Pimavanserin

Pronunciation

(pim a VAN ser in)

Index Terms

• ACP-103
• Pimavanserin Tartrate

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, Oral:

Nuplazid: 17 mg [contains saccharin sodium]

Brand Names: U.S.

• Nuplazid

Pharmacologic Category

• Second Generation (Atypical) Antipsychotic

Pharmacology

Pimavanserin acts as an inverse agonist and antagonist with high affinity for 5-HT_2A receptors and low affinity for 5-HT_2C and sigma 1 receptors; no affinity for 5-HT_2B, dopaminergic (including D₂), muscarinic, histaminergic, or adrenergic receptors, or to calcium channels.

Distribution

V_d: 2173 L

Metabolism

Primarily via CYP3A4 and CYP3A5; forms active N-desmethylated metabolite (AC-279)

Excretion

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

Time to Peak

6 hours (median: 4 to 24 hours)

Half-Life Elimination

Pimavanserin: ~57 hours; N-desmethylated metabolite: ~200 hours

Protein Binding

~95%

Use: Labeled Indications

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

Contraindications

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

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.

Administration

Oral: May be administered without regard to food.

Storage

Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C (59°F and 86°F).

Drug Interactions

Amifampridine: May enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Avoid combination

Aprepitant: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Bilastine: May enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Monitor therapy

Buprenorphine: May enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Monitor therapy

Conivaptan: May increase the serum concentration of CYP3A4 Substrates. Avoid combination

CYP3A4 Inducers (Strong): May decrease the serum concentration of Pimavanserin. Monitor therapy

CYP3A4 Inhibitors (Moderate): May decrease the metabolism of CYP3A4 Substrates. Monitor therapy

CYP3A4 Inhibitors (Strong): May increase the serum concentration of Pimavanserin. Consider therapy modification

Fosaprepitant: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates. Avoid combination

Highest Risk QTc-Prolonging Agents: May enhance the QTc-prolonging effect of other Highest Risk QTc-Prolonging Agents. Avoid combination

Hydroxychloroquine: May enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Avoid combination

Idelalisib: May increase the serum concentration of CYP3A4 Substrates. Avoid combination

Indapamide: May enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Consider therapy modification

MiFEPRIStone: May enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Avoid combination

Mizolastine: May enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Avoid combination

Moderate Risk QTc-Prolonging Agents: May enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Avoid combination

Netupitant: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Palbociclib: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Probucol: May enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Avoid combination

Promazine: May enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Avoid combination

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. Consider therapy modification

Simeprevir: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

St John's Wort: May decrease the serum concentration of Pimavanserin. 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. Consider therapy modification

Teneligliptin: May enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Monitor therapy

Vinflunine: May enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Avoid combination

Xipamide: May enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Monitor therapy

Adverse Reactions

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

<1% (Limited to important or life-threatening): Circumoral edema, pharyngeal edema, skin rash, tongue edema, urticaria

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]).

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).

Pregnancy Considerations

Adverse events were observed in some animal reproduction studies.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience nausea. Have patient report immediately to prescriber severe dizziness, passing out, tachycardia, abnormal heartbeat, swelling in the arms or legs, hallucinations, or confusion (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.