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Drug Interactions between methadone and Prozac

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

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Interactions between your drugs

Major

methadone FLUoxetine

Applies to: methadone and Prozac (fluoxetine)

MONITOR CLOSELY: Methadone may cause dose-related prolongation of the QT interval. Theoretically, coadministration with other agents that can prolong the QT interval such as fluoxetine may result in additive effects and increased risk of ventricular arrhythmias including torsade de pointes and sudden death. High dosages of methadone alone have been associated with QT interval prolongation and torsade de pointes. In a retrospective study of 17 methadone-treated patients who developed torsade de pointes, the mean daily dose was approximately 400 mg (range 65 to 1000 mg) and the mean corrected QT (QTc) interval on presentation was 615 msec. The daily methadone dose correlated positively with the QTc interval. Fourteen patients had at least one predisposing risk factor for arrhythmia (hypokalemia, hypomagnesemia, concomitant use of a medication known to prolong the QT interval or inhibit the metabolism of methadone, and structural heart disease), but these were not predictive of QTc interval. It is not known if any of the patients had congenital long QT syndrome.

The clinical significance of any potential pharmacokinetic interaction between fluoxetine and methadone is unclear. Fluoxetine has demonstrated weak inhibitory effect on CYP450 3A4, the isoenzyme primarily responsible for the metabolism of methadone. In nine patients receiving methadone maintenance 30 to 100 mg/day, the addition of fluoxetine 20 mg/day for the treatment of affective disorders did not significantly alter the methadone plasma concentration-to-dose ratio for the group. Other studies of patients in methadone maintenance programs also reported no significant effect of fluoxetine on methadone plasma concentrations. However, fluoxetine is also a potent inhibitor of CYP450 2D6, which is thought to be a minor metabolic pathway for methadone. When plasma samples were assayed for the individual enantiomers of methadone, investigators found that fluoxetine 20 mg/day increased the plasma concentration-to-dose ratio of the pharmacologically active R(+) enantiomer by 33%, but had no significant effect on that of the inactive S(-) enantiomer or the racemate. The clinical relevance of this observation is unknown. In one case report, a 42-year-old woman who had been on long-term methadone 140 mg/day for pain developed profound sedation and respiratory depression during coadministration with ciprofloxacin and fluoxetine, and required treatment with naloxone 0.4 mg intramuscularly. The interaction was primarily attributed to ciprofloxacin, since the patient had experienced sedation on three previous occasions during concomitant use of ciprofloxacin and regained normal alertness each time after its discontinuation. Nevertheless, the apparent increase in severity of interaction during the final episode of ciprofloxacin exposure coincided with a replacement of venlafaxine with fluoxetine, which would suggest some involvement of fluoxetine.

MANAGEMENT: Caution is recommended during concomitant use of methadone and fluoxetine, particularly in the setting of chronic pain management or methadone maintenance for opioid dependency where high dosages may be employed. Patients should be advised to seek prompt medical attention if they experience symptoms that could indicate the occurrence of torsade de pointes such as dizziness, lightheadedness, fainting, palpitation, irregular heart rhythm, shortness of breath, or syncope. The possibility of prolonged and/or increased pharmacologic effects of methadone, such as central nervous system and respiratory depression, should be considered.

