Bupropion Hydrochloride (000550)

CATEGORIES:

FDA DRUG CLASS: Antidepressants; CNS, Miscellaneous

BRAND NAMES: Wellbutrin (US); Wellbutrin SR (US); Zyban (US);

COST OF THERAPY: $ 239.24 (Depression; Tablet; 150 mg; 2/day; 90 days)


DESCRIPTION:

CLINICAL PHARMACOLOGY:
Immediate Release and Sustained Release Tablets
Pharmacodynamics and Pharmacological Actions

Immediate Release Tablets: The neurochemical mechanism of the antidepressant effect of bupropion is not known. Bupropion does not inhibit monoamine oxidase. Compared to classical tricyclic antidepressants, it is a weak blocker of the neuronal uptake of serotonin and norepinephrine; it also inhibits the neuronal re-uptake of dopamine to some extent. Bupropion produces dose-related CNS stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behavior tasks, and, at high doses, induction of mild stereotyped behavior.

Bupropion causes convulsions in rodents and dogs at doses approximately tenfold the dose recommended as the human antidepressant dose.

Sustained Release Tablets: Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine, serotonin, and dopamine, and does not inhibit monoamine oxidase. While the mechanism of action of bupropion, as with other antidepressants, is unknown, it is presumed that this action is mediated by noradrenergic and/or dopaminergic mechanisms. The mechanism by which bupropion enhances the ability of patients to abstain from smoking is unknown. However, it is presumed that this action is also mediated by nonadrenergic and/or dopaminergic mechanisms.

Following oral administration of bupropion sustained release tablets to healthy volunteers, peak plasma concentrations of bupropion are achieved within 3 hours. The mean peak concentration (C_max) values were 91 and 143 ng/ml from two single-dose (150 mg) studies. At steady state, the mean C_max following a 150 mg dose every 12 hours is 136 ng/ml.

In a single-dose study, food increased C_max by 11% and the extent of absorption as defined by area under the plasma concentration-time curve (AUC) of bupropion by 17%. The mean time to peak concentration (t_max) was prolonged by 1 hour. This effect was of no clinical significance.

In vitro tests show that bupropion is 84% bound to human albumin at plasma concentrations up to 200 mcg/ml. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. The volume of distribution (V_ss/F) estimated from a single 150-mg dose given to 17 subjects is 1950 L (20% CV).

Following oral administration of 200 mg of ¹⁴C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion HCl excreted unchanged was only 0.5%, a finding documenting the extensive metabolism of bupropion.

The mean elimination half-life (±SD) of bupropion after chronic dosing is 21 (±9) hours, and steady-state plasma concentrations of bupropion are reached within 8 days.

Plasma and urinary metabolites so far identified include biotransformation products formed via reduction of the carbonyl group and/or hydroxylation of the tert -butyl group of bupropion. Four basic metabolites have been identified. They are the erythro - and threo -amino alcohols of bupropion (erythrohydrobupropion and threohydrobupropion), the erythro -amino diol of bupropion, and a morpholinol metabolite (hydroxybupropion, formed from hydroxylation of the tert -butyl group of bupropion). These metabolites of bupropion are pharmacologically active, but their potency and toxicity relative to bupropion have not been fully characterized. They may be of clinical importance because the plasma concentrations of the metabolites are higher than those of bupropion.

Following a single dose in humans, peak plasma concentrations of the morpholinol metabolite (hydroxybupropion) occur approximately 6 hours after administration of bupropion HCl sustained release tablets. Peak plasma concentrations of the morpholinol metabolite are approximately 10 times the peak level of the parent drug at steady state with bupropion HCl sustained release tablets. The elimination half-life of the morpholinol metabolite is approximately 20 (±5) hours, and its AUC at steady state is about 17 times that of bupropion.

The times to peak concentrations for the erythro- and threo -amino alcohol metabolites (erythrohydrobuprobion and threohydrobupropion) are similar to that of the morpholinol metabolite. However, their elimination half-lives are longer, 33 (±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion.

The erythro -amino diol metabolite generally cannot be detected in the systematic circulation following a single oral dose of the parent drug.

In a study comparing chronic dosing with bupropion HCl sustained release tablets 150 mg twice a day to the immediate release formulation of bupropion at 100 mg three times a day, peak plasma concentrations of bupropion at steady state for bupropion HCl sustained release tablets were approximately 85% of those achieved with the immediate-release formulation. There was equivalence for both peak plasma concentration and AUCs for all three of the detectable bupropion metabolites. Thus, at steady state, bupropion sustained release tablets and the immediate-release formulation are essentially bioequivalent for both bupropion and the three quantitatively important metabolites.

Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg/day.

Bupropion is a racemic mixture. The pharmacologic activity and pharmacokinetics of the individual enantiomers have not been studied. Bupropion follows biphasic pharmacokinetics best described by a two-compartment model. The terminal phase has a mean half-life (±% CV) of about 21 hours (±20%), while the distribution phase has a mean half-life of 3 to 4 hours.

Bupropion has not been administered intravenously to humans; therefore, the absolute bioavailability of bupropion sustained-release tablets in humans has not been determined. In rat and dog studies, the bioavailability of bupropion ranged from 5% to 20%.

Bupropion is extensively metabolized in humans. There are three active metabolites: hydroxybupropion and the amino-alcohol isomers threohydrobupropion and erythrohydrobupropion, which are formed via hydroxylation of the tert -butyl group of bupropion and/or reduction of the carbonyl group. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potenticity and toxicity of the metabolites relative to bupropion have not been fully characterized; however, it has been demonstrated in mice that hydroxybupropion is comparable in potency to bupropion, while the other metabolites are one tenth to one half as potent. This may be of clinical importance because the plasma concentrations of the metabolites are higher than those of bupropion. In vitro findings suggest that cytochrome P450 2B6 (CYP2B6) is the principle isoenzyme involved in the formation of hydroxybupropion, which cytochrome P450 isoenzymes are not involved in the formation of threohydrobupropion.

Factors or conditions altering metabolic capacity (e.g. , liver disease, congestive heart failure, age, concomitant medications, etc.) or elimination may be expected to influence the degree and extent of accumulation of the active metabolites of bupropion. The elimination of the major metabolites of bupropion may be affected by reduced renal or hepatic function because they are moderately polar compounds and are likely to undergo further metabolism or conjugation in the liver prior to urinary excretion.

Hepatic: The disposition of bupropion following a single 200-mg oral dose was compared in eight healthy volunteers and eight weight- and age-matched volunteers with alcoholic liver disease. The half-life of the morpholinol metabolite (hydroxybupropion) was significantly prolonged in subjects with alcoholic liver disease (32 hours [±41%] versus 21 hours [±23%]). The differences in half-life for bupropion and the other metabolites in the two patient groups were minimal.

Renal: The effect of renal disease on the pharmacokinetics of bupropion has not been studied. The elimination of the major metabolites of bupropion may be affected by reduced renal function.

Left Ventricular Dysfunction: During a chronic dosing study with bupropion in 14 depressed patients with left ventricular dysfunction (history of congestive heart failure or an enlarged heart on x-ray), there was substantial interpatient variability (twofold to fivefold) in the trough steady-state concentrations of bupropion and the morpholinol and threo -amino alcohol metabolites. This variability was in the same range of the variability observed in healthy volunteers (threefold to eightfold). In addition, the steady-state plasma concentrations of these metabolites were 10 to 100 times the steady-state concentrations of the parent drug.

Age: The effects of age on the pharmacokinetics of bupropion and its metabolites have not been fully characterized, but an exploration of steady-state bupropion concentrations from several efficacy studies involving patients dosed in a range of 300 to 750 mg/day, on a three-times daily schedule, revealed no relationship between age (18 to 83 years) and plasma concentration of bupropion. These data suggest there is no prominent effect of age on bupropion concentration (see PRECAUTIONS, Geriatric Use).

Gender: A single-dose study involving 12 healthy male and 12 healthy female volunteers revealed no sex-related differences in the pharmacokinetic parameters of bupropion.

CLINICAL STUDIES:
Anti-Depression:

The efficacy of the immediate-release formulation of bupropion as a treatment for depression was established in two 4-week, placebo-controlled trials in adult inpatients with depression and in one 6-week, placebo-controlled trial in adult outpatients with depression. In the first study, patients were titrated in a bupropion dose range of 300 to 600 mg/day on a three times daily schedule; 78% of patients received maximum doses of 450 mg/day or less. This trial demonstrated the effectiveness of the immediate-release formulation of bupropion on the Hamilton Depresssion Rating Scale (HDRS) total score, the depressed mood item (i.e., 1) from that scale, and the Clinical Global Impressions (CGI) severity score. A second study included two fixed doses of the immediate-release formulation of bupropion (300 and 450 mg/day) and placebo. This trial demonstrated the effectiveness of the immediate-release formulation of bupropion, but only at 450-mg/day dose; the results were positive for the HDRS total score and the CGI severity score, but not for HDRS item 1. In the third study, outpatients received 300 mg/day of the immediate-release formulation of bupropion. This study demonstrated the effectiveness of the immediate-release formulation of bupropion on the HDRS total score, HDRS item 1, the Montgomery-Asberg Depression Rating Scale, the CGI severity score, and the CGI improvement score.

