Atomoxetine is a selective norepinephrine-reuptake inhibitor.1
Attention Deficit Hyperactivity Disorder
Atomoxetine hydrochloride is used for the treatment of attention deficit hyperactivity disorder (ADHD) in adults and pediatric patients 6 years of age and older.1
The efficacy and safety of atomoxetine in pediatric patients were established in 4 short-term (6-9 weeks) controlled studies and a longer-term (12 month) controlled study in children and adolescents.1, 4, 10, 12, 18
In 2 identical, randomized, double-blind, placebo-controlled studies, pediatric patients 7-13 years of age with ADHD were randomized to receive either atomoxetine, in divided doses in the early morning and late afternoon, or placebo for 9 weeks.1, 10 The dosage of atomoxetine was titrated on a weight-adjusted basis according to clinical response; the mean final dosage in both studies was about 1.6 mg/kg per day.1 The main efficacy measure was the mean change from baseline in the ADHD Rating Scale (ADHDRS) total score.1, 10 Atomoxetine was found to substantially reduce symptoms of ADHD based on the ADHDRS scale in both studies compared to placebo.1, 10 Substantial reductions were also observed with atomoxetine versus placebo on the Clinical Global Impressions-Severity (CGI-S) scale and the Conners' Parent Rating Scale-Revised: Short Form (CPRS-R:S).10
In another randomized, double-blind, placebo-controlled study in 171 pediatric patients 6-16 years of age with ADHD, patients were randomized to receive either atomoxetine as a once daily dose in the morning or placebo for 6 weeks.1, 4 The dosage of atomoxetine was titrated on a weight-adjusted basis according to clinical response; the mean final dosage of atomoxetine was 1.3 mg/kg per day.1 The main efficacy measure waschange from baseline in the ADHDRS score.1, 4 Atomoxetine therapy resulted in substantial reductions in the ADHDRS score compared to placebo.1, 4 Substantial reductions were also observed in the CGI-S score and the CPRS-R:S score with atomoxetine versus placebo.4
In a randomized, placebo-controlled, dose-response study, 297 pediatric patients 8-18 years of age with ADHD were randomized to receive placebo or atomoxetine (0.5 mg/kg per day, 1.2 mg/kg per day, or 1.8 mg/kg per day) for 8 weeks.1, 12 Patients randomized to atomoxetine received the drug in 2 divided doses in the morning and late afternoon.1, 12 The main efficacy measure was the change from baseline in the ADHDRS score.1, 12 Patients who received atomoxetine dosages of 1.2 or 1.8 mg/kg per day demonstrated substantial reductions in ADHD symptoms compared to patients who received placebo based on the ADHDRS scale.1, 12 Atomoxetine 0.5 mg/kg per day did not result in substantial reductions in ADHD symptoms compared to placebo.1
In a randomized, double-blind, placebo-controlled maintenance study, children and adolescents 6-15 years of age with ADHD initially received open-label atomoxetine (1.2-1.8 mg/kg daily in 2 divided doses) for 10 weeks.1, 18 The 416 patients who responded to therapy during the open-label phase were randomized at week 12 to receive either atomoxetine (at the same dosage as the final dosage in the open-label period) or placebo for an additional 9 months.1, 18 At study end point, relapse (defined as an increase in ADHDRS total score to 90% of baseline score and an increase of 2 or more points on the CGI-S scale) occurred in fewer patients receiving atomoxetine than those receiving placebo (22 versus 38%).18 When the more sensitive secondary definition of relapse (an increase in ADHDRS total score to 50% of baseline score and an increase of 2 or more points on the CGI-S scale) was used, the relapse rate also was substantially lower in atomoxetine-treated patients (28%) than in placebo-treated patients (48%).18 In addition, patients who continued receiving atomoxetine experienced a longer time to relapse and achieved superior psychosocial functioning compared to those receiving placebo.1, 18
The efficacy and safety of atomoxetine for the treatment of ADHD in adults were established in 2 identical randomized, double-blind, placebo-controlled 10-week studies.1, 11 Patients were randomized to receive atomoxetine, administered in divided doses in the early morning and late afternoon/early evening and titrated to clinical response (range: 60-120 mg per day), or placebo.1, 11 In both studies, the mean final dosage of atomoxetine was approximately 95 mg per day.1 The main efficacy outcome was the sum of the Inattention and Hyperactivity/Impulsivity subscales of the investigator-rated Conners' Adult ADHD Rating Scale (CAARS).1, 11 In both studies, patients receiving atomoxetine had substantial reductions from baseline in both inattentive and hyperactive/impulsive ADHD symptoms compared to patients receiving placebo.1, 11
