Drug class: Respiratory and CNS Stimulants

Medically reviewed by Drugs.com on Sep 10, 2024. Written by ASHP.

Introduction

Selective norepinephrine-reuptake inhibitor.

Uses for Atomoxetine

Attention Deficit Hyperactivity Disorder

Treatment of attention deficit hyperactivity disorder (ADHD) in adults and pediatric patients ≥6 years of age.

The American Academy of Pediatrics (AAP) has developed guidelines for children and adolescents with ADHD. For pediatric patients 6–12 years of age, FDA-labeled medications should be prescribed in addition to parent training in behavior management (PTBM) and/or behavioral classroom interventions. For choice of medication, evidence is particularly strong for stimulant medications (e.g., methylphenidate). Evidence is sufficient but not as strong for atomoxetine, extended-release guanfacine, and extended-release clonidine. For adolescents 12–18 years of age, FDA-labeled medications should be prescribed with the adolescent’s assent. The provider is also encouraged to prescribe behavioral and other evidence-based training interventions if available. Dosages should be titrated to achieve maximum benefit with tolerable side effects.

International experts have published recommendations for the treatment of ADHD in adults. Treatment of ADHD in adults should follow a multimodal approach that includes psychoeducation, pharmacotherapy, cognitive behavior therapy, and coaching. First-line pharmacotherapy agents include long-acting stimulants such as mixed amphetamine salts, methylphenidate, and lisdexamfetamine. Short-acting and intermediate-acting stimulants are considered second-line and can also be adjunctive agents. Atomoxetine may also be used as a second-line or adjunctive agent.

Autism Spectrum Disorder (ASD)

Has been used for the symptomatic treatment of inattention, impulsivity, and hyperactivity in pediatric patients with ASD^{† [off-label]}.

Guidelines from AAP suggest use of psychostimulants (e.g., methylphenidate, mixed amphetamine salts) for symptoms of hyperactivity, impulsivity, inattention, and distractibility in pediatric patients with ASD if problems persist after behavioral interventions. If psychostimulants cannot be used because of adverse effects or lack of efficacy, may consider use of atomoxetine or alpha-2 adrenergic agonists (e.g., clonidine, guanfacine).

Atomoxetine Dosage and Administration

General

Pretreatment Screening

• Weigh potential risk of suicidality against clinical need for atomoxetine prior to initiating therapy in children and adolescents.

• Screen for a personal or family history of bipolar disorder, mania, or hypomania.

• Screen for narrow angle glaucoma and avoid use of atomoxetne, if present.

• Perform a detailed family history and physical exam to screen for severe cardiac or vascular disorders. Conduct further evaluation if findings indicate disease.

• Obtain baseline hepatic function.

• Measure heart rate and BP at baseline.

Patient Monitoring

• Monitor for emergence of agitation, irritability, unusual behavioral changes, and suicidal thoughts and behaviors.

• Monitor weight and growth in pediatric patients.

• Monitor BP and heart rate following dosage increases and periodically during the treatment course.

• Monitor for exertional chest pain, unexplained syncope, and other symptoms of cardiac disease; if present, conduct a prompt cardiac evaluation.

• Monitor for symptoms of liver injury such as pruritus, dark urine, jaundice, right upper quadrant tenderness, or unexplained flu-like symptoms. Check enzyme levels upon first sign or symptom of liver dysfunction.

• Periodically re-assess usefulness of the drug in patients receiving long-term therapy.

Dispensing and Administration Precautions

• The Institute for Safe Medication Practices (ISMP) includes atomoxetine and atorvastatin on the ISMP List of Confused Drug Names, and recommends special safeguards to ensure the accuracy of prescriptions for these drugs; these may include strategies such as using both brand and generic names on prescriptions/labels and including the purpose of the medication on prescriptions.

Other General Considerations

• Do not use atomoxetine with monoamine oxidase inhibitors (MAOIs) or within 2 weeks of an MAOI. When atomoxetine is discontinued, allow at least 14 days to elapse before initiating an MAOI.

Administration

Oral Administration

Administer orally once daily in the morning or in 2 equally divided doses in the morning and late afternoon/early evening.

Administer without regard to meals.

Ocular irritant; swallow capsules whole. Do not open capsules or sprinkle contents on food.

