Methadone × Ritonavir

Ritonavir inhibits CYP3A4 but at the same time speeds up other methadone elimination pathways, including glucuronidation. The net result is lower methadone exposure: in a study, methadone AUC fell by 36% (ritonavir label). This can bring on withdrawal symptoms.

Methadone levels usually fall, and a patient on maintenance therapy develops withdrawal signs: watery eyes, runny nose, sneezing, yawning. If the methadone dose was raised and ritonavir is later stopped, methadone levels can rise: drowsiness, slow shallow breathing. Methadone prolongs the QT interval on the ECG; marked prolongation can cause fainting and torsades de pointes.

The combination can be used with monitoring. After ritonavir is started, watch a patient on methadone closely for withdrawal signs and raise the methadone dose if needed, guided by clinical response (ritonavir and methadone labels). If ritonavir is stopped, watch for drowsiness and slowed breathing and consider lowering the methadone dose: the US methadone label (FDA) asks for this with any change in concomitant drugs that can raise methadone levels. The Spanish methadone SmPC lists CYP3A4 inhibitors, ritonavir among them, as a risk factor for QT prolongation. Record an ECG before methadone starts, two weeks later and before each dose increase. Low potassium, calcium or magnesium also raise the risk, so these patients need closer monitoring (methadone SmPC).