VALDOXAN 25 MG

Indications

• Major depressive disorder

Dosage

Children: Refer to BNF for Children for specific dosing information, as safety and efficacy in children and adolescents have not been established.

Adults: 25 mg daily, taken at bedtime. The dose may be increased to 50 mg daily after 2 weeks if necessary.

Mechanism of action

Agomelatine acts as an agonist at melatonin receptors MT1 and MT2 and as an antagonist at serotonin receptor 5-HT2C. This dual action helps in regulating circadian rhythms and mood, potentially leading to improvements in sleep and depressive symptoms. By not affecting the reuptake of serotonin, noradrenaline, or dopamine, it may also reduce the risk of certain side effects commonly associated with traditional antidepressants.

Pharmacodynamics

The pharmacodynamics of agomelatine involve its role in modulating melatonin and serotonin pathways, which are crucial for mood regulation and sleep-wake cycles. It has been shown to improve sleep quality in patients with depression, which can further aid in alleviating depressive symptoms. The lack of significant effects on monoamine transporters suggests a different therapeutic profile compared to conventional antidepressants.

Pharmacokinetics

Agomelatine is well absorbed after oral administration and reaches peak plasma concentrations within 1 to 2 hours. It has a high bioavailability due to minimal first-pass metabolism. The drug is primarily metabolized in the liver via cytochrome P450 enzymes. It exhibits a half-life of approximately 1-2 hours but has a prolonged effect due to its active metabolites. Drug interactions should be considered, especially with other medications that affect liver enzyme activity.

Contra-indications

• Severe hepatic impairment
• Concurrent use of monoamine oxidase inhibitors (MAOIs)

Adverse effects

• Abdominal pain
• Anxiety
• Back pain
• Constipation
• Diarrhoea
• Dizziness
• Drowsiness
• Fatigue
• Headaches
• Nausea
• Sleep disorders
• Vomiting
• Mood alterations
• Confusion
• Hyperhidrosis
• Suicidal behaviours
• Hallucinations
• Vision blurred
• Angioedema
• Oedema of the face
• Tinnitus
• Altered movement disorders
• Paraesthesia

Interactions

• Severe interaction with fluvoxamine (increases exposure)
• Moderate interaction with givosiran (increases exposure)
• Unknown interactions with axitinib (increases exposure), leflunomide (decreases exposure), mexiletine (increases exposure), osilodrostat (increases exposure), rucaparib (increases exposure), teriflunomide (decreases exposure), vemurafenib (increases exposure), and ritonavir (decreases exposure)

Precautions

• Caution in patients with elevated transaminases
• Monitor for suicidal behaviours, especially in children and young adults
• Elderly patients may require lower initial doses
• Avoid in patients with a history of mania or hypomania

Pregnancy

Manufacturer advises to avoid use during pregnancy due to lack of safety data.

Breast-feeding

Avoid use while breastfeeding as it is present in milk in animal studies.

Storage

Store in a cool, dry place away from direct sunlight. Keep out of reach of children.

Formulations

• 25 mg tablets
• 50 mg tablets

Mechanism of action

The novel antidepressant agent, agomelatine, behaves as an agonist at melatonin receptors (MT1 and MT2) and as an antagonist at serotonin (5-HT)(2C) receptors.

Pharmacodynamics

Agomelatine resynchronises circadian rhythms in animal models of delayed sleep phase syndrome and other circadian rhythm disruptions. It increases noradrenaline and dopamine release specifically in the frontal cortex and has no influence on the extracellular levels of serotonin. Agomelatine has shown an antidepressant-like effect in animal depression models, (learned helplessness test, despair test, and chronic mild stress) circadian rhythm desynchronisation, and in stress and anxiety models. In humans, agomelatine has positive phase shifting properties; it induces a phase advance of sleep, body temperature decline and melatonin onset. Controlled studies in humans have shown that agomelatine is as effective as the SSRI antidepressants paroxetine and sertraline in the treatment of major depression