The Institute for Safe Medication Practices (ISMP) questions the approval of Acadia Pharmaceuticals’ antipsychotic therapy Nuplazid (pimavanserin) in the face of reports that it is ineffective in treating Parkinson’s disease and leads to severe adverse effects, including death.
Researchers shared these concerns in an article, “Safety Signals for Two Novel Drugs,” that appeared in the ISMP publication QuarterWatch. In it, the Pennsylvania-based ISMP issued a safety alert for the medication, and cautioned against combining Nuplazid with Seroquel (quetiapine) or other antipsychotics. It cautioned that such treatments are not recommended for older people, nor are they approved for use in Parkinson’s.
Unlike traditional antipsychotic medications — which mainly block dopamine signaling in the brain, Nuplazid blocks certain types of serotonin receptors. Blocking dopamine using other antipsychotics may trigger worsened movement symptoms in Parkinson’s patients, as these medications essentially counter the effect of levodopa and similar Parkinson’s treatments.
The U.S. Food and Drug Administration (FDA) approved Nuplazid in 2016, despite limited evidence of its effectiveness, ISMP noted.
The institute has access the all adverse events data, best known as MedWatch reports, sent to the FDA. The team noted that Nuplazid was among the 66 medications for which the FDA received 1,000 or more adverse events reports.
ISMP examined four main groups of adverse events for the treatment over the course of a year since Nuplazid’s approval. While the medication intends to treat psychotic symptoms — hallucinations and delusions — the main reported adverse event was hallucinations.
Nearly 22 percent of all reported adverse events were hallucinations. On second place were reports of lack of effectiveness, making up 15 percent of all reports. Confusion and death were the other two frequently reported issues.
This indicates that either the treatment is ineffective, or it worsens psychotic symptoms in some patients, ISMP said. Moreover, the data is consistent with that from the Phase 3 clinical trial (NCT01174004), which led to the medication’s approval.
In that study, both hallucinations and confusion were more common in treated patients compared with patients getting a placebo. An FDA medical reviewer had also underscored that Nuplazid treatment more than doubled the risk of death and serious adverse events in this trial, the ISMP underscored.
The reviewer had recommended against the approval of the treatment, based on this finding and the fact that Nuplazid was minimally effective — an effect assessed with an unvalidated tool. In addition, three earlier trials had failed to show a benefit from the treatment.
These facts made the ISMP side with the cautious reviewer, stating that “We found that pimavanserin was FDA-approved on limited scientific evidence that its benefits outweighed its risks.”
In addition to the adverse events reports, ISMP researchers also noted that many patients used Nuplazid together with Seroquel or other antipsychotics that block dopamine signaling. In addition to not being recommended or approved for the treatment of Parkinson’s psychosis, a recent review noted that there is no evidence that such combinations are effective.
The ISMP, however, gave Nuplazid’s maker, Acadia, a chance to comment on the observations.
The large numbers of adverse event reports, Acadia said, could partly be explained by the company’s extensive contact with health professionals and consumers through a specialty pharmacy network that distributes Nuplazid. Acadia also run a patient support program, which may improve reporting.
But the company also said that reports of hallucinations may reflect the slow onset of Nuplazid’s treatment effect — it takes four weeks for the treatment to be fully effective. Reported hallucinations may, therefore, have occurred before the drug became fully effective, it claimed.
“We share the FDA medical officer’s concerns about the approval of pimavanserin in the face of weak evidence of effectiveness, on the basis of a single small trial, and with increased rates of serious adverse events including death. The early but substantial adverse event data further support these concerns,” the ISMP concluded.
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