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Pimavanserin: Drug information

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Special Alerts

Benzodiazepines and Opioid Medicines Safety Alert August 2016

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
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will also continue to evaluate the evidence regarding combined use of benzodiazepines or other
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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
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Further information may be found at


http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProd
ucts/ucm518710.htm?source=govdelivery&utm_medium=email&utm_source=govdelivery.

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:

Strong CYP3A4 inhibitors (eg, ketoconazole): 17 mg once daily

Strong CYP3A4 inducers: 34 mg once daily; however, monitor for reduced efficacy; dosage
increase may be necessary

Discontinuation of therapy: The American Psychiatric Association (APA), Canadian Psychiatric


Association (CPA), and World Federation of Societies of Biological Psychiatry (WFSBP) guidelines
recommend gradually tapering antipsychotics to avoid withdrawal symptoms and minimize the
risk of relapse (APA [Lehman 2004]; Cerovecki 2013; CPA [Addington 2005]; WFSBP [Hasan
2012]); risk for withdrawal symptoms may be highest with highly anti-cholinergic or
dopaminergic antipsychotics (Cerovecki 2013). When stopping antipsychotic therapy in patients
with schizophrenia, the CPA guidelines recommend a gradual taper over 6 to 24 months, and
the APA guidelines recommend reducing the dose by 10% each month (APA [Lehman 2004]; CPA
[Addington 2005]). Continuing anti-parkinsonism agents for a brief period after discontinuation
may prevent withdrawal symptoms (Cerovecki 2013). When switching antipsychotics, 3
strategies have been suggested: Cross-titration (gradually discontinuing the first antipsychotic
while gradually increasing the new antipsychotic), overlap and taper (maintaining the dose of
the first antipsychotic while gradually increasing the new antipsychotic, then tapering the first
antipsychotic), and abrupt change (abruptly discontinuing the first antipsychotic and either
increasing the new antipsychotic gradually or starting it at a treatment dose). Evidence
supporting ideal switch strategies and taper rates is limited, and results are conflicting
(Cerovecki 2013; Remington 2005).

Dosing: Geriatric

Refer to adult dosing.

Dosing: Renal Impairment

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.

Dosing: Hepatic 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:

Nuplazid: 17 mg [contains saccharin sodium]

Generic Equivalent Available: US No

Administration

Oral: May be administered without regard to food.

Use

Parkinson disease psychosis: Treatment of hallucinations and delusions associated with


Parkinson disease psychosis

Medication Safety Issues

Geriatric Patients: High-Risk Medication:

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%:

Cardiovascular: Peripheral edema (7%)

Central nervous system: Confusion (6%), hallucination (5%), abnormal gait (2%)

Gastrointestinal: Nausea (7%), constipation (4%)

Frequency not defined: Cardiovascular: Prolonged Q-T interval on ECG

Contraindications:

There are no contraindications listed within the manufacturer's labeling.

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).

• 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:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or


frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult
drug interactions database for more detailed information.

Other warnings/precautions:

• Discontinuation of therapy: When discontinuing antipsychotic therapy, the American


Psychiatric Association (APA), Canadian Psychiatric Association (CPA), and World Federation of
Societies of Biological Psychiatry (WFSBP) guidelines recommend gradually tapering
antipsychotics to avoid physical withdrawal symptoms, including anorexia, anxiety,
diaphoresis, diarrhea, dizziness, dyskinesia, headache, myalgia, nausea, paresthesia,
restlessness, tremulousness, and vomiting (APA [Lehman 2004]; CPA [Addington 2005];
Lambert 2007; WFSBP [Hasan 2012]). The risk of withdrawal symptoms is highest following
abrupt discontinuation of highly anti-cholinergic or dopaminergic antipsychotics (Cerovecki
2013). Additional factors such as duration of antipsychotic exposure, the indication for use,
medication half-life, and risk for relapse should be considered. In schizophrenia, there is no
reliable indicator to differentiate the minority who will not from the majority who will relapse
with drug discontinuation. However, studies in which the medication of well-stabilized patients
were discontinued indicate that 75% of patients relapse within 6 to 24 months. Indefinite
maintenance antipsychotic medication is generally recommended, and especially for patients
who have had multiple prior episodes or 2 episodes within 5 years (APA [Lehman 2004]).

Metabolism/Transport Effects

Substrate of CYP3A4 (major); Note: Assignment of Major/Minor substrate status based on


clinically relevant drug interaction potential

Drug Interactions

(For additional information: Launch drug interactions program)

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

Adverse events were observed in some animal reproduction studies.

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.

Pharmacodynamics and Pharmacokinetics

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 (<2%); urine (<1% as unchanged drug)

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.

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REFERENCES

1. American Geriatrics Society 2015 Beers Criteria Update Expert Panel. American
geriatrics society 2015 updated beers criteria for potentially inappropriate medication
use in older adults [published online October 8, 2015]. J Am Geriatr Soc.
2015;63(11):2227-2246. [PubMed 26446832]
2. Canadian Psychiatric Association. Clinical practice guidelines. Treatment of
schizophrenia. Can J Psychiatry. 2005;50(13)(suppl 1):7S-57S. [PubMed 16529334]
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.
2012;13(5):318-378. doi: 10.3109/15622975.2012.696143. [PubMed 22834451]
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]
6. 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]
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
schizophrenia. Am J Psychiatry. 2004;161(8):1334-1349. [PubMed 15285957]
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]

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