CONTRAINDICATIONS
Immediate Release and Sustained Release Tablets
Bupropion HCl is contraindicated in patients with a seizure disorder.
Buproprion HCl is contraindicated in patients treated with other medications that contain
bupropion because the incidence of seizure is dose-dependent.
Bupropion HCl is also contraindicated in patients with a current or prior diagnosis of
bulimia or anorexia nervosa because of a higher incidence of seizures noted in such
patients treated for bulimia with bupropion HCl immediate-relase formulation.
The concurrent administration of bupropion HCl and a monoamine oxidase (MAO)
inhibitor is contraindicated. At least 14 days should elapse between discontinuation of an
MAO inhibitor and initiation of treatment with bupropion HCl.
Bupropion HCl is contraindicated in patients who have shown an allergic response to
bupropion or the other ingredients that make up bupropion HCl.
WARNINGS
Patients should be made aware that Wellbutrin (bupropion HCl used to treat
depression) contains the same active ingredient found in Zyban (bupropion HCl
used as an aid for to smoking cessation treatment) and that Wellbutrin should not
be used in combination with Zyban, or any other medications that contain
bupropion.
Seizures
At doses of up to 300 mg/day, the incidence of seizures is approximately 0.1%
(1/1000) but increases to approximately 0.4% (4/1000) at the recommended dose
(for treatment of depression) of 400 mg/day of the sustained-release formulation
or 450 mg/day of the immediate-release formulation. The risk of seizure also
appears to be strongly associated with the presence of predisposing factors.
Immediate Release Formulation: Data for the immediate release bupropion
revealed a seizure incidence of approximately 0.4% (i.e., 13 of 3200 patients
followed propectively) in patients treated at doses in a range of 300 to 450 mg/day.
The 450 mg/day upper limit of this dose range is close to the currently
recommended maximum dose (for treatment of depression) of 400 mg/day for
bupropion sustained release tablets. The seizure incidence (0.4%) may exceed
that of other marketed antidepressants and doses of bupropion sustained release
tablets up to 300 mg/day by as much as fourfold. This relative risk is only an
approximate estimate because no direct comparative studies have been
conducted.
Additional data accumulated for the immediate release formulation of bupropion
suggested that the estimated seizure incidence increases almost tenfold between
450 and 600 mg/day, which is twice the usually required daily dose (300 mg) and
11/3 the maximum recommended daily dose (400 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 HCl experienced seizures. At the time of seizure, 7 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/day (2.3% incidence); 6 additional patients had 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 5 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. 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.
Sustained Release Formulations: Data for bupropion sustained release tablets
revealed a seizure incidence of approximately 0.1% (i.e., 3 of 3100 patients
followed prospectively) in patients treated during an 8-week treatment exposure
at doses in a range of 100 to 300 mg/day. It is not possible to know if the lower
seizure incidence observed in this study involving the sustained-release
formulation of bupropion resulted from the different formulation or the lower dose
used. However, the immediate-release and sustained-release formulations are
bioequivalent regarding both rate and extent of absorption during steady state,
(the most pertinent condition to estimating seizure incidence) since most
observed seizures occur under steady-state conditions.
Risk Factors: The risk of seizure is also related to patient factors, clinical
situations, and concomitant medications, which must be considered in selection of
patients for therapy with bupropion HCl.
Patient Factors: Predisposing factors that may increase the risk of seizure
with bupropion use include history of head trauma or prior seizure, central
nervous system (CNS) tumor, and concomitant medications that lower
seizure threshold.
Clinical Situations: Circumstances associated with an increased seizure risk
include, among others, excessive use of alcohol; abrupt withdrawal from
alcohol or other sedatives; addiction to opiates, cocaine, or stimulants; use
of over-the-counter stimulants and anorectics; and diabetes treated with
oral hypoglycemics or insulin.
Concomitant Medications: Many medications (e.g., antipsychotics,
antidepressants, theophylline, systemic steroids) and treatment regimens
(e.g., abrupt discontinuation of benzodiazepines) are known to lower seizure
threshold.
