Dosage & administration
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Nuplazid prescribing information
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
NUPLAZID® is indicated for the treatment of hallucinations and delusions associated with Parkinson's disease psychosis
The efficacy of NUPLAZID 34 mg as a treatment of hallucinations and delusions associated with Parkinson's disease (PD) psychosis was demonstrated in a 6-week, randomized, placebo-controlled, parallel-group study. In this outpatient study, 199 patients were randomized in a 1:1 ratio to NUPLAZID 34 mg or placebo once daily. Study patients (male or female and aged 40 years or older) had a diagnosis of PD (with or without dementia) established at least 1 year prior to study entry and had psychotic symptoms (hallucinations and/or delusions) that started after the PD diagnosis and that were severe and frequent enough to warrant treatment with an antipsychotic. At entry, patients were required to have a Mini-Mental State Examination (MMSE) score ≥21 and to be able to self-report symptoms. The majority of patients were on PD medications at entry; these medications were required to be stable for at least 30 days prior to study start and throughout the study period.
The PD-adapted Scale for the Assessment of Positive Symptoms (SAPS-PD) was used to evaluate the efficacy of NUPLAZID 34 mg. SAPS-PD is a 9-item scale adapted for PD from the Hallucinations and Delusions domains of the SAPS. Each item is scored on a scale of 0-5, with 0 being none and 5 representing severe and frequent symptoms. Therefore, the SAPS-PD total score can range from 0 to 45 with higher scores reflecting greater severity of illness. A negative change in score indicates improvement. Primary efficacy was evaluated based on change from baseline to Week 6 in SAPS-PD total score.
As shown in
| Endpoint | Treatment Group | Mean Baseline Score (SD) | LS Mean Change from Baseline (SE) | Placebo-subtracted DifferenceDifference (drug minus placebo) in least-squares mean change from baseline.(95% CI) |
|---|---|---|---|---|
| SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: confidence interval. | ||||
SAPS-PD | NUPLAZID | 15.9 (6.12) | -5.79 (0.66) | -3.06Statistically significantly superior to placebo.(-4.91, -1.20) |
| Placebo | 14.7 (5.55) | -2.73 (0.67) | -- | |
| SAPS-PD HallucinationsSupportive analysis. | NUPLAZID | 11.1 (4.58) | -3.81 (0.46) | -2.01 (-3.29, -0.72) |
| Placebo | 10.0 (3.80) | -1.80 (0.46) | -- | |
| SAPS-PD Delusions | NUPLAZID | 4.8 (3.59) | -1.95 (0.32) | -0.94 (-1.83, -0.04) |
| Placebo | 4.8 (3.82) | -1.01 (0.32) | -- | |
The effect of NUPLAZID on SAPS-PD improved through the six-week trial period, as shown in
| Complete response = SAPS-PD score reduced to zero from baseline value. |
| Patients with missing values were counted as non-responders. |
|
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) (
| LSM: least-squares mean; SE: standard error. The error bars extend one SE below the LSM. |
Figure 5 Motor Function Change from Baseline to Week 6 in UPDRS Parts II+III (LSM - SE) |
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- Recommended dose is 34 mg taken orally once daily, without titration. ()
2.1 Recommended DosageThe recommended dose of NUPLAZID is 34 mg taken orally once daily, without titration.
- Can be taken with or without food. ()
2.2 Administration InformationNUPLAZID 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.
- Capsules may be swallowed whole or opened and entire contents sprinkled over a tablespoon of certain types of soft food. ()
2.2 Administration InformationNUPLAZID 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.
NUPLAZID (pimavanserin) is available as:
- 34 mg strength capsules. The capsules are opaque white and light green with "PIMA" and "34" printed in black.
- 10 mg strength tablets. The orange, round, coated tablets are debossed on one side with a "P" and "10" on the reverse side.
There are no data on NUPLAZID 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 pimavanserin to 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
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 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.
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.
NUPLAZID is contraindicated in patients with a history of a hypersensitivity reaction to pimavanserin or any of its components. Rash, urticaria, and reactions consistent with angioedema (e.g., tongue swelling, circumoral edema, throat tightness, and dyspnea) have been reported
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.