The American Academy of Pediatrics (AAP) has developed guidelines for children and adolescents with ADHD.19 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.19 For choice of medication, the evidence is particularly strong for stimulant medications (e.g., methylphenidate).19 Evidence is sufficient but not as strong for atomoxetine, extended-release guanfacine, and extended-release clonidine.19 For adolescents 12-18 years of age, FDA-labeled medications should be prescribed with the adolescent's assent.19 The provider is also encouraged to prescribe behavioral and other evidence-based training interventions if available.19 Dosages should be titrated to achieve maximum benefit with tolerable side effects.19
International experts have published recommendations for the treatment of ADHD in adults.20, 21 Treatment of ADHD in adults should follow a multimodal approach that includes psychoeducation, pharmacotherapy, cognitive behavior therapy, and coaching.20 First-line pharmacotherapy agents include long-acting stimulants such as mixed amphetamine salts, methylphenidate, and lisdexamfetamine.21 Short-acting and intermediate-acting stimulants are considered second-line and can also be adjunctive agents.21 Atomoxetine may also be used as a second-line or adjunctive agent.21
Atomoxetine has been used for the symptomatic treatment of inattention, impulsivity, and hyperactivity in pediatric patients with autism spectrum disorder (ASD)† .22
The AAP has developed guidelines for children and adolescents with ASD.22 While there are no currently available medications that correct core social and communication symptoms in patients with ASD, there are medications that may be used to help manage behavioral and psychiatric symptoms.22 For symptoms of hyperactivity, impulsivity, inattention, and distractibility, the AAP suggests the use of psychostimulants (e.g., methylphenidate, mixed amphetamine salts) after behavioral approaches are implemented, if problems persist.22 If psychostimulants cannot be used because of adverse effects or lack of efficacy, use of atomoxetine or alpha-2 adrenergic agonists (e.g., clonidine, guanfacine) may be considered.22
Dispensing and Administration Precautions
Atomoxetine hydrochloride is administered orally once daily in the morning or in 2 equally divided doses in the morning and late afternoon/early evening.1 The drug is administered without regard to meals.1
The manufacturer states that atomoxetine is an ocular irritant; therefore, the capsules should be swallowed whole and should not be broken or opened, nor should the capsule contents be sprinkled on food.1
If a dose of atomoxetine is missed, the missed dose should be taken as soon as it is remembered; however, the amount of atomoxetine taken within a 24-hour period should not exceed the prescribed total daily dosage of the drug.1
Atomoxetine hydrochloride capsules should be stored at 20-25°C (excursions permitted between 15-30°C).1
Dosage of atomoxetine hydrochloride is expressed in terms of atomoxetine.1
Atomoxetine may be discontinued without tapering the dosage.1
Attention Deficit Hyperactivity Disorder (ADHD)
For the acute treatment of ADHD in adults, the recommended starting dosage of atomoxetine is 40 mg daily.1 The dosage may be increased after a minimum of 3 days to a target dosage of approximately 80 mg daily.1 If an optimum response has not been achieved after 2-4 additional weeks of therapy, dosage may be increased to a maximum of 100 mg daily; dosages exceeding 100 mg daily have not been shown in clinical trials to result in additional therapeutic benefit.1
Some patients may require maintenance/long-term pharmacologic treatment of ADHD; periodically reevaluate the long-term usefulness of atomoxetine for individual patients.1
For the acute treatment of ADHD in children and adolescents 6 years of age and older weighing >70 kg, the recommended starting dosage of atomoxetine is 40 mg daily.1 The dosage may be increased after a minimum of 3 days to a target dosage of approximately 80 mg daily.1 If an optimum response has not been achieved after 2-4 additional weeks of therapy, dosage may be increased to a maximum of 100 mg daily; dosages exceeding 100 mg daily have not been shown in clinical trials to result in additional therapeutic benefit.1
For the acute treatment of ADHD in children and adolescents 6 years of age and older weighing ≤70 kg, the recommended starting dosage of atomoxetine is approximately 0.5 mg/kg daily; dosage may be increased after a minimum of 3 days to a target dosage of approximately 1.2 mg/kg daily.1 The total daily dose of atomoxetine in children and adolescents ≤70 kg should not exceed 100 mg or 1.4 mg/kg, whichever is less; dosages exceeding 1.2 mg/kg daily have not been shown in clinical trials to result in additional therapeutic benefit.1
Some patients may require maintenance/long-term pharmacologic treatment of ADHD; periodically reevaluate the long-term usefulness of atomoxetine for individual patients.1
Dosage Modification for Drug Interactions