Recommendations for Reducing the Risk of Seizure with the Sustained Release
Formulation: Retrospective analysis of clinical experience gained during the
development of bupropion suggests that the risk of seizure may be minimized if
The total daily dose of bupropion HCl sustained release tablets does not
exceed 400 mg for treatment of depression (450 mg for the
immediate-release tablet) or 300 mg, the maximum recommended dose for
smoking cessation.
The daily dose is administered twice daily (3 times daily for the immediate
release tablet).
The rate of incrementation of dose (for treatment of depression) is very
gradual.
No single dose should exceed 200 mg (150 mg, immediate-release tablet)
for treatment of depression or 150 mg for smoking cessation to avoid high
peak concentrations of bupropion and/or its metabolites.
Bupropion HCl should be administered with extreme caution to patients
with a history of seizure, cranial trauma, or other predisposition(s) toward
seizure, or patients treated with other agents (e.g., antipsychotics, other
antidepressants, theophylline, systemic steroids, 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.
PRECAUTIONS
General
Agitation and Insomnia: Patients in placebo-controlled trials with bupropion HCl
sustained release tablets experienced agitation, anxiety, and insomnia as shown in TABLE
3. For the immeditate release tablets, a substantial portion of patients experienced
increased relestness in addition to agitation, anxiety, and insomnia.
TABLE 3 Incidence of Agitation, Anxiety, and Insomnia in
Placebo-Controlled Trials
Adverse
Event Term
Bupropion HCl SR
300 mg/day (n=376)
Bupropion HCl SR
400 mg/day (n=114)
Placebo
(n=385)
Agitation
3%
9%
2%
Anxiety
5%
6%
3%
Insomnia
11%
16%
6%
In clinical studies of both the immediate and sustained release formulations of bupropion
HCl, these symptoms were sometimes of sufficient magnitude to require treatment with
sedative/hypnotic drugs.
Symptoms were sufficiently severe to require discontinuation of treatment in 1% and
2.6% of patients treated with 300 and 400 mg/day, respectively, of bupropion HCl
sustained release tablets and 0.8% of patients treated with placebo.
Immediate Release Tablets: In approximately 2% of patients, symptoms were
sufficiently severe to require discontinuation of treatment with bupropion HCl.
Bupropion HCl for Smoking Cessation: In the dose-responsive smoking cessation trial,
29% of patients treated with 150 mg/day of bupropion HCl sustained release tablets and
35% of patients treated with 300 mg/day of bupropion HCl sustained release tablets
experienced insomnia, compared to 21% of placebo-treated patients. Symptoms were
sufficiently severe to require discontinuation of treatment in 0.6% of patients treated with
bupropion HCl and none of the patients treated with placebo.
In the comparative trial, 40% of the patients treated with 300 mg/day of bupropion HCl
sustained release tablets, 28% of the patients treated with 21 mg/day of NTS, and 45%
of the patients treated with the combination of bupropion HCl sustained release tablets
and NTS experienced insomnia compared with 18% of placebo-treated patients.
Symptoms were sufficiently severe to require discontinuation of treatment in 0.8% of
patients treated with bupropion HCl and none of the patients in the other three treatment
groups.
Insomnia may be minimized by avoiding bedtime doses and, if necessary, reduction in
dose.
Pyschosis, Confusion, and Other Neuropyschiatric Phenomena: Depressed patients
treated with an immediate-release formulation of bupropion or with the sustained release
tablets have been reported to show a variety of neuropsychiatric signs and symptoms,
including delusions, hallucinations, pyschosis, concentration disturbance, paranoia, and
confusion. In some cases, these symptoms abated upon dose reduction and/or
withdrawal of treatment. In clinical trials with bupropion HCl sustained release tablets
conducted in nondepressed smokers, the incidence of neuropsychiatric side effects was
generally comparable to placebo. 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 HCl.
Activation of Psychosis and/or Mania: Antidepressants can precipitate manic episodes
in bipolar disorder patients during the depressed phase of their illness and may activate
latent pyschosis in other susceptible patients. Bupropion HCl sustained release
formulation is expected to pose similar risks. There were no reports of activation of
psychosis or mania in clinical trials with bupropion HCl sustained release formulation
conducted in nondepressed smokers.
Altered Appetite and Weight: In placebo-controlled studies with the sustained release
tablets, patients experienced weight gain or weight loss as shown in TABLE 4.
