Adult: Initially, 40 mg daily, maintained for a minimum of 7 days prior to an upward dose titration according to clinical response and tolerability. May gradually increase dose to 80 mg daily. Max: 100 mg daily. All doses may be given as a single daily dose in the morning or as equally divided doses in the morning and later afternoon or early evening. Child: ≥6 years ≤70 kg: Initially, 0.5 mg/kg daily, maintained for a minimum of 7 days prior to an upward dose titration according to clinical response and tolerability. May gradually increase dose to 1.2 mg/kg daily based on patient’s weight and available dosage strengths. >70 kg: Initially, 40 mg daily, maintained for a minimum of 7 days prior to an upward dose titration according to clinical response and tolerability. May gradually increase dose to 80 mg daily. Max: 100 mg daily. All doses may be given as a single daily dose in the morning or as equally divided doses in the morning and later afternoon or early evening.
Special Patient Group
Patient taking strong CYP2D6 inhibitors (e.g. paroxetine, fluoxetine, quinidine, terbinafine):
Adult and children over 70 kg: Initially, 40 mg daily, may be increased to 80 mg daily only if symptoms fail to improve after 4 weeks and if initial dose is well tolerated.
Children up to 70 kg: Initially, 0.5 mg/kg daily, may be increased to 1.2 mg/kg daily only if symptoms fail to improve after 4 weeks and if initial dose is well tolerated.
Pharmacogenomics
Atomoxetine is metabolised primarily by CYP2D6 isoenzyme to form 4-hydroxyatomoxetine (active metabolite). CYP2D6 polymorphism may affect the pharmacokinetic response, efficacy, and safety of atomoxetine.
Individuals with reduced CYP2D6 enzyme activity, known as CYP2D6 poor metabolisers may experience several-fold higher atomoxetine exposure and increased risk of side effects (e.g. dry mouth, blurred vision, sleep disturbances, decreased weight or appetite, constipation, depression, tremor, feeling jittery, excoriation, dry eye or conjunctivitis, syncope, urinary retention, hyperhidrosis, peripheral coldness, and elevated blood pressure) as compared to extensive metabolisers. The prevalence of CYP2D6 poor metabolisers is estimated at approx 7% in Caucasians and 2% in African Americans.
CYP2D6 genetic testing may serve as a guide to help clinicians in prescribing atomoxetine. Plasma drug concentration testing may also be used to estimate atomoxetine exposure in the event that patient response becomes inadequate.
CYP2D6 ultrarapid metabolisers (carriers of duplications of functional alleles e.g. *1/*1xN, *1/*2xN, *2/*2xN)
Unlikely to achieve adequate serum concentrations for the intended effect at standard dosing.
Adult: Initially, 40 mg daily, increased to 80 mg daily after 3 days. If no clinical response and in the absence of adverse events after 14 days is observed, consider increasing dose to 100 mg daily. If no clinical response observed after 14 days, consider obtaining a peak plasma concentration 1-2 hours after dosing. If concentration is <200 ng/mL, consider proportional dose increase to approach 400 ng/mL level. Doses >100 mg daily may be necessary to achieve target levels.
Child: Initially, 0.5 mg/kg daily, increased to 1.2 mg/kg daily after 3 days. If no clinical response and in the absence of adverse events after 14 days is observed, consider obtaining a peak plasma concentration 1-2 hours after dosing. If concentration is <200 ng/mL, consider proportional dose increase to approach 400 ng/mL level.
May select an alternative drug not metabolised by CYP2D6.
CYP2D6 normal metabolisers (carriers of 2 normal function alleles or 1 normal function and 1 decreased function allele e.g. *1/*1, *1/*2, *1/*9, *1/*41, *2/*2)
Lower likelihood of response and increased discontinuation due to lack of efficacy as compared to poor metabolisers.
Adult: Initially, 40 mg daily, increased to 80 mg daily after 3 days. If no clinical response and in the absence of adverse events after 14 days is observed, consider increasing dose to 100 mg daily. If no clinical response observed after 14 days, consider obtaining a peak plasma concentration 1-2 hours after dosing. If concentration is <200 ng/mL, consider proportional dose increase to approach 400 ng/mL level. Doses >100 mg daily may be necessary to achieve target levels.
