Atomoxetine
Generic: ATOMOXETINE
Basic Information
Manufacturer
Bryant Ranch Prepack
Product Type
HUMAN PRESCRIPTION DRUG
Route of Administration
ORAL
FDA Set ID
92de0ca1-6a02-4925-aefc-b32573d349a7
Indications & Usage
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 capsules are indicated for the treatment of Attention-Deficit/Hyperactivity Disorder (ADHD).
The efficacy of atomoxetine capsules was established in seven clinical trials in outpatients with ADHD: four 6 to 9-week trials in pediatric patients (ages 6 to 18), two 10-week trial in adults, and one maintenance trial in pediatrics (ages 6 to 15) [see Clinical Studies (14) ].
1.2 Diagnostic Considerations A diagnosis of ADHD (DSM-IV) implies the presence of hyperactive-impulsive or inattentive symptoms that cause impairment and that were present before age 7 years.
The symptoms must be persistent, must be more severe than is typically observed in individuals at a comparable level of development, must cause clinically significant impairment, e.g., in social, academic, or occupational functioning, and must be present in 2 or more settings, e.g., school (or work) and at home.
The symptoms must not be better accounted for by another mental disorder.
The specific etiology of ADHD is unknown, and there is no single diagnostic test.
Adequate diagnosis requires the use not only of medical but also of special psychological, educational, and social resources.
Learning may or may not be impaired.
The diagnosis must be based upon a complete history and evaluation of the patient and not solely on the presence of the required number of DSM-IV characteristics.
For the Inattentive Type, at least 6 of the following symptoms must have persisted for at least 6 months: lack of attention to details/careless mistakes, lack of sustained attention, poor listener, failure to follow through on tasks, poor organization, avoids tasks requiring sustained mental effort, loses things, easily distracted, forgetful.
For the Hyperactive-Impulsive Type, at least 6 of the following symptoms must have persisted for at least 6 months: fidgeting/squirming, leaving seat, inappropriate running/climbing, difficulty with quiet activities, “on the go,” excessive talking, blurting answers, can’t wait turn, intrusive.
For a Combined Type diagnosis, both inattentive and hyperactive-impulsive criteria must be met.
1.3 Need for Comprehensive Treatment Program Atomoxetine capsules are indicated as an integral part of a total treatment program for ADHD that may include other measures (psychological, educational, social) for patients with this syndrome.
Drug treatment may not be indicated for all patients with this syndrome.
Drug treatment is not intended for use in the patient who exhibits symptoms secondary to environmental factors and/or other primary psychiatric disorders, including psychosis.
Appropriate educational placement is essential in children and adolescents with this diagnosis and psychosocial intervention is often helpful.
When remedial measures alone are insufficient, the decision to prescribe drug treatment medication will depend upon the physician’s assessment of the chronicity and severity of the patient’s symptoms.
(1.1) 1.1 Attention-Deficit/Hyperactivity Disorder (ADHD) Atomoxetine capsules are indicated for the treatment of Attention-Deficit/Hyperactivity Disorder (ADHD).
The efficacy of atomoxetine capsules was established in seven clinical trials in outpatients with ADHD: four 6 to 9-week trials in pediatric patients (ages 6 to 18), two 10-week trial in adults, and one maintenance trial in pediatrics (ages 6 to 15) [see Clinical Studies (14) ].
1.2 Diagnostic Considerations A diagnosis of ADHD (DSM-IV) implies the presence of hyperactive-impulsive or inattentive symptoms that cause impairment and that were present before age 7 years.
The symptoms must be persistent, must be more severe than is typically observed in individuals at a comparable level of development, must cause clinically significant impairment, e.g., in social, academic, or occupational functioning, and must be present in 2 or more settings, e.g., school (or work) and at home.
The symptoms must not be better accounted for by another mental disorder.
The specific etiology of ADHD is unknown, and there is no single diagnostic test.
Adequate diagnosis requires the use not only of medical but also of special psychological, educational, and social resources.
Learning may or may not be impaired.
The diagnosis must be based upon a complete history and evaluation of the patient and not solely on the presence of the required number of DSM-IV characteristics.
For the Inattentive Type, at least 6 of the following symptoms must have persisted for at least 6 months: lack of attention to details/careless mistakes, lack of sustained attention, poor listener, failure to follow through on tasks, poor organization, avoids tasks requiring sustained mental effort, loses things, easily distracted, forgetful.
