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Pimozide

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
Brands: Orap

Warning(s)

Special Alerts:

[Posted 02/22/2011] ISSUE: FDA notified healthcare professionals that the Pregnancy section of drug labels for the entire class of antipsychotic drugs has been updated. The new drug labels now contain more and consistent information about the potential risk for abnormal muscle movements (extrapyramidal signs or EPS) and withdrawal symptoms in newborns whose mothers were treated with these drugs during the third trimester of pregnancy.

The symptoms of EPS and withdrawal in newborns may include agitation, abnormally increased or decreased muscle tone, tremor, sleepiness, severe difficulty breathing, and difficulty in feeding. In some newborns, the symptoms subside within hours or days and do not require specific treatment; other newborns may require longer hospital stays.

BACKGROUND: Antipsychotic drugs are used to treat symptoms of psychiatric disorders such as schizophrenia and bipolar disorder.

RECOMMENDATION: Healthcare professionals should be aware of the effects of antipsychotic medications on newborns when the medications are used during pregnancy. Patients should not stop taking these medications if they become pregnant without talking to their healthcare professional, as abruptly stopping antipsychotic medications can cause significant complications for treatment. For more information visit the FDA website at: and .

[Posted 06/16/2008] FDA notified healthcare professionals that both conventional and atypical antipsychotics are associated with an increased risk of mortality in elderly patients treated for dementia-related psychosis. In April 2005, FDA notified healthcare professionals that patients with dementia-related psychosis treated with atypical antipsychotic drugs are at an increased risk of death. Since issuing that notification, FDA has reviewed additional information that indicates the risk is also associated with conventional antipsychotics. Antipsychotics are not indicated for the treatment of dementia-related psychosis. The prescribing information for all antipsychotic drugs will now include the same information about this risk in a BOXED WARNING and the WARNINGS section. For more information visit the FDA website at: , and .

Introduction

Antipsychotic agent; diphenylbutylpiperidine-derivative.1 2 3 4 5

Uses for Pimozide

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

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).1 2 8 48 49 50 51 52 53 54 57 159 172 (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.1 2 8

Reserve for use in patients whose development and/or daily life function is severely compromised by the presence of motor and vocal tics.1 2

Has been used concomitantly with a stimulant in children with tic disorders (e.g., Tourette’s syndrome) and comorbid attention deficit hyperactivity disorder (ADHD) in whom stimulants alone cannot control tics.171

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Schizophrenia

Has been used for the symptomatic management of a variety of psychiatric illnesses,58 59 60 61 62 63 64 65 66 67 68 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 principally schizophrenia,58 59 60 61 62 63 64 65 66 67 68 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 but other agents generally are preferred.69 70

Pimozide Dosage and Administration

General

  • Perform ECG before initiation of therapy and periodically thereafter, particularly during periods of dosage adjustment.1 2 (See Cardiovascular Effects under Cautions.)

Administration

Oral Administration

Administer orally,1 2 usually once daily;152 153 also may administer in divided doses, particularly if once-daily dosing is not well tolerated.1 152

Some clinicians recommend administration as a single dose at bedtime to minimize adverse effects.153

Dosage

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Initiate therapy with low dosage and adjust dosage gradually.1 2 159

Pediatric Patients

Tourette’s Syndrome
Oral

Children <12 years of age: Reliable dose-response data for drug effects on tic manifestations not available.1 2

Children ≥12 years of age: Initially, 0.05 mg/kg daily, preferably at bedtime.1 May increase dosage every third day to a maximum of 0.2 mg/kg daily, not to exceed 10 mg daily.1 167

During prolonged maintenance therapy, use lowest possible effective dosage.1 2 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.1 2

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.1 2 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.1 2

If therapy is to be discontinued, gradually reduce dosage.1 2

Adults

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Tourette’s Syndrome
Oral

Initially, 1–2 mg daily in divided doses.1 2 159 164 May increase dosage every other day according to patient’s tolerance and therapeutic response.1 2 165 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.153 164

If minimal adverse effects occur (e.g., not interfering with functioning) before adequate response is achieved, hold further dosage increase until adverse effects resolve.164 If adverse effects interfere with functioning but are not severe, can reduce dosage by 1-mg increments at weekly intervals until such effects resolve.164

