Atomoxetine hydrochloride
Generic: ATOMOXETINE HYDROCHLORIDE
Basic Information
Manufacturer
Advagen Pharma Ltd.
Product Type
HUMAN PRESCRIPTION DRUG
Route of Administration
ORAL
FDA Set ID
16096e9c-2dcd-4c84-a1a8-1c85d6d6898c
Indications & Usage
1 INDICATIONS AND USAGE Atomoxetine oral solution is indicated for the treatment of attention-deficit/hyperactivity disorder (ADHD) in adult and pediatric patients 6 years of age and older.
Atomoxetine oral solution is indicated as an integral part of a total treatment program for ADHD that may include other measures (psychological, educational, social) for patients with ADHD.
Atomoxetine oral solution is a selective norepinephrine reuptake inhibitor (SNRI) indicated for the treatment of ADHD in adults and pediatric patients 6 years of age and older.
( 1 )
Atomoxetine oral solution is indicated as an integral part of a total treatment program for ADHD that may include other measures (psychological, educational, social) for patients with ADHD.
Atomoxetine oral solution is a selective norepinephrine reuptake inhibitor (SNRI) indicated for the treatment of ADHD in adults and pediatric patients 6 years of age and older.
( 1 )
Adverse Reactions
6 ADVERSE REACTIONS Most common adverse reactions (≥5% and at least twice the incidence of placebo patients): Pediatric Clinical Studies: Nausea, vomiting, fatigue, decreased appetite, abdominal pain, and somnolence.
( 6.1 ) Adult Clinical Studies: Constipation, dry mouth, nausea, decreased appetite, dizziness, erectile dysfunction, and urinary hesitation.
( 6.1 ) Patients should be instructed to use caution when driving a car or operating hazardous machinery (because of somnolence) until they are reasonably certain that their performance is not affected by atomoxetine oral solution ( 6.1 ).
To report SUSPECTED ADVERSE REACTIONS, contact Advagen Pharma Ltd, at 1-866-488-0312 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .
6.1 Clinical Trials Experience 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.
The safety of atomoxetine oral solution has been established from adequate and well-controlled studies of atomoxetine capsules (also referred to as another atomoxetine product) in patients 6 years of age and older with ADHD [see Clinical Studies (14) ] .
Below is a display of the adverse reactions of [atomoxetine capsules in these adequate and well-controlled studies.
Atomoxetine capsules were administered to 5,382 pediatric patients 6 years of age and older in clinical ADHD studies (Studies 1, 2, 3, 4, and 5) [see Clinical Studies (14.1) ] and 1,007 adults in clinical ADHD studies (Studies 6 and 7) [see Clinical Studies (14.2) ] .
In the ADHD clinical trials, 2,529 pediatric patients were treated for over 6 months, which included 1,625 pediatric patients who were treated for longer than 1 year.
Adverse Reactions in the Clinical Trials of Pediatric Patients 6 Years of Age and Older with ADHD Discontinuation of Treatment Due to Adverse Reactions in the Clinical Studies of Pediatric Patients 6 Years of Age and Older: In the acute placebo-controlled studies of pediatric patients 6 years of age and older with ADHD, 3% (48/1,613) of atomoxetine capsules-treated pediatric patients and 1.4% (13/945) of placebo-treated pediatric patients discontinued due to an adverse reaction.
Among atomoxetine capsules-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.
For all studies, (including open-label and long-term studies), 6% of atomoxetine capsules-treated pediatric patients who were other CYP2D6 metabolizer types (ultrarapid, normal, and intermediate) and 11% of those who were CYP2D6 poor metabolizers discontinued due to an adverse reaction.
Common Adverse Reactions in the Clinical Studies of Pediatric Patients 6 Years of Age and Older: Common adverse reactions (incidence of 2% or greater in atomoxetine capsules-treated patients and with a higher incidence in atomoxetine capsules-treated patients compared to placebo-treated patients) in pediatric patients 6 years of age and older with ADHD are listed in Table 3.
