Version May 2024
Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Pimavanserin is not approved for the treatment of patients with dementia who experience psychosis unless their hallucinations and delusions are related to Parkinson disease.
Parkinson disease psychosis: Oral: 34 mg once daily.
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
Discontinuation of therapy: In general with antipsychotic therapy, gradual dose reduction is advised when possible (eg, depending on dosage forms and availability) to detect a re-emergence of symptoms and to avoid withdrawal reactions (eg, agitation, alternating feelings of warmth and chill, anxiety, diaphoresis, dyskinesias, GI symptoms, insomnia, irritability, myalgia, paresthesia, psychosis, restlessness, rhinorrhea, tremor, vertigo) unless discontinuation is due to significant adverse effects (Ref). Due to the limited dosage forms (34 mg capsule and 10 mg tablet) it may not be possible to taper from 34 mg to discontinue.
Switching antipsychotics: An optimal universal strategy for switching antipsychotic drugs has not been established. Strategies include: Cross-titration (gradually discontinuing the first antipsychotic while gradually increasing the new antipsychotic) and abrupt change (abruptly discontinuing the first antipsychotic and either increasing the new antipsychotic gradually or starting it at a treatment dose). Some experts recommend the following strategies when switching from clozapine or quetiapine to pimavanserin (Ref):
Clozapine:
≤100 mg/day: Add 34 mg pimavanserin to current dose (≤100 mg/day) of clozapine; after 6 weeks reduce clozapine dose over at least 4 weeks by 6.25 mg weekly until discontinued. If effectiveness decreases during taper, may return to previous dose level and try taper again in 1 week.
>100 mg/day: Add 34 mg pimavanserin to current dose (≤100 mg/day) of clozapine; after 6 weeks reduce clozapine dose over at least 4 weeks by 25 mg weekly until discontinued. If effectiveness decreases during taper, may return to previous dose level and try taper again in 1 week.
Quetiapine:
≤100 mg/day: Add 34 mg pimavanserin to current dose (≤100 mg/day) of quetiapine; after 4 weeks reduce quetiapine dose by 50% weekly until reaching 12.5 mg, then discontinue. If effectiveness decreases during taper, may return to previous dose level and try taper again in 1 week.
>100 mg/day: Add 34 mg pimavanserin to current dose (>100 mg/day) of quetiapine; after 4 weeks reduce quetiapine dose by 25% weekly until reaching 12.5 mg, then discontinue. If effectiveness decreases during taper, may return to previous dose level and try taper again in 1 week.
Note: Renal function may be estimated using the Cockcroft-Gault formula for dosage adjustment purposes.
CrCL ≥30 mL/minute: No dosage adjustment necessary.
CrCL <30 mL/minute: No dosage adjustment necessary; however, use with caution (increased exposure in patients with severe impairment).
ESRD on dialysis: Nondialyzable (<10% recovered in dialysate): No dosage adjustment necessary; however, use with caution (increased exposure in patients with severe impairment).
No dosage adjustment necessary.
Note: Avoid for behavioral problems associated with dementia or delirium unless alternative nonpharmacologic therapies have failed and patient may harm self or others. If used, consider deprescribing attempts to assess continued need and/or lowest effective dose (Ref).
Refer to adult dosing.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.
1% to 10%:
Cardiovascular: Peripheral edema (7%)
Central nervous system: Confusion (6%), hallucination (5%), abnormal gait (2%)
Gastrointestinal: Nausea (7%), constipation (4%)
Frequency not defined: Cardiovascular: Prolonged QT interval on ECG
<1%, postmarketing, and/or case reports: Aggressive behavior, agitation, angioedema, drowsiness, falling, skin rash, urticaria
History of hypersensitivity reaction (eg, rash, urticaria, symptoms consistent with angioedema [eg, tongue swelling, circumoral edema, throat tightness, dyspnea]) to pimavanserin or any component of the formulation.
