Pimavanserin
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
Brands: Nuplazid
Medically reviewed by Drugs.com. Last updated on Nov 19, 2020.
Warning
- 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
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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
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Most fatalities appeared to result from cardiovascular-related events (e.g., heart failure, sudden death) or infections (mostly pneumonia).1 3
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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
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
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Exhibits potent inverse agonist activity at 5-HT2A receptors;2 5 7 8 lesser affinity for 5-HT2C receptors.1 6 8
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No appreciable affinity for 5-HT2B, dopaminergic, muscarinic, histaminergic, or adrenergic receptors.1 2 5 6
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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.
Routes |
Dosage Forms |
Strengths |
Brand Names |
Manufacturer |
---|---|---|---|---|
Oral |
Tablets, film-coated |
17 mg (of pimavanserin) |
Nuplazid |
Acadia |
AHFS DI Essentials™. © Copyright 2021, Selected Revisions November 29, 2016. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, 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. http://www.ncbi.nlm.nih.gov/pubmed/24183563?dopt=AbstractPlus
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. http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm053171.htm
4. Food and Drug Administration. Information for Healthcare Professionals: Conventional antipsychotics. Silver Spring, MD; 2008 Jun 16. From the FDA website: http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm124830.htm
5. . Pimavanserin (Nuplazid) for Parkinson's disease psychosis. Med Lett Drugs Ther. 2016; 58:74-5. http://www.ncbi.nlm.nih.gov/pubmed/27249096?dopt=AbstractPlus
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. http://www.ncbi.nlm.nih.gov/pubmed/16469866?dopt=AbstractPlus
7. Goldman JG, Holden S. Treatment of psychosis and dementia in Parkinson's disease. Curr Treat Options Neurol. 2014; 16:281. http://www.ncbi.nlm.nih.gov/pubmed/24464490?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=3994190&blobtype=pdf
8. Markham A. Pimavanserin: First Global Approval. Drugs. 2016; 76:1053-7. http://www.ncbi.nlm.nih.gov/pubmed/27262680?dopt=AbstractPlus
9. Food and Drug Administration. Center for Drug Evaluation and Research. Application number 207318Orig1s000: Clinical pharmacology and biopharmaceutics review(s). From FDA website. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2016/207318Orig1s000ClinPharmR.pdf
10. Food and Drug Administration. Center for Drug Evaluation and Research. Application number 207318Orig1s000: Summary review. From FDA website. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2016/207318Orig1s000SumR.pdf
11. Chang A, Fox SH. Psychosis in Parkinson's Disease: Epidemiology, Pathophysiology, and Management. Drugs. 2016; 76:1093-118. http://www.ncbi.nlm.nih.gov/pubmed/27312429?dopt=AbstractPlus
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. http://www.ncbi.nlm.nih.gov/pubmed/24682754?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=4172996&blobtype=pdf
More about pimavanserin
- Side Effects
- During Pregnancy
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- Drug Interactions
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- Drug class: atypical antipsychotics
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Other brands: Nuplazid