Atomoxetine Hydrochloride (atomoxetine 100 mg) Dailymed
Generic: atomoxetine hydrochloride
IMPRINT: MYLAN 8060 SHAPE: capsule
Boxed Warning
Warning: Suicidal Ideation In Children And Adolescents
-
• Increased risk of suicidal ideation in children or adolescents (5.1 ) -
• No suicides occurred in clinical trials (5.1 ) -
• Patients started on therapy should be monitored closely (5.1 )
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Recent Major Changes Section
Contraindications, Pheochromocytoma (4.4 )Â 03/2011
Warnings and Precautions: Allergic Events (5.8 ) 07/2010
Warning: Suicidal Ideation In Children And Adolescents
Atomoxetine hydrochloride increased the risk of suicidal ideation in short-term studies in children or adolescents with Attention-Deficit/Hyperactivity Disorder (ADHD). Anyone considering the use of atomoxetine hydrochloride in a child or adolescent must balance this risk with the clinical need. Comorbidities occurring with ADHD may be associated with an increase in the risk of suicidal ideation and/or behavior. Patients who are started on therapy should be monitored closely for suicidality (suicidal thinking and behavior), clinical worsening or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber. Atomoxetine hydrochloride is approved for ADHD in pediatric and adult patients. Atomoxetine hydrochloride is not approved for major depressive disorder.
Pooled analyses of short-term (6 to 18 weeks) placebo-controlled trials of atomoxetine hydrochloride in children and adolescents (a total of 12 trials involving over 2,200 patients, including 11 trials in ADHD and one trial in enuresis) have revealed a greater risk of suicidal ideation early during treatment in those receiving atomoxetine hydrochloride compared to placebo. The average risk of suicidal ideation in patients receiving atomoxetine hydrochloride was 0.4% (5/1,357 patients), compared to none in placebo-treated patients (851 patients). No suicides occurred in these trials [see Warnings and Precautions (5.1)].
WARNING: SUICIDAL IDEATION IN CHILDREN AND ADOLESCENTS
See full prescribing information for complete boxed warning.
• Increased risk of suicidal ideation in children or adolescents (5.1 )• No suicides occurred in clinical trials (5.1 )• Patients started on therapy should be monitored closely (5.1 )
1 Indications And Usage
Atomoxetine hydrochloride is a selective norepinephrine reuptake inhibitor indicated for the treatment of Attention-Deficit/Hyperactivity Disorder (ADHD). (1.1 )
1.1 Attention-Deficit/Hyperactivity Disorder (ADHD)
Atomoxetine hydrochloride capsules are indicated for the treatment of Attention-Deficit/Hyperactivity Disorder (ADHD).
The efficacy of atomoxetine hydrochloride 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 trials 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 two 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 six of the following symptoms must have persisted for at least 6 months: lack of attention to details/careless mistakes, lack of sustained attention, poor ulener, 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 six 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 hydrochloride 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 Dosage And Administration
Initial, Target and Maximum Daily Dose (2.1 )(Acute and Maintenance/Extended Treatment)
Body Weight
Initial Daily Dose
Target Total Daily Dose
Maximum Total Daily Dose
Children and adolescents up to 70 kg
0.5 mg/kg
1.2 mg/kg
1.4 mg/kg
Children and adolescents over 70 kg and adults
40 mg
80 mg
100 mg
Dosing adjustment — Hepatic Impairment, Strong CYP2D6 Inhibitor and in patients known to be CYP2D6 poor metabolizers (PMs) (2.4 ,12.3 )
2.1 Acute Treatment
Dosing of Children and Adolescents Up to 70 Kg Body Weight
Atomoxetine hydrochloride capsules should be initiated at a total daily dose of approximately 0.5 mg/kg and increased after a minimum of 3 days to a target total daily dose of approximately 1.2 mg/kg administered either as a single daily dose in the morning or as evenly divided doses in the morning and late afternoon/early evening. No additional benefit has been demonstrated for doses higher than 1.2 mg/kg/day [see Clinical Studies (14)].
The total daily dose in children and adolescents should not exceed 1.4 mg/kg or 100 mg, whichever is less.
Dosing of Children and Adolescents Over 70 Kg Body Weight and Adults
Atomoxetine hydrochloride capsules should be initiated at a total daily dose of 40 mg and increased after a minimum of 3 days to a target total daily dose of approximately 80 mg administered either as a single daily dose in the morning or as evenly divided doses in the morning and late afternoon/early evening. After 2 to 4 additional weeks, the dose may be increased to a maximum of 100 mg in patients who have not achieved an optimal response. There are no data that support increased effectiveness at higher doses [see Clinical Studies (14)].
The maximum recommended total daily dose in children and adolescents over 70 kg and adults is 100 mg.
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 capsules 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 capsules 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 hydrochloride 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 hydrochloride capsules may be taken with or without food.
Atomoxetine hydrochloride capsules can be discontinued without being tapered.
Atomoxetine hydrochloride capsules are not intended to be opened, they should be taken whole [see Patient Counseling Information (17.6)].
The safety of single doses over 120 mg and total daily doses above 150 mg have not been systematically evaluated.
2.4 Dosing in Specific Populations
Dosing Adjustment for Hepatically Impaired Patients
For those ADHD patients who have hepatic insufficiency (HI), dosage adjustment is recommended as follows: For patients with moderate HI (Child-Pugh Class B), initial and target doses should be reduced to 50% of the normal dose (for patients without HI). For patients with severe HI (Child-Pugh Class C), initial dose and target doses should be reduced to 25% of normal [see Use in Specific Populations (8.6)].
Dosing Adjustment For Use With A Strong CYP2D6 Inhibitor or in Patients Who are Known to be CYP2D6 PMs
In children and adolescents up to 70 kg body weight administered strong CYP2D6 inhibitors, e.g., paroxetine, fluoxetine and quinidine or in patients who are known to be CYP2D6 PMs, atomoxetine hydrochloride capsules should be initiated at 0.5 mg/kg/day and only increased to the usual target dose of 1.2 mg/kg/day if symptoms fail to improve after 4 weeks and the initial dose is well tolerated.
In children and adolescents over 70 kg body weight and adults administered strong CYP2D6 inhibitors, e.g., paroxetine, fluoxetine and quinidine, atomoxetine hydrochloride capsules should be initiated at 40 mg/day and only increased to the usual target dose of 80 mg/day if symptoms fail to improve after 4 weeks and the initial dose is well tolerated.
3 Dosage Forms And Strengths
Each capsule contains atomoxetine hydrochloride equivalent to 10 mg, 18 mg, 25 mg, 40 mg, 60 mg, 80 mg or 100 mg of atomoxetine.
Each capsule contains atomoxetine hydrochloride equivalent to 10 mg, 18 mg, 25 mg, 40 mg, 60 mg, 80 mg or 100 mg of atomoxetine. (3 ,11 ,16 )
4 Contraindications
• Hypersensitivity to atomoxetine or other constituents of product. (4.1 )• Atomoxetine hydrochloride use within 2 weeks after discontinuing MAOI or other drugs that affect brain monoamine concentrations. (4.2 ,7.1 )• Narrow Angle Glaucoma. (4.3 )• Pheochromocytoma or history of pheochromocytoma. (4.4 )4.1 Hypersensitivity
Atomoxetine hydrochloride capsules are contraindicated in patients known to be hypersensitive to atomoxetine or other constituents of the product [see Warnings and Precautions (5.7)].
4.2 Monoamine Oxidase Inhibitors (MAOI)
Atomoxetine hydrochloride 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 hydrochloride. 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 narrow 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 hydrochloride should not be taken by patients with pheochromocytoma or a history of pheochromocytoma.
