Usage
- Agomelatine is prescribed for the treatment of major depressive episodes in adults. It is also used for generalized anxiety disorder.
- Pharmacological classification: Agomelatine is a melatonergic antidepressant. It acts as a melatonin receptor agonist (MT1 and MT2) and a 5-HT2C receptor antagonist.
- Mechanism of Action: Agomelatine resynchronizes circadian rhythms, which are often disrupted in depression. It enhances noradrenergic and dopaminergic neurotransmission specifically in the frontal cortex.
Alternate Names
- International Nonproprietary Name (INN): Agomelatine
- Brand Names: Valdoxan, Thymanax
How It Works
- Pharmacodynamics: Agomelatine’s antidepressant and anxiolytic effects are thought to be mediated through its actions on melatonin receptors (MT1 and MT2) and serotonin 5-HT2C receptors. Its unique mechanism of action offers advantages in terms of sexual side effects and discontinuation symptoms compared to some other antidepressants. Agomelatine improves sleep quality and reduces early morning awakenings without sedative effects.
- Pharmacokinetics:
- Absorption: Agomelatine is rapidly absorbed after oral administration, reaching peak plasma concentrations within 1-2 hours.
- Metabolism: Extensively metabolized in the liver, primarily by CYP1A2 (90%) and to a lesser extent CYP2C9 and CYP2C19.
- Elimination: Mainly through hepatic metabolism with renal excretion of metabolites. The elimination half-life is 1-2 hours.
- Mode of Action: Agomelatine acts as an agonist at MT1 and MT2 receptors and an antagonist at 5-HT2C receptors. This combination of effects contributes to its ability to resynchronize circadian rhythms and regulate neurotransmitter release.
- Receptor Binding/Enzyme Inhibition: Agomelatine binds to MT1 and MT2 receptors, activating them, and also blocks 5-HT2C receptors. It does not inhibit monoamine oxidase (MAO) and has low affinity for other receptors, including adrenergic, histaminergic, cholinergic, dopaminergic, and benzodiazepine receptors.
- Elimination Pathways: Primarily hepatic metabolism followed by renal excretion of inactive metabolites.
Dosage
Standard Dosage
Adults:
- Initial dose: 25 mg once daily at bedtime.
- Maintenance dose: May be increased to 50 mg once daily at bedtime after two weeks if no improvement is observed.
- Maximum dose: 50 mg/day.
Children:
- Not recommended for use in children and adolescents below 18 years of age due to lack of data on safety and efficacy.
Special Cases:
- Elderly Patients (<75 years): Standard adult dose. No dose adjustment is required based on age alone, but use with caution.
- Elderly Patients (≥75 years): Not recommended.
- Patients with Renal Impairment: No dose adjustment is necessary but use with caution in moderate to severe renal impairment.
- Patients with Hepatic Dysfunction: Contraindicated.
- Patients with Comorbid Conditions: Caution is advised in patients with diabetes, cardiovascular disease, or other relevant comorbidities.
Clinical Use Cases
Agomelatine is specifically indicated for major depressive episodes and generalized anxiety disorder. It is not indicated for use in settings like intubation, surgical procedures, mechanical ventilation, ICU use, or emergency situations.
Dosage Adjustments
Dose adjustments may be necessary based on individual patient response and tolerability. Consider lower starting doses or slower titration in patients with certain comorbidities.
Side Effects
Common Side Effects
- Headache
- Nausea
- Dizziness
- Somnolence
- Insomnia
- Diarrhea
- Abdominal pain
- Increased liver enzymes (transient and usually mild)
Rare but Serious Side Effects
- Hepatic injury (hepatitis, jaundice, hepatic failure): Requires monitoring of liver function tests.
- Mania/hypomania
- Suicidal ideation
Long-Term Effects
- Potential for long-term effects on liver function requires ongoing monitoring with periodic liver function tests.
