Atomoxetine

Atomoxetine is a non-stimulant treatment for attention deficit hyperactivity disorder in children aged 6 years and over, adolescents and adults. It is not a controlled drug and has no misuse potential, which makes it useful when stimulants are unsuitable, when there is a substance misuse or tic history, or when anxiety is prominent. The effect is slower than with stimulants, taking 2 to 4 weeks to begin and up to 12 weeks to reach full benefit.

Classification. Selective noradrenaline reuptake inhibitor, non-stimulant.

Mechanism. Selectively blocks the presynaptic noradrenaline transporter, which increases noradrenaline (and dopamine) in the prefrontal cortex.

Pharmacokinetics. Well absorbed orally, peak in 1 to 2 hours. Metabolised by CYP2D6 to the weakly active 4-hydroxyatomoxetine. Half-life about 5 hours in extensive metabolisers and about 21 hours in poor CYP2D6 metabolisers (a minority of patients). Ultrarapid metabolisers may have lower exposure, but genotype testing is not routine.

All regimens are oral with no loading dose.

ADHD, children and adolescents over 6 years weighing up to 70 kg.

• Start 0.5 mg/kg daily for at least 7 days.
• Titration: increase to a target of 1.2 mg/kg daily.
• Maximum 1.4 mg/kg daily (1.8 mg/kg in some labels) or 100 mg, whichever is lower.

ADHD, children and adolescents over 70 kg and adults.

• Start 40 mg daily for at least 7 days.
• Titration: increase to 80 mg daily; after 2 to 4 weeks may increase to 100 mg.
• Maximum 100 mg daily.

Give once daily in the morning, or in two divided doses (morning and late afternoon or early evening) if sedation or nausea occurs.

Dose limits. Poor CYP2D6 metabolisers and patients taking strong CYP2D6 inhibitors (fluoxetine, paroxetine, bupropion, quinidine): start at the usual starting dose but increase only if tolerated after 4 weeks. Moderate liver impairment: use 50% of the usual dose. Severe liver impairment: use 25% of the usual dose. Kidney impairment: no adjustment.

Contraindications. Concurrent monoamine oxidase inhibitor or within 14 days of stopping one, narrow-angle glaucoma, phaeochromocytoma, severe cardiovascular or cerebrovascular disease, hypersensitivity. Major warning of suicidal thinking in children and adolescents.

Serious adverse effects. Suicidal thoughts and behaviour (especially in the first months and after dose changes), severe liver injury (rare; stop if jaundice, dark urine or abdominal pain), hypertension and tachycardia, urinary retention, priapism, mania or aggression, seizures (rare), allergic reactions, QT prolongation at high exposure.

Common adverse effects. Nausea, reduced appetite, dry mouth, abdominal pain, headache, insomnia or somnolence, fatigue, constipation, dizziness, erectile dysfunction, urinary hesitancy.

Interactions. Monoamine oxidase inhibitors are contraindicated. Strong CYP2D6 inhibitors (fluoxetine, paroxetine, bupropion, quinidine) raise levels several-fold. High-dose salbutamol and other pressor agents add cardiovascular effects. Other QT-prolonging medicines add risk. Antihypertensives may be affected.

Common prescribing errors. Expecting rapid effect and stopping at 2 weeks; not reducing the dose with strong CYP2D6 inhibitors; failing to warn about suicidal thoughts; combining with a monoamine oxidase inhibitor; not monitoring blood pressure and pulse.

Special groups.

• Pregnancy: limited data; avoid unless the benefit clearly outweighs the risk.
• Breastfeeding: small amounts in milk; avoid or monitor the infant.
• Children: licensed from 6 years; monitor mood and growth.
• Older adults: limited data.
• Kidney impairment: no adjustment.
• Liver impairment: 50% of the usual dose in moderate and 25% in severe impairment.

Formulations. Capsules 10 mg, 18 mg, 25 mg, 40 mg, 60 mg, 80 mg and 100 mg; oral solution in some regions. Swallow capsules whole; do not open them because the contents irritate the eyes. With or without food.

Baseline. Blood pressure, pulse, height and weight, cardiovascular history, mood and suicide risk, liver function if there is a history of liver disease, medicines list for CYP2D6 inhibitors.

Monitoring. Review mood and suicidal thinking weekly for the first 4 weeks and after every dose change. Check blood pressure, pulse and weight every 3 to 6 months, and height every 6 months in children. Review need yearly. Check liver tests if symptoms of liver injury appear.

Stopping. No taper is needed; stop with review.

Referral and escalation. Refer to a specialist for suicidality, mania, psychosis or lack of response. Jaundice, dark urine or severe abdominal pain needs the drug stopped and urgent liver tests.