The most commonly observed adverse reactions in atomoxetine capsules-treated patients (incidence of ≥5% and ≥twice the incidence in placebo-treated patients), for either twice daily or once daily dosing were: nausea, vomiting, fatigue, decreased appetite, abdominal pain, and somnolence (see Tables 3 and 4).
Table 3: Common Adverse Reactions a in Acute Studies (up to 18 weeks) in Pediatric Patients 6 Years and Older with ADHD Atomoxetine Capsules (N=1,597) Placebo (N=934) Headache 19% 15% Abdominal pain b 18% 10% Decreased appetite 16% 4% Somnolence c 11% 4% Vomiting 11% 6% Nausea 10% 5% Fatigue 8% 3% Irritability 6% 3% Dizziness 5% 2% Decrease weight 3% 0% Anorexia 3% 1% Rash 2% 1% a Adverse reactions reported by at least 2% of atomoxetine capsules-treated patients and greater than placebo-treated patients.
b Abdominal pain includes the terms: upper abdominal pain and epigastric discomfort.
c Somnolence includes the term sedation.
Adverse reaction in the atomoxetine capsules-treated patients who received twice daily, and once daily dosing are shown in Table 4 (adverse reactions based on statistically significant Breslow-Day tests).
Table 4: Common Adverse Reactions in Acute studies (up to 18 weeks) in Pediatric Patients 6 Years and Older with ADHD ADHD Studies with Twice Daily Dosing ADHD Studies with Once Daily Dosing Atomoxetine Capsules (N=715) Placebo (N=434) Atomoxetine Capsules (N=882) Placebo (N=500) Abdominal pain a 17% 13% 18% 7% Vomiting 11% 8% 11% 4% Nausea 7% 6% 13% 4% Fatigue 6% 4% 9% 2% Mood swings b 2% 0% 1% 1% Constipation c 2% 1% 1% 0% a Abdominal pain includes the terms: upper abdominal pain upper, epigastric discomfort.
b Mood swings didn’t meet the statistical significance on Breslow-Day test at 0.05 level, but p-value was <0.1 (trend).
c Constipation didn’t meet the statistical significance on Breslow-Day test but is included in the table because of pharmacologic plausibility.
Common Adverse Reactions by CYP2D6 Metabolizer Status in the Clinical Studies of Pediatric Patients 6 Years of Age and Older: Table 5 displays adverse reactions occurred in at least 2% of atomoxetine capsules-treated pediatric patients who were CYP2D6 poor metabolizers and were statistically significantly more frequent in CYP2D6 poor metabolizers compared with other CYP2D6 metabolizer types (ultrarapid, normal, and intermediate).
Table 5: Common Adverse Reactions a in Acute Studies (up to 18 weeks) in Atomoxetine Capsules-Treated Pediatric Patients 6 Years and Older with ADHD by CYP2D6 Metabolizer Types Atomoxetine Capsules CYP2D6 Poor Metabolizers (N=5,019) Atomoxetine Capsules Other CYP2D6 Metabolizer Types (N=355) Insomnia 11% 6% Decreased weight 7% 4% Constipation 7% 4% Depression b 7% 4% Tremor 5% 1% Excoriation 4% 2% Sedation 4% 2% Middle insomnia 3% 1% Conjunctivitis 3% 1% Syncope 3% 1% Early morning awakening 2% 1% Mydriasis 2% 1% a Adverse reactions that occurred in at least 2% of atomoxetine capsules-treated pediatric patients who were CYP2D6 poor metabolizers and were statistically significantly more frequent in poor metabolizers compared with other CYP2D6 metabolizer types (ultrarapid, normal, and intermediate).
b Depression included the following terms: major depression, depressive symptoms, depressed mood, dysphoria.
