ATOMOXETINE HCL (Generic for STRATTERA)

General Administration Information
For storage information, see the specific product information within the How Supplied section.

Route-Specific Administration

Oral Administration
Oral Solid Formulations
-Administer capsules whole; do not cut, crush, or chew.
-May give with or without food. If nausea occurs, it may be helpful to administer after a meal.
-Do not open capsules. Atomoxetine is an ocular irritant. If contact with the eye occurs, instruct the patients to immediately flush the affected eye with water and seek medical advice. Hands or contaminated surfaces should be washed promptly.

During clinical trials, atomoxetine was administered to 5382 children and adolescents with attention-deficit hyperactivity disorder (ADHD). Of these, 2529 patients were treated for longer than 6 months and 1625 patients were treated for longer than 1 year. The safety of single doses over 120 mg and total daily doses above 150 mg have not been systematically evaluated. The most commonly reported adverse events (>= 5% and twice the incidence vs. placebo) involved the central nervous system (CNS) and gastrointestinal tract (GI). Poor metabolizers (PMs) of CYP2D6 substrates have been shown to be at higher risk for adverse drug reactions. For all studies in children and adolescents, 6.3% of extensive metabolizers (EMs) and 11.2% of poor metabolizers (PMs) discontinued therapy due to an adverse event.

Seizures occurred in 0.2% of pediatric patients during clinical trials of atomoxetine; patients with pre-existing seizure disorders were excluded from these trials. The seizure risk was greater among poor metabolizers (PMs) (0.3%) than extensive metabolizers (EMs) (0.2%). Causality to the drug has not been established. Seizures have been reported in those with and without risk factors for seizures or preexisting seizure disorders during post-marketing use of the drug.

Central nervous system (CNS) effects are among the most commonly reported adverse events with atomoxetine. CNS effects reported during pediatric clinical trials at a rate more frequent than placebo include: drowsiness (11%), fatigue (6-9%), and dizziness (5%), early morning awakenings (< 2%), and asthenia (< 2%). Abnormal dreams (4%) and feeling cold were also reported during adult clinical trials. Poor metabolizers (PMs) of CYP2D6 substrates have been shown to be at higher risk for adverse drug reactions. The following CNS adverse events occurred in at least 2% of child and adolescent PMs and were either twice as frequent or statistically significantly more frequent in PMs compared with extensive metabolizers (EMs): insomnia (11% of PMs, 6% of EMs), tremor (5% of PMs, 1% of EMs), middle insomnia (3% of PMs, 1% of EMs), sedation (4% of PMs, 2% of EMs), and early morning awakening (2% of PMs, 1% of EMs). Seizures occurred in 0.3% of PMs and 0.2% of EMs in clinical trials. Lethargy has been reported during post-marketing use of atomoxetine; however, the frequency is unknown and causality to the drug has not been established.

Irritability (6%) and emotional lability (mood swings 1% to 2%) occurred more frequently with atomoxetine than placebo (3% and 0% to 1%, respectively) during clinical trials in children and adolescents with attention-deficit hyperactivity disorder (ADHD). Agitation, restlessness, and anxiety were reported during adult clinical trials. Emergent hostility-related adverse reactions were reported in 1.6% of atomoxetine-treated pediatric patients vs. 1.1% of placebo-treated patients. Psychotic or manic symptoms (e.g., hallucinations, delusional thinking, or mania) were reported in 0.2% of pediatric patients without a prior history of a psychotic disorder or bipolar disorder receiving atomoxetine (no incidence reported in placebo control group). If psychotic or manic symptoms develop, consider discontinuing atomoxetine therapy. Poor metabolizers (PMs) of CYP2D6 substrates are at higher risk for adverse drug reactions. Depression (7% of PMs, 4% of EMs) and excoriation (4% of PMs, 2% of EMs) were more frequent in pediatric PM patients; jitteriness was more frequent in adult PM patients (5% of PMs, 2% of EMs). Depression, depressed mood, and anxiety have been reported during postmarketing use of the drug; these may also be co-morbid disorders in ADHD patients. Monitor patients closely for clinical worsening, as well as agitation, aggressiveness, akathisia, anxiety, hostility, hypomania, mania, impulsivity, irritability, insomnia, panic attacks, suicidal thinking or behaviors, and unusual changes in behavior, especially during the initial few months of therapy or when the dose is changed (increased or decreased). While all of these adverse reactions have not been specifically reported or associated with atomoxetine treatment, many of these symptoms may be precursors to suicidal behavior. Co-morbidities occurring with ADHD may increase the risk of suicidal ideation and/or behavior. Eleven clinical trials conducted in children with ADHD and 1 trial in children with enuresis identified an increased risk of suicidal ideation when taking atomoxetine. There was 1 suicide attempt by a patient who received atomoxetine among more than 2,200 patients in the trials (1,357 patients receiving atomoxetine and 851 receiving a placebo). The analysis showed that 0.4% of children (5 cases) treated with atomoxetine reported suicidal thinking compared to no cases in children treated with placebo. There were no completed suicides among any age group. Health care providers should discuss with parents and/or caregivers the need to actively monitor pediatric patients for behavioral changes. In addition, atomoxetine should be prescribed in the smallest quantity consistent with good patient management in order to reduce the risk of overdose. According the Institute for Safe Medication Practices (ISMP), atomoxetine has been reported as a frequently suspected drug in serious adverse drug reactions in children. Of the serious reactions reported to the FDA during a 5-year time span (2008 to 2012), psychiatric (e.g., suicidal behaviors, aggression, psychosis or psychotic episodes) and cardiac events were predominant. Because reports submitted to the FDA likely represent only a portion of actual events and may be skewed, further investigation to determine frequency of occurrence and causality to the drug is warranted.