Although there are not as yet independent trials demonstrating the antidepressant effectiveness of the sustained-release formulation of bupropion, studies have demonstrated the bioequivalence of the immediate-release and sustained-release forms of bupropion under steasy state conditions, i.e. , bupropion sustained-release 150 mg twice daily was shown to be bioequivalent to the 100 mg, three-times daily dose of the immediate-release formulation of bupropion, with regard to both rate and extent of absorption, for parent drug and metabolites.

The efficacy of bupropion as an aid to smoking cessation was demonstrated in two placebo-controlled, double-blind trials in nondepressed chronic cigarette smokers (n=1508, 15 cigarettes per day). In these studies, bupropion was used in conjuction with individual smoking cessation counseling.

The first study was a dose-response trial conducted at three clinical centers. Patients in this study were treated for 7 weeks with one of three doses of bupropion sustained elease tablets (100, 150, or 300 mg/day) or placebo; quitting was defined as total abstinene during the last 4 weeks of treatment (weeks 4 through 7). Abstinence was determined by patient daily diaries and verified by carbon monoxide levels in expired air.

Results of this dose-response trial with bupropion sustained release tablets demonstrated a dose-dependent increase in the percentage of patients able to achieve 4-week abstinence (weeks 4 through 7). Treatment with bupropion sustained release tablets at both 150 and 300 mg/day was significantly more effective than placebo in this study.

TABLE 1 presents quit rates over time in the multicenter trial by treatment group. The quit rates are the proportions of all persons initially enrolled (i.e. , intent to treat analysis) who abstained from week 4 of the study through the specified week. Treatment with bupropion sustained release tablets (150 or 300 mg/day) was more effective than placebo in helping patients achieve 4-week abstinence. In addition, treatment with bupropion sustained release tablets (7 weeks at 300 mg/day) was more effective than placebo in helping patients maintain continuous abstinence through week 26 (6 months) of the study.

TABLE 2 presents quit rates over time by treatment group for the comparative trial. Both bupropion sustained release tablets and NTS were more effective than placebo in helping patients maintain abstinence through week 10 of the study. The treatmetn combination of bupropion sustained release tablets and NTS displayed the highest rates of continuous abstinence throughout the study.

INDICATIONS AND USAGE:
Sustained Release and Immediate Release Tablets: Treatment for Depression

Bupropion HCl is indicated for the treatment of depression.

A physician considering bupropion SR tablets for the management of a patient's first episode of depression should be aware that the drug may cause generalized seizures in a dose-dependent manner with an approximate incidence of 0.4% (4/1,000) at the upper end of the recommended dose range, i.e. , 400 mg/day, and an incidence of 0.1% (1/1,000) at a bupropion dose of 300 mg/day. Bupropion's seizure incidence at the 400-mg/day dose may exceed that of other marketied 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 (see WARNINGS).

The efficacy of bupropion in the treatment of depression was established in two 4-week controlled trials of depressed inpatients and in one 6-week controlled trial of depressed outpatients whose diagnoses corresponded most closely to the Major Depression category of the APA Diagnostic and Statistical Manual (DSM) (see CLINICAL PHARMACOLOGY.)

A major depressive episode (DSM-IV) implies the presence of 1) depressed mood or 2) loss of interest or pleasure; in addition, at least five of the following symptoms have been present during the same 2-week period and represent a change from previous functioning: depressed mood, markedly diminished interest or pleasure in usual activities, significant change in weight and/or appetite, insomnia or hypersomia, psychomotor agitation or retardation, increased fatigue, feeling of guilt or worthlessness, slowed thinking or impaired concentration, a suicide attempt or suicidal ideation.

Effectiveness of bupropion in long-term use (more than 6 weeks) has not been systematically evaluated in controlled trials. Therefore, the physician who elects to use bupropion sustained release tablets for extended periods should periodically reevaluate the long-term usefulness of the drug for the individual patient.

Bupropion is indicated as a smoking cessation treatment.

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 an 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 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 contained in the formulations.