In adults and pediatric patients weighing >70 kg who are receiving concomitant therapy with strong inhibitors of cytochrome P-450 (CYP) isoenzyme 2D6 (e.g., paroxetine, fluoxetine, quinidine), the initial atomoxetine dosage should be 40 mg daily; the dosage should be increased 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.1
In children and adolescents weighing ≤70 kg who are receiving concomitant therapy with strong CYP2D6 inhibitors (e.g., paroxetine, fluoxetine, quinidine), the initial atomoxetine dosage should be 0.5 mg/kg daily; the dosage should be increased 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.1
For patients with moderate hepatic impairment (Child-Pugh Class B), initial and target dosages of atomoxetine should be reduced to 50% of the dosage used in patients with normal hepatic function.1 For patients with severe hepatic impairment (Child-Pugh Class C), initial and target dosages of atomoxetine should be reduced to 25% of the dosage used in patients with normal hepatic function.1
The manufacturer states that no dosage adjustments are required in patients with any degree of renal impairment.1
The manufacturer does not make dosage adjustment recommendations for geriatric patients; the safety and efficacy of atomoxetine have not been evaluated in geriatric patients.1
Pharmacogenomic Considerations
In children and adolescents weighing ≤70 kg who are poor CYP2D6 metabolizers, the manufacturer recommends an initial atomoxetine dosage of 0.5 mg/kg daily; dosage should be increased 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.1
The Clinical Pharmacogenetics Implementation Consortium (CPIC) provides alternative dosing recommendations for atomoxetine based on CYP2D6 phenotypes in children and adults.800 Recommendations are summarized in Tables 1 and 2.800
CYP2D6 Phenotype | Dosage | Follow-up |
|---|---|---|
Ultrarapid metabolizers Normal metabolizers Normal/intermediate (with no *10 allele present) metabolizers | Initiate therapy with the recommended starting dosage of 40 mg/day and increase to 80 mg/day after 3 days | After 2 weeks, if there is no response and no reported adverse effects, consider increasing dosage to 100 mg/day. If no response is observed after 2 weeks, consider checking a peak plasma atomoxetine concentration 1—2 hours after dose administration. If the concentration is <200 ng/mL, consider a proportional dosage increase to approach 400 ng/mL |
Normal/intermediate (with *10 allele present) metabolizers Intermediate metabolizers Poor metabolizers | Initiate therapy with the recommended starting dosage of 40 mg/day | After 2 weeks, if there is no response and no reported adverse effects, increase to 80 mg/day. If no response after 2 weeks, consider checking a peak plasma atomoxetine concentration 2—4 hours after dose administration. If the concentration is <200 ng/mL, consider a proportional dosage increase to approach 400 ng/mL Reduce dosage if unacceptable adverse effects occur |
CYP2D6 Phenotype | Dosage | Follow-up |
|---|---|---|
Ultrarapid metabolizers Normal metabolizers Normal/intermediate (with no *10 allele present) metabolizers | Initiate therapy with the recommended starting dosage of 0.5 mg/kg per day and increase to 1.2 mg/kg per day after 3 days | After 2 weeks, if there is no response and no reported adverse effects, consider checking a peak plasma atomoxetine concentration 1—2 hours after dose administration. If the concentration is <200 ng/mL, consider a proportional dosage increase to approach 400 ng/mL |
Normal/intermediate (with *10 allele present) metabolizers Intermediate metabolizers | Initiate therapy with the recommended starting dosage of 0.5 mg/kg per day | After 2 weeks, if there is no response and no reported adverse effects, consider checking a peak plasma atomoxetine concentration 2—4 hours after dose administration. If the concentration is <200 ng/mL, consider a proportional dosage increase to approach 400 ng/mL Reduce dosage if unacceptable adverse effects occur |
Poor metabolizers | Initiate therapy with the recommended starting dosage of 0.5 mg/kg per day | After 2 weeks, if there is no response and no reported adverse effects, consider checking a peak plasma atomoxetine concentration 4 hours after dose administration. If the concentration is <200 ng/mL, consider a proportional dosage increase to approach 400 ng/mL Reduce dosage if unacceptable adverse effects occur |
Atomoxetine may increase the risk of suicidal ideation in children and adolescents with attention deficit hyperactivity disorder (ADHD), and a boxed warning about this risk has been including in the prescribing information for the drug.1 Pooled analyses of 12 short-term (6-18 weeks) placebo-controlled trials in over 2200 pediatric patients reported an average risk of suicidal ideation of 0.4% with atomoxetine compared with 0% in placebo-treated patients.1 No suicides occurred in these trials.1 All instances of this adverse event occurred in patients 12 years or younger during the first month of treatment.1 It is unknown whether the risk of suicidal ideation extends to longer-term use.1 The increased risk of suicidal ideation was not observed in a similar analysis in an adult population.1
