Skip to main content

Drug Interactions between itraconazole and terfenadine

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

Edit list (add/remove drugs)

Interactions between your drugs

Major

itraconazole terfenadine

Applies to: itraconazole and terfenadine

CONTRAINDICATED: Coadministration with azole antifungal agents may significantly increase the plasma concentrations of terfenadine. The mechanism is azole inhibition of CYP450 3A4, the isoenzyme responsible for the metabolic clearance of terfenadine. High plasma levels of terfenadine 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. In six healthy volunteers, fluconazole (200 mg daily for 7 days) had no effect on the steady-state plasma concentrations of terfenadine (60 mg twice a day for 15 days) or the cardiac repolarization as measured by Holter QTc intervals. However, another study using fluconazole dosages of 400 and 800 mg/day demonstrated significant increases in the plasma levels of terfenadine.

MANAGEMENT: The use of terfenadine with most azole antifungal agents, including fluconazole at multiple doses of 400 mg or higher, is considered contraindicated. Some authorities consider concomitant administration of terfenadine 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. Cantilena LR Jr, Ferguson CL, Monahan BP "Torsades de pointes occurring in association with terfenadine use." JAMA 266 (1991): 2376
  2. "Product Information. Nizoral (ketoconazole)." Janssen Pharmaceuticals 1992 (2001):
  3. Eller MG, Okerholm RA "Pharmacokinetic interaction between terfenadine and ketoconazole." Clin Pharmacol Ther 49 (1991): 130
  4. Zimmermann M, Duruz H, Guinand O, et al. "Torsades de Pointes after treatment with terfenadine and ketoconazole." Eur Heart J 13 (1992): 1002-3
  5. Mathews DR, McNutt B, Okerholm R, et al. "Torsades de pointes occurring in association with terfenadine use." JAMA 266 (1991): 2375-6
  6. Monahan BP, Ferguson CL, Killeavy ES, et al. "Torsades de pointes occurring in association with terfenadine use." JAMA 264 (1990): 2788-90
  7. Honig PK, Wortham DC, Zamani K, et al. "Terfenadine-ketoconazole interaction: pharmacokinetic and electrocardiographic consequences." JAMA 269 (1993): 1513-8
  8. Pohjola-Sintonen S, Viitasalo M, Toivonene L, Neuvonen P "Torsades de pointes after terfenadine-itraconazole interaction." BMJ 306 (1993): 186
  9. Woosley RL, Chen Y, Freiman JP, Gillis RA "Mechanism of the cardiotoxic actions of terfenadine." JAMA 269 (1993): 1532-6
  10. "Product Information. Sporonox (itraconazole)." Janssen Pharmaceutica, Titusville, NJ.
  11. "Product Information. Seldane (terfenadine)." Hoechst Marion Roussel PROD (2001):
  12. Honig PK, Worham DC, Zamani K, Mullin JC, Conner DP, Cantilena LR "The effect of fluconazole on the steady-state pharmacokinetics and electrocardiographic pharmacodynamics of terfenadine in humans." Clin Pharmacol Ther 53 (1993): 630-6
  13. Crane JK, Shih HT "Syncope and cardiac arrhythmia due to an interaction between itraconazole and terfenadine." Am J Med 95 (1993): 445-6
  14. Honig PK, Wortham DC, Hull R, Zamani K, Smith JE, Cantilena LR "Itraconazole affects single-dose terfenadine pharmacokinetics and cardiac repolarization pharmacodynamics." J Clin Pharmacol 33 (1993): 1201-6
  15. Honig PK, Cantilena LR "Ketoconazole and fluconazole drug interactions." Arch Intern Med 154 (1994): 1038-41
  16. Kivisto KT, Neuvonen PJ, Klotz U "Inhibition of terfenadine metabolism - pharmacokinetic and pharmacodynamic consequences." Clin Pharmacokinet 27 (1994): 1-5
  17. Smith SJ "Cardiovascular toxicity of antihistamines." Otolaryngol Head Neck Surg 111 Suppl (1994): 348-54
  18. Salata JJ, Jurkiewicz NK, Wallace AA, Stupienski RF, Guinosso PJ, Lynch JJ "Cardiac electrophysiological actions of the histamine h-1-receptor antagonists astemizole and terfenadine compared with chlorpheniramine and pyrilamine." Circ Res 76 (1995): 110-9
  19. Berul CI, Morad M "Regulation of potassium channels by nonsedating antihistamines." Circulation 91 (1995): 2220-5
  20. "Product Information. Diflucan (fluconazole)." Roerig Division PROD (2001):
  21. Vonmoltke LL, Greenblatt DJ, Duan SX, Harmatz JS, Wright CE, Shader RI "Inhibition of terfenadine metabolism in vitro by azole antifungal agents and by selective serotonin reuptake inhibitor antidepressants: relation to pharmacokinetic interactions in vivo." J Clin Psychopharmacol 16 (1996): 104-12
  22. Woosley RL "Cardiac actions of antihistamines." Annu Rev Pharmacol Toxicol 36 (1996): 233-52
  23. Ament PW, Paterson A "Drug interactions with the nonsedating antihistamines." Am Fam Physician 56 (1997): 223
  24. June RA, Nasr I "Torsades de pointes with terfenadine ingestion." Am J Emerg Med 15 (1997): 542-3
  25. Jurima-Romet M, Crawford K, Cyr T, Inaba T "Terfenadine metabolism in human liver. In vitro inhibition by macrolide antibiotics and azole antifungals." Drug Metab Dispos 22 (1994): 849-57
  26. Pratt CM, Mason J, Russell T, Reynolds R, Ahlbrandt R "Cardiovascular safety of fexofenadine HCl." Am J Cardiol 83 (1999): 1451-4
  27. Dresser GK, Spence JD, Bailey DG "Pharmacokinetic-pharmacodynamic consequences and clinical relevance of cytochrome P450 3A4 inhibition." Clin Pharmacokinet 38 (2000): 41-57
  28. Venkatakrishnan K, von Moltke LL, Greenblatt DJ "Effects of the antifungal agents on oxidative drug metabolism: clinical relevance." Clin Pharmacokinet 38 (2000): 111-80
  29. "Product Information. VFEND (voriconazole)." Pfizer U.S. Pharmaceuticals (2002):
  30. "Product Information. Noxafil (posaconazole)." Schering-Plough Corporation (2006):
  31. Cerner Multum, Inc. "Australian Product Information." O 0
View all 31 references

