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Monitoring of liver function: Caution should be exercised before initiation of treatment and close surveillance should be performed during continuing treatment, especially during combined use with medicines associated with risk of hepatic injury or where risk factors for hepatic injury are present.
In post-marketing experience cases of liver injury, including elevations of liver enzymes (> 10 times upper limit of the normal range), hepatic failure, hepatitis and jaundice have been reported in patients treated with agomelatine, most often during the first months of treatment (see Adverse Reactions).
Isolated cases of transplantation or death in patients with hepatic failure have been reported following the use of agomelatine. Some patients had hepatic risk factors. This highlights the importance of performing liver function tests in all patients.
The pattern of liver damage is predominantly hepatocellular with serum transaminases usually returning to normal levels following discontinuation of agomelatine. In clinical trials, elevations of serum transaminases (> 3 times the upper limit of the normal range) have been observed in patients treated with agomelatine more commonly on a 50 mg dose.
Before initiation of treatment: Treatment with agomelatine should only be initiated after careful consideration of the benefits and risk in patients with hepatic injury risk factors e.g.: overweight, obesity, non-alcoholic fatty liver disease, diabetes or use with medicines associated with risk of hepatic injury; alcohol use disorder and/or substantial alcohol intake.
Baseline liver function tests should be performed in all patients before initiation of treatment. Treatment with agomelatine should not be initiated if serum transaminase levels are > 3 times the upper limit of the normal range (see Contraindications). Caution should be exercised when agomelatine is administered to patients with pre-treatment elevated transaminases (i.e. between the upper limit of the normal ranges and up to ≤ 3 times the upper limit of the normal range).
Frequency of liver function tests: Before starting treatment and then: around 3 weeks; around 6 weeks (end of acute phase); around 12 weeks; around 24 weeks (end of maintenance phase); thereafter when clinically indicated.
When increasing the dosage, liver function tests should again be performed at the same frequency as when starting treatment. Patients who develop any increased serum transaminases should have their liver function tests repeated within 48 hours.
During treatment: Therapy should be discontinued immediately if any of the following are observed: an increase in serum transaminases > 3 times the upper limit of normal (see Contraindications); signs or symptoms of potential liver injury (such as dark urine, light coloured stools, yellow skin/eyes, pain in the upper right abdomen, sustained new-onset and unexplained fatigue).
Liver function tests should continue to be performed regularly following discontinuation of therapy until serum transaminases return to normal.
Suicide Ideation/Suicidality: In clinical trials, agomelatine is not associated with an increased risk of suicide ideation/suicidality.
The risk of suicide attempt is inherent in patients with depression and may persist until significant remission occurs. This risk must be considered in all patients with depression.
Patients with depression may experience worsening of their depressive symptoms and/or the emergence of suicidal ideation and behaviours (suicidality) whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. As improvement may not occur during the first few weeks or more of treatment, patients should be closely monitored for clinical worsening and suicidality, especially at the beginning of a course of treatment, or at the time of dose changes, either increases or decreases. Patients with a history of suicide-related events or those exhibiting suicidality prior to commencement of treatment are known to be at greater risk of suicidal thoughts or suicide attempts and should be monitored during treatment.
Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse or whose emergent suicidality is severe, abrupt in onset, or was not part of the patient's presenting symptoms. Patients (and caregivers of patients) should be alerted about the need to monitor for any worsening of their condition and/or the emergence of suicidal ideation/behaviour or thoughts of harming themselves and to seek medical advice immediately if these symptoms present. Patients with comorbid depression associated with other psychiatric disorders being treated with antidepressants should be similarly observed for clinical worsening and suicidality.
Pooled analyses of 24 short-term (4 to 16 weeks), placebo controlled trials of nine antidepressant medicines (SSRIs and others) in 4,400 children and adolescents with MDD (16 trials), obsessive compulsive disorder (four trials) or other psychiatric disorders (four trials) have revealed a greater risk of adverse events representing suicidality during the first few months of treatment in those receiving antidepressants. The average risk of such events in patients treated with an antidepressant was 4% compared with 2% of patients given placebo. There was considerable variation in risk among the antidepressants, but there was a tendency towards an increase for almost all antidepressants studied. The risk of suicidality was most consistently observed in the MDD trials, but there were signals of risk arising from trials in other psychiatric indications (obsessive compulsive disorder and social anxiety disorder) as well. No suicides occurred in these trials. It is unknown whether the suicidality risk in children and adolescent patients extends to use beyond several months. The nine antidepressant medications in the pooled analyses included five SSRIs (citalopram, fluoxetine, fluvoxamine, paroxetine, sertraline) and four non-SSRIs (bupropion, mirtazapine, nefazodone, venlafaxine).
