Atomoxetine

Atomoxetine capsules are indicated for the treatment of attention-deficit/hyperactivity disorder (ADHD) in adults and pediatric patients 6 years of age and older. Atomoxetine capsules 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 capsules are selective norepinephrine reuptake inhibitor (SNRI) indicated for the treatment of ADHD in adults and pediatric patients 6 years of age and older. ( 1 )

Capsules:

• 10 mg of atomoxetine (Opaque White, Opaque White)
• 18 mg of atomoxetine (Opaque Yellow, Opaque White)
• 25 mg of atomoxetine (Opaque Blue, Opaque White)
• 40 mg of atomoxetine (Opaque Blue, Opaque Blue)
• 60 mg of atomoxetine (Opaque Blue, Opaque Yellow)
• 80 mg of atomoxetine (Opaque Reddish Brown, Opaque White)
• 100 mg of atomoxetine (Opaque Reddish Brown, Opaque Reddish Brown) Capsules: contain 10 mg, 18 mg, 25 mg, 40 mg, 60 mg, 80 mg, or 100 mg of atomoxetine. ( 3 , 11 , 16 )

Atomoxetine capsules is contraindicated in patients:

• With known hypersensitivity reaction to atomoxetine capsules or other constituents of atomoxetine capsules. Hypersensitivity reactions included anaphylaxis, angioneurotic edema, urticaria, and rash [see Warnings and Precautions ( 5.8 )] .
• Taking, or within 14 days of stopping, a monoamine oxidase inhibitor (MAOI) [see Drug Interactions ( 7 )] .
• With narrow angle glaucoma. In clinical trials, atomoxetine capsules use was associated with an increased risk of mydriasis.
• With pheochromocytoma or a history of pheochromocytoma. Serious reactions, including elevated blood pressure and tachyarrhythmia, have been reported in patients with pheochromocytoma or a history of pheochromocytoma who received atomoxetine capsules.
• With severe cardiac or vascular disorders whose condition would be expected to deteriorate if they had a clinically important increase in blood pressure or heart rate (e.g., 15 to 20 mm Hg in blood pressure or 20 beats per minute in heart rate) [ see Warnings and Precautions ( 5.4 ) ]. Contraindicated in patients (4):
• With known hypersensitivity to atomoxetine or other constituents of atomoxetine
• Taking or within 14 days of stopping, a monoamine oxidase inhibitor (MAOI)
• With narrow angle glaucoma
• With pheochromocytoma or history of pheochromocytoma
• With severe cardiac or vascular disorders whose condition would be expected to deteriorate with clinically important increases in blood pressure or heart rate

• Severe Liver Injury: atomoxetine should be discontinued and not restarted in patients with jaundice or laboratory evidence of liver injury. ( 5.2 )
• Serious Cardiovascular Reactions : Prior to atomoxetine treatment, patients should have a careful history and physical exam to assess for presence of cardiovascular (CV) disease. atomoxetine generally should not be used in pediatric patients with known serious cardiac abnormalities, cardiomyopathy, serious arrhythmias. Consideration should be given to not using atomoxetine in adults with clinically significant cardiac abnormalities. Patients who develop symptoms suggestive of cardiac disease during atomoxetine treatment should stop atomoxetine and undergo a prompt cardiac evaluation. ( 5.3 )
• Increase in Blood Pressure and Heart Rate : Heart rate and blood pressure should be measured at baseline, following atomoxetine dosage increase, and periodically while on therapy. ( 5.4 )
• New Psychotic or Manic Symptoms and Activation of Mania: If psychotic or manic symptoms occur, consider discontinuing atomoxetine. ( 5.5 )
• Aggressive Behavior or Hostility: Monitor for the appearance or worsening of aggressive behavior or hostility. ( 5.7 )
• Effects on Urine Outflow: Urinary retention or hesitancy may occur. ( 5.9 )
• Priapism: Prompt medical attention is required in the event of suspected priapism. ( 5.10 )
• Effect on Growth in Pediatric Patients: Closely monitor growth (e.g., weight, height) in pediatric patients. ( 5.11 )