If severe adverse effects occur, immediately reduce dosage by 50% or withhold drug.1 2 164 Once serious adverse effects resolve, can reinstitute with more gradual titration, increasing dosage at intervals ranging from 7–30 days.164

Most patients are adequately treated with dosages <0.2 mg/kg daily or 10 mg daily, whichever is less; higher dosages not recommended.1 2

During prolonged maintenance therapy, use lowest possible effective dosage.1 2 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.1 2

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.1 2 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.1 2

If therapy is to be discontinued, gradually reduce dosage.1 2

Prescribing Limits

Pediatric Patients

Tourette’s Syndrome
Oral

Children ≥12 years of age: Maximum 0.2 mg/kg, not exceeding 10 mg daily.1

Adults

Tourette’s Syndrome
Oral

Dosages >0.2 mg/kg or 10 mg daily not recommended.1

Cautions for Pimozide

Contraindications

  • Simple tics or tics other than those associated with Tourette’s syndrome.1

  • 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.1

  • Congenital long QT syndrome, history of cardiac arrhythmias, concomitant therapy with other drugs that prolong QT interval, or known hypokalemia or hypomagnesemia.1 202 (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).1 200 205 206 207 208 209 210 211 (See Interactions.)

  • Severe toxic CNS depression or comatose states from any cause.1

  • Hypersensitivity to pimozide;1 use caution in patients who have demonstrated hypersensitivity to other antipsychotic drugs.1

Warnings/Precautions

Warnings

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Tardive Dyskinesia

Tardive dyskinesia, a syndrome of potentially irreversible, involuntary, dyskinetic movements, may develop in patients receiving antipsychotic agents, including pimozide.1 2 3 71 92 94 96 Consider discontinuance.1

May occur during long-term administration or following discontinuance.1 2 3 71

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.1 2 146

Hyperpyrexia not associated with NMS also reported with antipsychotic agents.1

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.1 168 170 Possibly due to QT interval prolongation, predisposing patients to ventricular arrhythmia.1 2

Various ECG changes (e.g., QT [including QTc] interval prolongation; flattening, notching, and inversion of the T wave; appearance of U waves) have occurred.1 2 164 165 202

Perform ECG evaluations before and periodically during therapy, especially during periods of dosage adjustment.1 2 202

Some clinicians recommend consultation with a cardiologist before therapy initiation in patients with a baseline QTc interval >440 ms.164

Consider stopping further dosage increases and dosage reduction for QTc 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.1 2 164 Also consider dosage reduction if bradycardia (<50 bpm) occurs.164

Some clinicians recommend withholding drug if T-wave inversion, U waves, or cardiac arrhythmia occurs and reinstituting only after ECG findings are normal.164

Use with caution in patients with cardiovascular disorders.3 164 165

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.1 2

Mutagenicity and Carcinogenicity

Dose-related increase in benign pituitary tumors observed in female mice; clinical importance is not known.1 2 Carefully consider tumorigenic potential in decision to use drug, especially if patient is young and long-term therapy is anticipated.1 2

General Precautions

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

CNS Effects

Possible risk of seizures;1 2 3 140 141 167 may lower seizure threshold.1 Use with caution in patients with history of seizures or EEG abnormalities or in those receiving anticonvulsants.1 Maintain adequate anticonvulsant therapy.1

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.1

Extrapyramidal symptoms occur frequently;1 2 3 9 40 50 52 58 59 60 68 71 73 78 81 85 87 88 90 92 93 94 96 97 99 100 102 104 122 145 especially during first few days of therapy.1 2 52 122 In most patients, reactions consist of parkinsonian symptoms1 2 4 68 71 78 81 92 94 99 100 102 159 that are mild to moderate in severity and usually reversible following discontinuance.1 2

Anticholinergic Effects

Causes adverse anticholinergic effects; use with caution in individuals whose condition may be aggravated by such effects.1

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.1 2 Not known whether gradual withdrawal will reduce occurrence; pending further evidence, withdraw gradually.1 2

Specific Populations

Pregnancy

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Category C.1

Lactation

Not known whether pimozide is distributed into human milk; discontinue nursing or the drug.1

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.1 2 Limited clinical evidence suggests that safety profile in children 2–12 years of age generally is comparable to that in older patients.1

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.1 2

Geriatric Use

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Prevalence of tardive dyskinesia appears to be highest among geriatric patients, particularly geriatric women.1 2 3 59

