1.1 Attention-Deficit/Hyperactivity Disorder (ADHD)

Atomoxetine capsules are indicated for the treatment of Attention-Deficit/Hyperactivity Disorder (ADHD). 

The efficacy of atomoxetine capsules was established in seven clinical trials in outpatients with ADHD: four 6 to 9-week trials in pediatric patients (ages 6 to 18), two 10-week trial in adults, and one maintenance trial in pediatrics (ages 6 to 15) [see Clinical Studies (14)].

1.2 Diagnostic Considerations

A diagnosis of ADHD (DSM-IV) implies the presence of hyperactive-impulsive or inattentive symptoms that cause impairment and that were present before age 7 years. The symptoms must be persistent, must be more severe than is typically observed in individuals at a comparable level of development, must cause clinically significant impairment, e.g., in social, academic, or occupational functioning, and must be present in 2 or more settings, e.g., school (or work) and at home. The symptoms must not be better accounted for by another mental disorder.

The specific etiology of ADHD is unknown, and there is no single diagnostic test. Adequate diagnosis requires the use not only of medical but also of special psychological, educational, and social resources. Learning may or may not be impaired. The diagnosis must be based upon a complete history and evaluation of the patient and not solely on the presence of the required number of DSM-IV characteristics.

For the Inattentive Type, at least 6 of the following symptoms must have persisted for at least 6 months: lack of attention to details/careless mistakes, lack of sustained attention, poor listener, failure to follow through on tasks, poor organization, avoids tasks requiring sustained mental effort, loses things, easily distracted, forgetful. For the Hyperactive-Impulsive Type, at least 6 of the following symptoms must have persisted for at least 6 months: fidgeting/squirming, leaving seat, inappropriate running/climbing, difficulty with quiet activities, “on the go,” excessive talking, blurting answers, can’t wait turn, intrusive. For a Combined Type diagnosis, both inattentive and hyperactive-impulsive criteria must be met.

1.3 Need for Comprehensive Treatment Program

Atomoxetine capsules are indicated as an integral part of a total treatment program for ADHD that may include other measures (psychological, educational, social) for patients with this syndrome. Drug treatment may not be indicated for all patients with this syndrome. Drug treatment is not intended for use in the patient who exhibits symptoms secondary to environmental factors and/or other primary psychiatric disorders, including psychosis. Appropriate educational placement is essential in children and adolescents with this diagnosis and psychosocial intervention is often helpful. When remedial measures alone are insufficient, the decision to prescribe drug treatment medication will depend upon the physician’s assessment of the chronicity and severity of the patient’s symptoms.

2.1 Acute Treatment

2.2 Maintenance/Extended Treatment

It is generally agreed that pharmacological treatment of ADHD may be needed for extended periods. The benefit of maintaining pediatric patients (ages 6 to 15 years) with ADHD on atomoxetine hydrochloride after achieving a response in a dose range of 1.2 to 1.8 mg/kg/day was demonstrated in a controlled trial. Patients assigned to atomoxetine hydrochloride in the maintenance phase were generally continued on the same dose used to achieve a response in the open label phase. The physician who elects to use atomoxetine capsules for extended periods should periodically reevaluate the long-term usefulness of the drug for the individual patient [see Clinical Studies (14.1)].

2.3 General Dosing Information

Atomoxetine capsules may be taken with or without food. 

Atomoxetine capsules can be discontinued without being tapered. 

Atomoxetine capsules are not intended to be opened, they should be taken whole [see Patient Counseling Information (17)] .

The safety of single doses over 120 mg and total daily doses above 150 mg have not been systematically evaluated.

2.4 Screen for Bipolar Disorder Prior to Starting Atomoxetine

Prior to initiating treatment with atomoxetine, screen patients for a personal or family history of bipolar disorder, mania, or hypomania [see Warnings and Precautions (5.6)].

2.5 Dosing in Specific Populations

4.1 Hypersensitivity

Atomoxetine capsules are contraindicated in patients known to be hypersensitive to atomoxetine or other constituents of the product [see Warnings and Precautions(5.8)].

4.2 Monoamine Oxidase Inhibitors (MAOI)

Atomoxetine capsules should not be taken with an MAOI, or within 2 weeks after discontinuing an MAOI. Treatment with an MAOI should not be initiated within 2 weeks after discontinuing atomoxetine capsules. With other drugs that affect brain monoamine concentrations, there have been reports of serious, sometimes fatal reactions (including hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, and mental status changes that include extreme agitation progressing to delirium and coma) when taken in combination with an MAOI. Some cases presented with features resembling neuroleptic malignant syndrome. Such reactions may occur when these drugs are given concurrently or in close proximity [see Drug Interactions (7.1)].

4.3 Narrow Angle Glaucoma

In clinical trials, atomoxetine hydrochloride use was associated with an increased risk of mydriasis and therefore its use is not recommended in patients with narro w angle glaucoma.

4.4 Pheochromocytoma

Serious reactions, including elevated blood pressure and tachyarrhythmia, have been reported in patients with pheochromocytoma or a history of pheochromocytoma who received atomoxetine hydrochloride. Therefore, atomoxetine capsules should not be taken by patients with pheochromocytoma or a history of pheochromocytoma.

