PIMAVANSERIN
Clinical safety rating
safeAnimal studies have demonstrated safety
Pimavanserin is a selective serotonin 5-HT2A receptor inverse agonist and antagonist, with no affinity for dopamine receptors, modulating glutamate and dopamine signaling in the cortex and striatum.
| Metabolism | Primarily metabolized by CYP3A4 and CYP3A5, with minor contributions from CYP2J2 and CYP2D6. The major metabolite is N-desmethylpimavanserin, which is pharmacologically active. |
| Excretion | Primarily hepatic metabolism, with approximately 60% excreted in feces and 20% in urine as metabolites; less than 5% excreted as unchanged drug. |
| Half-life | Terminal elimination half-life is approximately 50 hours, allowing once-daily dosing; steady state reached in about 2 weeks. |
| Protein binding | Approximately 95% bound to plasma proteins, primarily albumin. |
| Volume of Distribution | Volume of distribution is approximately 400 L (about 4.7 L/kg), indicating extensive extravascular distribution. |
| Bioavailability | Oral bioavailability is approximately 20% due to extensive first-pass metabolism. |
| Onset of Action | Oral: Clinical effects on Parkinson's disease psychosis may be observed within 2 weeks, but optimal response may take several weeks. |
| Duration of Action | Duration of action is 24 hours due to once-daily dosing; continuous therapy is required for sustained antipsychotic effect. |
| Molecular Weight | 401.48 |
34 mg orally once daily.
| Dosage form | CAPSULE |
| Renal impairment | No dose adjustment required for mild to moderate renal impairment. Not recommended in severe renal impairment (eGFR <30 mL/min/1.73 m²) due to lack of data. |
| Liver impairment | No dose adjustment for mild hepatic impairment (Child-Pugh class A). Not recommended in moderate to severe hepatic impairment (Child-Pugh class B or C) due to increased exposure and risk of QT prolongation. |
| Pediatric use | Safety and efficacy not established in pediatric patients (<18 years). No dosing recommendation. |
| Geriatric use | No specific dose adjustment; use caution due to potential increased sensitivity and risk of QT prolongation. Monitor renal function and electrolytes. |
| 1st trimester | Insufficient human data; animal studies show no teratogenicity at clinically relevant doses, but increased post-implantation loss at high doses. Use only if potential benefit justifies risk. |
| 2nd trimester | Insufficient human data; avoid unless clearly needed. |
| 3rd trimester | Insufficient human data; avoid due to potential neonatal adverse effects (e.g., extrapyramidal symptoms) if used near term. |
Clinical note
Strong CYP3A4 inhibitors may increase levels and inducers may decrease levels Can prolong the QT interval.
| Placental transfer | Likely crosses placenta (molecular weight <500 Da; lipophilic). No human quantification. |
| Breastfeeding | No data on presence in human milk. Due to long half-life and CNS effects, monitor infant for sedation, irritability, or abnormal movements. Alternatives preferred. |
| Lactation Rating | L4 (Possibly Hazardous) |
| Teratogenic Risk | Pimavanserin is classified as Pregnancy Category C. There are no adequate and well-controlled studies in pregnant women. In animal reproduction studies, no evidence of fetal harm was observed at doses up to 8 times the maximum recommended human dose. However, because animal studies are not always predictive of human response, pimavanserin should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. First trimester risks are unknown; second and third trimester risks are not characterized. Use caution. |
| Fetal Monitoring | Monitor maternal QT interval prolongation risk (ECG at baseline and during therapy). Assess for increased somnolence, falls, and neuropsychiatric symptoms. No specific fetal monitoring required; standard prenatal care. |
| Fertility Effects | In animal studies, no adverse effects on fertility were observed at exposures up to 8 times the MRHD. Human data are lacking. Based on mechanism (5-HT2A antagonist), no direct reproductive toxicity expected. |
■ FDA Black Box Warning
No FDA boxed warning.
| Common Effects | QT prolongation |
| Serious Effects |
Known hypersensitivity to pimavanserin or any excipientsUse with strong CYP3A4 inducers (e.g., rifampin) decreases exposure
| Precautions | Risk of QT interval prolongation; avoid use in patients with known QT prolongation or with drugs that prolong QT interval., Not recommended for use in patients with severe hepatic impairment (Child-Pugh Class C)., May cause somnolence, orthostatic hypotension, and gastrointestinal effects., Gradual dose titration recommended to minimize adverse effects. |
| Food/Dietary | Avoid grapefruit and grapefruit juice due to potential for increased pimavanserin exposure and QT prolongation risk. No other significant food interactions reported. |
| Clinical Pearls | Pimavanserin is a 5-HT2A inverse agonist approved for Parkinson's disease psychosis. It does not worsen motor symptoms due to lack of dopamine receptor affinity. QT prolongation risk is dose-dependent; monitor ECG at baseline and after dose changes. Avoid use in patients with dementia-related psychosis due to increased mortality risk. A 1-week washout prior to initiation is recommended if switching from other antipsychotics. Dose adjustment required in renal impairment (CrCl <30 mL/min). |
| Patient Advice | Avoid grapefruit juice as it may increase drug levels. · Report any irregular heartbeat, fainting, or dizziness. · Do not drive or operate heavy machinery until effect on coordination is known. · Take this medication with or without food exactly as prescribed. · Do not stop abruptly without consulting your doctor. |
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