Pimozide (Monograph)

Brand name: Orap
Drug class: Antipsychotics, Miscellaneous
VA class: CN709
Chemical name: 1-(1-(4,4-bis(4-fluorophenyl)butyl)-4-piperidinyl)-1,3-dihydro-2H-benzimidazole-2-one
Molecular formula: C₂₈H₂₉F₂N₃O
CAS number: 2062-78-4

Medically reviewed by Drugs.com on Mar 20, 2024. Written by ASHP.

Introduction

Antipsychotic agent; diphenylbutylpiperidine-derivative.

Uses for Pimozide

Tourette’s Syndrome

Suppression of motor and vocal tics of Tourette’s syndrome (Gilles de la Tourette’s syndrome) in adults and children who have failed to respond adequately to, or who do not tolerate, conventional therapy (e.g., haloperidol). (See Pediatric Use under Cautions.)

Not intended as a treatment of first choice, nor is it intended for suppression of tics that are only annoying or cosmetically troublesome.

Reserve for use in patients whose development and/or daily life function is severely compromised by the presence of motor and vocal tics.

Has been used concomitantly with a stimulant in children with tic disorders (e.g., Tourette’s syndrome) and comorbid attention deficit hyperactivity disorder (ADHD)^{† [off-label]} in whom stimulants alone cannot control tics.

Schizophrenia

Has been used for the symptomatic management of a variety ofpsychiatric illnesses^{† [off-label]}, principally schizophrenia^{† [off-label]}, but other agents generally are preferred.

Pimozide Dosage and Administration

General

• Perform ECG before initiation of therapy and periodically thereafter, particularly during periods of dosage adjustment. (See Cardiovascular Effects under Cautions.)

Administration

Oral Administration

Administer orally, usually once daily; also may administer in divided doses, particularly if once-daily dosing is not well tolerated.

Some clinicians recommend administration as a single dose at bedtime to minimize adverse effects.

Dosage

Initiate therapy with low dosage and adjust dosage gradually.

Pediatric Patients

Tourette’s Syndrome

Oral

Children <12 years of age^{† [off-label]}: Reliable dose-response data for drug effects on tic manifestations not available.

Children ≥12 years of age: Initially, 0.05 mg/kg daily, preferably at bedtime. May increase dosage every third day to a maximum of 0.2 mg/kg daily, not to exceed 10 mg daily.

During prolonged maintenance therapy, use lowest possible effective dosage. Once adequate response is achieved, make periodic attempts (e.g., every 6–12 months) to reduce dosage to determine whether initial intensity and frequency of tics persist.

In attempts to reduce dosage, consider possibility that observed increases of tic intensity and frequency may represent a transient, withdrawal-related phenomenon rather than return of the syndrome’s symptoms. Allow 1–2 weeks to elapse before concluding that an increase in tic manifestations is a function of the underlying disorder rather than a response to drug withdrawal.

If therapy is to be discontinued, gradually reduce dosage.

Adults

Tourette’s Syndrome

Oral

Initially, 1–2 mg daily in divided doses. May increase dosage every other day according to patient’s tolerance and therapeutic response. Some clinicians suggest that dosage be increased at longer intervals (e.g., every 5–7 days) until manifestations decrease by ≥70%, adverse effects occur without symptomatic benefit, or symptomatic benefit and adverse effects occur simultaneously.

If minimal adverse effects occur (e.g., not interfering with functioning) before adequate response is achieved, hold further dosage increase until adverse effects resolve. If adverse effects interfere with functioning but are not severe, can reduce dosage by 1-mg increments at weekly intervals until such effects resolve.

If severe adverse effects occur, immediately reduce dosage by 50% or withhold drug. Once serious adverse effects resolve, can reinstitute with more gradual titration, increasing dosage at intervals ranging from 7–30 days.

Most patients are adequately treated with dosages <0.2 mg/kg daily or 10 mg daily, whichever is less; higher dosages not recommended.

During prolonged maintenance therapy, use lowest possible effective dosage. Once adequate response is achieved, make periodic attempts (e.g., every 6–12 months) to reduce dosage to determine whether initial intensity and frequency of tics persist.

In attempts to reduce dosage, consider possibility that observed increases of tic intensity and frequency may represent a transient, withdrawal-related phenomenon rather than return of the syndrome’s symptoms. Allow 1–2 weeks to elapse before concluding that an increase in tic manifestations is a function of the underlying disorder rather than a response to drug withdrawal.

If therapy is to be discontinued, gradually reduce dosage.

Prescribing Limits

Pediatric Patients

Tourette’s Syndrome

Oral

Children ≥12 years of age: Maximum 0.2 mg/kg, not exceeding 10 mg daily.

Adults

Tourette’s Syndrome

Oral

Dosages >0.2 mg/kg or 10 mg daily not recommended.

Cautions for Pimozide

Contraindications

• Simple tics or tics other than those associated with Tourette’s syndrome.