Headache (19%) occurred more frequently with atomoxetine than placebo (15%) in pediatric clinical trials, resulting in treatment discontinuation in 0.1% of patients. Paresthesias, hypoesthesia, sensory disturbances, and tics have been reported in pediatric patients during post-marketing use of atomoxetine; however, the frequency is unknown and causality to the drug has not been established.

Gastrointestinal (GI) effects are among the most commonly reported adverse events with atomoxetine. GI effects reported during pediatric clinical trials at a rate more frequent than placebo include: abdominal pain (17-18%), vomiting (11%), nausea (7-13%), and constipation (1-7%). Nausea was reported at nearly double the frequency during once daily dosing trials (13%) compared to twice daily dosing trials (7%), indicating that twice-daily dosing may help limit intolerable GI effects. Xerostomia, thirst, dyspepsia, diarrhea, dysgeusia, and oropharyngeal pain were reported in adult clinical trials. Poor metabolizers (PMs) of CYP2D6 substrates have been shown to be at higher risk for adverse drug reactions. In clinical trials, constipation was reported in 7% of pediatric poor metabolizers (PMs) and 4% of extensive metabolizers (EMs); xerostomia was more frequent in adult PM patients (35% PMs, 17% EMs).

Urinary hesitation and urinary retention have been reported in pediatric patients during post-marketing use, as well as male pelvic pain. Reported frequencies are unknown and causality to the drug has not been established. In addition, dysuria, urinary urgency, and pollakiuria (increased urinary frequency), dysmenorrhea, menstrual irregularity, prostatitis, and testicular pain have been reported in adult patients during clinical trials. Poor metabolizers (PMs) of CYP2D6 substrates are at higher risk for adverse drug reactions; urinary retention was more frequent in adult PM patients (6% of PMs, 1% of EMs).

Atomoxetine may cause hypertension. In pediatric patients, clinical trials reported a systolic blood pressure increase >= 20 mmHg in 4.9-12.5% of atomoxetine-treated patients at any 1 time during clinical trial evaluation or study endpoint. Diastolic blood pressure was increased >= 15 mmHg in 9.3-21.5% of treated patients. Atomoxetine is contraindicated in patients with severe cardiac conditions that would be expected to deteriorate from potentially significant increases in blood pressure (e.g., 15-20 mmHg); caution is recommended for less severe conditions (e.g., mild hypertension) that may be worsened by increased blood pressure. Blood pressure measurements should be obtained at baseline, after dosage increases, and periodically throughout atomoxetine therapy.

Orthostatic hypotension (0.2-1.8%) and syncope (0.8%) were been reported during pediatric placebo-controlled trials. Poor metabolizers (PMs) of CYP2D6 substrates are at higher risk for adverse reactions. Syncope was reported by 3% of pediatric PMs and 1% of extensive metabolizers (EMs). Use atomoxetine with caution in patients with a predisposition to hypotension or other conditions associated with abrupt heart rate or blood pressure changes. According the Institute for Safe Medication Practices (ISMP), atomoxetine has been reported as a frequently suspected drug in serious adverse drug events in children. Of the serious events reported to the FDA during a 5-year time span (2008-2012), psychiatric and cardiac (e.g., syncope, chest pain, ECG changes) events were predominant. Because reports submitted to the FDA likely represent only a portion of actual events and may be skewed, further investigation to determine frequency of occurrence and causality to the drug is warranted.

