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Drug Interactions between dirithromycin and Orap

This report displays the potential drug interactions for the following 2 drugs:

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Interactions between your drugs

Major

pimozide dirithromycin

Applies to: Orap (pimozide) and dirithromycin

CONTRAINDICATED: Coadministration with the ketolide, telithromycin, as well as certain macrolide antibiotics may increase the plasma concentrations of pimozide. The mechanism is inhibition of pimozide metabolism via CYP450 3A4. High plasma levels of pimozide have been associated with prolongation of the QT interval on the ECG; ventricular arrhythmias including ventricular tachycardia, ventricular fibrillation, and torsade de pointes; cardiac arrest; and sudden death. Macrolides that may significantly inhibit CYP450 3A4 include clarithromycin, erythromycin, and troleandomycin. In a study involving 12 healthy subjects, clarithromycin (500 mg orally every 12 hours for 5 days) increased the mean peak plasma concentration (Cmax) and area under the concentration-time curve (AUC) of pimozide (6 mg single oral dose) by 39% and 113%, respectively, compared to placebo. These alterations corresponded with significant prolongations of the maximum QTc interval that exceeded those produced by pimozide alone. Isolated cases of sudden death have been reported following addition of clarithromycin to ongoing pimozide therapy.

MANAGEMENT: The use of pimozide with telithromycin or macrolide antibiotics is considered contraindicated by the manufacturers, although azithromycin and dirithromycin are generally believed to have little, if any, effect on CYP450 3A4.

References

  1. Amsden GW (1995) "Macrolides versus azalides: a drug interaction update." Ann Pharmacother, 29, p. 906-17
  2. "Product Information. Orap (pimozide)." Gate Pharmaceuticals
  3. Desta Z, Kerbusch T, Flockhart DA (1999) "Effect of clarithromycin on the pharmacokinetics and pharmacodynamics of pimozide in healthy poor and extensive metabolizers of cytochrome P450 2D6 (CYP2D6)." Clin Pharmacol Ther, 65, p. 10-20
  4. Desta Z, Soukhova N, Flockhart DA (2002) "In Vitro Inhibition of Pimozide N-Dealkylation by Selective Serotonin Reuptake Inhibitors and Azithromycin." J Clin Psychopharmacol, 22, p. 162-168
  5. Krahenbuhl S, Sauter B, Kupferschmidt H, Krause M, Wyss PA, Meier PJ (1995) "Case report: reversible QT prolongation with torsades de pointes in a patient with pimozide intoxication." Am J Med Sci, 309, p. 315-6
  6. Flockhart DA, Drici MD, Kerbusch T, et al. (2000) "Studies on the mechanism of a fatal clarithromycin-pimozide interaction in a patient with tourette syndrome." J Clin Psychopharmacol, 20, p. 317-24
  7. (2004) "Product Information. Ketek (telithromycin)." Aventis Pharmaceuticals
  8. European Agency for the Evaluation of Medicinal Products. Committee for Proprietary Medicinal Products (2004) European Public Assessment Report Ketek (telithromycin) (Rev. 2) http:www.emea.eu.int/humandocs/Humans/EPAR/Ketek/Ketek.htm
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Drug and food interactions

Major

pimozide food

Applies to: Orap (pimozide)

GENERALLY AVOID: Theoretically, the coadministration with grapefruit juice may increase the plasma concentrations of pimozide. The mechanism is decreased clearance of pimozide due to inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruits. The use of pimozide alone has been associated with dose-dependent prolongation of the QT interval. Although clinical data are lacking, this interaction may result in potentiation of the proarrhythmic effect of pimozide and consequently an increased risk of ventricular arrhythmias such as ventricular tachycardia and torsade de pointes. In addition, alcohol may potentiate some of the pharmacologic effects of pimozide. Use in combination may result in additive central nervous system depression and/or impairment of judgment, thinking, and psychomotor skills.

MANAGEMENT: The manufacturer recommends avoiding grapefruit juice (and probably grapefruits) during therapy with pimozide. Patients should also be advised to avoid or limit consumption of alcohol.

References

  1. "Product Information. Orap (pimozide)." Gate Pharmaceuticals
  2. Dresser GK, Spence JD, Bailey DG (2000) "Pharmacokinetic-pharmacodynamic consequences and clinical relevance of cytochrome P450 3A4 inhibition." Clin Pharmacokinet, 38, p. 41-57

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Therapeutic duplication warnings

No warnings were found for your selected drugs.

Therapeutic duplication warnings are only returned when drugs within the same group exceed the recommended therapeutic duplication maximum.

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Drug Interaction Classification

These classifications are only a guideline. The relevance of a particular drug interaction to a specific individual is difficult to determine. Always consult your healthcare provider before starting or stopping any medication.
Major Highly clinically significant. Avoid combinations; the risk of the interaction outweighs the benefit.
Moderate Moderately clinically significant. Usually avoid combinations; use it only under special circumstances.
Minor Minimally clinically significant. Minimize risk; assess risk and consider an alternative drug, take steps to circumvent the interaction risk and/or institute a monitoring plan.
Unknown No interaction information available.

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