2.1 Recommended Dosage

The recommended dose of NUPLAZID is 34 mg taken orally once daily, without titration.

2.2 Administration Information

NUPLAZID can be taken with or without food [see Clinical Pharmacology (12.3)].

NUPLAZID capsules can be taken whole, or opened and the entire contents sprinkled over a tablespoon (15 mL) of applesauce, yogurt, pudding, or a liquid nutritional supplement. Consume the drug/food mixture immediately without chewing; do not store for future use.

2.3 Dosage Modifications for Concomitant Use with CYP3A4 Inhibitors and Inducers

5.1 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. NUPLAZID is not approved for the treatment of patients with dementia who experience psychosis unless their hallucinations and delusions are related to Parkinson's disease [see Boxed Warning].

5.2 QT Interval Prolongation

NUPLAZID prolongs the QT interval. The use of NUPLAZID 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) [see Drug Interactions (7.1)]. NUPLAZID 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 [see Clinical Pharmacology (12.2)].

6.1 Clinical Trials Experience

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 NUPLAZID consists of over 1200 subjects and patients exposed to one or more doses of NUPLAZID. 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 NUPLAZID 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 NUPLAZID 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% NUPLAZID 34 mg vs. 2% placebo) and confusional state (6% NUPLAZID 34 mg vs. 3% placebo).

6.2 Postmarketing Experience

The following adverse reactions have been identified during postapproval use of NUPLAZID. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These reactions include rash, urticaria, reactions consistent with angioedema (e.g., tongue swelling, circumoral edema, throat tightness, and dyspnea), somnolence, falls, agitation, aggression, and fecal incontinence.

7.1 Drugs Having Clinically Important Interactions with NUPLAZID

7.2 Drugs Having No Clinically Important Interactions with NUPLAZID

Based on pharmacokinetic studies, no dosage adjustment of carbidopa/levodopa is required when administered concomitantly with NUPLAZID [see Clinical Pharmacology (12.3)].

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

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

8.5 Geriatric 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 NUPLAZID [see Adverse Reactions (6.1)] 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.

8.6 Patients with Renal Impairment

No dosage adjustment for NUPLAZID is needed in patients with mild to severe renal impairment or end stage renal disease (ESRD); however, increased exposure (Cmax and AUC) to NUPLAZID occurred in patients with severe renal impairment (CrCL <30 mL/min, Cockcroft-Gault) in a renal impairment study [see Clinical Pharmacology (12.3)].

NUPLAZID should be used with caution in patients with severe renal impairment and end stage renal disease.

In a renal impairment study, dialysis did not appear to significantly affect the concentrations of NUPLAZID [see Clinical Pharmacology (12.3)].

8.7 Patients with Hepatic Impairment

No dosage adjustment for NUPLAZID is recommended in patients with hepatic impairment based on the exposure differences observed in patients with and without hepatic impairment in a hepatic impairment study [see Clinical Pharmacology (12.3)].

8.8 Other Specific Populations

No dosage adjustment is required based on patient's age, sex, ethnicity, or weight. These factors do not affect the pharmacokinetics of NUPLAZID [see Clinical Pharmacology (12.3)].

9.1 Controlled Substance

NUPLAZID is not a controlled substance.

9.2 Abuse

NUPLAZID has not been systematically studied in humans for its potential for abuse, tolerance, or physical dependence.

While short-term, placebo-controlled and long-term, open-label clinical trials did not reveal increases in drug-seeking behavior, the limited experience from the clinical trials do not predict the extent to which a CNS-active drug will be misused, diverted, and/or abused once marketed.

10.1 Human Experience

The pre-marketing clinical trials involving NUPLAZID 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.

10.2 Management of Overdose

There are no known specific antidotes for NUPLAZID. In managing overdose, cardiovascular monitoring should commence immediately and should include continuous ECG monitoring to detect possible arrhythmias [see Warnings and Precautions (5.2)]. 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 NUPLAZID [see Drug Interactions (7.1)]. 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.