Switch to consumer interaction data

Drug and food interactions

Major

terfenadine food

Applies to: terfenadine

CONTRAINDICATED: The consumption of grapefruit juice has been associated with significantly increased plasma concentrations of terfenadine. The mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall induced by certain compounds present in grapefruits. Terfenadine in high serum levels has been associated with prolongation of the QT interval and development of torsade de pointes, a potentially fatal ventricular arrhythmia.

MANAGEMENT: Due to the risk of cardiotoxicity, patients receiving the drug should be advised to avoid consumption of grapefruit products. Loratadine, cetirizine, and fexofenadine may be safer alternatives in patients who may have trouble adhering to the dietary restriction.

References

  1. Honig PK, Woosley RL, Zamani K, Conner DP, Cantilena LR Jr "Changes in the pharmacokinetics and electrocardiographic pharmacodynamics of terfenadine with concomitant administration of erythromycin." Clin Pharmacol Ther 52 (1992): 231-8
  2. Zimmermann M, Duruz H, Guinand O, et al. "Torsades de Pointes after treatment with terfenadine and ketoconazole." Eur Heart J 13 (1992): 1002-3
  3. Mathews DR, McNutt B, Okerholm R, et al. "Torsades de pointes occurring in association with terfenadine use." JAMA 266 (1991): 2375-6
  4. Monahan BP, Ferguson CL, Killeavy ES, et al. "Torsades de pointes occurring in association with terfenadine use." JAMA 264 (1990): 2788-90
  5. Honig PK, Wortham DC, Zamani K, et al. "Terfenadine-ketoconazole interaction: pharmacokinetic and electrocardiographic consequences." JAMA 269 (1993): 1513-8
  6. Pohjola-Sintonen S, Viitasalo M, Toivonene L, Neuvonen P "Torsades de pointes after terfenadine-itraconazole interaction." BMJ 306 (1993): 186
  7. Cortese LM, Bjornson DC "Potential interaction between terfenadine and macrolide antibiotics." Clin Pharm 11 (1992): 675
  8. Paris DG, Parente TF, Bruschetta HR, Guzman E, Niarchos AP "Torsades-de-pointes induced by erythromycin and terfenadine." Am J Emerg Med 12 (1994): 636-8
  9. Zechnich AD, Haxby DG "Drug interactions associated with terfenadine and related nonsedating antihistamines." West J Med 164 (1996): 68-9
  10. Honig PK, Wortham DC, Lazarev A, Cantilena LR "Grapefruit juice alters the systemic bioavailability and cardiac repolarization of terfenadine in poor metabolizers of terfenadine." J Clin Pharmacol 36 (1996): 345-51
  11. Woosley RL "Cardiac actions of antihistamines." Annu Rev Pharmacol Toxicol 36 (1996): 233-52
  12. Benton RE, Honig PK, Zamani K, Cantilena LR, Woosley RL "Grapefruit juice alters terfenadine pharmacokinetics resulting in prolongation of repolarization on the electrocardiogram." Clin Pharmacol Ther 59 (1996): 383-8
  13. Hsieh MH, Chen SA, Chiang CE, et al. "Drug-induced torsades de pointes in one patient with congenital long QT syndrome." Int J Cardiol 54 (1996): 85-8
  14. Clifford CP, Adams DA, Murray S, Taylor GW, Wilkins MR, Boobis AR, Davies DS "Pharmacokinetic and cardiac effects of terfenadine after inhibition of its metabolism by grapefruit juice." Br J Clin Pharmacol 42 (1996): p662
  15. Rau SE, Bend JR, Arnold JMO, Tran LT, Spence JD, Bailey DG "Grapefruit juice terfenadine single-dose interaction: Magnitude, mechanism, and relevance." Clin Pharmacol Ther 61 (1997): 401-9
  16. Bailey DG, Malcolm J, Arnold O, Spence JD "Grapefruit juice-drug interactions." Br J Clin Pharmacol 46 (1998): 101-10
  17. Bailey DG, Dresser GR, Kreeft JH, Munoz C, Freeman DJ, Bend JR "Grapefruit-felodipine interaction: Effect of unprocessed fruit and probable active ingredients." Clin Pharmacol Ther 68 (2000): 468-77
View all 17 references

