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Active ingredient: Pimozide - Brands, Medical Use, Clinical Data

Brands, Medical Use, Clinical Data

Drug Category

  • Anti-Dyskinesia Agents
  • Antipsychotic Agents
  • Dopamine Antagonists

Dosage Forms

  • Tablet

Brands / Synonyms

Haldol decanoate; Halomonth; Neoperidole; Opiran; Orap; Pimozide [USAN:BAN:INN:JAN]; Pimozidum [INN-Latin]; Primozida [INN-Spanish]

Indications

Used for the suppression of motor and phonic tics in patients with Tourette's Disorder who have failed to respond satisfactorily to standard treatment.

Pharmacology

Pimozide is an orally active antipsychotic drug product which shares with other antipsychotics the ability to blockade dopaminergic receptors on neurons in the central nervous system. However, receptor blockade is often accompanied by a series of secondary alterations in central dopamine metabolism and function which may contribute to both pimozide's therapeutic and untoward effects. In addition, pimozide, in common with other antipsychotic drugs, has various effects on other central nervous system receptor systems which are not fully characterized. Pimozide also has less potential for inducing sedation and hypotension as it has more specific dopamine receptor blocking activity than other neuroleptic agents (and is therefore a suitable alternative to haloperidol).

Mechanism of Action

The ability of pimozide to suppress motor and phonic tics in Tourette's Disorder is thought to be primarily a function of its dopaminergic blocking activity. Pimozide binds to the dopamine D2 receptor in the CNS. It also appears to block voltage-operated calcium channels and acts as an antagonist at opiate receptors (OP2).

Absorption

Greater than 50% absorption after oral administration. Serum peak appears 6-8 hours post ingestion.

Toxicity

LD50 = 1100 mg/kg (rat, oral), 228 mg/kg (mouse, oral)

Biotrnasformation / Drug Metabolism

Notable first-pass metabolism in the liver, primarily by N-dealkylation via the cytochrome P450 isoenzymes CYP3A and CYP1A2 (and possibly CYP2D6). The activity of the two major metabolites has not been determined.

Contraindications

1. ORAP (pimozide) is contraindicated in the treatment of simple tics or tics other than those associated with Tourette's Disorder.

2. ORAP should not be used in patients taking drugs that may, themselves, cause motor and phonic tics (e.g., pemoline, methylphenidate and amphetamines) until such patients have been withdrawn from these drugs to determine whether or not the drugs, rather than Tourette's Disorder, are responsible for the tics.

3. Because ORAP prolongs the QT interval of the electrocardiogram it is contraindicated in patients with congenital long QT syndrome, patients with a history of cardiac arrhythmias, or patients taking other drugs which prolong the QT interval of the electrocardiogram.

4. ORAP is contraindicated in patients with severe toxic central nervous system depression or comatose states from any cause.

5. ORAP is contraindicated in patients with hypersensitivity to it. As it is not known whether crosssensitivity exists among the antipsychotics, pimozide should be used with appropriate caution in patients who have demonstrated hypersensitivity to other antipsychotic drugs.

6. Ventricular arrhythmias have been rarely associated with the use of macrolide antibiotics in patients with prolonged QT intervals, as might be produced by ORAP. Specifically, two sudden deaths have been reported when clarithromycin was added to ongoing pimozide therapy. Furthermore, some evidence suggests that pimozide is metabolized partly by the enzyme system cytochrome P450 3A (CYP 3A). macrolide antibiotics are inhibitors of CYP 3A, and thus could potentially impede pimozide metabolism. For these reasons, ORAP is contraindicated in patients receiving the macrolide antibiotics clarithromycin, erythromycin, azithromycin, dirithromycin, and troleandomycin.

Because azole antifungal agents are also inhibitors of the CYP 3A enzymes and thus may likewise impair pimozide metabolism, ORAP is contraindicated in patients receiving the azole antifungal agents itraconazole and ketoconazole.

Similarly, protease inhibitor drugs are also inhibitors of CYP 3A, and thus ORAP is contraindicated in patients receiving protease inhibitors such as ritonavir, saquinovir, indinavir, and nelfinavir.

Nefazodone is a potent inhibitor of CYP 3A, and its concomitant use with ORAP is also contraindicated.

Other drugs that are relatively less potent inhibitors of CYP 3A4 should also be avoided, in view of the risks: e.g. zileuton, fluvoxamine.

Concomitant use of pimozide in patients taking sertraline is contraindicated.

Drug Interactions

Because ORAP prolongs the QT interval of the electrocardiogram, an additive effect on QT interval would be anticipated if administered with other drugs, such as phenothiazines, tricyclic antidepressants or antiarrhythmic agents, which prolong the QT interval. Accordingly, pimozide should not be given with dofetilide, sotalol, quinidine, other Class Ia and III anti-arrhythmics, mesoridazine, thioridazine, chlorpromazine, droperidol, sparfloxacin, gatifloxacin, moxifloxacin, halofantrine, mefloquine, pentamidine, arsenic trioxide, levomethadyl acetate, dolasetron mesylate, probucol, tacrolimus, ziprasidone, or other drugs that have demonstrated QT prolongation as one of their pharmacodynamic effects. Also, the use of macrolide antibiotics in patients with prolonged QT intervals has been rarely associated with ventricular arrhythmias. Such concomitant administration should not be undertaken.

Since ORAP is partly metabolized via CYP 3A4, it should not be administered concomitantly with inhibitors of this metabolic system, such as azole antifungal agents and protease inhibitor drugs.

As CYP 1A2 may also contribute to the metabolism of ORAP, prescribers should be aware of the theoretical potential for drug interactions with inhibitors of this enzymatic system

ORAP may be capable of potentiating CNS depressants, including analgesics, sedatives, anxiolytics, and alcohol.

Rare case reports have suggested possible additive effects of pimozide and fluoxetine leading to bradycardia.

Concomitant administration of pimozide and sertraline should be contraindicated.

Interaction with Food

Patients should avoid grapefruit juice because it may inhibit the metabolism of pimozide by CYP 3A4.

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