For the Hyperactive-Impulsive Type, at least 6 of the following symptoms must have persisted for at least 6 months: fidgeting/squirming, leaving seat, inappropriate running/climbing, difficulty with quiet activities, “on the go,” excessive talking, blurting answers, can’t wait turn, intrusive.
For a Combined Type diagnosis, both inattentive and hyperactive-impulsive criteria must be met.
1.3 Need for Comprehensive Treatment Program Atomoxetine capsules are indicated as an integral part of a total treatment program for ADHD that may include other measures (psychological, educational, social) for patients with this syndrome.
Drug treatment may not be indicated for all patients with this syndrome.
Drug treatment is not intended for use in the patient who exhibits symptoms secondary to environmental factors and/or other primary psychiatric disorders, including psychosis.
Appropriate educational placement is essential in children and adolescents with this diagnosis and psychosocial intervention is often helpful.
When remedial measures alone are insufficient, the decision to prescribe drug treatment medication will depend upon the physician’s assessment of the chronicity and severity of the patient’s symptoms.
Adverse Reactions
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, dizziness, erectile dysfunction and urinary hesitation.
(6.1) To report SUSPECTED ADVERSE REACTIONS, contact Dr. Reddy’s Laboratories Inc., at 1-888-375-3784 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .
6.1 Clinical Trials Experience Atomoxetine hydrochloride was administered to 5382 children or adolescent patients with ADHD and 1007 adults with ADHD in clinical studies.
During the ADHD clinical trials, 1625 children and adolescent patients were treated for longer than 1 year and 2529 children and adolescent patients were treated for over 6 months.
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
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% (48/1613) 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 1 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% (12/5073) 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% (11/4741) 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 2.
Results were similar in the BID and the QD trial except as shown in Table 3, 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 2 and 3 ).
Additional data from ADHD clinical trials (controlled and uncontrolled) has shown that approximately 5 to 10% of pediatric patients experienced potentially clinically important changes in heart rate (≥20 beats per min) or blood pressure (≥15 to 20 mm Hg) [see Contraindications (4) and Warnings and Precautions (5) ].
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 a Percentage of Patients Reporting Reaction Atomoxetine Hydrochloride (N=1597) Placebo (N=934) Gastrointestinal Disorders Abdominal pain b 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 c 11 4 Dizziness 5 2 Skin and Subcutaneous Tissue Disorders Rash 2 1 a Reactions 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 (terminal insomnia), flushing, mydriasis, sinus tachycardia, asthenia, palpitations, mood swings, constipation and dyspepsia.
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.
b Abdominal pain includes the terms: abdominal pain upper, abdominal pain, stomach discomfort, abdominal discomfort, epigastric discomfort.
c Somnolence includes the terms: sedation, somnolence.
Table 3: 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 Atomoxetine Hydrochloride (N=715) Placebo (N=434) Atomoxetine Hydrochloride (N=882) Placebo (N=500) Gastrointestinal Disorders Abdominal Pain a 17 13 18 7 Vomiting 11 8 11 4 Nausea 7 6 13 4 Constipation b 2 1 1 0 General Disorders Fatigue 6 4 9 2 Psychiatric Disorders Mood swings c 2 0 1 1 a Abdominal pain includes the terms: abdominal pain upper, abdominal pain, stomach discomfort, abdominal discomfort, epigastric discomfort.
b Constipation didn’t meet the statistical significance on Breslow-Day test but is included in the table because of pharmacologic plausibility.
c Mood swings didn’t meet the statistical significance on Breslow-Day test at 0.05 level but p-value was <0.1 (trend).
The following adverse reactions occurred in at least 2% of child and adolescent CYP2D6 PM patients and were statistically significantly more frequent in PM patients compared with CYP2D6 EM patients: insomnia (11% of PMs, 6% of EMs); weight decreased (7% of PMs, 4% of EMs); constipation (7% of PMs, 4% of EMs); depression 1 (7% of PMs, 4% of EMs); tremor (5% of PMs, 1% of EMs); excoriation (4% of PMs, 2% of EMs); middle insomnia (3% of PMs, 1% 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); sedation (4% of PMs, 2% of EMs).
1 Depression includes the following terms: depression, major depression, depressive symptoms, depressed mood, dysphoria.
Adult Clinical Trials 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 3.0% (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 1 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.
Commonly observed adverse reactions in acute adult placebo-controlled trial s - 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 4.
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, decreased appetite, dizziness, erectile dysfunction, and urinary hesitation (see Table 4 ).