4.5 Severe Cardiovascular Disorders

Atomoxetine capsules should not be used in patients with severe cardiac or vascular disorders whose condition would be expected to deteriorate if they experience increases in blood pressure or heart rate that could be clinically important (for example, 15 to 20 mm Hg in blood pressure or 20 beats per minute in heart rate. [see Warnings and Precautions (5.4)]. 

5.1 Suicidal Ideation

Atomoxetine hydrochloride increased the risk of suicidal ideation in short-term studies in children and adolescents with Attention-Deficit/Hyperactivity Disorder (ADHD). Pooled analyses of short-term (6 to 18 weeks) placebo-controlled trials of atomoxetine hydrochloride in children and adolescents have revealed a greater risk of suicidal ideation early during treatment in those receiving atomoxetine hydrochloride. There were a total of 12 trials (11 in ADHD and 1 in enuresis) involving over 2200 patients (including 1357 patients receiving atomoxetine hydrochloride and 851 receiving placebo). The average risk of suicidal ideation in patients receiving atomoxetine hydrochloride was 0.4% (5/1357 patients), compared to none in placebo-treated patients. There was 1 suicide attempt among these approximately 2200 patients, occurring in a patient treated with atomoxetine hydrochloride. No suicides occurred in these trials. All reactions occurred in children 12 years of age or younger. All reactions occurred during the first month of treatment. It is unknown whether the risk of suicidal ideation in pediatric patients extends to longer-term use. A similar analysis in adult patients treated with atomoxetine hydrochloride for either ADHD or major depressive disorder (MDD) did not reveal an increased risk of suicidal ideation or behavior in association with the use of atomoxetine hydrochloride.

All pediatric patients being treated with atomoxetine hydrochloride should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases.

The following symptoms have been reported with atomoxetine hydrochloride: anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania and mania. Although a causal link between the emergence of such symptoms and the emergence of suicidal impulses has not been established, there is a concern that such symptoms may represent precursors to emerging suicidality. Thus, patients being treated with atomoxetine hydrochloride should be observed for the emergence of such symptoms.

Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients who are experiencing emergent suicidality or symptoms that might be precursors to emerging suicidality, especially if these symptoms are severe or abrupt in onset, or were not part of the patient’s presenting symptoms.

Families and caregivers of pediatric patients being treated with atomoxetine hydrochloride should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to healthcare providers. Such monitoring should include daily observation by families and caregivers.

5.2 Severe Liver Injury

Postmarketing reports indicate that atomoxetine hydrochloride can cause severe liver injury. Although no evidence of liver injury was detected in clinical trials of about 6000 patients, there have been rare cases of clinically significant liver injury that were considered probably or possibly related to atomoxetine hydrochloride use in postmarketing experience. Rare cases of liver failure have also been reported, including a case that resulted in a liver transplant. Because of probable underreporting, it is impossible to provide an accurate estimate of the true incidence of these reactions. Reported cases of liver injury occurred within 120 days of initiation of atomoxetine in the majority of cases and some patients presented with markedly elevated liver enzymes [>20 X upper limit of normal (ULN)], and jaundice with significantly elevated bilirubin levels (>2 X ULN), followed by recovery upon atomoxetine discontinuation. In one patient, liver injury, manifested by elevated hepatic enzymes up to 40 X ULN and jaundice  with bilirubin up to 12 X ULN, recurred upon rechallenge, and was followed by recovery upon drug discontinuation, providing evidence that atomoxetine hydrochloride likely caused the liver injury. Such reactions may occur several months after therapy is started, but laboratory abnormalities may continue to worsen for several weeks after drug is stopped. The patient described above recovered from his liver injury, and did not require a liver transplant.

Atomoxetine hydrochloride should be discontinued in patients with jaundice or laboratory evidence of liver injury, and should not be restarted. Laboratory testing to determine liver enzyme levels should be done upon the first symptom or sign of liver dysfunction (e.g., pruritus, dark urine, jaundice, right upper quadrant tenderness, or unexplained “flu like” symptoms) [see Warnings and Precautions (5.12); Patient Counseling Information (17 )].

5.3 Serious Cardiovascular Events

5.4 Effects on Blood Pressure and Heart Rate

Atomoxetine hydrochloride should be used with caution in patients whose underlying medical conditions could be worsened by increases in blood pressure or heart rate such as certain patients with hypertension, tachycardia, or cardiovascular or cerebrovascular disease. It should not be used 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 [see Contraindications (4.5)]. Pulse and blood pressure should be measured at baseline, following atomoxetine hydrochloride dose increases, and periodically while on therapy to detect possible clinically important increases.  

The following table provides short-term, placebo-controlled clinical trial data for the proportions of patients having an increase in: diastolic blood pressure ≥15 mm Hg; systolic blood pressure ≥20 mm Hg; heart rate greater than or equal to 20 bpm, in both the pediatric and adult populations (see Table 1). 

Table 1a

a Abbreviations: bpm=beats per minute; DBP=diastolic blood pressure; HR=heart rate; mm Hg=millimeters mercury; SBP=systolic blood pressure.

b Proportion of patients meeting threshold at any one time during clinical trial.  

