AHFS Class:

• Atypical Antipsychotics 28:16.08.04

Generic Name(s):

• Pimavanserin Tartrate

• Pimavanserin

Pimavanserin tartrate is an atypical antipsychotic agent.1,2,5

Parkinson's Disease Psychosis

Pimavanserin is used for the management of hallucinations and delusions associated with Parkinson's disease psychosis.1,2 Safety and efficacy of pimavanserin for this use were established based on a 6-week, randomized, placebo-controlled study; a subsequent 4-week open-label extension study; and a long-term open-label extension period.1,2,13,14 Guidelines generally recommend clozapine or pimavanserin for the treatment of psychosis associated with Parkinson's disease.15

Because antipsychotic drugs have been associated with an increased risk of death in geriatric patients with dementia-related psychosis, pimavanserin should not be used for the treatment of dementia-related psychosis not related to the hallucinations and delusions associated with Parkinson's disease psychosis.1

Clinical Experience

Efficacy of pimavanserin for the management of hallucinations and delusions associated with Parkinson's disease psychosis was established in a 6-week, randomized, placebo-controlled study that included 199 adults (mean age of 72 years) with Parkinson's disease psychosis.1,2 For inclusion in the study, patients were required to have established Parkinson's disease for at least one year and psychotic symptoms (hallucinations and/or delusions) that developed after the diagnosis of Parkinson's disease and were severe and frequent enough to require treatment with an antipsychotic agent.1,2 Patients also were required to have a Mini-Mental State Examination (MMSE) score of 21 or greater and no delirium at study entry.1,2 Use of other antipsychotic agents was not permitted during the study, but drugs used for the management of Parkinson's disease (at stable dosages) were allowed; the majority (99%) of patients were receiving dopaminergic drugs at baseline and throughout the study.1,2 Patients were randomized to receive pimavanserin 34 mg or placebo once daily.1,2 The primary outcome measure was evaluated in terms of the Parkinson's disease-adapted Scale for the Assessment of Positive Symptoms (SAPS-PD), a 9-item scale used to assess symptoms and severity of hallucinations and delusions.1,2 Total scores on the SAPS-PD range from 0-45, with higher scores indicating greater severity of illness and a negative change in score reflecting improvement.1 Because treatment of psychosis in patients with Parkinson's disease can potentially worsen motor symptoms associated with the disease, a secondary outcome of this study assessed the patient's underlying symptoms of Parkinson's disease using the Unified Parkinson's Disease Rating Scale (UPDRS) parts II (evaluating activities of daily living) and III (evaluating motor symptoms).1,10

Pimavanserin was substantially more effective than placebo in decreasing the frequency and/or severity of hallucinations and delusions in patients with Parkinson's disease psychosis as assessed by independent blinded raters using the SAPS-PD scale; the placebo-subtracted difference in SAS-PD score for patients receiving pimavanserin was -3.06.1,2 Pimavanserin demonstrated an effect on both the hallucinations and delusions components of the SAPS-PD.1 In a post-hoc analysis, complete response (defined as no hallucinations or delusions) was achieved in 14% of patients receiving pimavanserin compared with 1% of those receiving placebo.10 Pimavanserin did not worsen motor function in this study based on a similar change in UPDRS score from baseline to 6 weeks in patients receiving pimavanserin and those receiving placebo.1,10

Two long-term safety and efficacy studies have been published evaluating the use of pimavanserin therapy beyond 6 weeks of treatment.13,14 In an open-label extension study including patients from 3 core double-blind, placebo-controlled studies, patients demonstrated a mean change of -1.8 in the SAPS-PD score after an additional 4 weeks of treatment (10 weeks total); patients previously receiving placebo during the core studies experienced greater improvements in their SAPS-PD scores during the open-label extension.13 Another long-term study included patients from a previous double-blind, placebo-controlled study or a previous open-label extension study, and evaluated use of pimavanserin for a median treatment duration of approximately 15 months.14 No new safety concerns or increased mortality were identified with longer-term treatment.14 The durability of response, assessed using the Clinical Global Impression-Severity (CGI-S) scale and the Caregiver Burden Scale (CBS), generally remained stable for up to 192 weeks.14

