Atomoxetine HCl

Clinical Trials Experience

STRATTERA was administered to 5382 children or adolescent patients with ADHD and 1007 adults with ADHD in clinical studies. During the ADHD clinical trials, 1625 children and adolescent patients were treated for longer than 1 year and 2529 children and adolescent patients were treated for over 6 months.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Child And Adolescent Clinical Trials

Reasons For Discontinuation Of Treatment Due To Adverse Reactions In Child And Adolescent Clinical Trials

In acute child and adolescent placebo-controlled trials, 3.0% (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 STRATTERA-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

STRATTERA has not been systematically evaluated in pediatric patients with seizure disorder as these patients were excluded from clinical studies during the product’s premarket testing. In the clinical development program, seizures were reported in 0.2% (12/5073) of children whose average age was 10 years (range 6 to 16 years). In these clinical trials, the seizure risk among poor metabolizers was 0.3% (1/293) compared to 0.2% (11/4741) for extensive metabolizers.

Commonly Observed Adverse Reactions In Acute Child And Adolescent, Placebo-Controlled Trials

Commonly observed adverse reactions associated with the use of STRATTERA (incidence of 2% or greater) and not observed at an equivalent incidence among placebo-treated patients (STRATTERA 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 STRATTERA (incidence of 5% or greater and at least twice the incidence in placebo patients, for either BID or QD dosing) were: nausea, vomiting, fatigue, decreased appetite, abdominal pain, and somnolence (see Tables 2 and 3).

Additional data from ADHD clinical trials (controlled and uncontrolled) has shown that approximately 5 to 10% of pediatric patients experienced potentially clinically important changes in heart rate (≥20 beats per min) or blood pressure (≥15 to 20 mm Hg) [see CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS].

Table 2: Common Treatment–Emergent Adverse Reactions Associated with the Use of STRATTERA in Acute (up to 18 weeks) Child and Adolescent Trials

Adverse Reactiona	Percentage of Patients Reporting Reaction
System Organ Class/ Adverse Reaction	STRATTERA (N=1597)	Placebo (N=934)
Gastrointestinal Disorders
Abdominal painb	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
Somnolencec	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 STRATTERA 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
	STRATTERA (N=715)	Placebo (N=434)	STRATTERA (N=882)	Placebo (N=500)
Gastrointestinal Disorders
Abdominal paina	17	13	18	7
Vomiting	11	8	11	4
Nausea	7	6	13	4
Constipationb	2	1	1	0
General Disorders
Fatigue	6	4	9	2
Psychiatric Disorders
Mood swingsc	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.

Adult Clinical Trials

Reasons For Discontinuation Of Treatment Due To Adverse Reactions In Acute Adult Placebo-Controlled Trials

In the acute adult placebo-controlled trials, 11.3% (61/541) atomoxetine subjects and 3.0% (12/405) placebo subjects discontinued for adverse reactions. Among STRATTERA-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

STRATTERA 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 STRATTERA (incidence of 2% or greater) and not observed at an equivalent incidence among placebo-treated patients (STRATTERA incidence greater than placebo) are listed in Table 4. The most commonly observed adverse reactions in patients treated with STRATTERA (incidence of 5% or greater and at least twice the incidence in placebo patients) were: constipation, dry mouth, nausea, decreased appetite, dizziness, erectile dysfunction, and urinary hesitation (see Table 4). Additional data from ADHD clinical trials (controlled and uncontrolled) has shown that approximately 5 to 10% of adult patients experienced potentially clinically important changes in heart rate (≥20 beats per min) or blood pressure (≥15 to 20 mm Hg) [see CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS].

Table 4: Common Treatment-Emergent Adverse Reactions Associated with the Use of STRATTERA in Acute (up to 25 weeks) Adult Trials

Adverse Reactiona	Percentage of Patients Reporting Reaction
System Organ Class/ Adverse Reaction	STRATTERA (N=1697)	Placebo (N=1560)
Cardiac Disorders
Palpitations	3	1
Gastrointestinal Disorders
Dry mouth	20	5
Nausea	26	6
Constipation	8	3
Abdominal painb	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
Somnolencec	8	5
Paraesthesia	3	0
Psychiatric Disorders
Abnormal dreams	4	3
Insomniad	15	8
Libido decreased	3	1
Sleep disorder	3	1
Renal and Urinary Disorders
Urinary hesitatione	6	1
Dysuria	2	0
Reproductive System and Breast Disorders
Erectile dysfunctionf	8	1
Dysmenorrheag	3	2
Ejaculation delayedf and/or ejaculation disorderf	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. bAbdominal pain includes the terms: abdominal pain upper, abdominal pain, stomach discomfort, abdominal discomfort,epigastric discomfort. cSomnolence includes the terms: sedation, somnolence. d Insomnia includes the terms: insomnia, initial insomnia, middle insomnia, and terminal insomnia. eUrinary hesitation includes the terms: urinary hesitation, urine flow decreased. fBased on total number of males (STRATTERA, N=943; placebo, N=869). gBased on total number of females (STRATTERA, N=754; placebo, N=691).