In placebo-controlled registration studies involving pediatric patients, tachycardia was identified as an adverse event for 0.3% (5/1,597) of these atomoxetine hydrochloride patients compared with 0% (0/934) of placebo patients. The mean heart rate increase in extensive metabolizer (EM) patients was 5 beats/minute, and in poor metabolizer (PM) patients 9.4 beats/minute.  

In adult clinical trials where EM/PM status was available, the mean heart rate increase in PM patients was significantly higher than in EM patients (11 beats/minute versus 7.5 beats/minute). The heart rate effects could be clinically important in some PM patients.  

In placebo-controlled registration studies involving adult patients, tachycardia was identified as an adverse event for 1.5% (8/540) of atomoxetine hydrochloride patients compared with 0.5% (2/402) of placebo patients.

In adult clinical trials where EM/PM status was available, the mean change from baseline in diastolic blood pressure in PM patients was higher than in EM patients (4.21 versus 2.13 mm Hg) as was the mean change from baseline in systolic blood pressure (PM: 2.75 versus EM: 2.40 mm Hg). The blood pressure effects could be clinically important in some PM patients.

Orthostatic hypotension and syncope have been reported in patients taking atomoxetine hydrochloride. In child and adolescent registration studies, 0.2% (12/5,596) of atomoxetine hydrochloride-treated patients experienced orthostatic hypotension and 0.8% (46/5,596) experienced syncope. In short-term child and adolescent registration studies, 1.8% (6/340) of atomoxetine hydrochloride-treated patients experienced orthostatic hypotension compared with 0.5% (1/207) of placebo-treated patients. Syncope was not reported during short-term child and adolescent placebo-controlled ADHD registration studies. Atomoxetine hydrochloride should be used with caution in any condition that may predispose patients to hypotension, or conditions associated with abrupt heart rate or blood pressure changes.

5.5 Emergence of New Psychotic or Manic Symptoms

Treatment emergent psychotic or manic symptoms, e.g., hallucinations, delusional thinking, or mania in children and adolescents without a prior history of psychotic illness or mania can be caused by atomoxetine at usual doses. If such symptoms occur, consideration should be given to a possible causal role of atomoxetine, and discontinuation of treatment should be considered. In a pooled analysis of multiple short-term, placebo-controlled studies, such symptoms occurred in about 0.2% (4 patients with reactions out of 1,939 exposed to atomoxetine for several weeks at usual doses) of atomoxetine-treated patients compared to 0 out of 1,056 placebo-treated patients. 

5.6 Screening Patients for Bipolar Disorder

In general, particular care should be taken in treating ADHD in patients with comorbid bipolar disorder because of concern for possible induction of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described above represent such a conversion is unknown. However, prior to initiating treatment with atomoxetine hydrochloride, patients with comorbid depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. 

5.7 Aggressive Behavior or Hostility

Patients beginning treatment for ADHD should be monitored for the appearance or worsening of aggressive behavior or hostility. Aggressive behavior or hostility is often observed in children and adolescents with ADHD. In pediatric short-term controlled clinical trials, 21/1,308 (1.6%) of atomoxetine patients versus 9/806 (1.1%) of placebo-treated patients spontaneously reported treatment emergent hostility-related adverse events (overall risk ratio of 1.33 [95% C.I. 0.67 to 2.64 – not statistically significant]). In adult placebo-controlled clinical trials, 6/1,697 (0.35%) of atomoxetine patients versus 4/1,560 (0.26%) of placebo-treated patients spontaneously reported treatment emergent hostility-related adverse events (overall risk ratio of 1.38 [95% C.I. 0.39 to 4.88 – not statistically significant]).  Although this is not conclusive evidence that atomoxetine hydrochloride causes aggressive behavior or hostility, these behaviors were more frequently observed in clinical trials among children, adolescents, and adults treated with atomoxetine hydrochloride compared to placebo.

5.8 Allergic Events

Although uncommon, allergic reactions, including analycial reactions, angioneurotic edema, urticaria, and rash, have been reported in patients taking atomoxetine hydrochloride.

5.9 Effects on Urine Outflow from the Bladder

In adult ADHD controlled trials, the rates of urinary retention 1.7% (9/540) and urinary hesitation 5.6% (30/540) were increased among atomoxetine subjects compared with placebo subjects (0%, 0/402 ; 0.5%, 2/402, respectively). Two adult atomoxetine subjects and no placebo subjects discontinued from controlled clinical trials because of urinary retention. A complaint of urinary retention or urinary hesitancy should be considered potentially related to atomoxetine. 

5.10 Priapism

Rare postmarketing cases of priapism, defined as painful and nonpainful penile erection lasting more than 4 hours, have been reported for pediatric and adult patients treated with atomoxetine hydrochloride. The erections resolved in cases in which follow-up information was available, some following discontinuation of atomoxetine hydrochloride. Prompt medical attention is required in the event of suspected priapism.

5.11 Effects on Growth

Data on the long-term effects of atomoxetine hydrochloride on growth come from open-label studies, and weight and height changes are compared to normative population data. In general, the weight and height gain of pediatric patients treated with atomoxetine hydrochloride lags behind that predicted by normative population data for about the first 9 to 12 months of treatment. Subsequently, weight gain rebounds and at about 3 years of treatment, patients treated with atomoxetine hydrochloride have gained 17.9 kg on average, 0.5 kg more than predicted by their baseline data. After about 12 months, gain in height stabilizes, and at 3 years, patients treated with atomoxetine hydrochloride have gained 19.4 cm on average, 0.4 cm less than predicted by their baseline data (see Figure 1 below).