Cardiovascular events, including sudden death, have been associated with atomoxetine use in pediatric patients with structural cardiac abnormalities or other serious heart problems. Cardiovascular effects associated with atomoxetine use in the general population range in severity from mild to life-threatening and include palpitations (< 2%), sinus tachycardia (< 2%), hypertension, myocardial infarction (reported in adults), and stroke (reported in adults). Patients who develop symptoms such as exertional chest pain (unspecified), unexplained syncope, or other symptoms suggestive of cardiac disease during atomoxetine treatment should undergo a prompt cardiac evaluation. Minor manifestations of any of these symptoms may indicate a need for dosage reduction or discontinuation. In pediatric patients receiving atomoxetine, approximately 12-23% experienced increases in heart rate of at least 20 beats/minute. Mean increases in heart rate were higher among pediatric patients who were poor metabolizers (PMs) than extensive metabolizers (EMs), reported as increases of 9.4 beats/minute and 5 beats/minute, respectively. These differences may be clinically significant in PM patients. Atomoxetine is contraindicated in patients with severe cardiac conditions that would be expected to deteriorate from potentially significant increases in heart rate (e.g., 20 beats/min); caution is recommended for less severe conditions that may be worsened by an increase in heart rate. Blood pressure and pulse measurements should be obtained at baseline, after dosage increases, and periodically throughout atomoxetine therapy. According the Institute for Safe Medication Practices (ISMP), atomoxetine has been reported as a frequently suspected drug in serious adverse drug events in children. Of the serious events reported to the FDA during a 5-year time span (2008-2012), psychiatric and cardiac (e.g., chest pain, fainting, prolonged QT interval) effects were predominant for atomoxetine. Because reports submitted to the FDA likely represent only a portion of actual events and may be skewed, further investigation to determine frequency of occurrence and causality to the drug is warranted.


QT prolongation has been reported during post-marketing use of atomoxetine. A randomized, double-blind, crossover trial involving 120 healthy males who were poor metabolizers of CYP2D6-metabolized drugs assessed the effect of atomoxetine on QT prolongation. Positive (moxifloxacin 400 mg) and placebo controls were used. Subjects received atomoxetine twice daily (20 mg and 60 mg) for 1 week. No large QTc interval changes (> 60 msec from baseline, absolute QTc > 480 msec) were detected. Small QTc interval changes cannot be ruled out, as the trial failed to establish assay sensitivity. A slight increase in QTc interval was seen with increased atomoxetine concentration. One case report describes a QTc interval of 607 msec in a 15 year old male 3 hours after the ingestion of 1200 mg of atomoxetine. Subsequently, the QTc interval decreased to 435 msec at 6 hours post-ingestion. According the Institute for Safe Medication Practices (ISMP), atomoxetine has been reported as a frequently suspected drug in serious adverse drug events in children. Of the serious events reported to the FDA during a 5-year time span (2008-2012), psychiatric and cardiac (e.g., chest pain, fainting, prolonged QT interval) effects were reported. Because reports submitted to the FDA likely represent only a portion of actual events and may be skewed, further investigation to determine frequency of occurrence and causality to the drug is warranted. Use atomoxetine cautiously in patients with known congenital heart disease, cardiac conduction defects, or structural heart disease. Pulse and blood pressure measurements should be obtained at baseline, after dose increases, and periodically throughout atomoxetine therapy. Any unexplained cardiac symptoms should be promptly investigated.

Raynaud's phenomenon (peripheral vasoconstriction of new onset and exacerbation of preexisting condition), flushing (< 2%), hyperhidrosis (4% of adults), and chills (3% of adults) have been reported with atomoxetine use. Poor metabolizers (PMs) of CYP2D6 substrates have been shown to be at higher risk for adverse drug reactions. In adult patients, peripheral coldness (3% of PMs, 1% of extensive metabolizers [EMs]) and hyperhidrosis (15% of PMs, 7% of EMs) occurred more frequently in patients who were PMs.

Prolonged erections and priapism have been reported with post-marketing use of atomoxetine. Prolonged erections (> 4 hours) in male patients should be promptly reported, as immediate diagnosis and treatment are essential to avoid tissue damage. Priapism can occur in males of any age; younger males, particularly those who have not reached puberty, may not recognize the problem or may be embarrassed to tell anyone if it occurs. In a review of methylphenidate products by the FDA, the median age of patients who experienced priapism was 12.5 years (range: 8-33 years). Reported cases of priapism occurred after a period of time on stimulant therapy and often subsequent to a dose increase. Priapism was also reported during periods of stimulant drug withdrawal (e.g., drug holidays or discontinuation). Although priapism has been associated with stimulant medications, atomoxetine appears to carry a higher risk of the condition.

Atomoxetine is associated with an increased risk of mydriasis (< 2% in children and adolescents) and therefore is not recommended for use in patients with narrow angle glaucoma. Poor metabolizers (PMs) of CYP2D6 substrates are at higher risk for adverse drug reactions compared to extensive metabolizers (EMs). Among pediatric PM patients, mydriasis (2% of PMs, 1% of EMs) and conjunctivitis (3% of PMs, 1% of EMs) occurred more frequently in PMs. Blurred vision was more frequent in adult PM patients (4% of PMs, 1% of EMs).

