Each film-coated tablet contains 25 mg of agomelatine. Excipient: lactose monohydrate 61.84 mg

Film-coated tablet [tablet]. Orange-yellow, oblong, film-coated tablet with blue imprint of company logo on one side.

Treatment of major depressive episodes in adults

The recommended dose is 25 mg once daily taken orally at bedtime.

After two weeks of treatment, if there is no improvement of symptoms, the dose may be increased to 50 mg once daily, i.e. two 25 mg tablets, taken together at bedtime.

Liver function tests should be performed in all patients: at initiation of treatment, and then periodically after around six weeks (end of acute phase), twelve weeks and twenty four weeks (end of maintenance phase) and thereafter when clinically indicated.

Patients with depression should be treated for a sufficient period of at least 6 months to ensure that they are free of symptoms.

Valdoxan tablets may be taken with or without food.

Patients with 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 Valdoxan in depressed patients with severe or moderate renal impairment with major depressive episodes is available. Therefore, caution should be exercised when prescribing Valdoxan to these patients.

Patients with hepatic impairment:

Valdoxan is contra-indicated in patients with hepatic impairment.

Treatment discontinuation:

No dosage tapering is needed on treatment discontinuation.

Valdoxan is not recommended for use in children and adolescents below 18 years of age due to a lack of data on safety and efficacy.

Efficacy has not been clearly demonstrated in the elderly ( 65 years). Only limited clinical data is available on the use of Valdoxan in elderly patients 65 years old with major depressive episodes. Therefore, caution should be exercised when prescribing Valdoxan to these patients.

Hypersensitivity to the active substance or to any of the excipients.

Hepatic impairment (i.e. cirrhosis or active liver disease)

Concomitant use of potent CYP1A2 inhibitors (e.g. fluvoxamine, ciprofloxacin)

Use in children and adolescents:

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

Use in elderly patients with dementia:

Valdoxan should not be used for the treatment of major depressive episodes in elderly patients with dementia since the safety and efficacy of Valdoxan have not been established in these patients.

Mania / Hypomania:

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

Suicide/suicidal thoughts:

Depression is associated with an increased risk of suicidal thoughts, self-harm and suicide (suicide-related events). This risk persists until significant remission occurs. As improvement may not occur during the first few weeks or more of treatment, patients should be closely monitored until such improvement occurs. It is general clinical experience that the risk of suicide may increase in the early stages of recovery.

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.

Combination with CYP1A2 inhibitors

Combination with potent CYP1A2 inhibitors is contra-indicated. Caution should be exercised when prescribing Valdoxan with moderate CYP1A2 inhibitors (e.g. propranolol, grepafloxacin, enoxacin) which may result in increased exposure of agomelatine.

Increased serum transaminases:

In clinical studies, elevations of serum transaminases (>3 times the upper limit of the normal range) have been observed in patients treated with Valdoxan particularly on a 50 mg dose (see section 4.8). When Valdoxan was discontinued in these patients, the serum transaminases usually returned to normal levels. Liver function tests should be performed in all patients: at initiation of treatment and then periodically after around six weeks (end of acute phase), after around twelve and twenty four weeks (end of maintenance phase) and thereafter when clinically indicated. Any patient who develops increased serum transaminases should have his/her liver function tests repeated within 48 hours. Therapy should be discontinued if the increase in serum transaminases exceeds 3X upper limit of normal and liver function tests should be performed regularly until serum transaminases return to normal.

If any patient develops symptoms suggesting hepatic dysfunction liver function tests should be performed. The decision whether to continue the patient on therapy with Valdoxan should be guided by clinical judgement pending laboratory evaluations. If jaundice is observed therapy should be discontinued.

Caution should be exercised when Valdoxan is administered to patients who consume substantial quantities of alcohol or who are treated with medicinal products associated with risk of hepatic injury.

Lactose intolerance:

Valdoxan contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Potential interactions affecting 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 Valdoxan with potent CYP1A2 inhibitors (e.g. fluvoxamine, ciprofloxacin) is contra-indicated.

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, grepafloxacin, enoxacin) until more experience has been gained  

Potential for agomelatine to affect other medicinal products:

In vivo, agomelatine does not induce CYP450 isoenzymes. Agomelatine inhibits neither CYP1A2 in vivo nor the other CYP450 in vitro. Therefore, agomelatine will not modify exposure to medicinal products metabolised by CYP 450.

Medicinal products highly bound to plasma protein:

Agomelatine does not modify free concentrations of medicinal products highly bound to plasma proteins or vice versa.

Other medicinal products:

No evidence of pharmacokinetic or pharmacodynamic interaction with medicinal products which could be prescribed concomitantly with Valdoxan in the target population was found in phase I clinical trials: benzodiazepines, lithium, paroxetine, fluconazole and theophylline.

Alcohol:

The combination of Valdoxan and alcohol is not advisable.

Electroconvulsive therapy (ECT):

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

In clinical trials, over 3,900 depressed patients have received Valdoxan.

Adverse reactions were usually mild or moderate and occurred within the first two weeks of treatment. The most common adverse reactions were nausea and dizziness.

These adverse reactions were usually transient and did not generally lead to cessation of therapy.

Depressed patients display a number of symptoms that are associated with the illness itself. It is therefore sometimes difficult to ascertain which symptoms are a result of the illness itself and which are a result of treatment with Valdoxan.

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.

Nervous system disorders:

Common: headache, dizziness, somnolence, insomnia, migraine,

Uncommon: paraesthesia

Eye disorders:

Uncommon: blurred vision

Gastrointestinal disorders:

Common: nausea, diarrhoea, constipation, upper abdominal pain

Skin and subcutaneous tissue disorders

Common: hyperhidrosis

Uncommon: eczema

Rare: erythematous rash

Musculoskeletal and connective tissue disorders

Common: back pain

General disorders and administration site conditions:

Common: fatigue

Hepato-biliary disorders:

Common increases (>3 times the upper limit of the normal range) in ALAT and/or ASAT (i.e. 1.1% on agomelatine 25/50 mg vs 0.7% on placebo).

Rare: hepatitis

Psychiatric disorders:

Common: anxiety

Frequency not known: Suicidal thoughts or behaviour

Servier Laboratories Limited