Warnings
Seizures:
Bupropion is associated with seizures in approximately 0.4% (4/1000) of patients treated at doses up to 450 mg/day. This incidence of seizures may exceed that of other marketed antidepressants by as much as fourfold. This relative risk is only
an approximate estimate because no direct comparative studies have been conducted. The estimate seizure incidence for bupropion increases almost tenfold between 450 and 600 mg/day, which is twice the usually required daily dose (300 mg) and
one and one-third the maximum recommended daily dose (450 mg). Given the wide variability among individuals and their capacity to metabolize and eliminate drugs, this disproportionate increase in seizure incidence with dose incrementation calls
for caution in dosing.
During the initial development, 25 among approximately 2400 patients treated with bupropion experienced seizures. At the time of seizure, seven patients were receiving daily doses of 450 mg or below for an incidence of 0.33% (3/1000) within
the recommended dose range. Twelve patients experienced seizures at 600 mg per day (2.3% incidence); six additional patients has seizures at daily doses between 600 and 900 mg (2.8% incidence).
A separate, prospective study was conducted to determine the incidence of seizure during an 8-week treatment exposure in approximately 3200 additional patients who received daily doses of up to 450 mg. Patients were permitted to continue treatment
beyond 8 weeks if clinically indicated. Eight seizures occurred during the initial 8-week treatment period and five seizures were reported in patients continuing treatment beyond 8 weeks, resulting in a total seizure incidence of 0.4%.
The risk of seizure appears to be strongly associated with dose and the presence of predisposing factors. A significant seizure, CNS tumor, concomitant medications that lower seizure threshold, etc.) was present in approximately one-half of
the patients experiencing a seizure. Sudden and large increments in dose may contribute to increased risk. While many seizures occurred early in the course of treatment, some seizures did occur after several weeks at fixed dose.
Recommendations for reducing the risk of seizure:
Retrospective analysis of clinical experience gained during the development of bupropion suggests that the risk of seizure may be minimized if (1) the total daily dose of bupropion does not exceed 450 mg, (2) the daily dose is administered t.i.d.,
with each single dose not to exceed 150 mg to avoid high peak concentrations of bupropion and/or its metabolites, and (3) the rate of incrementation of dose is very gradual. Extreme caution should be used when bupropion is (1) administered to
patients with a history of seizure, cranial trauma, or other predisposition(s) toward seizure, or (2) prescribed with other agents (e.g., antipsychotics, other antidepressants, etc.) or treatment regimens (e.g., abrupt discontinuation of a benzodiazepine)
that lower seizure threshold.
Potential for Hepatotoxicity:
In rats receiving large doses of bupropion chronically, there was an increase in incidence of hepatic hyperplastic nodules and hepatocellular hypertrophy. In dogs receiving large doses of bupropion chronically, various histologic changes were
seen in the liver, and laboratory tests suggesting mild hepatocellular injury were noted. Although scattered abnormalities in liver function tests were detected in patients participating in clinical trials, there is no clinical evidence that
bupropion acts as a hepatotoxin in humans.
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