Pharmascript October 2016: New Drug Update: Pimavanserin (Nuplazid™)
Thursday, October 20, 2016
Posted by: Alysa Craig
Brenna Baals, PharmD Candidate 2017, Shenandoah University Bernard J. Dunn School of Pharmacy
Kathryn Dane, PharmD, PGY-2 Pharmacotherapy Resident, the Johns Hopkins Hospital
Sujin Weinstein, PharmD, BCPP, Clinical Pharmacist, the Johns Hopkins Hospital
In April 2016, the Food and Drug Administration (FDA) approved pimavanserin (NuplazidTM), an atypical antipsychotic indicated for the treatment of hallucinations and delusions in Parkinson’s disease psychosis (PDP). 1 Although motor symptoms in Parkinson's disease remain the primary focus of therapy, non-motor symptoms have been reported in at least 60% of patients, and often require medication management.2 Prior to the FDA approval of pimavanserin, therapeutic options targeting PDP symptoms included clozapine, olanzapine, quetiapine, and risperidone, the use of which are limited by variable therapeutic benefits and prevalent adverse effects.3 Unlike other currently available antipsychotic agents, pimavanserin exerts its therapeutic effects via inverse agonism at serotonin-2A (5HT2A) receptors.4 This unique mechanism effectively alleviates psychotic symptoms, and results in a favorable adverse effect profile. Pimavanserin lacks significant activity at receptors responsible for the orthostatic, anticholinergic, sedating, and extrapyramidal effects characteristic of the antipsychotic class.4 Additionally, pimavanserin administration is devoid of the monitoring requirements and access challenges associated with clozapine use.4
The efficacy and safety of pimavanserin were evaluated in a six-week, multi-center, randomized, double- blind, placebo-controlled trial. Patients were eligible to participate if they had been diagnosed with Parkinson’s disease at least one year prior to study entry and experienced sustained hallucinations and/or delusions.5 Patients were randomly assigned to treatment with pimavanserin 34 mg daily (n = 95) or placebo (n = 90). The primary outcome was the change in key symptoms of PDP from baseline to day 43, as measured by the Scale for Assessment of Positive Symptoms in Parkinson’s Disease (SAPS-PD) score.5 Pimavanserin use was associated with a significant reduction in PDP symptoms versus placebo (37% vs. 14%, p = 0.0014). The most commonly reported adverse effects included urinary tract infections (13%), falls (11%), and peripheral edema (7%).5 Notably, no extrapyramidal adverse effects occurred with pimavanserin administration. In addition, patients receiving pimavanserin experienced a mean increase in QTc of 7.3 ms from baseline.5
Preliminary evidence evaluating the therapeutic efficacy of pimavanserin is promising, and the tolerability of this agent appears favorable. Yet, pharmacists should note the following warnings and precautions when involved in the treatment of patients receiving this medication.6 Due to the mild QTc prolongation associated with pimavanserin use, caution is warranted when administered with concomitant QTc-prolonging medications or in high risk patients.6 As with all antipsychotic agents, pimavanserin carries a black box warning for increased mortality risk in elderly patients with dementia-related psychosis, and should only be used in this population after careful assessment of potential benefits and risks. Additionally, pimavanserin undergoes metabolism via cytochrome P450 3A4, and therefore, pharmacists should be vigilant in identifying potential drug interactions in patients receiving this medication. The recommended dose of pimavanserin for PDP treatment is 34 mg daily, and will be supplied as 17 mg tablets, with an anticipated wholesale acquisition cost of $1,950 for 60 tablets.6,7
1. Press Announcements. Food and Drug Administration website. http://www.fda.gov/newsevents/newsroom/pressannouncements/ucm498442.htm. May 2, 2016. Accessed May 22, 2016.
2. Hacksell U, Burstein ES, McFarland K, et al. On the discovery and development of pimavanserin: a novel drug candidate for Parkinson’s psychosis. Neurochem Res. 2014;39(10):2008-2017.
3. Zahodne LB, Fernandez HH. A review of the pathophysiology and treatment of psychosis in Parkinson’s disease. Drugs Aging. 2008;25(8):665–682.
4. Meyer JM. Pimavanserin for psychosis in patients with Parkinson’s disease. Curr Psychiatr. 2016;15(9):81-87.
5. Cummings J, Isaacson S, Mills R, et al. Pimavanserin for patients with Parkinson's disease psychosis: a randomised, placebo-controlled phase 3 trial. The Lancet. 2014;383(9916):533-540.
6. NUPLAZIDTM [package insert]. San Diego, CA: ACADIA Pharmaceuticals Inc; 2016.
7. Personal Communication. Yi P, Director, Patient Access and Channel Operations. ACADIA Pharmaceuticals. 15 June 2016. E-mail correspondence.