Concerns related to adverse effects:
• CNS depression: May cause CNS depression, which may impair physical or mental abilities; patients must be cautioned about performing tasks that require mental alertness (eg, operating machinery, driving) (Hermanowicz 2016).
• Esophageal dysmotility/aspiration: Antipsychotic use has been associated with esophageal dysmotility and aspiration; risks increase with age. Use with caution in patients at risk for aspiration pneumonia (ie, Alzheimer disease), particularly in patients >75 years of age (Herzig 2017; Maddalena 2004).
• Falls: May increase the risk for falls due to somnolence, orthostatic hypotension, and motor or sensory instability (Landi 2005; Seppala 2018).
• Orthostatic hypotension: May cause orthostatic hypotension; use with caution in patients at risk of this effect or in those who would not tolerate transient hypotensive episodes (cerebrovascular disease, cardiovascular disease, hypovolemia, or concurrent medication use which may predispose to hypotension/bradycardia) (Hermanowicz 2016).
• QT prolongation: Use is associated with QTc prolongation. Avoid use in patients with a history of cardiac arrhythmias, history of QT prolongation, concomitant use of medications that prolong the QT interval, and other circumstances that may increase the risk of torsades de pointes and/or sudden death (including symptomatic bradycardia, hypokalemia, and/or hypomagnesemia, and congenital long QT syndrome).
Disease-related concerns:
• Dementia: Older adults with dementia-related psychosis treated with antipsychotics are at a higher risk of death compared to placebo. Most deaths appeared to be either cardiovascular (eg, heart failure, sudden death) or infectious (eg, pneumonia) in nature. Use with caution in dementia with Lewy bodies; antipsychotics may worsen dementia symptoms, and patients with dementia with Lewy bodies are more sensitive to the extrapyramidal side effects (APA [Reus 2016]). Pimavanserin is not approved for the treatment of dementia psychosis unless hallucinations and delusions are related to Parkinson disease.
Other warnings/precautions:
• Discontinuation of therapy: In general, when discontinuing antipsychotic therapy, gradually taper antipsychotics when possible (eg, depending on dosage forms and availability) to avoid physical withdrawal symptoms and rebound symptoms (Black 2018). Withdrawal symptoms may include agitation, alternating feelings of warmth and cold, anxiety, diaphoresis, dyskinesia, GI symptoms, insomnia, irritability, myalgia, paresthesia, psychosis, restlessness, rhinorrhea, tremor, and vertigo (Black 2018; Lambert 2007).
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Capsule, Oral, as tartrate:
Nuplazid: 34 mg [contains fd&c blue #1 (brilliant blue)]
Tablet, Oral, as tartrate:
Nuplazid: 10 mg
No
Capsules (Nuplazid Oral)
34 mg (per each): $199.80
Tablets (Nuplazid Oral)
10 mg (per each): $199.80
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Oral: May be administered without regard to food. Capsules may be swallowed whole or entire contents emptied onto 1 tablespoonful (15 mL) of applesauce, yogurt, pudding, or liquid nutritional supplement to be used immediately without chewing; do not store for future use.
Parkinson disease psychosis: Treatment of hallucinations and delusions associated with Parkinson disease psychosis.
Beers Criteria: Antipsychotics are identified in the Beers Criteria as potentially inappropriate medications to be avoided in patients 65 years of age and older due to an increased risk of stroke and a greater rate of cognitive decline and mortality in patients with dementia. Evidence also suggests there may be an increased risk of mortality with use independent of dementia. Avoid antipsychotics for behavioral problems associated with dementia or delirium unless alternative nonpharmacologic therapies have failed and patient may harm self or others. In addition, antipsychotics should be used with caution in older adults due to their potential to cause or exacerbate syndrome of inappropriate antidiuretic hormone secretion (SIADH) or hyponatremia; monitor sodium closely with initiation or dosage adjustments in older adults. Use of antipsychotics may be appropriate for labeled indications including schizophrenia, bipolar disorder, Parkinson disease psychosis, adjunctive therapy in major depressive disorder, or for short-term use as an antiemetic (Beers Criteria [AGS 2023]).