References

  1. Fisch C "Effect of fluoxetine on the electrocardiogram." J Clin Psychiatry 46 (1985): 42-4
  2. "Product Information. Prozac (fluoxetine)." Dista Products Company PROD (2001):
  3. Appleby M, Mbewu A, Clarke B "Fluoxetine and ventricular torsade - is there a link?" Int J Cardiol 49 (1995): 178-80
  4. Bertschy G, Eap CB, Powell K, Baumann P "Fluoxetine addition to methadone in addicts: pharmacokinetic aspects." Ther Drug Monit 18 (1996): 570-2
  5. Baker B, Dorian P, Sandor P, Shapiro C, Schell C, Mitchell J, Irvine MJ "Electrocardiographic effects of fluoxetine and doxepin in patients with major depressive disorder." J Clin Psychopharmacol 17 (1997): 15-21
  6. Iribarne C, Berthou F, Baird S, Dreano Y, Picart D, Bail JP, Beaune P, Menez JF "Involvement of cytochrome P450 3A4 enzyme in the N-demethylation of methadone in human liver microsomes." Chem Res Toxicol 9 (1996): 365-73
  7. Roose SP, Glassman AH, Attia E, et al. "Cardiovascular effects of fluoxetine in depressed patients with heart disease." Am J Psychiatry 155 (1998): 660-5
  8. Ravina T, Suarez MLR, MendezCastrillon J "Fluoxetine-induced QTU interval prolongation, T wave alternans and syncope." Int J Cardiol 65 (1998): 311-3
  9. Michalets EL, Smith LK, Van Tassel ED "Torsade de pointes resulting from the addition of droperidol to an existing cytochrome P450 drug interaction." Ann Pharmacother 32 (1998): 761-5
  10. Herrlin K, Segerdahl M, Gustafsson LL, Kalso E "Methadone, ciprofloxacin, and adverse drug reactions." Lancet 356 (2000): 2069-70
  11. Varriale P "Fluoxetine (Prozac) as a cause of QT prolongation." Arch Intern Med 161 (2001): 612
  12. Oda Y, Kharasch ED "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 (2001): 1021-32
  13. Thomas D, Gut B, Wendt-Nordahl G, Kiehn J "The antidepressant drug fluoxetine is an inhibitor of human ether-a-go-go-related gene (HERG) potassium channels." J Pharmacol Exp Ther 300 (2002): 543-8
  14. Abebe-Campino G, Offer D, Stahl B, Merlob P "Cardiac arrhythmia in a newborn infant associated with fluoxetine use during pregnancy." Ann Pharmacother 36 (2002): 533-4
  15. Viskin S, Justo D, Halkin A, Zeltser D "Long QT syndrome caused by noncardiac drugs." Prog Cardiovasc Dis 45 (2003): 415-27
  16. Nykamp DL, Blackmon CL, Schmidt PE, Roberson AG "QTc prolongation associated with combination therapy of levofloxacin, imipramine, and fluoxetine." Ann Pharmacother 39 (2005): 543-6
  17. Foster DJ, Somogyi AA, Bochner F "Methadone N-demethylation in human liver microsomes: lack of stereoselectivity and involvement of CYP3A4." Br J Clin Pharmacol 47 (1999): 403-12
  18. Wilting I, Smals OM, Holwerda NJ, Meyboom RH, De Bruin ML, Egberts TC "QTc prolongation and torsades de pointes in an elderly woman taking fluoxetine." Am J Psychiatry 163 (2006): 325
  19. Ehret GB, Voide C, Gex-Fabry M, et al. "Drug-Induced Long QT Syndrome in Injection Drug Users Receiving Methadone: High Frequency in Hospitalized Patients and Risk Factors." Arch Intern Med 166 (2006): 1280-7
  20. Pacher P, Kecskemeti V "Cardiovascular side effects of new antidepressants and antipsychotics: new drugs, old concerns?" Curr Pharm Des 10 (2004): 2463-75
  21. Alvarez PA, Pahissa J "QT Alterations in Psychopharmacology: Proven Candidates and Suspects." Curr Drug Saf 5 (2010): 97-104
  22. Upward JW, Edwards JG, Goldie A, Waller DG "Comparative effects of fluoxetine and amitriptyline on cardiac function." Br J Clin Pharmacol 26 (1988): 399-402
  23. Gintant GA, Limberis JT, McDermott JS, Wegner CD, Cox BF "The canine Purkinje fiber: an in vitro model system for acquired long QT syndrome and drug-induced arrhythmogenesis." J Cardiovasc Pharmacol 37 (2001): 607-18
  24. Moody DE, Alburges ME, Parker RJ, Collings JM, Strong JM "The involvement of cytochrome P450 3A4 in the N-demethylation of L-alpha-acetylmethadol (LAAM), norLAAM, and methadone." Drug Metab Dispos 25 (1997): 1347-53
  25. Buchanan Keller K, Lemberg L "Torsade." Am J Crit Care 17 (2008): 77-81
  26. Rajamani S, Eckhardt LL, Valdivia CR, et al. "Drug-induced long QT syndrome: hERG K+ channel block and disruption of protein trafficking by fluoxetine and norfluoxetine." Br J Pharmacol 149 (2006): 481-9
  27. Hancox JC, Mitcheson JS "Combined hERG channel inhibition and disruption of trafficking in drug-induced long QT syndrome by fluoxetine: a case-study in cardiac safety pharmacology." Br J Pharmacol 149 (2006): 457-9
  28. Cubeddu LX "Iatrogenic QT abnormalities and fatal arrhythmias: mechanisms and clinical significance." Curr Cardiol Rev 5 (2009): 166-76
  29. Dubnov G, Fogelman R, Merlob P "Prolonged QT interval in an infant of a fluoxetine treated mother." Arch Dis Child 90 (2005): 972-3
View all 29 references

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Drug and food interactions

Moderate

methadone food

Applies to: 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 "Involvement of cytochrome P450 3A4 enzyme in the N-demethylation of methadone in human liver microsomes." Chem Res Toxicol 9 (1996): 365-73
  2. Oda Y, Kharasch ED "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 (2001): 1021-32
  3. Benmebarek M, Devaud C, Gex-Fabry M, et al. "Effects of grapefruit juice on the pharmacokinetics of the enantiomers of methadone." Clin Pharmacol Ther 76 (2004): 55-63
  4. Foster DJ, Somogyi AA, Bochner F "Methadone N-demethylation in human liver microsomes: lack of stereoselectivity and involvement of CYP3A4." Br J Clin Pharmacol 47 (1999): 403-12
View all 4 references

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Moderate

FLUoxetine food

Applies to: Prozac (fluoxetine)

GENERALLY AVOID: Alcohol may potentiate some of the pharmacologic effects of CNS-active agents. Use in combination may result in additive central nervous system depression and/or impairment of judgment, thinking, and psychomotor skills.

MANAGEMENT: Patients receiving CNS-active agents should be warned of this interaction and advised to avoid or limit consumption of alcohol. Ambulatory patients should be counseled to avoid hazardous activities requiring complete mental alertness and motor coordination until they know how these agents affect them, and to notify their physician if they experience excessive or prolonged CNS effects that interfere with their normal activities.

References

  1. Warrington SJ, Ankier SI, Turner P "Evaluation of possible interactions between ethanol and trazodone or amitriptyline." Neuropsychobiology 15 (1986): 31-7
  2. Gilman AG, eds., Nies AS, Rall TW, Taylor P "Goodman and Gilman's the Pharmacological Basis of Therapeutics." New York, NY: Pergamon Press Inc. (1990):
  3. "Product Information. Fycompa (perampanel)." Eisai Inc (2012):
  4. "Product Information. Rexulti (brexpiprazole)." Otsuka American Pharmaceuticals Inc (2015):
View all 4 references

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Moderate

methadone food

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

Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.

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