The FDA has granted the first-ever approval for an atypical antipsychotic, pimavanserin (Nuplazid), to treat psychosis brought on by Parkinson's disease. Other antipsychotics like olanzapine are also used as an off-label treatment, however, most antipsychotics may worsen the motor symptoms associated with Parkinson's disease. Pimavanserin (Nuplazid) exerts little effects on histaminergic, adrenergic, muscarinic, and dopaminergic receptors.

Pimavanserin (Nuplazid) Uses:

• Parkinson disease psychosis:
  • It is prescribed to treat the hallucinations and delusions connected to Parkinson disease psychosis.

Pimavanserin (Nuplazid) Dose in Adults

Pimavanserin (Nuplazid) Dose in the treatment of Parkinson disease psychosis:

• 34 mg orally once a day.
• Dosage adjustment for concomitant therapy:
  • Strong CYP3A4 inhibitors such as ketoconazole: 10 mg once daily.
  • Strong or moderate CYP3A4 inducers: Concomitant use of the drug should be avoided with strong or moderate CYP3A4 inducers.
• Discontinuation of therapy:
  • Most authorities recommend gradually withdrawing antipsychotics to minimize withdrawal effects.
  • A gradual taper over 6 - 24 months or at a rate of 10% monthly is recommended.
• Switching from one antipsychotic to another:
  • Three strategies are generally followed:
  • Cross-titration:
    • It is the gradual increase of one antipsychotic and decrease in the dose of the antipsychotic already being used.
  • Overlap and taper:
    • This approach suggests continuing to utilise the current antipsychotic while introducing the new antipsychotic gradually. The initial antipsychotic is then gradually tapered off after that.
  • Abrupt change:
    • The new antipsychotic is started at the treatment dose or at a lower dose and gradually titrated while the first antipsychotic is abruptly discontinued.
  • Any of the three methods can be used while switching antipsychotic drugs. There is limited data available that shows superiority of one method over another.

Use in Children:

Not indicated.   

Pimavanserin Pregnancy Risk Category: N (Not assigned)

• In some studies on animal reproduction, adverse fetal outcomes were observed.

Use of Pimavanserin during lactation:

• The drug's potential for excretion into breastmilk is unknown.
• The benefits and dangers of drug exposure for the mother should be weighed against the risks to the unborn child, according to the manufacturers.

Pimavanserin (Nuplazid) Dose in Kidney Disease:

Note:

• The Cockcroft-Gault formula may be utilised for dose modifications in patients with reduced renal functioning.
• CrCL ≥30 mL/minute:
  • Adjustment in the dose is not necessary.
• CrCL <30 mL/minute:
  • Adjustment in the dose is not necessary; however, because of increased drug exposure in patients with severe impairment, it may be used with caution.
• ESRD on dialysis:
  • It is nondialyzable (Less than 10% is recovered in dialysate).
  • Adjustment in the dose is not necessary; however, because of increased drug exposure in patients with severe impairment, it may be used with caution.

Dose in Liver disease:

Adjustment in the dose is not necessary in patients with liver disease.   

Side Effects of Pimavanserin (Nuplazid):

• Cardiovascular:
  • Peripheral Edema
• Central Nervous System:
  • Confusion
  • Hallucination
  • Abnormal Gait
• Gastrointestinal:
  • Nausea
  • Constipation

Rare Side effects of Pimavanserin (Nuplazid):

• Cardiovascular:
  • Prolonged Q-T interval on ECG
• Central nervous system:
  • Fatigue

Contraindications to Pimavanserin (Nuplazid):

• Hypersensitivity to pimavanserin and any component thereof may cause allergic reactions, such as urticaria, tongue swelling or dyspnea.

Warnings and precautions

• Depression in the CNS:
  • CNS depression may be caused by antipsychotics, which can impair mental or physical abilities.
  • Before initiating treatment, patients must be notified, especially if they are operating heavy machinery or performing tasks that require mental alertness.
• Esophageal dysmotility/aspiration
  • Antipsychotic drugs can increase the likelihood of aspiration and esophageal dysmotility.
  • Aspiration and esophageal dysmotility are more common with age.
  • Patients at high risk for aspiration pneumonia, such as those over 75 years old or with Alzheimer's disease, should not use this drug.
• Orthostatic hypotension
  • It can lead to orthostatic hypotension.
  • Orthostatic hypotension is a condition that affects patients who are taking antihypertensives, diuretics, beta-blockers or other medications that can cause hypotension and bradycardia.
  • Patients with cerebrovascular disease, heart disease, or hypovolemia are also susceptible to orthostatic hypotension.
• Extension of QT
  • It could cause QTc prolongation.
  • Patients at high risk for developing cardiac arrhythmias should avoid it. Hypokalemia, hypomagnesemia and congenital long QT syndrome.
• Dementia: [US Boxed Warning]
  • Antipsychotics for dementia-related schizophrenia are more dangerous than a placebo for elderly patients.
  • Most patients who were treated with antipsychotics in clinical trials died from sudden death, heart failure, or pneumonia.
  • Patients with dementia with Lewy bodies should not use it. They are more likely to experience extrapyramidal side effect.
  • It is not approved to treat dementia-related hallucinations and delusions that are not related with Parkinson's disease psychosis.

Pimavanserin: Drug Interaction

Note: Drug Interaction Categories:

• Risk Factor C: Monitor When Using Combination
• Risk Factor D: Consider Treatment Modification
• Risk Factor X: Avoid Concomitant Use

Monitoring parameters:

• Monitor mental status of the patient
• Vital signs as indicated
• Yearly Renal and liver functions and as clinically indicated
• ECG if clinically indicated.

How to administer Pimavanserin (Nuplazid)?

It may be administered without regard to food intake.   

Mechanism of action of Pimavanserin (Nuplazid):

• Pimavanserin is an inverse agonist/antagonist with high affinity for 5-HT-2A and low affinity for 5-HT-2C receptors.
• It is not a good candidate for 5-HT-2B, D-2, muscarinic or adrenergic receptors, nor calcium channels.

Protein binding:

• About 95%

Metabolism:

• It is metabolized primarily via CYP3A4 and CYP3A5 into the active N-desmethylated metabolite (AC279).

Half-life elimination:

• About 57 hours
• The half-life of its N-desmethylated metabolite is about 200 hours.

Time to peak:

• 6 hours (median time: 4 - 24 hours)

Excretion:

• Feces (<1.5% as unchanged drug);
• urine (<1% as unchanged drug; <1% as metabolites)

International Brands of Pimavanserin:

• Nuplazid

Pimavanserin Brand Names in Pakistan:

No Brands Available in Pakistan.