TABLE 4 Incidence of Weight Gain and Weight Loss in
Placebo-Controlled Trials
Weight
Change
Bupropion HCl
Sustained Release 300
mg/day (n=339)
Bupropion HCl
Sustained Release 400
mg/day (n=112)
Placebo
(n=347)
Gained >5
lbs
3%
2%
4%
Lost >5 lbs
14%
19%
6%
In studies conducted with the immediate-release formulation of bupropion, a weight loss
of greater than 5 pounds occurred in 28% of bupropion HCl patients. This incidence is
approximately double that seen in comparable patients treated with tricyclics or placebo.
Furthermore, 35% of patients receiving tricyclic antidepressants gained weight, compared
to 9% of patients treated with the immediate-release formulation of bupropion. If weight
loss is a major presenting sign of a patient's depressive illness, the anorectic and/or
weight-reducing potential of bupropion HCl sustained release tablets 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 HCl should be
written for the smallest number of tablets consistent with good patient management.
Allergic Reactions: Anaphylactoid/anaphylactic reactions characterized by symptoms
such as pruritis, urticaria, angioedema, and dyspnea requiring medical treatment have
been reported for bupropion HCl for smoking cessation (at a rate of about 1-3 per
thousand) in clinical trials of bupropion HCl. In addition, there have been rare
spontaneous postmarketing reports of erythema multiforme, Stevens-Johnson syndrome,
and anaphylactic shock associated with bupropion. A patient should stop taking
bupropion HCl and consult a doctor if experiencing allergic or anaphylactic reactions
(e.g., skin rash, pruritus, hives, chest pain, edema, and shortness of breath) during
treatment.
Use in Patients With Systemic Illness
There is no clinical experience establishing the safety of bupropion HCl sustained release
tablets 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 depressed patients who had previously developed orthostatic hypotension
while receiving tricyclic antidepressants, The sustained release tablets was also generally
well tolerated in a group of 36 depressed inpatients with stable congestive heart failure
(CHF). However, bupropion was associated with a rise in supine blood pressure in the
study of patients with CHF, resulting is discontinuation of treatment in two patients for
exacerbation of baseline hypertension.
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 to a
greater extent than usual. The patient should be closely monitored for possible toxic
effects of elevated blood and tissue levels of drug and metabolites.
In the comparative trial of bupropion as an aid to smoking cessation, 6.1% of patients
treated with the combination of bupropion HCl sustained release tablets and NTS had
treatment-emergent hypertension compared to 2.5%, 1.6%, and 3.1% of patients treated
with bupropion HCl, NTS, and placebo respectively. The majority of these patients had
evidence of preexisting hypertension. Three patients (1.2%) treated with the combination
of bupropion HCl and NTS and one patient (0.4%) treated with NTS had study
medication discontinued due to hypertension compared to none of the patients treated
with bupropion or placebo. Monitoring for treatment-emergent hypertension is
recommended in patients receiving the combination of bupropion HCl sustained release
tablets and NTS.
Information for the Patient
See PATIENT PACKAGE INSERT.
Patients should be made aware that Zyban, used as an aid to smoking cessation, contains
the same active ingredient found in Wellbutrin and Wellbutrin SR used to treat depression
and that Zyban should not be used in conjunction with Wellbutrin, Wellbutrin SR, or any
other medications that contain bupropion HCl.
Physicians Are Advised to Discuss the Following Issues with Patients Treated for
Depression:
As dose is increased during initial titration to doses above 150 mg/day, patients
should be instructed to take bupropion sustained release tablets in two divided
doses, preferably with at least eight hours between successive doses, to minimize
the risk of seizures.
Patients should be told that any CNS-active drug like bupropion HCl may impair
their ability to perform tasks requiring judgement or motor and cognitive skills.
Consequently, until they are reasonably certain that bupropion HCl 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 the cessation of use of alcohol may alter
seizure threshold, and, therefore, that the consumption of alcohol should be
minimized, and if possible, avoided completely.
Patients should be advised to inform their physicians if they are taking or plan to
take any prescription or over-the-counter drugs. Concern is warranted because
bupropion HCl and other drugs may affect each other's metabolism.
