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Adverse Events Leading to Discontinuation of Treatment With Wellbutrin or Wellbutrin SR: In placebo-controlled clinical trials, 9% and 11% of patients treated with 300 and 400 mg/day, respectively, of the sustained-release formulation of bupropion and 4% of patients treated with placebo discontinued treatment due to adverse events. The specific adverse events in these trials that led to discontinuation in at least 1% of patients treated with either 300 mg/day or 400 mg/day of Wellbutrin SR and at a rate at least twice the placebo rate are listed in Table 6. (See Table 6.)
Click on icon to see table/diagram/imageIn clinical trials with the immediate-release formulation of bupropion, 10% of patients and volunteers discontinued due to an adverse event. Events resulting in discontinuation, in addition to those listed previously for the sustained-release formulation of bupropion, include vomiting, seizures and sleep disturbances.
Adverse Events Occurring at an Incidence of ≥1% Among Patients Treated With Wellbutrin or Wellbutrin SR: Table 7 enumerates treatment-emergent adverse events that occurred among patients treated with 300 and 400 mg/day of the sustained-release formulation of bupropion and with placebo in controlled trials. Events that occurred in either the 300 or 400 mg/day group at an incidence of ≥1% and were more frequent than in the placebo group are included. Reported adverse events were classified using a COSTART-based dictionary.
Accurate estimates of the incidence of adverse events associated with the use of any drug are difficult to obtain. Estimates are influenced by drug dose, detection technique, setting, physician judgments, etc. The figures cited cannot be used to predict precisely the incidence of untoward events in the course of usual medical practice where patient characteristics and other factors differ from those that prevailed in the clinical trials. These incidence figures also cannot be compared with those obtained from other clinical studies involving related drug products as each group of drug trials is conducted under a different set of conditions.
Finally, it is important to emphasize that the tabulation does not reflect the relative severity and/or clinical importance of the events. A better perspective on the serious adverse events associated with the use of bupropion is provided in Warnings and Precautions. (See Table 7.)
Click on icon to see table/diagram/imageAdditional events to those listed in Table 7 that occurred at an incidence of at least 1% in controlled clinical trials of the immediate-release formulation of bupropion (300-600 mg/day) and that were numerically more frequent than placebo were: Cardiac arrhythmias (5% vs 4%), hypertension (4% vs 2%), hypotension (3% vs 2%), tachycardia (11% vs 9%), appetite increase (4% vs 2%), dyspepsia (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%).
Incidence of Commonly Observed Adverse Events in Controlled Clinical Trials: Adverse events from Table 7 occurring in at least 5% of patients treated with the sustained-release formulation of bupropion and at a rate at least twice the placebo rate are listed as follows for the 300 and 400 mg/day dose groups.
Wellbutrin SR 300 mg/day: Anorexia, dry mouth, rash, sweating, tinnitus and tremor.
Wellbutrin SR 400 mg/day: Abdominal pain, agitation, anxiety, dizziness, dry mouth, insomnia, myalgia, nausea, palpitation, pharyngitis, sweating, tinnitus and urinary frequency.
Seasonal Affective Disorder: Adverse Events Leading to Discontinuation of Treatment with Wellbutrin XL: In placebo-controlled clinical trials, 9% of patients treated with Wellbutrin XL and 5% of patients treated with placebo discontinued treatment due to adverse events. The adverse events in these trials that led to discontinuation in at least 1% of patients treated with Wellbutrin XL and at a rate numerically greater than the placebo rate are insomnia (2% vs <1%) and headache (1% vs <1%).
Adverse Events Occurring at an Incidence of ≥2% Among Patients Treated With Wellbutrin XL: Table 8 enumerates treatment-emergent adverse events that occurred among patients treated with Wellbutrin XL for up to approximately 6 months in 3 placebo-controlled trials. Events that occurred at an incidence of ≥2% and were more frequent than in the placebo group are included. Reported adverse events were classified using a MedDRA-based dictionary.
Accurate estimates of the incidence of adverse events associated with the use of any drug are difficult to obtain. Estimates are influenced by drug dose, detection technique, setting, physician judgments, etc. The figures cited cannot be used to predict precisely the incidence of untoward events in the course of usual medical practice where patient characteristics and other factors differ from those that prevailed in the clinical trials. These incidence figures also cannot be compared with those obtained from other clinical studies involving related drug products as each group of drug trials is conducted under a different set of conditions; eg, different patient populations, different treatment durations.
Finally, it is important to emphasize that the tabulation does not reflect the relative severity and/or clinical importance of the events. A better perspective on the serious adverse events associated with the use of bupropion is provided in Warnings and Precautions. (See Table 8.)
Click on icon to see table/diagram/imageIncidence of Commonly Observed Adverse Events in Controlled Clinical Trials: Adverse events from Table 8 that occurred in at least 5% of patients treated with Wellbutrin XL and at a rate at least twice the placebo rate were constipation and flatulence.
