Atomoxetine Hydrochloride (Page 3 of 8)

5.8 Allergic Events

Although uncommon, allergic reactions, including anaphylactic reactions, angioneurotic edema, urticaria, and rash, have been reported in patients taking atomoxetine hydrochloride.

5.9 Effects on Urine Outflow from the Bladder

In adult ADHD controlled trials, the rates of urinary retention (1.7%, 9/540) and urinary hesitation (5.6%, 30/540) were increased among atomoxetine subjects compared with placebo subjects (0%, 0/402 ; 0.5%, 2/402, respectively). Two adult atomoxetine subjects and no placebo subjects discontinued from controlled clinical trials because of urinary retention. A complaint of urinary retention or urinary hesitancy should be considered potentially related to atomoxetine.

5.10 Priapism

Rare postmarketing cases of priapism, defined as painful and nonpainful penile erection lasting more than 4 hours, have been reported for pediatric and adult patients treated with atomoxetine hydrochloride. The erections resolved in cases in which follow-up information was available, some following discontinuation of atomoxetine hydrochloride. Prompt medical attention is required in the event of suspected priapism.

5.11 Effects on Growth

Data on the long-term effects of atomoxetine hydrochloride capsules on growth come from open-label studies, and weight and height changes are compared to normative population data. In general, the weight and height gain of pediatric patients treated with atomoxetine hydrochloride lags behind that predicted by normative population data for about the first 9 to 12 months of treatment. Subsequently, weight gain rebounds and at about 3 years of treatment, patients treated with atomoxetine hydrochloride have gained 17.9 kg on average, 0.5 kg more than predicted by their baseline data. After about 12 months, gain in height stabilizes, and at 3 years, patients treated with atomoxetine hydrochloride have gained 19.4 cm on average, 0.4 cm less than predicted by their baseline data (see Figure 1 below).

atomoxetine-fig1
(click image for full-size original)
Figure 1: Mean Weight and Height Percentiles Over Time for Patients With Three Years of Atomoxetine Hydrochloride Treatment

This growth pattern was generally similar regardless of pubertal status at the time of treatment initiation. Patients who were pre-pubertal at the start of treatment (girls ≤8 years old, boys ≤9 years old) gained an average of 2.1 kg and 1.2 cm less than predicted after three years. Patients who were pubertal (girls >8 to ≤13 years old, boys >9 to ≤14 years old) or late pubertal (girls >13 years old, boys >14 years old) had average weight and height gains that were close to or exceeded those predicted after three years of treatment.

Growth followed a similar pattern in both extensive and poor metabolizers (EMs, PMs). PMs treated for at least two years gained an average of 2.4 kg and 1.1 cm less than predicted, while EMs gained an average of 0.2 kg and 0.4 cm less than predicted.

In short-term controlled studies (up to 9 weeks), atomoxetine hydrochloride-treated patients lost an average of 0.4 kg and gained an average of 0.9 cm, compared to a gain of 1.5 kg and 1.1 cm in the placebo-treated patients. In a fixed-dose controlled trial, 1.3%, 7.1%, 19.3%, and 29.1% of patients lost at least 3.5% of their body weight in the placebo, 0.5, 1.2, and 1.8 mg/kg/day dose groups.

5.12 Laboratory Tests

Routine laboratory tests are not required.

[see Adverse Reactions (6.1)].

5.13 Concomitant Use of Potent CYP2D6 Inhibitors or Use in patients who are known to be CYP2D6 PMs

Atomoxetine is primarily metabolized by the CYP2D6 pathway to 4-hydroxyatomoxetine. Dosage adjustment of atomoxetine hydrochloride may be necessary when coadministered with potent CYP2D6 inhibitors (e.g., paroxetine, fluoxetine, and quinidine) or when administered to CYP2D6 PMs. [see Dosage and Administration (2.4) and Drug Interactions (7.2)].

