In April 2016, pimavanserin (Nuplazid, Acadia Pharmaceuticals) became the first FDA-approved drug to treat delusions and hallucinations associated with Parkinson disease psychosis.

Hallucination is defined as seeing or hearing things that are not there, while delusions are defined as having false beliefs. Around 50,000 Americans are diagnosed with Parkinson disease every year, with about half of them developing hallucinations or delusions throughout the course of the disease.1

Dosing and Administration

Pimavanserin is taking at 34 mg orally, every day with or without food. If patients are taking a strong CYP3A4 inhibitor (eg, ketoconazole, clarithromycin, lopinavir), the dose of pimavanserin will need to be reduced to 10 mg once daily (tablet formulation). Patients taking a strong CYP3A4 inducer (eg, rifampin, carbamazepine) may need higher doses of pimavanserin.2

Pharmacology

Pimavanserin is thought to exert its effect by being a 5-HT2A and, to a smaller degree, 5-HT2C receptor inverse agonist and antagonist. High-fat meals did not have a significant effect on pimavanserin. Age, sex, ethnicity, and weight were not factors relevant to the effects of pimavanserin. Patients with mild to moderate renal impairment had similar effects as patients with normal renal function. Severe renal impairments (CrCl <30ml/min) may result in increased exposure to pimavanserin but also does not require an initial dose adjustment. Patients with hepatic impairment had similar effects as patients with normal hepatic function.2
 
Table 1. Method of Supply
Pimavanserin is formulated and supplied under two dosage forms and two different strengths: 10-mg tablet and 34-mg capsule according to the package insert. A 17-mg tablet formulation is also available.2,3
 
Drug Strength/Packaging NDC Information
34-mg capsule: bottle of 30 capsules 63090-340-30
 
10-mg tablet: bottle of 30 tablets
 
63090-100-30
17-mg tablet: bottle of 60 tablets
 
63090-0170-60
NDC indicates National Drug Code.

Storage

Pimavanserin capsules and tablets should be stored at room temperature 20°C to 25°C (68°F-77°F), with a permitted temperature range of 15 to 30°C (59°F-86°F). Capsules should be stored away from light, as light will cause the capsule’s color to fade.2

Drug Interactions and Contraindications

Drugs that can prolong the QT interval may increase the risk of cardiac arrhythmias when used together with pimavanserin. Drugs that have documented risk of QT prolongation are antiarrhythmics (quinidine, amiodarone, sotalol, procainamide, disopyramide), antipsychotics (ziprasidone, thioridazine, chlorpromazine), and antibiotics (gatifloxacin, moxifloxacin). Avoid using any drug that may cause QT prolongation with pimavanserin.2

Pimavanserin is a known substrate of CYP3A4 and other enzymes. CYP3A4 inhibitors will increase pimavanserin concentrations, while CYP3A4 inducers will decrease pimavanserin concentrations. Reduced doses of pimavanserin to 10 mg daily will be needed when used in combination with strong CYP3A4 inhibitors such as ketoconazole, itraconazole, clarithromycin, or indinavir. Increased doses of pimavanserin may be needed with strong CYP3A4 inducers such as rifampin, St. John’s Wort, phenytoin, or carbamazepine. 

Carbidopa/levodopa does not require a dosage adjustment when used together with pimavanserin.

Pimavanserin is contraindicated in any patient with an allergic reaction to pimavanserin or any of its components.

Warnings and Precautions

Pimavanserin has a black box warning of increased all-cause deaths associated with dementia-related psychosis in elderly patients. In a clinical trial, the rate of death in this population was 4.5% in patients taking pimavanserin compared with 2.6% in patients taking placebo. The reasons for death vary but are most likely to be associated with cardiovascular and infections. A diagnosis of Parkinson disease psychosis is paramount when deciding whether to use pimavanserin.2

Pimavanserin prolongs QT interval. It should not be used with drugs that can also cause QT prolongation or in patients who already have a history of cardiac arrhythmias.

Adverse Reactions

Common adverse reactions, regarded as an incidence rate of ≥5%, are listed in the table below. Hallucinations, urinary tract infections, and fatigue are some adverse events (AEs) more commonly seen in patients taking pimavanserin than placebo that led to discontinuation of pimavanserin. Other relevant AEs included constipation (4%) and gait disturbance (2%).2
 
Table 2. Adverse Reactions From Placebo-Controlled Clinical Trials
Adverse Reactions Percentages
Nausea 7%
Peripheral Edema 7%
Confusion 6%
Hallucinations 5%

Pregnancy and Lactation

There are no data on pregnancy and lactation in pregnant women. pimavanserin was evaluated for teratogenicity in animal studies. In rats, there was maternal toxicity at 2 times the maximum recommended human dose (MRHD; 34 mg/day), including mortality, dehydration, and decreases in body weight and food consumption. There was also decreased pup survival, litter size, pup weight, and food consumption. In rabbits, pimavanserin was not teratogenic at 12 times the MRHD. Maternal toxicity had the same clinical signs as rats did, but only at doses 12 times the MRHD.2

Geriatric Use

There are no dose adjustments required for elderly patients or in patients with less/more severe cognitive impairment.2

Clinical Studies

The efficacy of pimavanserin was demonstrated in one placebo-controlled clinical study. In this trial, a Parkinson Disease-Adapted Scale Assessment of Positive Symptoms (SAPS-PD) was used to assess hallucinations and delusions. After a period of 6 weeks, pimavanserin showed significant superiority compared with placebo in terms of SAPS-PD hallucinations and delusions. SAPS-PD hallucination had a mean score difference of 2.01 compared with placebo. SAPS-PD delusions had a mean score difference of 0.94 compared with placebo.2

Notably, pimavanserin did not exhibit an effect on motor function improvements in patients with Parkinson disease, as measured through the United Parkinson Disease Rating Scale Part II and III, compared to placebo.

