STRATTERA

Atomoxetine, USP is a selective norepinephrine reuptake inhibitor.

Atomoxetine hydrochoride is the

R (-) isomer as determined by x-ray diffraction.

The chemical designation is (-).

• N -Methyl-3-phenyl-3-( o -tolyloxy)-propylamine hydrochloride.

The molecular formula is

C 17 H 21 NO•HCl, which corresponds to a molecular weight of 291.81.

The chemical structure is

Atomoxetine hydrochloride, USP is a white to off-white crystalline powder.

Sparingly soluble in water.

Atomoxetine capsules, USP are intended for oral administration only.

Each capsule contains atomoxetine hydrochloride, USP equivalent to 10, 18, 25, 40, 60, 80, and 100 mg of atomoxetine.

The capsules also contain dimethicone and pregelatinized starch.

The capsule shells contain gelatin, sodium lauryl sulfate, titanium dioxide, FD &C Blue 2 (25 mg, 40 mg, 60 mg), iron oxide red (80 mg, 100 mg) and iron oxide yellow (18 mg, 60 mg, 80 mg, 100 mg).

The imprinting edible black ink contains black iron oxide, potassium hydroxide, propylene glycol, shellac, strong ammonia solution.

The botanical source for

Pregelatinized starch is corn starch. structure.

Atomoxetine capsule is a selective norepinephrine reuptake inhibitor indicated for the treatment of Attention-Deficit/Hyperactivity Disorder (ADHD). 1.1 Attention-Deficit/Hyperactivity Disorder (ADHD) Atomoxetine capsule is 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 to 9-week trials in pediatric patients (ages to 18), two 10-week trial in adults, and one maintenance trial in pediatrics (ages to 15) . 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.

Type, at least 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.

Type, at least 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.

Type diagnosis, both inattentive and hyperactive-impulsive criteria must be met. 1.3 Need for Comprehensive Treatment Program Atomoxetine capsule is 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.

The precise mechanism by which atomoxetine produces its therapeutic effects in Attention-Deficit/Hyperactivity Disorder (ADHD) is unknown, but is thought to be related to selective inhibition of the pre-synaptic norepinephrine transporter, as determined in ex vivo uptake and neurotransmitter depletion studies. 12.2 Pharmacodynamics An exposure-response analysis encompassing doses of atomoxetine (0.5, 1.2 or 1.8 mg/kg/day) or placebo demonstrated atomoxetine exposure correlates with efficacy as measured by the Attention-Deficit/Hyperactivity Disorder Rating Scale-IV-Parent Version: Investigator administered and scored.

The exposure-efficacy relationship was similar to that observed between dose and efficacy with median exposures at the two highest doses resulting in near maximal changes from baseline.

Electrophysiology — The effect of atomoxetine on QTc prolongation was evaluated in a randomized, double-blinded, positive-(moxifloxacin 400 mg) and placebo-controlled, cross-over study in healthy male CYP2D6 poor metabolizers.

A total of 120 healthy subjects were administered atomoxetine (20 mg and 60 mg) twice daily for 7 days.

No large changes in

QTc interval (i.e., increases >60 msec from baseline, absolute QTc >480 msec) were observed in the study.

However, small changes in QTc interval cannot be excluded from the current study, because the study failed to demonstrate assay sensitivity.

There was a slight increase in

QTc interval with increased atomoxetine concentration. 12.3 Pharmacokinetics Atomoxetine is well-absorbed after oral administration and is minimally affected by food.

It is eliminated primarily by oxidative metabolism through the cytochrome P450 2D6 (CYP2D6) enzymatic pathway and subsequent glucuronidation.

Atomoxetine has a half-life of about 5 hours.

A fraction of the population (about 7% of Caucasians and 2% of African Americans) are poor metabolizers (PMs) of CYP2D6 metabolized drugs.

These individuals have reduced activity in this pathway resulting in 10-fold higher AUCs, 5-fold higher peak plasma concentrations, and slower elimination (plasma half-life of about 24 hours) of atomoxetine compared with people with normal activity [extensive metabolizers (Ems).

Drugs that inhibit

CYP2D6, such as fluoxetine, paroxetine, and quinidine, cause similar increases in exposure.

The pharmacokinetics of atomoxetine have been evaluated in more than 400 children and adolescents in selected clinical trials, primarily using population pharmacokinetic studies.

Single-dose and steady-state individual pharmacokinetic data were also obtained in children, adolescents, and adults.

When doses were normalized to a mg/kg basis, similar half-life, C max, and AUC values were observed in children, adolescents, and adults.

