In last week's blog I provided some of our recent findings from QuarterWatch, an Institute for Safe Medication Practices (ISMP) drug surveillance program that regularly monitors all serious, disabling and fatal adverse drug events reported to the Food and Drug Administration. These reports are sent to FDA by drug manufacturers, health-care practitioners and consumers, and the raw data is made available to the public as quarterly computer excerpts. The institute uses this data in the hope that we can improve patient safety through identification of "signals" that may represent serious drug safety issues. We recently looked at the last quarter of 2010.

Last week I focused on the heart drug Pradaxa. Here are some additional findings:

CHANTIX (varenicline) update. After both FDA and an independent analysis found an increased risk of serious cardiovascular events with the smoking cessation drug in patients with heart disease, Pfizer and  FDA recently added  a new section about this risk in the prescribing information. While FDA declared the risks to be "small," the adverse event data we reviewed for the 4th quarter of 2010 suggests that these studies may have underestimated the overall cardiovascular adverse effects by limiting the focus to only the most serious events. In the analysis, we also found seven additional potential adverse cardiovascular effects -  such as hypertension, dizziness, visual impairment, memory impairment, speech disorder, and confusion – that had not been included. All may be linked to the way Chantix works, by binding with nicotine receptors in the brain. These same events also may have contributed to the risk of getting into an accident, which is a prominent warning in the labeling information. Given that a primary benefit of smoking cessation is a reduction in cardiovascular  risks, this safety profile is troubling.

MULTAQ (dronedarone) update. Evidence is mounting, from reported adverse events and other sources, that the heart drug Multaq may trigger or worsen heart failure and potentially lethal heart rhythm disturbances. This raises a question of whether the treatment is beneficial or harmful. For a second time, Multaq has been associated with an increased risk of death in a randomized clinical trial. The manufacturer, Sanofi-Aventis, announced in July 2011 that a safety monitoring board had halted a clinical trial of dronedarone in patients with permanent atrial fibrillation because of excess mortality. The trial also demonstrated an increased risk or worsening of heart failure — the most prominent effect seen in an earlier clinical trial.

Dronedarone has also been associated with cases of acute liver failure and potentially lethal heart rhythm disorders. The drug interacts with many other medications taken by the target patient population. Adverse event reports for the 4th quarter mirror the more authoritative findings of the halted trial. Of special concern were 26 case reports of heart failure and 16 possible cases of fatal and life threatening disruption of the two ventricles, the main pumping chambers of the hearts. Also seen in the adverse event reports were indications of the other safety questions, including possible liver toxicity, interaction with warfarin, and possible cases of kidney failure and impairment. The risk of liver toxicity and excess mortality associated with dronedarone use raise the fundamental question of whether this drug is, overall, harmful or beneficial.

AMPYRA (dalfampridine). Ampyra is a new drug approved for an unusual indication: to improve walking speed in multiple sclerosis patients. Other MS drugs have been shown to reduce disease progression or relapses. This new drug accounted for 217 reported serious adverse effects in the 4th quarter of 2010, which were more cases than hundreds of drugs used in much larger patient populations. The adverse effects included seizures, a known adverse effect of the drug; problems walking rather than improved walking speed; and various presentations of altered mental states.

The manufacturer, Acorda Therapeutics, noted that report totals may have been high because Ampyra is a new drug with a new indication, and because it is only available from 12 specialty pharmacies that send follow-up queries to patients if the prescription is not renewed. The company also noted that many reported side effects were similar to the underlying disease.

The large number of reported adverse events is notable given the pre-approval debate about whether the drug's benefits were clinically meaningful. Critics, including FDA's medical reviewer, said the benefit — an increase from baseline of 3 seconds in walking speed over a 25 foot runway — was not clinically significant. Acorda Therapeutics called patients who walked any faster down the runway "responders." By this measure, 34.8% of Ampyra patients were responders compared to 8.3% of patients on a placebo; the results were similar in a second trial. FDA and an advisory committee of outside experts concluded that an adequate benefit had been demonstrated to warrant approval.

We believe these reports provide a signal that the neurological adverse effects potentially identified in clinical testing are now resulting in reported patient injuries that are serious and even life-threatening. With the seemingly limited benefits observed with this drug, it does not take much to tip the risk-benefit balance in an unfavorable direction. At a minimum, guidelines for early discontinuation should be considered in patients who do not perceive a marked improvement in walking or other movements within the first month of treatment.

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