Pimavanserin (Monograph)

Brand name: Nuplazid
Drug class: Atypical Antipsychotics
- 5-HT2A Receptor Inverse Agonists
- Serotonin 2A (5-HT2A) Receptor Inverse Agonists
Chemical name: (2R,3R)-2,3-dihydroxybutanedioate (2:1) N-[(4-fluorophenyl)methyl]-N-(1-methyl-4-piperidinyl)-N′-[[4-(2-methylpropoxy)phenyl]methyl]-urea
Molecular formula: (C₂₅H₃₄FN₃O₂)₂•C₄H₆O₆ C₂₅H₃₄FN₃O₂
CAS number: 706782-28-7

Medically reviewed by Drugs.com on Dec 23, 2022. Written by ASHP.

Introduction

Atypical antipsychotic agent.

Uses for Pimavanserin

Parkinson's Disease Psychosis

Management of hallucinations and delusions associated with Parkinson's disease psychosis.

A 2019 evidence-based medicine review by the International Parkinson and Movement Disorder Society states that clozapine and pimavanserin are “clinically useful” agents for the treatment of psychosis associated with Parkinson’s disease.

Not approved for treatment of dementia-related psychosis not related to the hallucinations and delusions associated with Parkinson’s disease psychosis.

Pimavanserin Dosage and Administration

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. Avoid pimavanserin use in such patients.

• 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.

Administration

Oral Administration

Administer orally (as tablets or capsules) without regard to food.

Swallow capsules whole, or opened and sprinkled over 15 mL (1 tablespoon) of applesauce, yogurt, pudding, or liquid nutritional supplement. If the capsule is opened and a drug/food mixture is created, swallow the mixture immediately and do not save for future use.

Dosage

Available as pimavanserin tartrate; dosage expressed in terms of pimavanserin.

Adults

Parkinson's Disease Psychosis

Oral

34 mg once daily without dosage titration.

If used concomitantly with a potent CYP3A4 inhibitor, reduce dosage to 10 mg once daily.

Avoid concomitant use with potent or moderate CYP3A4 inducers.

Special Populations

Hepatic Impairment

No dosage adjustment required.

Renal Impairment

No dosage adjustment required; however, increased exposure to pimavanserin observed in patients with severe renal impairment (Cl_cr≤30 mL/minute). Use with caution in severe renal impairment and end-stage renal disease.

Geriatric Patients

No dosage adjustment required.

Age, Ethnicity, Sex, Weight

No dosage adjustment required.

Cautions for Pimavanserin

Contraindications

• Known hypersensitivity to pimavanserin or any of its components.

Warnings/Precautions

Warnings

Increased Mortality in Geriatric Patients with Dementia-related Psychosis

Possible increased risk of death with antipsychotics in geriatric patients with dementia-related psychosis. (See Boxed Warning.)

Pimavanserin is not approved for the management of patients with dementia-related psychosis not related to hallucinations and delusions associated with Parkinson’s disease psychosis.

Other Warnings and Precautions

QT Interval Prolongation

Risk of QT interval prolongation.

Avoid use in patients with known QT interval prolongation and in those receiving drugs that prolong the QT interval. Avoid use in patients with 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).

Specific Populations

Pregnancy

No available data in pregnant women. Animal reproduction studies revealed no evidence of teratogenic effects; however, maternal toxicity and reduced pup survival and growth observed.

Lactation

Not known whether distributed into human milk. Also not known if drug has any effect on milk production or the nursing infant.

Consider benefits of breast-feeding along with importance of pimavanserin to the woman and any potential adverse effects on infant from the drug or underlying maternal condition.

Pediatric Use

Safety and efficacy not established.

Geriatric Use

Majority of patients in clinical studies were ≥65 years of age. No clinically important differences in safety or efficacy observed between patients 65–75 years of age and those >75 years of age.

Hepatic Impairment

No dosage adjustments necessary based on exposure differences observed in patients with and without hepatic impairment.

Renal Impairment

Pimavanserin exposure in patients with mild to moderate renal impairment similar to that in patients with normal renal function.

Pimavanserin exposure increased in patients with severe renal impairment based on peak plasma concentrations and AUC. Use with caution in patients with severe renal impairment and end-stage renal disease. Dialysis not shown to alter concentrations of pimavanserin.

Common Adverse Effects

Adverse effects reported in ≥5% of patients receiving pimavanserin in clinical studies at more than twice the rate as with placebo include peripheral edema and confusional state.

Drug Interactions

Metabolized principally by CYP3A4 and 3A5. Does not cause clinically important inhibition or induction of CYP3A4. The active metabolite does not induce CYP3A to a clinically important extent and is not expected to induce other CYP enzymes. Neither pimavanserin nor its active metabolite appears to inhibit any of the major CYP isoenzymes involved in drug metabolism (CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, and 3A4).

Not a substrate of P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), or organic anion transport proteins (OATP) 1B1 and 1B3.

Drugs Affecting Hepatic Microsomal Enzymes

Potent inhibitors of CYP3A4: Possible increased exposure of pimavanserin. Reduce pimavanserin dosage to 10 mg once daily.

Potent and moderate inducers of CYP3A4: Avoid concomitant use.

Drugs Associated with QT Prolongation

Potential additive effects on QT interval prolongation, which may increase risk of cardiac arrhythmias. Avoid concomitant use.

Specific Drugs

Pimavanserin Pharmacokinetics

Absorption

Bioavailability

> 99.7% following oral administration.

Exhibits dose-proportional pharmacokinetics following single oral doses (range 17–255 mg).

Food

Food exhibits no substantial effect; peak plasma concentration decreased by approximately 9%, while AUC increased by 8% when administered with a high-fat meal.

Distribution

Extent

Not known if distributed into human milk.

Plasma Protein Binding

Approximately 95%.

Elimination

Metabolism

Metabolized principally by CYP3A4/5, and to a lesser extent by CYP2D6, CYP2J2, and various other CYP and flavin-containing monooxygenase isoenzymes.

Elimination Route

Approximately 0.6% of radiolabeled dose excreted in urine as unchanged drug, and 1.5% eliminated in feces after 10 days.

<1% of administered dose of pimavanserin and its active metabolite recovered in urine.

Half-life

Approximately 57 hours; 200 hours for active metabolite.

Stability

Storage

Oral

Capsules and tablets

20–25°C (excursions permitted to 15–30°C).

Actions

• Exact mechanism of antipsychotic action unclear; may be mediated by a combination of inverse agonist and antagonist activity at serotonin type 2A (5-HT_2A) receptors, and to a lesser extent at 5-HT_2C receptors.

• Exhibits potent inverse agonist activity at 5-HT_2A receptors; lesser affinity for 5-HT_2C receptors.

• No appreciable affinity for 5-HT_2B, dopaminergic, muscarinic, histaminergic, or adrenergic receptors.

• Structurally and pharmacologically distinct from other atypical antipsychotic agents.

Advice to Patients

• Importance of advising patients and caregivers that geriatric patients with dementia-related psychosis treated with antipsychotic agents are at an increased risk of death. 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.

• 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.

• Importance of informing clinicians of existing or contemplated therapy, including prescription and OTC drugs, as well as any concomitant illnesses.

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.

• Importance of informing patients of other important precautionary information. (See Cautions.)

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.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Pimavanserin is available only from designated specialty distributors and pharmacies. The manufacturer should be contacted for additional information.

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