Child: Initially, 0.5 mg/kg daily, increased to 1.2 mg/kg daily after 3 days. If no clinical response and in the absence of adverse events after 14 days is observed, consider obtaining a peak plasma concentration 1-2 hours after dosing. If concentration is <200 ng/mL, consider proportional dose increase to approach 400 ng/mL level.
CYP2D6 intermediate metabolisers (carriers of 1 decreased function allele and 1 no function allele e.g. *4/*10, *4/*41, *5/*9)
Decreased atomoxetine metabolism resulting in higher plasma concentrations as compared to normal metabolisers, and at an increased risk of discontinuation as compared to poor metabolisers.
Adult: Initially, 40 mg daily. If no clinical response and in the absence of adverse events after 14 days is observed, increase dose to 80 mg daily. If response is inadequate after 14 days, consider obtaining a plasma concentration 2-4 hours after dosing. If concentration is <200 ng/mL, consider proportional dose increase to approach 400 ng/mL level. If adverse effects occur at any time, consider dose reduction.
Child: Initially, 0.5 mg/kg daily. If no clinical response and in the absence of adverse events after 14 days is observed, consider obtaining plasma concentrations 2-4 hours after dosing. If response is inadequate and concentration is <200 ng/mL, consider proportional dose increase to approach 400 ng/mL level. If adverse effects occur at any time, consider dose reduction.
CYP2D6 poor metabolisers (carriers of only non-functional alleles e.g. *3/*4,*4/*4, *5/*5, *5/*6)
Significantly decreased atomoxetine metabolism resulting in higher plasma concentrations and increased risk of side effects, but with greater symptom improvement as compared to non-poor metabolisers in those who tolerate treatment.
Adult: Initially, 40 mg daily. If no clinical response and in the absence of adverse events after 14 days is observed, increase dose to 80 mg daily. If response is inadequate after 14 days, consider obtaining a plasma concentration 2-4 hours after dosing. If concentration is <200 ng/mL, consider proportional dose increase to approach 400 ng/mL level. If adverse effects occur at any time, consider dose reduction.
Child: Initially, 0.5 mg/kg daily. If no clinical response and in the absence of adverse events after 14 days is observed, consider obtaining plasma concentration 4 hours after dosing. If response is inadequate and concentration is <200 ng/mL, consider proportional dose increase to approach 400 ng/mL level. If adverse effects occur at any time, consider dose reduction.
Hepatic Impairment
Moderate (Child-Pugh class B): Reduce to 50% of the usual dose. Severe (Child-Pugh class C): Reduce to 25% of the usual dose.
Administration
May be taken with or without food. Swallow whole, do not open cap.
Contraindications
Narrow-angle glaucoma, current or history of phaeochromocytoma, severe CV disorder (e.g. severe hypertension, heart failure, arterial occlusive disease, angina, haemodynamically significant congenital heart disease, cardiomyopathies, MI, potentially fatal arrhythmias and channelopathies, known serious structural cardiac abnormalities, coronary artery disease), severe cerebrovascular disorders (e.g. cerebral aneurysm, stroke). Concomitant use with or within 14 days after discontinuing treatment with MAOIs.
Special Precautions
Patients with comorbid bipolar disorder, existing anxiety disorders, depression, and tics related to Tourette’s syndrome; known or suspected long QT interval or family history of QT prolongation, underlying conditions (e.g. hypertension, tachycardia, CV or cerebrovascular disease), history of seizures, urinary retention or bladder outlet obstruction. Hepatic impairment. Children. Pregnancy and lactation. CYP2D6 ultrarapid, normal, intermediate, and poor metabolisers.
