Bupropion Hydrochloride XL (Page 3 of 10)

5.3 Seizure

Bupropion hydrochloride extended-release tablets (XL) can cause seizure. The risk of seizure is dose-related. The dose should not exceed 300 mg once daily. Increase the dose gradually. Discontinue bupropion hydrochloride extended-release tablets (XL) and do not restart treatment if the patient experiences a seizure.

The risk of seizures is also related to patient factors, clinical situations, and concomitant medications that lower the seizure threshold. Consider these risks before initiating treatment with bupropion hydrochloride extended-release tablets (XL). Bupropion hydrochloride extended-release tablets (XL) is contraindicated in patients with a seizure disorder or conditions that increase the risk of seizure (e.g., severe head injury, arteriovenous malformation, CNS tumor or CNS infection, severe stroke, anorexia nervosa or bulimia, or abrupt discontinuation of alcohol, benzodiazepines, barbiturates, and antiepileptic drugs [see Contraindications (4)]. The following conditions can also increase the risk of seizure: concomitant use of other medications that lower the seizure threshold (e.g., other bupropion products, antipsychotics, tricyclic antidepressants, theophylline, and systemic corticosteroids), metabolic disorders (e.g., hypoglycemia, hyponatremia, severe hepatic impairment, and hypoxia), or use of illicit drugs (e.g., cocaine) or abuse or misuse of prescription drugs such as CNS stimulants. Additional predisposing conditions include diabetes mellitus treated with oral hypoglycemic drugs or insulin, use of anorectic drugs, excessive use of alcohol, benzodiazepines, sedative/hypnotics, or opiates.

Incidence of Seizure with Bupropion Use

The incidence of seizure with bupropion hydrochloride extended-release tablets (XL) have not been formally evaluated in clinical trials. In studies using bupropion HCl sustained-release up to 300 mg per day the incidence of seizure was approximately 0.1% (1/1000 patients). In a large prospective, follow-up study, the seizure incidence was approximately 0.4% (13/3200) with bupropion HCl immediate-release in the range of 300 mg to 450 mg per day.

Additional data accumulated for bupropion immediate-release suggests that the estimated seizure incidence increases almost tenfold between 450 and 600 mg/day. The risk of seizure can be reduced if the bupropion hydrochloride extended-release tablets (XL) dose does not exceed 450 mg once daily and the titration rate is gradual.

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 HCl, nicotine transdermal system (NTS), the combination of sustained-release bupropion 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 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 the 3 trials of bupropion HCl extended-release in seasonal affective disorder, there were significant elevations in blood pressure. Hypertension was reported as an adverse reaction for 2% of the bupropion group (11/537) and none in the placebo group (0/511). In the SAD trials, 2 patients treated with bupropion discontinued from the study because they developed hypertension. None of the placebo group discontinued because of hypertension. The mean increase in systolic blood pressure was 1.3 mmHg in the bupropion group and 0.1 mmHg in the placebo group. The difference was statistically significant (p = 0.013). The mean increase in diastolic blood pressure was 0.8 mmHg in the bupropion group and 0.1 mmHg in the placebo group. The difference was not statistically significant (p = 0.075). In the SAD trials, 82% of patients were treated with 300 mg per day, and 18% were treated with 150 mg per day. The mean daily dose was 270 mg per day. The mean duration of bupropion exposure was 126 days.

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 subjects, 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 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:

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)

Body (General)

Headache

Infection

Abdominal pain

Asthenia

Chest pain

Pain

Fever

23%

6%

2%

2%

1%

2%

26%

8%

3%

2%

3%

2%

1%

25%

9%

9%

4%

4%

3%

2%

Cardiovascular

Palpitation

Flushing

Migraine

Hot flashes

2%

1%

1%

2%

1%

1%

1%

6%

4%

4%

3%

Digestive

Dry mouth

Nausea

Constipation

Diarrhea

Anorexia

Vomiting

Dysphagia

7%

8%

7%

6%

2%

2%

0%

17%

13%

10%

5%

5%

4%

0%

24%

18%

5%

7%

3%

2%

2%

Musculoskeletal

Myalgia

Arthralgia

Arthritis

Twitch

3%

1%

0%

2%

1%

0%

1%

6%

4%

2%

2%

Nervous System

Insomnia

Dizziness

Agitation

Anxiety

Tremor

Nervousness

Somnolence

Irritability

Memory decreased

Paresthesia

Central nervous system stimulation

6%

5%

2%

3%

1%

3%

2%

2%

1%

1%

1%

11%

7%

3%

5%

6%

5%

2%

3%

1%

2%

16%

11%

9%

6%

3%

3%

3%

2%

3%

2%

1%

Respiratory

Pharyngitis

Sinusitis

Increased cough

2%

2%

1%

3%

3%

1%

11%

1%

2%

Skin

Sweating

Rash

Pruritus

Urticaria

2%

1%

2%

0%

6%

5%

2%

2%

5%

4%

4%

1%

Special Senses

Tinnitus

Taste perversion

Blurred vision or diplopia

2%

2%

6%

2%

3%

6%

4%

2%

Urogenital

Urinary frequency

Urinary urgency

Vaginal hemorrhage

Urinary tract infection

2%

0%

2%

0%

1%

5%

2%

2%

0%

The following additional adverse reactions occurred in controlled trials of bupropion HCl immediate-release (300 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

Nausea

Constipation

Flatulence

Abdominal pain

15%

8%

2%

3%

< 1%

26%

13%

9%

6%

2%

Nervous System Disorders

Headache

Dizziness

Tremor

26%

5%

< 1%

34%

6%

3%

Infections and Infestations

Nasopharyngitis

Upper respiratory tract infection

Sinusitis

12%

8%

4%

13%

9%

5%

Psychiatric Disorders

Insomnia

Anxiety

Abnormal dreams

Agitation

13%

5%

2%

< 1%

20%

7%

3%

2%

Musculoskeletal and Connective Tissue Disorders

Myalgia

Pain in extremity

2%

2%

3%

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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