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Drug Interactions between alprazolam and Clotrimazole Troche

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

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Interactions between your drugs

Moderate

ALPRAZolam clotrimazole

Applies to: alprazolam and Clotrimazole Troche (clotrimazole)

GENERALLY AVOID: Coadministration with potent inhibitors of CYP450 3A4 including azole antifungal agents may significantly increase the plasma concentrations of benzodiazepines that are primarily metabolized by the isoenzyme. In pharmacokinetic studies, itraconazole (200 mg/day) and ketoconazole (400 mg/day) individually increased the systemic exposure (AUC) of a single 0.25 mg oral dose of triazolam and a 7.5 mg oral dose of midazolam by more than 22-fold and 10-fold, respectively, compared to placebo. The AUC of a single 2 mg IV dose of midazolam increased 5-fold after pretreatment with ketoconazole. Itraconazole and ketoconazole increased the AUC of alprazolam (0.8 and 1 mg single oral dose) 2.5- and 4-fold, respectively, compared to placebo. Fluconazole, a weaker CYP450 3A4 inhibitor, increased the AUC of a single 0.25 mg oral dose of triazolam by 1.6-, 2.1- and 4.4-fold at dosages of 50 mg, 100 mg and 200 mg once a day, respectively, relative to placebo. A single oral dose of fluconazole 150 mg plus midazolam 10 mg resulted in only modest increases in midazolam plasma concentrations and pharmacologic effects. Overall, pharmacodynamic changes associated with the interaction include increased and prolonged sedation, enhanced benzodiazepine-related EEG effects, and increased impairment of psychomotor performance. The interaction has not been studied with clotrimazole troches or miconazole buccal tablets. Although systemic absorption following mucous membrane exposure is limited, the potential for interaction with drugs metabolized by CYP450 3A4 such as triazolam, midazolam, and alprazolam cannot be ruled out.

MANAGEMENT: Given the potential for significant interaction, the concomitant use of triazolam with clotrimazole or miconazole mucous membrane preparations should be avoided if possible. The same precaution probably applies also to oral midazolam and high dosages of intravenous midazolam. Caution is advised during coadministration with alprazolam. Patients should be monitored for potentially excessive or prolonged CNS and respiratory depression if these agents are used together. Alternatively, benzodiazepines that are not metabolized by CYP450 3A4 (e.g., lorazepam, oxazepam, temazepam) may be considered in patients requiring treatment with azole antifungal agents.