WARNINGS:

Patients should be made aware that Wellbutrin SR (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 SR should not be used in combination with Zyban, or any other medications that contain bupropion.

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 usual adult target dose and one-half the maximum recommended daily dose (400 mg) of bupropion sustained release tablets. 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.

Sustained Release Formulations: Data for bupropion sustained release tablets revealed a seizure incidence of approximately 0.1% (i.e., 3 of 3100 patients followed propspectively) in patients treated 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 inclue 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 sustained release tablets does not exceed 400 mg for treatment of depression (450 mg for the immediate-release tablet) or 300 mg for smoking cessation.
• The daily dose is administered twice daily.
• The rate of incrementation of dose (for treatment of depression) is 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, or other antideperessants, 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 sustained release tablets experienced agitation, anxiety, and insomnia as shown in TABLE 3.

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.

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 sustained release tablets may impair their ability to perform tasks requiring judgement or motor and cognitive skills. Consequently, until they are reasonably certain that bupropion sustained release tablets do not adversely affect their performance, they should refrain from driving an automobile or operating complex, hazardous machinery.
• Patients should be told that the use of, 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 sustained release tablets 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 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 information leaflet at the end of this monograph. Physicians are advised to review the leaflet with their patients.

There are no specific laboratory tests recommended.

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.

A fertility study in rats at doses up to 300 mg/kg revealed no evidence of impaired fertility.

Teratology studies have been performed at doses up to 450 mg/kg in rats, and at doses up to 150 mg/kg in rabbits (approximately 7 to 11 and 7 times the MRHD for depression treatment, and 14 and 10 times the MRHD for smoking cessation, respectively, 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.

The effect of bupropion sustained release tablets on labor and delivery in humans is unknown.

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.

The safety and effectiveness of bupropion sustained release tablets in pediatric patients below 18 years of age have not been established. 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.

In general, older patients are known to metabolize drugs more slowly and to be more sensitive to the anticholinergic, sedative, and cardiovascular side effects of antidepressant drugs. A single-dose pharmacokinetic study demonstrated that the disposition of bupropion and its metabolites in elderly subjects was similar to that of younger subjects (see CLINICAL PHARMACOLOGY.) Of the approximately 5600 patients who participated in clinical trials with bupropion sustained release tablets (depression and smoking cessation studies), 303 were 60 to 69 years old and 88 were 70 years of age or older. The experience with patients 60 years of age or older was similar to that in younger patients.

DRUG INTERACTIONS:

Studies in animals demonstrate that the acute toxicity of bupropion 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 levodopa. Administration of bupropion sustained release tablets to patients receiving levodopa concurrently should be undertaken with caution, using small initial doses and gradual dose increases.

Concurrent administration of bupropion sustained release tablets and agents (e.g., antipyschotics, other antidepressants, etc.) or treatment regimens (abrupt discontinuation of benzodiazepines) that lower seizure threshold should be undertaken only with extreme caution (see WARNINGS.) Low initial dosing and gradual dose increases should be employed.

ADVERSE REACTIONS:

(See WARNINGS and PRECAUTIONS).

The information included in CLINICAL STUDIES is based on data from controlled clinical trials with bupropion sustained release tablets for treatment of depression. Information on additional adverse events associated with bupropion sustained release tablets in the entire development program for that formulation and with the immediate release formulation of bupropion is included in a separate subsection (see Other Events).

Adverse Events Associated With Discontinuation of Treatment Among Patients Treated With Bupropion Sustained Release Tablets: In placebo-controlled clinical trials, 9% and 11% of patients treated with 300 and 400 mg/day, respectively, of bupropion sustained release tablets 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 or 400 mg/day of bupropion sustained release tablets and at a rate at least twice the placebo rate are listed in TABLE 5.

Adverse Events Occurring at an Incidence of 1% or More Among Patients Treated With Bupropion Sustained Release Tablets: TABLE 6 enumerates treatment-emergent adverse events that occurred among patients treated with 300 and 400 mg/day of bupropion sustained release tablets and with placebo in placebo-controlled trials. Events that occurred in either the 300- or 400-mg/day group at an incidence of 1% or more and were more frequent than in the placebo 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 judgements, 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 sustained release tablets is provided in the WARNINGS and PRECAUTIONS.

Incidence of Commonly Observed Adverse Events in Controlled Clinical Trials: Adverse events from TABLE 4 occurring in at least 5% of patients treated with bupropion sustained release tablets and at a rate at least twice the placebo rate are listed below for the 300- and 400-mg/day dose groups.

