VALDOXAN

Treatment of major depressive episodes.

AGOMELATINE ZENTIVA is indicated in adults.

Potential interactions with agomelatine

Agomelatine is mainly metabolized by cytochrome P450 1A2 (CYP1A2) (90%) and CYP2C9/19 (10%). Drugs interacting with these isoenzymes may reduce or increase the bioavailability of agomelatine.

Fluvoxamine, a potent CYP1A2 inhibitor and moderate CYP2C9 inhibitor, causes significant inhibition of agomelatine metabolism, increasing plasma exposure to agomelatine by 60-fold (between 12 and 412).

Consequently, concomitant use of AGOMELATINE ZENTIVA and potent CYP1A2 inhibitors (for example: fluvoxamine, ciprofloxacin) is contraindicated.

The combination of agomelatine with estrogens (moderate CYP1A2 inhibitors) increases plasma exposure to agomelatine several-fold. Although no specific safety problem has been reported in the 800 patients treated in association with estrogens, agomelatine should be prescribed with caution when combined with other moderate CYP1A2 inhibitors (for example: propranolol, enoxacin) pending additional data (see section 4.4).

Rifampicin, an inducer of the three cytochromes involved in agomelatine metabolism, may decrease the bioavailability of agomelatine.

Tobacco induces CYP1A2 and decreases the bioavailability of agomelatine, particularly in heavy smokers (> 15 cigarettes / day) (see section 5.2).

Potential effect of agomelatine on other medicines

In vivo, agomelatine has no inducing effect on CYP450 isoenzymes. Agomelatine inhibits neither CYP1A2 in vivo nor other CYP450 in vitro. Consequently, agomelatine will not modify exposure to drugs metabolized by CYP450.

Other medicines

No sign of pharmacokinetic or pharmacodynamic interaction with medicines that may be prescribed with agomelatine in the target population was observed in phase I clinical trials: benzodiazepines, lithium, paroxetine, fluconazole and theophylline.

Alcohol

Alcohol consumption is not recommended during treatment with AGOMELATINE ZENTIVA.

Electroconvulsive therapy (ECT)

No data are available on the concomitant use of agomelatine with electroconvulsive therapy. Animal studies have not shown proconvulsant properties (see section 5.3). Consequently, the combination of agomelatine treatment and electroconvulsive therapy should not lead to clinical consequences.

Paediatric population

Interaction studies have only been performed in adults.

Pregnancy

There are no data or there is limited data (less than 300 pregnancies) on the use of agomélatine in pregnant women. Animal studies have not shown direct or indirect deleterious effects on gestation, embryonic or foetal development, parturition or post-natal development (see section 5.3). As a precaution, it is preferable to avoid using AGOMELATINE ZENTIVA during pregnancy.

Breastfeeding

The excretion of agomélatine and its metabolites in human breast milk is unknown. Pharmacodynamic and toxicology data in animals have shown the excretion of agomélatine and its metabolites in breast milk (see section 5.3). A risk to newborns or infants cannot be excluded. The decision to discontinue breastfeeding or to discontinue treatment with AGOMELATINE ZENTIVA should be made, taking into account the benefits of breastfeeding for the child and the treatment for the mother.

Fertility

Reproduction studies conducted in rats and rabbits have shown no effect of agomélatine on fertility (see section 5.3).

Agomelatine has a minor influence on the ability to drive vehicles and use machines.

Given that dizzy sensations and drowsiness are frequent adverse effects, patients should be warned in case of driving vehicles and using machines.