Precautions
General:
Agitation and Insomnia: A substantial proportion of patients treated with bupropion experience some degree of increased restlessness, agitation, anxiety, and insomnia, especially shortly after initiation of treatment. In clinical studies,
these symptoms were sometimes of sufficient magnitude to require treatment with sedative/hypnotic drugs. In approximately 2% of patients, symptoms were sufficiently severe to require discontinuation of treatment with bupropion.
Psychosis, Confusion, and Other Neuropsychiatric Phenomena: Patients treated with bupropion have been reported to show a variety of neuropsychiatric signs and symptoms including delusions, hallucinations, psychotic episodes, confusion,
and paranoia. Because of the uncontrolled nature of many studies, it is impossible to provide a precise estimate of the extent of risk imposed by treatment with bupropion. In several cases, neuropsychitric phenomena abated upon dose reduction
and/or withdrawal of treatment.
Activation of Psychosis and/or Mania: Antidepressants can precipitate manic episodes in Bipolar Manic Depressive patients during the depressed phase of their illness and may activate latent psychosis in other susceptible patients. Bupropion
is expected to pose similar risks.
Altered Appetite and Weight: A weight loss of greater than 5 pounds occurred in 28% of patients receiving bupropion. This incidence is approximately double that seen in comparable patients treated with tricyclics or placebo. Furthermore,
while 34.5% of patients receiving tricyclic antidepressants gained weight, only 9.4% of patients treated with bupropion 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 should be considered.
Suicide: The possibility of a suicide attempt is inherent in depression and may persist until significant remission occurs. Accordingly, prescriptions for bupropion should be written for the smallest number of tablets consistent with
good patient management.
Use in Patients with Systemic Illness:
There is no clinical experience establishing the safety of bupropion in patients with a recent history of myocardial infarction or unstable heart disease. Therefore, care should be exercised if it is used in these groups. Bupropion was well
tolerated in patients who has previously developed orthostatic hypotension while receiving tricyclic antidepressants.
Because bupropion HCl and its metabolites are almost completely excreted through the kidney and metabolites are likely to undergo conjugation in the liver prior to urinary excretion, treatment of patients with renal or hepatic, impairment should
be initiated at reduced dosage as bupropion and its metabolites may accumulate in such patients beyond concentrations expected in patients without renal or hepatic impairment. The patient should be closely monitored for possible toxic effects
of elevated blood and tissue levels of drug and metabolites.
Information for Patients:
Physicians are advised to discuss the following issues with patients:
Patients should be instructed to take bupropion in equally divided doses three or four times a day to minimize the risk of seizure.
Patients should be told that any CNS-active drug like bupropion may impair their ability to perform tasks requiring judgment or motor and cognitive skills. Consequently, until they are reasonably certain that bupropion does not adversely affect
their performance, they should refrain from driving an automobile or operating complex, hazardous machinery.
Patients should be told that the use and cessation of use of alcohol may alter the seizure threshold, and, therefore, that the consumption of alcohol should be minimized, and, if possible, avoided completely.
Patients should be advised to inform their physician if they are taking or plan to take any prescription or over-the-counter drugs. Concern is warranted because bupropion and other drugs may affect each others metabolism.
Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during therapy.
Drug Interactions:
No systematic data have been collected on the consequences of the concomitant administration of bupropion and other drugs.
However, animal data suggest that bupropion may be an inducer of drug metabolizing enzymes. This may be of potential clinical importance because the blood levels of co-administered drugs may be altered.
Alternatively, because bupropion is extensively metabolized, the co-administration of other drugs may affect its clinical activity. In particular, care should be exercised when administering drugs known to affect hepatic drug-metabolizing enzyme
systems (e.g., carbamazepine, cimetidine, phenobarbital, phenytoin).
Studies in animals demonstrate that the acute toxicity of buproprion is enhanced by the MAO inhibitor phenelzine (see CONTRAINDICATIONS).
Limited clinical data suggest a higher incidence of adverse experiences in patients receiving concurrent administration of bupropion and L-dopa. Administration of bupropion to patients receiving L-dopa concurrently should be undertaken with
caution, using small initial doses and small gradual dose increases.
Concurrent administration of bupropion and agents which lower seizure threshold should be undertaken only with extreme caution (see WARNINGS). Low initial dosing and small gradual dose increases should be employed.
Carcinogenesis, Mutagenesis, Impairment of Fertility:
Lifetime carcinogenicity studies were performed in rats and mice at doses up to 300 and 150 mg/kg/day, respectively. In the rat study there was an increase in nodular proliferative lesions of the liver at doses of 100 to 300 mg/kg/day; lower
doses were not tested. The question of whether or not such lesions may be precursors of neoplasms of the liver is currently unresolved. Similar liver lesions were not seen in the mouse study, and no increase in malignant tumors of the liver
and other organs was seen in either study.
Bupropion produced a borderline positive response (2 to 3 times control mutation rate) in some strains in the Ames bacterial mutagenicity test, and a high oral dose (300, but not 100 or 200 mg/kg) produced a low incidence of chromosomal aberrations
in rats. The relevance of these results in estimating the risk of human exposure to therapeutic doses is unknown.
A fertility study was performed in rats; no evidence of impairment of fertility was encountered at oral doses up to 300 mg/kg/day.
Pregnancy: Teratogenic Effects:
Pregnancy Category B: Reproduction studies have been performed in rabbits and rats at doses up to 15 to 45 times the human daily dose and have revealed no definitive evidence of impaired fertility or harm to the fetus due to bupropion. (In rabbits,
a slightly increased incidence of fetal abnormalities was seen in two studies, but there was no increase in any specific abnormality.) There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are
not always predictive of human response, this drug should be used during pregnancy only if clearly needed.
Labor and Delivery:
The effect of bupropion on labor and delivery in humans is unknown.
Nursing Mothers:
Because of the potential for serious adverse reactions in nursing infants from bupropion, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
Pediatric Use:
The safety and effectiveness of bupropion in individuals under 18 years old have not been established.
Use in the Elderly:
Bupropion has not been systematically evaluated in older patients.
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