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Special Alerts
An FDA review has found that the combined use of opioid medicines with benzodiazepines or
other drugs that depress the CNS resulted in serious adverse reactions, including slowed or
difficult breathing and deaths. Based on these findings, the FDA is requiring that new Boxed
Warnings be added to the labeling of prescription opioid pain and prescription opioid cough
medicines, and benzodiazepines, as well as new or revised patient Medication Guides. The FDA
will also continue to evaluate the evidence regarding combined use of benzodiazepines or other
CNS depressants with medication-assisted therapy drugs used to treat opioid addiction and
dependence, and whether labeling changes will be needed for other CNS depressants. Health
care providers should limit prescribing opioid pain medicines with benzodiazepines or other CNS
depressants only to patients for whom alternative treatment options are inadequate. If these
medicines are prescribed together, the dosages and duration of each drug should be limited to
the minimum needed to achieve the desired clinical effect. Patients and caregivers should be
warned about the risks of slowed or difficult breathing and/or sedation, and the associated signs
and symptoms. The prescribing of opioid cough medicines for patients taking benzodiazepines
or other CNS depressants, including alcohol, should also be avoided. Patients taking opioids with
benzodiazepines, other CNS depressant medicines, or alcohol, and caregivers of these patients,
should seek medical attention immediately if the symptoms of unusual dizziness or
lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness occur.
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:
Dosing: Adult
Strong CYP3A4 inducers: 34 mg once daily; however, monitor for reduced efficacy; dosage
increase may be necessary
Dosing: Geriatric
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: Use is not recommended; has not been studied in patients with severe
renal impairment.
Use is not recommended; has not been studied in patients with hepatic impairment.
Dosage Forms: US
Excipient information presented when available (limited, particularly for generics); consult
specific product labeling.
Tablet, Oral:
Administration
Use
Beers Criteria: Based on pharmacologic class concerns for antipsychotics in the Beers Criteria,
pimavanserin may be a potentially inappropriate medication to be avoided in patients 65 years
and older with dementia due to an increased risk of mortality, cerebrovascular accidents
(stroke), and a greater rate of cognitive decline with use; avoid antipsychotics for behavioral
problems associated with dementia or delirium unless alternative nonpharmacologic therapies
have failed and patient may harm self or others. Use may be appropriate in geriatric patients
with schizophrenia, bipolar disorder, or for short-term use as an antiemetic during
chemotherapy. 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 2015]).
Adverse Reactions Significant
1% to 10%:
Central nervous system: Confusion (6%), hallucination (5%), abnormal gait (2%)
Contraindications:
Warnings/Precautions
• 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).
• 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.
Concurrent drug therapy issues:
Other warnings/precautions:
Metabolism/Transport Effects
Drug Interactions
Aprepitant: May increase the serum concentration of CYP3A4 Substrates. Risk C: Monitor
therapy
Conivaptan: May increase the serum concentration of CYP3A4 Substrates. Risk X: Avoid
combination
CYP3A4 Inducers (Strong): May decrease the serum concentration of Pimavanserin. Risk C:
Monitor therapy
CYP3A4 Inhibitors (Moderate): May decrease the metabolism of CYP3A4 Substrates. Risk C:
Monitor therapy
CYP3A4 Inhibitors (Strong): May increase the serum concentration of Pimavanserin. Risk D:
Consider therapy modification
Fosaprepitant: May increase the serum concentration of CYP3A4 Substrates. Risk C: Monitor
therapy
Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates. Risk X:
Avoid combination
Highest Risk QTc-Prolonging Agents: May enhance the QTc-prolonging effect of other Highest
Risk QTc-Prolonging Agents. Risk X: Avoid combination
Idelalisib: May increase the serum concentration of CYP3A4 Substrates. Risk X: Avoid
combination
Indapamide: May enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents.
Risk D: Consider therapy modification
Ivabradine: May enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents.
Risk X: Avoid combination
Ivacaftor: May increase the serum concentration of CYP3A4 Substrates. Risk C: Monitor
therapy
Luliconazole: May increase the serum concentration of CYP3A4 Substrates. Risk C: Monitor
therapy
MiFEPRIStone: May enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents.
