular events.” Earlier this year, on June 16, the FDA issued its own warning on this subject based on a meta-analysis that was subsequently published on July 4 in the Canadian Medical Association Journal. CHMP said it had “identified a number of limitations of the meta-analysis, including the low number of events seen, the types of events counted, the higher drop-out rates in people receiving placebo, the lack of information on the timing of events, and the exclusion of studies in which no one had an event. Because of these limitations, the Committee could not draw robust conclusions from the meta-analysis.” CHMP said it will conduct an expedited review of an application to update varenicline’s product information and is aiming to offer a recommendation in September 2011.
Pioglitazone: The EMA said that CHMP had finished its review of pioglitazone and that “there is a small increased risk of bladder cancer in patients taking” medicines that contain pioglitazone. Nevertheless, it “confirmed that these medicines remain a valid treatment option for certain patients with type 2 diabetes.” CHMP said that the small increased risk of bladder cancer “could be reduced by appropriate patient selection and exclusion, including a requirement for periodic review of the efficacy and safety of the individual patient’s treatment.”
The FDA said that patients “should talk to their healthcare professional about whether they should continue to take Multaq for non-permanent atrial fibrillation.” The study is not published – the early information is not good – the real justification for the drug is in question – but how do manage as the facts are being assembled – and how do we convey to patients the facts that are emerging? The default is to say publicly that patients should talk with their doctors … but we doctors are trying to determine what to do. We are challenged to respond quickly to new information – and it is quite a challenge. Interested in what others do in this situation. Who do you look to for guidance?