Less Common Adverse Reactions in the Clinical Studies of Pediatric Patients 6 Years of Age and Older: The following reactions did not meet this criterion but were reported by more atomoxetine capsules-treated patients than placebo-treated patients and are possibly related to atomoxetine capsules 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.
Seizures in the Clinical Studies of Pediatric Patients 6 Years of Age and Older: Atomoxetine has not been systematically evaluated in pediatric patients with seizure disorder as these patients were excluded from clinical studies in the atomoxetine capsules studies.
In the clinical development program, seizures were reported in 0.2% (12/5,073) of atomoxetine capsules-treated pediatric patients whose average age was 10 years old (range 6 to 16 years of age).
In these clinical trials, for atomoxetine capsules-treated pediatric patients the seizure incidence among CYP2D6 poor metabolizers was 0.3% (1/293) compared to 0.2% (11/4,741) for other CYP2D6 metabolizer types.
Heart Rate and Blood Pressure Increases in the Clinical Studies of Pediatric Patients 6 Years of Age and Older: Additional data from ADHD clinical trials (controlled and uncontrolled) has shown that approximately 5 to 10% of pediatric patients treated with atomoxetine capsules experienced potentially clinically important changes in heart rate (≥20 beats per minute) or blood pressure (≥15 to 20 mm Hg) [see Contraindications (4) and Warnings and Precautions (5.4) ] .
Adverse Reactions in the Clinical Studies of Adults with ADHD Discontinuation of Treatment Due to Adverse Reactions in the Clinical Studies of Adults: In the acute adult placebo-controlled trials, 11% (61/541) atomoxetine capsules-treated pediatric patients and 3% (12/405) of placebo-treated patients discontinued for adverse reactions.
Among atomoxetine capsules-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.
Common Adverse Reactions in the Clinical Studies of Adults: Commonly observed adverse reactions associated with the use of atomoxetine capsules (incidence of 2% or greater) and not observed at an equivalent incidence among placebo-treated patients (atomoxetine capsules incidence greater than placebo) are listed in Table 6.
The most commonly observed adverse reactions in patients treated with atomoxetine capsules (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 6).
Table 6: Common Adverse Reactions a Associated in Acute Studies (up to 25 weeks) of Adult Patients with ADHD Atomoxetine Capsules (N=1697) Placebo (N=1560) Nausea 26% 6% Dry mouth 20% 5% Decreased appetite 16% 3% Insomnia d 15% 8% Fatigue 10% 6% Erectile dysfunction f 8% 1% Constipation 8% 3% Dizziness 8% 3% Somnolence c 8% 5% Abdominal pain b 7% 4% Urinary hesitation e 6% 1% Irritability 5% 3% Ejaculation delayedf and/or ejaculation disorder f 4% 1% Hyperhidrosis 4% 1% Dyspepsia 4% 2% Vomiting 4% 2% Abnormal dreams 4% 3% Chills 3% 0% Paraesthesia 3% 0% Hot flush 3% 0% Palpitations 3% 1% Libido decreased 3% 1% Sleep disorder 3% 1% Dysmenorrhea g 3% 2% Dysuria 2% 0% Thirst 2% 1% Weight decreased 2% 1% Feeling jittery 2% 1% a Reactions reported by at least 2% of patients treated with atomoxetine capsules, 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.
b Abdominal pain includes the terms: abdominal pain upper, abdominal pain, stomach discomfort, abdominal discomfort, epigastric discomfort.
c Somnolence includes the term sedation.
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 capsules, N=943; placebo, N=869).
g Based on total number of females (atomoxetine capsules, N=754; placebo, N=691).
Common Adverse Reactions by CYP2D6 Metabolizer Status in the Clinical Studies of Adults: Table 7 displays adverse reactions that occurred in at least 2% of atomoxetine capsules-treated adult patients who were CYP2D6 poor metabolizers and were statistically significantly more frequent compared to other CYP2D6 metabolizer types (ultrarapid, normal, and intermediate).