If a dose is missed, take the missed dose as soon as it is remembered, but do not exceed the prescribed total daily dosage within a 24-hour period.

Dosage

Available as atomoxetine hydrochloride; dosage expressed in terms of atomoxetine.

Atomoxetine may be discontinued without tapering the dosage.

Pediatric Patients

ADHD

Oral

Children and adolescents ≥6 years of age weighing ≤70 kg: Initially, approximately 0.5 mg/kg daily. Increase dosage after ≥3 days to target dosage of approximately 1.2 mg/kg daily. Do not exceed total daily dose of 1.4 mg/kg or 100 mg, whichever is less. Dosages >1.2 mg/kg daily have not been shown in clinical trials to result in additional therapeutic benefit.

Children and adolescents ≥6 years of age weighing >70 kg: Initially, 40 mg daily. Increase dosage after ≥3 days to target dosage of approximately 80 mg daily. If optimum response not achieved after 2–4 additional weeks of therapy, may increase dosage to maximum of 100 mg daily. Dosages >100 mg daily have not been shown in clinical trials to result in additional therapeutic benefit.

Some patients may require maintenance/long-term pharmacologic treatment of ADHD; periodically reevaluate the long-term usefulness of atomoxetine for individual patients.

Adults

ADHD

Oral

Initially, 40 mg daily. Increase dosage after ≥3 days to target dosage of approximately 80 mg daily. If optimum response not achieved after 2–4 additional weeks of therapy, may increase dosage to maximum of 100 mg daily. Dosages >100 mg daily have not been shown in clinical trials to result in additional therapeutic benefit.

Some patients may require maintenance/long-term pharmacologic treatment of ADHD; periodically reevaluate the long-term usefulness of atomoxetine for individual patients.

Dosage Modification for Drug Interactions

Adults and pediatric patients weighing >70 kg receiving concomitant therapy with strong CYP2D6 inhibitors (e.g., paroxetine, fluoxetine, quinidine): initially, 40 mg daily; increase to the usual target dosage of 80 mg daily only if ADHD symptoms fail to improve after 4 weeks of therapy and the initial dosage is well tolerated.

Children and adolescents weighing ≤70 kg receiving concomitant therapy with strong CYP2D6 inhibitors (e.g., paroxetine, fluoxetine, quinidine): initially, 0.5 mg/kg daily; increase to the usual target dosage of 1.2 mg/kg daily only if ADHD symptoms fail to improve after 4 weeks of therapy and the initial dosage is well tolerated.

Special Populations

Hepatic Impairment

In patients with moderate hepatic impairment (Child-Pugh class B), reduce initial and target dosages to 50% of the usual dosage.

In patients with severe hepatic impairment (Child-Pugh class C), reduce initial and target dosages to 25% of the usual dosage.

Renal Impairment

No dosage adjustments required.

Geriatric Patients

No specific dosage recommendations.

Pharmacogenomic Considerations

Children and adolescents weighing ≤70 kg who are poor CYP2D6 metabolizers: manufacturer recommends initial atomoxetine dosage of 0.5 mg/kg daily; increase to the usual target dosage of 1.2 mg/kg daily only if ADHD symptoms fail to improve after 4 weeks of therapy and the initial dosage is well tolerated.

Clinical Pharmacogenetics Implementation Consortium (CPIC) provides alternative dosing recommendations for atomoxetine based on CYP2D6 phenotypes in children and adults (see Tables 1 and 2).

Cautions for Atomoxetine

Contraindications

• Known hypersensitivity to atomoxetine or any ingredient in the formulation.

• Concomitant or recent use (within 2 weeks) of a monoamine oxidase inhibitor (MAOI).

• Narrow angle glaucoma.

• Pheochromocytoma.

• Severe cardiovascular disorders.

Warnings/Precautions

Warnings

Suicidal Ideation

Increased risk of suicidal thinking observed in a pooled analysis of short-term clinical trials in children and adolescents with ADHD (see Boxed Warning). Not known whether risk extends to long-term use of the drug. Similar analysis of data from adults with ADHD or major depressive disorder found no increased risk of suicidal ideation or behavior in those receiving atomoxetine.

Balance risk of suicidality against clinical need for the drug.