5 Warnings And Precautions
• Suicidal Ideation - Monitor for suicidality, clinical worsening and unusual changes in behavior. (5.1 )• Severe Liver Injury - Should be discontinued and not restarted in patients with jaundice or laboratory evidence of liver injury. (5.2 )• Serious Cardiovascular Events - Sudden death, stroke and myocardial infarction have been reported in association with atomoxetine treatment. Patients should have a careful history and physical exam to assess for presence of cardiovascular disease. Atomoxetine hydrochloride capsules generally should not be used in children or adolescents with known serious structural cardiac abnormalities, cardiomyopathy, serious heart rhythm abnormalities or other serious cardiac problems that may place them at increased vulnerability to its noradrenergic effects. Consideration should be given to not using atomoxetine hydrochloride in adults with clinically significant cardiac abnormalities. (5.3 ) Emergent Cardiovascular Symptoms - Patients should undergo prompt cardiac evaluation. (5.3 )• Effects on Blood Pressure and Heart Rate - Can increase blood pressure and heart rate; orthostasis, syncope and Raynaud’s phenomenon may occur. Use with caution in patients with hypertension, tachycardia or cardiovascular or cerebrovascular disease. (5.4 )• Emergent Psychotic or Manic Symptoms - Consider discontinuing treatment if such new symptoms occur. (5.5 )• Bipolar Disorder - Screen patients to avoid possible induction of a mixed/manic episode. (5.6 )• Aggressive behavior or hostility should be monitored. (5.7 )• Possible allergic reactions, including anaphylactic reactions, angioneurotic edema, urticaria and rash. (5.8 )• Effects on Urine Outflow - Urinary hesitancy and retention may occur. (5.9 )• Priapism - Prompt medical attention is required in the event of suspected priapism. (5.10 ,17.5 )• Growth - Height and weight should be monitored in pediatric patients. (5.11 )• Concomitant Use of Potent CYP2D6 Inhibitors or Use in patients known to be CYP2D6 PMs - Dose adjustment of atomoxetine hydrochloride may be necessary. (5.13 )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 2,200 patients (including 1,357 patients receiving atomoxetine hydrochloride and 851 receiving placebo). The average risk of suicidal ideation in patients receiving atomoxetine hydrochloride was 0.4% (5/1,357 patients), compared to none in placebo-treated patients. There was 1 suicide attempt among these approximately 2,200 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
Post-marketing reports indicate that atomoxetine hydrochloride can cause severe liver injury. Although no evidence of liver injury was detected in clinical trials of about 6,000 patients, there have been rare cases of clinically significant liver injury that were considered probably or possibly related to atomoxetine hydrochloride use in post-marketing experience. 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. However, severe liver injury due to any drug may potentially progress to acute liver failure resulting in death or the need for 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 (17.3)].
5.3 Serious Cardiovascular Events
Sudden Death and Preexisting Structural Cardiac Abnormalities or Other Serious Heart Problems
Sudden death has been reported in association with atomoxetine treatment at usual doses in children and adolescents with structural cardiac abnormalities or other serious heart problems. Although some serious heart problems alone carry an increased risk of sudden death, atomoxetine generally should not be used in children or adolescents with known serious structural cardiac abnormalities, cardiomyopathy, serious heart rhythm abnormalities or other serious cardiac problems that may place them at increased vulnerability to the noradrenergic effects of atomoxetine.
Sudden deaths, stroke and myocardial infarction have been reported in adults taking atomoxetine at usual doses for ADHD. Although the role of atomoxetine in these adult cases is also unknown, adults have a greater likelihood than children of having serious structural cardiac abnormalities, cardiomyopathy, serious heart rhythm abnormalities, coronary artery disease or other serious cardiac problems. Consideration should be given to not treating adults with clinically significant cardiac abnormalities.
Assessing Cardiovascular Status in Patients being Treated with Atomoxetine
Children, adolescents or adults who are being considered for treatment with atomoxetine should have a careful history (including assessment for a family history of sudden death or ventricular arrhythmia) and physical exam to assess for the presence of cardiac disease and should receive further cardiac evaluation if findings suggest such disease (e.g., electrocardiogram and echocardiogram). Patients who develop symptoms such as exertional chest pain, unexplained syncope or other symptoms suggestive of cardiac disease during atomoxetine treatment should undergo a prompt cardiac evaluation.
5.4 Effects on Blood Pressure and Heart Rate
Atomoxetine hydrochloride should be used with caution in patients with hypertension, tachycardia or cardiovascular or cerebrovascular disease because it can increase blood pressure and heart rate. Pulse and blood pressure should be measured at baseline, following atomoxetine hydrochloride dose increases and periodically while on therapy.
In pediatric placebo-controlled trials, atomoxetine hydrochloride-treated subjects experienced a mean increase in heart rate of about 6 beats/minute compared with placebo subjects. At the final study visit before drug discontinuation, 2.5% (36/1,434) of atomoxetine hydrochloride-treated subjects had heart rate increases of at least 25 beats/minute and a heart rate of at least 110 beats/minute, compared with 0.2% (2/850) of placebo subjects. There were 1.1% (15/1,417) pediatric atomoxetine hydrochloride-treated subjects with a heart rate increase of at least 25 beats/minute and a heart rate of at least 110 beats/minute on more than one occasion. Tachycardia was identified as an adverse event for 0.3% (5/1,597) of these pediatric subjects compared with 0% (0/934) of placebo subjects. The mean heart rate increase in extensive metabolizer (EM) patients was 5 beats/minute and in poor metabolizer (PM) patients 9.4 beats/minute.
Atomoxetine hydrochloride-treated pediatric subjects experienced mean increases of about 1.6 and 2.4 mm Hg in systolic and diastolic blood pressures, respectively compared with placebo. At the final study visit before drug discontinuation, 4.8% (59/1,226) of atomoxetine hydrochloride-treated pediatric subjects had high systolic blood pressure measurements compared with 3.5% (26/748) of placebo subjects. High systolic blood pressures were measured on two or more occasions in 4.4% (54/1,226) of atomoxetine hydrochloride-treated subjects and 1.9% (14/748) of placebo subjects. At the final study visit before drug discontinuation, 4% (50/1,262) of atomoxetine hydrochloride-treated pediatric subjects had high diastolic blood pressure measurements compared with 1.1% (8/759) of placebo subjects. High diastolic blood pressures were measured on two or more occasions in 3.5% (44/1,262) of atomoxetine hydrochloride-treated subjects and 0.5% (4/759) of placebo subjects. (High systolic and diastolic blood pressure measurements were defined as those exceeding the 95th percentile, stratified by age, gender and height percentile - National High Blood Pressure Education Working Group on Hypertension Control in Children and Adolescents.)
In adult placebo-controlled trials, atomoxetine hydrochloride-treated subjects experienced a mean increase in heart rate of 5 beats/minute compared with placebo subjects. Tachycardia was identified as an adverse event for 1.5% (8/540) of these adult atomoxetine subjects compared with 0.5% (2/402) of placebo subjects.
Atomoxetine hydrochloride-treated adult subjects experienced mean increases in systolic (about 2 mm Hg) and diastolic (about 1 mm Hg) blood pressures compared with placebo. At the final study visit before drug discontinuation, 2.2% (11/510) of atomoxetine hydrochloride-treated adult subjects had systolic blood pressure measurements ≥ 150 mm Hg compared with 1% (4/393) of placebo subjects. At the final study visit before drug discontinuation, 0.4% (2/510) of atomoxetine hydrochloride-treated adult subjects had diastolic blood pressure measurements ≥ 100 mm Hg compared with 0.5% (2/393) of placebo subjects. No adult subject had a high systolic or diastolic blood pressure detected on more than one occasion.
Orthostatic hypotension and syncope have been reported in patients taking atomoxetine hydrochloride. In child and adolescent trials, 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 controlled trials, 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 trials. 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.
Peripheral Vascular Effects
There have been spontaneous post-marketing reports of Raynaud’s phenomenon (new onset and exacerbation of preexisting condition).
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 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. 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 and adolescents treated with atomoxetine hydrochloride compared to placebo (overall risk ratio of 1.33 [95% C.I. 0.67 to 2.64 - not statistically significant]).
5.8 Allergic Events
Although uncommon, allergic reactions,including anaphylactic 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 post-marketing 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).
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Figure 1: Mean Weight and Height Percentiles Over Time for Patients With 3 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 3 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 3 years of treatment.
Growth followed a similar pattern in both extensive and poor metabolizers (EMs, PMs). PMs treated for at least 2 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.
CYP2D6 Metabolism
Poor metabolizers (PMs) of CYP2D6 have a 10-fold higher AUC and a 5-fold higher peak concentration to a given dose of atomoxetine hydrochloride compared with extensive metabolizers (EMs). Approximately 7% of a Caucasian population are PMs. Laboratory tests are available to identify CYP2D6 PMs. The blood levels in PMs are similar to those attained by taking strong inhibitors of CYP2D6. The higher blood levels in PMs lead to a higher rate of some adverse effects of atomoxetine hydrochloride [see Adverse Reactions (6.1)].
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 (2.4) and Drug Interactions (7.2)].
