QuarterWatchâ„¢ 2010 (Quarter 4 and annual summary) Signals for two newly approved drugs: dabigatran and dalfampridine
October 6, 2011

QuarterWatch is an ISMP surveillance program that monitors all serious, disabling, and fatal adverse drug events (ADEs) reported to the US Food and Drug Administration (FDA) by drug manufacturers and the public through its MedWatch reporting program. The goal of QuarterWatch is to improve patient safety through the identification of signals that may represent serious drug safety issues. The term signal means evidence that, in our judgment, is substantial enough to warrant further investigation to determine the frequency of occurrence and establish a causal relationship to the suspect drug.

Reporting totals and trends
For 2010 in its entirety, we identified 141,829 new cases of serious, disabling, or fatal ADEs reported to the FDA, a 21% increase since 2009. The increase (24,736 cases) in 2010 was the largest absolute (raw number) increase between years since 1998. Table 1 (in the PDF version of the newsletter) lists the drugs frequently identified as a primary suspect drug for reported serious events in 2010.

Fatal adverse event reports increased by 42.9% in 2010 to reach a total of 28,456. This deceptively alarming increase was heavily influenced by large numbers of reports from drug manufacturers about deaths in previous years in which a drug was taken but not necessarily linked to the deaths. This trend primarily reveals regulatory and compliance issues in the FDA’s monitoring program rather than a new danger to patients.

For the 4th quarter alone, reports meeting the QuarterWatch criteria totaled 38,733, an increase of 5.5% compared to the 4th quarter of 2009. The largest factor associated with the increase was a spike of more than 5,000 deaths involving three drugs used to treat pulmonary arterial hypertension: bosentan, treprostinil, and iloprost. Other contributors to the increase included problems associated with several recently approved drugs: dabigatran (307 cases), dalfampridine (217), and dronedarone (164).

Selected ADE signals
Dabigatran etexilate (PRADAXA). Within weeks of its launch in October 2010, this new drug approved to reduce the risk of stroke in patients with atrial fibrillation generated more reports (307) than 98.7% of the other drugs we regularly monitor. The predominant reported adverse effects were equally divided among hemorrhage or thromboembolic events. While there are advantages to using dabigatran over warfarin in that it doesn’t require frequent lab monitoring or interact with many drugs, warfarin still has an important advantage; the adverse effect of severe bleeding can be readily reversed with an antidote. No specific antidote exists for dabigatran reversal.

We believe this large surge of reports so soon after drug approval illustrates serious safety issues likely to grow as use of dabigatran increases and additional alternatives to warfarin are approved. First, the surge of reports show that inhibiting blood clotting in an elderly population with heart problems remains inherently risky with a significant capacity to cause injury. Next, a drug that does not require regular lab monitoring for dose adjustments does not significantly reduce the risk of serious bleeding. In addition, the large number of reports just weeks after approval show how quickly a new treatment can spread into wide clinical use.

We are also troubled that this new drug was immediately used off-label where its risks and benefits had not yet been systematically studied. Only 36% of reports that listed the indication noted that the drug was being used for the approved indication. Another 46% of reports said the drug was being used to prevent blood clots or stroke in general terms, and other reports clearly specified off-label uses, such as the prevention of deep vein thrombosis postoperatively after hip or knee arthroplasty. The data suggest that physicians were substituting dabigatran for warfarin across a wide spectrum of conditions.

Dalfampridine (AMPYRA). Dalfampridine is a new drug approved for an unusual indication: to improve walking speed in multiple sclerosis (MS) patients. Other MS drugs have been shown to reduce disease progression or relapses. The 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 dalfampridine 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 dalfampridine patients were responders compared to 8.3% of placebo patients; 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, 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.

Dronedarone (MULTAQ) update. For a second time, the cardiac drug dronedarone 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. 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.

Varenicline (CHANTIX) update. After both FDA and an independent meta-analysis found an increased risk of serious cardiovascular events with varenicline, a new section about this risk was added to the prescribing information. While FDA declared these risks to be “small,” the adverse event data for the 4th quarter of 2010 suggests these studies may have underestimated the overall cardiovascular adverse effects by limiting the focus to only the most serious events. We found seven additional potential vascular adverse effects not included in these studies, such as hypertension, dizziness, visual impairment, memory impairment, speech disorder, and confusion. All may be linked to vasoconstriction or vasodilation, effects related to the nicotinic receptors that are bound by varenicline. These same events may have also 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.

Meanwhile, the flow of reports of serious psychiatric side effects continued unabated. The Veterans Administration (VA) restricted the use of varenicline, citing risks of suicidal behavior and violence. The VA made varenicline a second-line drug to be used only if buPROPion (ZYBAN) or nicotine patches had failed. The VA also mandated a mental status exam before prescribing the drug to eliminate patients at greatest risk for psychiatric side effects.

Problems with the reporting system
Bosentan (TRACLEER). The startling number of deaths—4,133—with bosentan use does not indicate a drug catastrophe but does reveal an important breakdown in the FDA rules regarding how and when patient deaths should be reported. Because bosentan is a restricted distribution drug for a very specialized and seriously ill patient population with pulmonary arterial hypertension, the manufacturer, Actelion Pharmaceuticals, was often informed when a patient died. After an inspection, the FDA faulted Actelion for simply assuming the drug had no role in these patients’ deaths rather than investigating each case. This had been happening for at least 4 years.

In response to the FDA warning letter, Actelion reported every patient death it knew of since 2006. But the deaths still had not been investigated, and the reports contained little or no useful information about the event. The net result is that FDA’s reporting system was being flooded with low quality reports of patient deaths in which there was insufficient information to determine if the drug contributed to the event. Reports of patients’ deaths, instead of being fully investigated and detailed, are in fact more likely to be vague and uninformative.

We urge the FDA to make it a priority to improve the consistency and quality of fatal event reporting by drug manufacturers. The agency needs to develop new adverse event reporting guidelines and enforcement procedures to specify how patient deaths should be reported and investigated by the company. Current reporting practices weaken drug safety surveillance because manufacturers, worried about a possible violation, submit large numbers of adverse event reports about patient deaths when the drug was not a suspect at all, or when any drug role was simply unknown. While the quality of investigation and reporting after a patient’s death in a surveillance system ought to be superior, we find the opposite is true now. Current FDA reporting practices for fatal events impose substantial costs, provide little benefit, and impair the drug safety surveillance system.

Additional information and signals from other drugs are described in the full QuarterWatch Report at:

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