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QuarterWatch™ (2017 Quarter 1 Data): Safety Signals for Two Novel Drugs, Nuplazid and Entresto

The latest issue of ISMP’s QuarterWatch™ provides a review of drug safety issues identified through 297,010 new adverse drug event reports submitted to the US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) during the first quarter of 2017, including more than a quarter (26.8%) describing fatal or serious events in the US. In this report, we focus on early adverse event data reported during the first quarter of 2017, along with data from three previous quarters, for two new drugs with novel mechanisms of action that are intended for difficult-to-treat patient populations:

  • NUPLAZID (pimavanserin), approved in April 2016, provides a new biochemical approach to treating hallucinations and other symptoms of psychosis in Parkinson’s disease. We investigated a signal that the drug could be making the symptoms worse in some patients.
  • ENTRESTO (sacubitril and valsartan), approved in July 2015, targets a new pathway involved in the regulation of blood pressure and appears to improve mortality and cardiovascular outcomes in heart failure patients with reduced ejection fraction. However, hypotension-related events were reported in more than 1,500 patients.

Nuplazid and Hallucinations

Nuplazid was approved to treat hallucinations, delusions, and other symptoms of psychosis among patients with Parkinson’s disease after an internal FDA debate about whether its benefits outweigh its risks. The drug is now being tested for use in larger populations, including patients with Alzheimer’s disease and schizophrenia.

Hallucinations in Parkinson’s. Approximately 1 million people in the US, mostly over age 65, have Parkinson’s disease, a movement disorder in which dopamine-producing neurons are progressively lost. Hallucinations can be induced by the drugs commonly used to treat Parkinson’s, notably levodopa, a drug typically given in combination with carbidopa, and dopamine agonists (e.g., pramipexole [MIRAPEX]). This, along with progression of the disease, means that approximately 50% of people with Parkinson’s will develop hallucinations and other symptoms of psychosis. The antipsychotics used to treat hallucinations in schizophrenia block the normal function of dopamine, a problem Parkinson’s patients who are already losing dopamine function. In addition, antipsychotics induce parkinsonian symptoms in about 35% of patients and are not recommended for the elderly because of increased mortality. Nuplazid was developed as an alternative that does not block or stimulate dopamine receptors, but instead blocks serotonin receptors (5-HT2A) that may also contribute to hallucinations. However, these same serotonin receptors also play a central role in learning, memory, and cognition, and blocking normal signaling could result in significant adverse effects.

FDA approval. Initial FDA approval of Nuplazid was based on a single clinical trial (normally two or more are required) that indicated a small treatment effect using a new measurement scale. Three previous trials had failed to demonstrate a benefit in reducing hallucinations and other symptoms of psychosis. FDA’s medical reviewer recommended against the approval of Nuplazid. He noted that, although other psychiatric drugs were often approved with limited evidence of benefit, in the case of Nuplazid, treatment had more than doubled the risk of death and/or serious adverse events in its only positive trial. Despite these concerns, FDA approved the drug, explaining that while deaths and serious adverse events were increased in the treatment group, the results were not definitive and occurred across numerous organ systems rather than through one or more identifiable drug-related mechanisms.

FAERS data. The leading adverse events reported during the 12 months ending in March 2017 were remarkably similar to the concerns previously raised by the FDA medical reviewer and seen in previous clinical trials: hallucinations (n = 487), confusional state (n = 258), deaths (n = 244), and complaints that the drug was ineffective (n = 333). In the case of hallucinations, which could be mistaken for a symptom of worsening disease, we considered this a credible signal in part because the number of reports outnumbered similar reports for all other drugs, including antipsychotics. It was also notable that 74% of the reports came from health professionals, who would be expected to be familiar with the symptoms and mortality of patients with Parkinson’s disease psychosis, and therefore less likely to report these events unless a drug role was suspected.

We also identified a new safety concern: concomitant use of antipsychotic drugs. The reports revealed 318 cases of heavily medicated Parkinson’s patients (a median of 10 drugs) where Nuplazid had been added to other antipsychotic drugs (all but 7 cases were QUEtiapine [SEROQUEL]). No antipsychotic drugs have been approved for psychosis in Parkinson’s patients, although QUEtiapine is widely used. Now, it appears that Nuplazid is being prescribed along with QUEtiapine, although combination therapy has never been tested (QUEtiapine was banned in the Nuplazid clinical trials). In addition, both drugs are suspected of increasing mortality, and each blocks a key signaling pathway in the brain, either serotonin or dopamine.  

We shared our preliminary results with the manufacturer, Acadia Pharmaceuticals. The company said the large number of reports was in part due to its extensive contact with health professionals and consumers through a specialty pharmacy network and patient support program. The company also suggested that the reports of hallucinations might have occurred before the drug became fully effective 4 weeks after treatment started.

Conclusions. While the company’s contacts with health professionals and consumers likely expanded the number of adverse event reports after product launch, these reports nevertheless reflect the experiences of health professionals and consumers in a real-life postmarket setting. The overall message in these adverse event reports is that hundreds of health professionals are trying this new drug with their patients and reporting that either it is not providing the expected benefit or making some psychosis worse. The large number of deaths also remains a concern in a setting where increased mortality was at least suspected if not proven in the clinical trials. The FDA and manufacturer should consider additional warnings and other measures to deal with inappropriate combination therapy with antipsychotic drugs.


Although FDA has approved more than 100 medications and combinations to treat hypertension, Entresto promised something new. One component of Entresto, sacubitril, is the first approved drug to control blood pressure in chronic heart failure patients in part by inhibiting the enzyme neprilysin, which regulates biochemical processes in the kidneys, lungs, and brain. When sacubitril was added to valsartan, which has a different mechanism of action, the combination product appeared to produce better outcomes, including lower mortality, in patients with chronic heart failure and reduced ejection fraction. However, both the clinical trial results and the latest adverse event reports show hypotension risks may have been underestimated and may occur in 1 out of 4 patients.

FDA approval. The drug was approved with evidence of efficacy from a single, large 27-month clinical trial with 8,442 patients that was stopped early due to benefit after reducing cardiovascular mortality from 16.5% among patients taking enalapril, a drug already proven to be beneficial in heart failure patients, to 13.3% among patients taking Entresto. It produced roughly similar benefits across other endpoints. However, only patients with the best chance of benefiting from the drug were selected for the trial after a 6-week run-in period to ensure tolerance to the drug and eliminate those experiencing early adverse drug effects. In that study, 24.4% of patients experienced a hypotension-related adverse event, which FDA reviewers noted was likely an underestimate given that the trial was conducted only with patients already known to tolerate the drug without adverse events serious enough to warrant discontinuation.

FAERS data. Hypotension was the leading adverse drug event reported for Entresto during the 12 months ending in March 2017, with symptoms ranging from dizziness to blackouts, and other consequences serious enough to require hospitalization. We identified 1,684 adverse event reports indicating a hypotension-related event, more than with any other cardiovascular drug in this period. They occurred in older patients (median age 70 years), and although there were 69 reported deaths, the health consequences were not severe in two-thirds of the cases. The patient population taking this drug is substantial, with prescription growth increasing an average of 38% per quarter.

Conclusions. While Entresto had consistently positive results in its one large clinical trial, the adverse event data illustrate the importance of clinicians being alert to the risks of hypotension. We recommend that FDA and the manufacturer review existing safety data to see what additional warnings and precautions, such as more gradual escalation of the dose to the recommended level, might help reduce the risk of this adverse effect.

The full QuarterWatch™ report with references can be found here.