12.1 Mechanism of Action

The mechanism of action of pimavanserin in the treatment of hallucinations and delusions associated with PDP is unclear. However, the effect of pimavanserin could be mediated through a combination of inverse agonist and antagonist activity at serotonin 5-HT2A receptors and to a lesser extent at serotonin 5-HT2C receptors.

12.2 Pharmacodynamics

In vitro, pimavanserin acts as an inverse agonist and antagonist at serotonin 5-HT2A receptors with high binding affinity (Ki value 0.087 nM) and at serotonin 5-HT2C receptors with lower binding affinity (Ki value 0.44 nM). Pimavanserin shows low binding to sigma 1 receptors (Ki value 120 nM) and has no appreciable affinity (Ki value >300 nM), to serotonin 5-HT2B, dopaminergic (including D2), muscarinic, histaminergic, or adrenergic receptors, or to calcium channels.

12.3 Pharmacokinetics

Pimavanserin demonstrates dose-proportional pharmacokinetics after single oral doses from 17 to 255 mg (0.5- to 7.5-times the recommended dosage). The pharmacokinetics of pimavanserin are similar in both the study population and healthy subjects. The mean plasma half-lives for pimavanserin and the active metabolite (N-desmethylated metabolite) are approximately 57 hours and 200 hours, respectively.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

13.2 Animal Toxicology and/or Pharmacology

Phospholipidosis (foamy macrophages and/or cytoplasmic vacuolation) was observed in multiple tissues and organs of mice, rats, and monkeys following oral daily administration of pimavanserin. The occurrence of phospholipidosis was both dose- and duration-dependent. The most severely affected organs were the lungs and kidneys. In rats, diffuse phospholipidosis was associated with increased lung and kidney weights, respiratory-related clinical signs including rales, labored breathing, and gasping, renal tubular degeneration, and, in some animals, focal/multifocal chronic inflammation in the lungs at exposures ≥10-times those at the MRHD of 34 mg/day based on AUC. Phospholipidosis caused mortality in rats at exposures ≥16-times the MRHD of 34 mg/day based on AUC. The chronic inflammation in the rat lung was characterized by minimal to mild focal collagen positive fibroplasia as shown by specialized staining. Chronic inflammation of the lungs was not seen in monkeys treated for 12 months (exposures 9-times the MRHD). Based on the exposures at the estimated No Observed Effect Level (NOEL) for chronic lung inflammation in rats, there is a 5- to 9-times safety margin after 6-months of treatment and a 2- to 4-times safety margin after 24-months (lifetime) treatment compared to exposure at the MRHD. The relevance of these findings to human risk is not clear.

Motor Function in Patients with Hallucinations and Delusions Associated with Parkinson's Disease Psychosis

NUPLAZID 34 mg did not show an effect compared to placebo on motor function, as measured using the Unified Parkinson's Disease Rating Scale Parts II and III (UPDRS Parts II+III) (Figure 5). A negative change in score indicates improvement. The UPDRS Parts II+III was used to assess the patient's Parkinson's disease state during the 6-week double-blind treatment period. The UPDRS score was calculated as the sum of the 40 items from activities of daily living and motor examination, with a range of 0 to 160.

34 mg Capsule:

Opaque white and light green capsule with "PIMA" and "34" printed in black.

Bottle of 30:     NDC 63090-340-30

10 mg Tablet:

Orange, round, coated tablet debossed with "P" on one side and "10" on the reverse.

Bottle of 30:      NDC 63090-100-30

Storage

34 mg Capsule:

Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C (59°F and 86°F) [See USP Controlled Room Temperature]. To prevent potential capsule color fading, protect from light.

10 mg Tablet:

Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C (59°F and 86°F) [See USP Controlled Room Temperature].

Concomitant Medication

Advise patients to inform their healthcare providers if there are any changes to their current prescription or over-the-counter medications, since there is a potential for drug interactions [see Warnings and Precautions (5.2), Drug Interactions (7)].

Administration Instructions

Advise patients to take the capsule whole or sprinkled over a tablespoon (15 mL) of applesauce, yogurt, pudding, or a liquid nutritional supplement. Advise patients to consume the drug/food mixture immediately and not to store for future use [see Dosage and Administration (2.2)].