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Drug Interactions between Duo-Cyp and fluconazole

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

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Interactions between your drugs

Moderate

fluconazole estradiol

Applies to: fluconazole and Duo-Cyp (estradiol / testosterone)

MONITOR: Azole antifungal agents may increase the plasma concentrations of estrogens and progestins. The mechanism is decreased clearance of the hormones due to inhibition of CYP450 3A4 activity by azole antifungals. Coadministration of voriconazole (200 mg every 12 hours) and an oral contraceptive containing 35 mcg of ethinyl estradiol and 1 mg of norethindrone increased the steady-state peak plasma concentration (Cmax) and area under the concentration-time curve (AUC) of ethinyl estradiol by an average of 36% and 61%, respectively, and Cmax and AUC of norethindrone by 15% and 53%, respectively, in healthy volunteers. Fluconazole doses of 150 mg and 200 mg have also been shown to increase the serum concentrations of ethinyl estradiol and levonorgestrel in healthy women receiving low-dose oral contraceptives, while single and multiple doses of fluconazole 50 mg had no significant effect on the pharmacokinetics of a high-dose oral contraceptive containing 150 mcg ethinyl estradiol and norgestrel 300 mcg. Ironically, there have been isolated reports of breakthrough bleeding and unintended pregnancy during use of oral contraceptives with itraconazole, which would suggest decreased rather than increased effect of the contraceptives. However, the association to itraconazole is questionable.

MANAGEMENT: During concomitant therapy with azole antifungal agents, patients should be observed for increased or altered pharmacologic response to estrogens and progestins, and dosage(s) adjusted accordingly as necessary.

References

  1. Lazar JD, Wilner KD (1990) "Drug interactions with fluconazole." Rev Infect Dis, 12 Suppl 3, s327-33
  2. Pillans PI, Sparrow MJ (1993) "Pregnancy associated with a combined oral contraceptive and itraconazole." N Z Med J, 106, p. 436
  3. Devenport MH, Crook D, Wynn V, Lees LJ (1989) "Metabolic effects of low-dose fluconazole in healthy female users and non-users of oral contraceptives." Br J Clin Pharmacol, 27, p. 851-9
  4. Sinofsky FE, Pasquale SA (1998) "The effect of fluconazole on circulating ethinyl estradiol levels in women taking oral contraceptives." Am J Obstet Gynecol, 178, p. 300-4
  5. Weisberg E (1999) "Interactions between oral contraceptives and antifungals antibacterials - Is contraceptive failure the result?." Clin Pharmacokinet, 36, p. 309-13
  6. (2002) "Product Information. VFEND (voriconazole)." Pfizer U.S. Pharmaceuticals
View all 6 references

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Moderate

fluconazole testosterone

Applies to: fluconazole and Duo-Cyp (estradiol / testosterone)

MONITOR: Coadministration with fluconazole may increase the plasma concentrations of drugs that are substrates of CYP450 3A4. The mechanism is decreased clearance due to inhibition of CYP450 3A4-mediated metabolism by fluconazole, a moderate inhibitor of the isoenzyme. A 30% increase in serum carbamazepine has been observed during coadministration with fluconazole according to the product labeling. There have also been a few isolated case reports in the medical literature describing an approximate doubling of carbamazepine levels following the addition of fluconazole, resulting in toxicity. Other drugs metabolized by CYP450 3A4 whose plasma levels reportedly are increased by fluconazole include oral contraceptives (ethinyl estradiol and levonorgestrel), cyclosporine, tacrolimus, and cisapride. These interactions have usually been observed with higher dosages of fluconazole (200 mg/day or more).

MANAGEMENT: Caution is advised when fluconazole is used with medications that undergo metabolism by CYP450 3A4, particularly those with a narrow therapeutic range. Dosage adjustments as well as clinical and laboratory monitoring may be appropriate for some drugs whenever fluconazole is added to or withdrawn from therapy.

