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Drug Interaction Report

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

  • itraconazole
  • Xanax (alprazolam)

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Interactions between your drugs

Major

itraconazole ALPRAZolam

Applies to: itraconazole, Xanax (alprazolam)

CONTRAINDICATED: Coadministration with itraconazole or ketoconazole may significantly increase the plasma concentrations and pharmacologic effects of benzodiazepines that are primarily metabolized by CYP450 3A4. The mechanism is increased bioavailability and/or decreased clearance due to inhibition of intestinal and hepatic CYP450 3A4 by the azole antifungal agents. In pharmacokinetic studies, itraconazole (200 mg/day) and ketoconazole (400 mg/day) individually increased the peak plasma concentration (Cmax), area under the concentration-time curve (AUC) and elimination half-life (T1/2) of a single 0.25 mg oral dose of triazolam by more than 3-, 22- and 6-fold, respectively, compared to placebo. Similarly, Cmax, AUC and T1/2 of a single 7.5 mg oral dose of midazolam were more than 3,- 10- and 3-fold higher, respectively, during coadministration of itraconazole or ketoconazole relative to placebo. The AUC of a single 2 mg IV dose of midazolam increased 5-fold after pretreatment with ketoconazole. The results for alprazolam have been less dramatic, presumably due to limited first-pass metabolism in the intestine. In separate studies, itraconazole and ketoconazole increased the AUC of alprazolam (0.8 and 1 mg single oral dose) by 2.5- and 4-fold, respectively, compared to placebo, while Cmax was not significantly affected. Pharmacodynamic changes associated with the interaction include increased and prolonged sedation, enhanced benzodiazepine-related EEG effects, and increased impairment of psychomotor performance. The interaction is subject to a high degree of interpatient variability.

MANAGEMENT: The concomitant use of itraconazole or ketoconazole with alprazolam, oral midazolam, and triazolam is considered contraindicated. Some authorities consider concomitant administration of triazolam or oral midazolam and itraconazole to be contraindicated during and for 2 weeks after treatment with itraconazole. Fluconazole and miconazole are weaker inhibitors of CYP450 3A4 but may still cause the interaction, while terbinafine is not an inhibitor of CYP450 3A4 and has been shown to have no effect on the pharmacokinetics of midazolam and triazolam. Alternatively, benzodiazepines that are not metabolized by CYP450 3A4 (e.g., lorazepam, oxazepam, temazepam) may be considered in patients requiring itraconazole or ketoconazole.