Decreased appetite is a frequent side effect and occurred in 16% of pediatric patients during clinical trials. Anorexia (3%) and weight loss (3%) occurred more frequently with atomoxetine than placebo in clinical trials. Poor metabolizers (PMs) of CYP2D6 substrates are at higher risk for adverse drug reactions. Weight loss has been noted to have a greater incidence in pediatric PMs (7%) vs. extensive metabolizers (EMs) (4%); anorexia was more frequent in adult PMs (23% of PMs, 15% of EMs). The potential for growth inhibition should be monitored in children during continued therapy with atomoxetine. Monitor height at weight at treatment initiation and periodically thereafter. Short-term (9-week) studies have shown that up to 3.5% of body weight can be lost, and this loss may be dose-related. In a fixed-dose controlled trial, 1.3%, 7.1%, 19.3%, and 29.1% of patients lost at least 3.5% of their body weight in the placebo, 0.5, 1.2, and 1.8 mg/kg/day dose groups, respectively. Data from open-label trial extensions indicates that, in general, the weight and height gain of children treated with atomoxetine lags behind that predicted by normative population data for the first 9-12 months of treatment; subsequently, weight gain rebounds at about 3 years of treatment. After 18 months, gain in height stabilizes, and at 2 years, patients have gained only slightly less (0.44 cm) than predicted. Growth patterns are similar regardless of pubertal status; however, mean weight gain has been shown to be slower for PMs compared to EMs (2.4 kg less vs. 0.2 kg less than predicted, respectively), while height gain is similar between PMs and EMs (1.1 cm less vs. 0.4 cm less than predicted, respectively).

The risk for allergic reactions is possible with any drug, although allergic reactions were uncommon in clinical trials with atomoxetine. Angioedema, rash (unspecified), anaphylactoid reactions, pruritus, and urticaria have been reported in patients taking atomoxetine. In pediatric studies, rash was reported in 2% of those receiving active drug vs. 1% of those on placebo. Alopecia was reported during postmarketing use.

Postmarketing reports have included rare cases of severe idiosyncratic liver injury (hepatotoxicity), including jaundice, hepatitis, hepatic fibrosis, and hepatic necrosis. Concurrent laboratory abnormalities have included prolonged bleeding time, as well as significantly elevated hepatic enzymes (e.g., more than 20 times the upper limit of normal [ULN]) and bilirubin (e.g., more than 2 times ULN). One patient experienced elevations in hepatic enzymes of up to 40 times ULN and jaundice with hyperbilirubinemia up to 12 times ULN with a recurrence upon re-challenge. In an FDA review of 6 postmarketing cases of severe liver injury, 5 occurred in pediatric patients. The onset of symptoms ranged from 21 to 730 days after treatment initiation, with a median onset of 62.5 days. Four of the patients recovered after atomoxetine discontinuation. One adult male patient died as a result of hepatic failure and renal failure; however, causality to atomoxetine could not be definitively established. During pre-approval clinical trials, severe hepatotoxicity was not reported; however, 41 postmarketing cases were identified as having hepatobiliary events requiring additional analysis. The mechanism of atomoxetine-induced hepatic injury is unknown, and the incidence is uncertain due to probable under-reporting of postmarketing adverse events. Symptoms that are indicative of liver injury include unexplained flu-like symptoms (musculoskeletal pain, chills), fatigue, loss of appetite, pain in the right upper quadrant of the stomach, pruritus, nausea/vomiting, jaundice of the sclera or skin, or dark-colored urine. Monitoring of liver function tests is not routinely recommended for those who take atomoxetine. However, patients should be informed of the signs and symptoms of liver toxicity and should be instructed to promptly report such effects to their health care provider. Discontinue atomoxetine in any patient who exhibits jaundice or laboratory evidence of liver injury; atomoxetine should not be restarted in these patients.

Back pain and muscle cramps/spasms were reported in < 2% of adult patients during atomoxetine clinical trials.

Rhabdomyolysis has been reported with post-marketing use of atomoxetine; however, frequency and causality have not been established.

Atomoxetine is contraindicated in any patient with a known hypersensitivity to atomoxetine (e.g., angioedema or urticaria due to the drug) or any inactive ingredients in the product. There is risk for allergic reactions with any drug; however, allergic reactions were uncommon in clinical trials with atomoxetine. Anaphylaxis, angioedema, rash and urticaria have been reported in patients taking atomoxetine.

Atomoxetine is contraindicated in patients with pheochromocytoma or history of pheochromocytoma, as serious reactions (including increased blood pressure and tachyarrhythmia), and the potential risk for prolonged QT interval, have been reported during use.

Before initiating treatment with atomoxetine, patients should be adequately screened for risk factors for bipolar disorder such as a personal or family history of mania and depression. 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. 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 atomoxetine or a patient's underlying bipolar disorder. Patients should also be monitored for the appearance or worsening of aggressive behavior or hostility as there is evidence that atomoxetine may cause these behaviors during treatment. 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 these symptoms. If such symptoms occur during treatment, consider a possible causal role of atomoxetine. Psychotic or manic symptoms (e.g., hallucinations, delusional thinking, psychosis, or mania) in patients without a prior history of psychotic illness or mania may also be caused by atomoxetine at usual doses; if such symptoms occur, consider discontinuing atomoxetine.

