Schedule H

Oral

• Film-Coated Tablets: 25 mg

INDICATIONS + DOSING — FOR CLINICIAN USE ONLY

Primary Indications (Approved / Standard in India)

1. Major Depressive Disorder (MDD) — Adults

Parameter Recommendation

Starting dose 25 mg orally once daily at bedtime

Titration After 2 weeks, may increase to 50 mg once daily at bedtime if inadequate clinical response and hepatic function remains normal

Usual maintenance dose 25–50 mg once daily at bedtime

Maximum dose 50 mg/day

Clinical Notes:

• Must confirm normal hepatic function (LFTs) before initiating treatment

• Administer at bedtime due to melatonergic mechanism

• Assess therapeutic efficacy at 6 weeks; if no response, consider discontinuation

• Not recommended as first-line in elderly patients over 75 years

• No significant discontinuation syndrome reported; however, gradual tapering is prudent

• May improve sleep architecture without causing daytime sedation

Secondary Indications – Adults (Off-label, if any)

Indication Dose Duration Notes

Generalised Anxiety Disorder 25–50 mg once daily at bedtime 8–12 weeks trial OFF-LABEL; Specialist only; Evidence: Limited RCTs; Not standard practice in India

Seasonal Affective Disorder 25–50 mg once daily at bedtime Seasonal use OFF-LABEL; Specialist only; Evidence: International trials; Very limited Indian experience

PAEDIATRIC DOSING (Specialist Only)

Primary Indications (Approved / Standard in India)

NOT APPROVED for use in children and adolescents below 18 years in India.

• Safety and efficacy not established in paediatric population

• Risk of suicidal ideation may be increased in younger patients

• Indian regulatory sources (CDSCO) do not list paediatric indications

Secondary Indications – Paediatrics (Off-label, if any)

Not applicable.

• No off-label paediatric indications supported by Indian practice or published data

Not recommended below 18 years of age under any circumstances.

Mild to moderate impairment No dose adjustment required

ESRD / Haemodialysis Avoid use — insufficient safety data

Peritoneal Dialysis Avoid use — insufficient data

Baseline transaminases >3× ULN Contraindicated — do not initiate

• Known hypersensitivity to agomelatine or any excipient

• Active hepatic disease (cirrhosis, active hepatitis)

• Baseline transaminases (ALT/AST) >3× upper limit of normal

• Concurrent use with potent CYP1A2 inhibitors (fluvoxamine, ciprofloxacin)

• Moderate to severe hepatic impairment (Child-Pugh B or C)

• History of hepatic impairment or alcohol misuse — increased hepatotoxicity risk

• Mandatory LFT monitoring before and during treatment

• Bipolar disorder — may precipitate manic/hypomanic episodes; screen before initiation

• Elderly patients (65–75 years) — limited efficacy data; use with caution

• Elderly patients >75 years — not recommended due to unfavourable benefit-risk ratio

• Diabetes mellitus — monitor glycaemic control

• Dementia — limited data; not routinely recommended

• Driving or operating machinery — may cause dizziness and somnolence, especially initially

• Suicidal ideation — monitor closely, especially in early treatment phase and in patients under 25 years

• Smoking — tobacco induces CYP1A2; may reduce agomelatine efficacy

Parameter Details

Risk Category Limited human data; animal studies do not indicate direct teratogenicity but data insufficient

Recommendation Avoid if possible; use only if potential benefit clearly outweighs risk and safer alternatives are unsuitable

Preferred Alternatives SSRIs (sertraline, escitalopram) have more pregnancy safety data; psychological therapies as first-line

When May Be Used Only when SSRIs/SNRIs are contraindicated or not tolerated; requires specialist psychiatric and obstetric input

Monitoring Maternal hepatic function (LFTs) regularly throughout pregnancy; fetal growth surveillance

Parameter Details

Compatibility Not recommended during breastfeeding — insufficient data

Drug Levels in Milk Unknown; excretion in human milk not studied

Preferred Alternatives Sertraline (most lactation safety data); escitalopram

Recommendation If agomelatine is essential, advise against breastfeeding or choose alternative antidepressant

Infant Monitoring If inadvertent exposure, monitor infant for sedation, feeding difficulties, and adequate weight gain

Parameter Recommendation

Age 65–75 years Starting dose: 25 mg once daily at bedtime; do not exceed 25 mg/day; limited efficacy data

Age >75 years Not recommended — poor benefit-risk profile; limited efficacy demonstrated in clinical trials

Titration Not recommended; maintain at 25 mg if used

Special Risks Increased risk of hepatotoxicity; falls risk (dizziness, somnolence); polypharmacy increases interaction risk

Monitoring Baseline and periodic LFTs; falls risk assessment; cognitive function

Interacting Drug Mechanism / Effect Recommendation

Fluvoxamine Potent CYP1A2 inhibitor; increases agomelatine levels up to 60-fold Contraindicated — do not combine

Ciprofloxacin Potent CYP1A2 inhibitor; markedly increases agomelatine levels Contraindicated — do not combine

