Pimavanserin

Class: Atypical Antipsychotics
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
Brands: Nuplazid

Introduction

Atypical antipsychotic agent.^{1 2 5}

Uses for Pimavanserin

Parkinson's Disease Psychosis

Management of hallucinations and delusions associated with Parkinson's disease psychosis.^{1 2 10}

Not approved for treatment of dementia-related psychosis not related to the hallucinations and delusions associated with Parkinson’s disease psychosis.¹ (See Boxed Warning.)

Pimavanserin Dosage and Administration

Administration

Oral Administration

Administer orally without regard to food.¹

Dosage

Available as pimavanserin tartrate; dosage expressed in terms of pimavanserin.¹

Adults

Parkinson's Disease Psychosis

Oral

34 mg (two 17-mg tablets) once daily without dosage titration.¹

If used concomitantly with a potent CYP3A4 inhibitor, reduce dosage to 17 mg once daily.¹

If used concomitantly with a potent CYP3A4 inducer, monitor patients for reduced efficacy; dosage increase may be necessary.¹

Special Populations

Hepatic Impairment

Use not recommended.¹

Renal Impairment

No dosage adjustment required in patients with mild to moderate renal impairment (Cl_cr ≥30 mL/minute); use not recommended in patients with severe renal impairment (Cl_cr <30 mL/minute).¹

Geriatric Patients

No dosage adjustment required.¹

Age, Ethnicity, Gender, Weight

No dosage adjustment required.¹

Cautions for Pimavanserin

Contraindications

• None.¹

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.^{1 3 4} (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.¹

Other Warnings and Precautions

QT Interval Prolongation

Risk of QT interval prolongation.¹

Avoid use in patients with known QT interval prolongation and in those receiving drugs that prolong the QT interval.¹ (See Drugs that Prolong QT Interval under Interactions.) 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).¹

Specific Populations

Pregnancy

No available data in pregnant women.¹ Animal reproduction studies revealed no evidence of teratogenic effects; however, maternal toxicity and reduced pup survival and growth observed.¹

Lactation

Not known whether distributed into human milk.¹ Also not known if drug has any effect on milk production or the nursing infant.¹

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.¹

Pediatric Use

Safety and efficacy not established.¹

Geriatric Use

Majority of patients in clinical studies were ≥65 years of age.¹ No clinically important differences in safety or efficacy observed between patients 65–75 years of age and those >75 years of age.¹

Hepatic Impairment

Not evaluated in patients with hepatic impairment; use not recommended.¹

Renal Impairment

Pimavanserin exposure in patients with mild to moderate renal impairment similar to that in patients with normal renal function.¹

Not evaluated in patients with severe renal impairment; use not recommended.¹

Common Adverse Effects

Nausea,¹ peripheral edema,^{1 2} confusional state,^{1 2} hallucinations (visual, auditory, tactile, and somatic),^{1 2} constipation,¹ gait disturbance.¹

Interactions for Pimavanserin

Metabolized principally by CYP3A4 and 3A5.¹ Does not cause clinically important inhibition or induction of CYP3A4.^{1 9} The active metabolite does not induce CYP3A to a clinically important extent and is not expected to induce other CYP enzymes.^{1 9} 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).¹

Not a substrate of P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), or organic anion transport proteins (OATP) 1B1 and 1B3.⁹

Drugs Affecting Hepatic Microsomal Enzymes

Potent inhibitors of CYP3A4: Possible increased exposure of pimavanserin.¹ Reduce pimavanserin dosage to 17 mg once daily.¹

Potent inducers of CYP3A4: Possible decreased exposure of pimavanserin.¹ Monitor patients for reduced efficacy; dosage increase of pimavanserin may be required.¹

Drugs that Prolong QT Interval

Potential additive effects on QT interval prolongation, which may increase risk of cardiac arrhythmias.¹ (See QT Interval Prolongation under Cautions.) Avoid concomitant use.¹

Specific Drugs

Pimavanserin Pharmacokinetics

Absorption

Bioavailability

> 99.7% following oral administration.⁹

Exhibits dose-proportional pharmacokinetics following single oral doses (range 17–255 mg).¹

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.¹

Distribution

Extent

Not known if distributed into human milk.¹

Plasma Protein Binding

Approximately 95%.^{1 9}

Elimination

Metabolism

Metabolized principally by CYP3A4/5, and to a lesser extent by CYP2D6, CYP2J2, and various other CYP and flavin-containing monooxygenase isoenzymes.¹

Elimination Route

Approximately 0.6% of radiolabeled dose excreted in urine as unchanged drug, and 1.5% eliminated in feces after 10 days.¹

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

Half-life

Approximately 57 hours; 200 hours for active metabolite.¹

Stability

Storage

Oral

Tablets

20–25°C (may be exposed to 15–30°C).¹

Actions

• Exact mechanism of antipsychotic action not known; 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.¹

• Exhibits potent inverse agonist activity at 5-HT_2A receptors;^{2 5 7 8} lesser affinity for 5-HT_2C receptors.^{1 6 8}

• No appreciable affinity for 5-HT_2B, dopaminergic, muscarinic, histaminergic, or adrenergic receptors.^{1 2 5 6}

• Structurally and pharmacologically distinct from other atypical antipsychotic agents.^{5 10 12}

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.^{1 3 4} Inform patients and caregivers 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 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

• Importance of informing patients of other important precautionary information.¹ (See Cautions.)

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.