4.1. Therapeutic indications

Valdoxan is indicated for the treatment of major depressive episodes in adults.

4.2. Posology and method of administration

Posology

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.

Decision of dose increase has to be balanced with a higher risk of transaminases elevation. Any dose increase to 50 mg should be made on an individual patient benefit/risk basis and with strict respect of Liver Function Test monitoring.

Liver function tests should be performed in all patients before starting treatment. Treatment should not be initiated if transaminases exceed 3 X upper limit of normal (see sections 4.3 and 4.4).

During treatment transaminases should be monitored periodically after around three weeks, six weeks (end of acute phase), twelve weeks and twenty four weeks (end of maintenance phase) and thereafter when clinically indicated (see also section 4.4). Treatment should be discontinued if transaminases exceed 3 X upper limit of normal (see sections 4.3 and 4.4).

When increasing the dosage, liver function tests should again be performed at the same frequency as when initiating treatment.

Treatment duration

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

Switching therapy from SSRI/SNRI antidepressant to agomelatine

Patients may experience discontinuation symptoms after cessation from an SSRI/SNRI antidepressant. The SmPC of the actual SSRI/SNRI should be consulted on how to withdraw the treatment to avoid this. Agomelatine can be started immediately while tapering the dosage of an SSRI/SNRI (see section 5.1).

Treatment discontinuation

No dosage tapering is needed on treatment discontinuation.

Special populations

Elderly

The efficacy and safety of agomelatine (25 to 50mg/day) have been established in elderly depressed patients (<75years). No effect is documented in patients ≥75 years. Therefore agomelatine should not be used by patients in this age group (see sections 4.4 and 5.1). No dose adjustment is required in relation to age (see section 5.2).

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.

Hepatic impairment

Agomelatine is contraindicated in patients with hepatic impairment (see sections 4.3, 4.4 and 5.2).

Paediatric population

Children from birth to <7 years

There is no relevant use of agomelatine in children from birth to <7 years for treatment of major depressive episodes. No data are available.

Children and adolescents from 7 to 17 years

The safety and efficacy of agomelatine in children and adolescents aged from 7 to 17 years for treatment of major depressive episodes have not been established. Currently available data are described in sections 4.4, 4.8, 5.1 and 5.2, but no recommendation on a posology can be made.

Method of administration

For oral use.

Valdoxan film-coated tablets may be taken with or without food.

4.3. Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Hepatic impairment (i.e. cirrhosis or active liver disease) or transaminases exceeding 3 X upper limit of normal (see sections 4.2 and 4.4).

Concomitant use of potent CYP1A2 inhibitors (e.g. fluvoxamine, ciprofloxacin) (see section 4.5).

4.4. Special warnings and precautions for use

Monitoring of liver function

Cases of liver injury, including hepatic failure (few cases were exceptionally reported with fatal outcome or liver transplantation in patients with hepatic risk factors), elevations of liver enzymes exceeding 10 times upper limit of normal, hepatitis and jaundice have been reported in patients treated with agomelatine in the post-marketing setting (see section 4.8). Most of them occurred during the first months of treatment. The pattern of liver damage is predominantly hepatocellular with increased serum transaminases which usually return to normal levels on cessation of agomelatine.

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.

Before starting treatment

Treatment with Valdoxan 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 (see section 4.3). Caution should be exercised when Valdoxan 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.

During treatment period

Valdoxan treatment should be discontinued immediately if:

- patient develops symptoms or signs of potential liver injury (such as dark urine, light coloured stools, yellow skin/eyes, pain in the upper right belly, sustained new-onset and unexplained fatigue).

- the increase in serum transaminases exceeds 3 X upper limit of normal.

Following discontinuation of Valdoxan therapy liver function tests should be repeated until serum transaminases return to normal.

Paediatric population

Valdoxan is not recommended in the treatment of depression in patients under 18 years of age since the safety and efficacy of agomelatine have not been established . 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 .

For agomelatine reported suicidal events were too few to make any meaningful comparison between agomelatine and placebo. Pooled data from clinical trials with agomelatine 25 mg have shown that suicidal events occurred at a higher frequency in adolescents (3.1%) compared to adults (1.2%), see section on Suicide/suicidal thoughts below and section 4.8.

In pooled data from clinical trials hepatic adverse events were more frequently reported by adolescents (6.3%) compared to adults (1.7%).

Long-term safety data is limited. This includes long-term experience on growth, pubertal development (see section 5.1) and cognitive function.

Elderly

No effect of agomelatine is documented in patients ≥75 years, therefore agomelatine should not be used by patients in this age group (see also sections 4.2 and 5.1).

Use in elderly 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.

Bipolar disorder/ mania / hypomania

Valdoxan 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 (see section 4.8).

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 (see sections 4.3 and 4.5)

Caution should be exercised when prescribing Valdoxan with moderate CYP1A2 inhibitors (e.g. propranolol, enoxacin) which may result in increased exposure of agomelatine

Lactose intolerance

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

Level of sodium

Valdoxan contains less than 1mmol sodium (23mg) per tablet, i.e. essentially 'sodium-free'.

4.5. Interaction with other medicinal products and other forms of interaction

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 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 (e.g. propranolol, enoxacin) until more experience has been gained (see section 4.4).

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) (see section 5.2).

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 CYP450.

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 agomelatine 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 properties (see section 5.3). Therefore, clinical consequences of ECT performed concomitantly with agomelatine treatment are considered to be unlikely.

Paediatric population

Interaction studies have only been performed in adults.

4.6. Fertility, pregnancy and lactation

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 (see section 5.3). As a precautionary measure, it is preferable to avoid the use of Valdoxan during pregnancy.

Breast-feeding

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 (see section 5.3). A risk to the newborns/infants cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from Valdoxan 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 (see section 5.3).

4.7. 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.

4.8. Undesirable effects

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.

System organ class

Frequency

Preferred Term

Psychiatric disorders

Common

Anxiety

Abnormal dreams*

Uncommon

Suicidal thoughts or behaviour (see section 4.4)

Agitation and related symptoms* (such as irritability and restlessness)

Aggression*

Nightmares*

Mania/hypomania*

These symptoms may also be due to the underlying disease (see section 4.4).

Confusional state*

Rare

Hallucinations*

Nervous system disorders

Very common

Headache

Common

Dizziness

Somnolence

Insomnia

Uncommon

Migraine

Paraesthesia

Restless leg syndrome*

Rare

Akathisia*

Eyes 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

Uncommon

Myalgia*

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.

Pediatric 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) (see section 4.4.).

Long-term safety data for agomelatine 25 mg in adolescents is limited. This includes long-term experience on growth, pubertal development (see section 5.1) and cognitive function.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

Symptoms

There is limited experience with agomelatine overdose. Experience with agomelatine in overdose has indicated that epigastralgia, somnolence, fatigue, agitation, anxiety, tension, dizziness, cyanosis or malaise have been reported.

One person having ingested 2,450 mg agomelatine, recovered spontaneously without cardiovascular and biological abnormalities.

Management

No specific antidotes for agomelatine are known. Management of overdose should consist of treatment of clinical symptoms and routine monitoring. Medical follow-up in a specialised environment is recommended.