6 Adverse Reactions
Most common adverse reactions (≥ 5% and at least twice the incidence of placebo patients)
• Child and Adolescent Clinical Trials - Nausea, vomiting, fatigue, decreased appetite, abdominal pain and somnolence. (6.1 )• Adult Clinical Trials - Constipation, dry mouth, nausea, fatigue, decreased appetite, insomnia, erectile dysfunction, urinary hesitation and/or urinary retention and/or dysuria, dysmenorrhea and hot flush. (6.1 )
To report SUSPECTED ADVERSE REACTIONS, contact Mylan Pharmaceuticals Inc. at 1-877-446-3679 (1-877-4-INFO-RX) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
6.1 Clinical Trials Experience
Atomoxetine hydrochloride was administered to 5,382 children or adolescent patients with ADHD and 1,007 adults with ADHD in clinical studies. During the ADHD clinical trials, 1,625 children and adolescent patients were treated for longer than one year and 2,529 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.
Child and Adolescent Clinical Trials
In acute child and adolescent placebo-controlled trials, 3% (48/1,613) of atomoxetine subjects and 1.4% (13/945) placebo subjects discontinued for adverse reactions. For all studies, (including open-label and long-term studies), 6.3% of extensive metabolizer (EM) patients and 11.2% of poor metabolizer (PM) patients discontinued because of an adverse reaction. Among atomoxetine hydrochloride-treated patients, irritability (0.3%, N = 5); somnolence (0.3%, N = 5); aggression (0.2%, N = 4); nausea (0.2%, N = 4); vomiting (0.2%, N = 4); abdominal pain (0.2%, N = 4); constipation (0.1%, N = 2); fatigue (0.1%, N = 2); feeling abnormal (0.1%, N = 2); and headache (0.1%, N = 2) were the reasons for discontinuation reported by more than one patient.
Atomoxetine hydrochloride has not been systematically evaluated in pediatric patients with seizure disorder as these patients were excluded from clinical studies during the product’s premarket testing. In the clinical development program, seizures were reported in 0.2% (12/5,073) of children whose average age was 10 years (range 6 to 16 years). In these clinical trials, the seizure risk among poor metabolizers was 0.3% (1/293) compared to 0.2% (11/4,741) for extensive metabolizers.
Commonly observed adverse reactions associated with the use of atomoxetine hydrochloride (incidence of 2% or greater) and not observed at an equivalent incidence among placebo-treated patients (atomoxetine hydrochloride incidence greater than placebo) are uled in Table 1. Results were similar in the BID and the QD trial except as shown in Table 2, which shows both BID and QD results for selected adverse reactions based on statistically significant Breslow-Day tests. The most commonly observed adverse reactions in patients treated with atomoxetine hydrochloride (incidence of 5% or greater and at least twice the incidence in placebo patients, for either BID or QD dosing) were: nausea, vomiting, fatigue, decreased appetite, abdominal pain and somnolence (see Tables 1 and 2).
Table 1: Common Treatment-Emergent Adverse Reactions Associated with the Use of Atomoxetine Hydrochloride in Acute (up to 18 weeks) Child and Adolescent Trials
Adverse ReactionReactions reported by at least 2% of patients treated with atomoxetine and greater than placebo. The following reactions did not meet this criterion but were reported by more atomoxetine-treated patients than placebo-treated patients and are possibly related to atomoxetine treatment: blood pressure increased, early morning awakening, flushing, mydriasis, sinus tachycardia, asthenia, palpitations, mood swings, constipation. The following reactions were reported by at least 2% of patients treated with atomoxetine and equal to or less than placebo: pharyngolaryngeal pain, insomnia (insomnia includes the terms, insomnia, initial insomnia, middle insomnia). The following reaction did not meet this criterion but shows a statistically significant dose relationship: pruritus.
Percentage of Patients Reporting Reaction
Â
Atomoxetine Hydrochloride(N = 1,597)
Placebo(N = 934)
Gastrointestinal Disorders
Â
Â
    Abdominal painAbdominal pain includes the terms: abdominal pain upper, abdominal pain, stomach discomfort, abdominal discomfort, epigastric discomfort.
18
10
    Vomiting
11
6
    Nausea
10
5
General Disorders and Administration Site Conditions
Â
Â
    Fatigue
8
3
    Irritability
6
3
    Therapeutic response unexpected
2
1
Investigations
Â
Â
    Weight decreased
3
0
Metabolism and Nutritional Disorders
Â
Â
    Decreased appetite
16
4
    Anorexia
3
1
Nervous System Disorders
Â
Â
    Headache
19
15
    SomnolenceSomnolence includes the terms: sedation, somnolence.
11
4
    Dizziness
5
2
Skin and Subcutaneous Tissue Disorders
Â
Â
    Rash
2
1
Table 2: Common Treatment-Emergent Adverse Reactions Associated with the Use of Atomoxetine Hydrochloride in Acute (up to 18 weeks) Child and Adolescent Trials
Adverse Reaction
Percentage of Patients Reporting Reaction from BID Trials
Percentage of Patients Reporting Reaction from QD Trials
Â
AtomoxetineHydrochloride(N = 715)
Placebo(N = 434)
AtomoxetineHydrochloride(N = 882)
Placebo(N = 500)
Gastrointestinal Disorders
Â
Â
Â
Â
    Abdominal painAbdominal pain includes the terms: abdominal pain upper, abdominal pain,  stomach discomfort, abdominal discomfort, epigastric discomfort.
17
13
18
7
    Vomiting
11
8
11
4
    Nausea
7
6
13
4
    ConstipationConstipation didn't meet the statistical significance on Breslow-Day test but is included in the table because of pharmacologic plausibility.
2
1
1
0
General Disorders
Â
Â
Â
Â
    Fatigue
6
4
9
2
Psychiatric Disorders
Â
Â
Â
Â
    Mood swingsMood swings didn't meet the statistical significance on Breslow-Day test at 0.05 level but p-value was < 0.1 (trend).
2
0
1
1
The following adverse reactions occurred in at least 2% of PM patients and were either twice as frequent or statistically significantly more frequent in PM patients compared with EM patients: insomnia (15% of PMs, 10% of EMs); weight decreased (7% of PMs, 4% of EMs); constipation (7% of PMs, 4% of EMs); depressionDepression includes the following terms: depression, major depression, depressive symptoms, depressed mood, dysphoria. (7% of PMs, 4% of EMs); tremor (5% of PMs, 1% of EMs); excoriation (4% of PMs, 2% of EMs); conjunctivitis 3% of PMs, 1% of EMs); syncope (3% of PMs, 1% of EMs); early morning awakening (2% of PMs, 1% of EMs); mydriasis (2% of PMs, 1% of EMs).
Adult Clinical Trials
In the acute adult placebo-controlled trials, 11.3% (61/541) atomoxetine subjects and 3% (12/405) placebo subjects discontinued for adverse reactions. Among atomoxetine hydrochloride-treated patients, insomnia (0.9%, N = 5); nausea (0.9%, N = 5); chest pain (0.6%, N = 3); fatigue (0.6%, N = 3); anxiety (0.4%, N = 2); erectile dysfunction (0.4%, N = 2); mood swings (0.4%, N = 2); nervousness (0.4%, N = 2); palpitations (0.4%, N = 2); and urinary retention (0.4%, N = 2) were the reasons for discontinuation reported by more than one patient.
Atomoxetine hydrochloride has not been systematically evaluated in adult patients with a seizure disorder as these patients were excluded from clinical studies during the product’s premarket testing. In the clinical development program, seizures were reported on 0.1% (1/748) of adult patients. In these clinical trials, no poor metabolizers (0/43) reported seizures compared to 0.1% (1/705) for extensive metabolizers.
Commonly observed adverse reactions associated with the use of atomoxetine hydrochloride (incidence of 2% or greater) and not observed at an equivalent incidence among placebo-treated patients (atomoxetine hydrochloride incidence greater than placebo) are uled in Table 3. The most commonly observed adverse reactions in patients treated with atomoxetine hydrochloride (incidence of 5% or greater and at least twice the incidence in placebo patients) were: constipation, dry mouth, nausea, fatigue, decreased appetite, insomnia, erectile dysfunction, urinary hesitation and/or urinary retention and/or dysuria, dysmenorrhea and hot flush (see Table 3).
