atomoxetine (Rx)

>10%

Xerostomia (dry mouth) (21%)

Headache (2-19%)

Abdominal pain (7-18%)

Decreased appetite (11-16%)

Insomnia (2-15%)

Cough (11%)

Somnolence (11%)

Vomiting (3-11%)

1-10%

Nausea (10%)

Increases in blood pressure (BP; ≥15-20 mm Hg) and heart rate (HR; ≥20 beats/min) (5-10%)

Erectile dysfunction (9%)

Hot flashes (8%)

Dizziness (5-8%)

Urinary hesitation or retention (7%)

Decreased weight (4-7%)

Depression (4-7%)

Irritability (<6%)

Dyspepsia (4%)

Ejaculation disorder (3%)

Sinus headache (3%)

Constipation (2%)

Dermatitis (2%)

Menstrual disorder (2%)

Mood swings (1-2%)

Postmarketing Reports

Paresthesia

Cardiovascular: QT prolongation, syncope

Peripheral vascular: Raynaud phenomenon

General: Lethargy

Neurologic: Hypesthesia, paresthesia in children and adolescents, sensory disturbances, tics

Psychiatric: Depression and depressed mood, anxiety

Seizures: Cases include patients with preexisting seizure disorders and those with identified risk factors for seizures, as well as patients with neither history of nor identified risk factors for seizures; exact relation between atomoxetine and seizures is difficult to evaluate because of uncertainty about background risk of seizures in patients with attention-deficit/hyperactivity disorder (ADHD)

Skin: Hyperhidrosis

Urogenital: Male pelvic pain, urinary hesitation or retention in children and adolescents

Musculoskeletal: Rhabdomyolysis

Alopecia

Contraindications

Hypersensitivity

Narrow-angle glaucoma

Administration concomitantly with or within 14 days of monoamine oxidase inhibitor (MAOI) therapy; risk of potentially fatal reaction, including hyperthermia, myoclonus, altered mental status, and neuroleptic malignant syndrome (NMS)-like symptoms

Pheochromocytoma: Serious reactions, including elevated blood pressure and tachyarrhythmia, have been reported in patients with current or previous pheochromocytoma

Severe cardiovascular disorders where condition would deteriorate because BP increases by 15-20 mm Hg or HR increases by 20 beats/min; risk is greater in poor CYP2D6 metabolizers

Cautions

If drug is given concomitantly with CYP2D6 inhibitor, wait 4 weeks after initiation before adjusting dosage

Liver injury reported within 120 days of initiation of atomoxetine; patients may present with elevated liver enzymes (>20 × ULN) and jaundice with significantly elevated bilirubin levels (>2 × ULN), followed by recovery upon discontinuance of atomoxetine

Orthostatic hypotension and syncope reported

Risk of suicidal thoughts in children and adolescents

Small risk of allergic reaction

Use caution in hypertension, tachycardia (see Contraindications)

Sudden deaths, stroke, and myocardial infarction reported in patients with structural cardiac abnormalities or other serious heart problems taking stimulants at usual doses; patients should have a careful history and physical exam to assess for presence of cardiovascular disease; consider not using atomoxetine in adults with clinically significant cardiac abnormalities

Patients who develop symptoms such as exertional chest pain, unexplained syncope, or other symptoms suggestive of cardiac disease during stimulant treatment should undergo a prompt cardiac evaluation

Particular care should be taken in using stimulants to treat ADHD patients with comorbid bipolar disorder because of concern for possible induction of mixed/manic episode in such patients

Aggressive behavior or hostility is often observed in children and adolescents with ADHD; monitor for the appearance of or worsening of aggressive behavior or hostility

Monitor growth of children ages 7 to 10 years during treatment with stimulants; may need to interrupt therapy in patients not growing or gaining weight as expected

Urinary hesitancy or sexual dysfunction may occur

Rare instances of priapism reported, sometimes necessitating surgical intervention; typically not reported during initiation but often occurring subsequent to dosage increase; immediate medical attention should be sought for abnormally sustained or frequent and painful erections

Drug can be discontinued without being tapered

Hypesthesia, paresthesia in children and adolescents, sensory disturbances

Rare reports of allergic reactions, including anaphylactic reactions, angioneurotic edema, urticaria, and rash

Use with caution in patietns with bipolar disorder, history of hypertension, hepatic impairment, existing anxiety disorder, history of urinary retention, or tics related to Tourette disorder

Pregnancy

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to ADHD medications, during pregnancy; healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for ADHD Medications at 1-866-961-2388 or visiting https://womensmentalhealth.org/adhd-medications

Available published studies with atomoxetine use in pregnant women are insufficient to establish drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes

Animal data

• Some animal reproduction studies of atomoxetine had adverse developmental outcomes; one of 3 studies in pregnant rabbits dosed during organogenesis resulted in decreased live fetuses and an increase in early resorptions, as well as slight increases in the incidences of atypical origin of carotid artery and absent subclavian artery
• These effects were observed at plasma levels (AUC) 3 times and 0.4 times the human plasma levels in extensive and poor metabolizers receiving the maximum recommended human dose (MRHD), respectively; in rats dosed prior to mating and during organogenesis a decrease in fetal weight (female only) and an increase in the incidence of incomplete ossification of the vertebral arch in fetuses were observed at a dose approximately 5 times the MRHD on a mg/m² basis
• In one of 2 studies in which rats were dosed prior to mating through periods of organogenesis and lactation, decreased pup weight and decreased pup survival were observed at doses corresponding to 5-6 times MRHD on a mg/m² basis; no adverse fetal effects were seen in pregnant rats dosed during the organogenesis period

Lactation

There are no data on presence of atomoxetine or its metabolite in human milk, effects on breastfed child, or on milk production; drug is present in animal milk; when a drug is present in animal milk, it is likely that drug will be present in human milk

Developmental and health benefits of breastfeeding should be considered along with mother’s clinical need for therapy and any potential adverse effects on breastfed child from drug or from underlying maternal condition

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

Selective inhibition of presynaptic norepinephrine reuptake

Absorption

Bioavailability: 63-94%

Onset: 2-4 wk

Peak plasma time: 1-2 hr

Distribution

Vd: 0.85 L/kg (IV)

Protein bound: 98%

Vd: 0.85 L/kg

Metabolism

Metabolized in liver by CYP2D6

Metabolites: 4-Hydroxyatomoxetine (equipotent), N-desmethylatomoxetine (less potent)

Elimination

Half-life: 5.2 hr

Total body clearance: 0.35 L/hr/kg

Excretion: Urine (80%), feces (17%)