Additional data from ADHD clinical trials (controlled and uncontrolled) has shown that approximately 5 to 10% of adult patients experienced potentially clinically important changes in heart rate (≥20 beats per min) or blood pressure (≥15 to 20 mm Hg) [see Contraindications (4) and Warnings and Precautions (5) ].
Table 4: Common Treatment-Emergent Adverse Reactions Associated with the Use of Atomoxetine Hydrochloride in Acute (up to 25 weeks) Adult Trials Adverse Reaction a Percentage of Patients Reporting Reaction Atomoxetine Hydrochloride (N=1697) Placebo (N=1560) Cardiac Disorders Palpitations 3 1 Gastrointestinal Disorders Dry mouth 20 5 Nausea 26 6 Constipation 8 3 Abdominal pain b 7 4 Dyspepsia 4 2 Vomiting 4 2 General Disorders and Administration Site Conditions Fatigue 10 6 Chills 3 0 Feeling jittery 2 1 Irritability 5 3 Thirst 2 1 Investigations Weight decreased 2 1 Metabolism and Nutritional Disorders Decreased appetite 16 3 Nervous System Disorders Dizziness 8 3 Somnolence c 8 5 Paraesthesia 3 0 Psychiatric Disorders Abnormal dreams 4 3 Insomnia d 15 8 Libido decreased 3 1 Sleep disorder 3 1 Renal and Urinary Disorders Urinary hesitation e 6 1 Dysuria 2 0 Reproductive System and Breast Disorders Erectile dysfunction f 8 1 Dysmenorrhea g 3 2 Ejaculation delayed f and/or ejaculation disorder f 4 1 Skin and Subcutaneous Tissue Disorders Hyperhidrosis 4 1 Vascular Disorders Hot flush 3 0 a Reactions 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: peripheral coldness, tachycardia, prostatitis, testicular pain, orgasm abnormal, flatulence, asthenia, feeling cold, muscle spasm, dysgeusia, agitation, restlessness, micturition urgency, pollakiuria, pruritus, urticaria, flushing, tremor, menstruation irregular, rash, and urinary retention.
The following reactions were reported by at least 2% of patients treated with atomoxetine, and equal to or less than placebo: anxiety, diarrhea, back pain, headache, and oropharyngeal pain.
b Abdominal pain includes the terms: abdominal pain upper, abdominal pain, stomach discomfort, abdominal discomfort, epigastric discomfort.
c Somnolence includes the terms: sedation, somnolence.
d Insomnia includes the terms: insomnia, initial insomnia, middle insomnia, and terminal insomnia.
e Urinary hesitation includes the terms: urinary hesitation, urine flow decreased.
f Based on total number of males (atomoxetine hydrochloride, N=943; placebo, N=869).
g Based on total number of females (atomoxetine hydrochloride, N=754; placebo, N=691).
The following adverse events occurred in at least 2% of adult CYP2D6 poor metaboliser (PM) patients and were statistically significantly more frequent in PM patients compared to CYP2D6 extensive metaboliser (EM) patients: vision blurred (4% of PMs, 1% of EMs); dry mouth (35% of PMs, 17% of EMs); constipation (11% of PMs, 7% of EMs); feeling jittery (5% of PMs, 2% of EMs); decreased appetite (23% of PMs, 15% of EMs); tremor (5% of PMs, 1% of EMs); insomnia (19% of PMs, 11% of EMs); sleep disorder (7% of PMs, 3% of EMs); middle insomnia (5% of PMs, 3% of EMs); terminal insomnia (3% of PMs, 1% of EMs); urinary retention (6% of PMs, 1% of EMs); erectile dysfunction (21% of PMs, 9% of EMs); ejaculation disorder (6% of PMs, 2% of EMs); hyperhidrosis (15% of PMs, 7% of EMs); peripheral coldness (3% of PMs, 1% of EMs).
Male and Female Sexual Dysfunction - 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 4 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 Postmarketing Spontaneous Reports The following adverse reactions have been identified during post approval use of atomoxetine hydrochloride.
Unless otherwise specified, these adverse reactions have occurred in adults and children and adolescents.
Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Cardiovascular system – QT prolongation, syncope.
Peripheral vascular effects — Raynaud’s phenomenon General disorders and administration site conditions — Lethargy.
Musculoskeletal system — Rhabdomyolysis Nervous system disorders — Hypoaesthesia, paraesthesia in children and adolescents; sensory disturbances; tics Psychiatric disorders — Depression and depressed mood; anxiety, libido changes.
Seizures — Seizures have been reported in the postmarketing period.
The postmarketing seizure cases include patients with pre-existing seizure disorders and those with identified risk factors for seizures, as well as patients with neither a history of nor identified risk factors for seizures.