• Concurrent therapy with drugs that cause motor and vocal tics (e.g., amphetamines, methylphenidate, pemoline [no longer commercially available in the US]) until such drugs have been withdrawn to determine whether tics were caused by the drug rather than Tourette’s syndrome.

• Congenital long QT syndrome, history of cardiac arrhythmias, concomitant therapy with other drugs that prolong QT interval, or known hypokalemia or hypomagnesemia. (See Cardiovascular Effects under Cautions.)

• Concomitant therapy with drugs that inhibit CYP3A4 or drugs that prolong the QT interval (e.g., azole antifungals, macrolide antibiotics, protease inhibitors, SSRIs [citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline], nefazodone, zileuton). (See Interactions.)

• Severe toxic CNS depression or comatose states from any cause.

• Hypersensitivity to pimozide; use caution in patients who have demonstrated hypersensitivity to other antipsychotic drugs.

Warnings/Precautions

Warnings

Tardive Dyskinesia

Tardive dyskinesia, a syndrome of potentially irreversible, involuntary, dyskinetic movements, may develop in patients receiving antipsychotic agents, including pimozide. Consider discontinuance.

May occur during long-term administration or following discontinuance.

Neuroleptic Malignant Syndrome

Neuroleptic malignant syndrome (NMS), a potentially fatal syndrome requiring immediate discontinuance of the drug and intensive symptomatic treatment, has been reported with antipsychotic agents, including pimozide.

Hyperpyrexia not associated with NMS also reported with antipsychotic agents.

Cardiovascular Effects

Sudden, unexpected deaths have occurred in some patients receiving high doses (>10 mg; in the range of 1 mg/kg) for conditions other than Tourette’s syndrome or in patients receiving concomitant pimozide and clarithromycin. Possibly due to QT interval prolongation, predisposing patients to ventricular arrhythmia.

Various ECG changes (e.g., QT [including QTc] interval prolongation; flattening, notching, and inversion of the T wave; appearance of U waves) have occurred.

Perform ECG evaluations before and periodically during therapy, especially during periods of dosage adjustment.

Some clinicians recommend consultation with a cardiologist before therapy initiation in patients with a baseline QT_c interval >440 ms.

Consider stopping further dosage increases and dosage reduction for QT_c interval prolongation >470 ms in children or 520 ms in adults or >25% beyond patient’s pretreatment value, or development of other T-wave abnormalities. Also consider dosage reduction if bradycardia (<50 bpm) occurs.

Some clinicians recommend withholding drug if T-wave inversion, U waves, or cardiac arrhythmia occurs and reinstituting only after ECG findings are normal.

Use with caution in patients with cardiovascular disorders.

Because hypokalemia has been associated with ventricular arrhythmias, correct potassium insufficiency because of diuretics, diarrhea, or other causes before pimozide initiation; maintain normal serum potassium concentrations during therapy.

Mutagenicity and Carcinogenicity

Dose-related increase in benign pituitary tumors observed in female mice; clinical importance is not known. Carefully consider tumorigenic potential in decision to use drug, especially if patient is young and long-term therapy is anticipated.

General Precautions

CNS Effects

Possible risk of seizures; may lower seizure threshold. Use with caution in patients with history of seizures or EEG abnormalities or in those receiving anticonvulsants. Maintain adequate anticonvulsant therapy.

Possible impairment of ability to perform activities requiring mental alertness or physical coordination (e.g., operating machinery, driving a motor vehicle), especially during first few days of therapy.

Extrapyramidal symptoms occur frequently; especially during first few days of therapy. In most patients, reactions consist of parkinsonian symptoms that are mild to moderate in severity and usually reversible following discontinuance.

Anticholinergic Effects

Causes adverse anticholinergic effects; use with caution in individuals whose condition may be aggravated by such effects.

Abrupt Withdrawal

Possible transient dyskinetic signs after abrupt withdrawal in some patients receiving maintenance therapy; in some cases, dyskinetic movements are indistinguishable from tardive dyskinesia except for duration. Not known whether gradual withdrawal will reduce occurrence; pending further evidence, withdraw gradually.

Specific Populations

Pregnancy

Category C.

Risk for extrapyramidal and/or withdrawal symptoms (e.g., agitation, hypertonia, hypotonia, tardive dyskinetic-like symptoms, tremor, somnolence, respiratory distress, feeding disorder) in neonates exposed to antipsychotic agents during the third trimester; monitor neonates exhibiting such symptoms. Symptoms were self-limiting in some neonates but varied in severity; some infants required intensive support and prolonged hospitalization.

Lactation

Not known whether pimozide is distributed into human milk; discontinue nursing or the drug.

Pediatric Use

Onset of Tourette’s syndrome usually occurs between ages of 2 and 15 years, but data on use and efficacy in children <12 years of age are limited. Limited clinical evidence suggests that safety profile in children 2–12 years of age generally is comparable to that in older patients.