Table 7: Common Adverse Reactions a in Acute Studies (up to 18 weeks) in Atomoxetine Capsules-Treated Adults with ADHD by CYP2D6 Metabolizer Types Atomoxetine Capsules CYP2D6 Poor Metabolizers (N=203) Atomoxetine Capsules Other CYP2D6 Metabolizer Types (N=3,599) Dry mouth 35% 17% Decreased appetite 23% 15% Erectile dysfunction 21% 9% Insomnia 19% 11% Hyperhidrosis 15% 7% Constipation 11% 7% Sleep disorder 7% 3% Urinary retention 6% 1% Ejaculation disorder 6% 2% Tremor 5% 1% Feeling jittery 5% 2% Middle insomnia 5% 3% Blurred vision 4% 1% Terminal insomnia 3% 1% Peripheral coldness 3% 1% a Adverse reactions that occurred in at least 2% of atomoxetine capsules-treated pediatric patients who were CYP2D6 poor metabolizers and were statistically significantly more frequent in CYP2D6 poor metabolizers compared with other CYP2D6 metabolizer types (ultrarapid, normal, and intermediate).
Less Common Adverse Reactions in the Clinical Studies of Adults: The following reactions did not meet this criterion but were reported by more atomoxetine capsules-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.
Seizures in the Clinical Studies of Adults: Atomoxetine 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 treated with atomoxetine capsules.
In these clinical trials, no CYP2D6 poor metabolizers (0/43) reported seizures compared to 0.1% (1/705) for other CYP2D6 metabolizer types.
Heart Rate and Blood Pressure Increases in the Clinical Studies of Adults: Table 8 displays the proportion of atomoxetine capsules-treated and placebo-treated patients who had an increase in diastolic blood pressure (DBP) ≥15 mm Hg, systolic blood pressure (SBP) ≥20 mm Hg, or heart rate ≥ 20 bpm in short-term, placebo-controlled clinical studies of in pediatric and adult patients with ADHD [see Warnings and Precautions (5.4) ] .
Table 8: Proportion of ADHD Patients With an Increase ≥15 mm Hg in DBP, ≥20 mm Hg in SBP, or ≥20 bpm in Heart Rate a Pediatric Acute ADHD Studies Adult Acute ADHD Studies Maximum b Endpoint Maximum b Endpoint Atomoxetine Capsules Placebo Atomoxetine Capsules Placebo Atomoxetine Capsules Placebo Atomoxetine Capsules Placebo DBP (≥15 mm Hg) 22% 14% 9% 5% 13% 9% 5% 4% SBP (≥20 mm Hg) 13% 9% 5% 3% 12% 8% 4% 3% HR (≥20 bpm) 23% 12% 12% 4% 22% 8% 10% 2% a Abbreviations: bpm=beats per minute; DBP=diastolic blood pressure; HR=heart rate; mm Hg=millimeters mercury; SBP=systolic blood pressure.
b Proportion of patients meeting threshold at any one time during the clinical studies.
Additional data from ADHD clinical trials (controlled and uncontrolled) showed that approximately 5 to 10% of adult patients treated with atomoxetine capsules had potentially clinically important changes in heart rate (≥20 beats per minute) or blood pressure (≥15 to 20 mm Hg) [see Contraindications (4) and Warnings and Precautions (5.4) ] .
Male and Female Sexual Dysfunction in the Clinical Studies of Adults: Atomoxetine capsules impaired sexual function in some patients.
Estimates of the incidence of untoward sexual experience and performance in these studies are likely to underestimate their actual incidence because patients and health care providers may be reluctant to discuss them.
Sexual adverse reactions reported by at least 2% of atomoxetine capsules-treated adult patients in the placebo-controlled studies of adults with ADHD (i.e., erectile dysfunction, dysmenorrhea, and ejaculation delayed and/or ejaculation disorder).
