Prescription Drug Information: Bupropion Hydrochloride (Page 2 of 7)

5.2 Neuropsychiatric Adverse Events and Suicide Risk in Smoking Cessation Treatment

Bupropion hydrochloride extended-release tablets (SR) are not approved for smoking cessation treatment; however, it contains the same active ingredient as the smoking cessation medication ZYBAN ® . Serious neuropsychiatric adverse events have been reported in patients taking bupropion for smoking cessation. These postmarketing reports have included changes in mood (including depression and mania), psychosis, hallucinations, paranoia, delusions, homicidal ideation, aggression, hostility, agitation, anxiety, and panic, as well as suicidal ideation, suicide attempt, and completed suicide [ see Adverse Reactions ( 6.2)]. Some patients who stopped smoking may have been experiencing symptoms of nicotine withdrawal, including depressed mood. Depression, rarely including suicidal ideation, has been reported in smokers undergoing a smoking cessation attempt without medication. However, some of these adverse events occurred in patients taking bupropion who continued to smoke.

Neuropsychiatric adverse events occurred in patients without and with pre-existing psychiatric disease; some patients experienced worsening of their psychiatric illnesses. Observe patients for the occurrence of neuropsychiatric adverse events. Advise patients and caregivers that the patient should stop taking bupropion hydrochloride extended-release tablets and contact a healthcare provider immediately if agitation, depressed mood, or changes in behavior or thinking that are not typical for the patient are observed, or if the patient develops suicidal ideation or suicidal behavior. In many postmarketing cases, resolution of symptoms after discontinuation of bupropion was reported. However, the symptoms persisted in some cases; therefore, ongoing monitoring and supportive care should be provided until symptoms resolve.

5.3 Seizure

Bupropion hydrochloride extended-release tablets (SR) can cause seizure. The risk of seizure is dose-related. The dose should not exceed 400 mg per day. Increase the dose gradually. Discontinue bupropion hydrochloride extended-release tablets (SR) 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 (SR). Bupropion hydrochloride extended-release tablets (SR) are contraindicated in patients with a seizure disorder, current or prior diagnosis of anorexia nervosa or bulimia, or undergoing abrupt discontinuation of alcohol, benzodiazepines, barbiturates, and antiepileptic drugs [ see Contraindications ( 4) and Drug Interactions ( 7.3)]. The following conditions can also increase the risk of seizure: severe head injury; arteriovenous malformation; CNS tumor or CNS infection; severe stroke; 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); 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; and excessive use of alcohol, benzodiazepines, sedative/hypnotics, or opiates.

Incidence of Seizure With Bupropion Use

When bupropion hydrochloride extended-release tablets (SR) are dosed up to 300 mg per day, the incidence of seizure is approximately 0.1% (1/1,000) and increases to approximately 0.4% (4/1,000) at the maximum recommended dose of 400 mg per day.

The risk of seizure can be reduced if the dose of bupropion hydrochloride extended-release tablets (SR) does not exceed 400 mg per day, given as 200 mg twice daily, and the titration rate is gradual.

5.4 Hypertension

Treatment with bupropion hydrochloride extended-release tablets (SR) can result in elevated blood pressure and hypertension. Assess blood pressure before initiating treatment with bupropion hydrochloride extended-release tablets (SR), and monitor periodically during treatment. The risk of hypertension is increased if bupropion hydrochloride extended-release tablets (SR) 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 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 with 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 subjects, leading to discontinuation of bupropion treatment. There are no controlled trials 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 (SR), 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 (SR) are not approved for use in treating bipolar depression.

5.6 Psychosis and Other Neuropsychiatric Reactions

Depressed patients treated with bupropion hydrochloride extended-release tablets (SR) 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. Instruct patients to contact a healthcare professional if such reactions occur.

5.7 Angle-Closure Glaucoma

The pupillary dilation that occurs following use of many antidepressant drugs including bupropion hydrochloride extended-release tablets (SR) 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 (SR) 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 serum sickness-like symptoms 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 adolescents and young adults [see Boxed Warning and Warnings and Precautions ( 5.1) ]
  • Neuropsychiatric symptoms 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 reactions [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 with rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

Adverse Reactions Leading to Discontinuation of Treatment

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

Table 2. Treatment Discontinuations Due to Adverse Reactions in Placebo-Controlled Trials

Adverse Reaction

Placebo

(n = 385)

Bupropion Hydrochloride Extended-Release Tablets (SR)

300 mg/day

(n = 376)

Bupropion Hydrochloride Extended-Release Tablets (SR)

400 mg/day

(n = 114)

Rash

Nausea

Agitation

Migraine

0.0%

0.3%

0.3%

0.3%

2.4%

0.8%

0.3%

0.0%

0.9%

1.8%

1.8%

1.8%

Commonly Observed Adverse Reactions

Adverse reactions from Table 3 occurring in at least 5% of subjects treated with bupropion hydrochloride extended-release tablets (SR) and at a rate at least twice the placebo rate are listed below for the 300 and 400-mg-per-day dose groups.

Bupropion Hydrochloride Extended-release Tablets (SR) 300 mg per day

Anorexia, dry mouth, rash, sweating, tinnitus, and tremor.

Bupropion Hydrochloride Extended-release Tablets (SR) 400 mg per day

Abdominal pain, agitation, anxiety, dizziness, dry mouth, insomnia, myalgia, nausea, palpitation, pharyngitis, sweating, tinnitus, and urinary frequency.

Adverse reactions reported in placebo-controlled trials are presented in Table 3. Reported adverse reactions were classified using a COSTART-based Dictionary.