A further pooled analysis of short-term placebo controlled trials of antidepressant medicines (SSRIs and others) showed the increased risk of suicidality during the initial treatment period (generally the first one to two months) extends to young adults (aged 18-24 years) with MDD and other psychiatric disorders. These trials did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction in risk with antidepressants compared to placebo in adults aged 65 years and older.
Symptoms of anxiety, agitation, panic attacks, insomnia, irritability, hostility (aggressiveness), impulsivity, akathisia (psychomotor restlessness), hypomania and mania have been reported in adults, adolescents and children being treated with antidepressants for MDD as well as for other indications, both psychiatric and non-psychiatric. Although a causal link between the emergence of such symptoms and either worsening of depression and/or emergence of suicidal impulses has not been established, there is concern that such symptoms may be precursors of emerging suicidality.
Families and caregivers of children and adolescents being treated with antidepressants for MDD or for any other condition (psychiatric or non-psychiatric) should be informed about the need to monitor these patients for the emergence of agitation, irritability, unusual changes in behaviour and other symptoms described previously, as well as the emergence of suicidality, and to report such symptoms immediately to healthcare providers. It is particularly important that monitoring be undertaken during the initial few months of antidepressant treatment or at times of dose increase or decrease.
When treatment duration was considered the incidence of suicidal events was 0.28 per 100 patient-months for agomelatine compared with 0.50 per 100 patient-months for placebo.
Bipolar disorder/Mania/Hypomania: A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed that treating such an episode with an antidepressant alone can increase the likelihood of precipitation of a mixed/manic episode in patients at risk of bipolar disorder. Prior to initiating treatment with an antidepressant, patients should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder and depression.
As with other antidepressants, agomelatine should be used with caution in patients with history of bipolar disorder, mania or hypomania and should be discontinued if a patient develops manic symptoms.
Lactose intolerance: VALDOXAN (agomelatine) tablets contain lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Alcohol: As with all antidepressants, patients should be advised to avoid alcohol consumption.
Combination with CYP1A2 inhibitors (see Contraindications, Interactions and Pharmacology: Pharmacodynamics under Actions): Use caution when combining agomelatine with moderate CYP1A2 inhibitors (e.g. propranolol) as these medicines may result in increased exposure to agomelatine.
Electroconvulsive therapy (ECT): There is no experience with the combined use of agomelatine and ECT. In animals agomelatine has no proconvulsant properties. Therefore, adverse consequences of combined ECT and agomelatine treatment are considered to be unlikely.
Abuse potential: Agomelatine has no abuse potential. This was assessed in healthy volunteer trials on a specific visual analogue scale or the Addiction Research Centre Inventory 49 (ARCI) checklist.
Use in hepatic impairment: VALDOXAN (agomelatine) is contraindicated in patients with hepatic impairment (see Contraindications).
Use in renal impairment: As only limited clinical data on the use of agomelatine in patients with moderate or severe renal impairment are available, caution should be exercised when prescribing VALDOXAN (agomelatine) to these patients.
Effects on laboratory tests: No data available.
Effects on Ability to Drive and Use Machines: No trials on the effects on the ability to drive and use machines have been performed. While clinical pharmacodynamic trials have shown that agomelatine treatment does not impair cognitive or psychomotor function in healthy volunteers, dizziness and somnolence were reported during clinical trials. As with all psychoactive medicines, patients should be cautioned about their ability to drive a car or operate machinery.
Use in Children: As safety and efficacy have not been established in this age group, the use of agomelatine in children and adolescents (aged < 18 years) is not recommended.
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 the Elderly: No adjustment in the usual dose is recommended for elderly patients solely because of their age.
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 demonstrated in elderly patients aged ≥ 75 years, agomelatine should not be used in this patient group (see Dosage & Administration).
Agomelatine should not be used for the treatment of MDD or GAD in elderly patients with dementia since the safety and efficacy of agomelatine have not been established in these patients.
Data on the use of agomelatine in elderly patients with GAD are limited. Therefore, agomelatine is not recommended to treat GAD in the elderly aged > 65 years (see Dosage & Administration and Pharmacology: Pharmacodynamics under Actions).
