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VALDOXAN Film-coated tablets (2019)

Active ingredients: Agomelatine

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).

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.

Use in paediatric population

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 (see section 4.2).

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 (suiciderelated 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 placebocontrolled 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 1 mmol sodium (23 mg) per tablet, i.e. essentially ‘sodium-free’.

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.

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).

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.

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 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 (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*

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.

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 national reporting system listed in Appendix V.

Incompatibilities

Not applicable.