Figure 1: Mean Weight and Height Percentiles Over Time for Patients with Three Years of Atomoxetine Hydrochloride Treatment

This growth pattern was generally similar regardless of pubertal status at the time of treatment initiation. Patients who were pre-pubertal at the start of treatment (girls ≤8 years old, boys ≤9 years old) gained an average of 2.1 kg and 1.2 cm less than predicted after three years. Patients who were pubertal (girls >8 to ≤13 years old, boys >9 to ≤14 years old) or late pubertal (girls >13 years old, boys >14 years old) had average weight and height gains that were close to or exceeded those predicted after three years of treatment.

Growth followed a similar pattern in both extensive and poor metabolizers (EMs, PMs). PMs treated for at least two years gained an average of 2.4 kg and 1.1 cm less than predicted, while EMs gained an average of 0.2 kg and 0.4 cm less than predicted.

In short-term controlled studies (up to 9 weeks), atomoxetine hydrochloride-treated patients lost an average of 0.4 kg and gained an average of 0.9 cm, compared to a gain of 1.5 kg and 1.1 cm in the placebo-treated patients. 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.

Growth should be monitored during treatment with atomoxetine hydrochloride.

5.12 Laboratory Tests

Routine laboratory tests are not required.

5.13 Concomitant Use of Potent CYP2D6 Inhibitors or Use in Patients who are known to be CYP2D6 PMs

Atomoxetine is primarily metabolized by the CYP2D6 pathway to 4-hydroxyatomoxetine. Dosage adjustment of atomoxetine hydrochloride may be necessary when coadministered with potent CYP2D6 inhibitors (e.g., paroxetine, fluoxetine, and quinidine) or when administered to CYP2D6 PMs. [see Dosage and Administration (2.5) and Drug Interactions (7.2)].

6.1 Clinical Trials Experience

Atomoxetine hydrochloride was administered to 5382 children or adolescent patients with ADHD and 1007 adults with ADHD in clinical studies. During the ADHD clinical trials, 1625 children and adolescent patients were treated for longer than 1 year and 2529 children and adolescent patients were treated for over 6 months. 

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. 

6.2 Postmarketing Spontaneous Reports

The following adverse reactions have been identified during post approval use of atomoxetine hydrochloride. Unless otherwise specified, these adverse reactions have occurred in adults and children and adolescents. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. 

Cardiovascular system – QT prolongation, syncope.

Peripheral vascular effects — Raynaud’s phenomenon 

General disorders and administration site conditions — Lethargy.  

Musculoskeletal system — Rhabdomyolysis

Nervous system disorders — Hypoaesthesia, paraesthesia in children and adolescents; sensory disturbances; tics 

Psychiatric disorders — Depression and depressed mood; anxiety, libido changes.

Seizures — Seizures have been reported in the postmarketing period. The postmarketing seizure cases include patients with pre-existing seizure disorders and those with identified risk factors for seizures, as well as patients with neither a history of nor identified risk factors for seizures. The exact relationship between atomoxetine hydrochloride and seizures is difficult to evaluate due to uncertainty about the background risk of seizures in ADHD patients. 

Skin and subcutaneous tissue disorders — Alopecia, hyperhidrosis.

Urogenital System— Male pelvic pain; urinary hesitation in children and adolescents; urinary retention in children and adolescents.

7.1 Monoamine Oxidase Inhibitors

With other drugs that affect brain monoamine concentrations, there have been reports of serious, sometimes fatal reactions (including hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, and mental status changes that include extreme agitation progressing to delirium and coma) when taken in combination with an MAOI. Some cases presented with features resembling neuroleptic malignant syndrome. Such reactions may occur when these drugs are given concurrently or in close proximity [seeContraindications (4.2)].

7.2 Effect of CYP2D6 Inhibitors on Atomoxetine

In extensive metabolizers (EMs), inhibitors of CYP2D6 (e.g., paroxetine, fluoxetine, and quinidine) increase atomoxetine steady-state plasma concentrations to exposures similar to those observed in poor metabolizers (PMs). In EM individuals treated with paroxetine or fluoxetine, the AUC of atomoxetine is approximately 6- to 8-fold and Css, max is about 3- to 4-fold greater than atomoxetine alone. 

In vitro studies suggest that coadministration of cytochrome P450 inhibitors to PMs will not increase the plasma concentrations of atomoxetine.

7.3 Antihypertensive Drugs and Pressor Agents 

Because of possible effects on blood pressure, atomoxetine hydrochloride should be used cautiously with antihypertensive drugs and pressor agents (e.g., dopamine, dobutamine) or other drugs that increase blood pressure.

7.4 Albuterol

Atomoxetine hydrochloride should be administered with caution to patients being treated with systemically-administered (oral or intravenous) albuterol (or other beta2 agonists) because the action of albuterol on the cardiovascular system can be potentiated resulting in increases in heart rate and blood pressure. Albuterol (600 mcg iv over 2 hours) induced increases in heart rate and blood pressure. These effects were potentiated by atomoxetine (60 mg BID for 5 days) and were most marked after the initial coadministration of albuterol and atomoxetine. However, these effects on heart rate and blood pressure were not seen in another study after the coadministration with inhaled dose of albuterol (200 to 800 mcg) and atomoxetine (80 mg QD for 5 days) in 21 healthy Asian subjects who were excluded for poor metabolizer status.