Monitor pediatric patients closely for clinical worsening, suicidal ideation or behaviors, or unusual changes in behavior, particularly during the first few months of therapy and following dosage adjustment. Monitoring should include daily observation by family members and caregivers and frequent contact with the prescribing clinician, particularly if the patient’s behavior changes or is a concern.

Consider discontinuance of therapy in patients with emergent suicidality or manifestations that may be precursors to emerging suicidality (e.g., anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia, hypomania, mania), particularly if such manifestations are severe or abrupt in onset or were not part of the patient’s presenting symptoms.

Other Warnings and Precautions

Severe Liver Injury

Severe hepatic injury reported rarely; manifested by increased hepatic enzymes (up to 40 times ULN) and jaundice (bilirubin up to 12 times ULN). In some cases, progressed to acute hepatic failure or required liver transplantation.

Adverse hepatic effects may occur several months after atomoxetine initiation; laboratory abnormalities may continue to worsen for several weeks after discontinuance.

Determine hepatic enzyme concentrations if signs or symptoms ofhepatic dysfunction (e.g., pruritus, dark urine, jaundice, right upper quadrant tenderness, unexplained flu-like symptoms) occur. Discontinue atomoxetine in patients with jaundice or laboratory evidence of hepatic injury and do not reinitiate.

Serious Cardiovascular Events

Sudden unexplained death, stroke, and MI reported in adults with ADHD receiving usual dosages of atomoxetine; sudden death also reported in children and adolescents with structural cardiac abnormalities or other serious cardiac conditions receiving usual dosages of the drug.

Thoroughly review medical history (including evaluation for family history of sudden death or ventricular arrhythmia) and perform physical examination in all children, adolescents, and adults being considered for atomoxetine therapy; if initial findings suggest presence of cardiac disease, perform further cardiac evaluation (e.g., ECG, echocardiogram).

In general, avoid use in patients with known serious structural cardiac abnormalities, cardiomyopathy, serious heart rhythm abnormalities, CAD, or other serious cardiac conditions.

Conduct prompt cardiac evaluation in patients who develop exertional chest pain, unexplained syncope, or other manifestations suggestive of cardiac disease during atomoxetine therapy.

Effects on BP and Heart Rate

Use with caution in patients whose underlying medical conditions could be worsened by increases in BP or heart rate (e.g., certain patients with hypertension, tachycardia, or cardiovascular or cerebrovascular disease).

Use with caution in patients predisposed to hypotension and patients with conditions associated with abrupt heart rate or BP changes.

Do not use in patients with severe cardiac or vascular disorders whose condition would be expected to deteriorate if they experienced clinically important increases in BP or heart rate.

Measure pulse and BP at baseline, following atomoxetine dosage increases, and periodically while on therapy to detect possible clinically important increases.

Emergence of New Psychotic or Manic Effects

Psychotic or manic symptoms (e.g., hallucinations, delusional thinking, or mania) may occur with usual dosages in children and adolescents without prior history of psychotic illness. If psychotic symptoms occur, consider causal relationship to atomoxetine, and discontinue therapy as appropriate.

Screening Patients for Bipolar Disorder

Increased risk of developing mania or mixed episodes in patients with or at risk for bipolar disorder. Adequately screen for risk factors for bipolar disorder such as a personal or family history of mania and depression before initiating treatment with atomoxetine.

Aggressive Behavior or Hostility

Emergence or worsening of aggressive behavior or hostility can occur; monitor patients accordingly. If such symptoms occur during treatment, consider a possible causal role of atomoxetine.

Allergic Events

Allergic reactions, including anaphylactic reactions, angioneurotic edema, urticaria, and rash reported.

Effects of Urine Outflow from the Bladder

Possible urinary retention and urinary hesitation.

Priapism

Priapism reported rarely in pediatric and adult patients; requires prompt medical attention.

Effects on Growth

Monitor growth of pediatric patients receiving atomoxetine. Potential for temporary suppression of normal height and/or weight patterns following initiation of therapy.

Pharmacogenomic Considerations

Atomoxetine is primarily metabolized by CYP2D6. Poor metabolizers of CYP2D6 have significantly higher plasma concentrations of atomoxetine compared with extensive metabolizers; higher blood levels can lead to higher rates of some adverse effects. Blood levels in poor metabolizers are similar to those attained by taking strong inhibitors of CYP2D6 with atomoxetine.