The following adverse events occurred in at least 2% of adult CYP2D6 poor metaboliser (PM) patients and were statistically significantly more frequent in PM patients compared to CYP2D6 extensive metaboliser (EM) patients: vision blurred (4% of PMs, 1% of EMs); dry mouth (35% of PMs, 17% of EMs); constipation (11% of PMs, 7% of EMs); feeling jittery (5% of PMs, 2% of EMs); decreased appetite (23% of PMs, 15% of EMs); tremor (5% of PMs, 1% of EMs); insomnia (19% of PMs, 11% of EMs); sleep disorder (7% of PMs, 3% of EMs); middle insomnia (5% of PMs, 3% of EMs); terminal insomnia (3% of PMs, 1% of EMs); urinary retention (6% of PMs, 1% of EMs); erectile dysfunction (21% of PMs, 9% of EMs); ejaculation disorder (6% of PMs, 2% of EMs); hyperhidrosis (15% of PMs, 7% of EMs); peripheral coldness (3% of PMs, 1% of EMs).

Male And Female Sexual Dysfunction

Atomoxetine appears to impair sexual function in some patients. Changes in sexual desire, sexual performance, and sexual satisfaction are not well assessed in most clinical trials because they need special attention and because patients and physicians may be reluctant to discuss them. Accordingly, estimates of the incidence of untoward sexual experience and performance cited in product labeling are likely to underestimate the actual incidence. Table 4 above displays the incidence of sexual side effects reported by at least 2% of adult patients taking STRATTERA in placebo-controlled trials.

There are no adequate and well-controlled studies examining sexual dysfunction with STRATTERA treatment. While it is difficult to know the precise risk of sexual dysfunction associated with the use of STRATTERA, physicians should routinely inquire about such possible side effects.

Postmarketing Spontaneous Reports

The following adverse reactions have been identified during post approval use of STRATTERA. Unless otherwise specified, these adverse reactions have occurred in adults and children and adolescents. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Cardiovascular system - QT prolongation, syncope.

Peripheral vascular effects - Raynaud’s phenomenon.

General disorders and administration site conditions - Lethargy.

Musculoskeletal system - Rhabdomyolysis.

Nervous system disorders - Hypoaesthesia; paraesthesia in children and adolescents; sensory disturbances; tics.

Psychiatric disorders - Depression and depressed mood; anxiety, libido changes.

Seizures - Seizures have been reported in the postmarketing period. The postmarketing seizure cases include patients with pre-existing seizure disorders and those with identified risk factors for seizures, as well as patients with neither a history of nor identified risk factors for seizures. The exact relationship between STRATTERA and seizures is difficult to evaluate due to uncertainty about the background risk of seizures in ADHD patients.

Skin and subcutaneous tissue disorders - Alopecia, hyperhidrosis.

Urogenital system - Male pelvic pain; urinary hesitation in children and adolescents; urinary retention in children and adolescents.

You should not use atomoxetine if you are allergic to it, or if you have glaucoma or pheochromocytoma (tumor of the adrenal gland).

Do not use atomoxetine if you have used an MAO inhibitor such as furazolidone (Furoxone), isocarboxazid (Marplan), phenelzine (Nardil), rasagiline (Azilect), selegiline (Eldepryl, Emsam, Zelapar), or tranylcypromine (Parnate) in the last 14 days. A dangerous drug interaction could occur, leading to serious side effects.

Some ADHD medicines have caused sudden death in children and adolescents with serious heart problems or congenital heart defects.

To make sure you can safely take atomoxetine, tell your doctor if you have any of these other conditions:

• a congenital heart defect;
• heart disease, a heart rhythm disorder, or recent heart attack;
• coronary artery disease;
• a history of stroke, blood clots, or heart attack;
• high or low blood pressure;
• liver disease;
• problems with urination;
• a personal or family history of mental illness, psychotic disorder, bipolar illness, depression, or suicide attempt; or
• if anyone in your family has died suddenly from a heart problem.

You may have suicidal thoughts or behavior while taking atomoxetine. Watch for symptoms of depression, unusual behavior, or thoughts of hurting yourself. Your doctor may need to check you at regular visits while you are taking this medication.

In addition to you watching for changes in your mood or behavior, your family or caregivers should be alert to changes in your mood or symptoms.

FDA pregnancy category C. It is not known whether atomoxetine is harmful to an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant while using this medication.

It is not known whether atomoxetine passes into breast milk or if it could harm a nursing baby. Do not use this medication without telling your doctor if you are breast-feeding a baby.

Atomoxetine is not meant for long-term use. Because ADHD may be a long-term condition, especially in children and young adults, your doctor may recommend another ADHD medication after you stop taking atomoxetine.

Long-term use of atomoxetine can slow a child's growth. Tell your doctor if the child using this medication is not growing or gaining weight properly.

Do not give atomoxetine to a child younger than 6 years old without the advice of a doctor.

Your pharmacist can provide more information about atomoxetine.

Remember, keep this and all other medicines out of the reach of children, never share your medicines with others, and use this medication only for the indication prescribed.

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