Bupropion Sustained Release 300 mg/day: Anorexia, dry mouth, rash, sweating, tinnitus, and tremor.
Bupropion Sustained Release 400 mg/day: Abdominal pain, agitation, anxiety, dizziness, dry mouth, insomnia, myalgia, nausea, palpitation, pharyngitis, sweating, tinnitus, and urinary freqency.



Incidence of Adverse Reactions in Controlled Trials of Bupropion Sustained Release Tablets for Smoking Cessation

This information included under ADVERSE REACTIONS is based primarily on data from the dose-response trial and the comparative trial that evaluated bupropion for smoking cessation (see CLINICAL STUDIES). Information on additional adverse events associated with bupropion sustained release tablets in depression trials, as well as the immediate release formulation of bupropion, is included in a separate subsection (see Other Events).

Adverse Events Associated withDiscontinuation of Treatment: Adverse events were sufficiently troublesome to cause discontinuation of treatment in 8% of the 706 patients treated with bupropion sustained release tablets and 5% of the 313 patients treated with placebo. The more common events leading to discontinuation of treatment with bupropion included nervous system disturbances (3.4%), primarily tremors, and skin disorders (2.4%), primarily rashes.

Incidence of Commonly Observed Adverse Events: The most commonly observed adverse events consistently associated with the use of bupropion HCl were dry mouth and insomnia. The most commonly observed adverse events were defined as those that consistently occurred at a rate of five percentage points greater than that for placebo across clinical studies.

Dose Dependency of Adverse Events: The incidence of dry mouth and insomnia may be related to the dose of bupropion. The occurrence of these adverse events may be minimized by reducing the dose of bupropion. In addition, insomnia may be minimized by avoiding bedtime doses.

Adverse Events Occurring at an Incidence of 1% or More Among Patients Treated with Bupropion for Smoking Cessation: TABLE 7 enumerates selected treatment-emergent adverse events from the dose-response trial that occurred at an incidence of 1% or more and were more common in patients treated with bupropion compared to those treated with placebo. TABLE 8 enumerates selected treatment-emergent adverse events from the comparative trial that occurred at an incidence of 1% or more and were more common in patients treated with bupropion, NTS, or the combination of bupropion and NTS compared to those treated with placebo. Reported adverse events were classified using a COSTART-based dictionary.

The frequencies presented represent the proportion of patients who experienced a treatment-emergent adverse event on at least one occasion in placebo-controlled studies for depression (n=987) or smoking cessation (n=1013) or patients who experienced an adverse event requiring discontinuation in an open-label surveillance study with bupropion SR tablets (n=3100). All treatment-emergent adverse events are included except those listed in TABLES 5 through 8, those events listed in other safety-related sections, those 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 only one patient. Events of major clinical importance are described in the 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 1/1000 patients, while rare events are those occurring in less than 1/1000 patients.

Body (General): Frequent: Asthenia, fever, and headache. Infrequent: Back pain, facial edema, chills, ingurial hernia, musculskeletal chest pain, pain, and photosensivity. Rare: Malaise.
Cardiovascular: Infrequent: Flushing, migraine, postural hypotension, stroke, tachycardia, and vosodilation. Rare: Syncope.
Digestive: Frequent: Dyspepsia, flatulence, and vomiting. Infrequent: Abnormal liver function, bruxism, dysphagia, gastric reflux, gingivitix, glossitis, increased salivation, jaundice, mouth ulcers, stomatitis, and thirst. Rare: Edema of tongue.
Endocrine: Also observed was syndrome of inappropriate antidiuretic hormone.
Hemic and Lymphatic: Infrequent: Ecchymosis.
Metabolic and Nutrional: Infrequent: Edema, increased weight, and peripheral edema.
Musculoskeletal: Infrequent: Leg cramps and twitching.
Nervous system: Frequent: Agitation, depression, and irritability. Infrequent: Abnormal coordination, CNS stimulation, confusion, decreased libido, decreased memory, depersonalization, dysphoria, emotional labity, hostility, hyperkinesia, hypertonia, hypesthesia, paresthesia, suicidal ideation, and vertigo. Rare: Amnesia, ataxia, derealization, and hypomania.
Respiratory: Rare: Bronchospasm.
Skin: Frequent: Sweating. Infrequent: Acne and dry skin. Rare: Maculopapular rash.
Special Senses: Frequent: Amblyopia. Infrequent: Accomodation abnormality and dry eye.
Urogenital: Frequent: Urinary frequency. Infrequent: Impotence, polyuria, urinary urgency, and prostate disorder.