Transient hypotension for several hours after administration has occurred in some geriatric or debilitated patients.3

Hepatic Impairment

Use with caution.1

Renal Impairment

Use with caution.1

Common Adverse Effects

Extrapyramidal reactions (e.g., pseudoparkinsonism, dystonia, dyskinesia, akathisia), dry mouth, drowsiness, sedation, adverse behavior effect, asthenia, somnolence.1

Interactions for Pimozide

Metabolized by CYP3A41 and, to a lesser extent, by CYP1A2.1 168 170

Drugs and Foods Affecting Hepatic Microsomal Enzymes

Potential pharmacokinetic interaction (decreased metabolism) with inhibitors of CYP3A41 200 or CYP1A2.1

Prolongation of QT interval and, rarely, serious cardiovascular effects, including ventricular arrhythmias and death, reported in patients receiving CYP3A4 inhibitors and pimozide concomitantly;1 168 170 concomitant use contraindicated.1 (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 QTc interval.1 200 207 208 209 (See Contraindications and Cardiovascular Effects under Cautions and also Specific Drugs and Foods under Interactions.)

Specific Drugs and Foods

Drug or Food

Interaction

Comments

Antiarrhythmic agents (e.g., dofetilide, quinidine, sotalol, other class IA and III antiarrhythmics)1

Additive effects on prolongation of QT interval1

Concomitant use contraindicated1

Antidepressants, tricyclics

Additive effects on prolongation of QT interval1

Concomitant use not recommended1

Antidepressants, SSRIs (e.g., citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline)

Decreased pimozide metabolism; increased risk of prolongation of QT interval1 200 201 204 205 206 207 208 209 210 211

Concomitant use contraindicated1 200 205 206 207 208 209 210 211

Antifungals, azole (e.g., itraconazole, ketoconazole, voriconazole)

Decreased pimozide metabolism; increased risk of prolongation of QT interval1

Concomitant use contraindicated1

Aprepitant

Increased plasma pimozide concentrations; potential for serious or life-threatening reaction

Concomitant use contraindicated

Arsenic trioxide

Additive effects on prolongation of QT interval1

Concomitant use contraindicated1

CNS agents (e.g., opiates or other analgesics, barbiturates or other sedatives, anxiolytics, alcohol)

Additive CNS effects or potentiated action of CNS depressant1 2 4 146 151

Use concomitantly with caution to avoid excessive CNS depression1 2

Delavirdine

Potential for serious or life-threatening reactions (e.g., cardiac arrhythmias)

Concomitant use contraindicated

Dolasetron

Additive effects on prolongation of QT interval1

Concomitant use contraindicated1

Droperidol

Additive effects on prolongation of QT interval1

Concomitant use contraindicated1

Fluoroquinolones (e.g., gatifloxacin, moxifloxacin, sparfloxacin)

Additive effects on prolongation of QT interval1

Concomitant use contraindicated1

Grapefruit juice

Decreased pimozide metabolism1

Avoid grapefruit juice during therapy1

Halofantrine (licensed in the US but not commercially available)

Additive effects on prolongation of QT interval1

Concomitant use contraindicated1

HIV protease inhibitors (e.g., amprenavir [no longer commercially available in the US], atazanavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir)

Decreased pimozide metabolism; increased risk of prolongation of QT interval1

Concomitant use contraindicated1

Imatinib

Increased pimozide concentrations

Use with caution because pimozide has a narrow therapeutic window

Levomethadyl acetate (no longer commercially available in the US)

Additive effects on prolongation of QT interval1

Concomitant use contraindicated1

Macrolides (e.g., azithromycin, clarithromycin, dirithromycin, erythromycin, troleandomycin)

Decreased pimozide metabolism; increased risk of prolongation of QT interval and ventricular arrhythmias1

Sudden death reported in at least 2 patients when clarithromycin added to ongoing pimozide therapy1

Concomitant use contraindicated1

Mefloquine

Additive effects on prolongation of QT interval1

Concomitant use contraindicated1

Nefazodone

Decreased pimozide metabolism; increased risk of prolongation of QT interval1

Concomitant use contraindicated1

Pentamidine

Additive effects on prolongation of QT interval1

Concomitant use contraindicated1

Phenothiazines (e.g., chlorpromazine, mesoridazine [no longer commercially available in US], thioridazine1 )