The exact relationship between atomoxetine hydrochloride and seizures is difficult to evaluate due to uncertainty about the background risk of seizures in ADHD patients.
Skin and subcutaneous tissue disorders — Alopecia, hyperhidrosis.
Urogenital System — Male pelvic pain; urinary hesitation in children and adolescents; urinary retention in children and adolescents.
(6.1) Adult Clinical Trials - Constipation, dry mouth, nausea, fatigue, decreased appetite, dizziness, erectile dysfunction and urinary hesitation.
(6.1) To report SUSPECTED ADVERSE REACTIONS, contact Dr. Reddy’s Laboratories Inc., at 1-888-375-3784 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .
6.1 Clinical Trials Experience Atomoxetine hydrochloride was administered to 5382 children or adolescent patients with ADHD and 1007 adults with ADHD in clinical studies.
During the ADHD clinical trials, 1625 children and adolescent patients were treated for longer than 1 year and 2529 children and adolescent patients were treated for over 6 months.
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
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% (48/1613) 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 1 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% (12/5073) 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% (11/4741) 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 2.
Results were similar in the BID and the QD trial except as shown in Table 3, 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 2 and 3 ).
Additional data from ADHD clinical trials (controlled and uncontrolled) has shown that approximately 5 to 10% of pediatric patients experienced potentially clinically important changes in heart rate (≥20 beats per min) or blood pressure (≥15 to 20 mm Hg) [see Contraindications (4) and Warnings and Precautions (5) ].
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 a Percentage of Patients Reporting Reaction Atomoxetine Hydrochloride (N=1597) Placebo (N=934) Gastrointestinal Disorders Abdominal pain b 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 c 11 4 Dizziness 5 2 Skin and Subcutaneous Tissue Disorders Rash 2 1 a Reactions 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 (terminal insomnia), flushing, mydriasis, sinus tachycardia, asthenia, palpitations, mood swings, constipation and dyspepsia.
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.
b Abdominal pain includes the terms: abdominal pain upper, abdominal pain, stomach discomfort, abdominal discomfort, epigastric discomfort.
c Somnolence includes the terms: sedation, somnolence.
Table 3: 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 Atomoxetine Hydrochloride (N=715) Placebo (N=434) Atomoxetine Hydrochloride (N=882) Placebo (N=500) Gastrointestinal Disorders Abdominal Pain a 17 13 18 7 Vomiting 11 8 11 4 Nausea 7 6 13 4 Constipation b 2 1 1 0 General Disorders Fatigue 6 4 9 2 Psychiatric Disorders Mood swings c 2 0 1 1 a Abdominal pain includes the terms: abdominal pain upper, abdominal pain, stomach discomfort, abdominal discomfort, epigastric discomfort.
b Constipation didn’t meet the statistical significance on Breslow-Day test but is included in the table because of pharmacologic plausibility.
c Mood swings didn’t meet the statistical significance on Breslow-Day test at 0.05 level but p-value was <0.1 (trend).
The following adverse reactions occurred in at least 2% of child and adolescent CYP2D6 PM patients and were statistically significantly more frequent in PM patients compared with CYP2D6 EM patients: insomnia (11% of PMs, 6% of EMs); weight decreased (7% of PMs, 4% of EMs); constipation (7% of PMs, 4% of EMs); depression 1 (7% of PMs, 4% of EMs); tremor (5% of PMs, 1% of EMs); excoriation (4% of PMs, 2% of EMs); middle insomnia (3% of PMs, 1% 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); sedation (4% of PMs, 2% of EMs).
1 Depression includes the following terms: depression, major depression, depressive symptoms, depressed mood, dysphoria.
Adult Clinical Trials 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 3.0% (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 1 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.
Commonly observed adverse reactions in acute adult placebo-controlled trial s - 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 4.
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, decreased appetite, dizziness, erectile dysfunction, and urinary hesitation (see Table 4 ).
Additional data from ADHD clinical trials (controlled and uncontrolled) has shown that approximately 5 to 10% of adult patients experienced potentially clinically important changes in heart rate (≥20 beats per min) or blood pressure (≥15 to 20 mm Hg) [see Contraindications (4) and Warnings and Precautions (5) ].
