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Drug Interactions between Dolophine and miconazole

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

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Interactions between your drugs

Moderate

methadone miconazole

Applies to: Dolophine (methadone) and miconazole

MONITOR: Coadministration with fluconazole, voriconazole, or other azole antifungal agents may increase the serum concentrations of methadone. The mechanism is inhibition of methadone metabolism via CYP450 2C9 and/or 3A4. In a study of volunteers receiving methadone maintenance therapy, mean methadone peak serum concentration (Cmax), systemic exposure (AUC) and trough serum concentration (Cmin) increased by 27%, 35% and 48%, respectively, relative to baseline in the group treated concomitantly with fluconazole 200 mg/day for 14 days. No alterations in methadone pharmacokinetics were reported in the placebo group. In another study involving subjects on methadone maintenance (30 to 100 mg daily), repeat dosing of voriconazole twice daily for 5 days increased the Cmax and AUC of the pharmacologically active R(+) enantiomer of methadone by 31% and 47%, respectively. The Cmax and AUC of the S(-) enantiomer increased by 65% and 103%, respectively. Although significant adverse effects were not reported in the studies, high dosages and serum levels of methadone have been associated with QT interval prolongation and torsades de pointes arrhythmia. Respiratory depression has also been described in a cancer patient treated with methadone 2 days following initiation of intravenous fluconazole (100 mg once a day) therapy. Naloxone was necessary to reverse the effects.

MANAGEMENT: Caution is advised if methadone must be used in combination with fluconazole, voriconazole, or other azole antifungal agents. Pharmacologic response to methadone should be closely monitored and the dosage adjusted accordingly, particularly following initiation or discontinuation of azole therapy in patients who are stabilized on their methadone regimen. Patients should be advised to report excessive drowsiness, nausea, or asthenia to their physician, and to seek medical attention if they experience symptoms that could indicate the occurrence of torsades de pointes such as dizziness, palpitations, irregular heartbeat, shortness of breath, or syncope.

References

  1. Harder S, Thurmann P (1996) "Clinically important drug interactions with anticoagulants: an update." Clin Pharmacokinet, 30, p. 416-44
  2. Iribarne C, Berthou F, Baird S, Dreano Y, Picart D, Bail JP, Beaune P, Menez JF (1996) "Involvement of cytochrome P450 3A4 enzyme in the N-demethylation of methadone in human liver microsomes." Chem Res Toxicol, 9, p. 365-73
  3. Cobb MN, Desai J, Brown LS Jr, Zannikos PN, Rainey PM (1998) "The effect of fluconazole on the clinical pharmacokinetics of methadone." Clin Pharmacol Ther, 63, p. 655-62
  4. Oda Y, Kharasch ED (2001) "Metabolism of methadone and levo-alpha-acetylmethadol (LAAM) by human intestinal cytochrome P450 3A4 (CYP3A4): potential contribution of intestinal metabolism to presystemic clearance and bioactivation." J Pharmacol Exp Ther, 298, p. 1021-32
  5. (2002) "Product Information. VFEND (voriconazole)." Pfizer U.S. Pharmaceuticals
  6. Zhang W, Ramamoorthy Y, Kilicarslan T, Nolte H, Tyndale RF (2002) "Inhibition of cytochromes P450 by antifungal imidazole derivatives." Drug Metab Dispos, 30, p. 314-8
  7. Tarumi Y, Pereira J, Watanabe S (2002) "Methadone and fluconazole: respiratory depression by drug interaction." J Pain Symptom Manage, 23, p. 148-53
  8. Krantz MJ, Lewkowiez L, Hays H, et al. (2002) "Torsade de pointes associated with very-high-dose methadone." Ann Intern Med, 137, p. 501-4
  9. Walker PW, Klein D, Kasza L (2003) "High dose methadone and ventricular arrhythmias: a report of three cases." Pain, 103, p. 321-4
  10. Krantz MJ, Kutinsky IB, Robertson AD, Mehler PS (2003) "Dose-related effects of methadone on QT prolongation in a series of patients with torsade de pointes." Pharmacotherapy, 23, p. 802-5
  11. De Bels D, Staroukine M, Devriendt J (2003) "Torsades de pointes due to methadone." Ann Intern Med, 139, E156
  12. Krantz MJ, Mehler PS (2003) "Synthetic opioids and QT prolongation." Arch Intern Med, 163, 1615; author reply 1615
  13. Sala M, Anguera I, Cervantes M (2003) "Torsade de pointes due to methadone." Ann Intern Med, 139, W64
  14. Mokwe EO, Ositadinma O (2003) "Torsade de pointes due to methadone." Ann Intern Med, 139, W64
  15. Gil M, Sala M, Anguera I, et al. (2003) "QT prolongation and Torsades de Pointes in patients infected with human immunodeficiency virus and treated with methadone." Am J Cardiol, 92, p. 995-7
  16. Foster DJ, Somogyi AA, Bochner F (1999) "Methadone N-demethylation in human liver microsomes: lack of stereoselectivity and involvement of CYP3A4." Br J Clin Pharmacol, 47, p. 403-12
  17. Ehret GB, Desmeules JA, Broers B (2007) "Methadone-associated long QT syndrome: improving pharmacotherapy for dependence on illegal opioids and lessons learned for pharmacology." Expert Opin Drug Saf, 6, p. 289-303
  18. Moody DE, Alburges ME, Parker RJ, Collings JM, Strong JM (1997) "The involvement of cytochrome P450 3A4 in the N-demethylation of L-alpha-acetylmethadol (LAAM), norLAAM, and methadone." Drug Metab Dispos, 25, p. 1347-53
View all 18 references

