Pimavanserin

Uses

Pimavanserin is used for the treatment of hallucinations and delusions associated with Parkinson's disease psychosis.
Pediatric Use: Safety and effectiveness of Pimavanserin have not been established in pediatric patients.

Geriatric Use: No dose adjustment is required for elderly patients.

Renal Impairment: No dosage adjustment for Pimavanserin is needed in patients with mild to moderate (CrCL ≥30 mL/min, Cockcroft-Gault) renal impairment.

Hepatic Impairment: Use of Pimavanserin is not recommended in patients with hepatic impairment. Pimavanserin has not been evaluated in this patient population.

Pimavanserin is also used to associated treatment for these conditions: Parkinson's Disease Psychosis

How Pimavanserin works

Parkinson's disease psychosis (PDP) is a imbalance of serotonin and dopamine from disruption of the normal balance between the serotonergic and dopaminergic receptors and neurotransmitters in the brain.

The mechanism by which pimavanserin treats hallucinations and delusions associated with Parkinson’s disease psychosis is not fully established. It is possible that pimavanserin acts via inverse agonist and antagonist activity at serotonin 5-HT2A receptors with limited effects on serotonin 5-HT2C receptors. Pimavanserin is an inverse agonist and antagonist of serotonin 5-HT2A receptors with high binding affinity, demonstrating low binding affinity to serotonin 5-HT2C receptors. In addition, this drug exhibits low affinity binding to sigma 1 receptors. Pimavanserin lacks activity at muscarinic, dopaminergic, adrenergic, and histaminergic receptors, preventing various undesirable effects typically associated with antipsychotics.

Dosage

Pimavanserin dosage

The recommended dose of Pimavanserin is 34 mg, taken orally as two 17 mg strength tablets once daily, without titration. Pimavanserin can be taken with or without food.

Side Effects

Nausea, Constipation, Peripheral edema, Gait disturbance, Hallucination, Confusional state.

Toxicity

LD50 information for pimavanserin is not readily available in the literature. Pre-marketing clinical trials involving pimavanserin in approximately 1200 subjects and patients do not report symptoms of overdose. In healthy subject studies, nausea and vomiting were reported. There are no known antidotes for an overdose with this drug. Cardiovascular monitoring should begin immediately in the case of an overdose and continuous ECG monitoring is recommended. If antiarrhythmic drugs are administered in an overdose of pimavanserin, disopyramide, procainamide, and quinidine should not be used due to their potential for QT-prolonging effects. In the case of an overdose, consider the 57 hour plasma half-life of pimavanserin and the possibility of multiple drug involvement.

Precaution

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. Pimavanserin is not approved for the treatment of patients with dementia-related psychosis unrelated to the hallucinations and delusions associated with Parkinson’s disease psychosis.

QT Interval Prolongation: Pimavanserin prolongs the QT interval. The use of Pimavanserin 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). Pimavanserin 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

Interaction

• Strong CYP3A4 Inhibitors (e.g., ketoconazole): Reduce Pimavanserin dose by one-half.
• Strong CYP3A4 Inducers: Monitor for reduced efficacy. Increase in Pimavanserin dosage may be needed.

Food Interaction

• Avoid grapefruit products. Dose adjustment may be necessary if taking grapefruit products or other CYP3A4 inhibitors.
• Avoid St. John's Wort. This may induce the CYP3A4 metabolism of pimavanserin, which may cause reduced efficacy.
• Take with or without food.

Pimavanserin Drug Interaction

Major: buprenorphine, buprenorphine, citalopram, clozapine, escitalopramModerate: aripiprazole, polyethylene glycol 3350, sertralineUnknown: erenumab, naproxen, fexofenadine, zolpidem, zolpidem, azelastine nasal, diphenhydramine, loratadine, carvedilol, fluticasone nasal, acetaminophen, ranitidine

Pimavanserin Disease Interaction

Major: dementia, NMS, tardive dyskinesia, hepatic impairment, QT prolongationModerate: seizure, hematologic abnormalities, hyperglycemia/diabetes, hyperprolactinemia, renal impairment

Volume of Distribution

Following administration of a single dose of 34 mg, the average apparent volume of distribution was 2173 L in clinical studies.

Elimination Route

The median Tmax of pimavanserin in clinical studies was 6 hours, regardless of the dose. Bioavailability of an oral tablet of pimavanserin and a solution were almost identical. The major active circulating N-desmethylated metabolite, AC-279, has a median Tmax of 6 hours.

Half Life

The average plasma half-lives for pimavanserin and its active metabolite (AC-279) are estimated at 57 hours and 200 hours, respectively.

Elimination Route

About 0.55% of a 34 mg oral dose was excreted unchanged in the urine and 1.53% was eliminated in feces within 10 days. Less than 1% of the administered dose and its active metabolite AC-279 were recovered in urine during clinical studies.

Pregnancy & Breastfeeding use

There are no data on Pimavanserin 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 pimavanserin 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 Pimavanserin and any potential adverse effects on the breastfed infant from Pimavanserin or from the underlying maternal condition.

Storage Condition

Store at 20°C to 25°C.

Innovators Monograph

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