BUPROPION HYDROCHLORIDE (Page 4 of 9)

6 ADVERSE REACTIONS

The following adverse reactions are discussed in greater detail in other sections of the labeling:

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.

Commonly Observed Adverse Reactions in Controlled Clinical Trials of Sustained-Release Bupropion Hydrochloride

Adverse reactions that occurred in at least 5% of patients treated with bupropion HCl sustained-release (300 mg and 400 mg per day) and at a rate at least twice the placebo rate are listed below.

300 mg/day of bupropion HCl sustained-release: anorexia, dry mouth, rash, sweating, tinnitus, and tremor.

400 mg/day of bupropion HCl sustained-release: abdominal pain, agitation, anxiety, dizziness, dry mouth, insomnia, myalgia, nausea, palpitation, pharyngitis, sweating, tinnitus, and urinary frequency.

Bupropion hydrochloride extended-release tablets (XL) have been demonstrated to have similar bioavailability both to the immediate-release and sustained-release formulations of bupropion. The information included under this subsection and under subsection 6.2 is based primarily on data from controlled clinical trials with the sustained-release and extended-release formulations of bupropion hydrochloride.

Major Depressive Disorder

Adverse Reactions Leading to Discontinuation of Treatment with Bupropion HCl Immediate-Release, Bupropion HCl Sustained-Release, and Bupropion HCl Extended-Release in Major Depressive Disorder Trials

In placebo-controlled clinical trials with bupropion HCl sustained-release, 4%, 9%, and 11% of the placebo, 300 mg/day and 400 mg/day groups, respectively, discontinued treatment because of adverse reactions. The specific adverse reactions leading to discontinuation in at least 1% of the 300 mg/day or 400 mg/day groups and at a rate at least twice the placebo rate are listed in Table 2.

Table 2: Treatment Discontinuation Due to Adverse Reactions in Placebo-Controlled Trials in MDD
Adverse Reaction Term Placebo (n=385) Bupropion HCl Sustained-Release 300 mg/day (n=376) Bupropion HCl Sustained-Release 400 mg/day (n=114)

Rash

0.0%

2.4%

0.9%

Nausea

0.3%

0.8%

1.8%

Agitation

0.3%

0.3%

1.8%

Migraine

0.3%

0.0%

1.8%

In clinical trials with bupropion HCl immediate-release, 10% of patients and volunteers discontinued due to an adverse reaction. Reactions resulting in discontinuation (in addition to those listed above for the sustained-release formulation) included vomiting, seizures, and sleep disturbances.

Adverse Reactions Occurring at an Incidence of >1% in Patients Treated with Bupropion HCl Immediate-Release or Bupropion HCl Sustained-Release in MDD

Table 3 summarizes the adverse reactions that occurred in placebo-controlled trials in patients treated with bupropion HCl sustained-release 300 mg/day and 400 mg/day. These include reactions that occurred in either the 300 mg or 400 mg group at an incidence of 1% or more and were more frequent than in the placebo group.

Table 3: Adverse Reactions in Placebo-Controlled Trials in Patients with MDD
Body System/Adverse Reaction Placebo (n=385) Bupropion HCl Sustained-Release 300 mg/day (n=376) Bupropion HCl Sustained-Release 400 mg/day (n=114)
*
Incidence based on the number of female patients.
Hyphen denotes adverse reactions occurring in greater than 0 but less than 0.5% of patients.

Body (General)