Atomoxetine is not approved for the treatment of major depressive disorder (MDD). Atomoxetine increased the risk of suicidal thoughts and behavior in children and adolescents in short-term studies; the risk appears to be the greatest early in treatment. Co-morbidities occurring with ADHD may increase the risk of suicidal ideation and/or behavior. Monitor all patients receiving atomoxetine closely for clinical worsening, suicidal ideation, and unusual behavioral changes, such as anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia, hypomania, and mania, especially during the first few months of therapy and after any dosage adjustment. Instruct caregivers and patients to immediately notify the prescriber of changes in behavior or suicidal ideation. Consider changing the therapeutic regimen or discontinuing the medication in patients with persistent or worrisome symptoms, especially if these symptoms are severe, abrupt in onset, or were not part of the patient's presenting symptoms. In clinical trials, all reactions occurred in children 12 years and younger and within the first month of therapy. No suicides occurred in these trials. It is unknown whether the risk of suicidal ideation in pediatric patients extends to longer-term use.

Sudden death has been associated with atomoxetine use at usual doses in children and adolescents with structural congenital heart disease or other serious cardiac disease. According to the manufacturer, atomoxetine generally should not be used in patients with known serious structural cardiac abnormalities, serious cardiac arrhythmias, or other serious cardiac problems that may make them more vulnerable to the noradrenergic effects of atomoxetine. Sudden death, myocardial infarction, and stroke have occurred in adults receiving standard dosages of atomoxetine. In contrast, a retrospective cohort study including over 1.2 million patients 2 to 24 years of age did not find an increased risk of serious cardiovascular events in current users of drugs for the treatment of ADHD compared to nonusers (adjusted hazard ratio 0.75; 95% CI 0.31 through 1.85); the portion of these patients using atomoxetine was not specified. The authors concluded that although the absolute magnitude of risk appears to be low, a modest increase in risk could not be ruled out. The American Heart Association (AHA) states that it is reasonable to consider the use of medications for the treatment of ADHD in pediatric patients with congenital heart disease without current hemodynamic or arrhythmic concerns or congenital heart disease that is considered stable by the patient's pediatric cardiologist, unless the cardiologist has specific concerns. However, these patients should be closely monitored and treatment discontinuation should be considered if the patient develops any of the following conditions: heart condition associated with sudden cardiac death (SCD); arrhythmia requiring cardiopulmonary resuscitation; direct current cardioversion or defibrillation, or overdrive pacing; arrhythmia associated with SCD; any clinically significant arrhythmia that is not treated or controlled; QTc on electrocardiogram (ECG) longer than 0.46 sec; or heart rate or blood pressure greater than 2 standard deviations above the mean for age. All patients being considered for pharmacologic treatment of ADHD should have a careful history taken, including assessment for a family history of sudden death or ventricular arrhythmia, and a physical exam to assess for the presence of cardiac disease. If cardiac disease is suspected, further cardiac evaluation including an ECG and echocardiogram is warranted. For pediatric patients, the AHA states that it may be useful to obtain a baseline ECG as a part of the initial evaluation. If a child or adolescent has any significant findings on physical examination, ECG, or family history, consult a pediatric cardiologist before initiating the medication.

Atomoxetine undergoes extensive hepatic metabolism resulting in an active metabolite and exposures to the drug are increased with moderate to severe hepatic disease. Reduce atomoxetine dosage in those with moderate to severe hepatic impairment. Rare cases of severe drug-induced liver injury (hepatotoxicity) causally associated with atomoxetine have been reported postmarketing; in these cases most patients recovered with normal liver function after stopping the medication. Routine liver function tests are not a standard recommendation during atomoxetine treatment; hepatotoxicity is unpredictable and rare. Patients should be informed of the signs and symptoms of liver toxicity and to notify their health care provider immediately if they notice such effects. Discontinue atomoxetine in patients who exhibit jaundice (yellowing of the skin or the whites of the eyes) or laboratory evidence of liver injury; do not restart atomoxetine. Perform laboratory testing to determine liver enzyme concentrations at the first symptom or sign of liver dysfunction (e.g., pruritus, dark urine, jaundice, right upper quadrant tenderness, or unexplained flu-like symptoms).