There are no adequate and well-controlled studies examining sexual dysfunction with atomoxetine treatment.
While it is difficult to know the precise risk of sexual dysfunction associated with the use of atomoxetine, health care providers should routinely inquire about sexual dysfunction.
6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of atomoxetine.
Unless otherwise specified, these adverse reactions have occurred in adults and pediatric patients.
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 pediatric patients; sensory disturbances; tics.
Psychiatric disorders: Depression and depressed mood; anxiety, libido changes.
Seizures: Seizures have been reported and included patients with pre-existing seizure disorders, those with identified risk factors for seizures, and patients with neither a history of nor identified risk factors for seizures.
The exact relationship between atomoxetine 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 pediatric patients; urinary retention in pediatric patients.
( 6.1 ) Adult Clinical Studies: Constipation, dry mouth, nausea, decreased appetite, dizziness, erectile dysfunction, and urinary hesitation.
( 6.1 ) Patients should be instructed to use caution when driving a car or operating hazardous machinery (because of somnolence) until they are reasonably certain that their performance is not affected by atomoxetine oral solution ( 6.1 ).
To report SUSPECTED ADVERSE REACTIONS, contact Advagen Pharma Ltd, at 1-866-488-0312 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .
6.1 Clinical Trials Experience 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.
The safety of atomoxetine oral solution has been established from adequate and well-controlled studies of atomoxetine capsules (also referred to as another atomoxetine product) in patients 6 years of age and older with ADHD [see Clinical Studies (14) ] .
Below is a display of the adverse reactions of [atomoxetine capsules in these adequate and well-controlled studies.
Atomoxetine capsules were administered to 5,382 pediatric patients 6 years of age and older in clinical ADHD studies (Studies 1, 2, 3, 4, and 5) [see Clinical Studies (14.1) ] and 1,007 adults in clinical ADHD studies (Studies 6 and 7) [see Clinical Studies (14.2) ] .
In the ADHD clinical trials, 2,529 pediatric patients were treated for over 6 months, which included 1,625 pediatric patients who were treated for longer than 1 year.
Adverse Reactions in the Clinical Trials of Pediatric Patients 6 Years of Age and Older with ADHD Discontinuation of Treatment Due to Adverse Reactions in the Clinical Studies of Pediatric Patients 6 Years of Age and Older: In the acute placebo-controlled studies of pediatric patients 6 years of age and older with ADHD, 3% (48/1,613) of atomoxetine capsules-treated pediatric patients and 1.4% (13/945) of placebo-treated pediatric patients discontinued due to an adverse reaction.
Among atomoxetine capsules-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.
For all studies, (including open-label and long-term studies), 6% of atomoxetine capsules-treated pediatric patients who were other CYP2D6 metabolizer types (ultrarapid, normal, and intermediate) and 11% of those who were CYP2D6 poor metabolizers discontinued due to an adverse reaction.
Common Adverse Reactions in the Clinical Studies of Pediatric Patients 6 Years of Age and Older: Common adverse reactions (incidence of 2% or greater in atomoxetine capsules-treated patients and with a higher incidence in atomoxetine capsules-treated patients compared to placebo-treated patients) in pediatric patients 6 years of age and older with ADHD are listed in Table 3.
The most commonly observed adverse reactions in atomoxetine capsules-treated patients (incidence of ≥5% and ≥twice the incidence in placebo-treated patients), for either twice daily or once daily dosing were: nausea, vomiting, fatigue, decreased appetite, abdominal pain, and somnolence (see Tables 3 and 4).