Headache

23%

26%

25%

Infection

6%

8%

9%

Abdominal pain

2%

3%

9%

Asthenia

2%

2%

4%

Chest pain

1%

3%

4%

Pain

2%

2%

3%

Fever

1%

2%

Cardiovascular

Palpitation

2%

2%

6%

Flushing

1%

4%

Migraine

1%

1%

4%

Hot flashes

1%

1%

3%

Digestive

Dry mouth

7%

17%

24%

Nausea

8%

13%

18%

Constipation

7%

10%

5%

Diarrhea

6%

5%

7%

Anorexia

2%

5%

3%

Vomiting

2%

4%

2%

Dysphagia

0%

0%

2%

Musculoskeletal

Myalgia

3%

2%

6%

Arthralgia

1%

1%

4%

Arthritis

0%

0%

2%

Twitch

1%

2%

Nervous System

Insomnia

6%

11%

16%

Dizziness

5%

7%

11%

Agitation

2%

3%

9%

Anxiety

3%

5%

6%

Tremor

1%

6%

3%

Nervousness

3%

5%

3%

Somnolence

2%

2%

3%

Irritability

2%

3%

2%

Memory decreased

1%

3%

Paresthesia

1%

1%

2%

Central nervous system stimulation

1%

2%

1%

Respiratory

Pharyngitis

2%

3%

11%

Sinusitis

2%

3%

1%

Increased cough

1%

1%

2%

Skin

Sweating

2%

6%

5%

Rash

1%

5%

4%

Pruritus

2%

2%

4%

Urticaria

0%

2%

1%

Special Senses

Tinnitus

2%

6%

6%

Taste perversion

2%

4%

Blurred vision or diplopia

2%

3%

2%

Urogenital

Urinary frequency

2%

2%

5%

Urinary urgency

0%

2%

Vaginal hemorrhage *

0%

2%

Urinary tract infection

1%

0%

The following additional adverse reactions occurred in controlled trials of bupropion HCl immediate-release (300 mg to 600 mg per day) at an incidence of at least 1% more frequently than in the placebo group were: cardiac arrhythmia (5% vs. 4%), hypertension (4% vs. 2%), hypotension (3% vs. 2%), menstrual complaints (5% vs. 1%), akathisia (2% vs. 1%), impaired sleep quality (4% vs. 2%), sensory disturbance (4% vs. 3%), confusion (8% vs. 5%), decreased libido (3% vs. 2%), hostility (6% vs. 4%), auditory disturbance (5% vs. 3%), and gustatory disturbance (3% vs. 1%).

Seasonal Affective Disorder

In placebo-controlled clinical trials in SAD, 9% of patients treated with bupropion hydrochloride extended-release tablets (XL) and 5% of patients treated with placebo discontinued treatment because of adverse reactions. The adverse reactions leading to discontinuation in at least 1% of patients treated with bupropion and at a rate numerically greater than the placebo rate were insomnia (2% vs. <1%) and headache (1% vs. <1%).

Table 4 summarizes the adverse reactions that occurred in patients treated with bupropion hydrochloride extended-release tablets (XL) for up to approximately 6 months in 3 placebo-controlled trials. These include reactions that occurred at an incidence of 2% or more and were more frequent than in the placebo group.

Table 4: Adverse Reactions in Placebo-Controlled Trials in Patients with SAD
System Organ Class/Preferred Term Placebo (n=511) Bupropion HCl Extended-Release (n=537)

Gastrointestinal Disorder

Dry mouth

15%

26%

Nausea

8%

13%

Constipation

2%

9%

Flatulence

3%

6%

Abdominal pain

<1%

2%

Nervous System Disorders

Headache

26%

34%

Dizziness

5%

6%

Tremor

<1%

3%

Infections and Infestations

Nasopharyngitis

12%

13%

Upper respiratory tract infection

8%

9%

Sinusitis

4%

5%

Psychiatric Disorders

Insomnia

13%

20%

Anxiety

5%

7%

Abnormal dreams

2%

3%

Agitation

<1%

2%

Musculoskeletal and Connective Tissue Disorders

Myalgia

2%

3%

Pain in extremity

2%

3%

Respiratory, Thoracic, and Mediastinal Disorders

Cough

3%

4%

General Disorders and Administration Site Conditions

Feeling jittery

2%

3%

Skin and Subcutaneous Tissue Disorders

Rash

2%

3%

Metabolism and Nutrition Disorders

Decreased appetite

1%

4%

Reproductive System and Breast Disorders

Dysmenorrhea

<1%

2%

Ear and Labyrinth Disorders

Tinnitus

<1%

3%

Vascular Disorders

Hypertension

0%

2%

Changes in Body Weight

Table 5 presents the incidence of body weight changes (≥5 lbs) in the short-term MDD trials using bupropion HCl sustained-release. There was a dose-related decrease in body weight.

Table 5: Incidence of Weight Gain or Weight Loss (≥5 lbs) in MDD Trials Using Bupropion HCl Sustained-Release
Weight Change Bupropion HCl Sustained-Release 300 mg/day (n=339) Bupropion HCl Sustained-Release 400 mg/day (n=112) Placebo (n=347)

Gained >5 lbs

3%

2%

4%

Lost >5 lbs

14%

19%

6%

Table 6 presents the incidence of body weight changes (≥5 lbs) in the 3 SAD trials using bupropion HCl extended-release. A higher proportion of subjects in the bupropion group (23%) had a weight loss ≥5 lbs, compared to the placebo group (11%). These were relatively long-term trials (up to 6 months).

Table 6: Incidence of Weight Gain or Weight Loss (≥5 lbs) in SAD Trials Using Bupropion HCl Extended-Release
Weight Change Bupropion HCl Extended-Release 150 to 300 mg/day (n=537) Placebo (n=511)

Gained >5 lbs

11%

21%

Lost >5 lbs

23%

11%

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