Atomoxetine is contraindicated for use in patients who have severe cardiac or vascular conditions that could deteriorate from significant increases in blood pressure (15 to 20 mmHg) or heart rate (20 beats per minute), such as serious structural cardiac abnormalities, serious cardiac rhythm disturbances (e.g., ventricular arrhythmias), symptomatic heart failure, cardiomyopathy, advanced arteriosclerosis, severe coronary artery disease, severe hypertension, ventricular dysfunction. Sudden death has been associated with usual atomoxetine doses in children and adolescents who have structural congenital heart disease or other serious cardiac disease. Use with caution in patients who have conditions that could be worsened by increased blood pressure or heart rate, such as controlled or mild hypertension, tachycardia, cardiac-related diseases, or cerebrovascular disease. There is a possible risk of torsade de pointes (TdP) with use. Use atomoxetine with caution in patients with conditions that may increase the risk of QT prolongation including congenital long QT syndrome, bradycardia, AV block, heart failure, stress-related cardiomyopathy, myocardial infarction, stroke, hypomagnesemia, hypokalemia, hypocalcemia, or in patients receiving medications known to prolong the QT interval or cause electrolyte imbalances. Females, people 65 years and older, patients with sleep deprivation, pheochromocytoma, sickle cell disease, hypothyroidism, hyperparathyroidism, hypothermia, systemic inflammation (e.g., human immunodeficiency virus (HIV) infection, fever, and some autoimmune diseases including rheumatoid arthritis, systemic lupus erythematosus (SLE), and celiac disease) and patients undergoing apheresis procedures (e.g., plasmapheresis [plasma exchange], cytapheresis) may also be at increased risk for QT prolongation. Measure pulse and blood pressure at baseline, after dosage increases, and periodically throughout treatment. Consider discontinuing atomoxetine in patients with stable cardiac conditions who develop: heart condition associated with sudden cardiac death (SCD); arrhythmia requiring cardiopulmonary resuscitation; direct current cardioversion or defibrillation, or overdrive pacing; any clinically significant arrhythmia that is not treated or controlled; QTc longer than 0.46 sec; or heart rate or blood pressure more than 2 standard deviations above the mean for age.

The use of atomoxetine is contraindicated in patients with closed-angle glaucoma. In clinical trials, atomoxetine use was associated with an increased risk for mydriasis.

Urinary retention and urinary hesitancy in pediatric patients have been identified in postmarketing reports of atomoxetine use. New or worsened urinary retention or hesitancy could potentially be related to atomoxetine use. Despite the low affinity of atomoxetine for cholinergic receptors, constipation and xerostomia have also been reported. Therefore, atomoxetine should be used cautiously in patients with bladder obstruction, GI obstruction, or ileus.

Seizures occurred in 0.2% of pediatric patients in clinical trials that followed premarket testing. Within these trials, the seizure risk among pediatric patients was greater among poor metabolizers (PMs) (0.3%) than extensive metabolizers (EMs) (0.2%). Causality to the drug has not been established. Seizures have been reported in those with risk factors for seizures or with a preexisting seizure disorder; therefore, atomoxetine should be used cautiously under these conditions until further information becomes available.

In rare instances, atomoxetine may cause prolonged and sometimes painful erections (priapism). All male patients and their caregivers should be counseled on the signs and symptoms of priapism and the importance of seeking immediate medical attention if an erection lasting > 4 hours occurs. Immediate diagnosis and treatment are essential to avoid tissue damage. Priapism can occur in males of any age; younger males, particularly those who have not reached puberty, may not recognize the problem or may be embarrassed to tell anyone if it occurs. In a review of methylphenidate products by the FDA, the median age of patients who experienced priapism was 12.5 years (range: 8-33 years). Reported cases occurred after a period of time on stimulant therapy and often subsequent to a dose increase. Priapism was also reported during periods of stimulant drug withdrawal (e.g., drug holidays or discontinuation). Although priapism has been associated with stimulant medications, atomoxetine appears to carry a higher risk of the condition.

Patients should exercise caution when performing activities requiring coordination and concentration (e.g., gymnastics or riding a bicycle) until the full effects of atomoxetine are known. Atomoxetine may cause drowsiness, dizziness, or fatigue. For patients in whom alcohol consumption is a possibility (e.g., adolescents), counsel them to avoid taking atomoxetine with ethanol and to avoid ethanol intoxication.

Orthostatic hypotension and syncope have been reported in clinical studies of atomoxetine in children and adolescents. Use atomoxetine with caution in patients with a history of orthostatic hypotension, or any condition that may predispose them to orthostatic hypotension, including hypovolemia, low blood pressure, use of antihypertensive medications, dehydration, or a history of abrupt heart rate or blood pressure changes.

Atomoxetine is contraindicated with concurrent use or use within 14 days of MAOI therapy.

Monitor pediatric patients for the potential for growth inhibition during atomoxetine therapy. Monitor height and weight at treatment initiation and periodically thereafter. Short-term (9-week) studies have shown that up to 3.5% of body weight can be lost, and this loss may be dose-related. Data from open-label trials indicate that in general, the weight and height gain of children treated with atomoxetine lags behind that predicted by normative population data for the first 9 to 12 months of treatment; subsequently, weight gain rebounds and at about 3 years of treatment, patients have gained slightly more weight (0.5 kg) than predicted by their baseline data. After about 12 months, gain in height stabilizes, and at 3 years, patients have gained only slightly less (0.4 cm) than predicted. Growth patterns are similar regardless of pubertal status; however, mean weight gain has been shown to be slower for CYP2D6 poor metabolizers (PMs) compared to extensive metabolizers (EMs) (2.4 kg less vs. 0.2 kg less than predicted, respectively), while height gain is similar between PMs and EMs (1.1 cm less vs. 0.4 cm less than predicted, respectively).