Switch to consumer interaction data

Moderate

itraconazole food

Applies to: itraconazole

ADJUST DOSING INTERVAL: Food increases the absorption of itraconazole capsules but decreases the absorption of itraconazole oral solution. Cola beverages may increase the bioavailability of itraconazole capsules. Itraconazole capsules require an acidic gastric pH for adequate dissolution and subsequent absorption. Cola beverages help lower gastric pH and improve absorption.

GENERALLY AVOID: Grapefruit juice may impair the absorption of itraconazole capsules, resulting in decreased antifungal effects. In a small, randomized, crossover study, the administration of itraconazole capsules with double-strength grapefruit juice (compared to water) was associated with significantly decreased (43%) plasma concentrations of itraconazole and its pharmacologically active hydroxy metabolite, as well as delayed times to reach peak concentrations of both. The exact mechanism of interaction is unknown but may involve reduced absorption of itraconazole secondary to enhanced activity of intestinal P-glycoprotein drug efflux pumps and delayed gastric emptying induced by certain compounds present in grapefruits. Another study reported no pharmacokinetic changes with single-strength grapefruit juice. Whether or not these observations apply to itraconazole oral solution is unknown.

MANAGEMENT: The manufacturer recommends that the capsules be taken immediately after a full meal and the solution be taken on an empty stomach to ensure maximal absorption. Cola beverages may help increase the bioavailability of itraconazole capsules, particularly in patients with hypochlorhydria or those treated concomitantly with gastric acid suppressants. Until more information is available, it may be advisable to avoid the consumption of grapefruits and grapefruit juice during itraconazole therapy.

References

  1. Van Peer A, Woestenborghs R, Heykants J, et al. "The effects of food and dose on the oral systemic availability of itraconazole in healthy subjects." Eur J Clin Pharmacol 36 (1989): 423-6
  2. Wishart JM "The influence of food on the pharmacokinetics of itraconazole in patients with superficial fungal infection." J Am Acad Dermatol 17 (1987): 220-3
  3. "Product Information. Sporanox (itraconazole)." Janssen Pharmaceuticals PROD (2002):
  4. Barone JA, Koh JG, Bierman RH, Colaizzi JL, Swanson KA, Gaffar MC, Moskovitz BL, Mechlinski W, Van de Velde V "Food interaction and steady-state pharmacokinetics of itraconazole capsules in healthy male volunteers." Antimicrob Agents Chemother 37 (1993): 778-84
  5. Zimmermann T, Yeates RA, Albrecht M, Laufen H, Wildfeuer A "Influence of concomitant food intake on the gastrointestinal absorption of fluconazole and itraconazole in japanese subjects." Int J Clin Pharmacol Res 14 (1994): 87-93
  6. "Product Information. Sporanox (itraconazole)." Janssen Pharmaceuticals (2022):
  7. Kawakami M, Suzuki K, Ishizuka T, Hidaka T, Matsuki Y, Nakamura H "Effect of grapefruit juice on pharmacokinetics of itraconazole in healthy subjects." Int J Clin Pharmacol Ther 36 (1998): 306-8
  8. Barone JA, Moskotitz BL, Guarnieri J, Hassell AE, Colaizzi JL, Bierman RH, Jessen L "Food interaction and steady-state pharmacokinetics of itraconazole oral solution in healthy volunteers." Pharmacotherapy 18 (1998): 295-301
  9. Penzak SR, Gubbins PO, Gurley BJ, Wang PL, Saccente M "Grapefruit juice decreases the systemic availability of itraconazole capsules in healthy volunteers." Ther Drug Monit 21 (1999): 304-9
  10. Katz HI "Drug interactions of the newer oral antifungal agents." Br J Dermatol 141 (1999): 26-32
View all 10 references

Switch to consumer interaction data

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.

See also

Report options

Loading...
QR code containing a link to this page

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

Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.

Medical Disclaimer