Table 3: Common Treatment-Emergent Adverse Reactions Associated with the Use of Atomoxetine Hydrochloride in Acute (up to 25 weeks) Adult Trials
Adverse ReactionReactions reported by at least 2% of patients treated with atomoxetine and greater than placebo. The following reactions did not meet this criterion but were reported by more atomoxetine-treated patients than placebo-treated patients and are possibly related to atomoxetine treatment: early morning awakening, peripheral coldness, tachycardia, prostatitis, testicular pain and orgasm abnormal. The following reactions were reported by at least 2% of patients treated with atomoxetine and equal to or less than placebo; headache, pharyngolaryngeal pain, irritability.
Percentage of Patients Reporting Reaction
System Organ Class/Adverse Reaction
Atomoxetine Hydrochloride(N = 540)
Placebo(N = 402)Â
Cardiac Disorders
Â
Â
    Palpitations
 3
1
Gastrointestinal Disorders
Â
Â
    Dry mouth
21
7
    Nausea
21
5
    Constipation
9
3
    Abdominal painAbdominal pain includes the terms: abdominal pain upper, abdominal pain, stomach discomfort, abdominal discomfort, epigastric discomfort.
7
5
    Dyspepsia
4
2
    Vomiting
3
2
General Disorders and Administration Site Conditions
Â
Â
    Fatigue
9
4
    Chills
3
1
    Therapeutic response unexpected
3
1
    Feeling jittery
2
0
Investigations
Â
Â
    Weight decreased
2
1
Metabolism and Nutritional Disorders
Â
Â
    Decreased appetite
11
2
Nervous System Disorders
Â
Â
    Dizziness
6
4
    SomnolenceSomnolence includes the terms: sedation, somnolence.
4
3
     Paraesthesia
3
1
    Sinus headache
3
1
    Tremor
2
0
Psychiatric Disorders
Â
Â
    InsomniaInsomnia includes the terms: insomnia, initial insomnia, middle insomnia.
15
7
    Libido decreased
4
2
    Sleep disorder
3
1
Renal and Urinary Disorders
Â
Â
    Urinary hesitation and/or urinary retention
7
1
    Dysuria
3
0
Reproductive System and Breast Disorders
Â
Â
    Erectile dysfunctionBased on total number of males (atomoxetine hydrochloride, N = 326; placebo, N = 260).
9
1
    DysmenorrheaBased on total number of females (atomoxetine hydrochloride, N = 214; placebo, N = 142).
6
2
    Ejaculation delayed¶ and/or ejaculation disorder¶
3
1
    Menstruation irregular#
2
0
Skin and Subcutaneous Tissue Disorders
Â
Â
    Hyperhidrosis
4
1
    Rash
2
1
Vascular Disorders
Â
Â
    Hot flush
8
1
Atomoxetine appears to impair sexual function in some patients. Changes in sexual desire, sexual performance and sexual satisfaction are not well assessed in most clinical trials because they need special attention and because patients and physicians may be reluctant to discuss them. Accordingly, estimates of the incidence of untoward sexual experience and performance cited in product labeling are likely to underestimate the actual incidence. Table 3 above displays the incidence of sexual side effects reported by at least 2% of adult patients taking atomoxetine hydrochloride in placebo-controlled trials.
There are no adequate and well controlled studies examining sexual dysfunction with atomoxetine hydrochloride treatment. While it is difficult to know the precise risk of sexual dysfunction associated with the use of atomoxetine hydrochloride, physicians should routinely inquire about such possible side effects.
6.2 Post-Marketing 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.
General Disorders and Administration Site Conditions: Lethargy.
Nervous System Disorders: Hypoaesthesia, paraesthesia in children and adolescents; sensory disturbances; tics.
Psychiatric Disorders: Depression and depressed mood; anxiety.
Seizures: Seizures have been reported in the post-marketing period. The post-marketing seizure cases include patients with preexisting 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: Hyperhidrosis.
Urogenital System: Male pelvic pain; urinary hesitation in children and adolescents; urinary retention in children and adolescents.
7 Drug Interactions
• Monoamine Oxidase Inhibitors. (4.2 ,7.1 )• CYP2D6 Inhibitors - Concomitant use may increase atomoxetine steady-state plasma concentrations in EMs. (7.2 )• Pressor Agents - Possible effects on blood pressure. (7.3 )• Albuterol (or other beta2 agonists) - Action of albuterol on cardiovascular system can be potentiated. (7.4 )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 [see Contraindications (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 Pressor Agents
Because of possible effects on blood pressure, atomoxetine hydrochloride should be used cautiously with pressor agents (e.g., dopamine, dobutamine).
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 i.v. 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 mcg 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.
CYP3A Substrate (e.g., Midazolam)
Coadministration of atomoxetine hydrochloride (60 mg BID for 12 days) with midazolam, a model compound for CYP3A4 metabolized drugs (single dose of 5 mg), resulted in 15% increase in AUC of midazolam. No dose adjustment is recommended for drugs metabolized by CYP3A.
CYP2D6 Substrate (e.g., Desipramine)
Coadministration of atomoxetine hydrochloride (40 mg or 60 mg BID for 13 days) with desipramine, a model compound for CYP2D6 metabolized drugs (single dose of 50 mg), did not alter the pharmacokinetics of desipramine. No dose adjustment is recommended for drugs metabolized by CYP2D6.
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 Use In Specific Populations
• Pregnancy/Lactation - Pregnant or nursing women should not use unless potential benefit justifies potential risk to fetus or infant. (8.1 ,8.3 )• Hepatic Insufficiency - Increased exposure (AUC) to atomoxetine than with normal subjects in EM subjects with moderate (Child-Pugh Class B) (2-fold increase) and severe (Child-Pugh Class C) (4-fold increase). (8.6 )• Renal Insufficiency - Higher systemic exposure to atomoxetine than healthy subjects for EM subjects with end stage renal disease – no difference when exposure corrected for mg/kg dose. (8.7 )• Patients with Concomitant Illness - Does not worsen tics in patients with ADHD and comorbid Tourette’s Disorder. (8.10 )• Patients with Concomitant Illness – Does not worsen anxiety in patients with ADHD and comorbid Anxiety Disorders. (8.10 )8.1 Pregnancy
Pregnancy Category C
Pregnant rabbits were treated with up to 100 mg/kg/day of atomoxetine by gavage throughout the period of organogenesis. At this dose, in one of three studies, a decrease in live fetuses and an increase in early resorptions was observed.
Slight increases in the incidences of atypical origin of carotid artery and absent subclavian artery were observed. These findings were observed at doses that caused slight maternal toxicity. The no-effect dose for these findings was 30 mg/kg/day. The 100 mg/kg dose is approximately 23 times the maximum human dose on a mg/m2 basis; plasma levels (AUC) of atomoxetine at this dose in rabbits are estimated to be 3.3 times (extensive metabolizers) or 0.4 times (poor metabolizers) those in humans receiving the maximum human dose.
Rats were treated with up to approximately 50 mg/kg/day of atomoxetine (approximately 6 times the maximum human dose on a mg/m2 basis) in the diet from 2 weeks (females) or 10 weeks (males) prior to mating through the periods of organogenesis and lactation. In one of two studies, decreases in pup weight and pup survival were observed. The decreased pup survival was also seen at 25 mg/kg (but not at 13 mg/kg). In a study in which rats were treated with atomoxetine in the diet from 2 weeks (females) or 10 weeks (males) prior to mating throughout the period of organogenesis, a decrease in fetal weight (female only) and an increase in the incidence of incomplete ossification of the vertebral arch in fetuses were observed at 40 mg/kg/day (approximately 5 times the maximum human dose on a mg/m2 basis) but not at 20 mg/kg/day.
No adverse fetal effects were seen when pregnant rats were treated with up to 150 mg/kg/day (approximately 17 times the maximum human dose on a mg/m2 basis) by gavage throughout the period of organogenesis.
No adequate and well controlled studies have been conducted in pregnant women. Atomoxetine hydrochloride should not be used during pregnancy unless the potential benefit justifies the potential risk to the fetus.
8.2 Labor and Delivery
Parturition in rats was not affected by atomoxetine. The effect of atomoxetine hydrochloride on labor and delivery in humans is unknown.
8.3 Nursing Mothers
Atomoxetine and/or its metabolites were excreted in the milk of rats. It is not known if atomoxetine is excreted in human milk. Caution should be exercised if atomoxetine hydrochloride is administered to a nursing woman.