Treatment of Parkinson Disease Psychosis

Before the approval of pimavanserin, there were no FDA-approved treatments of Parkinson disease psychosis. Instead, many clinicians would use second-generation antipsychotics off label to help reduce these symptoms for their patients. Clozapine was the agent that has shown to be the most effective in treating Parkinson disease psychosis. The issue with clozapine is its safety profile. Clozapine has numerous AEs, including agranulocytosis. Patients are required to have blood drawn at certain intervals prior to clozapine being dispensed at a pharmacy. This can make it rather inconvenient to prescribe clozapine.4,5

Quetiapine is another drug that is used for Parkinson disease psychosis. Unlike clozapine, there are not many clinical trials that prove quetiapine’s efficacy. However, quetiapine has a better safety profile than clozapine, with most of its AEs from metabolic syndromes.4 In studies comparing clozapine to quetiapine head-on, clozapine was shown to have an advantage in controlling hallucinations and reducing delusions. The approval of pimavanserin is a significant practical implication as it allows clinicians to select another drug for usage in these patients. There have been no trials comparing clozapine or quetiapine to pimavanserin.5

Costs and Availability

Pimavanserin is covered by all Medicare Part D programs, with 90% of the programs not charging a copay higher than $25. Patients with commercial insurance may qualify for $0 copay card. Patients with no insurance may qualify for financial assistance and may also require no payment. Clinicians can request a 14-day free supply of medications by going to www.nuplazidhcp.com and filling out the form.4,5
 
Table 3. Costs of Pimavanserin from Red Book Online
Drug/Strength NDC Quantity Wholesale Acquisition Cost Average Wholesale Price
pimavanserin 34 mg capsules 63090-0340-30
 
30 capsules $2778.00
 
$3333.60
 
pimavanserin 17 mg tablets 63090-0170-60 60 tablets $2778.00
 
$3333.60
 
pimavanserin 10 mg tablets 63090-0100-30 30 tablets $2778.00
 
$3333.60
 
NDC indicates National Drug Code.

Patient Counseling

Pimavanserin is the first FDA-approved drug for treatment of hallucinations and delusions related to Parkinson disease psychosis. Patients should take one 34-mg capsule by mouth daily with or without food. If a patient forgets to take a dose, they can take the dose if they remember it, but should skip the dose if it is close to their next dose. Missed doses should not be doubled. Overdoses should be reported immediately to the clinician as ECG monitoring will be required to monitor for arrhythmias. pimavanserin should be stored at room temperature and away from light.2

Patients should let their clinician know all the medications that they are taking. Drugs that may prolong the QT interval (anti-arrhythmic drugs with pro-arrhythmic AEs, antibiotics, antipsychotics) should be avoided. Strong CYP3A4 inhibitors (ketoconazole) lead to increased exposure to pimavanserin and will require dose reductions to pimavanserin 10 mg a day. Strong CYP3A4 inducers (rifampin) may require dose increases.

AEs that may occur when taking pimavanserin include peripheral edema, nausea, hallucinations, and confusion. Patients should let their clinician know if any of these symptoms persist or bother them. Hypersensitivity to pimavanserin has occurred, and the drug should be discontinued after a reaction. Pimavanserin has a black-box warning for increased deaths in elderly patients with dementia-related psychosis. Pimavanserin is also known to cause QT prolongation. 

There is not enough information on pregnancy and lactation in humans while taking pimavanserin. There are no dose adjustments on any renal or hepatic impairment. However, patients with severe renal impairment may have increased exposure to pimavanserin compared with patients with normal renal function.
REFERENCES
1. FDA approves first drug to treat hallucinations and delusions associated with Parkinson disease [press release]. Silver Spring, MD: FDA; April 29, 2016. /www.fda.gov/newsevents/newsroom/pressannouncements/ucm498442.htm. Accessed August 27, 2018.
2. Pimavanserin [prescribing information]. San Diego, California: Acadia; 2016. nuplazidhcp.com/sites/nuplazid/files/pdf/NUPLAZID_Prescribing_Information.pdf. Accessed August 27, 2018.
3. Pimavanserin. Red Book Online. Micromedex Healthcare Series [online database]. Greenwood Village, CO: Truven Health Analytics; 2017. Accessed August 27, 2018.
4. Combs BL, Cox AG. Update on the treatment of Parkinson disease psychosis: role of pimavanserin. Neuropsychiatr Dis Treat. 2017;13:737-744. doi:10.2147/ndt.s108948.
5. Taddei RN, Cankaya S, Dhaliwal S, Chaudhuri, KR. Management of psychosis in Parkinson disease: emphasizing clinical subtypes and pathophysiological mechanisms of the condition. Parkinsons Dis. 2017;20187:3256542. Doi:10.1155/2017/3256542.