Monitor pediatric patients closely for clinical worsening, suicidality (suicidal ideation or behaviors), or unusual changes in behavior, particularly during the first few months after initiation of atomoxetine therapy and during periods of dosage adjustments.1 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.1
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.1 Atomoxetine is indicated for the treatment of ADHD in pediatric patients and adults, and is not approved for the treatment of major depressive disorder.1
Other Warnings and Precautions
Postmarketing reports indicate that atomoxetine can cause liver injury.1 Rare cases of clinically significant liver injury or liver failure (including a liver transplant) have been reported.1 A true incidence is incalculable due to underreporting.1 Liver injury occurred within 120 days of initiation of atomoxetine in the majority of cases; some patients presented with markedly elevated liver enzymes (>20 times the upper limit of normal [ULN]), and jaundice with significantly elevated bilirubin levels (>2 times the ULN), followed by recovery upon atomoxetine discontinuation.1 In one patient, liver injury, manifested by elevated hepatic enzymes up to 40 times the ULN and jaundice with bilirubin up to 12 times the ULN, recurred upon rechallenge, and was followed by recovery upon drug discontinuation, providing evidence that atomoxetine likely caused the liver injury.1 Such reactions may occur several months after therapy is started, but laboratory abnormalities may continue to worsen for several weeks after the drug is discontinued.1
Discontinue atomoxetine in patients with jaundice or laboratory evidence of liver injury, and do not restart.1
Conduct laboratory testing to determine liver enzyme levels upon the first symptom or sign of liver dysfunction (e.g., pruritus, dark urine, jaundice, right upper quadrant tenderness, or unexplained “flu like” symptoms).1
Sudden death has been reported in association with atomoxetine treatment at usual dosages in children and adolescents with structural cardiac abnormalities or other serious heart problems.1 Although some serious heart problems alone carry an increased risk of sudden death, avoid atomoxetine use in children or adolescents with known serious structural cardiac abnormalities, cardiomyopathy, serious heart rhythm abnormalities, or other serious cardiac problems that may place them at increased vulnerability to the noradrenergic effects of atomoxetine.1
In adults, sudden deaths, stroke, and myocardial infarction have been reported with usual atomoxetine dosages for ADHD.1 Although the role of atomoxetine in these adult cases is also unknown, adults have a greater likelihood than children of having serious structural cardiac abnormalities, cardiomyopathy, serious heart rhythm abnormalities, coronary artery disease, or other serious cardiac problems.1 Consider avoiding atomoxetine use in adults with clinically significant cardiac abnormalities.1
Conduct a thorough medical history review (including evaluation for family history of sudden death or ventricular arrhythmia) and perform a physical examination in all children, adolescents, and adults being considered for atomoxetine therapy; if initial findings suggest the presence of cardiac disease, perform further cardiac evaluation (e.g., ECG, echocardiogram).1
Patients who develop exertional chest pain, unexplained syncope, or other manifestations suggestive of cardiac disease during atomoxetine therapy should undergo prompt cardiac evaluation.1
Effects on Blood Pressure and Heart Rate
Use atomoxetine with caution in patients whose underlying medical conditions could be worsened by increases in blood pressure or heart rate (e.g., certain patients with hypertension, tachycardia, or cardiovascular or cerebrovascular disease).1 Use with caution in any condition that may predispose patients to hypotension, or conditions associated with abrupt heart rate or blood pressure changes.1 Do not use atomoxetine in patients with severe cardiac or vascular disorders whose condition would be expected to deteriorate if they experienced clinically important increases in blood pressure or heart rate.1 Measure pulse and blood pressure at baseline, following atomoxetine dosage increases, and periodically while on therapy to detect possible clinically important increases.1
Emergence of New Psychotic or Manic Effects
Psychotic or manic symptoms (e.g., hallucinations, delusional thinking, or mania) in patients without a prior history of psychotic illness or mania can be caused by atomoxetine at usual dosages.1 If such symptoms occur, consider discontinuing atomoxetine.1
Screening Patients for Bipolar Disorder