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Drug and food interactions

Moderate

methadone food

Applies to: Dolophine (methadone)

GENERALLY AVOID: Coadministration with grapefruit juice may increase the plasma concentrations of methadone. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruits. In 8 study subjects stabilized on methadone maintenance treatment, ingestion of regular strength grapefruit juice (200 mL one-half hour before and 200 mL simultaneously with the daily methadone dose) for five days resulted in an approximately 17% mean increase in methadone peak plasma concentration (Cmax) and systemic exposure (AUC) and a 14% mean decrease in apparent clearance for both the R(+) and S(-) enantiomers. Grapefruit juice did not affect the time to peak level (Tmax), terminal half-life, or apparent volume of distribution of methadone. No signs or symptoms of methadone toxicity or changes in intensity of withdrawal symptoms were reported in the study.

MANAGEMENT: Given the interindividual variability in the pharmacokinetics of methadone, a more significant interaction with grapefruit juice in certain patients cannot be ruled out. Patients treated with methadone should preferably avoid or limit the consumption of grapefruit juice, particularly during the induction of maintenance treatment.

References

  1. Iribarne C, Berthou F, Baird S, Dreano Y, Picart D, Bail JP, Beaune P, Menez JF (1996) "Involvement of cytochrome P450 3A4 enzyme in the N-demethylation of methadone in human liver microsomes." Chem Res Toxicol, 9, p. 365-73
  2. Oda Y, Kharasch ED (2001) "Metabolism of methadone and levo-alpha-acetylmethadol (LAAM) by human intestinal cytochrome P450 3A4 (CYP3A4): potential contribution of intestinal metabolism to presystemic clearance and bioactivation." J Pharmacol Exp Ther, 298, p. 1021-32
  3. Benmebarek M, Devaud C, Gex-Fabry M, et al. (2004) "Effects of grapefruit juice on the pharmacokinetics of the enantiomers of methadone." Clin Pharmacol Ther, 76, p. 55-63
  4. Foster DJ, Somogyi AA, Bochner F (1999) "Methadone N-demethylation in human liver microsomes: lack of stereoselectivity and involvement of CYP3A4." Br J Clin Pharmacol, 47, p. 403-12
View all 4 references

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Moderate

methadone food

Applies to: Dolophine (methadone)

GENERALLY AVOID: Ethanol may potentiate the central nervous system (CNS) depressant effects of opioid analgesics. Concomitant use may result in additive CNS depression and impairment of judgment, thinking, and psychomotor skills. In more severe cases, hypotension, respiratory depression, profound sedation, coma, or even death may occur.

MANAGEMENT: Concomitant use of opioid analgesics with ethanol should be avoided.

References

  1. Linnoila M, Hakkinen S (1974) "Effects of diazepam and codeine, alone and in combination with alcohol, on simulated driving." Clin Pharmacol Ther, 15, p. 368-73
  2. Sturner WQ, Garriott JC (1973) "Deaths involving propoxyphene: a study of 41 cases over a two-year period." JAMA, 223, p. 1125-30
  3. Girre C, Hirschhorn M, Bertaux L, et al. (1991) "Enhancement of propoxyphene bioavailability by ethanol: relation to psychomotor and cognitive function in healthy volunteers." Eur J Clin Pharmacol, 41, p. 147-52
  4. Levine B, Saady J, Fierro M, Valentour J (1984) "A hydromorphone and ethanol fatality." J Forensic Sci, 29, p. 655-9
  5. Sellers EM, Hamilton CA, Kaplan HL, Degani NC, Foltz RL (1985) "Pharmacokinetic interaction of propoxyphene with ethanol." Br J Clin Pharmacol, 19, p. 398-401
  6. Carson DJ (1977) "Fatal dextropropoxyphene poisoning in Northern Ireland. Review of 30 cases." Lancet, 1, p. 894-7
  7. Rosser WW (1980) "The interaction of propoxyphene with other drugs." Can Med Assoc J, 122, p. 149-50
  8. Edwards C, Gard PR, Handley SL, Hunter M, Whittington RM (1982) "Distalgesic and ethanol-impaired function." Lancet, 2, p. 384
  9. Kiplinger GF, Sokol G, Rodda BE (1974) "Effect of combined alcohol and propoxyphene on human performance." Arch Int Pharmacodyn Ther, 212, p. 175-80
View all 9 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.

Further information

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