Laboratory tests are available to identify CYP2D6 poor metabolizers.

Dosage adjustment may be necessary when administered to CYP2D6 poor metabolizers.

Concomitant Use of Strong CYP2D6 Inhibitors

Because atomoxetine is primarily metabolized by CYP2D6, dosage adjustment may be necessary when coadministered with strong CYP2D6 inhibitors (e.g., paroxetine, fluoxetine, and quinidine).

Tics in Patients with ADHD and Comorbid Tourette's Disorder

Atomoxetine does not appear to worsen tics in patients with ADHD and comorbid Tourette’s disorder.

Anxiety in Patients with ADHD and Comorbid Anxiety Disorder

Postmarketing trials have not demonstrated worsening anxiety in patients with ADHD and comorbid anxiety disorder.

Specific Populations

Pregnancy

Available data in pregnant women are insufficient to establish a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Some animal reproduction studies found adverse developmental outcomes when atomoxetine was administered during organogenesis.

A pregnancy registry has been established to monitor pregnancy outcomes in women exposed to ADHD medications. Register pregnant patients by calling the National Pregnancy Registry for ADHD Medications at 1-866-961-2388 or visiting [Web].

Lactation

Distributed into animal milk; not known whether atomoxetine is distributed into human milk. Consider the developmental and health benefits of breast-feeding along with the mother’s clinical need for atomoxetine and any potential adverse effects on the breast-fed child from the drug or underlying maternal condition.

Pediatric Use

Safety and efficacy not established in children <6 years of age.

Increased risk of suicidal ideation observed in a pooled analysis of 12 short-term controlled clinical trials in pediatric patients with ADHD (11 studies) or enuresis (1 study); risk of suicidal ideation was about 0.4% in those receiving atomoxetine versus 0% in those receiving placebo. All events representing suicidal behavior or thinking occurred in children ≤12 years of age and occurred during first month of therapy. Not known whether risk extends to long-term use. Balance risk of suicidality against clinical need for the drug.

Sudden death reported in children and adolescents with structural cardiac abnormalities or other serious cardiac conditions receiving usual dosages of stimulants.

Potential for temporary (e.g., 9–12 months) suppression of normal height and/or weight patterns following initiation of atomoxetine therapy in pediatric patients; rebound in height and weight gains reported with continued therapy. Monitor growth of patients receiving atomoxetine therapy.

Geriatric Use

Safety and efficacy not established.

Hepatic Impairment

Increased systemic exposure observed in patients with moderate or severe hepatic impairment. Dosage adjustment recommended.

Renal Impairment

Increased systemic exposure observed in end stage renal disease; however, no dosage adjustment is necessary.

Common Adverse Effects

Most common adverse reactions (≥5%) in children and adolescents included nausea, vomiting, fatigue, decreased appetite, abdominal pain, and somnolence.

Most common adverse reactions (≥5%) in adults included constipation, dry mouth, nausea, decreased appetite, dizziness, erectile dysfunction, and urinary hesitation.

Drug Interactions

Metabolized principally by CYP2D6. Does not cause clinically important inhibition or induction of CYP enzymes, including 1A2, 3A, 2D6, and 2C9.

Drugs Affecting Hepatic Microsomal Enzymes

Strong CYP2D6 inhibitors (e.g., paroxetine, fluoxetine, quinidine): Potential for increased plasma atomoxetine concentrations. Dosage adjustment of atomoxetine required if used concomitantly.

CYP2D6 substrates (e.g., desipramine):Pharmacokinetics of CYP2D6 substrate not altered. No dosage adjustment is required for drugs metabolized by CYP2D6.

CYP3A substrates (e.g., midazolam): Pharmacokinetics of CYP3A substrate not substantially altered. No dosage adjustment is required for drugs metabolized by CYP3A.

Drugs Affecting Gastric pH

No important pharmacokinetic interactions reported with drugs that increase gastric pH.

Specific Drugs

Atomoxetine Pharmacokinetics

Absorption

Bioavailability

Rapidly absorbed following oral administration, with peak plasma concentration attained in approximately 1–2 hours.

Absolute bioavailability is 63% in extensive metabolizers of CYP2D6 and 94% in poor metabolizers.