5.1 Suicidal Thoughts and Behaviors in Pediatric Patients 6 Years of Age and Older

• All atomoxetine-treated pediatric patients should be monitored and observed closely for clinical worsening, suicidal thoughts and behavior, and unusual changes in behavior, especially during the initial few months of atomoxetine therapy, or at times of dosage changes, either increases or decreases.
• Families and caregivers of atomoxetine-treated pediatric patients should be alerted about the need to monitor patients daily for the emergence of agitation, irritability, unusual changes in behavior, and mental health-related symptoms, as well as the emergence of suicidal thoughts and behavior, and to report such symptoms immediately to a health care provider.
• Consider changing the therapeutic regimen, including stopping atomoxetine, in patients who experience emergent suicidality or symptoms that might be precursors to emerging suicidal thoughts and behavior, especially if these symptoms are severe or abrupt in onset, or were not part of the patient’s presenting symptoms. Atomoxetine increased the risk of suicidal ideation in pediatric patients 6 years and older with ADHD in pooled placebo-controlled short-term studies (6 to 18 weeks). In 12 studies (11 studies in patients with ADHD and 1 study in another population) with over 2,200 pediatric patients, the mean incidence of suicidal ideation in atomoxetine-treated pediatric patients was 0.4% (5/1,357) (including one patient with a suicide attempt) compared to 0% (0/851) in placebo-treated pediatric patients. No suicides occurred in these studies. All the suicidal ideations occurred in pediatric patients 6 to 12 years of age, and all occurred during the first month of atomoxetine 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 for ADHD did not reveal an increased risk of suicidal ideation or behavior. The following psychiatric symptoms have been reported with atomoxetine: 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.

5.2 Severe Liver Injury Atomoxetine should be discontinued and not restarted in patients with jaundice or laboratory evidence of liver injury, Liver enzyme and function tests should be obtained upon the first symptom or sign of liver dysfunction (e.g., pruritus, dark urine, jaundice, right upper quadrant tenderness, or unexplained “flu like” symptoms). Postmarketing reports indicate that atomoxetine 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 use during postmarketing use.

• Rare cases of liver failure have been reported during postmarketing use, including a case that resulted in a liver transplant.
• Reported cases of liver injury occurred within 120 days of initiation of atomoxetine in most cases and some patients presented with markedly elevated liver enzymes (>20 times upper limit of normal (ULN)), and jaundice with significantly elevated bilirubin levels (>2 times ULN), followed by recovery upon atomoxetine discontinuation. In one patient, liver injury, manifested by elevated hepatic enzymes up to 40 times ULN and jaundice with bilirubin up to 12 times ULN, recurred upon rechallenge, and was followed by recovery upon atomoxetine discontinuation, providing evidence that atomoxetine likely caused the liver injury. Such reactions may occur several months after atomoxetine is started, but laboratory abnormalities may continue to worsen for several weeks after atomoxetine is stopped.

5.3 Serious Cardiovascular Reactions Risk Management Recommendations for Serious Cardiovascular Reactions Prior to atomoxetine treatment, adults or pediatric patients 6 years of age or older 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 cardiovascular disease, and should receive further cardiac evaluation if findings suggest such disease (e.g., electrocardiogram echocardiogram).

• Although some serious heart problems alone carry an increased risk of sudden death, atomoxetine generally should not be used in pediatric patients with known serious structural cardiac abnormalities, cardiomyopathy, serious arrhythmias, or other serious cardiac problems.
• Consideration should be given to not treating adults with atomoxetine with clinically significant cardiac abnormalities. Patients who develop symptoms such as exertional chest pain, unexplained syncope, or other symptoms suggestive of cardiac disease during atomoxetine treatment should stop atomoxetine and undergo a prompt cardiac evaluation. Sudden Death and Pre-existing Structural Cardiac Abnormalities or Other Serious Heart Problems Pediatric Patients 6 Years of Age and Older: Sudden death has been reported in association with atomoxetine treatment at the recommended dosage in pediatric patients 6 years of age and older with structural cardiac abnormalities or other serious heart problems. Adults: Sudden deaths, stroke, and myocardial infarction have been reported in atomoxetine-treated adults at the recommended ADHD dosage. Although the role of atomoxetine in these adult cases is also unknown, adults have a greater likelihood than pediatric patients of having serious structural cardiac abnormalities, cardiomyopathy, serious arrhythmias, coronary artery disease, or other serious cardiac problems.