Adverse Events During Taper or Following Discontinuation of Wellbutrin XL: Adverse events with onset during the 2 weeks following down-titration of Wellbutrin XL from 300 mg/day to 150 mg/day were reported by 14% of patients compared to 18% of patients who continued on placebo.
Adverse events with onset during the 2 weeks following discontinuation of Wellbutrin XL were reported by 9% of patients compared with 12% of patients following discontinuation of placebo.
Other Events Observed During the Clinical Development and Post-Marketing Experience of Bupropion: In addition to the adverse events noted previously, the following events have been reported in clinical trials and post-marketing experience with the sustained-release formulation of bupropion in depressed patients and in non-depressed smokers, as well as in clinical trials and post-marketing clinical experience with the immediate-release formulation of bupropion.
Adverse events for which frequencies are provided as follows occurred in clinical trials with the sustained-release formulation of bupropion. The frequencies represent the proportion of patients who experienced a treatment-emergent adverse event on at least 1 occasion in placebo-controlled studies for depression (n=987) or smoking cessation (n=1,013) or patients who experienced an adverse event requiring discontinuation of treatment in an open-label surveillance study with the sustained-release formulation of bupropion (n=3,100). All treatment-emergent adverse events are included except those listed in Tables 2, 3, 4, 5, 6, 7 and 8, those events listed in other safety-related sections, those adverse events subsumed under COSTART terms that are either overly general or excessively specific so as to be uninformative, those events not reasonably associated with the use of the drug and those events that were not serious and occurred in fewer than 2 patients. Events of major clinical importance are described in Warnings and Precautions.
Events are further categorized by body system and listed in order of decreasing frequency according to the following definitions of frequency: Frequent adverse events are defined as those occurring in at least 1/100 patients. Infrequent adverse events are those occurring in 1/100 to 1/1,000 patients, while rare events are those occurring in <1/1,000 patients.
Adverse events for which frequencies are not provided occurred in clinical trials or post-marketing experience with bupropion. Only those adverse events not previously listed for sustained-release bupropion are included. The extent to which these events may be associated with Wellbutrin XL is unknown.
Body (General): Infrequent were chills, facial edema, musculoskeletal chest pain and photosensitivity. Rare was malaise. Also observed were arthralgia, myalgia and fever with rash and other symptoms suggestive of delayed hypersensitivity. These symptoms may resemble serum sickness (see Precautions).
Cardiovascular: Infrequent were postural hypotension, stroke, tachycardia and vasodilation. Rare was syncope. Also observed were complete atrioventricular block, extrasystoles, hypotension, hypertension (in some cases severe, see Precautions), myocardial infarction, phlebitis and pulmonary embolism.
Digestive: Infrequent were abnormal liver function, bruxism, gastric reflux, gingivitis, glossitis, increased salivation, jaundice, mouth ulcers, stomatitis and thirst. Rare was edema of tongue. Also observed were colitis, esophagitis, gastrointestinal hemorrhage, gum hemorrhage, hepatitis, intestinal perforation, liver damage, pancreatitis and stomach ulcer.
Endocrine: Also observed were hyperglycemia, hypoglycemia and syndrome of inappropriate antidiuretic hormone (SIADH).
Hemic and Lymphatic: Infrequent was ecchymosis. Also observed were anemia, leukocytosis, leukopenia, lymphadenopathy, pancytopenia and thrombocytopenia. Altered prothrombin time (PT) and/or international normalized ratio (INR), infrequently associated with hemorrhagic or thrombotic complications, were observed when bupropion was co-administered with warfarin.
Metabolic and Nutritional: Infrequent were edema and peripheral edema. Also observed was glycosuria.
Musculoskeletal: Infrequent were leg cramps. Also observed were muscle rigidity/fever/rhabdomyolysis and muscle weakness.
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. Also observed were abnormal EEG, aggression, akinesia, aphasia, coma, delirium, delusions, dysarthria, dyskinesia, dystonia, euphoria, extrapyramidal syndrome, hallucinations, hypokinesia, increased libido, manic reaction, neuralgia, neuropathy, paranoid ideation, restlessness and unmasking tardive dyskinesia.
Respiratory: Rare was bronchospasm. Also observed was pneumonia.
Skin: Rare was maculopapular rash. Also observed were alopecia, angioedema, exfoliative dermatitis and hirsutism.
Special Senses: Infrequent were accommodation abnormality and dry eye. Also observed were deafness, diplopia, increased intraocular pressure and mydriasis.
Urogenital: Infrequent were impotence, polyuria and prostate disorder. Also observed were abnormal ejaculation, cystitis, dyspareunia, dysuria, gynecomastia, menopause, painful erection, salpingitis, urinary incontinence, urinary retention and vaginitis.
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