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Drug Interactions between astemizole and ketoconazole

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

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Interactions between your drugs

Major

ketoconazole astemizole

Applies to: ketoconazole and astemizole

CONTRAINDICATED: Coadministration with azole antifungal agents may significantly increase the plasma concentrations of astemizole. The proposed mechanism is azole inhibition of CYP450 3A4, the isoenzyme responsible for the metabolic clearance of astemizole. High plasma levels of astemizole have been associated with prolongation of the QT interval on the ECG; ventricular arrhythmias including ventricular tachycardia and torsade de pointes; cardiac arrest; and sudden death. Within the azole class, ketoconazole and itraconazole are considered the most potent inhibitors, while fluconazole is comparatively weak and generally causes clinically significant interactions with CYP450 3A4 substrates only at dosages of 200 mg/day or more.

MANAGEMENT: The use of astemizole with most azole antifungal agents is considered contraindicated. Some authorities consider concomitant administration of astemizole and itraconazole to be contraindicated during and for 2 weeks after treatment with itraconazole (AU). Loratadine, cetirizine, or fexofenadine may be safer alternatives during therapy with azole antifungal agents.

References

  1. (2001) "Product Information. Nizoral (ketoconazole)." Janssen Pharmaceuticals, 1992
  2. "Product Information. Sporonox (itraconazole)." Janssen Pharmaceutica, Titusville, NJ.
  3. (2002) "Product Information. Hismanal (astemizole)." Janssen Pharmaceuticals
  4. (2002) "Product Information. Diflucan (fluconazole)." Roerig Division
  5. Craft TM (1986) "Torsade de pointes after astemizole overdose." Br Med J, 292, p. 660
  6. Simons FE, Kesselman MS, Giddins NG, Pelech AN, Simons KJ (1988) "Astemizole-induced torsade de pointes." Lancet, 2, p. 624
  7. Snook J, Boothman-Burrell D, Watkins J, Colin-Jones D (1988) "Torsade de pointes ventricular tachycardia associated with astemizole overdose." Br J Clin Pract, 42, p. 257-9
  8. Saviuc P, Danel V, Dixmerias F (1993) "Prolonged QT interval and torsade de pointes following astemizole overdose." J Toxicol Clin Toxicol, 31, p. 121-5
  9. Goss JE, Ramo BW, Blake K (1993) "Torsades de pointes associated with astemizole (hismanal) therapy." Arch Intern Med, 153, p. 2705
  10. Honig PK, Cantilena LR (1994) "Ketoconazole and fluconazole drug interactions." Arch Intern Med, 154, p. 1038-41
  11. Rao KA, Adlakha A, Vermaansil B, Meloy TD, Stanton MS (1994) "Torsades de pointes ventricular tachycardia associated with overdose of astemizole." Mayo Clin Proc, 69, p. 589-93
  12. Smith SJ (1994) "Cardiovascular toxicity of antihistamines." Otolaryngol Head Neck Surg, 111 Suppl, p. 348-54
  13. Salata JJ, Jurkiewicz NK, Wallace AA, Stupienski RF, Guinosso PJ, Lynch JJ (1995) "Cardiac electrophysiological actions of the histamine h-1-receptor antagonists astemizole and terfenadine compared with chlorpheniramine and pyrilamine." Circ Res, 76, p. 110-9
  14. Berul CI, Morad M (1995) "Regulation of potassium channels by nonsedating antihistamines." Circulation, 91, p. 2220-5
  15. (2001) "Product Information. Diflucan (fluconazole)." Roerig Division
  16. Heidemann SM, Sarnaik AP (1996) "Arrhythmias after astemizole overdose." Pediatr Emerg Care, 12, p. 102-4
  17. Woosley RL (1996) "Cardiac actions of antihistamines." Annu Rev Pharmacol Toxicol, 36, p. 233-52
  18. Vorperian VR, Zhou ZF, Mohammad S, Hoon TJ, Studenik C, January CT (1996) "Torsade de pointes with an antihistamine metabolite: potassium channel blockade with desmethylastemizole." J Am Coll Cardiol, 28, p. 1556-61
  19. Tsai WC, Tsai LM, Chen JH (1997) "Combined use of astemizole and ketoconazole resulting in torsade de pointes." J Formos Med Assoc, 96, p. 144-6
  20. Ament PW, Paterson A (1997) "Drug interactions with the nonsedating antihistamines." Am Fam Physician, 56, p. 223
  21. Pratt CM, Mason J, Russell T, Reynolds R, Ahlbrandt R (1999) "Cardiovascular safety of fexofenadine HCl." Am J Cardiol, 83, p. 1451-4
  22. Dresser GK, Spence JD, Bailey DG (2000) "Pharmacokinetic-pharmacodynamic consequences and clinical relevance of cytochrome P450 3A4 inhibition." Clin Pharmacokinet, 38, p. 41-57
  23. Venkatakrishnan K, von Moltke LL, Greenblatt DJ (2000) "Effects of the antifungal agents on oxidative drug metabolism: clinical relevance." Clin Pharmacokinet, 38, p. 111-80
  24. (2002) "Product Information. VFEND (voriconazole)." Pfizer U.S. Pharmaceuticals
  25. (2006) "Product Information. Noxafil (posaconazole)." Schering-Plough Corporation
  26. Cerner Multum, Inc. "Australian Product Information."
View all 26 references

