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Orap (Pimozide) - Drug Interactions, Contraindications, Overdosage, etc

 
 



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. 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 (see CONTRAINDICATIONS).

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

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

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

A single case report has suggested possible additive effects of pimozide and fluoxetine leading to bradycardia.

OVERDOSAGE

In general, the signs and symptoms of overdosage with ORAP (pimozide) would be an exaggeration of known pharmacologic effects and adverse reactions, the most prominent of which would be: 1) electrocardiographic abnormalities, 2) severe extrapyramidal reactions, 3) hypotension, 4) a comatose state with respiratory depression.

In the event of overdosage, gastric lavage, establishment of a patent airway and, if necessary, mechanically-assisted respiration are advised. Electrocardiographic monitoring should commence immediately and continue until the ECG parameters are within the normal range. Hypotension and circulatory collapse may be counteracted by use of intravenous fluids, plasma, or concentrated albumin, and vasopressor agents such as metaraminol, phenylephrine and norepinephrine. Epinephrine should not be used. In case of severe extrapyramidal reactions, antiparkinson medication should be administered. Because of the long half-life of pimozide, patients who take an overdose should be observed for at least 4 days. As with all drugs, the physician should consider contacting a poison control center for additional information on the treatment of overdose.

CONTAINDICATIONS

  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 (see PRECAUTIONS -- Drug Interactions).
  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 hyper-sensitivity to it. As it is not known whether cross-sensitivity 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. Futhermore, 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. (See PRECAUTIONS -- Drug Interactions.)
    Nefazone 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 3A should also be avoided, in view of the risks e.g. zileuton

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