Pimavanserin

Pimavanserin
Black Box Warning
Adult Indications & Dosage
Pediatric Indications & Dosage
Contraindications
Warnings & Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Administration & Monitoring
Overdosage
Pharmacology
Clinical Studies
How Supplied
Images
Patient Counseling Information
Precautions with Alcohol
Brand Names
Look-Alike Names

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Martin Nino, M.D. [2]

Disclaimer

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Black Box Warning

INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS See full prescribing information for complete Boxed Warning. Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Pimavanserin is not approved for the treatment of patients with dementia-related psychosis unrelated to the hallucinations and delusions associated with Parkinson's disease psychosis.

Overview

Pimavanserin is an atypical antipsychotic that is FDA approved for the treatment of patients with hallucinations and delusions associated with Parkinson's disease psychosis. There is a Black Box Warning for this drug as shown here. Common adverse reactions include peripheral edema and confusional state (≥5% and twice the rate of placebo)..

Adult Indications and Dosage

FDA-Labeled Indications and Dosage (Adult)

Indications

Pimavanserin is indicated for the treatment of hallucinations and delusions associated with Parkinson's disease psychosis.

Dosage

• General Dosing Information

The recommended dose of Pimavanserin is 34 mg, taken orally as two 17 mg strength tablets once daily, without titration.

Pimavanserin can be taken with or without food.

• Dosage Modifications for Concomitant Use with CYP3A4 Inhibitors and Inducers

• Coadministration with Strong CYP3A4 Inhibitors

The recommended dose of Pimavanserin when coadministered with strong CYP3A4 inhibitors (e.g., ketoconazole) is 17 mg, taken orally as one tablet once daily.

• Coadministration with Strong CYP3A4 Inducers

Monitor patients for reduced efficacy if Pimavanserin is used concomitantly with strong CYP3A4 inducers; an increase in Pimavanserin dosage may be needed.

Off-Label Use and Dosage (Adult)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Pimavanserin in adult patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Pimavanserin in adult patients.

Pediatric Indications and Dosage

FDA-Labeled Indications and Dosage (Pediatric)

Safety and effectiveness have not been established in pediatric patients.

Off-Label Use and Dosage (Pediatric)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Pimavanserin in pediatric patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Pimavanserin in pediatric patients.

Contraindications

None

Warnings

INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS See full prescribing information for complete Boxed Warning. Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Pimavanserin is not approved for the treatment of patients with dementia-related psychosis unrelated to the hallucinations and delusions associated with Parkinson's disease psychosis.

Increased Mortality in Elderly Patients with Dementia-Related Psychosis

Antipsychotic drugs increase the all-cause risk of death in elderly patients with dementia-related psychosis. Analyses of 17 dementia-related psychosis placebo-controlled trials (modal duration of 10 weeks and largely in patients taking atypical antipsychotic drugs) revealed a risk of death in the drug-treated patients of between 1.6- to 1.7-times that in placebo-treated patients. Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5%, compared to a rate of about 2.6% in placebo-treated patients.

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

QT Interval Prolongation

Pimavanserin prolongs the QT interval. The use of Pimavanserin should be avoided in patients with known QT prolongation or in combination with other drugs known to prolong QT interval including Class 1A antiarrhythmics (e.g., quinidine, procainamide) or Class 3 antiarrhythmics (e.g., amiodarone, sotalol), certain antipsychotic medications (e.g., ziprasidone, chlorpromazine, thioridazine), and certain antibiotics (e.g., gatifloxacin, moxifloxacin). Pimavanserin should also be avoided in patients with a history of cardiac arrhythmias, as well as other circumstances that may increase the risk of the occurrence of torsade de pointes and/or sudden death, including symptomatic bradycardia, hypokalemia or hypomagnesemia, and the presence of congenital prolongation of the QT interval.

Adverse Reactions

Clinical Trials Experience

The following serious adverse reactions are discussed elsewhere in the labeling:

• Increased Mortality in Elderly Patients with Dementia-Related Psychosis
• QT Interval Prolongation

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The clinical trial database for Pimavanserin consists of over 1200 subjects and patients exposed to one or more doses of Pimavanserin. Of these, 616 were patients with hallucinations and delusions associated with Parkinson's disease psychosis (PDP). In the placebo-controlled setting, the majority of experience in patients comes from studies evaluating once-daily Pimavanserin doses of 34 mg (N=202) compared to placebo (N=231) for up to 6 weeks. In the controlled trial setting, the study population was approximately 64% male and 91% Caucasian, and the mean age was about 71 years at study entry. Additional clinical trial experience in patients with hallucinations and delusions associated with PDP comes from two open-label, safety extension studies (total N=497). The majority of patients receiving long-term treatment received 34 mg once-daily (N=459). Over 300 patients have been treated for more than 6 months; over 270 have been treated for at least 12 months; and over 150 have been treated for at least 24 months.

The following adverse reactions are based on the 6-week, placebo-controlled studies in which Pimavanserin was administered once daily to patients with hallucinations and delusions associated with PDP.