7.5 Effect of Atomoxetine on P450 Enzymes

Atomoxetine did not cause clinically important inhibition or induction of cytochrome P450 enzymes, including CYP1A2, CYP3A, CYP2D6, and CYP2C9.

7.6 Alcohol

Consumption of ethanol with atomoxetine hydrochloride did not change the intoxicating effects of ethanol.

7.7 Methylphenidate

Coadministration of methylphenidate with atomoxetine hydrochloride did not increase cardiovascular effects beyond those seen with methylphenidate alone.

7.8 Drugs Highly Bound to Plasma Protein

In vitro drug-displacement studies were conducted with atomoxetine and other highly-bound drugs at therapeutic concentrations. Atomoxetine did not affect the binding of warfarin, acetylsalicylic acid, phenytoin, or diazepam to human albumin. Similarly, these compounds did not affect the binding of atomoxetine to human albumin.

7.9 Drugs that Affect Gastric pH

Drugs that elevate gastric pH (magnesium hydroxide/aluminum hydroxide, omeprazole) had no effect on atomoxetine hydrochloride bioavailability.

8.1 Pregnancy

8.2 Lactation

Risk Summary

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

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for atomoxetine hydrochloride and any potential adverse effects on the breastfed child from atomoxetine hydrochloride or from the underlying maternal condition.

8.4 Pediatric Use

Anyone considering the use of atomoxetine hydrochloride in a child or adolescent must balance the potential risks with the clinical need [see Boxed WarningandWarnings and Precautions (5.1)].

The pharmacokinetics of atomoxetine in children and adolescents are similar to those in adults. The safety, efficacy, and pharmacokinetics of atomoxetine hydrochloride in pediatric patients less than 6 years of age have not been evaluated.

A study was conducted in young rats to evaluate the effects of atomoxetine on growth and neurobehavioral and sexual development. Rats were treated with 1, 10, or 50 mg/kg/day (approximately 0.2, 2, and 8 times, respectively, the maximum human dose on a mg/m2 basis) of atomoxetine given by gavage from the early postnatal period (Day 10 of age) through adulthood. Slight delays in onset of vaginal patency (all doses) and preputial separation (10 and 50 mg/kg), slight decreases in epididymal weight and sperm number (10 and 50 mg/kg), and a slight decrease in corpora lutea (50 mg/kg) were seen, but there were no effects on fertility or reproductive performance. A slight delay in onset of incisor eruption was seen at 50 mg/kg. A slight increase in motor activity was seen on Day 15 (males at 10 and 50 mg/kg and females at 50 mg/kg) and on Day 30 (females at 50 mg/kg) but not on Day 60 of age. There were no effects on learning and memory tests. The significance of these findings to humans is unknown.

8.5 Geriatric Use

The safety, efficacy and pharmacokinetics of atomoxetine hydrochloride in geriatric patients have not been evaluated.

8.6 Hepatic Insufficiency

Atomoxetine exposure (AUC) is increased, compared with normal subjects, in EM subjects with moderate (Child-Pugh Class B) (2-fold increase) and severe (Child-Pugh Class C) (4-fold increase) hepatic insufficiency. Dosage adjustment is recommended for patients with moderate or severe hepatic insufficiency [see Dosage and Administration (2.3)].

8.7 Renal Insufficiency

EM subjects 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. Atomoxetine hydrochloride can therefore be administered to ADHD patients with end stage renal disease or lesser degrees of renal insufficiency using the normal dosing regimen.

8.8 Gender

Gender did not influence atomoxetine disposition.

8.9 Ethnic Origin

Ethnic origin did not influence atomoxetine disposition (except that PMs are more common in Caucasians).

8.10 Patients with Concomitant Illness

9.1 Controlled Substance

Atomoxetine hydrochloride is not a controlled substance.

9.2 Abuse

In a randomized, double-blind, placebo-controlled, abuse-potential study in adults comparing effects of atomoxetine hydrochloride and placebo, atomoxetine hydrochloride was not associated with a pattern of response that suggested stimulant or euphoriant properties. 

9.3 Dependence

Clinical study data in over 2,000 children, adolescents, and adults with ADHD and over 1,200 adults with depression showed only isolated incidents of drug diversion or inappropriate self-administration associated with atomoxetine hydrochloride. There was no evidence of symptom rebound or adverse reactions suggesting a drug-discontinuation or withdrawal syndrome.

10.1 Human Experience

There is limited clinical trial experience with atomoxetine hydrochloride overdose. During postmarketing, there have been fatalities reported involving a mixed ingestion overdose of atomoxetine hydrochloride and at least one other drug. There have been no reports of death involving overdose of atomoxetine hydrochloride alone, including intentional overdoses at amounts up to 1400 mg. In some cases of overdose involving atomoxetine hydrochloride, seizures have been reported. The most commonly reported symptoms accompanying acute and chronic overdoses of atomoxetine hydrochloride were gastrointestinal symptoms, somnolence, dizziness, tremor, and abnormal behavior. Hyperactivity and agitation have also been reported. Signs and symptoms consistent with mild to moderate sympathetic nervous system activation (e.g., tachycardia, blood pressure increased, mydriasis, dry mouth) have also been observed. Most events were mild to moderate. Less commonly, there have been reports of QT prolongation and mental changes, including disorientation and hallucinations [see Clinical Pharmacology (12.2)].