Patients with bipolar disorder or risk factors for bipolar disorder may be at increased risk of developing mania or mixed episodes during treatment with atomoxetine.1 It may not be possible to determine whether a manic or mixed episode that appears during treatment with atomoxetine is due to an adverse reaction to the drug or to the patient's underlying bipolar disorder.1 Adequately screen patients for risk factors for bipolar disorder such as a personal or family history of mania and depression before initiating treatment with atomoxetine.1
Aggressive Behavior or Hostility
There is evidence that atomoxetine may cause the emergence or worsening of aggressive behavior or hostility.1 Monitor patients beginning treatment with atomoxetine for the appearance or worsening of aggressive behavior or hostility.1 ADHD and other mental illnesses can be associated with irritability, which can make it difficult to determine if the drug or the underlying psychiatric condition is causing the emergence or worsening of aggressive behavior or hostility.1 If such symptoms occur during treatment, consider a possible causal role of atomoxetine.1
Although uncommon, allergic reactions, including anaphylactic reactions, angioneurotic edema, urticaria, and rash, have been reported in patients taking atomoxetine.1
Effects on Urine Outflow from the Bladder
In adult ADHD controlled trials, the rates of urinary retention (1.7%) and urinary hesitation (5.6%) were increased among atomoxetine-treated patients compared with patients who received placebo (0 and 0.5%, respectively).1 Two atomoxetine-treated patients and no patients receiving placebo discontinued from controlled clinical trials because of urinary retention.1 A complaint of urinary retention or urinary hesitancy should be considered potentially related to atomoxetine.1
Rare postmarketing cases of priapism, defined as painful and nonpainful penile erection lasting more than 4 hours, have been reported in pediatric and adult patients treated with atomoxetine.1 The erections resolved in cases in which follow-up information was available, some following discontinuation of atomoxetine.1 Prompt medical attention is required in the event of suspected priapism.1
The weight and height gain of pediatric patients treated with atomoxetine lags behind that predicted by normative population data for about the first 9-12 months of treatment.1 Subsequently, weight gain rebounds and at about 3 years of treatment, patients treated with atomoxetine have gained 17.9 kg on average, 0.5 kg more than predicted by their baseline data.1 After about 12 months, gain in height stabilizes, and at 3 years, patients treated with atomoxetine have gained 19.4 cm on average, 0.4 cm less than predicted by their baseline data.1 Monitor growth during atomoxetine treatment in pediatric patients.1
Pharmacogenomic Considerations
Atomoxetine is primarily metabolized by the cytochrome P-450 (CYP) 2D6 pathway to 4-hydroxyatomoxetine.1 Patients who are poor metabolizers of CYP2D6 have a 10-fold higher AUC and a 5-fold higher peak plasma concentration of atomoxetine compared with extensive metabolizers.1 Approximately 7% of a Caucasian population are poor CYP2D6 metabolizers.1 Laboratory tests are available to identify CYP2D6 poor metabolizers.1 The blood levels in poor metabolizers are similar to those attained by taking strong inhibitors of CYP2D6.1 The higher blood levels in poor metabolizers resulted in a higher rate of some adverse effects of atomoxetine.1 Dosage adjustment of atomoxetine may be necessary when the drug is administered to CYP2D6 poor metabolizers.1
Concomitant Use of Strong CYP2D6 Inhibitors
Because atomoxetine is primarily metabolized by CYP2D6, dosage adjustment is necessary when coadministered with strong CYP2D6 inhibitors (e.g., paroxetine, fluoxetine, quinidine).1
Tics in Patients with ADHD and Comorbid Tourette's Disorder
Tics have been documented in patients receiving atomoxetine during postmarketing experience.1 An 18-week, randomized, double-blind, placebo-controlled study of 148 pediatric patients with ADHD and comorbid tic disorder demonstrated, through a non-inferiority analysis, that atomoxetine did not worsen the tic disorder as assessed by the Yale Global Tic Severity Total Score (YGTSS).1
Anxiety in Patients with ADHD and Comorbid Anxiety Disorder
Postmarketing trials have not demonstrated worsening anxiety in patients receiving atomoxetine who have ADHD and a comorbid anxiety disorder.1
There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to ADHD medications, including atomoxetine, during pregnancy.1 Healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for ADHD Medications at 1-866-961-2388 or visiting [Web].1