Common Adverse Reactions (incidence ≥5% and at least twice the rate of placebo): peripheral edema (7% Pimavanserin 34 mg vs. 2% placebo) and confusional state (6% Pimavanserin 34 mg vs. 3% placebo).

Adverse Reactions Leading to Discontinuation of Treatment

A total of 8% (16/202) of Pimavanserin 34 mg-treated patients and 4% (10/231) of placebo-treated patients discontinued because of adverse reactions. The adverse reactions that occurred in more than one patient and with an incidence at least twice that of placebo were hallucination (2% Pimavanserin vs. <1% placebo), urinary tract infection (1% Pimavanserin vs. <1% placebo), and fatigue (1% Pimavanserin vs. 0% placebo).

Adverse reactions that occurred in 6-week, placebo-controlled studies and that were reported at an incidence of ≥2% and >placebo are presented in Table 1.

• Table 1 Adverse Reactions in Placebo-Controlled Studies of 6-Week Treatment Duration and Reported in ≥2% and >Placebo

This image is provided by the National Library of Medicine.

Adverse Reactions in Demographic Subgroups

Examination of population subgroups in the 6-week, placebo-controlled studies did not reveal any differences in safety on the basis of age (≤75 vs. >75 years) or sex. Because the study population was predominantly Caucasian (91%; consistent with reported demographics for PD/PDP), racial or ethnic differences in the safety profile of Pimavanserin could not be assessed. In addition, in the 6-week, placebo-controlled studies, no clinically relevant differences in the incidence of adverse reactions were observed among those with a Mini-Mental State Examination (MMSE) score at entry of <25 versus those with scores ≥25.

Postmarketing Experience

There is limited information regarding Pimavanserin Postmarketing Experience in the drug label.

Drug Interactions

Drugs Having Clinically Important Interactions with Pimavanserin

• Table 2 Clinically Important Drug Interactions with Pimavanserin

This image is provided by the National Library of Medicine.

Drugs Having No Clinically Important Interactions with Pimavanserin

Based on pharmacokinetic studies, no dosage adjustment of carbidopa/levodopa is required when administered concomitantly with Pimavanserin.

Use in Specific Populations

Pregnancy

Pregnancy Category (FDA):

• Risk Summary

There are no data on Pimavanserin use in pregnant women that would allow assessment of the drug-associated risk of major congenital malformations or miscarriage. In animal reproduction studies, no adverse developmental effects were seen when Pimavanserin was administered orally to rats or rabbits during the period of organogenesis at doses up to 10- or 12-times the maximum recommended human dose (MRHD) of 34 mg/day, respectively. Administration of Pimavanserinto pregnant rats during pregnancy and lactation resulted in maternal toxicity and lower pup survival and body weight at doses which are 2-times the MRHD of 34 mg/day.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

• Data

• Animal Data

Pimavanserin was not teratogenic in pregnant rats when administered during the period of organogenesis at oral doses of 0.9, 8.5, and 51 mg/kg/day, which are 0.2- and 10-times the maximum recommended human dose (MRHD) of 34 mg/day based on AUC at mid and high doses, respectively. Maternal toxicity included reduction in body weight and food consumption at the highest dose.

Administration of Pimavanserin to pregnant rats during pregnancy and lactation at oral doses of 8.5, 26, and 51 mg/kg/day, which are 0.14- to 14-times the MRHD of 34 mg/day based on AUC, caused maternal toxicity, including mortality, clinical signs including dehydration, hunched posture, and rales, and decreases in body weight, and/or food consumption at doses ≥26 mg/kg/day (2-times the MRHD based on AUC). At these maternally toxic doses there was a decrease in pup survival, reduced litter size, and reduced pup weights, and food consumption. Pimavanserin had no effect on sexual maturation, neurobehavioral function including learning and memory, or reproductive function in the first generation pups up to 14-times the MRHD of 34 mg/day based on AUC.

Pimavanserin was not teratogenic in pregnant rabbits during the period of organogenesis at oral doses of 4.3, 43, and 85 mg/kg/day, which are 0.2- to 12-times the MRHD of 34 mg/day based on AUC. Maternal toxicity, including mortality, clinical signs of dyspnea and rales, decreases in body weight and/or food consumption, and abortions occurred at doses 12-times the MRHD of 34 mg/day based on AUC.
Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Pimavanserin in women who are pregnant.

Labor and Delivery

There is no FDA guidance on use of Pimavanserin during labor and delivery.

Nursing Mothers

There is no information regarding the presence of Pimavanserin in human milk, the effects on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for Pimavanserin and any potential adverse effects on the breastfed infant from Pimavanserin or from the underlying maternal condition.

Pediatric Use

Safety and effectiveness of Pimavanserin have not been established in pediatric patients.

Geriatic Use

No dose adjustment is required for elderly patients.

Parkinson's disease is a disorder occurring primarily in individuals over 55 years of age. The mean age of patients enrolled in the 6-week clinical studies with Pimavanserin was 71 years, with 49% 65-75 years old and 31% >75 years old. In the pooled population of patients enrolled in 6-week, placebo-controlled studies (N=614), 27% had MMSE scores from 21 to 24 compared to 73% with scores ≥25. No clinically meaningful differences in safety or effectiveness were noted between these two groups.

