Atomoxetine

Oral
Attention deficit hyperactivity disorder

Patient taking strong CYP2D6 inhibitors (e.g. paroxetine, fluoxetine, quinidine, terbinafine):
Adult and children weighing >70 kg: Initially, 40 mg daily, may be increased to 80 mg daily only if initial dose is well tolerated but symptoms fail to improve after 4 weeks.
Children weighing up to 70 kg: Initially, 0.5 mg/kg daily, may be increased to 1.2 mg/kg daily only if initial dose is well tolerated but symptoms fail to improve after 4 weeks.
Treatment and dosage recommendations may vary among countries and individual products (refer to specific product guidelines).

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 as compared with individuals with normal activity known as 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.

Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline as of February 2018:

Phenotype/Genotype	Implications	Recommendations
CYP2D6 ultrarapid metabolisers Individuals carrying duplications of functional alleles (e.g. *1/*1xN, *1/*2xN, *2/*2xN)	Unlikely to achieve adequate atomoxetine serum concentrations resulting in decreased efficacy at standard doses.	Adult: Initially, 40 mg daily, increase to 80 mg daily after 3 days. If no observed clinical response and in the absence of adverse events after 14 days, consider increasing dose to 100 mg daily. If no observed clinical response after 14 days, consider obtaining a peak plasma concentration 1-2 hours after administration. If concentration is <200 ng/mL, consider proportional dose increase to approach 400 ng/mL. Doses >100 mg daily may be necessary to achieve target levels. Child: Initially, 0.5 mg/kg daily, increase to 1.2 mg/kg daily after 3 days. If no observed clinical response and in the absence of adverse events after 14 days, consider obtaining a peak plasma concentration 1-2 hours after administration. If concentration is <200 ng/mL, consider proportional dose increase to approach 400 ng/mL.
CYP2D6 normal metabolisers Individuals carrying 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 atomoxetine response and increased discontinuation due to lack of efficacy as compared to poor metabolisers.	Adult: Initially, 40 mg daily, increase to 80 mg daily after 3 days. If no observed clinical response and in the absence of adverse events after 14 days, consider increasing dose to 100 mg daily. If no observed clinical response after 14 days, consider obtaining a peak plasma concentration 1-2 hours after administration. If concentration is 200 ng/mL, consider proportional dose increase to approach 400 ng/mL. Doses >100 mg daily may be necessary to achieve target levels. Child: Initially, 0.5 mg/kg daily, increase to 1.2 mg/kg daily after 3 days. If no observed clinical response and in the absence of adverse events after 14 days, consider obtaining a peak plasma concentration 1-2 hours after administration. If concentration is <200 ng/mL, consider proportional dose increase to approach 400 ng/mL.
CYP2D6 normal or intermediate metabolisers Individuals carrying 2 decreased function alleles or 1 normal function and 1 no function allele (e.g. *1/*4, *1/*5, *41/*41) without *10 allele present	Possible higher atomoxetine concentrations compare to normal metabolisers but with questionable clinical significance, and enhanced risk of discontinuation compared to poor metabolisers.	Adult: Initially, 40 mg daily, increase to 80 mg daily after 3 days. If no observed clinical response and in the absence of adverse events after 14 days, consider increasing dose to 100 mg daily. If no observed clinical response after 14 days, consider obtaining a peak plasma concentration 1-2 hours after administration. If concentration is <200 ng/mL, consider proportional dose increase to approach 400 ng/mL. Doses >100 mg daily may be necessary to achieve target levels. Child: Initially, 0.5 mg/kg daily, increase to 1.2 mg/kg daily after 3 days. If no observed clinical response and in the absence of adverse events after 14 days, consider obtaining a peak plasma concentration 1-2 hours after administration. If concentration is <200 ng/mL, consider proportional dose increase to approach 400 ng/mL.