Clearance and volume of distribution after adjustment for body weight were also similar.

Absorption and distribution — Atomoxetine is rapidly absorbed after oral administration, with absolute bioavailability of about 63% in Ems and 94% in PMs.

Maximal plasma concentrations (C max ) are reached approximately to 2 hours after dosing.

Atomoxetine can be administered with or without food.

Administration of atomoxetine with a standard high-fat meal in adults did not affect the extent of oral absorption of atomoxetine (AUC), but did decrease the rate of absorption, resulting in a 37% lower C max, and delayed T max by 3 hours.

In clinical trials with children and adolescents, administration of atomoxetine with food resulted in a 9% lower C max.

The steady-state volume of distribution after intravenous administration is 0.85 L/kg indicating that atomoxetine distributes primarily into total body water.

Volume of distribution is similar across the patient weight range after normalizing for body weight.

At therapeutic concentrations, 98% of atomoxetine in plasma is bound to protein, primarily albumin.

Metabolism and elimination — Atomoxetine is metabolized primarily through the CYP2D6 enzymatic pathway.

People with reduced activity in this pathway (PMs) have higher plasma concentrations of atomoxetine compared with people with normal activity (Ems).

PMs, AUC of atomoxetine is approximately 10-fold and C ss, max is about 5-fold greater than Ems.

Laboratory tests are available to identify

Coadministration of atomoxetine with potent inhibitors of CYP2D6, such as fluoxetine, paroxetine, or quinidine, results in a substantial increase in atomoxetine plasma exposure, and dosing adjustment may be necessary.

Atomoxetine did not inhibit or induce the CYP2D6 pathway.

The major oxidative metabolite formed, regardless of CYP2D6 status, is 4-hydroxyatomoxetine, which is glucuronidated. 4-Hydroxyatomoxetine is equipotent to atomoxetine as an inhibitor of the norepinephrine transporter but circulates in plasma at much lower concentrations (1% of atomoxetine concentration in Ems and 0.1% of atomoxetine concentration in PMs). 4-Hydroxyatomoxetine is primarily formed by CYP2D6, but in PMs, 4-hydroxyatomoxetine is formed at a slower rate by several other cytochrome P450 enzymes.

N-Desmethylatomoxetine is formed by

CYP2C19 and other cytochrome P450 enzymes, but has substantially less pharmacological activity compared with atomoxetine and circulates in plasma at lower concentrations (5% of atomoxetine concentration in Ems and 45% of atomoxetine concentration in PMs).

Mean apparent plasma clearance of atomoxetine after oral administration in adult Ems is 0.35 L/hr/kg and the mean half-life is 5.2 hours.

Following oral administration of atomoxetine to

PMs, mean apparent plasma clearance is 0.03 L/hr/kg and mean half-life is 21.6 hours.

The elimination half-life of 4-hydroxyatomoxetine is similar to that of N-desmethylatomoxetine (6 to 8 hours) in EM subjects, while the half-life of N-desmethylatomoxetine is much longer in PM subjects (34 to 40 hours).

Atomoxetine is excreted primarily as 4-hydroxyatomoxetine.

• O -glucuronide, mainly in the urine (greater than 80% of the dose) and to a lesser extent in the feces (less than 17% of the dose).

Only a small fraction of the atomoxetine dose is excreted as unchanged atomoxetine (less than 3% of the dose), indicating extensive biotransformation. .

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.

• Adult Clinical Trials – Constipation, dry mouth, nausea, decreased appetite, dizziness, erectile dysfunction, and urinary hesitation.fda.gov/medwatch. 6.1 Clinical Trials Experience Atomoxetine 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.

Reasons for discontinuation of treatment due to adverse reactions in child and adolescent clinical trials — In acute child and adolescent placebo-controlled trials, 3.0% (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-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 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 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 (incidence of 2% or greater) and not observed at an equivalent incidence among placebo-treated patients (atomoxetine 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 (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.

Additional data from

ADHD clinical trials (controlled and uncontrolled) has shown that approximately 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) .

Table 2: Common Treatment-Emergent Adverse Reactions Associated with the Use of Atomoxetine in Acute (up to 18 weeks) Child and Adolescent Trials Adverse Reaction a Percentage of Patients Reporting Reaction Atomoxetine (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 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 (N=715) Placebo (N=434) Atomoxetine (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); depression1 (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). 1Depression includes the following terms: depression, major depression, depressive symptoms, depressed mood, dysphoria.