Clinical Perspective

In a 2019 evidence-based medicine review, the International Parkinson and Movement Disorder Society states that both clozapine and pimavanserin are considered “clinically useful” for the treatment of psychosis in Parkinson's disease.15 While both clozapine and pimavanserin are noted to have acceptable safety profiles, clozapine requires specialized monitoring.15 While pimavanserin is considered efficacious over the short-term for the treatment of psychosis, there is a lack of controlled safety data beyond 6 weeks of treatment; therefore, additional study is needed to determine optimal duration of treatment.14,15

General

Pretreatment Screening

• Assess patients for a history of cardiac arrhythmias, symptomatic bradycardia, hypokalemia, or hypomagnesemia that could increase the risk of torsades de pointes and/or sudden death with pimavanserin use.1 Avoid pimavanserin use in such patients.1
• Screen patients for known QT prolongation and the use of other medications known to prolong the QT interval such as class 1A (e.g., quinidine, procainamide), or class 3 antiarrhythmics (e.g., amiodarone, sotalol), certain antipsychotic medications (e.g., ziprasidone, chlorpromazine, thioridazine) and fluoroquinolones.1

Administration

Pimavanserin is administered orally (as capsules or tablets) without regard to food.1 Pimavanserin capsules can be swallowed whole, or opened and sprinkled over 15 mL (1 tablespoon) of applesauce, yogurt, pudding, or liquid nutritional supplement.1 If the capsule is opened and a drug/food mixture is created, swallow the mixture immediately and do not save for future use.1

Store pimavanserin capsules and tablets at 20-25°C (excursions permitted to 15-30°C).1

Dosage

Dosage of pimavanserin tartrate is expressed in terms of pimavanserin.1

Adults

For the management of hallucinations and delusions associated with Parkinson's disease psychosis, the recommended dosage of pimavanserin is 34 mg once daily without dosage titration.1

Dosage Modification for Concomitant Use with Cytochrome P-450 (CYP) 3A4 Inhibitors and Inducers

Potent Inhibitors of CYP3A4

If used concomitantly with a potent inhibitor of CYP3A4, dosage of pimavanserin should be reduced to 10 mg once daily.1

Potent or Moderate Inducers of CYP3A4

Avoid concomitant use of pimavanserin with potent or moderate inducers of CYP3A4.1

Special Populations

Hepatic Impairment

Dosage adjustment is not necessary in patients with hepatic impairment.1

Renal Impairment

Dosage adjustment is not necessary in patients with mild to severe renal impairment (creatinine clearance ≥30 mL/minute ) or end stage renal disease; however, increased exposure to pimavanserin has been observed in patients with severe renal impairment.1

Use pimavanserin with caution in patients with severe renal impairment and end stage renal disease.1

Geriatric Patients

No dosage adjustment is necessary in geriatric patients.1

Contraindications

• Known hypersensitivity to pimavanserin or any of its components.1

Warnings/Precautions

Warnings

Increased Mortality in Geriatric Patients with Dementia-related Psychosis

A boxed warning about the increased risk of death in geriatric patients with dementia-related psychosis treated with antipsychotic drugs is included in the prescribing information for pimavanserin.1,3,4 Analyses of 17 placebo-controlled trials (modal duration of 10 weeks) revealed a 1.6- to 1.7-fold increase in mortality among geriatric patients receiving atypical antipsychotic drugs (i.e., aripiprazole, olanzapine, quetiapine, risperidone) compared with that observed in patients receiving placebo.1,3 Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5% compared with a rate of about 2.6% in the placebo group.1 Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature.1,3 Pimavanserin is not approved for the management of patients with dementia-related psychosis not related to the hallucinations and delusions associated with Parkinson's disease psychosis.1