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 Warning and Warnings 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
Tics in Patients with ADHD and Comorbid Tourettes Disorder
Atomoxetine administered in a flexible dose range of 0.5 to 1.5 mg/kg/day (mean dose of 1.3 mg/kg/day) and placebo were compared in 148 randomized pediatric (age 7 to 17 years) subjects with a DSM-IV diagnosis of ADHD and comorbid tic disorder in an 18-week, double-blind, placebo-controlled study in which the majority (80%) enrolled in this trial with Tourette’s Disorder (Tourette’s Disorder: 116 subjects; chronic motor tic disorder: 29 subjects). A non-inferiority analysis revealed that atomoxetine did not worsen tics in these patients as determined by the Yale Global Tic Severity Scale Total Score (YGTSS). Out of 148 patients who entered the acute treatment phase, 103 (69.6%) patients discontinued the study. The primary reason for discontinuation in both the atomoxetine (38 of 76 patients, 50%) and placebo (45 of 72 patients, 62.5%) treatment groups was identified as lack of efficacy with most of the patients discontinuing at Week 12. This was the first visit where patients with a CGI-S ≥ 4 could also meet the criteria for “clinical non-responder” (CGI-S remained the same or increased from study baseline) and be eligible to enter an open-label extension study with atomoxetine. There have been post-marketing reports of tics [see Adverse Reactions (6.2)].
Anxiety in Patients with ADHD and Comorbid Anxiety Disorders
In two post-marketing, double-blind, placebo-controlled trials, it has been demonstrated that treating patients with ADHD and comorbid anxiety disorders with atomoxetine does not worsen their anxiety.
In a 12-week double-blind, placebo-controlled trial, 176 patients, aged 8 to 17, who met DSM-IV criteria for ADHD and at least one of the anxiety disorders of separation anxiety disorder, generalized anxiety disorder or social phobia were randomized. Following a 2-week double-blind placebo lead-in, atomoxetine was initiated at 0.8 mg/kg/day with increase to a target dose of 1.2 mg/kg/day (median dose 1.30 mg/kg/day +/- 0.29 mg/kg/day). Atomoxetine did not worsen anxiety in these patients as determined by the Pediatric Anxiety Rating Scale (PARS). Of the 158 patients who completed the double-blind placebo lead-in, 26 (16%) patients discontinued the study.
In a separate 16-week, double-blind, placebo-controlled trial, 442 patients aged 18 to 65, who met DSM-IV criteria for adult ADHD and social anxiety disorder (23% of whom also had generalized anxiety disorder) were randomized. Following a 2-week double-blind placebo lead-in, atomoxetine was initiated at 40 mg/day to a maximum dose of 100 mg/day (mean daily dose 83 mg/day +/- 19.5 mg/day). Atomoxetine did not worsen anxiety in these patients as determined by the Liebowitz Social Anxiety Scale (LSAS). Of the 436 patients who completed the double-blind placebo lead-in, 172 (39.4%) patients discontinued the study. There have been post-marketing reports of anxiety [see Adverse Reactions (6.2)].
9 Drug Abuse And Dependence
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.
Animal Experience
Drug discrimination studies in rats and monkeys showed inconsistent stimulus generalization between atomoxetine and cocaine.
10 Overdosage
10.1 Human Experience
No fatal overdoses occurred in clinical trials. There is limited clinical trial experience with atomoxetine hydrochloride overdose. During post-marketing, 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.
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.
11 Description
Atomoxetine hydrochloride is a selective norepinephrine reuptake inhibitor. Atomoxetine hydrochloride is the R(-) isomer as determined by x-ray diffraction. The chemical designation is (-)-N-Methyl-3-phenyl-3-(o-tolyloxy)-propylamine hydrochloride. The molecular formula is C17H21NO•HCl, which corresponds to a molecular weight of 291.82. The chemical structure is:
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Atomoxetine hydrochloride is a white to off-white powder, which has a solubility of 27.8 mg/mL in water.
Atomoxetine hydrochloride capsules are intended for oral administration only.
Each capsule contains atomoxetine hydrochloride equivalent to 10 mg, 18 mg, 25 mg, 40 mg, 60 mg, 80 mg or 100 mg of atomoxetine. The capsules also contain colloidal silicon dioxide, magnesium stearate, pregelatinized starch and sodium lauryl sulfate. In addition, each of the empty gelatin capsules contains gelatin, titanium dioxide and the following colorant agents:
10 mg - D&C Yellow No. 10, FD&C Yellow No. 6, D&C Red No. 28, D&C Red No. 33 and FD&C Red No. 4018 mg - D&C Yellow No. 10, FD&C Yellow No. 6, D&C Red No. 28 and FD&C Red No. 4025 mg - FD&C Blue No. 1 and FD&C Red No. 340 mg - D&C Red No. 28 and FD&C Blue No. 160 mg - D&C Yellow No. 10, FD&C Yellow No. 6, D&C Red No. 28 and FD&C Blue No. 180 mg - D&C Yellow No. 10, FD&C Yellow No. 6, D&C Red No. 28 100 mg - D&C Yellow No. 10, FD&C Yellow No. 6, FD&C Red No. 3 and red iron oxide.
The imprinting ink contains the following: black iron oxide, D&C Yellow No. 10 Aluminum Lake, FD&C Blue No. 1 Aluminum Lake, FD&C Blue No. 2 Aluminum Lake, FD&C Red No. 40 Aluminum Lake, propylene glycol and shellac glaze.
12 Clinical Pharmacology
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)].
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.
Absorption and Distribution
Atomoxetine is rapidly absorbed after oral administration, with absolute bioavailability of about 63% in EMs and 94% in PMs. Maximal plasma concentrations (Cmax) are reached approximately 1 to 2 hours after dosing.
Atomoxetine hydrochloride can be administered with or without food. Administration of atomoxetine hydrochloride with a standard high fat meal in adults did not affect the extent of oral absorption of atomoxetine (AUC), but did decrease the rate of absorption, resulting in a 37% lower Cmax and delayed Tmax by 3 hours. In clinical trials with children and adolescents, administration of atomoxetine hydrochloride with food resulted in a 9% lower Cmax.
The steady-state volume of distribution after intravenous administration is 0.85 L/kg indicating that atomoxetine distributes primarily into total body water. Volume of distribution is similar across the patient weight range after normalizing for body weight.
At therapeutic concentrations, 98% of atomoxetine in plasma is bound to protein, primarily albumin.
Metabolism and Elimination
Atomoxetine is metabolized primarily through the CYP2D6 enzymatic pathway. People with reduced activity in this pathway (PMs) have higher plasma concentrations of atomoxetine compared with people with normal activity (EMs). For PMs, AUC of atomoxetine is approximately 10-fold and Css,max is about 5-fold greater than EMs. Laboratory tests are available to identify CYP2D6 PMs. Coadministration of atomoxetine hydrochloride with potent inhibitors of CYP2D6, such as fluoxetine, paroxetine or quinidine, results in a substantial increase in atomoxetine plasma exposure and dosing adjustment may be necessary [see Warnings and Precautions (5.13) ]. Atomoxetine did not inhibit or induce the CYP2D6 pathway.
The major oxidative metabolite formed, regardless of CYP2D6 status, is 4-hydroxyatomoxetine, which is glucuronidated. 4-Hydroxyatomoxetine is equipotent to atomoxetine as an inhibitor of the norepinephrine transporter but circulates in plasma at much lower concentrations (1% of atomoxetine concentration in EMs and 0.1% of atomoxetine concentration in PMs). 4-Hydroxyatomoxetine is primarily formed by CYP2D6, but in PMs, 4-hydroxyatomoxetine is formed at a slower rate by several other cytochrome P450 enzymes. N-Desmethylatomoxetine is formed by CYP2C19 and other cytochrome P450 enzymes, but has substantially less pharmacological activity compared with atomoxetine and circulates in plasma at lower concentrations (5% of atomoxetine concentration in EMs and 45% of atomoxetine concentration in PMs).
Mean apparent plasma clearance of atomoxetine after oral administration in adult EMs is 0.35 L/hr/kg and the mean half-life is 5.2 hours. Following oral administration of atomoxetine to PMs, mean apparent plasma clearance is 0.03 L/hr/kg and mean half-life is 21.6 hours. For PMs, AUC of atomoxetine is approximately 10-fold and Css,max is about 5-fold greater than EMs. The elimination half-life of 4-hydroxyatomoxetine is similar to that of N-desmethylatomoxetine (6 to 8 hours) in EM subjects, while the half-life of N-desmethylatomoxetine is much longer in PM subjects (34 to 40 hours).
