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Pimozide

Pronunciation: PIM-oh-zide
Class: Phenylbutylpiperadine derivative

Trade Names

Orap
- Tablets, oral 1 mg
- Tablets, oral 2 mg

Apo-Pimozide (Canada)

Pharmacology

Blockage of dopaminergic receptors on neurons in the CNS.

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Pharmacokinetics

Absorption

More than 50% of oral dose absorbed. T max is 6 to 8 h.

Metabolism

Significant first-pass metabolism by N-dealkylation in the liver, catalyzed mainly by the CYP3A enzymatic system and, to a lesser extent, by CYP1A2, producing 2 major metabolites of undetermined activity.

Elimination

Primarily in the kidney, small amount in feces. Serum half-life is approximately 55 h.

Indications and Usage

Suppression of motor and phonic tics in patients with Tourette syndrome who fail to respond satisfactorily to standard treatment.

Contraindications

Treatment of simple tics or tics other than those associated with Tourette syndrome; drug-induced motor and phonic tics (eg, amphetamine, methylphenidate, pemoline) until it is determined whether the tics are caused by drugs or Tourette syndrome; patients with congenital long QT syndrome, history of cardiac arrhythmias; administration with other drugs that prolong the QT interval or inhibit CYP3A4; patients with hypokalemia or hypomagnesemia; patients receiving aprepitant or the azole antifungal agents itraconazole and ketoconazole; patients receiving the macrolide antibiotics azithromycin, clarithromycin, dirithromycin, erythromycin, and troleandomycin; patients receiving protease inhibitors (eg, amprenavir, indinavir, nelfinavir, ritonavir, saquinavir); coadministration of citalopram, escitalopram, fluvoxamine, nefazodone, sertraline, zileuton, or ziprasidone; severe toxic CNS depression or comatose states from any cause; hypersensitivity to pimozide.

Dosage and Administration

Adults

PO Initial dose is 1 to 2 mg/day in divided doses; the dose may be increased every other day. Maintenance dose is less than 0.2 mg/kg/day or 10 mg/day, whichever is less (max, 0.2 mg/kg, not to exceed 10 mg/day).

Children (12 y and older)

PO For the initial dose, give 0.05 mg/kg/day (preferably at bedtime); the dose may be increased every third day (max, 0.2 mg/kg, not to exceed 10 mg/day).

Storage/Stability

Store between 59° and 86°F.

Drug Interactions

CNS depressants (eg, analgesics, anxiolytics, sedatives)

Pimozide may potentiate effects of these agents.

Drugs that inhibit CYP1A2 (eg, cimetidine)

Because CYP1A2 may contribute to the metabolism of pimozide, be aware of the theoretical potential for drug interactions with this enzymatic system.

Drugs that inhibit CYP3A4 (eg, azole antifungal agents [eg, itraconazole, ketoconazole], delavirdine, efavirenz, protease inhibitors [eg, amprenavir, indinavir, nelfinavir, ritonavir, saquinavir], quinupristin/dalfopristin)

Coadministration of these agents with pimozide is contraindicated.

Drugs that may cause motor or phonic tics (eg, amphetamine, methylphenidate, pemoline)

Coadministration with pimozide is contraindicated until it is determined whether the drug, rather than Tourette syndrome, is responsible for the tics.

Drugs that prolong the QT interval (eg, aprepitant, arsenic trioxide, class Ia or III antiarrhythmic agents [eg, dofetilide, quinidine, sotalol], dolasetron mesylate, droperidol, halofantrine, haloperidol, levomethadyl acetate, macrolide antibiotics [eg, azithromycin, clarithromycin, dirithromycin, erythromycin], mefloquine, nefazodone, nilotinib, pentamidine, certain phenothiazines [eg, chlorpromazine, mesoridazine, thioridazine], probucol, certain quinolone antibiotics [gatifloxacin, moxifloxacin, sparfloxacin], SSRIs [eg, citalopram, fluoxetine, fluvoxamine, paroxetine, sertraline], tricyclic antidepressants [eg, amitriptyline], tacrolimus, telithromycin, voriconazole, zileuton, ziprasidone)

Coadministration of these agents with pimozide is contraindicated.

Grapefruit juice

May increase pimozide concentrations, increasing pharmacologic and adverse reactions. Avoid grapefruit juice and grapefruit products.

Adverse Reactions

Cardiovascular

ECG abnormal (3%); ECG changes, including prolongation of the QT interval, flattening, notching, inversion of T wave, and appearance of U waves; hypertension; hypotension; palpitations; postural hypotension; tachycardia.