Patients should be advised to notify their physicians if they become pregnant or
intend to become pregnant during therapy.
Patients should be advised to swallow bupropion HCl sustained release tablets
whole so that the release rate is not altered. Do not chew, divide, or crush tablets.
Information for Patients Using Bupropion Sustained Release Tablets as an Aid to
Smoking Cessation: See PATIENT PACKAGE INSERT. Physicians are advised to
review the information with their patients.
Laboratory Tests
There are no specific laboratory tests recommended.
Carcinogenesis, Mutagenesis, and Impairment of Fertility
Lifetime carcinogenicity studies were performed in rats and mice at doses up to 300 and
150 mg/kg per day, respectively. These doses are approximately seven and two times the
maximum recommended dose (MRHD) for depression treatment, respectively, and ten
and two times the MRHD for smoking cessation, respectively, on a mg/m2 basis. In the
rat study, there was an increase in nodular proliferation lesions of the liver at doses of 100
to 300 mg/kg per day (approximately two to seven times the MRHD for depression
treatment and three to ten times the MRHD for smoking cessation on a mg/m2 basis):
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 positive response (two to three times control mutation rate) in two
of five strains in the Ames bacterial mutagenicity test and an increase in chromosomal
aberrations in one of three in vivo rat bone marrow cytogenetic studies for the sustained
release tablets. For the immediate release tablets, a high oral dose (300 mg/kg, 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 in rats at doses up to 300 mg/kg revealed no evidence of impaired
fertility.
Pregnancy, Teratogenic Effects, Pregnancy Category B
Teratology studies have been performed at doses up to 450 mg/kg in rats (approximately
14 times the MRHD on a mg/m2 basis for the immediate release tablets and for smoking
cessation and 7 to 11 times the MRHD for the sustained release tablets for depression),
and at doses up to 150 mg/kg in rabbits (approximately 7 times the MRHD for the
sustained release tablets for depression treatment, 10 times the MRHD for the sustained
release tablets for smoking cessation, and 45 times the MRHD for the immediate release
tablets for depression on a mg/m2 basis), and have revealed no evidence of harm to the
fetus due to bupropion. There are 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. Pregnant
smokers should be encouraged to attempt cessation using educational and behavioral
interventions before pharmacological approaches are used.
To monitor fetal outcomes of pregnant women exposed to bupropion HCl, Glaxo
Wellcome Inc. maintains a Bupropion Pregnancy Registry. Health care providers are
encouraged to register patients by calling (800) 336-2176.
Labor and Delivery
The effect of bupropion sustained release tablets on labor and delivery in humans is
unknown.
Nursing Mothers
Like many other drugs, bupropion and its metabolites are secreted in human milk.
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
Clinical trials with bupropion HCl for smoking cessation did not include individuals under
the age of 18. Therefore, the safety and efficacy in a pediatric smoking population have
not been established. The immediate release formulation of bupropion was studied in 104
pediatric patients (age range, 6 to 16) in clinical trials of the drug for other indications.
Although generally well tolerated, the limited exposure is insufficient to assess the safety
of bupropion in pediatric patients.
Geriatric Use
Of the approximately 6000 patients who participated in clinical trials with bupropion
sustained-release tablets (depression and smoking cessation studies), 275 were 65 and
over and 47 were 75 and over. In addition, several hundred patients 65 and over
participated in clinical trials using the immediate-release formulation of bupropion
(depression studies). No overall differences in safety or effectiveness were observed
between these subjects and younger subjects, and other reported clinical experience has
not identified differences in responses between the elderly and younger patients, but
greater sensitivity of some older individuals cannot be ruled out.
A single-dose pharmacokinetic study demonstrated that the disposition of bupropion and
its metabolites in elderly subjects was similar to that of younger subjects; however,
another pharmacokinetic study, single and multiple dose, has suggested that the elderly
are at increased risk for accumulation of bupropion and its metabolites (see CLINICAL
PHARMACOLOGY).
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.
The risk of toxic reaction to this drug may be greater in patients with impaired renal
function. Because elderly patients are more likely to have decreased renal function, care
should be taken in dose selection, and it may be useful to monitor renal function (see Use
in Patients with Systemic Illness).