Drug Safety Watchdog Slams FDA Nuplazid Side Effects Review

Published on April 1, 2019 by Sandy Liebhard

A prominent drug safety watchdog is calling on federal regulators to take another look at Nuplazid, an antipsychotic medication used to reduce hallucinations that sometimes accompany Parkinson’s disease.

Nuplazid Death and Injury Reports

The U.S. Food & Drug Administration (FDA) approved Nuplazid (pimavanserin) in April 2016. Because it was considered a “breakthrough therapy, the agency cleared the medication on the basis of a single, 6-week clinical trial involving just 200 patients. During that study, patients using Nuplazid had double the rate of deaths and other serious adverse events compared to those who received a placebo.

By April 2018, the FDA’s adverse event database had received hundreds of reports of possible Nuplazid side effects, such a falls, insomnia, nausea, and fatigue. The drug was also implicated in 722 death reports, including more than 500 that listed Nuplazid as the only suspect medication the patient was taking. At least 1,000 patients continued to experience hallucinations and delusions after they began treatment.

In September 2018, the FDA issued a brief, 5-page Drug Safety Communication to announce that a subsequent review of those reports had found “no new or unexpected safety risks”. Among other things, the agency attributed the worrisome number of fatalities to the “older age, advanced Parkinson’s disease, and other medical conditions” typical of most Nuplazid patients.

What the FDA Got Wrong About Nuplazid Side Effects

But according to the Institute for Safe Medication Practices’ (ISMP) latest QuarterWatch Report, the underlying documents from the FDA’s review suggest that reassurance was unwarranted.

For one thing, most of the 893 Nuplazid death reports included in the FDA analysis lacked sufficient detail to determine if the medication contributed to a patient’s death. The number of reported fatalities have since risen to 1,339, but 39% lack details about the event or whether the drug contributed to the death.

The FDA review also found that doctors frequently prescribe Nuplazid in combination with other antipsychotics, particularly Seroquel, which are known to double the risk of death in Parkinson’s patients. While this could increase fatal outcomes and other Nuplazid side effects, the agency did not recommend any regulatory action to curb this practice.

Other data included in the FDA’s review suggested it was a mistake to approved Nuplazid after just a single, 6-week clinical trial.  For example, records of actual clinical use indicate that 45% of the patients started on Nuplazid had either died or discontinued the drug within two months. Additionally, a large new clinical trial in Alzheimer’s patients with psychosis found that any modest benefit disappeared by 12-weeks.

Finally, the FDA’s reviewers wrongly believed that the Nuplazid label included a Black Box Warning regarding an 70% increased risk of death. As the ISMP pointed out, however, the text actually describes a different class of antipsychotic drugs that is used to treat a different patient population.

ISMP Urges FDA to Reevaluate Nuplazid

“This reassessment of the FDA reviews provides no new reassurance that the benefits of pimavanserin treatment outweigh its risks,” the QuarterWatch report concluded. “Instead, the post-market data and new study warrant increased concern.”

The ISMP  called for a revised Black Box Warning  to clarify that Nuplazid might increase the risk of death similar to other antipsychotics . The text of that warning should also caution doctors not to prescribe Nuplazid in combination with other antipsychotics.

Finally, the ISMP urged the FDA to reconsider whether the potential for Nuplazid side effects outweigh its questionable benefits, especially in light of recent evidence suggesting a lack of efficacy at 12-weeks.