Agomelatine

Antidepressant – melatonin agonist and 5-HT2C antagonist

ATC code: N06AX22

Updated 24 Sep 2026 · Methodology

Indications

Major depressive disorder

Third line

A later-line option for major depressive disorder: NG222 (2022) reserves agomelatine for after an inadequate response to at least two other antidepressants, and the Spanish GuiaSalud depression guideline (2023 revision) keeps SSRIs as first-line. First-line is SSRIs and SNRIs (sertraline, escitalopram, venlafaxine). Agomelatine is used with concomitant sleep and circadian rhythm disturbance, with SSRI-related sexual side effects, or in seasonal depression. Dose 25 mg at bedtime; up to 50 mg. Effect develops over 2–4 weeks. The 2013 Cochrane review (Guaiana et al.) found no significant advantage over other antidepressants, with conclusions limited by few trials and a high risk of publication bias, since most RCTs were manufacturer-sponsored. The key safety requirement is liver-enzyme monitoring before treatment and at 3, 6, 12, and 24 weeks; agomelatine is contraindicated in active liver disease or transaminases above three times the upper limit of normal, needs caution in patients over 75, and must not be combined with strong CYP1A2 inhibitors (fluvoxamine, ciprofloxacin), which sharply raise its exposure and hepatotoxicity risk.

Sources

ICD-10: F32.9 · ICD-11: 6A70.Z

Generalized anxiety disorder

Individual decision

Agomelatine is sometimes used off-label for generalized anxiety disorder; the and AEMPS have approved it only for depression. The supporting evidence is real: a meta-analysis of three placebo-controlled RCTs (Stein et al., 2021) showed reduced anxiety on the Hamilton scale and less functional impairment at 25–50 mg, a 2025 network meta-analysis confirmed the effect, and the drug is listed in the 2023 WFSBP anxiety guidelines. The limitations are substantial: all pivotal trials were manufacturer-sponsored, raising the risk of publication bias; no Spanish or European guideline names agomelatine for anxiety; and first-line treatment remains SSRIs and SNRIs. The safety profile is the same as in depression: liver-enzyme monitoring is mandatory before treatment and at 3, 6, 12, and 24 weeks, and the drug is contraindicated in active liver disease. Whether to use it is an individual decision when standard options have failed.

Sources

ICD-10: F41.1 · ICD-11: 6B00

Marketing claims without evidence base

The drug is promoted for these uses outside international guidelines. Each entry below is analyzed against AEMPS, FDA, EMA, Cochrane and major RCTs.

Insomnia and sleep disorders

Not recommended

Agomelatine is an antidepressant that acts as a melatonin receptor agonist. It is prescribed only for major depression. For sleep and mood improvement outside a depression indication, agomelatine has no proven efficacy: there are no RCTs supporting benefit in primary insomnia and no approved indication. The main risk is severe hepatotoxicity up to acute liver failure ( PRAC 2014 mandated baseline liver-enzyme monitoring and rechecks at 3, 6, 12, and 24 weeks, then periodically). The combination of potentially dangerous risk and no benefit outside depression makes this prescription unjustified. If insomnia is a real problem, the foundation is cognitive-behavioral therapy for insomnia (CBT-I), and melatonin 1–5 mg an hour before bed is an accessible and safe option. If agomelatine was prescribed for sleep, consider seeking a second opinion.

Sources

ICD-10: G47.0 · ICD-11: 7A00

How to read tiers A–F

AStrong evidence – first or second line in international guidelines
BRecommended in selected cases
CStudy data contradict each other
DBenefit not proven, no documented harm
FDocumented harm, or risk without benefit

Mechanism of action

A structural melatonin analogue. Agonist at melatonin MT1 and MT2 receptors and antagonist at serotonin 5-HT2C receptors. Restores circadian rhythms and increases dopamine and noradrenaline release in the prefrontal cortex. Does not affect serotonin reuptake – differs from SSRIs by lacking typical side effects (sexual dysfunction, GI complaints, discontinuation discomfort). CYP1A2-metabolized, so smoking and strong CYP1A2 inhibitors (fluvoxamine, ciprofloxacin) significantly affect levels.