Reasons for discontinuation of treatment due to adverse reactions in acute adult placebo-controlled trials — In the acute adult placebo-controlled trials, 11.3% (61/541) atomoxetine subjects and 3% (12/405) placebo subjects discontinued for adverse reactions.

Among atomoxetine-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 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 trials — Commonly observed adverse reactions associated with the use of atomoxetine (incidence of 2% or greater) and not observed at an equivalent incidence among placebo-treated patients (atomoxetine incidence greater than placebo) are listed in Table 4.

The most commonly observed adverse reactions in patients treated with atomoxetine (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.

ADHD clinical trials (controlled and uncontrolled) has shown that approximately 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) .

Table 4: Common Treatment-Emergent Adverse Reactions Associated with the Use of Atomoxetine in Acute (up to 25 weeks) Adult Trials Adverse Reaction a Percentage of Patients Reporting Reaction Atomoxetine (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, N=943; placebo, N=869). g Based on total number of females (atomoxetine, 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 retentio.

There is limited clinical trial experience with atomoxetine overdose.

During postmarketing, there have been fatalities reported involving a mixed ingestion overdose of atomoxetine and at least one other drug.

There have been no reports of death involving overdose of atomoxetine alone, including intentional overdoses at amounts up to 1400 mg. In some cases of overdose involving atomoxetine, seizures have been reported.

The most commonly reported symptoms accompanying acute and chronic overdoses of atomoxetine were gastrointestinal symptoms, somnolence, dizziness, tremor, and abnormal behavior.

Hyperactivity and agitation have also been reported.

Signs and symptoms consistent with mild to moderate sympathetic nervous system activation (e.g., tachycardia, blood pressure increased, mydriasis, dry mouth) have also been observed.

Most events were mild to moderate.

Less commonly, there have been reports of QT prolongation and mental changes, including disorientation and hallucinations. 10.2 Management of Overdose Consult with a Certified Poison Control Center for up to date guidance and advice.

Because atomoxetine is highly protein-bound, dialysis is not likely to be useful in the treatment of overdose.

• Hypersensitivity to atomoxetine or other constituents of product.

• Atomoxetine capsules use within 2 weeks after discontinuing MAOI or other drugs that affect brain monoamine concentrations.

• Pheochromocytoma or history of pheochromocytoma.

Disorders that might deteriorate with clinically important increases in HR and BP. 4.1 Hypersensitivity Atomoxetine capsules are contraindicated in patients known to be hypersensitive to atomoxetine or other constituents of the product. 4.2 Monoamine Oxidase Inhibitors (MAOI) Atomoxetine capsules should not be taken with an MAOI, or within 2 weeks after discontinuing an MAOI.

Treatment with an

MAOI should not be initiated within 2 weeks after discontinuing atomoxetine capsules.

With other drugs that affect brain monoamine concentrations, there have been reports of serious, sometimes fatal reactions (including hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, and mental status changes that include extreme agitation progressing to delirium and coma) when taken in combination with an MAOI.

Some cases presented with features resembling neuroleptic malignant syndrome.

Such reactions may occur when these drugs are given concurrently or in close proximity. 4.3 Narrow Angle Glaucoma In clinical trials, atomoxetine capsules use was associated with an increased risk of mydriasis and therefore its use is not recommended in patients with narrow angle glaucoma. 4.4 Pheochromocytoma Serious reactions, including elevated blood pressure and tachyarrhythmia, have been reported in patients with pheochromocytoma or a history of pheochromocytoma who received atomoxetine capsules.

Therefore, atomoxetine capsules should not be taken by patients with pheochromocytoma or a history of pheochromocytoma. 4.5 Severe Cardiovascular.

Disorders Atomoxetine capsules should not be used in patients with severe cardiac or vascular disorders whose condition would be expected to deteriorate if they experience increases in blood pressure or heart rate that could be clinically important (for example, 15 to 20 mm Hg in blood pressure or 20 beats per minute in heart rate). .

Initial, Target and Maximum Daily Dose (Acute and Maintenance/Extended Treatment) Body Weight Initial Daily Dose Target Total Daily Dose Maximum Total Daily Dose Children and adolescents up to 70 kg 0.5 mg/kg 1.2 mg/kg 1.4 mg/kg Children and adolescents over 70 kg and adults 40 mg 80 mg 100 mg Dosing adjustment — Hepatic Impairment, Strong CYP2D6 Inhibitor, and in patients known to be CYP2D6 poor metabolizers (PMs). 2.1 Acute Treatment Dosing of children and adolescents up to 70 kg body weight.

