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Drug Interactions between itraconazole and Quin-Release

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

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Major

quiNIDine itraconazole

Applies to: Quin-Release (quinidine) and itraconazole

CONTRAINDICATED: Coadministration with azole antifungal agents may significantly increase the plasma concentrations of quinidine. The proposed mechanism is inhibition of quinidine metabolism via intestinal and hepatic CYP450 3A4. Additionally, itraconazole and ketoconazole are also potent P-glycoprotein inhibitors and may reduce the active renal efflux of quinidine. In nine healthy, nonsmoking volunteers, administration of a single 100 mg oral dose of quinidine sulfate on the last day of itraconazole treatment (200 mg once a day for 4 days) increased quinidine peak plasma concentration (Cmax) and systemic exposure (AUC) by an average of 1.6- and 2.4-fold, respectively, compared to administration with placebo. The elimination half-life of quinidine was prolonged 60% by itraconazole, and its renal clearance decreased by 50%. Another study in six healthy subjects reported an approximately 60% decrease each in total and renal clearance and a 35% increase in elimination half-life of a single 200 mg dose of quinidine sulfate when given with itraconazole (100 mg daily for 6 days). Likewise, plasma quinidine levels more than doubled within seven days after initiating ketoconazole 200 mg/day in an elderly man taking quinidine sulfate 300 mg four times a day, although there was no evidence of clinical toxicity in this case. The use of quinidine has been associated with prolongation of the QT interval, thus elevated plasma levels may potentiate the risk of ventricular arrhythmias such as ventricular tachycardia and torsade de pointes as well as cardiac arrest and sudden death. Some azole antifungal agents themselves have also rarely been associated with QT interval prolongation and/or torsade de pointes. Theoretically, additive proarrhythmic effects may occur when used with quinidine. A case of deafness has been associated with quinidine toxicity attributed to a suspected interaction with itraconazole.

MANAGEMENT: Given the potential for serious and life-threatening adverse cardiac events associated with increased plasma levels of quinidine, concomitant use with azole antifungal agents is considered contraindicated. Some authorities consider concomitant administration of quinidine and itraconazole to be contraindicated during and for 2 weeks after treatment with itraconazole.

References

  1. McNulty RM, Lazor JA, Sketch M (1989) "Transient increase in plasma quinidine concentrations during ketoconazole-quinidine therapy." Clin Pharm, 8, p. 222-5
  2. (2001) "Product Information. Nizoral (ketoconazole)." Janssen Pharmaceuticals, 1992
  3. Roden DM, Woosley RL, Primm RK (1986) "Incidence and clinical features of the quinidine-associated long QT syndrome: implications for patient care." Am Heart J, 111, p. 1088-93
  4. "Product Information. Sporonox (itraconazole)." Janssen Pharmaceutica, Titusville, NJ.
  5. (2002) "Product Information. Sporanox (itraconazole)." Janssen Pharmaceuticals
  6. "Product Information. Quiniglute (quinidine)." Berlex, Richmond, CA.
  7. Laakso M, Aberg A, Savola J, Pentikainen PJ, Pyorala K (1987) "Diseases and drugs causing prolongation of the QT interval." Am J Cardiol, 59, p. 862-5
  8. Raehl CL, Patel AK, LeRoy M (1985) "Drug-induced torsade de pointes." Clin Pharm, 4, p. 675-90
  9. (2001) "Product Information. Diflucan (fluconazole)." Roerig Division
  10. Stanek EJ, Simko RJ, DeNofrio D, Pavri BB (1997) "Prolonged quinidine half-life with associated toxicity in a patient with hepatic failure." Pharmacotherapy, 17, p. 622-5
  11. Kaukonen KM, Olkkola KT, Neuvonen PJ (1997) "Itraconazole increases plasma concentrations of quinidine." Clin Pharmacol Ther, 62, p. 510-7
  12. Damkier P, Hansen LL, Brosen K (1999) "Effect of diclofenac, disulfiram, itraconazole, grapefruit juice and erythromycin on the pharmacokinetics of quinidine." Br J Clin Pharmacol, 48, p. 829-38
  13. Katz HI (1999) "Drug interactions of the newer oral antifungal agents." Br J Dermatol, 141, p. 26-32
  14. (2002) "Product Information. VFEND (voriconazole)." Pfizer U.S. Pharmaceuticals
  15. Holford NH, Coates PE, Guentert TW, Riegelman S, Sheiner LB (1981) "The effect of quinidine and its metabolites on the electrocardiogram and systolic time intervals: concentration--effect relationships." Br J Clin Pharmacol, 11, p. 187-95
  16. Cerner Multum, Inc. "UK Summary of Product Characteristics."
  17. (2006) "Product Information. Noxafil (posaconazole)." Schering-Plough Corporation
  18. Cerner Multum, Inc. "Australian Product Information."
View all 18 references

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Drug and food interactions

Moderate

quiNIDine food

Applies to: Quin-Release (quinidine)

GENERALLY AVOID: In a small, randomized, crossover study, the administration of quinidine with grapefruit juice (compared to water) to healthy volunteers significantly prolonged the time to reach peak plasma quinidine concentrations and decreased the plasma concentrations of its major metabolite, 3-hydroxyquinidine. These changes were associated pharmacodynamically with both a delay and a reduction in the maximal effect on QTc interval. The proposed mechanism is delay of gastric emptying as well as inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall induced by certain compounds present in grapefruits.

MANAGEMENT: Given the drug's narrow therapeutic index, patients receiving quinidine therapy should avoid the consumption of grapefruits and grapefruit juice to prevent any undue fluctuations in plasma drug levels.

References

  1. Ace LN, Jaffe JM, Kunka RL (1983) "Effect of food and an antacid on quinidine bioavailability." Biopharm Drug Dispos, 4, p. 183-90
  2. Min DI, Ku YM, Geraets DR, Lee HC (1996) "Effect of grapefruit juice on the pharmacokinetics and pharmacodynamics of quinidine in healthy volunteers." J Clin Pharmacol, 36, p. 469-76
  3. Ha HR, Chen J, Leuenberger PM, Freiburghaus AU, Follah F (1995) "In vitro inhibition of midazolam and quinidine metabolism by flavonoids." Eur J Clin Pharmacol, 48, p. 367-71
  4. Bailey DG, Dresser GR, Kreeft JH, Munoz C, Freeman DJ, Bend JR (2000) "Grapefruit-felodipine interaction: Effect of unprocessed fruit and probable active ingredients." Clin Pharmacol Ther, 68, p. 468-77
View all 4 references

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

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