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Drug and food interactions

Major

astemizole food

Applies to: astemizole

GENERALLY AVOID: Some beverages such as tonic water contain varying amounts of quinine. Coadministration of a single 430 mg dose of quinine has been shown to increase plasma concentrations of astemizole and its metabolite, desmethylastemizole. Elevated levels of these agents may cause a prolongation of the electrocardiographic QT interval and potentially fatal ventricular arrhythmias. Although pharmacokinetic data have indicated that the amounts of quinine in beverages (up to 80 mg quinine in 32 oz of tonic water) are not sufficient to produce a significant effect, the potential for an interaction exists if large amounts of tonic water are ingested. Also, grapefruit juice has been shown to inhibit CYP450 enzymes, which may lead to increased serum astemizole concentrations. The risk of life-threatening ventricular arrhythmias may be increased.

MANAGEMENT: Patients should be counseled to limit consumption of quinine-containing beverages and avoid grapefruit juice while they are taking astemizole.

References

  1. (2002) "Product Information. Hismanal (astemizole)." Janssen Pharmaceuticals

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Moderate

ketoconazole food

Applies to: ketoconazole

GENERALLY AVOID: Excessive use of alcohol or products containing alcohol together with ketoconazole or levoketoconazole may potentiate the risk of liver injury. Serious hepatotoxicity has been reported with levoketoconazole. Hepatotoxicity requiring liver transplantation has been reported with the use of oral ketoconazole, of which levoketoconazole is an enantiomer. Some patients had no obvious risk factors for liver disease. In addition, use of alcohol or products containing alcohol during ketoconazole or levoketoconazole therapy may result in a disulfiram-like reaction in some patients. Symptoms of disulfiram-like reaction include flushing, rash, peripheral edema, nausea, and headache.

GENERALLY AVOID: Coadministration with grapefruit juice may increase the plasma concentrations of ketoconazole or levoketoconazole. The mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruits. Inhibition of hepatic CYP450 3A4 may also contribute. In general, the effect of grapefruit juice is concentration-, dose- and preparation-dependent, and can vary widely among brands. Certain preparations of grapefruit juice (e.g., high dose, double strength) have sometimes demonstrated potent inhibition of CYP450 3A4, while other preparations (e.g., low dose, single strength) have typically demonstrated moderate inhibition. Pharmacokinetic interactions involving grapefruit juice are also subject to a high degree of interpatient variability, thus the extent to which a given patient may be affected is difficult to predict.

When administered to healthy volunteers with a high-fat meal (875 calories; 62% fat), levoketoconazole systemic exposure (AUC) increased by 30% while peak plasma concentration (Cmax) did not change and the time to reach Cmax (Tmax) was delayed from 2 to 4 hours, compared to fasted conditions.

MANAGEMENT: Levoketoconazole may be administered with or without food. Excessive consumption of alcohol should generally be avoided during ketoconazole or levoketoconazole therapy. Patients should preferably avoid or limit consumption of grapefruit, grapefruit juice, or any supplement containing grapefruit extract during ketoconazole or levoketoconazole therapy. Patients receiving ketoconazole or levoketoconazole should be instructed to contact their doctor immediately if they experience swelling, skin rash, itching, loss of appetite, fatigue, nausea, vomiting, abdominal pain, dark colored urine, light colored stools, and/or yellowing of the skin or eyes, as these may be signs and symptoms of liver damage.

References

  1. (2019) "Product Information. Ketoconazole (ketoconazole)." Mylan Pharmaceuticals Inc
  2. (2022) "Product Information. Recorlev (levoketoconazole)." Xeris Pharmaceuticals Inc
  3. Auchus R, Pivonello R, Fleseriu M, et al. (2022) Levoketoconazole: a novel treatment for endogenous Cushing's syndrome. https://www.tandfonline.com/doi/pdf/10.1080/17446651.2021.1945440
  4. (2021) "Product Information. Ketoconazole (ketoconazole)." Burel Pharmaceuticals Inc
View all 4 references

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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.

Further information

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