References

  1. Brown MW, Maldonado AL, Meredith CG, Speeg KV (1985) "Effect of ketoconazole on hepatic oxidative drug metabolism." Clin Pharmacol Ther, 37, p. 290-7
  2. (2002) "Product Information. Xanax (alprazolam)." Pharmacia and Upjohn
  3. (2001) "Product Information. Halcion (triazolam)." Pharmacia and Upjohn
  4. Olkkola KT, Backman JT, Neuvonen PJ (1994) "Midazolam should be avoided in patients receiving the systemic antimycotics ketoconazole or itraconazole." Clin Pharmacol Ther, 55, p. 481-5
  5. Wrighton SA, Ring BJ (1994) "Inhibition of human CYP3A catalyzed 1'-hydroxy midazolam formation by ketoconazole, nifedipine, erythromycin, cimetidine, and nizatidine." Pharm Res, 11, p. 921-4
  6. Vonmoltke LL, Greenblatt DJ, Cotreaubibbo MM, Harmatz JS, Shader RI (1994) "Inhibitors of alprazolam metabolism in vitro: effect of serotonin-reuptake-inhibitor antidepressants, ketoconazole and quinidine." Br J Clin Pharmacol, 38, p. 23-31
  7. Varhe A, Olkkola KT, Neuvonen PJ (1994) "Oral triazolam is potentially hazardous to patients receiving systemic antimycotics ketoconazole or itraconazole." Clin Pharmacol Ther, 56, p. 601-7
  8. Greenblatt DJ, Vonmoltke LL, Harmatz JS, Harrel LM, Tobias S, Shader RI, Wright CE (1995) "Interaction of triazolam and ketoconazole." Lancet, 345, p. 191
  9. Ahonen J, Olkkola KT, Neuvonen PJ (1995) "Effect of itraconazole and terbinafine on the pharmacokinetics and pharmacodynamics of midazolam in healthy volunteers." Br J Clin Pharmacol, 40, p. 270-2
  10. Vanakoski J, Mattila MJ, Vainio P, Idanpaanheikkila JJ, Tornwall M (1995) "150 mg fluconazole does not substantially increase the effects of 10 mg midazolam or the plasma midazolam concentrations in healthy subjects." Int J Clin Pharmacol Ther, 33, p. 518-23
  11. Ahonen J, Olkkola KT, Neuvonen PJ (1996) "Lack of effect of antimycotic itraconazole on the pharmacokinetics or pharmacodynamics of temazepam." Ther Drug Monit, 18, p. 124-7
  12. Varhe A, Olkkola KT, Neuvonen PJ (1996) "Fluconazole, but not terbinafine, enhances the effects of triazolam by inhibiting its metabolism." Br J Clin Pharmacol, 41, p. 319-23
  13. Neuvonen PJ, Varhe A, Olkkola KT (1996) "The effect of ingestion time interval on the interaction between itraconazole and triazolam." Clin Pharmacol Ther, 60, p. 326-31
  14. Vonmoltke LL, Greenblatt DJ, Schmider J, Duan SX, Wright CE, Harmatz JS, Shader RI (1996) "Midazolam hydroxylation by human liver microsomes in vitro: inhibition by fluoxetine, norfluoxetine, and by azole antifungal agents." J Clin Pharmacol, 36, p. 783-91
  15. Varhe A, Olkkola KT, Neuvonen PJ (1996) "Effect of fluconazole dose on the extent of fluconazole-triazolam interaction." Br J Clin Pharmacol, 42, p. 465-70
  16. Backman JT, Kivisto KT, Olkkola KT, Neuvonen PJ (1998) "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, p. 53-8
  17. Greenblatt DJ, Wright CE, vonMoltke LL, Harmatz JS, Ehrenberg BL, Harrel LM, Corbett K, Counihan M, Tobias S, Shader RI (1998) "Ketoconazole inhibition of triazolam and alprazolam clearance: Differential kinetic and dynamic consequences." Clin Pharmacol Ther, 64, p. 237-47
  18. Yasui N, Kondo T, Otani K, Furukori H, Kaneko S, Ohkubo T, Nagasaki T, Sugawara K (1998) "Effect of itraconazole on the single oral dose pharmacokinetics and pharmacodynamics of alprazolam." Psychopharmacology, 139, p. 269-73
  19. Tsunoda SM, Velez RL, vonMoltke LL, Greenblatt DJ (1999) "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, p. 461-71
  20. Dresser GK, Spence JD, Bailey DG (2000) "Pharmacokinetic-pharmacodynamic consequences and clinical relevance of cytochrome P450 3A4 inhibition." Clin Pharmacokinet, 38, p. 41-57
  21. (2010) "Product Information. ORAVIG (miconazole)." Strativa Pharmaceuticals, a Division of Par Pharmaceuticals, Inc.
View all 21 references

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Drug and food interactions

Moderate

ALPRAZolam food

Applies to: 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. (2002) "Product Information. Xanax (alprazolam)." Pharmacia and Upjohn
  2. (2002) "Product Information. Valium (diazepam)." Roche Laboratories
  3. (2001) "Product Information. Halcion (triazolam)." Pharmacia and Upjohn
  4. (1995) "Grapefruit juice interactions with drugs." Med Lett Drugs Ther, 37, p. 73-4
  5. Kupferschmidt HHT, Ha HR, Ziegler WH, Meier PJ, Krahenbuhl S (1995) "Interaction between grapefruit juice and midazolam in humans." Clin Pharmacol Ther, 58, p. 20-8
  6. Hukkinen SK, Varhe A, Olkkola KT, Neuvonen PJ (1995) "Plasma concentrations of triazolam are increased by concomitant ingestion of grapefruit juice." Clin Pharmacol Ther, 58, p. 127-31
  7. 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 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.

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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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