CYP2D6 normal or intermediate metabolisers Individuals carrying 2 decreased function alleles or 1 normal function and 1 no function allele (e.g. *10/*10, *10/*41) with *10 allele present	Reduced atomoxetine metabolism resulting in higher plasma concentrations compared to normal metabolisers, and enhanced risk of discontinuation compared to poor metabolisers.	Adult: Initially, 40 mg daily, increase to 80 mg daily if no observed clinical response and in the absence of adverse events after 14 days. If response is inadequate after 14 days, consider obtaining a plasma concentration 2-4 hours after administration. If concentration is <200 ng/mL, consider proportional dose increase to approach 400 ng/mL. If adverse effects occur at any time, consider dose reduction. Child: Initially, 0.5 mg/kg daily. If no observed clinical response and in the absence of adverse events after 14 days, consider obtaining plasma concentration 2-4 hours after administration. If response is inadequate and concentration is <200 ng/mL, consider proportional dose increase to approach 400 ng/mL. If adverse effects occur at any time, consider dose reduction.
CYP2D6 intermediate metabolisers Individuals carrying 1 decreased function allele and 1 no function allele (e.g. *4/*10, *4/*41, *5/*9)	Reduced atomoxetine metabolism resulting in higher plasma concentrations compared to normal metabolisers, and enhanced risk of discontinuation compared to poor metabolisers.	Adult: Initially, 40 mg daily, increase to 80 mg daily if no observed clinical response and in the absence of adverse events after 14 days. If response is inadequate after 14 days, consider obtaining a plasma concentration 2-4 hours after administration. If concentration is <200 ng/mL, consider proportional dose increase to approach 400 ng/mL. If adverse effects occur at any time, consider dose reduction. Child: Initially, 0.5 mg/kg daily. If no observed clinical response and in the absence of adverse events after 14 days, consider obtaining plasma concentration 2-4 hours after administration. If response is inadequate and concentration is <200 ng/mL, consider proportional dose increase to approach 400 ng/mL. If adverse effects occur at any time, consider dose reduction.
CYP2D6 poor metabolisers Individuals carrying only non-functional alleles (e.g. *3/*4, *4/*4, *5/*5, *5/*6)	Significantly reduced atomoxetine metabolism resulting in higher plasma concentrations and enhanced risk of side effects, but with greater symptom improvement in those who tolerate treatment compared to non-poor metabolisers.	Adult: Initially, 40 mg daily, increase to 80 mg daily if no observed clinical response and in the absence of adverse events after 14 days. If response is inadequate after 14 days, consider obtaining a plasma concentration 2-4 hours after administration. If concentration is <200 ng/mL, consider proportional dose increase to approach 400 ng/mL. If adverse effects occur at any time, consider dose reduction. Child: Initially, 0.5 mg/kg daily. If no observed clinical response and in the absence of adverse events after 14 days, consider obtaining plasma concentration 4 hours after administration. If response is inadequate and concentration is <200 ng/mL, consider proportional dose increase to approach 400 ng/mL. If adverse effects occur at any time, consider dose reduction.

