Drug Interactions between amoxicillin / clarithromycin / vonoprazan and methadone

MONITOR CLOSELY: Methadone can cause dose-related prolongation of the QT interval. Coadministration with other agents that can prolong the QT interval 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 whether any of the patients had congenital long QT syndrome.

MONITOR CLOSELY: Coadministration with inhibitors of CYP450 3A4, 2B6, 2C19, 2C9, 2D6 and/or P-glycoprotein (P-gp) efflux transporter may increase the plasma concentrations of methadone, which is metabolized primarily by CYP450 3A4, 2B6, 2C19, and to a lesser extent by CYP450 2C9 and 2D6 and which is also a substrate of the P-gp efflux transporter. The possibility of prolonged and/or increased pharmacologic effects of methadone, such as central nervous system and respiratory depression should be considered, particularly when an inhibitor is added after a stable dose of methadone is achieved.

MANAGEMENT: Caution and close clinical monitoring for adverse effects associated with methadone are advised if concurrent use with a CYP450 3A4, 2B6, 2C19, 2C9, 2D6 and/or P-glycoprotein (P-gp) inhibitor that can also prolong the QT interval is required. Some authorities recommend against the concomitant use of methadone with drugs that can prolong the QT interval (UK). ECG monitoring should be considered. Respiratory depression, sedation and pharmacologic response to methadone should be closely monitored and the dosage adjusted accordingly, particularly following initiation or discontinuation of the CYP450 3A4, 2B6, 2C19, 2C9, 2D6 and/or P-gp inhibitor in patients who are stabilized on their methadone regimen. Patients should be advised to seek immediate 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.

MONITOR CLOSELY: Coadministration with inhibitors of CYP450 3A4, 2B6, 2C19, 2C9, 2D6 and/or P-glycoprotein (P-gp) efflux transporter may increase the plasma concentrations of methadone, which is metabolized primarily by CYP450 3A4, 2B6, 2C19, and to a lesser extent by CYP450 2C9 and 2D6 and which is also a substrate of the P-gp efflux transporter. The possibility of prolonged and/or increased pharmacologic effects of methadone, such as central nervous system and respiratory depression should be considered, particularly when an inhibitor is added after a stable dose of methadone is achieved. In addition, high dosages (particularly above 200 mg/day) and serum levels of methadone have been associated with QT interval prolongation and torsade de pointes arrhythmia.

MANAGEMENT: Caution and close clinical monitoring for adverse effects associated with methadone are advised if concurrent use with a CYP450 3A4, 2B6, 2C19, 2C9, 2D6 and/or P-glycoprotein (P-gp) inhibitor. ECG monitoring should be considered for patients on methadone with heart or liver disease; conduction abnormalities; electrolyte disturbances (i.e., hypokalemia, hypomagnesemia); concomitant use of drugs that may cause QT prolongation or electrolyte loss; or concomitant use of CYP450 3A4, 2B6, 2C19, 2C9, 2D6 and/or P-gp inhibitors. Respiratory depression, sedation and pharmacologic response to methadone should be closely monitored and the dosage adjusted accordingly, particularly following initiation or discontinuation of the CYP450 3A4, 2B6, 2C19, 2C9, 2D6 and/or P-gp inhibitors 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 immediate 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. If taking drugs that also cause CNS-depressant or orthostatic effects, patients should be made aware of the possibility of additive effects with methadone and counseled to avoid activities requiring mental alertness until they know how these agents affect them.

Although some in vitro data indicate synergism between macrolide antibiotics and penicillins, other in vitro data indicate antagonism. When these drugs are given together, neither has predictable therapeutic efficacy. Data are available for erythromycin, although theoretically this interaction could occur with any macrolide. Except for monitoring of the effectiveness of antibiotic therapy, no special precautions appear to be necessary.