Other Warnings and Precautions

QT Interval Prolongation

Pimavanserin is known to prolong the QT interval.1 Pharmacokinetic and pharmacodynamic analyses suggest that the prolongation occurs in a concentration-dependent manner.1

Use of pimavanserin should be avoided in patients with known QT interval prolongation and in those who are receiving drugs known to prolong the QT interval (e.g., class IA and III antiarrhythmic agents).1 Pimavanserin also should be avoided in patients with a history of cardiac arrhythmias or other conditions that may increase the risk of torsades de pointes and/or sudden death (e.g., symptomatic bradycardia, hypokalemia or hypomagnesemia).1

Specific Populations

Pregnancy

There are no available data on use of pimavanserin in pregnant women.1 Reproductive animal studies revealed no teratogenic effects when pimavanserin was administered orally during the period of organogenesis at doses up to 10 or 12 times the maximum recommended human dose.1 However, maternal toxicity and reduced pup survival and body weight were observed when the drug was administered to pregnant rats during pregnancy and lactation at doses 2 times the maximum recommended human dose.1

Lactation

It is not known whether pimavanserin is distributed into human milk or if the drug has any effect on milk production or the nursing infant.1 The known benefits of breast-feeding should be considered along with the importance of pimavanserin to the woman and any potential adverse effects on the breast-fed infant from either the drug or underlying maternal condition.1

Pediatric Use

Safety and efficacy of pimavanserin have not been established in pediatric patients.1

Geriatric Use

In placebo-controlled studies evaluating pimavanserin in patients with Parkinson's disease psychosis, 49% of patients were 65-75 years of age and 31% were older than 75 years of age.1 In the pooled population of patients enrolled in these studies, 27% had Mini-Mental State Examination (MMSE) scores of 21-24 and 73% of patients had scores of 25 or greater.1 No clinically important differences in safety or efficacy were noted between these 2 groups.1

Hepatic Impairment

Based on exposure differences observed in patients with and without hepatic impairment, no dosage adjustment is necessary in patients with hepatic impairment.1

Renal Impairment

A population pharmacokinetic analysis indicated that exposure of pimavanserin in patients with mild to moderate renal impairment was similar to that in patients with normal renal function.1

In a renal impairment study, increased exposure to pimavanserin based on peak plasma concentrations and AUC was observed in patients with severe renal impairment.1 Use pimavanserin with caution in patients with severe renal impairment and end stage renal disease.1

Dialysis has not been shown to alter concentrations of pimavanserin.1

Common Adverse Effects

Adverse effects reported in ≥5% of patients receiving pimavanserin in clinical studies include peripheral edema and confusional state.1

Pimavanserin is metabolized principally by cytochrome P-450 (CYP) isoenzymes 3A4 and 3A5.1 CYP3A4 is the main enzyme responsible for biotransformation of the drug to its major active metabolite (AC-279).1,9 In vitro studies indicate that pimavanserin does not cause clinically important inhibition or induction of CYP3A4.1,9 The active metabolite does not appear to induce CYP3A to a clinically important extent and is not expected to cause induction of any other CYP enzymes.1,9 Neither pimavanserin nor its active metabolite inhibits any of the major hepatic and intestinal human CYP isoenzymes involved in drug metabolism (CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, and 3A4).1

In vitro studies indicate that pimavanserin is not a substrate for the efflux transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) or organic anion transport proteins (OATP) 1B1 and 1B3.9

Drugs Affecting Hepatic Microsomal Enzymes

Potent Inhibitors of CYP3A4

Concomitant use of pimavanserin and potent inhibitors of CYP3A4 (e.g., clarithromycin, indinavir, itraconazole, ketoconazole) may increase exposure of pimavanserin.1 When used concomitantly with a potent CYP3A4 inhibitor, dosage of pimavanserin should be reduced to 10 mg once daily.1