Available published studies of atomoxetine use in pregnant women are insufficient to establish a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes.1 Some animal reproduction studies demonstrated adverse developmental outcomes with atomoxetine.1 In 1 of 3 studies in pregnant rabbits, administration of atomoxetine 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.1 These effects were observed at plasma levels (AUC) 3 times and 0.4 times the human plasma levels in extensive and poor CYP2D6 metabolizers receiving the maximum recommended human dose (MRHD), respectively.1 In rats, administration of atomoxetine prior to mating and during organogenesis resulted in a decrease in fetal weight (female only) and an increase in the incidence of incomplete ossification of the vertebral arch in fetuses at a dose approximately 5 times the MRHD on a mg/m2 basis.1 In 1 of 2 studies in which rats were dosed prior to mating through the periods of organogenesis and lactation, decreased pup weight and decreased pup survival were observed at doses corresponding to 5-6 times the MRHD on a mg/m2 basis.1 No adverse fetal effects were seen in pregnant rats dosed during the organogenesis period.1
There are no data on the presence of atomoxetine or its metabolite in human milk, the effects on the breast-fed child, or the effects on milk production.1 Atomoxetine is present in animal milk.1 When a drug is present in animal milk, it is likely that the drug will be present in human milk.1 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 from the underlying maternal condition.1
Safety and efficacy of atomoxetine have not been established in pediatric patients younger than 6 years of age.1
Atomoxetine may increase the risk of suicidal ideation in children and adolescents with ADHD.1 In a pooled analysis of 12 short-term controlled clinical studies in pediatric patients with ADHD (11 studies) or enuresis (1 study), the risk of suicidal ideation was about 0.4% in those receiving atomoxetine versus 0% in those receiving placebo.1 One child receiving the drug attempted suicide; no completed suicides were reported.1 All events representing suicidal behavior or thinking occurred in children 12 years of age or younger and occurred during the first month of therapy.1 It is not known whether the risk of suicidal ideation in pediatric patients extends to long-term use of the drug.1 A 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.1
The potential risks of suicidality should be weighed against the clinical need for the drug prior to initiating atomoxetine therapy in children or adolescents.1 Sudden death has been reported in children and adolescents with structural cardiac abnormalities or other serious cardiac conditions receiving usual dosages of stimulants.1 Temporary suppression of normal weight and/or height patterns has been reported during the first 9-12 months of atomoxetine therapy; however, weight and height gains have rebounded with continued treatment.1 Monitor the growth of pediatric patients receiving atomoxetine.1
Safety and efficacy of atomoxetine have not been established in geriatric patients.1
Systemic exposure to atomoxetine concentrations is increased 2-fold in patients who are extensive CYP2D6 metabolizers with moderate hepatic impairment (Child-Pugh class B) and 4-fold in patients who are extensive CYP2D6 metabolizers with severe hepatic impairment (Child-Pugh class C).1 Dosage adjustment of atomoxetine in patients with moderate or severe hepatic insufficiency is recommended.1
Extensive metabolizer patients with end stage renal disease had higher systemic exposure to atomoxetine than healthy subjects (about a 65% increase), but there was no difference when exposure was corrected for mg/kg dose.1 Atomoxetine can therefore be administered to ADHD patients with end stage renal disease or lesser degrees of renal insufficiency using the normal dosing regimen.1
The most common adverse reactions reported with atomoxetine (≥5% and at least twice the incidence observed in placebo patients) in children and adolescents included nausea, vomiting, fatigue, decreased appetite, abdominal pain, and somnolence.1
The most common adverse reactions reported with atomoxetine (≥5% and at least twice the incidence observed in placebo patients) in adults included constipation, dry mouth, nausea, decreased appetite, dizziness, erectile dysfunction, and urinary hesitation.1
Atomoxetine is metabolized principally by cytochrome P-450 (CYP) 2D6.1 It does not cause clinically important inhibition or induction of cytochrome P-450 enzymes, including CYP1A2, CYP3A, CYP2D6, and CYP2C9.1
Drugs Affecting or Affected by Hepatic Microsomal Enzymes
Strong CYP2D6 inhibitors: Concomitant administration of atomoxetine with strong inhibitors of CYP2D6 (e.g., paroxetine, fluoxetine, quinidine) can result in a substantial increase in plasma concentrations of atomoxetine.1 When atomoxetine is used concomitantly with a strong CYP2D6 inhibitor, dosage adjustment of atomoxetine is required.1
In extensive metabolizers of CYP2D6, CYP2D6 inhibitors (e.g., paroxetine, fluoxetine, and quinidine) increase atomoxetine steady-state plasma concentrations to exposures similar to those observed in poor metabolizers.1 In extensive metabolizers treated with paroxetine or fluoxetine, AUC of atomoxetine is approximately 6- to 8-fold and peak steady state concentration is about 3- to 4-fold greater than administration of atomoxetine alone.1 However, in vitro studies suggest that concomitant use of atomoxetine with CYP2D6 inhibitors will not increase plasma concentrations of atomoxetine in patients with the poor-metabolizer phenotype.1
