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

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

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 wshow 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

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 INFORMATION section.

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).