NUPLAZID
Clinical safety rating: caution
Comprehensive clinical and safety monograph for NUPLAZID (NUPLAZID).
Selective serotonin 5-HT2A receptor inverse agonist and antagonist; also has moderate affinity for 5-HT2C and 5-HT1A receptors.
| Metabolism | Primarily hepatic via CYP3A4 and CYP3A5, with minor contribution from CYP2J2 and other pathways. |
| Excretion | Fecal (approximately 60%) as unchanged drug and metabolites; renal (approximately 13%) as unchanged drug and metabolites. |
| Half-life | Terminal elimination half-life is approximately 50 hours (range 40-70 hours), allowing once-daily dosing. |
| Protein binding | Approximately 99% bound to plasma proteins, primarily albumin and alpha-1-acid glycoprotein. |
| Volume of Distribution | Volume of distribution is approximately 7 L/kg, indicating extensive tissue distribution. |
| Bioavailability | Oral bioavailability is approximately 50-60% (based on mass balance data); food does not significantly affect absorption. |
| Onset of Action | Oral: Clinical effects on psychosis may be observed within 2 weeks, but full therapeutic benefit may take 4-8 weeks. |
| Duration of Action | With once-daily dosing, sustained therapeutic effect is maintained over 24 hours; steady-state reached in approximately 11 days. |
| Molecular Weight | 419.5 |
34 mg orally once daily.
| Dosage form | CAPSULE |
| Renal impairment | No dose adjustment required for mild to moderate renal impairment (GFR ≥30 mL/min). Not recommended for use in severe renal impairment (GFR <30 mL/min). |
| Liver impairment | No dose adjustment required for mild hepatic impairment (Child-Pugh A). Use not recommended for moderate to severe hepatic impairment (Child-Pugh B or C). |
| Pediatric use | Not approved for use in pediatric patients. |
| Geriatric use | No specific dose adjustment required based on age alone; however, elderly patients may have increased sensitivity to side effects. Monitor renal function and adjust accordingly. |
| 1st trimester | Limited human data; based on animal studies, there may be a risk of fetal harm. Use only if potential benefit justifies risk. |
| 2nd trimester | Limited human data; consider monitoring for maternal hypotension and fetal effects. |
| 3rd trimester | May cause extrapyramidal symptoms and/or withdrawal symptoms in neonates. Avoid use near term. |
Clinical note
Comprehensive clinical and safety monograph for NUPLAZID (NUPLAZID).
| Placental transfer | Based on molecular weight and properties, expected to cross placenta. No specific human data. |
| Breastfeeding | Present in rat milk; unknown in human milk. Consider benefits of breastfeeding, mother's need for drug, and potential infant effects. Avoid breastfeeding if infant has electrolyte abnormalities or is at risk for QT prolongation. |
■ FDA Black Box 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.
| Serious Effects |
Hypersensitivity to pimavanserin or any excipients
| Precautions | QT interval prolongation; increased risk of cerebrovascular adverse reactions in elderly patients with dementia; neuroleptic malignant syndrome; falls; dyskinesias; hypersensitivity reactions. |
| Food/Dietary | Grapefruit juice may increase pimavanserin exposure; avoid concurrent consumption. No other known food interactions. Administration with a high-fat meal does not significantly alter absorption. |
Loading safety data…
| Lactation Rating |
| L4 |
| Teratogenic Risk | NUPLAZID (pimavanserin) is not recommended for use during pregnancy. In animal studies, pimavanserin was not teratogenic at doses up to 23 times the maximum recommended human dose (MRHD) in rats and 4 times in rabbits, but fetal toxicity (reduced fetal weight, delayed ossification) was observed at maternally toxic doses. There are no adequate and well-controlled studies in pregnant women. The risk of neural tube defects and major malformations is highest in the first trimester; however, specific human data are lacking. Use only if potential benefit justifies potential risk. |
| Fetal Monitoring | Monitor for maternal adverse effects during pregnancy, including QT prolongation, dizziness, and gastrointestinal disturbances. If used during pregnancy, fetal monitoring via ultrasound to assess growth and development may be considered. Neonates exposed in utero should be monitored for extrapyramidal symptoms, sedation, and withdrawal reactions after birth. |
| Fertility Effects | In animal studies, pimavanserin did not impair fertility in male or female rats at doses up to 8 times the MRHD. Effects on human fertility are unknown. No specific studies on reproductive function in humans have been conducted. |
| Clinical Pearls |
| NUPLAZID (pimavanserin) is indicated for hallucinations and delusions associated with Parkinson's disease psychosis. It is a selective serotonin 5-HT2A inverse agonist with no appreciable affinity for dopamine receptors, thus not worsening motor function. QT prolongation risk requires baseline and follow-up ECG monitoring. Avoid use in patients with recent myocardial infarction or uncompensated heart failure. Titrate slowly: start at 34 mg once daily, can increase to 34 mg plus 17 mg (51 mg total) based on response. Do not crush or split tablets; administer with or without food. Monitor for orthostatic hypotension and syncope. |
| Patient Advice | Take exactly as prescribed; do not crush or split the tablet. · May be taken with or without food. · Avoid grapefruit juice as it may affect drug levels. · Contact your doctor if you experience dizziness, fainting, or irregular heartbeat. · Do not drive or operate heavy machinery until you know how the drug affects you. · Report any new or worsening hallucinations or delusions. · Inform all healthcare providers you are taking this medication, especially before any ECG or surgery. · Do not stop abruptly without consulting your doctor. |