Moderate (Child-Pugh class B): Reduce to 50% of the usual dose. Severe (Child-Pugh class C): Reduce to 25% of the usual dose.

Atomoxetine May be taken with or without food. Swallow whole, do not open cap.

Narrow-angle glaucoma, current or history of phaeochromocytoma, severe CV disorders (e.g. severe hypertension, heart failure, angina, arterial occlusive disease, cardiomyopathies, MI, haemodynamically significant congenital heart disease, potentially fatal arrhythmias and channelopathies, known serious structural cardiac abnormalities), severe cerebrovascular disorders (e.g. cerebral aneurysm, stroke). Concomitant use with or within 14 days after discontinuing treatment with MAOIs.

Patient with known or suspected long QT interval or family history of QT prolongation, underlying medical conditions that could be worsened by increased heart rate or blood pressure (e.g. hypertension, tachycardia, CV or cerebrovascular disease), conditions predisposed to hypotension or associated with abrupt heart rate or blood pressure changes; bipolar disorder or risk factors for bipolar disorder (e.g. family history of depression and mania), existing anxiety disorders, tics related to Tourette's syndrome; history of seizures, urinary retention or bladder outlet obstruction. CYP2D6 polymorphisms. Hepatic impairment. Children. Pregnancy and lactation.

Significant: Suicide-related behaviour (e.g. suicide attempts, suicidal ideation), manic or psychotic 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, QT interval prolongation); seizures, urinary retention or hesitancy. Rarely, hepatic effects (e.g. elevated hepatic enzymes and bilirubin, jaundice, severe liver injury, acute hepatic failure); anxiety and depression or depressed mood, tics; allergic reactions (e.g. anaphylactic reactions, angioneurotic oedema, rash, urticaria), priapism.
Cardiac disorders: Palpitation, tachycardia.
Eye disorders: Mydriasis, blurred vision.
Gastrointestinal disorders: Nausea, vomiting, dry mouth, abdominal pain, constipation, dyspepsia, flatulence.
General disorders and administration 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, migraine, dysgeusia, tremor, hypoaesthesia, paraesthesia.
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. Rarely, Raynaud's phenomenon.
Potentially Fatal: Serious CV events (e.g. sudden death, stroke, MI).

PO: C

This drug may cause dizziness, somnolence or fatigue, if affected, do not drive or operate machinery.

Perform CYP2D6 genotyping prior to treatment initiation and obtain plasma drug concentration during therapy to estimate atomoxetine exposure if patient response becomes inadequate. Evaluate cardiac conditions (at baseline or if symptoms of cardiac disease develop during treatment). Assess risk factors for bipolar disorder (e.g. history of bipolar disorder, depression, mania or hypomania) before initiating treatment. Monitor blood pressure and heart rate at baseline, after increasing dose, and periodically during treatment; liver enzymes upon signs or symptoms of liver dysfunction and for several weeks after treatment discontinuation; appetite and growth (e.g. weight, height) in children; weight for adults. Closely monitor for signs of suicidal ideation and behavioural changes during initial months of therapy or periods of dose changes; and signs or symptoms of mania or hypomania, anxiety, depression or tics during treatment.

Symptoms: Dizziness, somnolence, gastrointestinal symptoms, rash, pruritus, tremor, abnormal behaviour, hyperactivity, agitation, mild to moderate sympathetic nervous system activation (e.g. mydriasis, dry mouth, tachycardia, increased blood pressure), and seizures. Rarely, QT prolongation. Management: Symptomatic and supportive treatment. Establish airway. May administer activated charcoal within 1 hour of ingestion to limit drug absorption. Observe patient and monitor cardiac and vital signs.

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, erythromycin, methadone, mefloquine, lithium, cisapride. Increased risk of seizures with SSRIs, TCAs, phenothiazines, butyrophenone, bupropion, tramadol, mefloquine and chloroquine. May reduce effectiveness of antihypertensive agents. May cause additive or synergistic effects with imipramine, venlafaxine, mirtazapine, pseudoephedrine, phenylephrine.
Potentially Fatal: Increased neurotoxic effects or fatal reactions (e.g. rigidity, myoclonus, hyperthermia, autonomic instability with potential rapid fluctuations of vital signs, and changes in the mental status such as severe agitation that may lead to delirium and coma) with MAOIs.

Reduced rate of absorption and delayed time to peak plasma concentration with high-fat meal.

Description:
Mechanism of Action: Atomoxetine is a highly selective and potent inhibitor of the pre-synaptic noradrenaline transporter which inhibits the reuptake of norepinephrine. It has minimal or no activity to other noradrenergic receptors or neuronal reuptake pumps or receptor sites.
Duration: Up to 24 hours.
Pharmacokinetics:
Absorption: Well absorbed from the gastrointestinal tract. Bioavailability: 63% (extensive metabolisers); 94% (poor metabolisers). Time to peak plasma concentration: Approx 1-2 hours; delayed 3 hours with high-fat meal.
Distribution: Widely distributed in the body. Plasma protein binding: Approx 98%, mainly to albumin.
Metabolism: Metabolised in the liver mainly by CYP2D6 and CYP2C19 into 4-hydroxyatomoxetine (active metabolite) and N-desmethylatomoxetine.
Excretion: Via urine (80% as conjugated 4-hydroxy metabolite; <3% as unchanged drug); faeces (<17%). Elimination half-life: Approx 5 hours (extensive metabolisers); up to 24 hours (poor metabolisers).

Source: National Center for Biotechnology Information. PubChem Compound Summary for CID 54841, Atomoxetine. https://pubchem.ncbi.nlm.nih.gov/compound/Atomoxetine. Accessed May 28, 2024.

Store between 15-30°C.

Other CNS Drugs & Agents for ADHD

N06BA09 - atomoxetine ; Belongs to the class of centrally-acting sympathomimetics. Used as CNS stimulant.

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