5.4 Increase in Blood Pressure and Heart Rate atomoxetine is contraindicated in patients with severe cardiac or vascular disorders whose condition would be expected to deteriorate if they had a clinically important increase in blood pressure or heart rate Atomoxetine 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. […]

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 . ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Northstar Rx LLC at 1800-206-7821 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. Atomoxetine was 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-treated pediatric patients and 1.4% (13/945) of placebo-treated pediatric patients discontinued due to an adverse reaction. Among atomoxetine-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-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-treated patients and with a higher incidence in atomoxetine-treated patients compared to placebo-treated patients) in pediatric patients 6 years of age and older with ADHD are listed in Table 2. The most commonly observed adverse reactions in atomoxetine-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 2 and 3). Table 2: Common Adverse Reactionsa in Acute Studies (up to 18 weeks) in Pediatric Patients 6 Years and Older with ADHD Adverse Reaction Atomoxetine (N=1,597) Placebo (N=934) Headache 19% 15% Abdominal painb 18% 10% Decreased appetite 16% 4% Somnolencec 11% 4% Vomiting 11% 6% Nausea 10% 5% Fatigue 8% 3% Irritability 6% 3% Dizziness 5% 2% Decreased weight 3% 0% Anorexia 3% 1% Rash 2% 1% a. Adverse reactions reported by at least 2% of atomoxetine-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-treated patients who received twice daily, and once daily dosing are shown in Table 3 (adverse reactions based on statistically significant Breslow-Day tests). Table 3: Common Adverse Reactions in Acute Studies (up to 18 weeks) in Pediatric Patients 6 Years and Older with ADHD Adverse Reaction ADHD Studies with Twice Daily Dosing ADHD Studies with Once Daily Dosing Atomoxetine (N=715) Placebo (N=434) Atomoxetine (N=882) Placebo (N=500) Abdominal paina 17% 13% 18% 7% Vomiting 11% 8% 11% 4% Nausea 7% 6% 13% 4% Fatigue 6% 4% 9% 2% Mood swingsb 2% 0% 1% 1% Constipationc 2% 1% 1% 0% a. Abdominal pain included the terms: upper abdominal pain, and 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 4 displays adverse reactions that occurred in at least 2% of atomoxetine-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 4: Common Adverse Reactions a in atomoxetine-treated Pediatric Patients 6 Years and Older with ADHD by CYP2D6 Metabolizer Types Adverse Reaction Atomoxetine CYP2D6 Poor Metabolizers (N=355) Atomoxetine Other CYP2D6 Metabolizer Types(N=5,019) Insomnia 11% 6% Decreased weight 7% 4% Constipation 7% 4% Depressionb 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-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-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. 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 atomoxetine studies. In the clinical development program, seizures were reported in 0.2% (12/5,073) of atomoxetine-treated pediatric patients whose average age was 10 years old (range 6 to 16 years of age). In these clinical trials, 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 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 )] . […]

See Table 8 for clinically significant drug interactions with atomoxetine and other drugs. Table 8: Clinically Significant Drug Interactions with atomoxetine and Other Drugs Monoamine Oxidase Inhibitors (MAOIs) Prevention or Management Atomoxetine is contraindicated in patients taking MAOIs, including MAOIs such as linezolid or intravenous methylene blue, or in patients who stopped an MAOI within 14 days. Mechanism and Clinical Effect(s) As with other drugs affecting brain monoamine concentrations, there have been reports of serious, sometimes fatal reactions (hyperthermia, rigidity, myoclonus, autonomic instability with fluctuations of vital signs, extreme agitation progressing to delirium/coma) with concomitant use of atomoxetine and an MAOI. Some cases presented with features resembling neuroleptic malignant syndrome. Strong CYP2D6 Inhibitors Prevention or Management With concomitant use of atomoxetine and a strong CYP2D6 inhibitor, increase the titration interval [see Dosage and Administration ( 2.5 ) and Clinical Pharmacology (12.3)]. Mechanism and Clinical Effect(s) Atomoxetine is a CYP2D6 substrate. The concomitant use of atomoxetine and a strong CYP2D6 inhibitor increases atomoxetine exposure [see Clinical Pharmacology ( 12.3 )] . Antihypertensive Drugs Prevention or Management Increase the frequency of monitoring blood pressure and adjust atomoxetine dosage as clinically appropriate. Mechanism and Clinical Effect(s) Because of increased risk of increased blood pressure, atomoxetine should be used cautiously with antihypertensive drugs, other drugs that increase blood pressure or pressor drugs (e.g., dopamine, dobutamine). Albuterol or Other Beta2 Agonists Prevention or Management Increase the frequency of monitoring blood pressure and heart rate and adjust atomoxetine dosage as clinically appropriate. Mechanism and Clinical Effect(s) Systemically administered albuterol (e.g., oral) can be potentiated by atomoxetine, resulting in increases in heart rate and blood pressure. [see Clinical Pharmacology ( 12.3 )].