CNS

Sedation (70%); akathisia, akinesia (40%); drowsiness (35%); somnolence (28%); adverse behavior effect (25%); headache (22%); asthenia (14%); depression, rigidity, speech disorder (10%); nervousness (8%); hyperkinesia (6%); handwriting changed (5%); abnormal dreams, headache, hyperkinesia, torticollis, tremor of limbs (3%); dizziness, dyskinesia, dystonia, excitement, extrapyramidal reactions, fainting, hyperpyrexia, motor restlessness, NMS, opisthotonos, parkinsonism, seizures, tardive dyskinesia, tremor (postmarketing).

Dermatologic

Rash (8%); skin irritation, sweating.

EENT

Decreased accommodation, visual disturbance (20%); sensitivity of eyes to light, taste change (5%); blurred vision, cataracts, fine vermicular movements of the tongue, oculogyric crises, periorbital edema.

GI

Dry mouth (25%); constipation (20%); increased salivation (14%); appetite increased, diarrhea, thirst (5%); dysphagia (3%); anorexia, GI distress, nausea, vomiting.

Genitourinary

Impotence (15%); loss of libido, nocturia, urinary frequency.

Metabolic-Nutritional

Hyponatremia, weight gain, weight loss (postmarketing)

Musculoskeletal

Muscle tightness (15%); stooped posture (10%); myalgia (3%).

Miscellaneous

Chest pain, sudden unexpected death (postmarketing).

Precautions

Pregnancy

Category C .

Lactation

Undetermined.

Children

Safety and efficacy have not been established in children younger than 12 y.

Renal Function

Use with caution.

Hepatic Function

Use with caution.

Special Risk Patients

Use with caution in patients with conditions that may be aggravated by anticholinergic activity, patients receiving anticonvulsant medication, and patients with a history of seizures or EEG abnormalities.

Neuroleptic malignant syndrome

This potentially fatal condition has been reported in association with antipsychotic agents. Signs and symptoms include hyperpyrexia, muscle rigidity, altered mental status, irregular pulse or BP, tachycardia, diaphoresis, or cardiac arrhythmias.

Sudden death

Sudden, unexpected deaths have occurred in patients receiving doses in the range of 1 mg/kg. Prolongation of the QT interval, predisposing patients to ventricular arrhythmia, is one possible mechanism for the deaths. Ensure ECG is performed before initiating therapy and periodically thereafter, especially during periods of dose adjustment. Correct potassium insufficiency and ensure healthy potassium levels are maintained during therapy. Withhold therapy if QTc interval prolongs beyond 0.47 sec (children), 0.52 sec (adults), or more than 25% above baseline QTc.

Tardive dyskinesia

This syndrome of potentially irreversible, involuntary dyskinetic movements has occurred with other antipsychotic agents. Incidence appears to be highest among elderly patients, especially women.

Overdosage

Symptoms

Comatose state with respiratory depression, ECG abnormalities, hypotension, severe extrapyramidal reactions.

Patient Information

  • Explain name, dose, action, and potential adverse effects of drug, including risk of developing tardive dyskinesia.
  • Advise patient that dose may be increased slowly until max benefit is achieved and not to take more than prescribed or increase the dose more rapidly than advised.
  • Instruct patient not to stop taking pimozide when symptoms improve.
  • Tell patient to immediately report fainting or loss of consciousness, palpitations, high fever, muscle rigidity, involuntary body or facial movements, altered mental status, irregular pulse, sweating, or seizures to health care provider.
  • Advise patient to avoid strenuous activity during periods of high temperature or humidity.
  • Instruct patient to avoid alcoholic beverages, grapefruit juice, and grapefruit products.
  • Advise patient to take sips of water, suck on ice chips or sugarless hard candy, or chew sugarless gum if dry mouth occurs.
  • Advise patient that drug may impair mental or physical abilities and to use caution while driving or performing other tasks requiring mental alertness.
  • Advise patient to notify health care provider of the following: excessive drowsiness, change in behavior, rapid pulse.
  • Advise patient that if a decision to withdraw therapy is made, not to stop the medication suddenly. Gradual withdrawal over several days to weeks may be necessary to prevent withdrawal symptoms.
  • Advise patient that follow-up visits and lab tests, including ECGs, will be required to monitor therapy; advise them to keep appointments.

Copyright © 2009 Wolters Kluwer Health.

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