Table 3. Adverse Reactions Reported by at Least 1% of Subjects and at a Greater Frequency than Placebo in Controlled Clinical Trials
*
Hyphen denotes adverse events occurring in greater than 0 but less than 0.5% of subjects.
Incidence based on the number of female subjects.

Body System/

Adverse Reaction

Bupropion Hydrochloride Extended-Release Tablets (SR)

300 mg/day

(n = 376)

Bupropion Hydrochloride Extended-Release Tablets (SR)

400 mg/day

(n = 114)

Placebo

(n = 385)

Body (General)

Headache

Infection

Abdominal pain

Asthenia

Chest pain

Pain

Fever

26%

8%

3%

2%

3%

2%

1%

25%

9%

9%

4%

4%

3%

2%

23%

6%

2%

2%

1%

2%

*

Cardiovascular

Palpitation

Flushing

Migraine

Hot flashes

2%

1%

1%

1%

6%

4%

4%

3%

2%

*

1%

1%

Digestive

Dry mouth

Nausea

Constipation

Diarrhea

Anorexia

Vomiting

Dysphagia

17%

13%

10%

5%

5%

4%

0%

24%

18%

5%

7%

3%

2%

2%

7%

8%

7%

6%

2%

2%

0%

Musculoskeletal

Myalgia

Arthralgia

Arthritis

Twitch

2%

1%

0%

1%

6%

4%

2%

2%

3%

1%

0%

*

Nervous system

Insomnia

Dizziness

Agitation

Anxiety

Tremor

Nervousness

Somnolence

Irritability

Memory decreased

Paresthesia

Central nervous
system stimulation

11%

7%

3%

5%

6%

5%

2%

3%

*

1%

2%

16%

11%

9%

6%

3%

3%

3%

2%

3%

2%

1%

6%

5%

2%

3%

1%

3%

2%

2%

1%

1%

1%

Respiratory

Pharyngitis

Sinusitis

Increased cough

3%

3%

1%

11%

1%

2%

2%

2%

1%

Skin

Sweating

Rash

Pruritus

Urticaria

6%

5%

2%

2%

5%

4%

4%

1%

2%

1%

2%

0%

Special senses

Tinnitus

Taste perversion

Blurred vision or
diplopia

6%

2%

3%

6%

4%

2%

2%

*

2%

Urogenital

Urinary frequency

Urinary urgency

Vaginal hemorrhage

Urinary tract infection

2%

*

0%

1%

5%

2%

2%

0%

2%

0%

*

*

Other Adverse Reactions Observed During the Clinical Development of Bupropion

In addition to the adverse reactions noted above, the following adverse reactions have been reported in clinical trials with the sustained-release formulation of bupropion in depressed subjects and in nondepressed smokers, as well as in clinical trials with the immediate-release formulation of bupropion.

Adverse reaction frequencies represent the proportion of subjects who experienced a treatment-emergent adverse reaction on at least one occasion in placebo-controlled trials for depression (n=987) or smoking cessation (n=1,013), or subjects who experienced an adverse reaction requiring discontinuation of treatment in an open-label surveillance trial with bupropion hydrochloride extended-release tablets (SR) (n=3,100). All treatment-emergent adverse reactions are included except those listed in Table 3 , those listed in other safety-related sections of the prescribing information, those subsumed under COSTART terms that are either overly general or excessively specific so as to be uninformative, those not reasonably associated with the use of the drug, and those that were not serious and occurred in fewer than 2 subjects.

Adverse reactions are further categorized by body system and listed in order of decreasing frequency according to the following definitions of frequency: Frequent adverse reactions are defined as those occurring in at least 1/100 subjects. Infrequent adverse reactions are those occurring in 1/100 to 1/1,000 subjects, while rare events are those occurring in less than 1/1,000 subjects.

Body (General)

Infrequent were chills, facial edema, and photosensitivity. Rare was malaise.

Cardiovascular

Infrequent were postural hypotension, stroke, tachycardia, and vasodilation. Rare were syncope and myocardial infarction.

Digestive

Infrequent were abnormal liver function, bruxism, gastric reflux, gingivitis, increased salivation, jaundice, mouth ulcers, stomatitis, and thirst. Rare was edema of tongue.

Hemic and Lymphatic

Infrequent was ecchymosis.

Metabolic and Nutritional

Infrequent were edema and peripheral edema.

Musculoskeletal

Infrequent were leg cramps.

Nervous System

Infrequent were abnormal coordination, decreased libido, depersonalization, dysphoria, emotional lability, hostility, hyperkinesia, hypertonia, hypesthesia, suicidal ideation, and vertigo. Rare were amnesia, ataxia, derealization, and hypomania.

Respiratory

Rare was bronchospasm.

Special Senses

Infrequent were accommodation abnormality and dry eye.

Urogenital

Infrequent were impotence, polyuria, and prostate disorder.

Changes in Body Weight

In placebo-controlled trials, subjects experienced weight gain or weight loss as shown in Table 4.

Table 4. Incidence of Weight Gain and Weight Loss (≥5 lbs) in Placebo-Controlled Trials

Weight Change

Bupropion Hydrochloride Extended-Release Tablets (SR)

300 mg/day (n = 339)

Bupropion Hydrochloride Extended-Release Tablets (SR)

400 mg/day (n = 112)

Placebo (n = 347)

Gained >5 lbs

Lost >5 lbs

3%

14%

2%

19%

4%

6%

In clinical trials conducted with the immediate-release formulation of bupropion, 35% of subjects receiving tricyclic antidepressants gained weight, compared with 9% of subjects treated with the immediate-release formulation of bupropion. If weight loss is a major presenting sign of a patient’s depressive illness, the anorectic and/or weight-reducing potential of bupropion hydrochloride extended-release tablets (SR) should be considered.

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