10.2 Management of Overdose

Consult with a Certified Poison Control Center for up to date guidance and advice. Because atomoxetine is highly protein-bound, dialysis is not likely to be useful in the treatment of overdose.

12.1 Mechanism of Action

The precise mechanism by which atomoxetine produces its therapeutic effects in Attention-Deficit/Hyperactivity Disorder (ADHD) is unknown, but is thought to be related to selective inhibition of the pre-synaptic norepinephrine transporter, as determined in ex vivo uptake and neurotransmitter depletion studies.

12.2 Pharmacodynamics

An exposure-response analysis encompassing doses of atomoxetine (0.5, 1.2 or 1.8 mg/kg/day) or placebo demonstrated atomoxetine exposure correlates with efficacy as measured by the Attention-Deficit/Hyperactivity Disorder Rating Scale-IV-Parent Version: Investigator administered and scored. The exposure-efficacy relationship was similar to that observed between dose and efficacy with median exposures at the two highest doses resulting in near maximal changes from baseline [see Clinical Studies (14.2)] .

Cardiac Electrophysiology — The effect of atomoxetine hydrochloride on QTc prolongation was evaluated in a randomized, double-blinded, positive-(moxifloxacin 400 mg) and placebo-controlled, cross-over study in healthy male CYP2D6 poor metabolizers. A total of 120 healthy subjects were administered atomoxetine hydrochloride (20 mg and 60 mg) twice daily for 7 days. No large changes in QTc interval (i.e., increases >60 msec from baseline, absolute QTc >480 msec) were observed in the study. However, small changes in QTc interval cannot be excluded from the current study, because the study failed to demonstrate assay sensitivity. There was a slight increase in QTc interval with increased atomoxetine concentration.

12.3 Pharmacokinetics

Atomoxetine is well-absorbed after oral administration and is minimally affected by food. It is eliminated primarily by oxidative metabolism through the cytochrome P450 2D6 (CYP2D6) enzymatic pathway and subsequent glucuronidation. Atomoxetine has a half-life of about 5 hours. A fraction of the population (about 7% of Caucasians and 2% of African Americans) are poor metabolizers (PMs) of CYP2D6 metabolized drugs. These individuals have reduced activity in this pathway resulting in 10-fold higher AUCs, 5-fold higher peak plasma concentrations, and slower elimination (plasma half-life of about 24 hours) of atomoxetine compared with people with normal activity [extensive metabolizers (Ems)]. Drugs that inhibit CYP2D6, such as fluoxetine, paroxetine, and quinidine, cause similar increases in exposure.

The pharmacokinetics of atomoxetine have been evaluated in more than 400 children and adolescents in selected clinical trials, primarily using population pharmacokinetic studies. Single-dose and steady-state individual pharmacokinetic data were also obtained in children, adolescents, and adults. When doses were normalized to a mg/kg basis, similar half-life, Cmax, and AUC values were observed in children, adolescents, and adults. Clearance and volume of distribution after adjustment for body weight were also similar.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

14.1 ADHD Studies in Children and Adolescents

14.2 ADHD Studies in Adults

The effectiveness of atomoxetine hydrochloride in the treatment of ADHD was established in 2 randomized, double-blind, placebo-controlled clinical studies of adult patients, age 18 and older, who met DSM-IV criteria for ADHD.

Signs and symptoms of ADHD were evaluated using the investigator-administered Conners Adult ADHD Rating Scale Screening Version (CAARS), a 30-item scale. The primary effectiveness measure was the 18-item Total ADHD Symptom score (the sum of the inattentive and hyperactivity/impulsivity subscales from the CAARS) evaluated by a comparison of mean change from baseline to endpoint using an intent-to-treat analysis.

In 2 identical, 10-week, randomized, double-blind, placebo-controlled acute treatment studies (Study 5, N=280; Study 6, N=256), patients received either atomoxetine hydrochloride or placebo. Atomoxetine hydrochloride was administered as a divided dose in the early morning and late afternoon/early evening and titrated according to clinical response in a range of 60 to 120 mg/day. The mean final dose of atomoxetine hydrochloride for both studies was approximately 95 mg/day. In both studies, ADHD symptoms were statistically significantly improved on atomoxetine hydrochloride, as measured on the ADHD Symptom score from the CAARS scale.

Examination of population subsets based on gender and age (<42 and ≥42) did not reveal any differential responsiveness on the basis of these subgroupings. There was not sufficient exposure of ethnic groups other than Caucasian to allow exploration of differences in these subgroups.

16.1 How Supplied

Atomoxetine capsules USP, 40 mg* are white to off-white powder filled in size ‘1’ hard gelatin capsules with opaque dark blue colored cap and opaque dark blue colored body imprinted “RDY” on cap and “521” on body with black ink. They are supplied:

Carton of 30 capsules (10 capsules each blister pack x 3), NDC 0904-6908-04

*Atomoxetine base equivalent.

