Agorest Tablet

Agorest is indicated for the major depressive disorder in adults especially in non-responders and intolerant to selective serotonin reuptake inhibitors (SSRIs) including prevention of relapse.

Agomelatine is a melatonergic agonist (MT₁ and MT2 receptors) and 5-HT_2C antagonist. Binding studies indicate that agomelatine has no effect on monoamine uptake and no affinity for a, (3 adrenergic, histaminergic, cholinergic, dopaminergic and benzodiazepine receptors. Agomelatine resynchronises circadian rhythms in animal models of circadian rhythm disruption. Agomelatine increases noradrenaline and dopamine release specifically in the frontal cortex and has no influence on the extracellular levels of serotonin.

The effective dose of agomelatine is 25 mg per day given once at bed time for two weeks and can be increased to 50 mg per day in patients with inadequate response. Night time dosing is recommended because agomelatine improves the quality of sleep without day time sedation. For oral administration with or without food. Most adult patients should take a dosage of 25 mg (one tablet) daily. It is usually taking prior to bed time. If no improvement is noticed after two weeks, the dosage can be increased to 50 mg (two tablets) daily.

Children under 18 years: Should be given only on medical advice.

Use in children and adolescents: Agomelatine is not recommended in the treatment of depression in patients <18 years since safety and efficacy of agomelatine have not been established in this age group. In clinical trials among children and adolescents treated with other antidepressants, suicide-related behavior (suicide attempt and suicidal thoughts), and hostility (predominantly aggression, oppositional behavior and anger) were more frequently observed compared to those treated with placebo.

Use in the elderly: The efficacy and safety of agomelatine (25 to 50 mg/day) have been established in elderly patients with MDD (aged <75 years). As  efficacy has not been established in every elder patients aged >75 years agomelatine should not be used in this patient group.

Agorest 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 Agorest. Fluvoxamine, a potent CYP1A2 and moderate CYP2C9 inhibitor markedly inhibits the metabolism of Agorest resulting in a 60-fold (range 12-412) increase of Agorest exposure. Consequently, co-administration of Agorest with potent CYP1A2 inhibitors (e.g. fluvoxamine, ciprofloxacin) is contraindicated.

Hypersensitivity to the active substances or to any of the excipients. Hepatic impairment (i.e cirrhosis or active liver disease), or transaminases exceeding 3 times upper limit of normal. Concomitant use of potent CYPIA2 inhibitors (eg. Fluvoxamine, ciprofloxacin).

The commonly reported adverse effects in the clinical trials of Agorest are headache, nausea and diarrhea. It is found to increase the level of liver enzymes and so monitoring of enzyme level is warranted before starting therapy and therefore every 6 weeks. It is also contraindicated in patients with hepatic impairment. A meta-analysis of the treatment emergent sexual dysfunction with antidepressants has revealed that it has no significant difference with placebo.

Use in pregnancy: For agomelatine, no clinical data on exposed pregnancies are available. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development. Caution should be exercised when prescribing to pregnant women.

Use in lactation: It is not known whether agomelatine is excreted into human milk. Agomelatine or its metabolites are excreted in the milk of lactating rats. Potential effects of agomelatine on the breastfeeding infant have not been established. If treatment with agomelatine is considered necessary, breastfeeding should be discontinued.

Caution should be exercised before starting treatment and close surveillance should be performed throughout the treatment period in all patients, especially if hepatic injury risk factors or concomitant medicinal products associated with risk of hepatic injury are present. 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 times upper limit of normal.

Agorest should be used with caution in the elderly (≥75 years) due to lack of clinical data. Agorest should not be used for the treatment of major depressive episodes in elderly patients with dementia since the safety and efficacy of Agorest have not been established in these patients.

Agorest is not recommended in the treatment of depression in patients under 18 years of age. Agorest should be used with caution in patients with a history of bipolar disorder, mania or hypomania.

There is limited experience with Agorest overdose. During the clinical development, there were a few reports of Agorest overdose, taken alone (up to 450 mg) or in combination (up to 525 mg) with other psychotropic medicinal products. Signs and symptoms of overdose were limited and included drowsiness and epigastralgia. No specific antidotes for Agorest are known. Management of overdose should consist of treatment of clinical symptoms and routine monitoring. Medical follow-up in a specialised environment is recommended.

Atypical anti-depressant drugs

To be dispensed only on the prescription of a registered physician. Store below 30°C, in a cool and dry place. Keep away from light. Keep out of the reach of children.