Substrate of CYP3A4 (major); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
Clofazimine: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk C: Monitor therapy
CYP3A4 Inducers (Moderate): May decrease the serum concentration of Pimavanserin. Risk X: Avoid combination
CYP3A4 Inducers (Strong): May decrease the serum concentration of Pimavanserin. Risk X: Avoid combination
CYP3A4 Inhibitors (Moderate): May increase the serum concentration of Pimavanserin. Risk C: Monitor therapy
CYP3A4 Inhibitors (Strong): May increase the serum concentration of Pimavanserin. Management: Decrease the pimavanserin dose to 10 mg daily when combined with strong CYP3A4 inhibitors. Risk D: Consider therapy modification
Fexinidazole: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk X: Avoid combination
Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk X: Avoid combination
Haloperidol: QT-prolonging Agents (Indeterminate Risk - Avoid) may enhance the QTc-prolonging effect of Haloperidol. Risk C: Monitor therapy
QT-prolonging Agents (Highest Risk): QT-prolonging Agents (Indeterminate Risk - Avoid) may enhance the QTc-prolonging effect of QT-prolonging Agents (Highest Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy
Thioridazine: Pimavanserin may enhance the QTc-prolonging effect of Thioridazine. Thioridazine may decrease the serum concentration of Pimavanserin. Risk X: Avoid combination
Adverse events were observed in some animal reproduction studies.
It is not known if pimavanserin is present in breast milk. According to the manufacturer, the decision to breastfeed during therapy should take into account the risk of exposure to the infant and the benefits of treatment to the mother.
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Frequency of Antipsychotic Monitoringa,b | ||
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Monitoring parameter |
Frequency of monitoring |
Comments |
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a For all monitoring parameters, it is appropriate for check at baseline and when clinically relevant (based on symptoms or suspected adverse reactions) in addition to the timeline. | ||
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b APA [Keepers 2020]; manufacturer's labeling. | ||
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c Risk factors for tardive dyskinesia include age >55 years; females; White or African ethnicity; presence of a mood disorder, intellectual disability, or CNS injury; past or current extrapyramidal symptoms. | ||
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Adherence |
Every visit |
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Blood chemistries (electrolytes, renal function, liver function, TSH) |
Annually |
Correct electrolyte imbalances (hypokalemia) prior to administration; may prolong QT interval |
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CBC |
As clinically indicated |
Check frequently during the first few months of therapy in patients with preexisting low WBC or history of drug-induced leukopenia/neutropenia |
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ECG |
As clinically indicated |
Check after significant dose increase or new QTc prolonging medication if there are cardiac risk factors |
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Fall risk |
Every visit |
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Mental status and alertness |
Every visit |
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Tardive dyskinesia |
Every visit; annually. Use a formalized rating scale at least annually or every 6 months if high riskc |
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Vital signs (BP, orthostatics, temperature, pulse, signs of infection) |
Every visit (at least weekly during first 3 to 4 weeks of treatment); 4 weeks after dose change. |
Correct bradycardia prior to administration; may prolong QT interval |
Pimavanserin acts as an inverse agonist and antagonist with high affinity for 5-HT2A receptors and low affinity for 5-HT2C and sigma 1 receptors; no affinity for 5-HT2B, dopaminergic (including D2), muscarinic, histaminergic, or adrenergic receptors, or to calcium channels.
Onset of action: Initial effects may be observed within 15 days (Cummings 2014).
Distribution: Vd: 2,173 L
Protein binding: ~95%
Metabolism: Primarily via CYP3A4 and CYP3A5; forms active N-desmethylated metabolite (AC-279)
Half-life elimination: Pimavanserin: ~57 hours; N-desmethylated metabolite: ~200 hours
Time to peak: 6 hours (median: 4 to 24 hours)
Excretion: Feces (<1.5% as unchanged drug); urine (<1% as unchanged drug; <1% as metabolites)
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