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

5.2 Neuropsychiatric Adverse Events and Suicide Risk in Smoking Cessation Treatment

Bupropion hydrochloride tablets 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 cessations 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 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 tablets can cause seizure. The risk of seizure is dose-related. The dose should not exceed 450 mg/day. Increase the dose gradually. Discontinue bupropion hydrochloride tablets 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 tablets. Bupropion hydrochloride tablets 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), 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

Bupropion is associated with seizures in approximately 0.4% (4/1,000) of patients treated at doses up to 450 mg/day. The estimated seizure incidence for bupropion hydrochloride tablets increases almost 10-fold between 450 and 600 mg/day.

The risk of seizure can be reduced if the dose of bupropion hydrochloride tablets does not exceed 450 mg/day, given as 150 mg 3 times daily, and the titration rate is gradual.

5.4 Hypertension

Treatment with bupropion hydrochloride tablets can result in elevated blood pressure and hypertension. Assess blood pressure before initiating treatment with bupropion hydrochloride tablets and monitor periodically during treatment. The risk of hypertension is increased if bupropion hydrochloride tablets 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 tablets, 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 tablets are not approved for use in treating bipolar depression.

5.6 Psychosis and Other Neuropsychiatric Reactions

Depressed patients treated with bupropion hydrochloride tablets 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 tablets 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 tablets 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, 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

Adverse reactions were sufficiently troublesome to cause discontinuation of treatment with bupropion hydrochloride tablets in approximately 10% of the 2,400 subjects and healthy volunteers who participated in clinical trials during the product’s initial development. The more common events causing discontinuation include neuropsychiatric disturbances (3.0%), primarily agitation and abnormalities in mental status; gastrointestinal disturbances (2.1%), primarily nausea and vomiting; neurological disturbances (1.7%), primarily seizures, headaches, and sleep disturbances; and dermatologic problems (1.4%), primarily rashes. It is important to note, however, that many of these events occurred at doses that exceed the recommended daily dose.

Commonly Observed Adverse Reactions

Adverse reactions commonly encountered in subjects treated with bupropion hydrochloride tablets are agitation, dry mouth, insomnia, headache/migraine, nausea/vomiting, constipation, tremor, dizziness, excessive sweating, blurred vision, tachycardia, confusion, rash, hostility, cardiac arrhythmia, and auditory disturbance.

Table 2 summarizes the adverse reactions that occurred in placebo-controlled trials at an incidence of at least 1% of subjects receiving bupropion hydrochloride tablets and more frequently in these subjects than in the placebo group.

Table 2. Adverse Reactions Reported by at Least 1% of Subjects and at a Greater Frequency than Placebo in Controlled Clinical Trials

Adverse Reaction Bupropion Hydrochloride Tablets (n = 323) % Placebo (n = 185) %
Cardiovascular
Cardiac arrhythmias 5.3 4.3
Dizziness 22.3 16.2
Hypertension 4.3 1.6
Hypotension 2.5 2.2
Palpitations 3.7 2.2
Syncope 1.2 0.5
Tachycardia 10.8 8.6
Dermatologic
Pruritus 2.2 0.0
Rash 8.0 6.5
Gastrointestinal
Appetite increase 3.7 2.2
Constipation 26.0 17.3
Dyspepsia 3.1 2.2
Nausea/vomiting 22.9 18.9
Genitourinary
Impotence 3.4 3.1
Menstrual complaints 4.7 1.1
Urinary frequency 2.5 2.2
Musculoskeletal
Arthritis 3.1 2.7
Neurological
Akathisia 1.5 1.1
Cutaneous temperature disturbance 1.9 1.6
Dry mouth 27.6 18.4
Excessive sweating 22.3 14.6
Headache/migraine 25.7 22.2
Impaired sleep quality 4.0 1.6
Insomnia 18.6 15.7
Sedation 19.8 19.5
Sensory disturbance 4.0 3.2
Tremor 21.1 7.6
Neuropsychiatric
Agitation 31.9 22.2
Anxiety 3.1 1.1
Confusion 8.4 4.9
Decreased libido 3.1 1.6
Delusions 1.2 1.1
Euphoria 1.2 0.5
Hostility 5.6 3.8
Nonspecific
Fever/chills 1.2 0.5
Special Senses
Auditory disturbance 5.3 3.2
Blurred vision 14.6 10.3
Gustatory disturbance 3.1 1.1

Other Adverse Reactions Observed during the Clinical Development of Bupropion Hydrochloride Tablets

The conditions and duration of exposure to bupropion hydrochloride tablets varied greatly, and a substantial proportion of the experience was gained in open and uncontrolled clinical settings. During this experience, numerous adverse events were reported; however, without appropriate controls, it is impossible to determine with certainty which events were or were not caused by bupropion hydrochloride tablets. The following enumeration is organized by organ system and describes events in terms of their relative frequency of reporting in the database.

The following definitions of frequency are used: 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.

Cardiovascular: Frequent was edema; infrequent were chest pain, electrocardiogram (ECG) abnormalities (premature beats and nonspecific ST-T changes), and shortness of breath/dyspnea; rare were flushing, and myocardial infarction.

Dermatologic: Infrequent was alopecia.

Endocrine: Infrequent was gynecomastia; rare was glycosuria.

Gastrointestinal: Infrequent were dysphagia, thirst disturbance, and liver damage/jaundice; rare was intestinal perforation..

Genitourinary: Frequent was nocturia; infrequent were vaginal irritation, testicular swelling, urinary tract infection, painful erection, and retarded ejaculation; rare were enuresis, and urinary incontinence.

Neurological: Frequent were ataxia/incoordination, seizure, myoclonus, dyskinesia, and dystonia; infrequent were mydriasis, vertigo, and dysarthria; rare were electroencephalogram (EEG) abnormality, and impaired attention.

Neuropsychiatric: Frequent were mania/hypomania, increased libido, hallucinations, decrease in sexual function, and depression; infrequent were memory impairment, depersonalization, psychosis, dysphoria, mood instability, paranoia, and formal thought disorder; rare was suicidal ideation.

Or al Complaints: Frequent was stomatitis; infrequent were toothache, bruxism, gum irritation, and oral edema.

Respiratory: Infrequent were bronchitis and shortness of breath/dyspnea; rare was pulmonary embolism.

Special Senses: Infrequent was visual disturbance; rare was diplopia.

Nonspecific: Frequent were flu-like symptoms; infrequent was nonspecific pain; rare was overdose.

Altered Appetite and Weight

A weight loss of greater than 5 lbs. occurred in 28% of subjects receiving bupropion hydrochloride tablets. This incidence is approximately double that seen in comparable subjects treated with tricyclics or placebo. Furthermore, while 35% of subjects receiving tricyclic antidepressants gained weight, only 9.4% of subjects treated with bupropion hydrochloride tablets did. Consequently, if weight loss is a major presenting sign of a patient’s depressive illness, the anorectic and/or weight-reducing potential of bupropion hydrochloride tablets should be considered.

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