Bupropion Hydrochloride (Page 3 of 8)

5.4 Hypertension

Treatment with bupropion hydrochloride extended-release tablets (XL) can result in elevated blood pressure and hypertension. Assess blood pressure before initiating treatment with bupropion hydrochloride extended-release tablets (XL), and monitor periodically during treatment. The risk of hypertension is increased if bupropion hydrochloride extended-release tablets (XL) are used concomitantly with MAOIs or other drugs that increase dopaminergic or noradrenergic activity [see Contraindications (4)].

Data from a comparative trial of the sustained-release formulation of bupropion hydrochloride, nicotine transdermal system (NTS), the combination of sustained-release bupropion hydrochloride plus NTS, and placebo as an aid to smoking cessation suggest a higher incidence of treatment-emergent hypertension in patients treated with the combination of sustained-release bupropion hydrochloride and NTS. In this trial, 6.1% of subjects treated with the combination of sustained-release bupropion and NTS had treatment-emergent hypertension compared to 2.5%, 1.6%, and 3.1% of subjects treated with sustained-release bupropion, NTS, and placebo, respectively. The majority of these subjects had evidence of pre-existing hypertension. Three subjects (1.2%) treated with the combination of sustained-release bupropion and NTS and 1 subject (0.4%) treated with NTS had study medication discontinued due to hypertension compared with none of the subjects treated with sustained-release bupropion or placebo. Monitoring of blood pressure is recommended in patients who receive the combination of bupropion and nicotine replacement.

In a clinical trial of bupropion immediate-release in MDD subjects with stable congestive heart failure (N = 36), bupropion was associated with an exacerbation of pre-existing hypertension in 2 patients, leading to discontinuation of bupropion treatment. There are no controlled studies assessing the safety of bupropion in patients with a recent history of myocardial infarction or unstable cardiac disease.

5.5 Activation of Mania/Hypomania

Antidepressant treatment can precipitate a manic, mixed, or hypomanic manic episode. The risk appears to be increased in patients with bipolar disorder or who have risk factors for bipolar disorder. Prior to initiating bupropion hydrochloride extended-release tablets (XL), screen patients for a history of bipolar disorder and the presence of risk factors for bipolar disorder (e.g., family history of bipolar disorder, suicide, or depression). Bupropion hydrochloride extended-release tablets (XL) are not approved for the treatment of bipolar depression.

5.6 Psychosis and Other Neuropsychiatric Reactions

Depressed patients treated with bupropion have had a variety of neuropsychiatric signs and symptoms, including delusions, hallucinations, psychosis, concentration disturbance, paranoia, and confusion. Some of these patients had a diagnosis of bipolar disorder. In some cases, these symptoms abated upon dose reduction and/or withdrawal of treatment. Discontinue bupropion hydrochloride extended-release tablets (XL) if these reactions occur.

5.7 Angle-closure Glaucoma

Angle-closure Glaucoma: The pupillary dilation that occurs following use of many antidepressant drugs including bupropion hydrochloride extended-release tablets (XL) may trigger an angle closure attack in a patient with anatomically narrow angles who does not have a patent iridectomy.

5.8 Hypersensitivity Reactions

Anaphylactoid/anaphylactic reactions have occurred during clinical trials with bupropion. Reactions have been characterized by symptoms such as pruritus, urticaria, angioedema, and dyspnea, requiring medical treatment. In addition, there have been rare, spontaneous postmarketing reports of erythema multiforme, Stevens-Johnson syndrome, and anaphylactic shock associated with bupropion. Instruct patients to discontinue bupropion hydrochloride extended-release tablets (XL) and consult a healthcare provider if they develop an allergic or anaphylactoid/anaphylactic reaction (e.g., skin rash, pruritus, hives, chest pain, edema, and shortness of breath) during treatment.

There are reports of arthralgia, myalgia, fever with rash, and other symptoms of serum sickness suggestive of delayed hypersensitivity.

6 ADVERSE REACTIONS

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

Suicidal thoughts and behaviors in children, adolescents, and young adults [see Warnings and Precautions (5.1)]
Neuropsychiatric adverse events and suicide risk in smoking cessation treatment [see Warnings and Precautions (5.2)]
Seizure [see Warnings and Precautions (5.3)]
Hypertension [see Warnings and Precautions (5.4)]
Activation of mania or hypomania [see Warnings and Precautions (5.5)]
Psychosis and other neuropsychiatric events [see Warnings and Precautions (5.6)]
Angle-closure Glaucoma [see Warnings and Precautions (5.7)]
Hypersensitivity reactions [see Warnings and Precautions (5.8)]

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 clinical 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 hydrochloride sustained-release (300 and 400 mg/day) and at a rate at least twice the placebo rate are listed below.

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

400 mg/day of bupropion hydrochloride 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) is bioequivalent to three 150 mg tablets of WELLBUTRIN XL® , which has been demonstrated to have similar bioavailability both to the immediate-release and the 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 Hydrochloride Immediate-release, Bupropion Hydrochloride Sustained-release, and Bupropion Hydrochloride Extended-release Formulations in Major Depressive Disorder Trials

In placebo-controlled clinical trials with bupropion hydrochloride 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 Major Depressive Disorder

Adverse Reaction Term

Placebo (N = 385)

Bupropion Hydrochloride Sustained-release300 mg/day (N = 376)

Bupropion Hydrochloride Sustained-release400 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 hydrochloride 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 Hydrochloride Immediate-release or Bupropion Hydrochloride Sustained-release Formulations in Major Depressive Disorder Trials

Table 3 summarizes the adverse reactions that occurred in placebo-controlled trials in patients treated with bupropion hydrochloride sustained-release at 300 mg/day and 400 mg/day. These include reactions that occurred in either the 300 mg/day or 400 mg/day 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 for Major Depressive Disorder
a = Incidence based on the number of female patients.— = Denotes adverse reactions occurring in greater than 0 but less than 0.5% of patients.

Body System/Adverse Reaction

Placebo

(N = 385)

Bupropion Hydrochloride Sustained-release300 mg/day (N = 376)

Bupropion Hydrochloride Sustained-release400 mg/day (N = 114)

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 a

0%

2%

Urinary tract infection

1%

0%

The following additional adverse reactions occurred in controlled trials of bupropion hydrochloride immediate-release (300 to 600 mg/day) at an incidence of at least 1% more frequently than in the placebo group: 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%).

Changes in Body Weight

Table 4 presents the incidence of body weight changes (≥ 5 lbs) in the short-term MDD trials using bupropion hydrochloride sustained-release. There was a dose-related decrease in body weight.

Table 4. Incidence of Weight Gain or Weight Loss (≥ 5 lbs) in Placebo-controlled Trials of Bupropion Hydrochloride Sustained-release Tablets for Major Depressive Disorder

Weight Change

Placebo (N = 347)

Bupropion Hydrochloride Sustained-release300 mg/day (N = 339)

Bupropion Hydrochloride Sustained-release400 mg/day (N = 112)

Gained > 5 lbs

4%

3%

2%

Lost > 5 lbs

6%

14%

19%

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