Moderate and Potent Inducers of CYP3A4

Concomitant use of pimavanserin and moderate and potent inducers of CYP3A4 (e.g., carbamazepine, phenytoin, rifampin, St. John's wort [ Hypericum perforatum ], modafinil, thioridazine, efavirenz, nafcillin) may decrease exposure of pimavanserin and potentially reduce the drug's efficacy.1 Avoid concomitant use of pimavanserin in patients receiving these drugs.1

Drugs Associated with QT Prolongation

Concomitant use of pimavanserin and drugs known to prolong the QT interval including class IA (e.g., disopyramide, procainamide, quinidine) and class III (e.g., amiodarone, sotalol) antiarrhythmic agents, certain antipsychotic agents (e.g., chlorpromazine, thioridazine, ziprasidone), and certain anti-infective agents (e.g., gatifloxacin, moxifloxacin) should be avoided.1 Such concomitant therapy may cause a potential additive effect on QT interval prolongation and increase the risk of cardiac arrhythmias.1

Carbidopa/Levodopa

No dosage adjustment of carbidopa/levodopa is necessary when used concomitantly with pimavanserin based on pharmacokinetic studies.1

Ketoconazole

Ketoconazole (a potent CYP3A4 inhibitor) increased peak plasma concentration and AUC of pimavanserin by 1.5- and 3-fold, respectively.1 Dosage of pimavanserin should be reduced to 10 mg once daily when used concomitantly with ketoconazole.1

Midazolam

There is no effect of pimavanserin on the pharmacokinetics of midazolam.1

Description

The exact mechanism of action of pimavanserin in the management of hallucinations and delusions associated with Parkinson's disease psychosis is unclear.1 However, the effects of the drug are thought to be mediated by its inverse agonist and antagonist activity at serotonin type 2A (5-HT_2A) receptors and, to a lesser extent, at 5-HT_2C receptors.1 Studies have shown that the delusions and hallucinations associated with Parkinson's disease psychosis may be linked to alterations in the serotonin system.2,11 Pimavanserin exhibits potent inverse agonist activity at 5-HT_2A receptors2,5,7 8 and lesser affinity for 5-HT_2C receptors; the drug has no appreciable affinity for 5-HT_2B, dopaminergic, muscarinic, histaminergic, or adrenergic receptors.1,2,5,6 Pimavanserin is structurally and pharmacologically distinct from other atypical antipsychotic agents; a distinguishing feature is the drug's relative lack of dopamine-blocking activity.5,10,12

Pimavanserin is extensively absorbed following oral administration.9 Relative bioavailability of the drug (tablet to solution) is approximately 99.7%.9 The median time to peak plasma concentration of pimavanserin is 6 hours (range 4-24 hours).1 When administered with a high-fat meal, peak plasma concentration of pimavanserin decreases by approximately 9%, while AUC increases by 8%.1 Pimavanserin exhibits dose-proportional pharmacokinetics following administration of single oral doses (range 17-255 mg).1 The drug is extensively (approximately 95%) bound to plasma proteins.1,9 The pharmacokinetics of pimavanserin do not appear to be affected by age, gender, ethnicity, or weight.1

Pimavanserin is metabolized principally by cytochrome P-450 (CYP) 3A4/5, and to a lesser extent by CYP2D6, CYP2J2, and various other CYP and flavin-containing monooxygenase isoenzymes.1 CYP3A4 is the principal isoenzyme involved in the formation of the major active metabolite of pimavanserin (AC-279).1 The mean plasma half-lives of pimavanserin and its active metabolite are approximately 57 and 200 hours, respectively.1 Approximately 0.6% of a radiolabeled dose of pimavanserin is excreted in urine as unchanged drug, and 1.5% is eliminated in feces after 10 days.1 Less than 1% of the administered dose of pimavanserin and its active metabolite are recovered in urine.1

