Agomelatine × Ciprofloxacin

The liver breaks down agomelatine mainly through the enzyme CYP1A2, which handles 90% of its metabolism. The remaining 10% goes through the enzymes CYP2C9 and CYP2C19. Ciprofloxacin inhibits CYP1A2, but there are no clinical data on this exact pair. The closest guide is fluvoxamine, a strong CYP1A2 inhibitor, which raised agomelatine exposure 60-fold (range 12 to 412). The ciprofloxacin label expects a similar effect. The agomelatine label lists ciprofloxacin next to fluvoxamine as a strong CYP1A2 inhibitor, while the ciprofloxacin label calls it a moderate one. Both drugs can damage the liver: hepatitis and liver failure have been reported with agomelatine, and liver necrosis with ciprofloxacin.

Common adverse effects of agomelatine include headache, dizziness, drowsiness, nausea, anxiety and raised levels of the liver enzymes alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Reported signs of agomelatine overdose include upper abdominal (epigastric) pain, drowsiness, tiredness, agitation, anxiety, tension, dizziness, cyanosis and general malaise. With agomelatine, liver injury mostly appears in the first months of treatment. It shows as dark urine, pale stools, yellow skin or eyes, pain in the upper right abdomen and sudden, unexplained, prolonged fatigue. The ciprofloxacin label adds loss of appetite, itching and abdominal tenderness to the signs of liver disease.

The combination is contraindicated. The agomelatine label forbids use with strong inhibitors of the enzyme CYP1A2 and names ciprofloxacin (agomelatine label, European Medicines Agency, EMA, and Spanish Agency of Medicines and Medical Devices, AEMPS). Do not take ciprofloxacin and agomelatine at the same time. The labels give no waiting period for switching from one drug to the other. If the two have been taken together, monitor the patient closely for signs of agomelatine overdose (ciprofloxacin label, AEMPS). There is no specific antidote for agomelatine: treat the symptoms and monitor the patient, preferably in a specialised setting (agomelatine label, EMA). Both drugs can damage the liver, and the agomelatine label asks for caution and close follow-up when it is combined with such drugs (agomelatine label, EMA). During agomelatine treatment, check liver function before the start, at about 3, 6, 12 and 24 weeks and then when clinically indicated. Repeat the tests within 48 hours if transaminases rise (agomelatine label, EMA). Stop agomelatine at once if signs of liver injury appear or transaminases exceed 3 times the upper limit of normal (agomelatine label, EMA). Stop ciprofloxacin at any sign of liver disease (ciprofloxacin label, AEMPS).