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 Adverse Reactions). 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 Contraindications). 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.
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 Adverse Reactions).
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.
Generalised anxiety disorder for which Valdoxan is prescribed can also be associated with an increased risk of suicide-related events. The same precautions observed when treating depressed patients should therefore be observed when treating patients with generalised anxiety disorder.
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 Contraindications and Interactions): 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, the Lapp 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'.
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.
Use in Children: Valdoxan is not recommended 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 Dosage & Administration).
Use in the Elderly: No effect of agomelatine is documented in depressed patients ≥75 years nor in elderly patients suffering from generalised anxiety disorder. Therefore agomelatine should not be used in these patients (see also Dosage & Administration and Pharmacology: Pharmacodynamics under Actions).
Use in elderly with dementia: Valdoxan should not be used for the treatment of major depressive episodes or generalised anxiety disorder in elderly patients with dementia since the safety and efficacy of Valdoxan have not been established in these patients.