References

  1. "Product Information. Sporanox (itraconazole)." Janssen Pharmaceutica, Titusville, NJ.
  2. Backman JT, Kivisto KT, Olkkola KT, Neuvonen PJ "The area under the plasma concentration-time curve for oral midazolam is 400-fold larger during treatment with itraconazole than with rifampicin." Eur J Clin Pharmacol 54 (1998): 53-8
  3. Wrighton SA, Ring BJ "Inhibition of human CYP3A catalyzed 1'-hydroxy midazolam formation by ketoconazole, nifedipine, erythromycin, cimetidine, and nizatidine." Pharm Res 11 (1994): 921-4
  4. Neuvonen PJ, Varhe A, Olkkola KT "The effect of ingestion time interval on the interaction between itraconazole and triazolam." Clin Pharmacol Ther 60 (1996): 326-31
  5. Tsunoda SM, Velez RL, vonMoltke LL, Greenblatt DJ "Differentiation of intestinal and hepatic cytochrome P450 3A activity with use of midazolam as an in vivo probe: Effect of ketoconazole." Clin Pharmacol Ther 66 (1999): 461-71
  6. Greenblatt DJ, Vonmoltke LL, Harmatz JS, Harrel LM, Tobias S, Shader RI, Wright CE "Interaction of triazolam and ketoconazole." Lancet 345 (1995): 191
  7. "Product Information. Halcion (triazolam)." Pharmacia and Upjohn, Kalamazoo, MI.
  8. Vonmoltke LL, Greenblatt DJ, Schmider J, Duan SX, Wright CE, Harmatz JS, Shader RI "Midazolam hydroxylation by human liver microsomes in vitro: inhibition by fluoxetine, norfluoxetine, and by azole antifungal agents." J Clin Pharmacol 36 (1996): 783-91
  9. Vonmoltke LL, Greenblatt DJ, Cotreaubibbo MM, Harmatz JS, Shader RI "Inhibitors of alprazolam metabolism in vitro: effect of serotonin-reuptake-inhibitor antidepressants, ketoconazole and quinidine." Br J Clin Pharmacol 38 (1994): 23-31
  10. Brown MW, Maldonado AL, Meredith CG, Speeg KV "Effect of ketoconazole on hepatic oxidative drug metabolism." Clin Pharmacol Ther 37 (1985): 290-7
  11. "Product Information. Xanax (alprazolam)." Pharmacia and Upjohn, Kalamazoo, MI.
  12. "Product Information. Sporonox (itraconazole)." Janssen Pharmaceutica, Titusville, NJ.
  13. Cerner Multum, Inc. "Australian Product Information." O 0
  14. "Product Information. Versed (midazolam)." Roche Laboratories, Nutley, NJ.
  15. Varhe A, Olkkola KT, Neuvonen PJ "Oral triazolam is potentially hazardous to patients receiving systemic antimycotics ketoconazole or itraconazole." Clin Pharmacol Ther 56 (1994): 601-7
  16. Yasui N, Kondo T, Otani K, Furukori H, Kaneko S, Ohkubo T, Nagasaki T, Sugawara K "Effect of itraconazole on the single oral dose pharmacokinetics and pharmacodynamics of alprazolam." Psychopharmacology 139 (1998): 269-73
  17. Olkkola KT, Backman JT, Neuvonen PJ "Midazolam should be avoided in patients receiving the systemic antimycotics ketoconazole or itraconazole." Clin Pharmacol Ther 55 (1994): 481-5
  18. Greenblatt DJ, Wright CE, vonMoltke LL, Harmatz JS, Ehrenberg BL, Harrel LM, Corbett K, Counihan M, Tobias S, Shader RI "Ketoconazole inhibition of triazolam and alprazolam clearance: Differential kinetic and dynamic consequences." Clin Pharmacol Ther 64 (1998): 237-47
  19. Ahonen J, Olkkola KT, Neuvonen PJ "Lack of effect of antimycotic itraconazole on the pharmacokinetics or pharmacodynamics of temazepam." Ther Drug Monit 18 (1996): 124-7
  20. Ahonen J, Olkkola KT, Neuvonen PJ "Effect of itraconazole and terbinafine on the pharmacokinetics and pharmacodynamics of midazolam in healthy volunteers." Br J Clin Pharmacol 40 (1995): 270-2
  21. Varhe A, Olkkola KT, Neuvonen PJ "Fluconazole, but not terbinafine, enhances the effects of triazolam by inhibiting its metabolism." Br J Clin Pharmacol 41 (1996): 319-23
View all 21 references

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Drug and food interactions

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. "Product Information. Sporanox oral solution (itraconazole)." Janssen Pharmaceutica, Titusville, NJ.
  2. 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
  3. "Product Information. Sporanox (itraconazole)." Janssen Pharmaceutica, Titusville, NJ.
  4. 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
  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. 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
  7. 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
  8. 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
  9. 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
  10. Katz HI "Drug interactions of the newer oral antifungal agents." Br J Dermatol 141 (1999): 26-32
View all 10 references

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Moderate

ALPRAZolam food

Applies to: Xanax (alprazolam)

GENERALLY AVOID: The pharmacologic activity of oral midazolam, triazolam, and alprazolam may be increased if taken after drinking grapefruit juice. The proposed mechanism is CYP450 3A4 enzyme inhibition. In addition, acute alcohol ingestion may potentiate CNS depression and other CNS effects of many benzodiazepines. Tolerance may develop with chronic ethanol use. The mechanism may be decreased clearance of the benzodiazepines because of CYP450 hepatic enzyme inhibition. Also, it has been suggested that the cognitive deficits induced by benzodiazepines may be increased in patients who chronically consume large amounts of alcohol.

MANAGEMENT: The manufacturer recommends that grapefruit juice should not be taken with oral midazolam. Patients taking triazolam or alprazolam should be monitored for excessive sedation. Alternatively, the patient could consume orange juice which does not interact with these drugs. Patients should be advised to avoid alcohol during benzodiazepine therapy.

References

  1. Hukkinen SK, Varhe A, Olkkola KT, Neuvonen PJ "Plasma concentrations of triazolam are increased by concomitant ingestion of grapefruit juice." Clin Pharmacol Ther 58 (1995): 127-31
  2. Kupferschmidt HHT, Ha HR, Ziegler WH, Meier PJ, Krahenbuhl S "Interaction between grapefruit juice and midazolam in humans." Clin Pharmacol Ther 58 (1995): 20-8
  3. 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
  4. "Product Information. Valium (diazepam)." Roche Laboratories, Nutley, NJ.
  5. "Product Information. Xanax (alprazolam)." Pharmacia and Upjohn, Kalamazoo, MI.
  6. "Grapefruit juice interactions with drugs." Med Lett Drugs Ther 37 (1995): 73-4
  7. "Product Information. Halcion (triazolam)." Pharmacia and Upjohn, Kalamazoo, MI.
View all 7 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.

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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