Advice to Patients

• Advise patients and caregivers that geriatric patients with dementia-related psychosis treated with antipsychotic agents are at an increased risk of death.1,3,4 Patients and caregivers also should be informed that pimavanserin is not approved for the management of patients with dementia-related psychosis not related to the hallucinations and delusions associated with Parkinson's disease psychosis.1
• Importance of patients informing their providers of any history of cardiac arrhythmias, symptomatic bradycardia, hypokalemia, or hypomagnesemia that could increase the risk of torsades de pointes or sudden death with pimavanserin use.1
• Importance of informing clinicians of existing or contemplated therapy, including prescription and OTC drugs, as well as any concomitant illnesses.1
• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1
• Inform patients of other important precautionary information.1

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

1. Acadia Pharmaceuticals Inc. Nuplazid^® (pimavanserin) tablets prescribing information. San Diego, CA; 2023 Sept. [Web]

2. Cummings J, Isaacson S, Mills R et al. Pimavanserin for patients with Parkinson's disease psychosis: a randomised, placebo-controlled phase 3 trial. Lancet . 2014; 383:533-40. [PubMed 24183563]

3. Food and Drug Administration. Public health advisory: Deaths with antipsychotics in elderly patients with behavioral disturbances. Silver Spring, MD; 2005 Apr 11. From the FDA website. [Web]

4. Food and Drug Administration. Information for Healthcare Professionals: Conventional antipsychotics. Silver Spring, MD; 2008 Jun 16. From the FDA website: [Web]

5. . Pimavanserin (Nuplazid) for Parkinson's disease psychosis. Med Lett Drugs Ther . 2016; 58:74-5. [PubMed 27249096]

6. Vanover KE, Weiner DM, Makhay M et al. Pharmacological and behavioral profile of N-(4-fluorophenylmethyl)-N-(1-methylpiperidin-4-yl)-N'-(4-(2-methylpropyloxy)phenylmethyl) carbamide (2R,3R)-dihydroxybutanedioate (2:1) (ACP-103), a novel 5-hydroxytryptamine(2A) receptor inverse agonist. J Pharmacol Exp Ther . 2006; 317:910-8. [PubMed 16469866]

7. Goldman JG, Holden S. Treatment of psychosis and dementia in Parkinson's disease. Curr Treat Options Neurol . 2014; 16:281. [PubMed 24464490]

8. Markham A. Pimavanserin: First Global Approval. Drugs . 2016; 76:1053-7. [PubMed 27262680]

9. Food and Drug Administration. Center for Drug Evaluation and Research. Application number 207318Orig1s000: Clinical pharmacology and biopharmaceutics review(s). From FDA website. [Web]

10. Food and Drug Administration. Center for Drug Evaluation and Research. Application number 207318Orig1s000. Summary review.. From FDA website. [Web]

11. Chang A, Fox SH. Psychosis in Parkinson's Disease: Epidemiology, Pathophysiology, and Management. Drugs . 2016; 76:1093-118. [PubMed 27312429]

12. 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; 39:2008-17. [PubMed 24682754]

13. Isaacson SH, Ballard CG, Kreitzman DL, et al. Efficacy results of pimavanserin from a multi-center, open-label extension study in Parkinson's disease psychosis patients. Parkinsonism Relat Disord . 2021;87:25-31. [PubMed 33933853]

14. Ballard CG, Kreitzman DL, Isaacson S, et al. Long-term evaluation of open-label pimavanserin safety and tolerability in Parkinson's disease psychosis. Parkinsonism Relat Disord . 2020;77:100-106. [PubMed 32712560]

15. Seppi K, Ray Chaudhuri K, Coelho M, et al. Update on treatments for nonmotor symptoms of Parkinson's disease-an evidence-based medicine review [published correction appears in Mov Disord . 2019 May;34(5):765]. Mov Disord . 2019;34(2):180-198. [PubMed 30653247]

16. Acadia Pharmaceuticals, Inc. From Nuplazid® for healthcare professionals website. 2022 June. Accessed 16 June 2022. [Web]