Atomoxetine (Page 4 of 9)

5.6 Screening Patients for Bipolar Disorder

  • In general, particular care should be taken in treating ADHD in patients with comorbid bipolar disorder because of concern for possible induction of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described above represent such a conversion is unknown. However, prior to initiating treatment with atomoxetine, patients with comorbid depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression.

5.7 Aggressive Behavior or Hostility

  • Patients beginning treatment for ADHD should be monitored for the appearance or worsening of aggressive behavior or hostility. Aggressive behavior or hostility is often observed in children and adolescents with ADHD. In pediatric short-term controlled clinical trials, 21/1308 (1.6%) of atomoxetine patients versus 9/806 (1.1%) of placebo-treated patients spontaneously reported treatment emergent hostility-related adverse events (overall risk ratio of 1.33 [95% C.I. 0.67 to 2.64 – not statistically significant]). In adult placebo-controlled clinical trials, 6/1697 (0.35%) of atomoxetine patients versus 4/1560 (0.26%) of placebo-treated patients spontaneously reported treatment emergent hostility-related adverse events (overall risk ratio of 1.38 [95% C.I. 0.39 to 4.88 – not statistically significant]). Although this is not conclusive evidence that atomoxetine causes aggressive behavior or hostility, these behaviors were more frequently observed in clinical trials among children, adolescents, and adults treated with atomoxetine compared to placebo.

5.8 Allergic Events

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

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. The erections resolved in cases in which follow-up information was available, some following discontinuation of atomoxetine. Prompt medical attention is required in the event of suspected priapism.

5.11 Effects on Growth

  • Data on the long-term effects of atomoxetine 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 lags behind that predicted by normative population data for about the first 9-12 months of treatment. Subsequently, weight gain rebounds and at about 3 years of treatment, patients treated with atomoxetine 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 have gained 19.4 cm on average, 0.4 cm less than predicted by their baseline data ( see Figure 1 below).
Z:\Regulatory Affairs 2\ANDAs\Atomoxetine (79019)\_Misc\0005\Pratik Labeling\RLD SPL\figure1.jpg
(click image for full-size original)
  • 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-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.
  • Growth should be monitored during treatment with atomoxetine.
Z:\Regulatory Affairs 2\ANDAs\Atomoxetine (79019)\_Misc\0005\Pratik Labeling\RLD SPL\figure1.jpg

5.12 Laboratory Tests

  • Routine laboratory tests are not required.
  • CYP2D6 metabolism — Poor metabolizers (PMs) of CYP2D6 have a 10-fold higher AUC and a 5-fold higher peak concentration to a given dose of atomoxetine compared with extensive metabolizers (EMs). Approximately 7% of a Caucasian population are PMs. Laboratory tests are available to identify CYP2D6 PMs. The blood levels in PMs are similar to those attained by taking strong inhibitors of CYP2D6. The higher blood levels in PMs lead to a higher rate of some adverse effects of atomoxetine [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 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 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 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 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 (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 ( 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 ( 4) and Warnings and Precautions ( 5)] .
Table 2: Common Treatment–Emergent Adverse Reactions Associated with the Use of Atomoxetine in Acute (up to 18 weeks) Child and Adolescent Trials
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.

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

Table 3: Common Treatment-Emergent Adverse Reactions Associated with the Use of Atomoxetine in Acute (up to 18 weeks) Child and Adolescent Trials
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).

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

  • 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); depression 1 (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).

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 3.0% (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 ( 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 ( 4) and Warnings and Precautions ( 5)] .
Table 4: Common Treatment-Emergent Adverse Reactions Associated with the Use of Atomoxetine in Acute (up to 25 weeks) Adult Trials
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).

Adverse Reaction a

Percentage of Patients Reporting Reaction

System Organ Class/Adverse 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

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

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