Duloxetine × Metronidazole

The metronidazole and duloxetine documents do not mention each other, neither the Spanish SmPCs nor the US Food and Drug Administration (FDA) labels. No kinetic pathway is described: duloxetine is cleared through CYP1A2 and CYP2D6 (duloxetine SmPC) and does not inhibit CYP2C9 or CYP3A (FDA duloxetine label), while the metronidazole SmPC lists interactions with warfarin, lithium, ciclosporin, phenytoin, 5-fluorouracil and busulfan but none with antidepressants. Metronidazole's own clearance is slowed by inhibitors of hepatic microsomal enzymes such as cimetidine (FDA metronidazole label), and duloxetine is not one of them. The documents give metronidazole no serotonergic activity, and the metronidazole warning about QT prolongation with QT-prolonging drugs does not apply to duloxetine: in the duloxetine SmPC approved by the European Medicines Agency (EMA) the rate-corrected QT interval of patients on duloxetine did not differ from placebo, and the FDA duloxetine label found no QT prolongation even at doses above the maximum. The only overlap is the liver: duloxetine has caused severe liver enzyme elevation, hepatitis and jaundice, and its SmPC asks for caution with other medicines associated with liver injury (EMA duloxetine SmPC). The metronidazole SmPC lists enzyme elevation, cholestatic or mixed hepatitis, hepatocellular damage and cases of liver failure among its adverse reactions and describes rapid, sometimes fatal hepatotoxicity in Cockayne syndrome.

The documents describe no symptoms specific to the interaction. Watch for the signs of liver injury that each document lists for its own drug: abdominal pain, enlarged liver, rising transaminases, jaundice (US Food and Drug Administration (FDA) duloxetine label and European Medicines Agency (EMA) duloxetine SmPC), raised liver enzymes and hepatitis with jaundice (metronidazole SmPC, section 4.8). In Cockayne syndrome, liver failure with metronidazole has developed as early as 2 days after the start of treatment (FDA metronidazole label).

By the documents, neither drug needs a dose change because of the other: the metronidazole and duloxetine documents do not mention the pair and describe no kinetic interaction. The only instruction concerns the liver: duloxetine is used with caution in patients taking other medicines associated with liver injury (duloxetine SmPC approved by the European Medicines Agency, EMA), and metronidazole's own SmPC places it among such medicines (section 4.8). So during a combined course, watch for signs of liver injury, and if jaundice or other evidence of clinically significant liver dysfunction appears, stop duloxetine and do not resume it unless another cause is established (US Food and Drug Administration (FDA) duloxetine label). In Cockayne syndrome metronidazole is contraindicated (FDA metronidazole label); the Spanish metronidazole SmPC allows it only when benefit outweighs risk and no alternative exists, with liver function tests before, during and after treatment and withdrawal if values rise markedly. Duloxetine is contraindicated in liver disease causing hepatic impairment (EMA duloxetine SmPC), and that restriction applies regardless of metronidazole. No electrocardiogram is needed for the combination: by its own documents duloxetine does not prolong the QT interval.