In patients with the poor CYP2D6 metabolizer phenotype, AUC and peak plasma concentrations of atomoxetine are 10- and 5-fold greater, respectively, than in extensive metabolizers.

Food

Standard high-fat meal decreases rate, but not extent, of absorption in adults, resulting in a 37% lower C_max and delayed T_max by 3 hours. In children and adolescents, food reduces peak plasma concentration by 9%.

Special Populations

In patients with moderate (Child-Pugh class B) or severe (Child-Pugh class C) hepatic impairment, systemic exposure is increased 2- or 4-fold, respectively.

Distribution

Extent

Not known whether atomoxetine is distributed into human milk.

Plasma Protein Binding

98% (principally albumin).

Elimination

Metabolism

Principally metabolized by CYP2D6 to an equipotent metabolite (4-hydroxyatomoxetine) that circulates in plasma at much lower concentrations; undergoes subsequent conjugation with glucuronic acid.

Elimination Route

Excreted mainly as metabolites in urine (80%) and feces (<17%).

Half-life

Extensive CYP2D6 metabolizers: 5.2 hours.

Poor CYP2D6 metabolizers: 21.6 hours.

Stability

Storage

Oral

Capsules

20–25°C (excursions permitted between 15–30°C).

Actions

• Mechanism of action in the management of ADHD appears to be related to selective inhibition of the presynaptic norepinephrine transporter.

• Minimal affinity for other noradrenergic receptors or for other neurotransmitter transporters or receptors.

• Not considered a stimulant.

Advice to Patients

• Provide the patient or caregiver with a copy of the manufacturer’s patient information (medication guide); discuss and answer questions about its contents (e.g., benefits and risks of atomoxetine therapy, appropriate use) as needed. Instruct the patient or caregiver to read and understand the contents of the medication guide before initiating therapy and each time the prescription is refilled.

• Advise patients, caregivers, and family members to immediately inform their clinician if clinical worsening, anxiety, agitation, panic attacks, insomnia, irritability, aggressive behaviors, hostility, impulsivity, restlessness, mania, depression, suicidal ideation or behaviors, or unusual changes in behavior occur, particularly during the first few months after initiation of therapy or following dosage adjustments.

• Advise patients and/or caregivers that hepatic dysfunction may develop rarely. Advise patients to inform their clinician immediately if symptoms of hepatic injury occur (e.g., pruritus, jaundice, dark urine, upper right-sided abdominal tenderness, unexplained flu-like symptoms).

• Advise patients and caregivers to look for signs of activation of mania/hypomania.

• Advise patients of the need to monitor BP and heart rate following dosage increases and periodically during the treatment course.

• Advise patients to inform their clinician if symptoms of exertional chest pain, unexplained syncope, or other symptoms of cardiac disease occur.

• Advise patients and caregivers to contact their healthcare provider as soon as possible if increases in aggression or hostility occur.

• Advise patients to exercise caution when driving or operating machinery until the effects of the drug on the individual are known.

• Advise patients to seek immediate medical attention if an erection persists for more than 4 hours.

• Advise patients to take atomoxetine exactly as prescribed. If a patient misses a dose of the drug, the missed dose should be taken as soon as it is remembered, but the amount of atomoxetine taken within a 24-hour period should not exceed the prescribed total daily dosage of the drug.

• Advise patients and/or caregivers that atomoxetine capsules should not be opened because the drug is an ocular irritant; if eye contact occurs, flush the affected eye(s) with water immediately, obtain medical advice, and wash hands and potentially contaminated surfaces as soon as possible.

• Advise patients to inform their clinician of any history of physical or mental disorders (e.g., cardiovascular disease, liver disease, depression).

• Advise patients to inform their clinician if they are or plan to become pregnant or plan to breast-feed. Advise patients that there is a pregnancy registry that monitors pregnancy outcomes in women exposed to atomoxetine during pregnancy: National Pregnancy Registry for ADHD Medications at 1-866-961-2388 or [Web].

• Advise patients to inform their clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary and herbal supplements, as well as any concomitant illnesses (e.g., glaucoma, suicidal ideation or behaviors, cardiac/cardiovascular disease, mental/psychiatric disorder, hepatic disease).

• Advise patients of other important precautionary information.

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

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