Safety

Contraindications

Agomelatine hypersensitivity
Active liver disease or transaminase elevation over 3× upper limit
Dementia
Concomitant strong CYP1A2 inhibitors (fluvoxamine, ciprofloxacin)
Age under 18

Serious adverse effects

Hepatotoxicity up to acute liver failure
Suicidal thoughts (especially early therapy in young patients)
Serotonin syndrome with other serotonergic drugs (rare)
Drug-induced cutaneous reactions

Common adverse effects

Headache
Drowsiness
Dizziness
Nausea
Elevated liver enzymes
Anxiety

Pregnancy: can you take Agomelatine?

Limited pregnancy data. Sertraline with more data is preferred in pregnant patients with depression.

Breastfeeding: can you take Agomelatine?

No data. Not recommended during lactation.

Calculate RID Full profile on NIH LactMed ↗

Reference information, not a clinical decision. Discuss feeding pauses or changes with your physician or an IBCLC.

Practical notes

Monitoring

Before start and at 3, 6, 12, 24 weeks check liver enzymes (ALT, AST) – hepatotoxicity risk described for agomelatine. in 2014 mandated this monitoring. With transaminases over 3× upper limit of normal, discontinue. Not used in active liver disease, baseline transaminase elevation, or alcohol misuse.

Drug–drug interactions

1 pair found. Sorted from critical to minor.

CriticalCiprofloxacinFluoroquinolone antibacterials

Mechanism

The liver breaks down agomelatine mainly through the enzyme CYP1A2, which handles 90% of its metabolism. The remaining 10% goes through the enzymes CYP2C9 and CYP2C19. Ciprofloxacin inhibits CYP1A2, but there are no clinical data on this exact pair. The closest guide is fluvoxamine, a strong CYP1A2 inhibitor, which raised agomelatine exposure 60-fold (range 12 to 412). The ciprofloxacin label expects a similar effect. The agomelatine label lists ciprofloxacin next to fluvoxamine as a strong CYP1A2 inhibitor, while the ciprofloxacin label calls it a moderate one. Both drugs can damage the liver: hepatitis and liver failure have been reported with agomelatine, and liver necrosis with ciprofloxacin.

Symptoms

Common adverse effects of agomelatine include headache, dizziness, drowsiness, nausea, anxiety and raised levels of the liver enzymes alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Reported signs of agomelatine overdose include upper abdominal (epigastric) pain, drowsiness, tiredness, agitation, anxiety, tension, dizziness, cyanosis and general malaise. With agomelatine, liver injury mostly appears in the first months of treatment. It shows as dark urine, pale stools, yellow skin or eyes, pain in the upper right abdomen and sudden, unexplained, prolonged fatigue. The ciprofloxacin label adds loss of appetite, itching and abdominal tenderness to the signs of liver disease.

Management

The combination is contraindicated. The agomelatine label forbids use with strong inhibitors of the enzyme CYP1A2 and names ciprofloxacin (agomelatine label, European Medicines Agency, , and Spanish Agency of Medicines and Medical Devices, AEMPS). Do not take ciprofloxacin and agomelatine at the same time. The labels give no waiting period for switching from one drug to the other. If the two have been taken together, monitor the patient closely for signs of agomelatine overdose (ciprofloxacin label, AEMPS). There is no specific antidote for agomelatine: treat the symptoms and monitor the patient, preferably in a specialised setting (agomelatine label, EMA). Both drugs can damage the liver, and the agomelatine label asks for caution and close follow-up when it is combined with such drugs (agomelatine label, EMA). During agomelatine treatment, check liver function before the start, at about 3, 6, 12 and 24 weeks and then when clinically indicated. Repeat the tests within 48 hours if transaminases rise (agomelatine label, EMA). Stop agomelatine at once if signs of liver injury appear or transaminases exceed 3 times the upper limit of normal (agomelatine label, EMA). Stop ciprofloxacin at any sign of liver disease (ciprofloxacin label, AEMPS).