6 ADVERSE REACTIONS

6.1 Clinical Trials Experience

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

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

Child and Adolescent Clinical Trials

Reasons for discontinuation of treatment due to adverse reactions in child and adolescent clinical trials — In acute child and adolescent placebo-controlled trials, 3% (48/1613) of atomoxetine subjects and 1.4% (13/945) placebo subjects discontinued for adverse reactions. For all studies, (including open-label and long-term studies), 6.3% of extensive metabolizer (EM) patients and 11.2% of poor metabolizer (PM) patients discontinued because of an adverse reaction. Among atomoxetine hydrochloride-treated patients, irritability (0.3%, N=5); somnolence (0.3%, N=5); aggression (0.2%, N=4); nausea (0.2%, N=4); vomiting (0.2%, N=4); abdominal pain (0.2%, N=4); constipation (0.1%, N=2); fatigue (0.1%, N=2); feeling abnormal (0.1%, N=2); and headache (0.1%, N=2) were the reasons for discontinuation reported by more than 1 patient.

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

Commonly observed adverse reactions in acute child and adolescent, placebo-controlled trials — Commonly observed adverse reactions associated with the use of atomoxetine hydrochloride (incidence of 2% or greater) and not observed at an equivalent incidence among placebo-treated patients (atomoxetine hydrochloride incidence greater than placebo) are listed in Table 1. Results were similar in the BID and the QD trial except as shown in Table 2, which shows both BID and QD results for selected adverse reactions based on statistically significant Breslow-Day tests. The most commonly observed adverse reactions in patients treated with atomoxetine hydrochloride (incidence of 5% or greater and at least twice the incidence in placebo patients, for either BID or QD dosing) were: nausea, vomiting, fatigue, decreased appetite, abdominal pain, and somnolence (see Tables 1 and 2).
Table 1: Common Treatment-Emergent Adverse Reactions Associated with the Use of Atomoxetine Hydrochloride in Acute (up to 18 weeks) Child and Adolescent Trials
Adverse Reaction *Percentage of Patients Reporting Reaction
Atomoxetine Hydrochloride (N=1597)Placebo (N=934)
*
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, flushing, mydriasis, sinus tachycardia, asthenia, palpitations, mood swings, constipation. 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.
Abdominal pain includes the terms: abdominal pain upper, abdominal pain, stomach discomfort, abdominal discomfort, epigastric discomfort.
Somnolence includes the terms: sedation, somnolence.
Gastrointestinal Disorders
Abdominal pain 1810
Vomiting116
Nausea105
General Disorders and Administration Site Conditions
Fatigue83
Irritability63
Therapeutic response unexpected21
Investigations
Weight decreased30
Metabolism and Nutritional Disorders
Decreased appetite164
Anorexia31
Nervous System Disorders
Headache1915
Somnolence 114
Dizziness52
Skin and Subcutaneous Tissue Disorders
Rash21
Table 2: Common Treatment-Emergent Adverse Reactions Associated with the Use of Atomoxetine Hydrochloride in Acute (up to 18 weeks) Child and Adolescent Trials
Adverse ReactionPercentage of Patients Reporting Reaction from BID TrialsPercentage of Patients Reporting Reaction from QD Trials
Atomoxetine Hydrochloride (N=715)Placebo (N=434)Atomoxetine Hydrochloride (N=882)Placebo (N=500)
*
Abdominal pain includes the terms : abdominal pain upper, abdominal pain, stomach discomfort, abdominal discomfort, epigastric discomfort.
Constipation didn’t meet the statistical significance on Breslow-Day test but is included in the table because of pharmacologic plausibility.
Mood swings didn’t meet the statistical significance on Breslow-Day test at 0.05 level but p-value was <0.1 (trend).
Gastrointestinal Disorders
Abdominal pain *1713187
Vomiting118114
Nausea76134
Constipation 2110
General Disorders
Fatigue6492
Psychiatric Disorders
Mood swings 2011

The following adverse reactions occurred in at least 2% of PM patients and were either twice as frequent or statistically significantly more frequent in PM patients compared with EM patients: insomnia (15% of PMs, 10% 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); 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).

