Side Effects of Nuplazid (pimavanserin)

Nuplazid (pimavanserin) is used to treat hallucinations and delusions associated with Parkinson’s disease psychosis. 

The mechanism of action of Nuplazid in the treatment of hallucinations and delusions associated with Parkinson’s disease psychosis is unknown. The effect of Nuplazid 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.

Common side effects of Nuplazid include

• nausea,
• constipation,
• swelling of extremities,
• gait disturbance,
• hallucinations, and
• confusion.

Serious side effects of Nuplazid include

• increased risk of death in elderly patients with dementia-related psychosis treated with antipsychotic drugs.

Drug interactions of Nuplazid include

• antiarrhythmics,
• antibiotics (gatifloxacin, moxifloxacin),
• strong CYP3A4 inhibitors (itraconazole, ketoconazole, clarithromycin, indinavir), and
• strong CYP3A4 inducers (rifampin, carbamazepine, phenytoin, St. John’s wort). 

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. 

There is no information regarding the presence of Nuplazid 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 Nuplazid and any potential adverse effects on the breastfed infant from Nuplazid or from the underlying maternal condition.

WARNING

Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Nuplazid is not approved for the treatment of patients with dementia-related psychosis unrelated to the hallucinations and delusions associated with Parkinson’s disease psychosis.

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

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

Common Adverse Reactions:

• Nausea,
• Constipation,
• Peripheral Edema,
• Gait disturbance,
• Hallucination,
• Confusional state.

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

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

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

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, and
• aggression.

Drugs Having Clinically Important Interactions With Nuplazid

Table 2 Clinically Important Drug Interactions 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.

Drug Abuse And Dependence

Controlled Substance

Nuplazid is not a controlled substance.

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.