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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

Warning(s)

  • Increased Mortality in Geriatric Patients with Dementia-related Psychosis
  • Geriatric patients with dementia-related psychosis treated with antipsychotic agents are at an increased risk of death.1 3 4

  • Analyses of 17 placebo-controlled trials in geriatric patients mainly receiving atypical antipsychotic agents revealed an approximate 1.6- to 1.7-fold increase in mortality compared with that in patients receiving placebo.1 3 4

  • Most fatalities appeared to result from cardiovascular-related events (e.g., heart failure, sudden death) or infections (mostly pneumonia).1 3

  • Antipsychotic agents, including pimavanserin, are not approved for the treatment of dementia-related psychosis.1 3 4

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 (Clcr ≥30 mL/minute); use not recommended in patients with severe renal impairment (Clcr <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

Drug

Interaction

Comments

Antiarrhythmic agents, class Ia and III (e.g., amiodarone, disopyramide, procainamide, quinidine, sotalol)

Potential additive effect on QT interval prolongation1

Avoid concomitant use1

Anticonvulsants (carbamazepine, phenytoin)

Possible decreased exposure of pimavanserin1

Monitor patients for reduced efficacy of pimavanserin; may require dosage increase1

Anti-infective agents that prolong QT interval (e.g., gatifloxacin, moxifloxacin)

Potential additive effect on QT interval prolongation1

Avoid concomitant use1

Antipsychotic agents that prolong QT interval (e.g., chlorpromazine, thioridazine, ziprasidone)

Potential additive effect on QT interval prolongation1

Avoid concomitant use1

Carbidopa/levodopa

No dosage adjustment of carbidopa/levodopa necessary1

Clarithromycin

Possible increased exposure of pimavanserin1

Reduce dosage of pimavanserin to 17 mg once daily1

Indinavir

Possible increased exposure of pimavanserin1

Reduce dosage of pimavanserin to 17 mg once daily1

Itraconazole

Possible increased exposure of pimavanserin1

Reduce dosage of pimavanserin to 17 mg once daily1

Ketoconazole

Increased peak plasma concentration and AUC of pimavanserin by 1.5- and 3-fold, respectively1

Reduce dosage of pimavanserin to 17 mg once daily1

Rifampin

Possible decreased exposure of pimavanserin1

Monitor patients for reduced efficacy of pimavanserin; may require dosage increase1

St. John's wort (Hypericum perforatum)

Possible decreased exposure of pimavanserin1

Monitor patients for reduced efficacy of pimavanserin; may require dosage increase1

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-HT2A) receptors, and to a lesser extent at 5-HT2C receptors.1

  • Exhibits potent inverse agonist activity at 5-HT2A receptors;2 5 7 8 lesser affinity for 5-HT2C receptors.1 6 8

  • No appreciable affinity for 5-HT2B, 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.

Pimavanserin Tartrate

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets, film-coated

17 mg (of pimavanserin)

Nuplazid

Acadia

AHFS DI Essentials. © Copyright 2016, Selected Revisions November 29, 2016. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. Acadia Pharmaceuticals Inc. Nuplazid (pimavanserin) tablets prescribing information. San Diego, CA; 2016 Apr.

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.

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

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.

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

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]

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