16.2 Storage and Handling

Store at 20°C to 25°C (68°F to 77°F);  [See USP Controlled Room Temperature].

What is the most important information I should know about atomoxetine capsules?

The following have been reported with use of atomoxetine capsules: 

1. Suicidal thoughts and actions in children and teenagers: 

Children and teenagers sometimes think about suicide, and many report trying to kill themselves. Results from atomoxetine hydrochloride clinical studies with over 2,200 child or teenage ADHD patients suggest that some children and teenagers may have a higher chance of having suicidal thoughts or actions. Although no suicides occurred in these studies, 4 out of every 1,000 patients developed suicidal thoughts. Tell your child or teenager’s doctor if your child or teenager (or there is a family history of):

 

has bipolar illness (manic-depressive illness)

 

had suicide thoughts or actions before starting atomoxetine capsules.

The chance for suicidal thoughts and actions may be higher:

•

early during atomoxetine hydrochloride treatment

•

during dose adjustments

Prevent suicidal thoughts and action in your child or teenager by:

•

paying close attention to your child or teenager’s moods, behaviors, thoughts, and feelings during atomoxetine hydrochloride treatment

•

keeping all follow-up visits with your child or teenager’s doctor as scheduled

Watch for the following signs in your child or teenager during atomoxetine capsules treatment:

•

anxiety

•

agitation

•

panic attacks

•

trouble sleeping

•

irritability

•

hostility

•

aggressiveness

•

impulsivity

•

restlessness

•

mania

•

depression

•

suicide thoughts

Call your child or teenager’s doctor right away if they have any of the above signs, especially if they are new, sudden, or severe. Your child or teenager may need to be closely watched for suicidal thoughts and actions or need a change in medicine.

2. Severe liver damage:

Atomoxetine capsules can cause liver injury in some patients. Call your doctor right away if you or your child has the following signs of liver problems:

•

itching

•

right upper belly pain

•

dark urine

•

yellow skin or eyes

•

unexplained flu-like symptoms

3. Heart-related problems:

•

sudden death in patients who have heart problems or heart defects

•

stroke and heart attack in adults

•

increased blood pressure and heart rate

Tell your doctor if you or your child has any heart problems, heart defects, high blood pressure, or a family history of these problems. Your doctor should check you or your child carefully for heart problems before starting atomoxetine capsules.Your doctor should check your blood pressure or your child’s blood pressure and heart rate regularly during treatment with atomoxetine capsules.

Call your doctor right away if you or your child has any signs of heart problems such as chest pain, shortness of breath, or fainting while taking atomoxetine capsules.

4. New mental (psychiatric) problems in children and teenagers:

•

new psychotic symptoms (such as hearing voices, believing things that are not true, being  suspicious) or new manic symptoms

Call your child or teenager’s doctor right away about any new mental symptoms because adjusting or stopping atomoxetine hydrochloride treatment may need to be considered.

What is atomoxetine hydrochloride?

Atomoxetine hydrochloride is a selective norepinephrine reuptake inhibitor medicine. It is used for the treatment of attention deficit and hyperactivity disorder (ADHD). Atomoxetine hydrochloride may help increase attention and decrease impulsiveness and hyperactivity in patients with ADHD.

Atomoxetine capsules should be used as a part of a total treatment program for ADHD that may include counseling or other therapies.

Atomoxetine capsules has not been studied in children less than 6 years old.

Who should not take atomoxetine capsules?

Atomoxetine capsules should not be taken if you or your child:  

•

are taking or have taken within the past 14 days an anti-depression medicine called a monoamine oxidase inhibitor or MAOI. Some names of MAOI medicines are Nardil® (phenelzine sulfate), Parnate® (tranylcypromine sulfate) and Emsam® (selegiline transdermal system).

•

have an eye problem called narrow angle glaucoma  

•

are allergic to anything in atomoxetine capsules. See the end of this Medication Guide for a complete list of ingredients.

•

have or have had a rare tumor called pheochromocytoma

Atomoxetine capsules may not be right for you or your child. Before starting atomoxetine capsules tell your doctor or your child’s doctor about all health conditions (or a family history of) including:

•

have or had suicide thoughts or actions  

•

heart problems, heart defects, irregular heart beat, high blood pressure, or low blood pressure  

•

mental problems, psychosis, mania, bipolar illness, or depression  

•

liver problems

•

are pregnant or plan to become pregnant. It is not known if atomoxetine capsules will harm your unborn baby. Talk to your doctor if you are pregnant or plan to become pregnant.

o

There is a pregnancy registry for females who are exposed to ADHD medications, including atomoxetine capsules, during pregnancy. The purpose of the registry is to collect information about the health of females exposed to atomoxetine capsules and their baby. If you or your child becomes pregnant during treatment with atomoxetine capsules, talk to your healthcare provider about registering with the National Pregnancy Registry of ADHD Medications at 1-866-961-2388 or visit online at https://womensmentalhealth.org/adhdmedications/.

•

are breastfeeding or plan to breastfeed. It is not known if atomoxetine hydrochloride passes into your breast milk. Talk to your doctor about the best way to feed your baby if you take atomoxetine capsules.

Can atomoxetine capsules be taken with other medicines?