Atomoxetine is excreted primarily as 4-hydroxyatomoxetine-O-glucuronide, mainly in the urine (greater than 80% of the dose) and to a lesser extent in the feces (less than 17% of the dose). Only a small fraction of the atomoxetine hydrochloride dose is excreted as unchanged atomoxetine (less than 3% of the dose), indicating extensive biotransformation [see Use in Specific Populations (8.4, 8.5, 8.6, 8.7, 8.8, 8.9)].
13 Nonclinical Toxicology
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis
Atomoxetine hydrochloride was not carcinogenic in rats and mice when given in the diet for 2 years at time-weighted average doses up to 47 and 458 mg/kg/day, respectively. The highest dose used in rats is approximately 8 and 5 times the maximum human dose in children and adults, respectively, on a mg/m2 basis. Plasma levels (AUC) of atomoxetine at this dose in rats are estimated to be 1.8 times (extensive metabolizers) or 0.2 times (poor metabolizers) those in humans receiving the maximum human dose. The highest dose used in mice is approximately 39 and 26 times the maximum human dose in children and adults, respectively, on a mg/m2 basis.
Mutagenesis
Atomoxetine hydrochloride was negative in a battery of genotoxicity studies that included a reverse point mutation assay (Ames Test), an in vitro mouse lymphoma assay, a chromosomal aberration test in Chinese hamster ovary cells, an unscheduled DNA synthesis test in rat hepatocytes and an in vivo micronucleus test in mice. However, there was a slight increase in the percentage of Chinese hamster ovary cells with diplochromosomes, suggesting endoreduplication (numerical aberration).
The metabolite N-desmethylatomoxetine HCl was negative in the Ames Test, mouse lymphoma assay and unscheduled DNA synthesis test.
Impairment of Fertility
Atomoxetine hydrochloride did not impair fertility in rats when given in the diet at doses of up to 57 mg/kg/day, which is approximately 6 times the maximum human dose on a mg/m2 basis.
14 Clinical Studies
14.1 ADHD Studies in Children and Adolescents
Acute Studies
The effectiveness of atomoxetine hydrochloride in the treatment of ADHD was established in four randomized, double-blind, placebo-controlled studies of pediatric patients (ages 6 to 18). Approximately one-third of the patients met DSM-IV criteria for inattentive subtype and two-thirds met criteria for both inattentive and hyperactive/impulsive subtypes.
Signs and symptoms of ADHD were evaluated by a comparison of mean change from baseline to endpoint for atomoxetine hydrochloride and placebo-treated patients using an intent-to-treat analysis of the primary outcome measure, the investigator administered and scored ADHD Rating Scale-IV-Parent Version (ADHDRS) total score including hyperactive/impulsive and inattentive subscales. Each li on the ADHDRS maps directly to one symptom criterion for ADHD in the DSM-IV.
In Study 1, an 8-week randomized, double-blind, placebo-controlled, dose-response, acute treatment study of children and adolescents aged 8 to 18 (N = 297), patients received either a fixed dose of atomoxetine hydrochloride (0.5, 1.2 or 1.8 mg/kg/day) or placebo. Atomoxetine hydrochloride was administered as a divided dose in the early morning and late afternoon/early evening. At the two higher doses, improvements in ADHD symptoms were statistically significantly superior in atomoxetine hydrochloride-treated patients compared with placebo-treated patients as measured on the ADHDRS scale. The 1.8 mg/kg/day atomoxetine hydrochloride dose did not provide any additional benefit over that observed with the 1.2 mg/kg/day dose. The 0.5 mg/kg/day atomoxetine hydrochloride dose was not superior to placebo.
In Study 2, a 6-week randomized, double-blind, placebo-controlled, acute treatment study of children and adolescents aged 6 to 16 (N = 171), patients received either atomoxetine hydrochloride or placebo. Atomoxetine hydrochloride was administered as a single dose in the early morning and titrated on a weight-adjusted basis according to clinical response, up to a maximum dose of 1.5 mg/kg/day. The mean final dose of atomoxetine hydrochloride was approximately 1.3 mg/kg/day. ADHD symptoms were statistically significantly improved on atomoxetine hydrochloride compared with placebo, as measured on the ADHDRS scale. This study shows that atomoxetine hydrochloride is effective when administered once daily in the morning.
In two identical, 9-week, acute, randomized, double-blind, placebo-controlled studies of children aged 7 to 13 (Study 3, N = 147; Study 4, N = 144), atomoxetine hydrochloride and methylphenidate were compared with placebo. Atomoxetine hydrochloride was administered as a divided dose in the early morning and late afternoon (after school) and titrated on a weight-adjusted basis according to clinical response. The maximum recommended atomoxetine hydrochloride dose was 2 mg/kg/day. The mean final dose of atomoxetine hydrochloride for both studies was approximately 1.6 mg/kg/day. In both studies, ADHD symptoms statistically significantly improved more on atomoxetine hydrochloride than on placebo, as measured on the ADHDRS scale.
Examination of population subsets based on gender and age (< 12 and 12 to 17) 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.
Maintenance Study
The effectiveness of atomoxetine hydrochloride in the maintenance treatment of ADHD was established in an outpatient study of children and adolescents (ages 6 to 15 years). Patients meeting DSM-IV criteria for ADHD who showed continuous response for about 4 weeks during an initial 10-week open-label treatment phase with atomoxetine hydrochloride (1.2 to 1.8 mg/kg/day) were randomized to continuation of their current dose of atomoxetine hydrochloride (N = 292) or to placebo (N = 124) under double-blind treatment for observation of relapse. Response during the open-label phase was defined as CGI-ADHD-S score ≤ 2 and a reduction of at least 25% from baseline in ADHDRS-IV-Parent:Inv total score. Patients who were assigned to atomoxetine hydrochloride and showed continuous response for approximately 8 months during the first double-blind treatment phase were again randomized to continuation of their current dose of atomoxetine hydrochloride (N = 81) or to placebo (N = 82) under double-blind treatment for observation of relapse. Relapse during the double-blind phase was defined as CGI-ADHD-S score increases of at least 2 from the end of open-label phase and ADHDRS-IV-Parent:Inv total score returns to ≥ 90% of study entry score for two consecutive visits. In both double-blind phases, patients receiving continued atomoxetine hydrochloride treatment experienced significantly longer times to relapse than those receiving placebo.
14.2 ADHD Studies in Adults
The effectiveness of atomoxetine hydrochloride in the treatment of ADHD was established in two 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-li scale. The primary effectiveness measure was the 18-li 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 two 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 How Supplied/storage And Handling
16.1 How Supplied
Atomoxetine Hydrochloride Capsules are available containing 10 mg, 18 mg, 25 mg, 40 mg, 60 mg, 80 mg or 100 mg of atomoxetine.
The 10 mg capsule is a hard-shell gelatin capsule with a red opaque cap and light yellow opaque body filled with white to off-white powder. The capsule is axially printed with MYLAN over 8010 in black ink on both the cap and the body. They are available as follows:
NDC 0378-8010-93bottles of 30 capsules
NDC 0378-8010-05bottles of 500 capsules
The 18 mg capsule is a hard-shell gelatin capsule with an orange opaque cap and light yellow opaque body filled with white to off-white powder. The capsule is axially printed with MYLAN over 8018 in black ink on both the cap and the body. They are available as follows:
NDC 0378-8018-93bottles of 30 capsules
NDC 0378-8018-05bottles of 500 capsules
The 25 mg capsule is a hard-shell gelatin capsule with a light blue opaque cap and white opaque body filled with white to off-white powder. The capsule is axially printed with MYLAN over 8025 in black ink on both the cap and the body. They are available as follows:
NDC 0378-8025-93bottles of 30 capsules
NDC 0378-8025-05bottles of 500 capsules
The 40 mg capsule is a hard-shell gelatin capsule with a blue opaque cap and light blue opaque body filled with white to off-white powder. The capsule is axially printed with MYLAN over 8040 in black ink on both the cap and body. They are available as follows:
NDC 0378-8040-93bottles of 30 capsules
NDC 0378-8040-05bottles of 500 capsules
The 60 mg capsule is a hard-shell gelatin capsule with a violet opaque cap and light yellow opaque body filled with white to off-white powder. The capsule is axially printed with MYLAN over 8060 in black ink on both the cap and the body. They are available as follows:
NDC 0378-8060-93bottles of 30 capsules
NDC 0378-8060-05bottles of 500 capsules
The 80 mg capsule is a hard-shell gelatin capsule with a light orange opaque cap and light yellow opaque body filled with white to off-white powder. The capsule is axially printed with MYLAN over 8080 in black ink on both the cap and the body. They are available as follows:
NDC 0378-8080-93bottles of 30 capsules
NDC 0378-8080-05bottles of 500 capsules
The 100 mg capsule is a hard-shell gelatin capsule with a light pink opaque cap and light yellow opaque body filled with white to off-white powder. The capsule is axially printed with MYLAN over 8110 in black ink on both the cap and the body. They are available as follows:
NDC 0378-8110-93bottles of 30 capsules
NDC 0378-8110-05bottles of 500 capsules
16.2 Storage and Handling
Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.]
Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure.
PHARMACIST: Dispense a Medication Guide with each prescription.
17 Patient Counseling Information
See FDA-approved Medication Guide .
17.1 General Information
Physicians should instruct their patients to read the Medication Guide before starting therapy with atomoxetine hydrochloride capsules and to reread it each time the prescription is renewed.
Prescribers or other health professionals should inform patients, their families and their caregivers about the benefits and risks associated with treatment with atomoxetine hydrochloride capsules and should counsel them in its appropriate use. The prescriber or health professional should instruct patients, their families and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have.
Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking atomoxetine hydrochloride capsules.
17.2 Suicide Risk
Patients, their families and their caregivers should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other unusual changes in behavior, depression and suicidal ideation, especially early during atomoxetine hydrochloride capsule treatment and when the dose is adjusted. Families and caregivers of patients should be advised to observe for the emergence of such symptoms on a day to day basis, since changes may be abrupt. Such symptoms should be reported to the patient’s prescriber or health professional, especially if they are severe, abrupt in onset or were not part of the patient’s presenting symptoms. Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior and indicate a need for very close monitoring and possibly changes in the medication.
17.3 Severe Liver Injury
Patients initiating atomoxetine hydrochloride capsules should be cautioned that severe liver injury may develop. Patients should be instructed to contact their physician immediately should they develop pruritus, dark urine, jaundice, right upper quadrant tenderness or unexplained “flu-like” symptoms [see Warnings and Precautions (5.2)].
17.4 Aggression or Hostility
Patients should be instructed to call their doctor as soon as possible should they notice an increase in aggression or hostility.
17.5 Priapism
Rare post-marketing 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 capsules. The parents or guardians of pediatric patients taking atomoxetine hydrochloride capsules and adult patients taking atomoxetine hydrochloride capsules should be instructed that priapism requires prompt medical attention.
17.6 Ocular Irritant
Atomoxetine hydrochloride is an ocular irritant. Atomoxetine hydrochloride capsules are not intended to be opened. In the event of capsule content coming in contact with the eye, the affected eye should be flushed immediately with water and medical advice obtained. Hands and any potentially contaminated surfaces should be washed as soon as possible.
17.7 Drug-Drug Interaction
Patients should be instructed to consult a physician if they are taking or plan to take any prescription or over-the-counter medicines, dietary supplements or herbal remedies.
17.8 Pregnancy
Patients should be instructed to consult a physician if they are nursing, pregnant or thinking of becoming pregnant while taking atomoxetine hydrochloride capsules.
17.9 Food
Patients may take atomoxetine hydrochloride capsules with or without food.
17.10 Missed Dose
If patients miss a dose, they should be instructed to take it as soon as possible, but should not take more than the prescribed total daily amount of atomoxetine hydrochloride capsules in any 24-hour period.
17.11 Interference with Psychomotor Performance
Patients should be instructed to use caution when driving a car or operating hazardous machinery until they are reasonably certain that their performance is not affected by atomoxetine.
Spl Medguide Section
MEDICATION GUIDE ATOMOXETINE HYDROCHLORIDE CAPSULES (a" toe mox' e teen hye" droe klor' ide)
Read the Medication Guide that comes with atomoxetine hydrochloride capsules before you or your child starts taking it and each time you get a refill. There may be new information. This Medication Guide does not take the place of talking to your doctor about your treatment or your child’s treatment with atomoxetine hydrochloride capsules.
What is the most important information I should know about atomoxetine hydrochloride capsules?
The following have been reported with use of atomoxetine hydrochloride 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 capsules 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 hydrochloride capsules The chance for suicidal thoughts and actions may be higher:
• early during atomoxetine hydrochloride capsule 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 capsule 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 hydrochloride capsule 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 hydrochloride 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 symptoms3. 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. Your doctor should check your blood pressure or your child’s blood pressure and heart rate regularly during treatment with atomoxetine hydrochloride 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 hydrochloride 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 capsule treatment may need to be considered.
What are atomoxetine hydrochloride capsules?
Atomoxetine is a selective norepinephrine reuptake inhibitor medicine. It is used for the treatment of attention deficit and hyperactivity disorder (ADHD). Atomoxetine hydrochloride capsules may help increase attention and decrease impulsiveness and hyperactivity in patients with ADHD.
Atomoxetine hydrochloride capsules should be used as a part of a total treatment program for ADHD that may include counseling or other therapies.
Atomoxetine hydrochloride capsules have not been studied in children less than 6 years old.
Who should not take atomoxetine hydrochloride capsules?
Atomoxetine hydrochloride 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 hydrochloride capsules. See the end of this Medication Guide for a complete ul of ingredients.• have or have had a rare tumor called pheochromocytoma.
Atomoxetine hydrochloride capsules may not be right for you or your child. Before starting atomoxetine hydrochloride 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
Tell your doctor if you or your child is pregnant, planning to become pregnant or breast-feeding.
Can atomoxetine hydrochloride 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 hydrochloride capsules and some medicines may interact with each other and cause serious side effects. Your doctor will decide whether atomoxetine hydrochloride 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 ul of your medicines with you to show your doctor and pharmacist.
Do not start any new medicine while taking atomoxetine hydrochloride capsules without talking to your doctor first.
How should atomoxetine hydrochloride capsules be taken?
• Take atomoxetine hydrochloride capsules exactly as prescribed. Atomoxetine hydrochloride capsules 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 hydrochloride capsules whole with water or other liquids. Tell your doctor if you or your child cannot swallow atomoxetine hydrochloride capsules whole. A different medicine may need to be prescribed.• Avoid touching a broken atomoxetine hydrochloride capsule. Wash hands and surfaces that touched an open atomoxetine hydrochloride 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 hydrochloride capsules can be taken with or without food.• Atomoxetine hydrochloride capsules are usually taken once or twice a day. Take atomoxetine hydrochloride capsules at the same time each day to help you remember. If you miss a dose of atomoxetine hydrochloride capsules, take it as soon as you remember that day. If you miss a day of atomoxetine hydrochloride 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 capsule treatment for a while to check ADHD symptoms.• Your doctor may do regular checks of the blood, heart and blood pressure while taking atomoxetine hydrochloride capsules. Children should have their height and weight checked often while taking atomoxetine hydrochloride capsules. Atomoxetine hydrochloride capsule treatment may be stopped if a problem is found during these check-ups.• If you or your child takes too much atomoxetine hydrochloride capsules or overdoses, call your doctor or poison control center right away or get emergency treatment.
What are possible side effects of atomoxetine hydrochloride capsules?
See “What is the most important information I should know about atomoxetine hydrochloride 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:     ▪ trouble starting or keeping a urine stream     ▪ 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• trouble sleeping• sexual side effects• menstrual cramps• 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 capsules. 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 capsules may affect your ability or your child’s ability to drive or operate heavy machinery. Be careful until you know how atomoxetine hydrochloride capsules affect 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 ul 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 hydrochloride capsules?
• Store atomoxetine hydrochloride capsules in a safe place at 20° to 25°C (68° to 77°F).• Keep atomoxetine hydrochloride capsules and all medicines out of the reach of children.
General information about atomoxetine hydrochloride capsules
Medicines are sometimes prescribed for purposes other than those uled in a Medication Guide. Do not use atomoxetine hydrochloride capsules for a condition for which it was not prescribed. Do not give atomoxetine hydrochloride 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 hydrochloride capsules. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about atomoxetine hydrochloride capsules that was written for healthcare professionals. For more information about atomoxetine hydrochloride capsules, call Mylan Pharmaceuticals Inc. toll free at 1-877-446-3679 (1-877-4-INFO-RX).
