Agomelatine

The combination of agomelatine and alcohol is not advisable.

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.

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.

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

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.

Patients with a history of suicide-related events or those exhibiting a significant degree of suicidal ideation prior to commencement of treatment are known to be at greater risk of suicidal thoughts or suicide attempts, and should receive careful monitoring during treatment. A meta-analysis of placebo-controlled clinical trials of antidepressants in adult patients with psychiatric disorders showed an increased risk of suicidal behaviour with antidepressants compared to placebo, in patients less than 25 years old.

Close supervision of patients and in particular those at high risk should accompany treatment especially in early treatment and following dose changes. Patients (and caregivers of patients) should be alerted to the need to monitor for any clinical worsening, suicidal behaviour or thoughts and unusual changes in behaviour and to seek medical advice immediately if these symptoms present.

There is no experience of concurrent use of agomelatine with ECT. Animal studies have not shown proconvulsant properties. Therefore, clinical consequences of ECT performed concomitantly with agomelatine treatment, are considered to be unlikely.

Treatment with agomelatine should only be prescribed after careful consideration of benefit and risk in patients with hepatic injury risk factors e.g.:

• obesity/overweight/non-alcoholic fatty liver disease, diabetes
• alcohol use disorder and/or substantial alcohol intake and in patients receiving concomitant medicinal products associated with risk of hepatic injury.

Baseline liver function tests should be undertaken in all patients and treatment should not be initiated in patients with baseline values of ALT and/or AST >3 X upper limit of normal. Caution should be exercised when agomelatine is administered to patients with pretreatment elevated transaminases (> the upper limit of the normal ranges and ≤3 times the upper limit of the normal range).

Frequency of liver function tests:

• before starting treatment
• and then:
  • after around 3 weeks,
  • after around 6 weeks (end of acute phase),
  • after around 12 and 24 weeks (end of maintenance phase),
  • and thereafter when clinically indicated.
• When increasing the dosage, liver function tests should again be performed at the same frequency as when initiating treatment.

Any patient who develops increased serum transaminases should have his/her liver function tests repeated within 48 hours.

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.

Tabulated list of adverse reactions

The below table gives the adverse reactions observed from adult placebo-controlled and adult 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.

^* 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.

Paediatric population

A total of 80 children aged 7 to less than 12 years old and 319 adolescent patients aged between 12 to 17 years with moderate to severe major depressive disorder were treated with agomelatine in a double-blind, active (fluoxetine) and placebo-controlled study.

In general, the safety profile of agomelatine 25 mg in adolescents in the pivotal study (double-blind controlled part) was similar to that seen in adults, except for nausea which occurred at a higher frequency in adolescents (13.3%) than in adults (6.3%).

Pooled data from clinical trials with agomelatine have shown that adverse events and serious adverse events (all-causality) were reported with higher frequency in the adolescents than in the adults (67.2% vs 60.4% of patients who reported at least one adverse event and 10.4% versus 3.5% of the patients who reported at least one serious adverse event).

Hepatic adverse events were reported by 6.3% of adolescents compared to adults (1.7%). Suicidal events (for instance suicidal behavior, suicide thoughts, suicide attempt and self-injury) occurred at a higher frequency in adolescents (3.1%, 10 events reported in 6 patients) compared to adults (1.2%, 66 events reported in 65 patients).

Long-term safety data for agomelatine 25 mg in adolescents is limited. This includes long-term experience on growth, pubertal development and cognitive function.