Serivan

Approved Indications:

• Parkinson’s Disease Psychosis (PDP):
  Treatment of hallucinations and delusions associated with Parkinson’s disease.
• Schizophrenia (in older adults):
  As an adjunctive treatment in patients with inadequate response to antipsychotic monotherapy (specific to the U.S. FDA-approved expanded label).
• Dementia-related psychosis (DRP):
  Approved for hallucinations and delusions associated with various forms of dementia, including Alzheimer’s disease, Parkinson’s disease dementia, frontotemporal dementia, and Lewy body dementia.

Clinically Accepted Off-label Uses:

• Major depressive disorder (MDD):
  As adjunctive therapy in treatment-resistant depression (under investigation and limited clinical use).
• Bipolar depression with psychotic features:
  Investigated as adjunct to mood stabilizers or atypical antipsychotics.

Route of Administration: Oral
Dosage Form: Tablets (17 mg)

Parkinson’s Disease Psychosis (Adults):

• Recommended dose: 34 mg once daily (administered as two 17 mg tablets)
• Timing: With or without food
• No titration required for initiation

Dementia-Related Psychosis (Adults):

• Recommended dose: 34 mg once daily
• Continue treatment only if benefit is observed and outweighs risks; periodic reassessment recommended

Schizophrenia (Adjunctive use in adults):

• Dose: 34 mg once daily (per FDA expansion of indications)

Renal Impairment:

• Mild to moderate (CrCl ≥30 mL/min): No adjustment required
• Severe impairment (CrCl <30 mL/min): Use with caution; limited data
• End-stage renal disease: Not recommended due to lack of data

Hepatic Impairment:

• Use with caution in moderate or severe hepatic impairment due to reduced clearance

Elderly:

• No dosage adjustment required, but monitor closely for increased sensitivity and risk of QT prolongation

Pimavanserin is a selective serotonin inverse agonist and antagonist targeting the 5-HT₂A receptors, with negligible affinity for dopaminergic (D2) receptors. It acts primarily through inverse agonism at 5-HT₂A receptors, which are implicated in the pathophysiology of hallucinations and delusions, especially in Parkinson's disease and dementia-related psychosis. By reducing the constitutive activity of 5-HT₂A receptors in the cortex and limbic regions, Pimavanserin helps alleviate psychotic symptoms without worsening motor function, a major advantage in Parkinsonian disorders.

• Absorption: Well absorbed orally; peak plasma concentration reached in ~6 hours
• Bioavailability: ~40%
• Distribution: Large volume of distribution; plasma protein binding ~95%
• Metabolism: Hepatically metabolized, primarily via CYP3A4 and CYP3A5, to active metabolite (AC-279)
• Half-life:
• Parent drug: ~57 hours
• Active metabolite: ~200 hours
• Elimination: Primarily via urine (approximately 95%)
• Steady-State: Achieved in 10–12 days with once-daily dosing

• Pregnancy:
• No adequate data in pregnant women. Animal studies showed no teratogenicity but did show embryo-fetal toxicity at high doses.
• Use only if clearly needed after assessing risk-benefit ratio.
• Lactation:
• Unknown if Pimavanserin is excreted into human milk.
• Due to potential adverse effects on the breastfed infant (e.g., sedation, QT prolongation), breastfeeding is not recommended during treatment.
• Recommendation:
• Use in pregnancy only when absolutely necessary.
• Avoid breastfeeding or discontinue drug under medical supervision.

• Primary Class: Atypical antipsychotic (Non-dopaminergic)
• Subclass: Selective serotonin 5-HT₂A inverse agonist/antagonist

• Known hypersensitivity to Pimavanserin or any component of the formulation
• Use in patients with QT prolongation or history of cardiac arrhythmia without proper ECG monitoring
• Concurrent use with strong CYP3A4 inhibitors, unless dosage adjustment is made

• Elderly with dementia-related psychosis:
  Increased risk of death; not approved for treatment of dementia-related psychosis unrelated to hallucinations or delusions
• QT interval prolongation:
  Pimavanserin can prolong the QT interval; caution in patients with:
• Known QT prolongation
• Electrolyte imbalance (hypokalemia, hypomagnesemia)
• Use of other QT-prolonging drugs
• Suicidality:
  Monitor patients with mood disorders for suicidal thoughts or behavior
• Hepatic impairment:
  Use with caution due to decreased clearance
• CYP3A4 inhibitors/inducers:
  Requires dose adjustment or close monitoring
• Clinical monitoring:
  ECG in high-risk patients, electrolyte levels, and psychiatric symptom evaluation

Common Adverse Effects:

• Neurologic/Psychiatric:
• Confusion
• Hallucination
• Peripheral edema
• Gait disturbance
• Gastrointestinal:
• Nausea
• Constipation
• General:
• Fatigue
• Weight gain

Serious Side Effects:

• QT prolongation
• Cardiac arrhythmia
• Syncope
• Worsening psychosis in off-label use

Rare Effects:

• Hypersensitivity reactions (rash, pruritus)
• Seizures (rare, especially in predisposed individuals)

Dose-dependence:

• Some side effects (e.g., QT prolongation, hallucination) are dose-dependent.

• CYP3A4 inhibitors (e.g., ketoconazole, clarithromycin):
• May increase Pimavanserin plasma concentration
• Reduce dose to 17 mg once daily when used concurrently
• CYP3A4 inducers (e.g., rifampin, carbamazepine):
• May reduce efficacy of Pimavanserin
• Other QT-prolonging agents (e.g., amiodarone, sotalol):
• Additive effect; avoid if possible
• Antipsychotics (e.g., risperidone, olanzapine):
• May have additive sedative or anticholinergic effects; use with caution
• Food:
• No significant food effect on absorption

• Expanded FDA labeling (2023):
  Pimavanserin approved for use in dementia-related psychosis with a recommendation for continued use only if benefit is maintained.
• Schizophrenia (adjunctive use):
  Recent FDA-approved indication for adjunctive use in adults with schizophrenia who exhibit inadequate response to standard antipsychotics.
• New prescribing guidance:
  The label now includes clearer dose adjustment instructions when used with strong CYP3A4 inhibitors.
• International use:
  Still under regulatory review or not yet approved in some countries; primarily available in the U.S.

• Storage Temperature: Store at 20°C to 25°C (68°F to 77°F)
• Permitted Range: Excursions allowed between 15°C and 30°C (59°F to 86°F)
• Humidity and Light: Store in a dry place, away from direct light and moisture
• Container: Keep in original container with tight closure
• Handling Precautions:
• Keep out of reach of children
• Do not use after expiration date
• No refrigeration or reconstitution required