Tell your doctor about all the medicines that you or your child takes including prescription and nonprescription medicines, vitamins, and herbal supplements. Atomoxetine capsules and some medicines may interact with each other and cause serious side effects. Your doctor will decide whether atomoxetine capsules can be taken with other medicines. 

Especially tell your doctor if you or your child takes:

•

asthma medicines  

•

anti-depression medicines including MAOIs  

•

blood pressure medicines 

•

cold or allergy medicines that contain decongestants

Know the medicines that you or your child takes. Keep a list of your medicines with you to show your doctor and pharmacist.

Do not start any new medicine while taking atomoxetine capsules without talking to your doctor first.

How shlould atomoxetine capsules be taken?

•

Take atomoxetine capsules exactly as prescribed. Atomoxetine hydrochloride comes in different dose strength capsules. Your doctor may adjust the dose until it is right for you or your child. 

•

Do not chew, crush, or open the capsules. Swallow atomoxetine capsules whole with water or other liquids. Tell your doctor if you or your child cannot swallow atomoxetine capsules whole. A different medicine may need to be prescribed.

•

Avoid touching a broken atomoxetine capsule. Wash hands and surfaces that touched an open atomoxetine capsule. If any of the powder gets in your eyes or your child’s eyes, rinse them with water right away and call your doctor. 

•

Atomoxetine capsules can be taken with or without food.

•

Atomoxetine capsules are usually taken once or twice a day. Take atomoxetine capsules at the same time each day to help you remember. If you miss a dose of atomoxetine capsules, take it as soon as you remember that day. If you miss a day of atomoxetine capsules, do not double your dose the next day. Just skip the day you missed.

•

From time to time, your doctor may stop atomoxetine hydrochloride treatment for a while to check ADHD symptoms.  

•

Your doctor may do regular checks of the blood, heart, and blood pressure while taking atomoxetine capsules. Children should have their height and weight checked often while taking atomoxetine capsules. Atomoxetine hydrochloride treatment may be stopped if a problem is found during these check-ups. 

•

If you or your child takes too much atomoxetine capsules or overdoses, call your doctor or poison control center right away, or get emergency treatment. 

What are possible side effects of atomoxetine capsules?

See “What is the most important information I should know about atomoxetine capsules?”for information on reported suicidal thoughts and actions, other mental problems, severe liver damage, and heart problems.

Other serious side effects include:

•

serious allergic reactions (call your doctor if you have trouble breathing,  see swelling or hives, or experience other allergic reactions) 

•

slowing of growth (height and weight) in children  

•

problems passing urine including

o

trouble starting or keeping a urine stream

o

cannot fully empty the bladder

Common side effects in children and teenagers include:

•

upset stomach  

•

decreased appetite 

•

nausea or vomiting 

•

dizziness  

•

tiredness  

•

mood swings

Common side effects in adults include:

•

constipation  

•

dry mouth

•

nausea  

•

decreased appetite  

•

dizziness  

•

sexual side effects 

•

problems passing urine

Other information for children, teenagers, and adults:

•

Erections that won’t go away (priapism) have occurred rarely during treatment with atomoxetine hydrochloride. If you have an erection that lasts more than 4 hours, seek medical help right away. Because of the potential for lasting damage, including the potential inability to have erections, priapism should be evaluated by a doctor immediately.  

•

Atomoxetine hydrochloride may affect your ability or your child’s ability to drive or operate heavy machinery. Be careful until you know how atomoxetine hydrochloride affects you or your child. 

•

Talk to your doctor if you or your child has side effects that are bothersome or do not go away.

This is not a complete list of possible side effects. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store atomoxetine capsules?

•

Store atomoxetine capsules in a safe place at room temperature, 20°C to 25°C (68°F to 77°F).

•

Keep atomoxetine capsules and all medicines out of the reach of children. 

General information about atomoxetine capsules

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use atomoxetine capsules for a condition for which it was not prescribed. Do not give atomoxetine capsules to other people, even if they have the same condition. It may harm them. 

This Medication Guide summarizes the most important information about atomoxetine capsules. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about atomoxetine capsules that was written for healthcare professionals. For more information about atomoxetine capsules call 1-888-375-3784.

What are the ingredients in atomoxetine capsules?

Active ingredient: atomoxetine hydrochloride

Inactive ingredients: pregelatinized starch, dimethicone,  FD&C Blue No. 2, gelatin, iron oxide red, iron oxide yellow, sodium lauryl sulfate and titanium dioxide. The capsules are imprinted with edible black ink. The edible black ink contains black iron oxide E172, butyl alcohol, dehydrated alcohol, isopropyl alcohol, potassium hydroxide, propylene glycol, shellac and strong ammonia solution.  

Nardil® is a registered trademark of Pfizer Inc.

Parnate® is a registered trademark of GlaxoSmithKline.

Emsam® is a registered trademark of Somerset Pharmaceuticals Inc. 

This Medication Guide has been approved by the US Food and Drug Administration. 

To reorder additional Medications Guides contact Dr. Reddy’s Customer Service at 1-866-733-3952.

Rx Only 

Distributor:

Dr. Reddy’s Laboratories Inc.,

Princeton, NJ 08540

Packaged and Distributed by:

MAJOR® PHARMACEUTICALS

Indianapolis, IN 46268 USA

Refer to package label for Distributor's NDC Number

Made in India

Revised: 0122