Gender

There is no FDA guidance on the use of Pimavanserin with respect to specific gender populations.

Race

There is no FDA guidance on the use of Pimavanserin with respect to specific racial populations.

Renal Impairment

No dosage adjustment for Pimavanserin is needed in patients with mild to moderate (CrCL ≥30 mL/min, Cockcroft-Gault) renal impairment.

Use of Pimavanserin is not recommended in patients with severe renal impairment (CrCL <30 mL/min, Cockcroft-Gault). Pimavanserin has not been evaluated in this patient population.

Hepatic Impairment

Use of Pimavanserin is not recommended in patients with hepatic impairment. Pimavanserin has not been evaluated in this patient population.

Females of Reproductive Potential and Males

There is no FDA guidance on the use of Pimavanserin in women of reproductive potentials and males.

Immunocompromised Patients

There is no FDA guidance one the use of Pimavanserin in patients who are immunocompromised.

Administration and Monitoring

Administration

The recommended dose of Pimavanserin is 34 mg, taken orally as two 17 mg strength tablets once daily, without titration.

Pimavanserin can be taken with or without food.

Monitoring

There is limited information regarding Pimavanserin Monitoring in the drug label.

IV Compatibility

There is limited information regarding the compatibility of Pimavanserin and IV administrations.

Overdosage

Human Experience The pre-marketing clinical trials involving Pimavanserin in approximately 1200 subjects and patients do not provide information regarding symptoms with overdose. In healthy subject studies, dose-limiting nausea and vomiting were observed.

Management of Overdose There are no known specific antidotes for Pimavanserin. In managing overdose, cardiovascular monitoring should commence immediately and should include continuous ECG monitoring to detect possible arrhythmias. If antiarrhythmic therapy is administered, disopyramide, procainamide, and quinidine should not be used, as they have the potential for QT-prolonging effects that might be additive to those of Pimavanserin. Consider the long plasma half-life of Pimavanserin (about 57 hours) and the possibility of multiple drug involvement. Consult a Certified Poison Control Center (1-800-222-1222) for up-to-date guidance and advice.

Pharmacology

Pimavanserin
Systematic (IUPAC) name
N-(4-fluorophenylmethyl)-N-(1-methylpiperidin-4-yl)-N'-(4-(2-methylpropyloxy)phenylmethyl)carbamide
Identifiers
CAS number	706779-91-1 706782-28-7 (tartrate)
ATC code	N05AX17
PubChem	10071196
DrugBank	DB05316
Chemical data
Formula	Template:OrganicBox atomTemplate:OrganicBox atomTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBox atomTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBox atomTemplate:OrganicBoxTemplate:OrganicBox atomTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBox
Mol. mass	427.553 g/mol
SMILES	eMolecules & PubChem
Synonyms	ACP-103
Pharmacokinetic data
Bioavailability	?
Protein binding	94–97%
Metabolism	Hepatic (CYP3A4, CYP3A5, CYP2J2)
Half life	54–56 hours
Excretion	?
Therapeutic considerations
Pregnancy cat.	?
Legal status	[[Prescription drug|Template:Unicode-only]](US)
Routes	Oral (tablets)

NUPLAZID tablets are intended for oral administration only. Each round, white to off-white, immediate-release, film-coated tablet contains 20 mg of pimavanserin tartrate, which is equivalent to 17 mg of pimavanserin free base. Inactive ingredients include pregelatinized starch, magnesium stearate, and microcrystalline cellulose. Additionally, the following inactive ingredients are present as components of the film coat: hypromellose, talc, titanium dioxide, polyethylene glycol, and saccharin sodium.

Mechanism of Action

There is limited information regarding Pimavanserin Mechanism of Action in the drug label.

Structure

There is limited information regarding Pimavanserin Structure in the drug label.

Pharmacodynamics

There is limited information regarding Pimavanserin Pharmacodynamics in the drug label.

Pharmacokinetics

There is limited information regarding Pimavanserin Pharmacokinetics in the drug label.

Nonclinical Toxicology

There is limited information regarding Pimavanserin Nonclinical Toxicology in the drug label.

Clinical Studies

There is limited information regarding Pimavanserin Clinical Studies in the drug label.

How Supplied

There is limited information regarding Pimavanserin How Supplied in the drug label.

Storage

There is limited information regarding Pimavanserin Storage in the drug label.

Images

Drug Images

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Package and Label Display Panel

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Patient Counseling Information

There is limited information regarding Pimavanserin Patient Counseling Information in the drug label.

Precautions with Alcohol

Alcohol-Pimavanserin interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication.

Brand Names

There is limited information regarding Pimavanserin Brand Names in the drug label.

Look-Alike Drug Names

There is limited information regarding Pimavanserin Look-Alike Drug Names in the drug label.

Drug Shortage Status

Price

References

The contents of this FDA label are provided by the National Library of Medicine.