Table 3: Common Adverse Reactions a in Acute Studies (up to 18 weeks) in Pediatric Patients 6 Years and Older with ADHD Atomoxetine Capsules (N=1,597) Placebo (N=934) Headache 19% 15% Abdominal pain b 18% 10% Decreased appetite 16% 4% Somnolence c 11% 4% Vomiting 11% 6% Nausea 10% 5% Fatigue 8% 3% Irritability 6% 3% Dizziness 5% 2% Decrease weight 3% 0% Anorexia 3% 1% Rash 2% 1% a Adverse reactions reported by at least 2% of atomoxetine capsules-treated patients and greater than placebo-treated patients.
b Abdominal pain includes the terms: upper abdominal pain and epigastric discomfort.
c Somnolence includes the term sedation.
Adverse reaction in the atomoxetine capsules-treated patients who received twice daily, and once daily dosing are shown in Table 4 (adverse reactions based on statistically significant Breslow-Day tests).
Table 4: Common Adverse Reactions in Acute studies (up to 18 weeks) in Pediatric Patients 6 Years and Older with ADHD ADHD Studies with Twice Daily Dosing ADHD Studies with Once Daily Dosing Atomoxetine Capsules (N=715) Placebo (N=434) Atomoxetine Capsules (N=882) Placebo (N=500) Abdominal pain a 17% 13% 18% 7% Vomiting 11% 8% 11% 4% Nausea 7% 6% 13% 4% Fatigue 6% 4% 9% 2% Mood swings b 2% 0% 1% 1% Constipation c 2% 1% 1% 0% a Abdominal pain includes the terms: upper abdominal pain upper, epigastric discomfort.
b Mood swings didn’t meet the statistical significance on Breslow-Day test at 0.05 level, but p-value was <0.1 (trend).
c Constipation didn’t meet the statistical significance on Breslow-Day test but is included in the table because of pharmacologic plausibility.
Common Adverse Reactions by CYP2D6 Metabolizer Status in the Clinical Studies of Pediatric Patients 6 Years of Age and Older: Table 5 displays adverse reactions occurred in at least 2% of atomoxetine capsules-treated pediatric patients who were CYP2D6 poor metabolizers and were statistically significantly more frequent in CYP2D6 poor metabolizers compared with other CYP2D6 metabolizer types (ultrarapid, normal, and intermediate).
Table 5: Common Adverse Reactions a in Acute Studies (up to 18 weeks) in Atomoxetine Capsules-Treated Pediatric Patients 6 Years and Older with ADHD by CYP2D6 Metabolizer Types Atomoxetine Capsules CYP2D6 Poor Metabolizers (N=5,019) Atomoxetine Capsules Other CYP2D6 Metabolizer Types (N=355) Insomnia 11% 6% Decreased weight 7% 4% Constipation 7% 4% Depression b 7% 4% Tremor 5% 1% Excoriation 4% 2% Sedation 4% 2% Middle insomnia 3% 1% Conjunctivitis 3% 1% Syncope 3% 1% Early morning awakening 2% 1% Mydriasis 2% 1% a Adverse reactions that occurred in at least 2% of atomoxetine capsules-treated pediatric patients who were CYP2D6 poor metabolizers and were statistically significantly more frequent in poor metabolizers compared with other CYP2D6 metabolizer types (ultrarapid, normal, and intermediate).
b Depression included the following terms: major depression, depressive symptoms, depressed mood, dysphoria.
Less Common Adverse Reactions in the Clinical Studies of Pediatric Patients 6 Years of Age and Older: The following reactions did not meet this criterion but were reported by more atomoxetine capsules-treated patients than placebo-treated patients and are possibly related to atomoxetine capsules 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.
Seizures in the Clinical Studies of Pediatric Patients 6 Years of Age and Older: Atomoxetine has not been systematically evaluated in pediatric patients with seizure disorder as these patients were excluded from clinical studies in the atomoxetine capsules studies.
In the clinical development program, seizures were reported in 0.2% (12/5,073) of atomoxetine capsules-treated pediatric patients whose average age was 10 years old (range 6 to 16 years of age).