CYP2D6 substrates: When atomoxetine 40 or 60 mg twice daily for 13 days was coadministered with a single 50 mg dose of desipramine, a model compound for CYP2D6 metabolized drugs, the pharmacokinetics of desipramine were not altered.1 No dosage adjustment is required for drugs metabolized by CYP2D6.1
CYP3A substrates: When atomoxetine 60 mg twice daily for 12 days was coadministered with a single 5 mg dose of midazolam, a model compound for CYP3A4 metabolized drugs, a 15% increase in AUC of midazolam was observed.1 No dosage adjustment is required for drugs metabolized by CYP3A.1
No important pharmacokinetic interactions have been reported when atomoxetine was administered concomitantly with drugs that increase gastric pH (e.g., antacids containing magnesium hydroxide and aluminum hydroxide, omeprazole).1
Pharmacokinetic interaction unlikely.1 In vitro studies indicate that atomoxetine is not displaced from binding sites by, and does not displace from binding sites, other highly protein-bound drugs (e.g., warfarin, aspirin, phenytoin, diazepam) in therapeutic concentrations.1
No change in the intoxicating effects of alcohol was observed when ingested by individuals receiving atomoxetine.1
Potential pharmacologic interaction (increased cardiovascular effects [e.g., increased heart rate and blood pressure]) when atomoxetine is used concomitantly with oral or parenteral β2-adrenergic agonists (e.g., albuterol).1 Use with caution.1
Antihypertensive Drugs and Pressor Agents
Atomoxetine may increase blood pressure; use caution when the drug is used concomitantly with antihypertensive agents and pressor agents (e.g., dopamine, dobutamine) or other drugs that increase blood pressure.1
No increase in cardiovascular effects was observed with concomitant use of methylphenidate and atomoxetine relative to the use of methylphenidate alone.1
Monoamine Oxidase Inhibitors (MAOIs)
Due to potential pharmacologic interaction (inhibition of catecholamine metabolism) and reports of serious, sometimes fatal reactions, concurrent use of atomoxetine and MAOIs is contraindicated and at least 14 days should elapse between discontinuation of one agent and initiation of the other agent.1
Atomoxetine is a selective norepinephrine-reuptake inhibitor.1, 3, 4, 5, 6, 7, 8, 10, 11 Atomoxetine is not considered a stimulant and also is structurally unrelated to other agents used for the treatment of attention deficit hyperactivity disorder (ADHD).1, 3, 4, 5, 6, 7, 8, 10, 11 The exact mechanism(s) of action of atomoxetine in the management of ADHD has not been fully elucidated but may be related to selective inhibition of the presynaptic norepinephrine transporter; the drug appears to have minimal affinity for other noradrenergic receptors or for other neurotransmitter transporters or receptors.1, 3, 4, 5, 6, 7, 8, 10, 11
Atomoxetine is readily absorbed following oral administration, with peak plasma concentrations attained in approximately 1-2 hours.1 The absolute bioavailability of atomoxetine is 63% in extensive metabolizers of cytochrome P-450 (CYP) 2D6 and 94% in poor metabolizers of CYP2D6.1 A standard high-fat meal decreases the rate, but not extent. of absorption in adults, resulting in a 37% lower maximum concentration and delayed time to maximum concentration by 3 hours.1 In children and adolescents, food reduces the peak plasma concentration of atomoxetine by 9%.1 The drug is approximately 98% bound to plasma proteins, principally albumin, at therapeutic concentrations.1 Atomoxetine is principally metabolized by CYP2D6 to an equipotent metabolite (4-hydroxyatomoxetine) that circulates in plasma at much lower concentrations; this metabolite then undergoes subsequent conjugation with glucuronic acid.1 Individuals who extensively metabolize atomoxetine via the CYP2D6 pathway exhibit the extensive-metabolizer phenotype, while those who have an impaired ability to metabolize the drug by this pathway exhibit the poor-metabolizer phenotype.1 In patients with the poor-metabolizer phenotype (about 7% of Caucasians and 2% of African Americans), metabolic clearance of atomoxetine may be decreased; a 5-fold increase in peak plasma concentrations of atomoxetine and a 10-fold increase in AUC have been reported in individuals with the poor-metabolizer phenotype relative to those with the extensive-metabolizer phenotype.1 The mean elimination half-life of atomoxetine is 5.2 or 21.6 hours in extensive or poor metabolizers, respectively.1 Atomoxetine does not inhibit or induce CYP2D6.1 Greater than 80% of the dose is excreted in the urine as the glucuronide metabolite; <17% is excreted in feces.1
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.