Sources

Pair details →Ciprofloxacin →

Label mentions11 mentions

Verbatim lines from the interaction sections, in the language of the label

From this drug’s label

CriticalCiprofloxacin
«Uso concomitante de inhibidores potentes del CYP1A2 (p. ej., fluvoxamina, ciprofloxacino) (ver sección 4.5).»
AEMPS, section 4.3 · Open on CIMA
CriticalFluvoxamine
«Uso concomitante de inhibidores potentes del CYP1A2 (p. ej., fluvoxamina, ciprofloxacino) (ver sección 4.5).»
AEMPS, section 4.3 · Open on CIMA
Moderateinhibidores del CYP1A2class named in the label
«Uso concomitante de inhibidores potentes del CYP1A2 (p. ej., fluvoxamina, ciprofloxacino) (ver sección 4.5).»
AEMPS, section 4.3 · Open on CIMA
ModeratePropranolol
«Posibles interacciones que afectan a la agomelatina: La asociación de agomelatina con estrógenos (inhibidores moderados del CYP1A2) produce que aumente varias veces la exposición a agomelatina…»
AEMPS, section 4.5 · Open on CIMA
benzodiazepinasclass named in the label
«En ensayos clínicos de fase I no se encontró evidencia de interacción farmacocinética o farmacodinámica con medicamentos que podrían ser prescritos de forma concomitante con agomelatina en la…»
AEMPS, section 4.5 · Open on CIMA
Fluconazole
«En ensayos clínicos de fase I no se encontró evidencia de interacción farmacocinética o farmacodinámica con medicamentos que podrían ser prescritos de forma concomitante con agomelatina en la…»
AEMPS, section 4.5 · Open on CIMA
Lithium
«En ensayos clínicos de fase I no se encontró evidencia de interacción farmacocinética o farmacodinámica con medicamentos que podrían ser prescritos de forma concomitante con agomelatina en la…»
AEMPS, section 4.5 · Open on CIMA
Paroxetine
«En ensayos clínicos de fase I no se encontró evidencia de interacción farmacocinética o farmacodinámica con medicamentos que podrían ser prescritos de forma concomitante con agomelatina en la…»
AEMPS, section 4.5 · Open on CIMA
Rifampicin
«Posibles interacciones que afectan a la agomelatina: Rifampicina, un inductor de los tres citocromos implicados en el metabolismo de la agomelatina puede disminuir la biodisponibilidad de la…»
AEMPS, section 4.5 · Open on CIMA
Theophylline
«En ensayos clínicos de fase I no se encontró evidencia de interacción farmacocinética o farmacodinámica con medicamentos que podrían ser prescritos de forma concomitante con agomelatina en la…»
AEMPS, section 4.5 · Open on CIMA

From other drugs’ labels

ModerateCiprofloxacin
«Citocromo P450: Ciprofloxacino inhibe el CYP1A2 y, por lo tanto, puede causar un aumento de la concentración sérica de fármacos que se metabolizan por esta vía, cuando se administran…»
AEMPS, section 4.4 · Open on CIMA

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Frequently asked

What is Agomelatine used for?

Agomelatine is evaluated for the following indications with varying evidence strength: Major depressive disorder (evidence tier B), Generalized anxiety disorder (evidence tier C), Insomnia and sleep disorders (evidence tier F). See the full indication matrix with dosing and citations above on this page.

What are the side effects of Agomelatine?

Common side effects of Agomelatine (≥ 1 in 100): Headache, Drowsiness, Dizziness, Nausea, Elevated liver enzymes, Anxiety. See the Safety section for uncommon and serious reactions.

Is Agomelatine safe during pregnancy?

Limited pregnancy data. Sertraline with more data is preferred in pregnant patients with depression.

Is Agomelatine compatible with breastfeeding?

No data. Not recommended during lactation.

Can you drink alcohol while taking Agomelatine?

Not used in active liver disease, baseline transaminase elevation, or alcohol misuse.

Who should not take Agomelatine?

Agomelatine is contraindicated in: Agomelatine hypersensitivity; Active liver disease or transaminase elevation over 3× upper limit; Dementia; Concomitant strong CYP1A2 inhibitors (fluvoxamine, ciprofloxacin); Age under 18. Full list in the Safety section.

Official sources

Direct links to regulator labels. Open in a new tab.

AEMPS / CIMALabel dated 11/05/2025
EMALabel dated 02/19/2009

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