In these clinical trials, for atomoxetine capsules-treated pediatric patients the seizure incidence among CYP2D6 poor metabolizers was 0.3% (1/293) compared to 0.2% (11/4,741) for other CYP2D6 metabolizer types.
Heart Rate and Blood Pressure Increases in the Clinical Studies of Pediatric Patients 6 Years of Age and Older: Additional data from ADHD clinical trials (controlled and uncontrolled) has shown that approximately 5 to 10% of pediatric patients treated with atomoxetine capsules experienced potentially clinically important changes in heart rate (≥20 beats per minute) or blood pressure (≥15 to 20 mm Hg) [see Contraindications (4) and Warnings and Precautions (5.4) ] .
Adverse Reactions in the Clinical Studies of Adults with ADHD Discontinuation of Treatment Due to Adverse Reactions in the Clinical Studies of Adults: In the acute adult placebo-controlled trials, 11% (61/541) atomoxetine capsules-treated pediatric patients and 3% (12/405) of placebo-treated patients discontinued for adverse reactions.
Among atomoxetine capsules-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.
Common Adverse Reactions in the Clinical Studies of Adults: Commonly observed adverse reactions associated with the use of atomoxetine capsules (incidence of 2% or greater) and not observed at an equivalent incidence among placebo-treated patients (atomoxetine capsules incidence greater than placebo) are listed in Table 6.
The most commonly observed adverse reactions in patients treated with atomoxetine capsules (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 6).
Table 6: Common Adverse Reactions a Associated in Acute Studies (up to 25 weeks) of Adult Patients with ADHD Atomoxetine Capsules (N=1697) Placebo (N=1560) Nausea 26% 6% Dry mouth 20% 5% Decreased appetite 16% 3% Insomnia d 15% 8% Fatigue 10% 6% Erectile dysfunction f 8% 1% Constipation 8% 3% Dizziness 8% 3% Somnolence c 8% 5% Abdominal pain b 7% 4% Urinary hesitation e 6% 1% Irritability 5% 3% Ejaculation delayedf and/or ejaculation disorder f 4% 1% Hyperhidrosis 4% 1% Dyspepsia 4% 2% Vomiting 4% 2% Abnormal dreams 4% 3% Chills 3% 0% Paraesthesia 3% 0% Hot flush 3% 0% Palpitations 3% 1% Libido decreased 3% 1% Sleep disorder 3% 1% Dysmenorrhea g 3% 2% Dysuria 2% 0% Thirst 2% 1% Weight decreased 2% 1% Feeling jittery 2% 1% a Reactions reported by at least 2% of patients treated with atomoxetine capsules, 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.
b Abdominal pain includes the terms: abdominal pain upper, abdominal pain, stomach discomfort, abdominal discomfort, epigastric discomfort.
c Somnolence includes the term sedation.
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 capsules, N=943; placebo, N=869).
g Based on total number of females (atomoxetine capsules, N=754; placebo, N=691).
Common Adverse Reactions by CYP2D6 Metabolizer Status in the Clinical Studies of Adults: Table 7 displays adverse reactions that occurred in at least 2% of atomoxetine capsules-treated adult patients who were CYP2D6 poor metabolizers and were statistically significantly more frequent compared to other CYP2D6 metabolizer types (ultrarapid, normal, and intermediate).
Table 7: Common Adverse Reactions a in Acute Studies (up to 18 weeks) in Atomoxetine Capsules-Treated Adults with ADHD by CYP2D6 Metabolizer Types Atomoxetine Capsules CYP2D6 Poor Metabolizers (N=203) Atomoxetine Capsules Other CYP2D6 Metabolizer Types (N=3,599) Dry mouth 35% 17% Decreased appetite 23% 15% Erectile dysfunction 21% 9% Insomnia 19% 11% Hyperhidrosis 15% 7% Constipation 11% 7% Sleep disorder 7% 3% Urinary retention 6% 1% Ejaculation disorder 6% 2% Tremor 5% 1% Feeling jittery 5% 2% Middle insomnia 5% 3% Blurred vision 4% 1% Terminal insomnia 3% 1% Peripheral coldness 3% 1% a Adverse reactions that occurred in at least 2% of atomoxetine capsules-treated pediatric patients who were CYP2D6 poor metabolizers and were statistically significantly more frequent in CYP2D6 poor metabolizers compared with other CYP2D6 metabolizer types (ultrarapid, normal, and intermediate).