• Monoamine Oxidase Inhibitors: Concomitant use contraindicated. ( 7 )
• Strong CYP2D6 Inhibitors: With concomitant use of atomoxetine and strong CYP2D6 inhibitors, increase the titration intervals. ( 7 )
• Antihypertensives: Increase the frequency of monitoring blood pressure and adjust atomoxetine dosage as clinically appropriate. ( 7 )
• Albuterol (or other beta 2 agonists) : Increase the frequency of monitoring blood pressure and heart rate. ( 7 )

• Hepatic Impairment: Increased exposure (AUC) to atomoxetine in subjects with moderate (Child-Pugh Class B) (2-fold increase) and severe (Child-Pugh Class C) (4-fold increase). compared to subjects with normal liver function. ( 8.6 and 12.3 )
• Use in Genomic Subgroups: CYP2D6 poor metabolizers have higher systemic exposures which may increase the risks of atomoxetine-related adverse reactions compared to other CYP2D6 metabolizer types (ultrarapid, normal, and intermediate) ( 8.7 )

8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to ADHD drugs, including atomoxetine, during pregnancy. Healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for ADHD Medications at 1-866-961-2388 or visiting https://womensmentalhealth.org/adhd-medications/ . Risk Summary Available published studies with atomoxetine use in pregnant women are insufficient to establish a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. Some animal reproduction studies of atomoxetine had adverse developmental outcomes. One of 3 studies in pregnant rabbits dosed during organogenesis resulted in decreased live fetuses and an increase in early resorptions, as well as slight increases in the incidences of atypical origin of carotid artery and absent subclavian artery. These effects were observed at plasma levels (AUC) 3 times and 0.4 times the human plasma levels in other CYP2D6 metabolizer types (ultrarapid, normal, and intermediate) and poor metabolizers receiving the maximum recommended human dose (MRHD), respectively. In rats dosed prior to mating and during organogenesis a decrease in fetal weight (female only) and an increase in the incidence of incomplete ossification of the vertebral arch in fetuses were observed at a dose approximately 5 times the MRHD on a mg/m 2 basis. In one of 2 studies in which rats were dosed prior to mating through the periods of organogenesis and lactation, decreased pup weight and decreased pup survival were observed at doses corresponding to 5 to 6 times the MRHD on a mg/m 2 basis. No adverse fetal effects were seen in pregnant rats dosed during the organogenesis period (see Data) . The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Data Animal Data : Pregnant rabbits were treated with up to 100 mg/kg/day of atomoxetine by gavage throughout the period of organogenesis. At this dose, in 1 of 3 studies, a decrease in live fetuses and an increase in early resorptions was observed. Slight increases in the incidences of atypical origin of carotid artery and absent subclavian artery were observed. These findings were observed at doses that caused slight maternal toxicity. The no-effect dose for these findings was 30 mg/kg/day. The 100 mg/kg dose is approximately 23 times the MRHD on a mg/m 2 basis; plasma levels (AUC) of atomoxetine at this dose in rabbits are estimated to be 3.3 times (other CYP2D6 metabolizer types) or 0.4 times (CYP2D6 poor metabolizers) those in humans receiving the MRHD. Rats were treated with up to approximately 50 mg/kg/day of atomoxetine (approximately 6 times the MRHD on a mg/m 2 basis) in the diet from 2 weeks (females) or 10 weeks (males) prior to mating through the periods of organogenesis and lactation. In 1 of 2 studies, decreases in pup weight and pup survival were observed. The decreased pup survival was also seen at 25 mg/kg (but not at 13 mg/kg). In a study in which rats were treated with atomoxetine in the diet from 2 weeks (females) or 10 weeks (males) prior to mating throughout the period of organogenesis, a decrease in fetal weight (female only) and an increase in the incidence of incomplete ossification of the vertebral arch in fetuses were observed at 40 mg/kg/day (approximately 5 times the MRHD on a mg/m 2 basis) but not at 20 mg/kg/day. No adverse fetal effects were seen when pregnant rats were treated with up to 150 mg/kg/day (approximately 17 times the MRHD on a mg/m 2 basis) by gavage throughout the period of organogenesis.

