By Lex Denysenko, MD, FAPM
Assistant Professor of Psychiatry in the Department of Psychiatry at Rowan University School of Osteopathic Medicine in Cherry Hill, New Jersey.
(This article was published on April 26, 2018)
Pimavanserin (brand name Nuplazid) is a novel antipsychotic with an FDA indication for Parkinson’s disease psychosis (PDP) that has virtually no activity at the dopamine receptor (see Pimavanserin (Nuplazid®): A novel antipsychotic).
Recently (as of April, 2018), concern regarding its safety has been raised, especially by an article in CNN. Here, I will summarize for you the relevant facts.
• One of the original FDA medical reviewers had recommended against approval noting that pimavanserin more than doubled the risk of death and /or serious adverse events in its pivotal clinical trial, but he was overruled.
• The non-profit Institute for Safe Medication Practices (www.ismp.org) published a report in November 2017, with concern that from June 2016 to March 2017, there were 244 cases of death. The ISMP raised concern that the drug is often being combined with other antipsychotics, and that it is being tested for larger patient populations than its narrow indication for PDP.
• As of December 31, 2017, The FDA Adverse Events Reporting System (FAERS) has received 712 cases of deaths associated with use of pimavanserin since 2016. Although the FAERS system cannot be used to confirm if a drug actually caused the reported death, nor can the data be used to determine incidence or compare different drugs, this number has raised serious concerns. For comparison, haloperidol has 471 reported cases of death since 1968, and ziprasidone has 324 since 2001.
• But, we should note that Parkinson’s disease psychosis, for which pimavanserin is primarily used, is associated with high mortality rates. The manufacturer, Acadia pharmaceuticals, has noted that the overall mortality rate for pimavanserin since launch has been 12.4 per 100 patient years and that this is lower than the Medicare Claims Database mortality rate of 28.2 per 100 patient years for PDP patients.
• The manufacturer has also noted that one reason for the large volume of adverse event reports may be due to its extensive contact with health professionals and patients via a specialty pharmacy network, and due to an extensive patient support program. That it, the rates of adverse events may appear higher because they are being reported more often.
• The FDA has put out a statement on April 10, 2018, stating they feel that pimavanserin has adequate labeling of its possible adverse effects, and that the FDA has not identified any specific new safety issues that have not already been described in the product labeling.
These reports raise the question of why pimavanserin could, hypothetically, be associated with an increased risk of death. Does it prolong QTc significantly and increase risk of torsades de pointes?
Based on two studies sponsored by Acadia, pimavanserin increases the QTc interval by a mean of 7 to 9 msec (Cummings et al., 2014; Ballard et al., 2018). These numbers suggest (by indirect comparison previous data studies of other antipsychotics), that pimavanserin is associated with less QT prolongation than risperidone, quetiapine, or ziprasidone, but more prolongation than olanzapine or haloperidol. So, pimavanserin does not appear to be significantly more or less likely to prolong the QT interval compared to other antipsychotics.
What do all these facts mean?
1. An increased incidence of death caused by pimavanserin has not been proven. We should keep in mind that Parkinson’s disease psychosis, for which pimavanserin is used, is itself associated with an increased risk of death, making it harder to attribute the deaths to pimavanserin.
2. While pimavanserin may be essentially free of motoric side effects compared to other antipsychotics, it, like other antipsychotics, is associated with a risk for QT interval prolongation. So, QT prolongation should be monitored as the clinical situation dictates.
3. It is unclear if the risk for adverse events, including death, is increased when pimavanserin is combined with other QT-prolonging agents, including antipsychotics, but this is plausible. As always, we should be careful about using multiple antipsychotics or multiple QT prolonging agents in patients with cardiac disease or in the elderly.
Simple and Practical Mental Health will update you on this issue as and when new information becomes available.
Ballard C, Banister C, Khan Z, Cummings J, Demos G, Coate B, Youakim JM, Owen
R, Stankovic S; ADP Investigators. Evaluation of the safety, tolerability, and efficacy of pimavanserin versus placebo in patients with Alzheimer’s disease psychosis: a phase 2, randomised, placebo-controlled, double-blind study. Lancet Neurol. 2018 Mar;17(3):213-222. Erratum in: Lancet Neurol. 2018 Feb 26;:. PubMed PMID: 29452684.
Cummings J, Isaacson S, Mills R, Williams H, Chi-Burris K, Corbett A, Dhall R, Ballard C. Pimavanserin for patients with Parkinson’s disease psychosis: a randomised, placebo-controlled phase 3 trial. Lancet. 2014 Feb 8;383(9916):533-40. Erratum
in: Lancet. 2014 Jul 5;384(9937):28. PubMed PMID: 24183563.
Copyright © 2018, Simple and Practical Mental Health. All rights reserved. May not be reproduced in any form without express written permission.
Disclaimer: The content on this website is provided as general education for medical professionals. It is not intended or recommended for patients or other laypersons or as a substitute for medical advice, diagnosis, or treatment. Patients must always consult a qualified health care professional regarding their diagnosis and treatment. Healthcare professionals should always check this website for the most recently updated information.