Adverse Reactions
Significant: Suicide-related behaviour (e.g. suicide attempts, suicidal ideation), psychotic or manic symptoms (e.g. hallucination, delusional thinking, mania, agitation), aggressive behaviour, hostility or emotional lability, CV effects (e.g. increased blood pressure and heart rate, orthostatic hypotension), altered cardiac conduction (e.g. QT interval prolongation), seizures, urinary retention or hesitancy, priapism. Rarely, anxiety and depression or depressed mood, tics; hepatic effects (e.g. elevated hepatic enzymes and bilirubin, jaundice, severe liver injury, hepatic failure), allergic reactions (e.g. anaphylactic reactions, angioneurotic oedema, rash, urticaria). Cardiac disorders: Palpitation, tachycardia. Eye disorders: Mydriasis, blurred vision. Gastrointestinal disorders: Nausea, vomiting, dry mouth, abdominal pain, constipation, dyspepsia, flatulence. General disorders and admin site conditions: Fatigue, lethargy, asthenia. Investigations: Weight decreased. Metabolism and nutrition disorders: Decreased appetite, anorexia. Musculoskeletal and connective tissue disorders: Muscle spasm. Nervous system disorders: Headache, somnolence, dizziness, dysgeusia, paraesthesia, tremor. Psychiatric disorders: Insomnia, irritability, mood swings, sleep disorder. Renal and urinary disorders: Dysuria, pollakiuria. Reproductive system and breast disorders: Dysmenorrhoea, male genital pain, ejaculation disorder, erectile dysfunction. Respiratory, thoracic and mediastinal disorders: Dyspnoea. Skin and subcutaneous tissue disorders: Pruritus, dermatitis, hyperhidrosis. Vascular disorders: Flushing, syncope, peripheral coldness, Raynaud’s phenomenon. Potentially Fatal: Serious CV events (e.g. sudden death, stroke, MI).
This drug may cause dizziness, somnolence or fatigue, if affected, do not drive or operate machinery. Capsules should not be opened as this drug is an ocular irritant. If the contents of the capsule accidentally come into contact with the eye, it must be flushed immediately with water. Hands and any potentially contaminated surface should be washed as soon as possible.
Monitoring Parameters
Monitor blood pressure and pulse at baseline, after increasing dose, and periodically during treatment; growth (e.g. weight, height) and appetite in children; liver enzymes upon signs or symptoms of liver dysfunction and for several weeks after treatment discontinuation; physical exam to assess cardiac disease at baseline or if symptoms of cardiac disease develop during treatment, and further work-up (e.g. ECG, echocardiogram) if exam findings suggest cardiac disease. Closely monitor for signs of suicidal ideation and behavioural changes during initial months of therapy or at times of dose changes.
Overdosage
Symptoms: Gastrointestinal symptoms, dizziness, somnolence, tremor, abnormal behaviour, hyperactivity, agitation, mild to moderate sympathetic nervous system activation (e.g. tachycardia, increased blood pressure, mydriasis, dry mouth), pruritus, rash, seizures and QT prolongation. Management: Symptomatic and supportive treatment. Monitor cardiac and vital signs. Establish airway. Activated charcoal may be useful in limiting drug absorption within 1 hour of ingestion.
Drug Interactions
Increased exposure with CYP2D6 inhibitors (e.g. fluoxetine, paroxetine, quinidine, terbinafine). May potentiate CV effects of salbutamol or other β2 agonists. Increased risk of QT interval prolongation with neuroleptics, class IA and III antiarrhythmics, TCAs, thiazide diuretics, moxifloxacin, eryhthromycin, methadone, mefloquine, lithium, cisapride. Increased risk of seizures with SSRIs, phenothiazines, butyrophenone, bupropion, tramadol. May decrease effectiveness of antihypertensive agents. May cause additive or synergistic effects with imipramine, venlafaxine, mirtazapine, pseudoephedrine, phenylephrine. Potentially Fatal: Increased neurotoxic effect with MAOIs.
Action
Description: Mechanism of Action: Atomoxetine is a highly selective and potent inhibitor of the pre-synaptic noradrenaline transporter with little or no activity at the other neuronal reuptake pumps or receptor sites. Duration: Up to 24 hours. Pharmacokinetics: Absorption: Rapidly and almost completely absorbed after oral administration. Bioavailability: 63% (extensive metabolisers); 94% (poor metabolisers). Time to peak plasma concentration: Approx 1-2 hours; delayed by approx 3 hours with high-fat meal. Distribution: Widely distributed in the body. Plasma protein binding: Approx 98% (mainly albumin). Metabolism: Metabolised in the liver via oxidation mainly by CYP2D6 and CYP2C19 to form 4-hydroxyatomoxetine (active metabolite) and N-desmethylatomoxetine. Excretion: Mainly via urine (80% as conjugated 4-hydroxy metabolite; <3% as unchanged drug); faeces (<17%). Elimination half-life: Approx 5 hours in extensive metabolisers; up to 24 hours in poor metabolisers.
Chemical Structure
Atomoxetine Source: National Center for Biotechnology Information. PubChem Database. Atomoxetine, CID=54841, https://pubchem.ncbi.nlm.nih.gov/compound/Atomoxetine (accessed on Jan. 21, 2020)
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