1 Depression includes the following terms: depression, major depression, depressive symptoms, depressed mood, dysphoria.

Adult Clinical Trials

Reasons for discontinuation of treatment due to adverse reactions in acute adult placebo-controlled trials — In the acute adult placebo-controlled trials, 11.3% (61/541) atomoxetine subjects and 3% (12/405) placebo subjects discontinued for adverse reactions. Among atomoxetine hydrochloride-treated patients, insomnia (0.9%, N=5); nausea (0.9%, N=5); chest pain (0.6%, N=3); fatigue (0.6%, N=3); anxiety (0.4%, N=2); erectile dysfunction (0.4%, N=2); mood swings (0.4%, N=2); nervousness (0.4%, N=2); palpitations (0.4%, N=2); and urinary retention (0.4%, N=2) were the reasons for discontinuation reported by more than 1 patient.

Seizures — Atomoxetine hydrochloride has not been systematically evaluated in adult patients with a seizure disorder as these patients were excluded from clinical studies during the product’s premarket testing. In the clinical development program, seizures were reported on 0.1% (1/748) of adult patients. In these clinical trials, no poor metabolizers (0/43) reported seizures compared to 0.1% (1/705) for extensive metabolizers.

Commonly observed adverse reactions in acute adult placebo-controlled trials — Commonly observed adverse reactions associated with the use of atomoxetine hydrochloride (incidence of 2% or greater) and not observed at an equivalent incidence among placebo-treated patients (Atomoxetine hydrochloride incidence greater than placebo) are listed in Table 3. The most commonly observed adverse reactions in patients treated with atomoxetine hydrochloride (incidence of 5% or greater and at least twice the incidence in placebo patients) were: constipation, dry mouth, nausea, fatigue, decreased appetite, insomnia, erectile dysfunction, urinary hesitation and/or urinary retention and/or dysuria, dysmenorrhea, and hot flush (see Table 3).
Table 3: Common Treatment-Emergent Adverse Reactions Associated with the Use of Atomoxetine Hydrochloride in Acute (up to 25 weeks) Adult Trials
Adverse Reaction *Percentage of Patients Reporting Reaction
System Organ Class/Adverse ReactionAtomoxetine Hydrochloride (N=540)Placebo (N=402)
*
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: early morning awakening, peripheral coldness, tachycardia, prostatitis, testicular pain, and orgasm abnormal. The following reactions were reported by at least 2 % of patients treated with atomoxetine, and equal to or less than placebo: headache, pharyngolaryngeal pain, irritability.
Abdominal pain includes the terms: abdominal pain upper, abdominal pain, stomach discomfort, abdominal discomfort, epigastric discomfort
Somnolence includes the terms: sedation, somnolence
§
Insomnia includes the terms: insomnia, initial insomnia, middle insomnia.
Based on total number of males (atomoxetine hydrochloride, N=326; placebo, N=260).
#
Based on total number of females (atomoxetine hydrochloride, N=214; placebo, N=142).
Cardiac Disorders
Palpitations31
Gastrointestinal Disorders
Dry mouth217
Nausea215
Constipation93
Abdominal pain 75
Dyspepsia42
Vomiting32
General Disorders and Administration Site Conditions
Fatigue94
Chills31
Therapeutic response unexpected31
Feeling jittery20
Investigations
Weight decreased21
Metabolism and Nutritional Disorders
Decreased appetite112
Nervous System Disorders
Dizziness64
Somnolence 43
Paraesthesia31
Sinus headache31
Tremor20
Psychiatric Disorders
Insomnia §157
Libido decreased42
Sleep disorder31
Renal and Urinary Disorders
Urinary hesitation and/or urinary retention71
Dysuria30
Reproductive System and Breast Disorders
Erectile dysfunction 91
Dysmenorrhea #62
Ejaculation delayed and/or ejaculation disorder 31
Menstruation irregular #20
Skin and Subcutaneous Tissue Disorders
Hyperhidrosis41
Rash21
Vascular Disorders
Hot flush81

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 3 above displays the incidence of sexual side effects reported by at least 2% of adult patients taking atomoxetine hydrochloride in placebo-controlled trials.

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