Nuplazid Drug Information

® is indicated for the treatment of hallucinations and delusions associated with Parkinson's disease psychosis . NUPLAZID is an atypical antipsychotic indicated for the treatment of hallucinations and delusions associated with Parkinson's disease psychosis.

Recommended Dosage

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

Administration Information

NUPLAZID can be taken with or without food . 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.

Dosage Modifications for

Concomitant Use with CYP3A4 Inhibitors and Inducers Coadministration with Strong CYP3A4 Inhibitors The recommended dose of NUPLAZID when coadministered with strong CYP3A4 inhibitors is 10 mg, taken orally as one tablet once daily. Coadministration with Strong or Moderate CYP3A4 Inducers Avoid concomitant use of strong or moderate CYP3A4 inducers with NUPLAZID .

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). Adverse Reactions Leading to Discontinuation of Treatment A total of 8% (16/202) of NUPLAZID 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% NUPLAZID vs. <1% placebo), urinary tract infection (1% NUPLAZID vs. <1% placebo), and fatigue (1% NUPLAZID 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 Percentage of Patients Reporting Adverse Reaction NUPLAZID 34 mg Placebo N=202 N=231 Gastrointestinal disorders Nausea 7% 4% Constipation 4% 3% General disorders Peripheral edema 7% 2% Gait disturbance 2% <1% Psychiatric disorders Hallucination 5% 3% Confusional state 6% 3% 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 NUPLAZID 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

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.

Drugs Having Clinically Important Interactions with

NUPLAZID Table 2 Clinically Important Drug Interactions with NUPLAZID QT Interval Prolongation Clinical Impact: Concomitant use of drugs that prolong the QT interval may add to the QT effects of NUPLAZID and increase the risk of cardiac arrhythmia. Intervention: Avoid the use of NUPLAZID in combination with other drugs known to prolong QT interval (e.g., Class 1A antiarrythmics, Class 3 antiarrythmics, certain antipsychotics or antibiotics) . Strong CYP3A4 Inhibitors Clinical Impact: Concomitant use of NUPLAZID with a strong CYP3A4 inhibitor increases pimavanserin exposure . Intervention: If NUPLAZID is used with a strong CYP3A4 inhibitor, reduce the dosage of NUPLAZID. Strong or Moderate CYP3A4 Inducers Clinical Impact: Concomitant use of NUPLAZID with strong or moderate CYP3A4 inducers reduces pimavanserin exposure. Intervention: Avoid concomitant use of strong or moderate CYP3A4 inducers with NUPLAZID .

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 .

Pregnancy Risk Summary 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 . 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 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.

Pediatric Use Safety and effectiveness of NUPLAZID in pediatric patients have not been established. Irritability Associated with Autism Spectrum Disorder The safety and effectiveness of NUPLAZID for the treatment of irritability associated with autism spectrum disorder have not been established in pediatric patients. Effectiveness was not demonstrated in a 6-week, double-blind, placebo-controlled, fixed-dose clinical study conducted in 237 pediatric patients 5 to 17 years of age with irritability associated with autism spectrum disorder diagnosed by the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) criteria (NCT05523895). In this study, 159 patients were treated with NUPLAZID and 78 were treated with placebo.

The most common adverse events (incidence ≥5%) reported among NUPLAZID-treated pediatric patients were upper respiratory tract infection (8% vs. 5% placebo) and headache (6% vs. 5% placebo). In this study, 1% (2/159) NUPLAZID-treated pediatric patients discontinued due to adverse events. Of the 237 patients from this study, 209 patients entered the open-label treatment study and received up to 52 weeks of daily treatment with NUPLAZID (NCT05555615). In the open-label study, the most common adverse events (incidence ≥5%) were upper respiratory tract infection (10%), vomiting (7%), headache (7%), nasopharyngitis (6%), and pyrexia (5%). In this study, 4% (9/209) of patients discontinued due to adverse events. Juvenile Animal Studies Juvenile rats were administered oral doses of pimavanserin of 15, 30, and 45 (12.8, 25.5, and 38.3 free base equivalents) mg/kg/day once daily beginning from postnatal day 21 through postnatal day 111, followed by a 4-week recovery (nondosing) period.

A decrease in growth (decreased body weight and femur length) was observed in males at ≥ 30 mg/kg/day and in females at all dose levels, which reversed following dose cessation. A delay in sexual maturation was observed in males at ≥ 30 mg/kg/day. There was no effect on fertility or reproductive performance for males or females; however, a slight decrease in the number of implantations and viable embryos was observed in mated females at all dose levels.

There were no adverse effects on neurobehavioral development or learning and memory up to the highest dose tested. All other drug-related effects, including an increased incidence of microscopic findings in the heart (minimal myofiber degeneration and fibrosis, and/or minimal to mild mononuclear cell infiltrate) observed in males and females at 45 mg/kg/day, were generally consistent with those observed in previous repeat-dose rat oral toxicity studies.

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 . Known hypersensitivity to NUPLAZID or any of its components.

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.

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 . 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. 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.