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.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Capsules | 10 mg (of atomoxetine)* | Atomoxetine Hydrochloride Capsules | |
18 mg (of atomoxetine)* | Atomoxetine Hydrochloride Capsules | |||
25 mg (of atomoxetine)* | Atomoxetine Hydrochloride Capsules | |||
40 mg (of atomoxetine)* | Atomoxetine Hydrochloride Capsules | |||
60 mg (of atomoxetine)* | Atomoxetine Hydrochloride Capsules | |||
80 mg (of atomoxetine)* | Atomoxetine Hydrochloride Capsules | |||
100 mg (of atomoxetine)* | Atomoxetine Hydrochloride Capsules |
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
1. Rising Pharma Holdings, Inc. Atomoxetine hydrochloride capsules prescribing information. East Brunswick, NJ; 2025 Apr.
3. Kratochvil CJ, Bohac D, Harrington M et al. An open-label trial of tomoxetine in pediatric attention deficit hyperactivity disorder. J Child Adolesc Psychopharmacol . 2001; 11:167-70. [PubMed 11436956]
4. Michelson D, Allen AJ, Busner J et al. Once daily atomoxetine treatment for children and adolescents with attention deficit hyperactivity disorder: a randomized, placebo-controlled study. Am J Psychiatry . 2002; 159:1896-901. [PubMed 12411225]
5. Spencer T, Biederman J, Wilens T et al. Effectiveness and tolerability of tomoxetine in adults with attention deficit hyperactivity disorder. Am J Psychiatry . 1998; 155:693-5. [PubMed 9585725]
6. Spencer T, Biederman J, Wilens TE et al. Adults with attention-deficit/hyperactivity disorder: a controversial diagnosis. J Clin Psychiatry . 1998; 59(suppl 7):59-68. [PubMed 9680054]
7. Spencer T, Biederman J, Heiligenstein J et al. An open-label, dose-ranging study of atomoxetine in children with attention deficit hyperactivity disorder. J Child Adolesc Psychopharmacol . 2001; 11:251-65. [PubMed 11642475]
8. Biederman J, Heiligenstein JH, Faries DE et al. Efficacy of atomoxetine versus placebo in school-age girls with attention-deficit/hyperactivity disorder. Pediatrics . 2002; 110:e75. [PubMed 12456942]
10. Spencer T, Heiligenstein JH, Biederman J et al. Results from 2 proof-of- concept, placebo-controlled studies of atomoxetine in children with attention-deficit/hyperactivity disorder. J Clin Psychiatry . 2002; 63:1140-7. [PubMed 12523874]
11. Michelson D, Adler L, Spencer T et al. Atomoxetine in adults with ADHD: two randomized, placebo-controlled studies. Biol Psychiatry . 2003;53:112-20. [PubMed 12547466]
12. Michelson D, Faries D, Wernicke J et al. Atomoxetine in the treatment of children and adolescents with attention-deficit/hyperactivity disorder: a randomized, placebo-controlled, dose-response study. Pediatrics . 2001; 108:e83. [PubMed 11694667]
18. Michelson D, Buitelaar JK, Danckaerts M et al. Relapse prevention in pediatric patients with ADHD treated with atomoxetine: A randomized, double-blind, placebo-controlled study. J Am Acad Child Adolesc Psychiatry . 2004; 43:896-904. [PubMed 15213591]
19. Wolraich ML, Hagan JF Jr, Allan C et al. Clinical Practice Guideline for the Diagnosis, Evaluation, and Treatment of Attention-Deficit/Hyperactivity Disorder in Children and Adolescents. Pediatrics. 2019; 144
20. Kooij JJS, Bijlenga D, Salerno L et al. Updated European Consensus Statement on diagnosis and treatment of adult ADHD. Eur Psychiatry. 2019; 56:14-34.
21. CADDRA - Canadian ADHD Resource Alliance. Canadian ADHD Practice Guidelines, 4.1 Edition, 2020. [Web]
22. Hyman SL, Levy SE, Myers SM; COUNCIL ON CHILDREN WITH DISABILITIES, SECTION ON DEVELOPMENTAL AND BEHAVIORAL PEDIATRICS. Identification, Evaluation, and Management of Children With Autism Spectrum Disorder. Pediatrics. 2020;145(1):e20193447.
243. ISMP List of Confused Names. Updated June 2024. Accessed June 23, 2025. [Web]
800. Brown JT, Bishop JR, Sangkuhl K, et al. Clinical Pharmacogenetics Implementation Consortium Guideline for Cytochrome P450 (CYP)2D6 Genotype and Atomoxetine Therapy. Clin Pharmacol Ther. 2019;106(1):94-102.