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 agomelatine 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.

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.

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.

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).

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.

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.

Fertility

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

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.

Summary of the safety profile

Adverse reactions were usually mild or moderate and occurred within the first two weeks of treatment. The most common adverse reactions were headache, nausea and dizziness. These adverse reactions were usually transient and did not generally lead to cessation of therapy.

List of adverse reactions

The below list gives the adverse reactions observed from placebo-controlled and active-controlled clinical trials.

Adverse reactions are listed below using the following convention: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000), not known (cannot be estimated from the available data). The frequencies have not been corrected for placebo.

Psychiatric disorders

Common: Anxiety, Abnormal dreams*

Uncommon: Suicidal thoughts or behaviour, Agitation and related symptoms* (such as irritability and restlessness), Aggression* Nightmares* Mania/hypomania* .These symptoms may also be due to the underlying disease. Confusional state*

Rare: Hallucinations*

Nervous system disorders

Very common: Headache

Common: Dizziness, Somnolence, Insomnia

Uncommon: Migraine, Paraesthesia, Restless leg syndrome*

Rare: Akathisia*

Eye disorders

Uncommon: Blurred vision

Ear and labyrinth disorders

Uncommon: Tinnitus*

Gastrointestinal Disorders

Common: Nausea, Diarrhoea, Constipation, Abdominal pain, Vomiting*

Hepato-biliary disorders

Common: Increased ALT and/or AST (in clinical trials, increases >3 times the upper limit of the normal range for ALT and/or AST were seen in 1.2% of patients on agomelatine 25 mg daily and 2.6 % on agomelatine 50 mg daily vs. 0.5% on placebo).

Uncommon: Increased gamma-glutamyltransferase* (GGT)(>3 times the upper limit of the normal range

Rare: Hepatitis, Increased alkaline phosphatase* (>3 times the upper limit of the normal range), Hepatic failure*¹, Jaundice*

Skin and subcutaneous tissue disorders

Uncommon: Hyperhidrosis Eczema Pruritus*, Urticaria*

Rare: Erythematous rash Face oedema and angioedema*

Musculoskeletal and connective tissue disorders

Common: Back pain

Renal and urinary disorders

Rare: Urinary retention*

General disorders and administration site conditions

Common: Fatigue

Investigations

Common: Weight increased*

Uncommon: Weight decreased*

* Frequency estimated from clinical trials for adverse reactions detected from spontaneous report
¹ Few cases were exceptionally reported with fatal outcome or liver transplantation in patients with hepatic risk factors.