Additive effects on prolongation of QT interval1

Concomitant use contraindicated1

Probucol (no longer commercially available in the US)

Additive effects on prolongation of QT interval1

Concomitant use contraindicated1

Tacrolimus

Additive effects on prolongation of QT interval1

Concomitant use contraindicated1

Zileuton

Decreased pimozide metabolism; increased risk of prolongation of QT interval1

Concomitant use contraindicated1

Ziprasidone

Increased risk of QT interval prolongation1

Concomitant use contraindicated1

Pimozide Pharmacokinetics

Absorption

Bioavailability

Slowly1 2 4 39 40 and variably absorbed1 2 4 39 after oral administration, with peak plasma concentrations of the drug1 2 4 39 40 and its metabolites39 attained within 6–8 hours (range: 4–12 hours).1 2 4 39 40

Appears to be at least 40–50% absorbed.1 2 4 39

Food

Effects of food on pharmacokinetics are not known.1

Special Populations

Effects of disease on pharmacokinetics are not known.1

Distribution

Extent

Distribution into human body tissues and fluids not well characterized.152 153 In animals, widely distributed after sub-Q administration, with highest concentrations attained in the liver,2 4 43 44 lungs,43 44 kidneys,43 44 and heart;43 44 also distributed into the brain,2 4 42 43 44 45 thymus,43 adrenals,43 thyroid,43 uterus,43 ovaries,43 and bile.46

Not known whether crosses placenta or is distributed into milk.1 2

Plasma Protein Binding

Extent of binding to plasma proteins is not known.152

Elimination

Metabolism

Appears to undergo extensive first-pass metabolism.1 39

Metabolized principally via oxidative N-dealkylation in the liver, catalyzed by CYP3A4 and, to a lesser extent, by CYP1A2.1 168 170 Pharmacologic activity of metabolites not determined,1 2 4 but results of animal studies suggest metabolites are inactive.4 37 45

Elimination Route

Excreted principally in urine1 2 4 39 (about 40%39 ) almost completely as metabolites,4 39 and, to a lesser extent, in feces (about 15%) mainly as unchanged drug.39

Not known if drug and/or its metabolites are removed by hemodialysis or peritoneal dialysis.152

Half-life

Approximately 55 hours after multiple oral doses in patients with chronic schizophrenic disorder.1 2 40

Special Populations

In patients with hepatic impairment, metabolism may be impaired.1

In patients with renal impairment, elimination may be decreased.1

Stability

Storage

Oral

Tablets

Tight, light-resistant containers1 2 at 25°C (may be exposed to 15–30°C).1

Actions

  • Principal pharmacologic effects are similar to those of haloperidol2 4 6 and, to a lesser extent, those of phenothiazines.1 2 4 6 10

  • Precise mechanism(s) of action in suppressing motor and vocal tics in patients with Tourette’s syndrome1 2 10 11 and its antipsychotic action4 15 17 19 20 not determined, but may be related principally to antidopaminergic effects.1 2 4 10 11 12 15 17 19 20 Appears to be a selective dopamine-2 (D2) receptor antagonist.10 21 156

  • Appears to have little effect on catecholamines other than dopamine,2 13 24 although turnover of brain norepinephrine may be increased at high doses.3 13

  • Like other antipsychotic agents, has various effects on CNS receptor systems (e.g., γ-aminobutyric acid [GABA]),42 which are not fully characterized.1 42

  • Exhibits some anticholinergic activity,1 2 3 4 9 50 62 78 93 136 although generally considered to be relatively weak compared with most other antipsychotic agents.4

Advice to Patients

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

  • Importance of taking medication exactly as prescribed by the clinician;1 necessity of ECG monitoring before and during therapy.1

  • Importance of avoiding driving, operating machinery, or performing hazardous tasks until gain experience with the drug’s effects.1

  • 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.1

  • 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).1 Importance of avoiding grapefruit juice.1 170

  • Importance of avoiding alcohol during therapy.1

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1

  • Importance of informing patients of other important precautionary information.1 (See Cautions.)

Preparations

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

Pimozide

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets

1 mg

Orap (scored)

Gate

2 mg

Orap (scored)

Gate

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 02/2014. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Orap 1MG Tablets (GATE): 60/$85.99 or 180/$247.98

Orap 2MG Tablets (GATE): 60/$109.99 or 180/$296.98

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions March 15, 2011. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

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