Adverse Drug Reactions (ADR)
- Angioedema
- Erythema multiforme
- Suicidal behavior
Contraindications
- Hypersensitivity to agomelatine or any of its components.
- Severe hepatic impairment (Child-Pugh C).
- History of manic episode.
- Concomitant use of strong CYP1A2 inhibitors (e.g., fluvoxamine, ciprofloxacin).
Drug Interactions
- CYP1A2 inhibitors: Increase agomelatine concentrations and risk of adverse effects (e.g., fluvoxamine, ciprofloxacin).
- CYP1A2 inducers: Decrease agomelatine concentrations and may reduce efficacy (e.g., smoking, rifampicin).
- Alcohol: Should be avoided or consumed in moderation.
- Other antidepressants: Use with caution.
Pregnancy and Breastfeeding
- Pregnancy: Limited data available. Use only if clearly needed and the potential benefits outweigh the risks.
- Breastfeeding: Not recommended. Agomelatine is likely excreted in breast milk.
Drug Profile Summary
- Mechanism of Action: MT1 and MT2 receptor agonist, 5-HT2C receptor antagonist. Resynchronizes circadian rhythms.
- Side Effects: Headache, nausea, dizziness, hepatic dysfunction.
- Contraindications: Hepatic impairment, CYP1A2 inhibitors.
- Drug Interactions: CYP1A2 inducers/inhibitors, alcohol.
- Pregnancy & Breastfeeding: Use with caution in pregnancy, not recommended during breastfeeding.
- Dosage: 25-50 mg once daily at bedtime.
- Monitoring Parameters: Liver function tests (LFTs) at baseline, periodically, and as clinically indicated.
Popular Combinations
While sometimes used with other antidepressants, this should be done cautiously due to potential interactions.
Precautions
- General Precautions: Monitor LFTs, assess for suicidal ideation, avoid alcohol.
- Specific Populations: Not recommended in severe hepatic impairment or elderly patients ≥75 years. Use with caution in pregnancy and renal impairment. Not recommended during breastfeeding.
- Lifestyle Considerations: Limit or avoid alcohol consumption.
FAQs (Frequently Asked Questions)
Q1: What is the recommended dosage for Agomelatine?
A: The recommended starting dose is 25 mg once daily at bedtime. This may be increased to 50 mg/day after two weeks if needed.
Q2: How does Agomelatine work?
A: Agomelatine works by targeting melatonin and serotonin receptors in the brain. It acts as an agonist at MT1 and MT2 melatonin receptors and an antagonist at 5-HT2C serotonin receptors. This action helps regulate sleep-wake cycles and improve mood.
Q3: What are the common side effects of Agomelatine?
A: Common side effects include headache, nausea, dizziness, and abnormal dreams.
Q4: What are the serious side effects of Agomelatine?
A: A rare but serious side effect is liver injury, so regular monitoring of liver function is essential. Suicidal thoughts and behaviors, though rare, have also been reported.
Q5: Who should not take Agomelatine?
A: Individuals with severe hepatic impairment, hypersensitivity to agomelatine, or those taking strong CYP1A2 inhibitors should not take Agomelatine.
Q6: Can Agomelatine be taken during pregnancy or breastfeeding?
A: Agomelatine is generally not recommended during pregnancy or breastfeeding.
Q7: Does Agomelatine interact with other medications?
A: Yes. Agomelatine interacts with strong CYP1A2 inhibitors (e.g., fluvoxamine, ciprofloxacin) and inducers (e.g., rifampicin, smoking). Concomitant use should be avoided or carefully managed. It can also interact with alcohol, so patients should avoid or limit alcohol while taking agomelatine.
Q8: How long does it take for Agomelatine to work?
A: It typically takes 1-2 weeks for Agomelatine to start working, with the full effect often seen within 4 weeks.
Q9: What should I do if I miss a dose of Agomelatine?
A: If a dose is missed, take it as soon as remembered, unless it is close to the time for the next dose. Do not double the dose to catch up.
