Drug interactions between Methadose and Prozac

methadone ↔ fluoxetine

Applies to:Methadose (methadone) and Prozac (fluoxetine)

MONITOR: 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.

MONITOR: Theoretical concerns exist that fluoxetine may have additive adverse cardiovascular effects in combination with other drugs such as methadone that are known to prolong the QT interval of the electrocardiogram. In some experimental models, fluoxetine and its metabolite norfluoxetine have been found to inhibit hERG-encoded cardiac potassium channels responsible for the rapid delayed rectifier K+ current (IKr)--an action that is considered a predictor of drug-induced QT prolongation. More recently, an indirect effect on IKr activity via selective disruption of hERG channel protein trafficking to cell surface membrane has also been identified. However, QT prolongation has very rarely been reported with fluoxetine in the absence of overdose or confounding factors such as congenital long QT syndrome or concomitant use of agents with known cardiotoxic effects. QT prolongation was not observed in clinical trials or in studies of healthy volunteers who were administered fluoxetine for 6 to 8 weeks. Large epidemiological controlled studies have also failed to identify an increased risk of sudden cardiac death in users of selective serotonin reuptake inhibitors. In general, the risk of an individual agent or a combination of agents causing ventricular arrhythmia in association with QT prolongation is largely unpredictable but may be increased by certain underlying risk factors such as congenital long QT syndrome, cardiac disease, and electrolyte disturbances (e.g., hypokalemia, hypomagnesemia). In addition, the extent of drug-induced QT prolongation is dependent on the particular drug(s) involved and dosage(s) of the drug(s).

MANAGEMENT: Until more data are available, it may be appropriate to monitor patients more closely during concomitant therapy of fluoxetine and methadone. The possibility of prolonged and/or increased pharmacologic effects of methadone, such as central nervous system and respiratory depression, should be considered. 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 torsade de pointes such as dizziness, palpitations, or syncope.