Safety and efficacy for management of other conditions in children not evaluated; use in children for any condition other than Tourette’s syndrome not recommended.

Geriatric Use

Prevalence of tardive dyskinesia appears to be highest among geriatric patients, particularly geriatric women.

Transient hypotension for several hours after administration has occurred in some geriatric or debilitated patients.

Hepatic Impairment

Use with caution.

Renal Impairment

Use with caution.

Common Adverse Effects

Extrapyramidal reactions (e.g., pseudoparkinsonism, dystonia, dyskinesia, akathisia), dry mouth, drowsiness, sedation, adverse behavior effect, asthenia, somnolence.

Drug Interactions

Metabolized by CYP3A4 and, to a lesser extent, by CYP1A2.

Drugs and Foods Affecting Hepatic Microsomal Enzymes

Potential pharmacokinetic interaction (decreased metabolism) with inhibitors of CYP3A4 or CYP1A2.

Prolongation of QT interval and, rarely, serious cardiovascular effects, including ventricular arrhythmias and death, reported in patients receiving CYP3A4 inhibitors and pimozide concomitantly; concomitant use contraindicated. (See Specific Drugs and Foods under Interactions.)

Drugs That Prolong QT Interval

Potential pharmacologic interaction (additive effect on QT interval prolongation; concomitant use contraindicated) when used with drugs that prolong QT_c interval. (See Contraindications and Cardiovascular Effects under Cautions and also Specific Drugs and Foods under Interactions.)

Specific Drugs and Foods

Pimozide Pharmacokinetics

Absorption

Bioavailability

Slowly and variably absorbed after oral administration, with peak plasma concentrations of the drug and its metabolites attained within 6–8 hours (range: 4–12 hours).

Appears to be at least 40–50% absorbed.

Food

Effects of food on pharmacokinetics are not known.

Special Populations

Effects of disease on pharmacokinetics are not known.

Distribution

Extent

Distribution into human body tissues and fluids not well characterized. In animals, widely distributed after sub-Q administration, with highest concentrations attained in the liver, lungs, kidneys, and heart; also distributed into the brain, thymus, adrenals, thyroid, uterus, ovaries, and bile.

Not known whether crosses placenta or is distributed into milk.

Plasma Protein Binding

Extent of binding to plasma proteins is not known.

Elimination

Metabolism

Appears to undergo extensive first-pass metabolism.

Metabolized principally via oxidative N-dealkylation in the liver, catalyzed by CYP3A4 and, to a lesser extent, by CYP1A2. Pharmacologic activity of metabolites not determined, but results of animal studies suggest metabolites are inactive.

Elimination Route

Excreted principally in urine (about 40% ) almost completely as metabolites, and, to a lesser extent, in feces (about 15%) mainly as unchanged drug.

Not known if drug and/or its metabolites are removed by hemodialysis or peritoneal dialysis.

Half-life

Approximately 55 hours after multiple oral doses in patients with chronic schizophrenic disorder.

Special Populations

In patients with hepatic impairment, metabolism may be impaired.

In patients with renal impairment, elimination may be decreased.

Stability

Storage

Oral

Tablets

Tight, light-resistant containers at 25°C (may be exposed to 15–30°C).

Actions

• Principal pharmacologic effects are similar to those of haloperidol and, to a lesser extent, those of phenothiazines.

• Precise mechanism(s) of action in suppressing motor and vocal tics in patients with Tourette’s syndrome and its antipsychotic action not determined, but may be related principally to antidopaminergic effects. Appears to be a selective dopamine-2 (D₂) receptor antagonist.

• Appears to have little effect on catecholamines other than dopamine, although turnover of brain norepinephrine may be increased at high doses.

• Like other antipsychotic agents, has various effects on CNS receptor systems (e.g., γ-aminobutyric acid [GABA]), which are not fully characterized.

• Exhibits some anticholinergic activity, although generally considered to be relatively weak compared with most other antipsychotic agents.

• Importance of taking medication exactly as prescribed by the clinician; necessity of ECG monitoring before and during therapy.

• Importance of avoiding driving, operating machinery, or performing hazardous tasks until gain experience with the drug’s effects.

• Importance of clinicians informing patients in whom chronic use is contemplated of risk of tardive dyskinesia, taking into account clinical circumstances and competency of patient to understand information provided.

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription or OTC drugs, dietary supplements, and herbal products, as well as any concomitant illnesses (e.g., cardiovascular). Importance of avoiding grapefruit juice.

• Importance of avoiding alcohol during therapy.

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed. Importance of clinicians informing patients about the benefits and risks of taking antipsychotics during pregnancy (see Pregnancy under Cautions). Importance of advising patients not to stop taking pimozide if they become pregnant without consulting their clinician; abruptly stopping antipsychotic agents may cause complications.

• Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

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