Description: Atomoxetine is a selective norepinephrine reuptake inhibitor (SNRI) and was the first nonstimulant drug approved for attention-deficit hyperactivity disorder (ADHD). It is structurally similar to fluoxetine, does not have a potential for abuse, and is not classified as a controlled substance. Well-controlled comparative data with stimulants are limited. However, when compared with stimulants (effect size = 1), atomoxetine has an effect size of 0.7. While atomoxetine is effective for the management of ADHD in many patients, the body of evidence supporting its use is smaller than traditional psychostimulants. Atomoxetine is a particularly attractive treatment option for patients in whom misuse or diversion is a concern due to its lack of abuse potential. Although it is not a stimulant medication, atomoxetine has been reported to increase blood pressure and heart rate and has been associated with rare sudden death in children with structural cardiac abnormalities or other serious heart conditions. The American Heart Association (AHA) recommends careful screening of all children and adolescents prior to initiating pharmacologic therapy for ADHD. Rare reports of drug-induced liver injury have been reported. There have also been reports of suicidal thinking in children and adolescents being treated for ADHD with atomoxetine and a boxed warning in the product label notes the increased risk of suicidality in children and adolescents. Patients being treated with atomoxetine should be closely monitored for clinical worsening, as well as agitation, irritability, suicidal thinking or behaviors, and unusual changes in moods or behavior. Atomoxetine is FDA approved for use in pediatric patients 6 years of age and older.

For the treatment of attention-deficit hyperactivity disorder (ADHD):
Oral dosage:
Children and Adolescents 6 to 17 years weighing 70 kg or less: 0.5 mg/kg/dose PO once daily in the morning or 0.25 mg/kg/dose PO twice daily, initially. After at least 3 days, may increase the dose to 1.2 mg/kg/day in 1 or 2 divided doses. Max: 1.4 mg/kg/day or 100 mg/day, whichever is less. For poor CYP2D6 metabolizers, only increase the dose to 1.2 mg/kg/day if symptoms fail to improve after 4 weeks and the initial dose is well tolerated. No additional benefit has been demonstrated for doses higher than 1.2 mg/kg/day. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
Children and Adolescents 6 to 17 years weighing more than 70 kg: 40 mg PO once daily in the morning or 20 mg PO twice daily, initially. After at least 3 days, increase the dose to 80 mg/day in 1 or 2 divided doses. May increase the dose to 100 mg/day if optimal response has not been achieved after an additional 2 to 4 weeks. Max: 100 mg/day. For poor CYP2D6 metabolizers, only increase the dose to 80 mg/day if symptoms fail to improve after 4 weeks and the initial dose is well tolerated. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.

Maximum Dosage Limits:
-Neonates
Safety and efficacy have not been established.
-Infants
Safety and efficacy have not been established.
-Children
< 6 years: Safety and efficacy have not been established.
>= 6 years (weight <= 70 kg): 1.4 mg/kg/day PO (Max: 100 mg/day).
>= 6 years (weight > 70 kg): 100 mg/day PO.
-Adolescents
weight <= 70 kg: 1.4 mg/kg/day PO (Max: 100 mg/day).
weight > 70 kg: 100 mg/day PO.

Patients with Hepatic Impairment Dosing
For moderate hepatic impairment (Child-Pugh Class B), reduce initial and target dosage by 50% of normal. For severe hepatic impairment (Child-Pugh Class C), reduce initial and target dosage by 75% of normal.

Patients with Renal Impairment Dosing
No dosage adjustments are needed.

*non-FDA-approved indication

Monograph content under development

Mechanism of Action: Although atomoxetine's precise mechanism of action for the management of attention-deficit hyperactivity disorder (ADHD) is unknown, it is thought that the drug exerts its effect through selective inhibition of the pre-synaptic norepinephrine (NE) transporter. Atomoxetine, the R(-) isomer, selectively inhibits the neuronal reuptake of NE. Atomoxetine binding sites in the brain are consistent with the known distribution of NE-containing neurons. It is hypothesized that the atomoxetine-induced increase in NE in the prefrontal cortex, a region involved in attention and memory, mediates the therapeutic effect of atomoxetine in patients with ADHD. Increased concentrations of NE ultimately result in desensitization of beta-adrenoreceptors. Atomoxetine has minimal to no affinity for dopamine and serotonin receptor sites. Researchers have suggested that atomoxetine may also act as an N-methyl-D-aspartate (NMDA) receptor antagonist, contributing to the drug's clinical effect.

Pharmacokinetics: Atomoxetine is administered orally. According to the manufacturer, atomoxetine primarily distributes into total body water with a mean volume of distribution (Vd) of 0.85 L/kg. However, in a study of pediatric patients ages 7-14 years (n = 16), Vd at steady state was 2.25 L/kg. Plasma protein binding (primarily to albumin) of atomoxetine is 98% at therapeutic concentrations.

