The following adverse reactions are discussed in greater detail in other sections of the labeling:
- Neuropsychiatric symptoms and suicide risk in smoking cessation treatment [see BOXED WARNING, WARNINGS AND PRECAUTIONS]
- Suicidal thoughts and behaviors in adolescents and young adults [see BOXED WARNING, WARNINGS AND PRECAUTIONS]
- Seizure [see WARNINGS AND PRECAUTIONS]
- Hypertension [see WARNINGS AND PRECAUTIONS]
- Activation of mania or hypomania [see WARNINGS AND PRECAUTIONS]
- Psychosis and other neuropsychiatric reactions [see WARNINGS AND PRECAUTIONS]
- Angle-closure glaucoma [see WARNINGS AND PRECAUTIONS]
- Hypersensitivity reactions [see WARNINGS AND PRECAUTIONS]
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 in 8% of the 706 subjects treated with ZYBAN and 5% of the 313 patients treated with placebo. The more common events leading to discontinuation of treatment with ZYBAN included nervous system disturbances (3.4%), primarily tremors, and skin disorders (2.4%), primarily rashes.
Commonly Observed Adverse Reactions
The most commonly observed adverse reactions consistently associated with the use of ZYBAN were dry mouth and insomnia. The incidence of dry mouth and insomnia may be related to the dose of ZYBAN. The occurrence of these adverse reactions may be minimized by reducing the dose of ZYBAN. In addition, insomnia may be minimized by avoiding bedtime doses.
Adverse reactions reported in the dose-response and comparator trials are presented in Table 2 and Table 3, respectively. Reported adverse reactions were classified using a COSTART-based dictionary.
Table 2: Adverse Reactions Reported by at Least 1% of Subjects and at a Greater Frequency than Placebo in the Dose-response Trial
|Adverse Reaction||ZYBAN 100 to 300 mg/day
(n = 461) %
(n = 150) %
|Neck pain||2||< 1|
|Increased appetite||2||< 1|
|Taste perversion||2||< 1|
Table 3: Adverse Reactions Reported by at Least 1% of Subjects on Active Treatment and at a Greater Frequency than Placebo in the Comparator Trial
|Adverse Experience (COSTART Term)||ZYBAN 300 mg/day
(n = 243)%
|Nicotine Transdermal System (NTS) 21 mg/day
(n = 243)%
|ZYBAN and NTS
(n = 244)%
(n = 159)%
|Chest pain||< 1||1||3||1|
|Neck pain||2||1||< 1||0|
|Facial edema||< 1||0||1||0|
|Thirst||< 1||< 1||2||0|
|Increased cough||3||5||< 1||1|
|Application site reactiona||11||17||15||7|
|a Subjects randomized to ZYBAN or placebo received placebo patches.|
Adverse reactions in a 1-year maintenance trial and a 12-week COPD trial with ZYBAN were quantitatively and qualitatively similar to those observed in the dose-response and comparator trials.
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 sustained-release tablets (n = 3,100). All treatment-emergent adverse reactions are included except those listed in Tables 2 and 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): Frequent were asthenia, fever, and headache. Infrequent were chills, inguinal hernia, and photosensitivity. Rare was malaise.
Cardiovascular: Infrequent were flushing, migraine, postural hypotension, stroke, tachycardia, and vasodilation. Rare was syncope.
Digestive: Frequent were dyspepsia and vomiting. Infrequent were abnormal liver function, bruxism, dysphagia, gastric reflux, gingivitis, jaundice, and stomatitis.
Hemic and Lymphatic: Infrequent was ecchymosis.
Metabolic and Nutritional: Infrequent were edema and peripheral edema.
Musculoskeletal: Infrequent were leg cramps and twitching.
Nervous System: Frequent were agitation, depression, and irritability. Infrequent were abnormal coordination, CNS stimulation, confusion, decreased libido, decreased memory, depersonalization, emotional lability, hostility, hyperkinesia, hypertonia, hypesthesia, paresthesia, suicidal ideation, and vertigo. Rare were amnesia, ataxia, derealization, and hypomania.
Respiratory: Rare was bronchospasm.
Skin: Frequent was sweating.
Special Senses: Frequent was blurred vision or diplopia. Infrequent were accommodation abnormality and dry eye.
Urogenital: Frequent was urinary frequency. Infrequent were impotence, polyuria, and urinary urgency.
The following adverse reactions have been identified during post-approval use of ZYBAN and are not described elsewhere in the label. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a relationship to drug exposure.
Body (General): Arthralgia, myalgia, and fever with rash and other symptoms suggestive of delayed hypersensitivity. These symptoms may resemble serum sickness [see WARNINGS AND PRECAUTIONS].
Cardiovascular: Cardiovascular disorder, complete AV block, extrasystoles, hypotension, myocardial infarction, phlebitis, and pulmonary embolism.
Digestive: Colitis, esophagitis, gastrointestinal hemorrhage, gum hemorrhage, hepatitis, increased salivation, intestinal perforation, liver damage, pancreatitis, stomach ulcer, and stool abnormality.
Endocrine: Hyperglycemia, hypoglycemia, and syndrome of inappropriate antidiuretic hormone.
Hemic and Lymphatic: Anemia, leukocytosis, leukopenia, lymphadenopathy, pancytopenia, and thrombocytopenia. Altered PT and/or INR, infrequently associated with hemorrhagic or thrombotic complications, were observed when bupropion was coadministered with warfarin.
Metabolic and Nutritional: Glycosuria.
Musculoskeletal: Arthritis and muscle rigidity/fever/rhabdomyolysis, and muscle weakness.
Nervous System: Abnormal electroencephalogram (EEG), aggression, akinesia, aphasia, coma, completed suicide, delirium, delusions, dysarthria, dyskinesia, dystonia, euphoria, extrapyramidal syndrome, hallucinations, hypokinesia, increased libido, manic reaction, neuralgia, neuropathy, paranoid ideation, restlessness, suicide attempt, and unmasking tardive dyskinesia.
Skin: Alopecia, angioedema, exfoliative dermatitis, hirsutism, and Stevens-Johnson syndrome.
Special Senses: Deafness, increased intraocular pressure, and mydriasis.
Urogenital: Abnormal ejaculation, cystitis, dyspareunia, dysuria, gynecomastia, menopause, painful erection, prostate disorder, salpingitis, urinary incontinence, urinary retention, urinary tract disorder, and vaginitis.