METHADONE IS METABOLISED IN THE LIVER PRIMARILY VIA THE CYTOCHROME P450 ISOENZYME CYP3A4; THE CYTOCHROMES CYP2D6, CYP2C9, CYP2C19, AND CYP1A2 ARE ALSO THOUGHT TO PLAY MINOR ROLES. CONSEQUENTLY, USE WITH OTHER DRUGS THAT INDUCE OR INHIBIT THESE ISOENZYMES MAY RESULT IN CHANGES IN PLASMA CONCENTRATIONS OF METHADONE AND, POSSIBLY ADVERSE EFFECTS. THERE IS A RISK OF CARDIAC EVENTS IN PATIENTS RECEIVING METHADONE WHO ARE ALSO TAKING DRUGS THAT AFFECT CARDIAC CONDUCTION OR ELECTROLYTE BALANCE. ALTHOUGH ANTI- RETROVIRAL DRUGS SUCH AS EFAVIRENZ, NELFINAVIR, NEVIRAPINE, RITONAVIR, AND LOPINAVIR+RITONAVIR COMBINATION ARE KNOWN TO INHIBIT CYPS, THEY ARE SHOWN TO REDUCE THE PLASMA LEVELS OF METHADONE, POSSIBLY DUE TO THEIR CYP INDUCTION ACTIVITY. THEREFORE, DRUGS ADMINISTERED CONCOMITANTLY WITH METHADONE SHOULD BE EVALUATED FOR INTERACTION POTENTIAL; CLINICIANS ARE ADVISED TO EVALUATE INDIVIDUAL RESPONSE TO DRUG THERAPY. PATIENTS RECEIVING OTHER OPIOID ANALGESICS, GENERAL ANESTHETICS, PHENOTHIAZINES OR OTHER TRANQUILIZERS, SEDATIVES, HYPNOTICS, OR OTHER CNS DEPRESSANTS (INCLUDING ALCOHOL) CONCOMITANTLY WITH METHADONE MAY EXPERIENCE RESPIRATORY DEPRESSION, HYPOTENSION, PROFOUND SEDATION, OR COMA.
HAVE ADDITIVE EFFECTS WHEN USED IN CONJUNCTION WITH ALCOHOL, OTHER OPIOIDS, OR ILLICIT DRUGS THAT CAUSE CNS DEPRESSION LIKE BENZODIAZEPINE.