Dosage Form: capsule
FULL PRESCRIBING INFORMATION
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)].
Indications and Usage for Atomoxetine
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)].
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 listener, failure to follow through on tasks, poor organization, avoids tasks requiring sustained mental effort, loses things, easily distracted, forgetful. For the Hyperactive-Impulsive Type, at least 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.
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.
Atomoxetine Dosage and Administration
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.
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)].
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.
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.
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.
Contraindications
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)].
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)].
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.
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.
Warnings and Precautions
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.
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)].
Serious Cardiovascular Events
Sudden Death and Preexisting Structural Cardiac Abnormalities or Other Serious Heart Problems
Children and Adolescents
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.
Adults
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.
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).
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.
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.
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]).
Allergic Events
Although uncommon, allergic reactions,including anaphylactic reactions, angioneurotic edema, urticaria and rash, have been reported in patients taking Atomoxetine hydrochloride.
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.
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.
Effects on Growth
Data on the long-term effects of Atomoxetine hydrochloride on growth come from open-label studies and weight and height changes are compared to normative population data. In general, the weight and height gain of pediatric patients treated with Atomoxetine hydrochloride lags behind that predicted by normative population data for about the first 9 to 12 months of treatment. Subsequently, weight gain rebounds and at about 3 years of treatment, patients treated with Atomoxetine hydrochloride have gained 17.9 kg on average, 0.5 kg more than predicted by their baseline data. After about 12 months, gain in height stabilizes and at 3 years, patients treated with Atomoxetine hydrochloride have gained 19.4 cm on average, 0.4 cm less than predicted by their baseline data (see Figure 1 below).
Figure 1: Mean Weight and Height Percentiles Over Time for Patients With 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.
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)].
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)].
Adverse Reactions
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
Reasons for Discontinuation of Treatment Due to Adverse Reactions in 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.
Seizures
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 in Acute Child and Adolescent, Placebo-Controlled Trials
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 listed 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).
| ||
| Adverse Reaction* | Percentage of Patients Reporting Reaction | |
| Atomoxetine Hydrochloride (N = 1,597) | Placebo (N = 934) | |
| Gastrointestinal Disorders | ||
| Abdominal pain† | 18 | 10 |
| Vomiting | 11 | 6 |
| Nausea | 10 | 5 |
| General Disorders and Administration Site Conditions | ||
| Fatigue | 8 | 3 |
| Irritability | 6 | 3 |
| Therapeutic response unexpected | 2 | 1 |
| Investigations | ||
| Weight decreased | 3 | 0 |
| Metabolism and Nutritional Disorders | ||
| Decreased appetite | 16 | 4 |
| Anorexia | 3 | 1 |
| Nervous System Disorders | ||
| Headache | 19 | 15 |
| Somnolence‡ | 11 | 4 |
| Dizziness | 5 | 2 |
| Skin and Subcutaneous Tissue Disorders | ||
| Rash | 2 | 1 |
| ||||
| Adverse Reaction | Percentage of Patients Reporting Reaction from BID Trials | Percentage of Patients Reporting Reaction from QD Trials | ||
| Atomoxetine Hydrochloride (N = 715) | Placebo (N = 434) | Atomoxetine Hydrochloride (N = 882) | Placebo (N = 500) | |
| Gastrointestinal Disorders | ||||
| Abdominal pain* | 17 | 13 | 18 | 7 |
| Vomiting | 11 | 8 | 11 | 4 |
| Nausea | 7 | 6 | 13 | 4 |
| Constipation† | 2 | 1 | 1 | 0 |
| General Disorders | ||||
| Fatigue | 6 | 4 | 9 | 2 |
| Psychiatric Disorders | ||||
| Mood swings‡ | 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); depression1 (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).
- 1
Depression includes the following terms: depression, major depression, depressive symptoms, depressed mood, dysphoria.
Reasons for Discontinuation of Treatment Due to Adverse Reactions in Acute Adult Placebo-Controlled 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.
Seizures
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.