References

  1. Sugar AM, Saunders C, Idelson BA, Bernard DB (1989) "Interaction of fluconazole and cyclosporine." Ann Intern Med, 110, p. 844
  2. Canafax DM, Graves NM, Hilligoss DM, et al. (1991) "Interaction between cyclosporine and fluconazole in renal allograft recipients." Transplantation, 51, p. 1014-8
  3. Torregrosa V, De la Torre M, Campistol JM, et al. (1992) "Interaction of fluconazole with ciclosporin A." Nephron, 60, p. 125-6
  4. Barbara JA, Clarkson AR, LaBrooy J, et al. (1993) "Candida albicans arthritis in a renal allograft recipient with an interaction between cyclosporin and fluconazole." Nephrol Dial Transplant, 8, p. 263-6
  5. (2002) "Product Information. Diflucan (fluconazole)." Roerig Division
  6. Lopez-Gil JA (1993) "Fluconazole-cyclosporin interaction: a dose-dependent effect?" Ann Pharmacother, 27, p. 427-30
  7. Baciewicz AM, Baciewicz FA, Jr (1993) "Ketoconazole and fluconazole drug interactions." Arch Intern Med, 153, p. 1970-6
  8. Assan R, Fredj G, Larger E, Feutren G, Bismuth H (1994) "FK 506/fluconazole interaction enhances FK 506 nephrotoxicity." Diabete Metab, 20, p. 49-52
  9. Osowski CL, Dix SP, Lin LS, Mullins RE, Geller RB, Wingard JR (1996) "Evaluation of the drug interaction between intravenous high-dose fluconazole and cyclosporine or tacrolimus in bone marrow transplant patients." Transplantation, 61, p. 1268-72
  10. Bedford TA, Rowbotham DJ (1996) "Cisapride: drug interactions of clinical significance." Drug Saf, 15, p. 167-75
  11. Sinofsky FE, Pasquale SA (1998) "The effect of fluconazole on circulating ethinyl estradiol levels in women taking oral contraceptives." Am J Obstet Gynecol, 178, p. 300-4
  12. Nair DR, Morris HH (1999) "Potential fluconazole-induced carbamazepine toxicity." Ann Pharmacother, 33, p. 790-2
  13. Dresser GK, Spence JD, Bailey DG (2000) "Pharmacokinetic-pharmacodynamic consequences and clinical relevance of cytochrome P450 3A4 inhibition." Clin Pharmacokinet, 38, p. 41-57
  14. Michalets EL, Williams CR (2000) "Drug interactions with cisapride: clinical implications." Clin Pharmacokinet, 39, p. 49-75
  15. Hilbert J, Messig M, Kuye O, Friedman H (2001) "Evaluation of interaction between fluconazole and an oral contraceptive in healthy women." Obstet Gynecol, 98, p. 218-23
  16. Ulivelli M, Rubegni P, Nuti D, Bartalini S, Giannini F, Rossi S (2004) "Clinical evidence of fluconazole-induced carbamazepine toxicity." J Neurol, 251, p. 622-3
  17. Tsouli S, Maranis S, Kyritsis AP (2011) "Fluconazole-carbamazepine interaction in a patient with bipolar disorder." Psychiatry Clin Neurosci, 65, p. 112
  18. Finch CK, Green CA, Self TH (2002) "Fluconazole-carbamazepine interaction." South Med J, 95, p. 1099-100
View all 18 references

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Drug and food interactions

Minor

estradiol food

Applies to: Duo-Cyp (estradiol / testosterone)

Coadministration with grapefruit juice may increase the bioavailability of oral estrogens. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall induced by certain compounds present in grapefruits. In a small, randomized, crossover study, the administration of ethinyl estradiol with grapefruit juice (compared to herbal tea) increased peak plasma drug concentration (Cmax) by 37% and area under the concentration-time curve (AUC) by 28%. Based on these findings, grapefruit juice is unlikely to affect the overall safety profile of ethinyl estradiol. However, as with other drug interactions involving grapefruit juice, the pharmacokinetic alterations are subject to a high degree of interpatient variability. Also, the effect on other estrogens has not been studied.

References

  1. Weber A, Jager R, Borner A, et al. (1996) "Can grapefruit juice influence ethinyl estradiol bioavailability?" Contraception, 53, p. 41-7
  2. Schubert W, Eriksson U, Edgar B, Cullberg G, Hedner T (1995) "Flavonoids in grapefruit juice inhibit the in vitro hepatic metabolism of 17B-estradiol." Eur J Drug Metab Pharmacokinet, 20, p. 219-24

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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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