What are the ingredients in atomoxetine hydrochloride capsules?
Active ingredient: atomoxetine hydrochloride.
Inactive ingredients: colloidal silicon dioxide, magnesium stearate, pregelatinized starch and sodium lauryl sulfate. In addition, each of the empty gelatin capsules contains gelatin, titanium dioxide and the following colorant agents:
10 mg – D&C Yellow No. 10, FD&C Yellow No. 6, D&C Red No. 28, D&C Red No. 33 and FD&C Red No. 4018 mg – D&C Yellow No. 10, FD&C Yellow No. 6, D&C Red No. 28 and FD&C Red No. 4025 mg – FD&C Blue No. 1 and FD&C Red No. 340 mg – D&C Red No. 28 and FD&C Blue No. 160 mg – D&C Yellow No. 10, FD&C Yellow No. 6, D&C Red No. 28 and FD&C Blue No. 180 mg – D&C Yellow No. 10, FD&C Yellow No. 6, D&C Red No. 28100 mg – D&C Yellow No. 10, FD&C Yellow No. 6, FD&C Red No. 3 and red iron oxide.
The imprinting ink contains the following: black iron oxide, D&C Yellow No. 10 Aluminum Lake, FD&C Blue No. 1 Aluminum Lake, FD&C Blue No. 2 Aluminum Lake, FD&C Red No. 40 Aluminum Lake, propylene glycol and shellac glaze.
Nardil® is the register trademark of Pfizer, Inc.Parnate® is a registered trademark of GlaxoSmithKline.Emsam® is a trademark of Somerset Pharmaceuticals, Inc.
This Medication Guide has been approved by the U.S. Food and Drug Administration.
Mylan Pharmaceuticals Inc.Morgantown, WV 26505 U.S.A.
REVISED OCTOBER 2011ATOM:R4mpbmt/MG:ATOM:R4
Package Label.principal Display Panel
PRINCIPAL DISPLAY PANEL - 10 mg
NDC 0378-8010-93
Atomoxetine Hydrochloride Capsules 10 mg*
PHARMACIST: Dispense the accompanying Medication Guide to each patient.
Rx only 30 CAPSULES
*Each capsule containsatomoxetine hydrochlorideequivalent to 10 mg ofatomoxetine.
Dispense in a tight, light-resistantcontainer as defined in the USPusing a child-resistant closure.
Keep container tightly closed.
Keep this and all medication out of the reach of children.
Store at 20° to 25°C (68° to 77°F ). [See USP Controlled Room Temperature.]
Usual Dosage: See accompanyingprescribing information.
Mylan Pharmaceuticals Inc. Morgantown, WV 26505 U.S.A.
www.mylan.com
RM8010H1
![]()
Package Label.principal Display Panel
PRINCIPAL DISPLAY PANEL - 18 mg
NDC 0378-8018-93
Atomoxetine Hydrochloride Capsules 18 mg*
PHARMACIST: Dispense the accompanying Medication Guide to each patient.
Rx only 30 CAPSULES
*Each capsule containsatomoxetine hydrochlorideequivalent to 18 mg ofatomoxetine.
Dispense in a tight, light-resistantcontainer as defined in the USPusing a child-resistant closure.
Keep container tightly closed.
Keep this and all medication out of the reach of children.
Store at 20° to 25°C (68° to 77°F ). [See USP Controlled Room Temperature.]
Usual Dosage: See accompanyingprescribing information.
Mylan Pharmaceuticals Inc. Morgantown, WV 26505 U.S.A.
www.mylan.com
RM8018H1
![]()
Package Label.principal Display Panel
PRINCIPAL DISPLAY PANEL - 25 mg
NDC 0378-8025-93
Atomoxetine Hydrochloride Capsules 25 mg*
PHARMACIST: Dispense the accompanying Medication Guide to each patient.
Rx only 30 CAPSULES
*Each capsule containsatomoxetine hydrochlorideequivalent to 25 mg ofatomoxetine.
Dispense in a tight, light-resistantcontainer as defined in the USPusing a child-resistant closure.
Keep container tightly closed.
Keep this and all medication out of the reach of children.
Store at 20° to 25°C (68° to 77°F ). [See USP Controlled Room Temperature.]
Usual Dosage: See accompanyingprescribing information.
Mylan Pharmaceuticals Inc. Morgantown, WV 26505 U.S.A.
www.mylan.com
RM8025H1
![]()
Package Label.principal Display Panel
PRINCIPAL DISPLAY PANEL - 40 mg
NDC 0378-8040-93
Atomoxetine Hydrochloride Capsules 40 mg*
PHARMACIST: Dispense the accompanying Medication Guide to each patient.
Rx only 30 CAPSULES
*Each capsule containsatomoxetine hydrochlorideequivalent to 40 mg ofatomoxetine.
Dispense in a tight, light-resistantcontainer as defined in the USPusing a child-resistant closure.
Keep container tightly closed.
Keep this and all medication out of the reach of children.
Store at 20° to 25°C (68° to 77°F ). [See USP Controlled Room Temperature.]
Usual Dosage: See accompanyingprescribing information.
Mylan Pharmaceuticals Inc. Morgantown, WV 26505 U.S.A.
www.mylan.com
RM8040H1
![]()
Package Label.principal Display Panel
PRINCIPAL DISPLAY PANEL - 60 mg
NDC 0378-8060-93
Atomoxetine Hydrochloride Capsules 60 mg*
PHARMACIST: Dispense the accompanying Medication Guide to each patient.
Rx only 30 CAPSULES
*Each capsule containsatomoxetine hydrochlorideequivalent to 60 mg ofatomoxetine.
Dispense in a tight, light-resistantcontainer as defined in the USPusing a child-resistant closure.
Keep container tightly closed.
Keep this and all medication out of the reach of children.
Store at 20° to 25°C (68° to 77°F ). [See USP Controlled Room Temperature.]
Usual Dosage: See accompanyingprescribing information.
Mylan Pharmaceuticals Inc. Morgantown, WV 26505 U.S.A.
www.mylan.com
RM8060H1
![]()
Package Label.principal Display Panel
PRINCIPAL DISPLAY PANEL - 80 mg
NDC 0378-8080-93
Atomoxetine Hydrochloride Capsules 80 mg*
PHARMACIST: Dispense the accompanying Medication Guide to each patient.
Rx only 30 CAPSULES
*Each capsule containsatomoxetine hydrochlorideequivalent to 80 mg ofatomoxetine.
Dispense in a tight, light-resistantcontainer as defined in the USPusing a child-resistant closure.
Keep container tightly closed.
Keep this and all medication out of the reach of children.
Store at 20° to 25°C (68° to 77°F ). [See USP Controlled Room Temperature.]
Usual Dosage: See accompanyingprescribing information.
Mylan Pharmaceuticals Inc. Morgantown, WV 26505 U.S.A.
www.mylan.com
RM8080H1
![]()
Package Label.principal Display Panel
PRINCIPAL DISPLAY PANEL - 100 mg
NDC 0378-8110-93
Atomoxetine Hydrochloride Capsules 100 mg*
PHARMACIST: Dispense the accompanying Medication Guide to each patient.
Rx only 30 CAPSULES
*Each capsule containsatomoxetine hydrochlorideequivalent to 100 mg ofatomoxetine.
Dispense in a tight, light-resistantcontainer as defined in the USPusing a child-resistant closure.
Keep container tightly closed.
Keep this and all medication out of the reach of children.
Store at 20° to 25°C (68° to 77°F ). [See USP Controlled Room Temperature.]
Usual Dosage: See accompanyingprescribing information.
Mylan Pharmaceuticals Inc. Morgantown, WV 26505 U.S.A.
www.mylan.com
RM8110H1
![]()
DISCLAIMER:
"This tool does not provide medical advice, and is for informational and educational purposes only, and is not a substitute for professional medical advice, treatment or diagnosis. Call your doctor to receive medical advice. If you think you may have a medical emergency, please dial 911."
"Do not rely on openFDA to make decisions regarding medical care. While we make every effort to ensure that data is accurate, you should assume all results are unvalidated. We may limit or otherwise restrict your access to the API in line with our Terms of Service."
"This product uses publicly available data from the U.S. National Library of Medicine (NLM), National Institutes of Health, Department of Health and Human Services; NLM is not responsible for the product and does not endorse or recommend this or any other product."
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