Interactions

Active ingredient Agomelatine interacts in the following cases:

Potent CYP1A2 inhibitors

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.

Moderate CYP1A2 inhibitors

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.

Severe or moderate renal impairment

No relevant modification in agomelatine pharmacokinetic parameters in patients with severe renal impairment has been observed. However, only limited clinical data on the use of agomelatine in depressed patients with severe or moderate renal impairment with major depressive episodes is available. Therefore, caution should be exercised when prescribing agomelatine to these patients.

Bipolar disorder, mania, hypomania

Agomelatine should be used with caution in patients with a history of bipolar disorder, mania or hypomania and should be discontinued if a patient develops manic symptoms.

Lactation

It is not known whether agomelatine/metabolites are excreted in human milk. Available pharmacodynamic/toxicological data in animals have shown excretion of agomelatine/metabolites in milk. A risk to the newborns/infants cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from agomelatine therapy taking into account the benefit of breast feeding for the child and the benefit of therapy for the woman.

Rifampicin

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

Effects on ability to drive and use machines

No studies on the effects on the ability to drive and use machines have been performed. However, considering that dizziness and somnolence are common adverse reactions patients should be cautioned about their ability to drive a car or operate machinery.

Smoking

Smoking induces CYP1A2 and has been shown to decrease the bioavailability of agomelatine, especially in heavy smokers (>15 cigarettes/day).

Pregnancy

There are no or limited amount of data (less than 300 pregnancy outcomes) from the use of agomelatine in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development. As a precautionary measure, it is preferable to avoid the use of agomelatine during pregnancy.

Nursing Mothers

It is not known whether agomelatine/metabolites are excreted in human milk. Available pharmacodynamic/toxicological data in animals have shown excretion of agomelatine/metabolites in milk. A risk to the newborns/infants cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from agomelatine therapy taking into account the benefit of breast feeding for the child and the benefit of therapy for the woman.

Carcinogenesis, Mutagenesis and Fertility

Fertility

Reproduction studies in the rat and the rabbit showed no effect of agomelatine on fertility.

Effects on Ability to Drive and Use Machines

Agomelatine has minor influence on the ability to drive and use machines. Considering that dizziness and somnolence are common adverse reactions, patients should be cautioned about their ability to drive or operate machines.