Less Common Adverse Reactions in the Clinical Studies of Adults: The following reactions did not meet this criterion but were reported by more atomoxetine capsules-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.
Seizures in the Clinical Studies of Adults: Atomoxetine 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 treated with atomoxetine capsules.
In these clinical trials, no CYP2D6 poor metabolizers (0/43) reported seizures compared to 0.1% (1/705) for other CYP2D6 metabolizer types.
Heart Rate and Blood Pressure Increases in the Clinical Studies of Adults: Table 8 displays the proportion of atomoxetine capsules-treated and placebo-treated patients who had an increase in diastolic blood pressure (DBP) ≥15 mm Hg, systolic blood pressure (SBP) ≥20 mm Hg, or heart rate ≥ 20 bpm in short-term, placebo-controlled clinical studies of in pediatric and adult patients with ADHD [see Warnings and Precautions (5.4) ] .
Table 8: Proportion of ADHD Patients With an Increase ≥15 mm Hg in DBP, ≥20 mm Hg in SBP, or ≥20 bpm in Heart Rate a Pediatric Acute ADHD Studies Adult Acute ADHD Studies Maximum b Endpoint Maximum b Endpoint Atomoxetine Capsules Placebo Atomoxetine Capsules Placebo Atomoxetine Capsules Placebo Atomoxetine Capsules Placebo DBP (≥15 mm Hg) 22% 14% 9% 5% 13% 9% 5% 4% SBP (≥20 mm Hg) 13% 9% 5% 3% 12% 8% 4% 3% HR (≥20 bpm) 23% 12% 12% 4% 22% 8% 10% 2% a Abbreviations: bpm=beats per minute; DBP=diastolic blood pressure; HR=heart rate; mm Hg=millimeters mercury; SBP=systolic blood pressure.
b Proportion of patients meeting threshold at any one time during the clinical studies.
Additional data from ADHD clinical trials (controlled and uncontrolled) showed that approximately 5 to 10% of adult patients treated with atomoxetine capsules had potentially clinically important changes in heart rate (≥20 beats per minute) or blood pressure (≥15 to 20 mm Hg) [see Contraindications (4) and Warnings and Precautions (5.4) ] .
Male and Female Sexual Dysfunction in the Clinical Studies of Adults: Atomoxetine capsules impaired sexual function in some patients.
Estimates of the incidence of untoward sexual experience and performance in these studies are likely to underestimate their actual incidence because patients and health care providers may be reluctant to discuss them.
Sexual adverse reactions reported by at least 2% of atomoxetine capsules-treated adult patients in the placebo-controlled studies of adults with ADHD (i.e., erectile dysfunction, dysmenorrhea, and ejaculation delayed and/or ejaculation disorder).
There are no adequate and well-controlled studies examining sexual dysfunction with atomoxetine treatment.
While it is difficult to know the precise risk of sexual dysfunction associated with the use of atomoxetine, health care providers should routinely inquire about sexual dysfunction.
6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of atomoxetine.
Unless otherwise specified, these adverse reactions have occurred in adults and pediatric patients.
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 pediatric patients; sensory disturbances; tics.
Psychiatric disorders: Depression and depressed mood; anxiety, libido changes.
Seizures: Seizures have been reported and included patients with pre-existing seizure disorders, those with identified risk factors for seizures, and patients with neither a history of nor identified risk factors for seizures.
The exact relationship between atomoxetine 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 pediatric patients; urinary retention in pediatric patients.