Potential interactions affecting agomelatine: Agomelatine is metabolised mainly by cytochrome P450 1A2 (CYP1A2) (90%) and by CYP2C9/19 (10%). Medicinal products that interact with these isoenzymes may decrease or increase the bioavailability of agomelatine.
Fluvoxamine, a potent CYP1A2 and moderate CYP2C9 inhibitor markedly inhibits the metabolism of agomelatine resulting in a 60-fold (range 12-412) increase of agomelatine exposure.
Consequently, co-administration of Valdoxan with potent CYP1A2 inhibitors (e.g. fluvoxamine, ciprofloxacin) is contraindicated.
Combination of agomelatine with oestrogens (moderate CYP1A2 inhibitors) results in a several fold increased exposure of agomelatine. While there was no specific safety signal in the 800 patients treated in combination with oestrogens, caution should be exercised when prescribing agomelatine with other moderate CYP1A2 inhibitors (e.g. propranolol, enoxacin) until more experience has been gained (see Precautions).
Rifampicin an inducer of all three cytochromes involved in the metabolism of agomelatine may decrease the bioavailability of agomelatine.
Smoking induces CYP1A2 and has been shown to decrease the bioavailability of agomelatine, especially in heavy smokers (≥ 15 cigarettes/day) (see Pharmacology: Pharmacokinetics under Actions).
Potential for agomelatine to affect other medicinal products: In vivo, agomelatine does not induce CYP450 isoenzymes. Agomelatine inhibits neither CYP1A2 in vivo nor the other CYP450 in vitro. Therefore, agomelatine will not modify exposure to medicinal products metabolised by CYP 450.
Other medicinal products: No evidence of pharmacokinetic or pharmacodynamic interaction with medicinal products which could be prescribed concomitantly with Valdoxan in the target population was found in phase I clinical trials: benzodiazepines, lithium, paroxetine, fluconazole and theophylline.
Alcohol: The combination of agomelatine and alcohol is not advisable.
Electroconvulsive therapy (ECT): There is no experience of concurrent use of agomelatine with ECT. Animal studies have not shown proconvulsant properties (see Pharmacology: Toxicology: Preclinical safety data under Actions). Therefore, clinical consequences of ECT performed concomitantly with agomelatine treatment are considered to be unlikely.
Paediatric population: Interaction studies have only been performed in adults.