Agomelatine

Registered South African indications:

• Major depressive episodes in adults

Registered South African contraindications

• Hypersensitivity to the active ingredient or any of its excipients
• Hepatic impairment (i.e cirrhosis or active liver disease)
• Coadministration with CYP1A2 inhibitors (e.g. fluvoxamine, ciprofloxacin)

Contraindications registered in other jurisdictions

• Hypersensitivity to the active ingredient or any of its excipients
• Hepatic impairment (i.e. cirrhosis or active liver disease) or transaminases exceeding 3 x upper limit of normal
• Concomitant use of potent CYP1A2 inhibitors (e.g. fluvoxamine, ciprofloxacin)

• Pregnancy
• Breastfeeding
• Moderate to severe renal impairment
• Elderly
  - ≥65 years (South African recommendations)
  - ≥75 years (Recommendations in other jurisdictions)
• Obesity
• Diabetes mellitus
• Non-alcoholic fatty liver disease
• Substantial alcohol intake
• Children
• Dementia
• History of bipolar disorder, mania or hypomania
• History of suicide-related events
• Significant suicidal ideation
• Galactose intolerance
• Lapp lactase deficiency
• Glucose-galactose malabsorption

Forms avail. in SA and covered in this monograph: fct

South African registered indications and dosages

Major depressive episodes in adults

• Oral (fct): 25mg, once daily at bedtime; If no improvement of symptoms after 2 weeks, dose can be increased to: 50mg, once daily at bedtime; 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

Agomelatine tablets can be taken with or without food

Liver function tests should be performed in all patients: At initiation of treatment, and then periodically after approx. 3 weeks, 6 weeks (end of acute phase), 12 weeks 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

South African registered indications and dosages

• Not established for use in children below 18 years

Pregnancy

South African recommendations

• Caution
• Safety and efficacy have not been established in pregnancy

Recommendations in other jurisdictions

• Caution; not recommended 
• 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. As a precautionary measure, it is preferable to avoid the use of agomelatine during pregnancy

Breastfeeding

South African recommendations

• Caution
• Safety and efficacy have not been established in breastfeeding

Recommendations in other jurisdictions

• Caution; not recommended
• 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 agomelatine therapy taking into account the benefit of breastfeeding for the child and the benefit of therapy for the woman

Fertility

South African recommendations

• No information available

Recommendations in other jurisdictions

• Reproduction studies in the rat and the rabbit showed no effect of agomelatine on fertility

Recommendations below are applicable to South Africa and other jurisdictions

• Mild: No dose adjustment recommended
• Moderate to severe: Caution; no dose adjustment recommended
  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

Recommendations below are applicable to South Africa and other jurisdictions

• Contraindicated

South African recommendations

• Caution; not recommended
  Limited clinical data in the elderly (≥65 years) treated for major depressive episodes did not clearly demonstrate efficacy in this age group
  Agomelatine is not recommended for the treatment of major depressive episodes in elderly patients (≥65 years)

Recommendations in other jurisdictions

• <75 years: No dose adjustment recommended
  The efficacy and safety of agomelatine (25-50mg/day) have been established in elderly depressed patients (<75 years)
  No dose adjustment is required in relation to age
• ≥75 years: Caution; not recommended
  No effect is documented in patients ≥ 75 years. Therefore agomelatine should not be used by patients in this age group

Central Nervous System Disorders

• Anxiety
• Abnormal dreams
• Suicidal thoughts or behaviour
• Agitation
• Aggression
• Mania or hypomania
• Confusion
• Hallucinations
• Headache
• Dizziness
• Somnolence
• Insomnia
• Migraine
• Paraesthesia
• Restless leg syndrome
• Akathisia
• Fatigue

Gastrointestinal Disorders

• Nausea and vomiting
• Diarrhoea
• Constipation
• Abdominal pain

Hepatobiliary Disorders

• Increased liver enzymes
• Hepatitis
• Hepatic failure
• Jaundice

Genitourinary Disorders

• Urinary retention

Endocrine and Metabolic Disorders

• Increased weight
• Decreased weight

Musculoskeletal Disorders

• Back pain

Skin and Subcutaneous Tissue Disorders

• Hyperhidrosis
• Eczema
• Pruritus
• Urticaria
• Erythematous rash
• Facial oedema
• Angioedema

Sensory Disorders

• Blurred vision
• Tinnitus

• CYP1A2 inhibitors
• Fluvoxamine
• Ciprofloxacin
• CYP2C9 inhibitors
• Rifampicin
• Tobacco
• Alcohol

Hepatic function 

Agomelatine is a melatonergic agonist and serotonin antagonist. Binding studies indicate that agomelatine has no effect on monoamine uptake and no affinity for alpha adrenergic, beta adrenergic, histaminergic, cholinergic, dopaminergic and benzodiazepine receptors. Agomelatine resynchronises circadian rhythms in animal models of circadian rhythm disruption. Agomelatine increases noradrenaline and dopamine release specifically in the frontal cortex and has no influence on the extracellular levels of serotonin.

Tablet 25mg

• Valdoxane (Servier) originator