Valdoxan Special Precautions

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 x ULN, hepatitis and jaundice have been reported in patients treated with Valdoxan in the post-marketing setting. Most of them occurred during the 1st months of treatment. The pattern of liver damage is predominantly hepatocellular with serum transaminases which usually return to normal levels on cessation of Valdoxan.
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 eg, obesity/overweight/non-alcoholic fatty liver disease, diabetes, substantial alcohol intake and in patients receiving concomitant medicinal products associated with risk of hepatic injury.
Baseline LFT should be undertaken in all patients and treatment should not be initiated in patients with baseline values of alanine transaminase (ALT) and/or aspartate transaminase (AST) >3 x ULN. Caution should be exercised when Valdoxan is administered to patients with pretreatment elevated transaminases (> the ULN 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, around 6 weeks (end of acute phase), around 12 and 24 weeks (end of maintenance phase), and thereafter when clinically indicated.
When increasing the dosage, LFT should again be performed at the same frequency as when initiating treatment.
Any patient who develops increased serum transaminases should have his/her LFT repeated within 48 hrs.
During Treatment Period: Valdoxan treatment should be discontinued immediately if: Patient develops symptoms or signs of potential liver injury (eg, 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 ULN.
Following discontinuation of Valdoxan therapy, LFT 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.
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 <25 years.
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: Caution should be exercised when prescribing Valdoxan with moderate CYP1A2 inhibitors (eg, 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 Valdoxan.
Effects on the Ability to Drive or Operate Machinery: No studies on the effects on the ability to drive and use machines have been performed.
However, considering that dizziness and somnolence are common adverse reactions, patients should be cautioned about their ability to drive a car or operate machinery.
Impairment of Fertility: Reproduction studies in the rat and the rabbit showed no effect of agomelatine on fertility.
Use in pregnancy: There are no or limited amount of data (<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. As a precautionary measure, it is preferable to avoid the use of Valdoxan during pregnancy.
Use in lactation: 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. A risk to the newborns/infants cannot be excluded. A decision must be made whether to discontinue breastfeeding or to discontinue/abstain from Valdoxan therapy taking into account the benefit of breastfeeding for the child and the benefit of therapy for the woman.
Use in children: The safety and efficacy of Valdoxan in children from 2 years onwards for treatment of major depressive episodes have not yet been established. No data are available.
There is no relevant use of Valdoxan in children from birth to 2 years for treatment of major depressive episodes.
Valdoxan is not recommended in the treatment of depression in patients <18 years 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 the elderly: No effect of agomelatine is documented in patients ≥75 years, therefore agomelatine should not be used by patients in this age group.
Use in the 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.