Other potent CYP1A2 inhibitors (enoxacin) Significantly increased agomelatine exposure Avoid combination

Alcohol Additive hepatotoxicity risk; may also increase CNS depression Avoid concurrent use; counsel patients

MAO Inhibitors Theoretical interaction; not adequately studied Avoid combination

Interacting Drug Mechanism / Effect Recommendation

Smoking (Tobacco) CYP1A2 induction; reduces agomelatine plasma levels Heavy smokers may have reduced efficacy; if patient quits smoking, agomelatine levels may increase — monitor

Oestrogens (oral contraceptives, HRT) Moderate CYP1A2 inhibition; may increase agomelatine levels Use with caution; monitor for adverse effects and hepatotoxicity

Rifampicin Strong CYP inducer; may reduce agomelatine levels Monitor for reduced efficacy

Carbamazepine CYP inducer; may reduce agomelatine levels Monitor for reduced efficacy

Propranolol Moderate CYP1A2 inhibitor Monitor for increased agomelatine effects

SSRIs/SNRIs (when switching or combining) Theoretical additive serotonergic effects Monitor for CNS adverse effects; theoretical serotonin syndrome risk

Warfarin No significant pharmacokinetic interaction but limited data Monitor INR when starting or stopping agomelatine

• Headache

• Dizziness

• Nausea

• Diarrhoea

• Fatigue / Somnolence

• Insomnia (paradoxical in some patients)

• Anxiety

• Abdominal pain

• Back pain

• Increased sweating

Note: Notably low incidence of sexual dysfunction and weight gain compared to SSRIs/SNRIs.

Adverse Effect Clinical Action

Hepatotoxicity (elevated transaminases, hepatitis, rarely fulminant hepatic failure) Discontinue immediately if ALT/AST >3× ULN or if symptoms of liver injury develop (dark urine, jaundice, fatigue, abdominal pain); do not rechallenge

Suicidal Ideation / Behaviour (especially in patients under 25 years or early in treatment) Close monitoring; psychiatric evaluation; may require discontinuation

Mania / Hypomania (in patients with bipolar disorder) Discontinue; reassess diagnosis; mood stabiliser may be needed

Severe Skin Reactions (rare) Discontinue; dermatology referral

Aggression / Agitation (rare) Evaluate; consider discontinuation

Week 3 Repeat LFTs

Week 6 Repeat LFTs; assess therapeutic response; if no improvement, consider discontinuation

Week 12 Repeat LFTs

Week 24 Repeat LFTs

After dose increase to 50 mg Repeat LFTs at same schedule (3, 6, 12, 24 weeks from dose increase)

Long-term Periodic LFTs as clinically indicated; monitor for suicidal ideation; reassess continued need

If symptoms of hepatic injury develop Immediate LFTs; discontinue if transaminases elevated

Hepatic Monitoring Protocol Summary:

• Baseline → Week 3 → Week 6 → Week 12 → Week 24 → periodically thereafter

• Repeat schedule if dose increased to 50 mg

• Valdoxan (Servier India) — Originator brand

• Agomel (Intas)

• Agoviz (Sun Pharma)

• Agopil (Cipla)

• Agomelan (Mankind)

Note: FDCs not applicable for agomelatine.

• Not included in NLEM; pricing not NPPA-controlled

• Originator brand (Valdoxan) at higher end of price range

• Generic versions available at lower cost

• Mandatory hepatic monitoring is unique among antidepressants — ensure patient understands and complies with LFT schedule; document informed consent regarding hepatotoxicity risk

• Excellent choice for patients who experienced sexual dysfunction or significant weight gain on SSRIs/SNRIs — agomelatine has minimal impact on sexual function and weight

• May improve sleep quality and circadian rhythm due to melatonergic mechanism — particularly useful in depression with prominent insomnia or circadian disruption; administer at bedtime

• Not effective as a sedative or hypnotic on its own — do not prescribe for primary insomnia without depression

• Smoking status matters — heavy smokers may have reduced drug levels due to CYP1A2 induction; if patient quits smoking during treatment, monitor for increased adverse effects

• Screen for bipolar disorder before initiation — may precipitate mania; not recommended for bipolar depression without mood stabiliser

Agomelatine; major depressive disorder; depression; melatonergic antidepressant; atypical antidepressant; hepatotoxicity risk; liver monitoring; CYP1A2 substrate; sleep-improving; no sexual dysfunction; elderly-caution; Schedule H

RxIndia v1.0 — 13 May 2025

• CDSCO approved product information

• Indian Pharmacopoeia (IP)

• National Formulary of India (NFI)

• NLEM 2022 (referenced for inclusion status)

• API Textbook of Medicine — Psychiatry chapter

• AIIMS Psychiatry Department Treatment Protocols

• Indian Psychiatric Society Clinical Practice Guidelines

• Goodman & Gilman's: The Pharmacological Basis of Therapeutics

• Valdoxan (Agomelatine) Product Insert — Servier India

• EMA Assessment Report (supportive reference for off-label data only)