In patients with normal CYP2D6 metabolic activity (extensive metabolizers, EMs), atomoxetine is primarily metabolized via the CYP2D6 enzymatic pathway and oxidated to form the active metabolite. Poor metabolizers (PMs) of CYP2D6-metabolized drugs (roughly 7% of Caucasians and 2% of African Americans) have reduced activity via the CYP2D6 pathway, resulting in 10-fold higher AUCs, 5-fold higher peak plasma concentrations, and slower elimination of atomoxetine compared to EMs. Similar increases in exposure are seen in EMs when atomoxetine is administered with a strong CYP2D6 inhibitor.

The major oxidative metabolite of atomoxetine is 4-hydroxyatomoxetine. 4-Hydroxyatomoxetine is as potent as atomoxetine, but circulates in much lower concentrations (1% of atomoxetine concentration in EMs and 0.1% in PMs). 4-Hydroxyatomoxetine is primarily formed by CYP2D6; in PMs, it is formed at a slower rate by several other CYP450 enzymes. In a study of pediatric EM patients, plasma concentrations of atomoxetine at steady state were approximately 35 times greater than the metabolite. In a pooled analysis of 589 pediatric patients (559 EMs and 30 PMs), mean peak concentrations at similar doses were approximately 5 times higher in PMs compared to EMs. A second metabolite, N-desmethylatomoxetine, is formed by CYP2C19 and other CYP450 enzymes, but has substantially less pharmacological activity compared with atomoxetine and circulates at lower concentrations (5% of atomoxetine concentration in EMs and 45% in PMs).

Plasma clearance of atomoxetine in adult EMs is 0.35 L/kg/hour, but in PMs, clearance drops to 0.03 L/kg/hour and half-life more than doubles. Accumulation of atomoxetine occurs in PMs but not EMs. Biotransformation is extensive, with < 3% of a dose being excreted as the parent drug. Atomoxetine is excreted primarily in the urine (> 80%) as 4-hydroxyatomoxetine-O-glucuronide and is excreted to a lesser extent in the feces (< 17%). The mean half-life in adult EMs is approximately 5 hours; half-life is extended to 24 hours in adult PMs. In pediatric EMs 7-14 years old, the mean half-life was found to be 3.28 hours.

With once-daily dosing of atomoxetine, plasma drug concentrations are low in most patients by late afternoon. How the drug's clinical effects persist with once-daily dosing despite low drug concentrations is uncertain. One investigator suggests that brain pharmacokinetics may be different than plasma pharmacokinetics, or neuroregulatory changes may exist beyond the time the drug is at the receptor site.

Atomoxetine pharmacokinetics have been evaluated in children, adolescents, and adults using population pharmacokinetic studies. Similar half-life, AUC, and Cmax values were observed in all 3 populations when normalized to a mg/kg basis. Clearance and Vd were similar when adjusted for body weight.

Affected cytochrome P450 isoenzymes: CYP2D6
Atomoxetine is a primary substrate of CYP2D6. Atomoxetine has not been shown to inhibit or induce CYP enzymes 1A2, 3A, 2D6, or 2C9. Poor metabolizers (PMs) of CYP2D6-metabolized drugs (roughly 7% of Caucasians and 2% of African Americans) have reduced activity via the CYP2D6 pathway, resulting in 10-fold higher AUCs, 5-fold higher peak plasma concentrations, and slower elimination of atomoxetine compared to EMs. Similar increases in exposure are seen in EMs when atomoxetine is administered with a strong CYP2D6 inhibitor. Although in vitro studies suggest that coadministration of CYP2D6 inhibitors to PMs will not further increase the plasma concentrations of atomoxetine, FDA-approved labeling indicates that dosage adjustment may be necessary. In addition, a dosage adjustment may be necessary in normal populations (i.e., EMs) when atomoxetine is administered concurrently with a strong CYP2D6 inhibitor. Dosage adjustments are not recommended for other drugs metabolized by the 2D6 or 3A4 enzyme system when coadministered with atomoxetine.


-Route-Specific Pharmacokinetics
Oral Route
Atomoxetine is rapidly absorbed from the GI tract. Bioavailability is roughly 94% in PMs and 63% in EMs. Drugs that elevate gastric pH have not been shown to affect atomoxetine bioavailability. The Cmax occurs 1-2 hours after dosing. In pediatric clinical trials, administration with food lowered the Cmax by 9%. In adult trials, food did not affect the overall extent of absorption (AUC) of atomoxetine, but did reduce the rate of absorption; Cmax was reduced by 37% and Tmax was delayed by 3 hours.


-Special Populations
Hepatic Impairment
The AUC for atomoxetine is increased in EM patients with moderate or severe hepatic impairment compared to EM patients with normal hepatic function; dosage adjustments are required in patients with hepatic impairment.

Renal Impairment
EM patients with end-stage renal disease had higher systemic exposure to atomoxetine vs. healthy subjects, but there was no difference when exposure was adjusted for weight. No dosage adjustments are recommended for patients with renal impairment.