Risk X: Avoid combination
Moderate Risk QTc-Prolonging Agents: May enhance the QTc-prolonging effect of Highest Risk
QTc-Prolonging Agents. Risk X: Avoid combination
Netupitant: May increase the serum concentration of CYP3A4 Substrates. Risk C: Monitor
therapy
Palbociclib: May increase the serum concentration of CYP3A4 Substrates. Risk C: Monitor
therapy
QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying): May enhance the QTc-
prolonging effect of Highest Risk QTc-Prolonging Agents. Management: Avoid such
combinations when possible. Use should be accompanied by close monitoring for evidence of
QT prolongation or other alterations of cardiac rhythm. Risk D: Consider therapy modification
Simeprevir: May increase the serum concentration of CYP3A4 Substrates. Risk C: Monitor
therapy
St John's Wort: May decrease the serum concentration of Pimavanserin. Risk C: Monitor
therapy
Stiripentol: May increase the serum concentration of CYP3A4 Substrates. Management: Use of
stiripentol with CYP3A4 substrates that are considered to have a narrow therapeutic index
should be avoided due to the increased risk for adverse effects and toxicity. Any CYP3A4
substrate used with stiripentol requires closer monitoring. Risk D: Consider therapy
modification
Vinflunine: May enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Risk
X: Avoid combination
Pregnancy Implications
Breast-Feeding Considerations
It is not known if pimavanserin is excreted 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
Mental status; vital signs (as clinically indicated); renal and liver function (annually and as
clinically indicated); ECG (as clinically indicated) (Lehman 2004; Marder 2004).
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.
Metabolism: Primarily via CYP3A4 and CYP3A5; forms active N-desmethylated metabolite (AC-
279)
Pricing: US
Tablets (Nuplazid Oral)
17 mg (60): $2340.00
Disclaimer: The pricing data provide a representative AWP and/or AAWP price from a single
manufacturer of the brand and/or generic product, respectively. The pricing data should be
used for benchmarking purposes only, and as such should not be used to set or adjudicate any
prices for reimbursement or purchasing functions. Pricing data is updated monthly.
REFERENCES
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geriatrics society 2015 updated beers criteria for potentially inappropriate medication
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3. Cerovecki A, Musil R, Klimke A, et al. Withdrawal symptoms and rebound syndromes
associated with switching and discontinuing atypical antipsychotics: theoretical
background and practical recommendations. CNS Drugs. 2013;27(7):545-572. doi:
10.1007/s40263-013-0079-5. [PubMed 23821039]
4. Hasan A, Falkai P, Wobrock T, et al; World Federation of Societies of Biological
Psychiatry (WFSBP) Task Force on Treatment Guidelines for Schizophrenia. World
Federation of Societies of Biological Psychiatry (WFSBP) Guidelines for Biological
Treatment of Schizophrenia, part 1: update 2012 on the acute treatment of
schizophrenia and the management of treatment resistance. World J Biol Psychiatry.
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5. 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]
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improving therapeutic outcomes. J Clin Psychiatry. 2007;68(suppl 6):10-13. [PubMed
17650054]
7. Lehman AF, Lieberman JA, Dixon LB, et al, American Psychiatric Association, Steering
Committee on Practice Guidelines. Practice guidelines for the treatment of patients
with schizophrenia, second edition. Am J Psychiatry. 2004;161(2 Suppl):S1-S56.
[PubMed 15000267]
8. Marder SR, Essock SM, Miller Al, et al. Physical health monitoring of patients with
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9. Nuplazid (pimavanserin) [prescribing information]. San Diego, CA: Acadia
Pharmaceuticals Inc: April 2016.
10. Remington G, Chue P, Stip E, Kopala L, Girard T, Christensen B. The crossover approach
to switching antipsychotics: what is the evidence? Schizophr Res. 2005;76(2-3):267-
272. doi: 10.1016/j.schres.2005.01.009. [PubMed 15949658]
11. 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]