Table 4: Common Treatment-Emergent Adverse Reactions Associated with the Use of Atomoxetine Hydrochloride in Acute (up to 25 weeks) Adult Trials Adverse Reaction a Percentage of Patients Reporting Reaction Atomoxetine Hydrochloride (N=1697) Placebo (N=1560) Cardiac Disorders Palpitations 3 1 Gastrointestinal Disorders Dry mouth 20 5 Nausea 26 6 Constipation 8 3 Abdominal pain b 7 4 Dyspepsia 4 2 Vomiting 4 2 General Disorders and Administration Site Conditions Fatigue 10 6 Chills 3 0 Feeling jittery 2 1 Irritability 5 3 Thirst 2 1 Investigations Weight decreased 2 1 Metabolism and Nutritional Disorders Decreased appetite 16 3 Nervous System Disorders Dizziness 8 3 Somnolence c 8 5 Paraesthesia 3 0 Psychiatric Disorders Abnormal dreams 4 3 Insomnia d 15 8 Libido decreased 3 1 Sleep disorder 3 1 Renal and Urinary Disorders Urinary hesitation e 6 1 Dysuria 2 0 Reproductive System and Breast Disorders Erectile dysfunction f 8 1 Dysmenorrhea g 3 2 Ejaculation delayed f and/or ejaculation disorder f 4 1 Skin and Subcutaneous Tissue Disorders Hyperhidrosis 4 1 Vascular Disorders Hot flush 3 0 a Reactions 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: peripheral coldness, tachycardia, prostatitis, testicular pain, orgasm abnormal, flatulence, asthenia, feeling cold, muscle spasm, dysgeusia, agitation, restlessness, micturition urgency, pollakiuria, pruritus, urticaria, flushing, tremor, menstruation irregular, rash, and urinary retention.
The following reactions were reported by at least 2% of patients treated with atomoxetine, and equal to or less than placebo: anxiety, diarrhea, back pain, headache, and oropharyngeal pain.
b Abdominal pain includes the terms: abdominal pain upper, abdominal pain, stomach discomfort, abdominal discomfort, epigastric discomfort.
c Somnolence includes the terms: sedation, somnolence.
d Insomnia includes the terms: insomnia, initial insomnia, middle insomnia, and terminal insomnia.
e Urinary hesitation includes the terms: urinary hesitation, urine flow decreased.
f Based on total number of males (atomoxetine hydrochloride, N=943; placebo, N=869).
g Based on total number of females (atomoxetine hydrochloride, N=754; placebo, N=691).
The following adverse events occurred in at least 2% of adult CYP2D6 poor metaboliser (PM) patients and were statistically significantly more frequent in PM patients compared to CYP2D6 extensive metaboliser (EM) patients: vision blurred (4% of PMs, 1% of EMs); dry mouth (35% of PMs, 17% of EMs); constipation (11% of PMs, 7% of EMs); feeling jittery (5% of PMs, 2% of EMs); decreased appetite (23% of PMs, 15% of EMs); tremor (5% of PMs, 1% of EMs); insomnia (19% of PMs, 11% of EMs); sleep disorder (7% of PMs, 3% of EMs); middle insomnia (5% of PMs, 3% of EMs); terminal insomnia (3% of PMs, 1% of EMs); urinary retention (6% of PMs, 1% of EMs); erectile dysfunction (21% of PMs, 9% of EMs); ejaculation disorder (6% of PMs, 2% of EMs); hyperhidrosis (15% of PMs, 7% of EMs); peripheral coldness (3% of PMs, 1% of EMs).
Male and Female Sexual Dysfunction - 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 4 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 Postmarketing Spontaneous Reports The following adverse reactions have been identified during post approval use of atomoxetine hydrochloride.
Unless otherwise specified, these adverse reactions have occurred in adults and children and adolescents.
Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Cardiovascular system – QT prolongation, syncope.
Peripheral vascular effects — Raynaud’s phenomenon General disorders and administration site conditions — Lethargy.
Musculoskeletal system — Rhabdomyolysis Nervous system disorders — Hypoaesthesia, paraesthesia in children and adolescents; sensory disturbances; tics Psychiatric disorders — Depression and depressed mood; anxiety, libido changes.
Seizures — Seizures have been reported in the postmarketing period.
The postmarketing seizure cases include patients with pre-existing seizure disorders and those with identified risk factors for seizures, as well as patients with neither a history of nor identified risk factors for seizures.
The exact relationship between atomoxetine hydrochloride and seizures is difficult to evaluate due to uncertainty about the background risk of seizures in ADHD patients.
Skin and subcutaneous tissue disorders — Alopecia, hyperhidrosis.
Urogenital System — Male pelvic pain; urinary hesitation in children and adolescents; urinary retention in children and adolescents.