• Atomoxetine capsules should be initiated at a total daily dose of approximately 0.5 mg/kg and increased after a minimum of 3 days to a target total daily dose of approximately 1.2 mg/kg administered either as a single daily dose in the morning or as evenly divided doses in the morning and late afternoon/early evening.

No additional benefit has been demonstrated for doses higher than 1.2 mg/kg/day.

The total daily dose in children and adolescents should not exceed 1.4 mg/kg or 100 mg, whichever is less.

Dosing of children and adolescents over 70 kg body weight and adults.

• Atomoxetine capsules should be initiated at a total daily dose of 40 mg and increased after a minimum of 3 days to a target total daily dose of approximately 80 mg administered either as a single daily dose in the morning or as evenly divided doses in the morning and late afternoon/early evening.

After to 4 additional weeks, the dose may be increased to a maximum of 100 mg in patients who have not achieved an optimal response.

There are no data that support increased effectiveness at higher doses.

The maximum recommended total daily dose in children and adolescents over 70 kg and adults is 100 mg. 2.2 Maintenance/Extended Treatment It is generally agreed that pharmacological treatment of ADHD may be needed for extended periods.

The benefit of maintaining pediatric patients (ages to 15 years) with ADHD on atomoxetine capsules after achieving a response in a dose range of 1.2 to 1.8 mg/kg/day was demonstrated in a controlled trial.

Patients assigned to atomoxetine capsules in the maintenance phase were generally continued on the same dose used to achieve a response in the open label phase.

The physician who elects to use atomoxetine capsules for extended periods should periodically reevaluate the long-term usefulness of the drug for the individual patient. 2.3 General Dosing Information Atomoxetine capsules may be taken with or without food.

Atomoxetine capsules can be discontinued without being tapered.

Atomoxetine capsules are not intended to be opened, they should be taken whole.

The safety of single doses over 120 mg and total daily doses above 150 mg have not been systematically evaluated. 2.4 Dosing in Specific Populations Dosing adjustment for hepatically impaired patients — For those ADHD patients who have hepatic insufficiency (HI), dosage adjustment is recommended as follows: For patients with moderate HI (Child-Pugh Class B), initial and target doses should be reduced to 50% of the normal dose (for patients without HI).

For patients with severe

HI (Child-Pugh Class C), initial dose and target doses should be reduced to 25% of normal.

Dosing adjustment for use with a strong CYP2D6 inhibitor or in patients who are known to be CYP2D6 PMs — In children and adolescents up to 70 kg body weight administered strong CYP2D6 inhibitors, e.g., paroxetine, fluoxetine, and quinidine, or in patients who are known to be CYP2D6 PMs, atomoxetine capsule should be initiated at 0.5 mg/kg/day and only increased to the usual target dose of 1.2 mg/kg/day if symptoms fail to improve after 4 weeks and the initial dose is well tolerated.

In children and adolescents over 70 kg body weight and adults administered strong CYP2D6 inhibitors, e.g., paroxetine, fluoxetine, and quinidine, atomoxetine capsule should be initiated at 40 mg/day and only increased to the usual target dose of 80 mg/day if symptoms fail to improve after 4 weeks and the initial dose is well tolerated.

50090-6143 NDC: 50090-6143-0 30 CAPSULE in a BOTTLE.

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to ADHD medications, 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 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 extensive 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 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.

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 to 4% and to 20%, respectively.

Pregnant rabbits were treated with up to 100 mg/kg/day of atomoxetine by gavage throughout the period of organogenesis.

At this dose, in 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 (extensive metabolizers) or 0.4 times (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 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.

Anyone considering the use of atomoxetine in a child or adolescent must balance the potential risks with the clinical need.

The pharmacokinetics of atomoxetine in children and adolescents are similar to those in adults.

The safety, efficacy, and pharmacokinetics of atomoxetine in pediatric patients less than 6 years of age have not been evaluated.

A study was conducted in young rats to evaluate the effects of atomoxetine on growth and neurobehavioral and sexual development.

Rats were treated with 1, 10, or 50 mg/kg/day (approximately 0.2, 2, and 8 times, respectively, the maximum human dose on a mg/m 2 basis) of atomoxetine given by gavage from the early postnatal period (Day 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 and 50 mg/kg and females at 50 mg/kg) and on Day 30 (females at 50 mg/kg) but not on Day of age.

There were no effects on learning and memory tests.

The significance of these findings to humans is unknown.

The safety, efficacy and pharmacokinetics of atomoxetine in geriatric patients have not been evaluated.