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Pimavanserin: Drug information

Pimavanserin: Drug information
(For additional information see "Pimavanserin: Patient drug information")

For abbreviations, symbols, and age group definitions used in Lexicomp (show table)
ALERT: US Boxed Warning
Increased mortality in elderly patients with dementia-related psychosis:

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-related psychosis unrelated to the hallucinations and delusions associated with Parkinson disease psychosis.

Brand Names: US
  • Nuplazid
Pharmacologic Category
  • Second Generation (Atypical) Antipsychotic
Dosing: Adult

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 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. (Black 2018; Lambert 2007).

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 (Black 2018):

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.

Dosing: Kidney Impairment: Adult

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).

Dosing: Hepatic Impairment: Adult

No dosage adjustment necessary.

Dosing: Older Adult

Refer to adult dosing.

Dosage Forms: US

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Capsule, Oral, as tartrate:

Nuplazid: 34 mg [contains brilliant blue fcf (fd&c blue #1)]

Tablet, Oral, as tartrate:

Nuplazid: 10 mg

Nuplazid: 17 mg [DSC] [contains saccharin sodium]

Generic Equivalent Available: US

No

Administration: Adult

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.

Use: Labeled Indications

Parkinson disease psychosis: Treatment of hallucinations and delusions associated with Parkinson disease psychosis

Medication Safety Issues
Geriatric Patients: High-Risk Medication:

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 cerebrovascular accidents (stroke) and a greater rate of cognitive decline and mortality in patients with dementia. Antipsychotics may be appropriate for schizophrenia, bipolar disorder, other mental health conditions or short-term use as antiemetic during chemotherapy but should be given in the lowest effective dose for the shortest duration possible. 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 (Beers Criteria [AGS 2019]).

Adverse Reactions

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

Contraindications

Hypersensitivity (eg, rash, urticaria, tongue swelling, circumoral edema, throat tightness, dyspnea) to pimavanserin or any component of the formulation.

Warnings/Precautions

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: [US Boxed Warning]: Elderly patients with dementia-related psychosis treated with antipsychotics are at an increased 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-related psychosis unrelated to the hallucinations and delusions associated with Parkinson disease psychosis.

Other warnings/precautions:

• Discontinuation of therapy: In general, when discontinuing antipsychotic therapy, gradually taper antipsychotics 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).

Metabolism/Transport Effects

Substrate of CYP3A4 (major); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential

Drug Interactions

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

Erdafitinib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Risk C: Monitor therapy

Erdafitinib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk C: Monitor therapy

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

Ivosidenib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). 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

Pregnancy Considerations

Adverse events were observed in some animal reproduction studies.

Breastfeeding Considerations

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.

Monitoring Parameters

Frequency of Antipsychotic Monitoringa,b

Monitoring parameter

Frequency of monitoring

Comments

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.

b APA [Keepers 2020]; manufacturer's labeling.

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.

Adherence

Every visit

Blood chemistries (electrolytes, renal function, liver function, TSH)

Annually

Correct electrolyte imbalances (hypokalemia) prior to administration; may prolong QT interval

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

ECG

As clinically indicated

Check after significant dose increase or new QTc prolonging medication if there are cardiac risk factors

Fall risk

Every visit

Mental status

Every visit

Tardive dyskinesia

Every visit; annually. Use a formalized rating scale at least annually or every 6 months if high riskc

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

Mechanism of Action

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.

Pharmacokinetics

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)

Pricing: US

Capsules (Nuplazid Oral)

34 mg (per each): $166.92

Tablets (Nuplazid Oral)

10 mg (per each): $166.92

Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.

Brand Names: International
  • Nuplazid (IN)


For country abbreviations used in Lexicomp (show table)

REFERENCES

  1. 2019 American Geriatrics Society Beers Criteria Update Expert Panel. American Geriatrics Society 2019 updated AGS Beers Criteria for Potentially Inappropriate Medication Use in Older Adults. J Am Geriatr Soc. 2019;67(4):674-694. doi:10.1111/jgs.15767 [PubMed 30693946]
  2. Black KJ, Nasrallah H, Isaacson S, et al. Guidance for switching from off-label antipsychotics to pimavanserin for Parkinson's disease psychosis: an expert consensus. CNS Spectr. 2018;23(6):402-413. doi:10.1017/S1092852918001359 [PubMed 30588905]
  3. Cummings J, Isaacson S, Mills R, Williams H, Chi-Burris K, Corbett A, Dhall R, Ballard C. Pimavanserin for patients with Parkinson's disease psychosis: a randomised, placebo-controlled phase 3 trial. Lancet. 2014;383(9916):533-540. doi:10.1016/S0140-6736(13)62106-6 [PubMed 24183563]
  4. Hermanowicz S and Hermanowicz N. The safety, tolerability and efficacy of pimavanserin tartrate in the treatment of psychosis in Parkinson’s disease. Expert Rev Neurother. 2016;16(6):625-633. [PubMed 26908168]
  5. Herzig SJ, LaSalvia MT, Naidus E, et al. Antipsychotics and the risk of aspiration pneumonia in individuals hospitalized for nonpsychiatric conditions: a cohort study. J Am Geriatr Soc. 2017;65(12):2580-2586. doi:10.1111/jgs.15066 [PubMed 29095482]
  6. Keepers GA, Fochtmann LJ, Anzia JM, et al. The American Psychiatric Association practice guideline for the treatment of patients with schizophrenia. Am J Psychiatry. 2020;177(9):868-872. doi:10.1176/appi.ajp.2020.177901 [PubMed 32867516]
  7. Lambert TJ. Switching antipsychotic therapy: what to expect and clinical strategies for improving therapeutic outcomes. J Clin Psychiatry. 2007;68(suppl 6):10-13. [PubMed 17650054]
  8. Landi F, Onder G, Cesari M, Barillaro C, Russo A, Bernabei R; Silver Network Home Care Study Group. Psychotropic medications and risk for falls among community-dwelling frail older people: an observational study. J Gerontol A Biol Sci Med Sci. 2005;60(5):622-6226. doi:10.1093/gerona/60.5.622 [PubMed 15972615]
  9. Maddalena AS, Fox M, Hofmann M, Hock C. Esophageal dysfunction on psychotropic medication. A case report and literature review. Pharmacopsychiatry. 2004;37(3):134-138. doi:10.1055/s-2004-818993 [PubMed 15138897]
  10. Nuplazid capsules and tablets (34 and 10 mg pimavanserin) [prescribing information]. San Diego, CA: Acadia Pharmaceuticals Inc; February 2022.
  11. Nuplazid (17 mg pimavanserin) [prescribing information]. San Diego, CA: Acadia Pharmaceuticals Inc; June 2018.
  12. Reus VI, Fochtmann LJ, Eyler AE, et al. American Psychiatric Association practice guideline on the use of antipsychotics to treat agitation or psychosis in patients with dementia. First edition. Am J Psychiatry. 2016;173(5):543-546. [PubMed 27133416]
  13. Seppala LJ, Wermelink AMAT, de Vries M, et al; EUGMS task and Finish group on fall-risk-increasing drugs. Fall-risk-increasing drugs: a systematic review and meta-analysis: II. Psychotropics. J Am Med Dir Assoc. 2018;19(4):371.e11-371.e17. doi:10.1016/j.jamda.2017.12.098 [PubMed 29402652]
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