8.2 Lactation Risk Summary There are no data on the presence of atomoxetine or its metabolite in human milk, the effects on the breastfed child, or the effects on milk production. Atomoxetine is present in animal milk. When a drug is present in animal milk, it is likely that the drug will be present in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for atomoxetine and any potential adverse effects on the breastfed child from atomoxetine or from the underlying maternal condition.

8.4 Pediatric Use The safety and effectiveness of atomoxetine for the treatment of ADHD have been established in pediatric patients 6 years of age and older. Anyone considering the use of atomoxetine in a pediatric patient should balance the potential risks with the clinical need [see Boxed Warning and Warnings and Precautions ( 5.1 , 5.3 , 5.4 , 5.10 )]. The atomoxetine pharmacokinetics in pediatric patients 6 years of age and older were similar to those in adults. The safety and effectiveness of atomoxetine in pediatric patients less than 6 years of age have not been established. Juvenile Toxicity Animal Data A study was conducted in young rats to evaluate the effects of atomoxetine on growth and neurobehavioral and sexual development. Rats were treated with 1, 10, or 50 mg/kg/day (approximately 0.2, 2, and 8 times, respectively, the maximum human dose on a mg/m 2 basis) of atomoxetine given by gavage from the early postnatal period (Day 10 of age) through adulthood. Slight delays in onset of vaginal patency (all doses) and preputial separation (10 and 50 mg/kg), slight decreases in epididymal weight and sperm number (10 and 50 mg/kg), and a slight decrease in corpora lutea (50 mg/kg) were seen, but there were no effects on fertility or reproductive performance. A slight delay in onset of incisor eruption was seen at 50 mg/kg. A slight increase in motor activity was seen on Day 15 (males at 10 and 50 mg/kg and females at 50 mg/kg) and on Day 30 (females at 50 mg/kg) but not on Day 60 of age. There were no effects on learning and memory tests. The significance of these findings to humans is unknown.

8.5 Geriatric Use The safety, efficacy and pharmacokinetics of atomoxetine in geriatric patients have not been evaluated. Clinical studies of atomoxetine did not include sufficient numbers of patients 65 years of age and older to determine whether they respond differently from younger adult patients.

8.6 Patients with Hepatic Impairment Compared with patients with normal hepatic function atomoxetine exposure (AUC) was increased in patients with moderate (Child-Pugh Class B) (2-fold increase) and in patients with severe hepatic impairment (Child-Pugh Class C) (4fold increase). The recommended dosage in patients with moderate or severe hepatic impairment is lower than in patients with normal hepatic function [see Dosage and Administration (2.4) and Clinical Pharmacology ( 12.3 )] .

8.7 Use in Genomic Subgroups The recommended titration interval (before increasing the atomoxetine dosage) is longer in CYP2D6 poor metabolizers than other CYP2D6 metabolizer types (ultrarapid, normal, and intermediate) [see Dosage and Administration ( 2.5 )] . Atomoxetine plasma concentrations were higher in CYP2D6 poor metabolizers which may increase the risk of atomoxetine-related adverse reactions. In pediatric and adult patients, the mean heart rate was higher in CYP2D6 poor metabolizers compared to other CYP2D6 metabolizer types. […]

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