Events Observed During Clinical Development and Postmarketing Experience With the Immediate Release Formulation of Bupropion

In addition to the adverse events noted in clinical trials with bupropion sustained release tablets, the following adverse events have been reported in clinical trials and postmarketing clinical experience with the immediate release formulation of bupropion. The extent to which these events may be associated with bupropion sustained release tablets is unkown.

Cardiovascular: Cardiovascular disorder, complete AV block, extrasystoles, hypotension, myocardial infarction, and phlebitis, and pulmonary embolism.
Digestive: Colitis, esophagitis, gastrointestinal hemorrhage, gum hemorrhage, hepatitis, intestinal perforation, liver damage, pancreatitis, stomach ulcer, and stool abnormality.
Hemic and Lymphatic: Anemia, leukocytosis, leukopenia, lymphadenopathy, and pancytopenia.
Metabolic and Nutritional: Glycosuria.
Musculoskeletal: Arthritis and muscle rigidiy/fever/rhabdomyolysis.
Nervous System: Abnormal electroencephalogram (EEG), akinesia, aphasia, coma, delirium, delusions, dysarthria, dyskinesia, dystonia, euphoria, extrapyramidal syndrome, hypokinesia, increased libido, manic reaction, neuralgia, neuropathy, paranoid reaction, suicidal ideation and unmasking tardive dyskinesia.
Respiratory: Pneumonia.
Skin: Angioedema, exfoliative dermatitis, hirutism.
Special Senses: Deafness, diplopia, and mydriasis.
Urogenital: Abnormal ejaculation, cystitis, dyspareunia, dysparenunia, dysuria, gynecomastia, menopause, painful erection, prostate disorder, salpingitis, urinary incontinence, urinary retention, urinary tract disorder, and vaginitis.



DRUG ABUSE AND DEPENDENCE:

Controlled Substance Class: Bupropion is not a controlled substance.

There have been few reported cases of drug dependence and withdrawal symptions associated with the immediated release form of bupropion. In human studies of abuse liability, individuals experienced with drugs of abuse reported that bupropion produced a feeling of euphoria and desirability. Controlled clinical studies of bupropion conducted in normal volunteers, in subjects with a history of multiple drug abuse, and in depressed patients showed some increase in motor activity and agitation/excitement.

In a population of individuals experienced with drugs of abuse, a single dose of 400 mg of bupropion produced mild amphetamine-like activity as compared to placebo on the morphine-Benzedrine subscale of the Addiction Research Center Index (ARCI), and a score intermediate between placebo and amphetimine on the Liking Scale of the ARCI. These scales measure general feelings of euphoria and drug desirability.

Findings in clinical trials, however, are not known to reliably predict the abuse potential of drugs. Nonetheless, evidence from single-dose studies suggest that the recommended daily dosage of bupropion when administered in divided doses is not likely to be especially reinforcing to amphetamine or stimulant abusers. However, higher doses that could not be tested because of the risk of seizure might be modestly attractive to those who abuse stimulant drugs.

Studies in rodents have shown that bupropion exhibits some pharmacological actions common to psychostimulants, including increases in locomotor activity and the production of a mild, stereotyped behavior and increases in rates of responding in several schedule-controlled behavior paradigms. In rats, bupropion produced amphetamine- and cocaine-like discriminative stimulous effects in drug discrimination paradigms used to characterize the subjective effects of psychoactive drugs. Rhesus monkeys have been shown to self-administer bupropion intravenously.

The possibility that bupropion may induce dependence should be kept in mind when evaluating the desirability of including the drug in smoking cessation programs of individual patients.

OVERDOSAGE:
Human Overdosage Experience

DOSAGE AND ADMINISTRATION:

General Dosing Considerations: It is particularly important to administer bupropion sustained release tablets in a manner most likely to minimize the risk of seizure (see WARNINGS.) Gradual escalation in dosage is also important if agitation, motor restlessness, and insomnia, often seen during the initial days of treatment, are to be minimized. If necessary, these effects may be managed by temporary reduction of dose or the short-term administration of an intermediate to long-acting sedative hypnotic. A sedative hypnotic usually is not required beyond the first week of treatment. Insomnia may also be minimized by avoiding bedtime doses. If distressing, untoward effects supervene, dose escalation should be stopped.

Sustained Release: The usual adult target dose for bupropion sustained release tablets is 300 mg/day, given as 150 mg, twice daily. Dosing with bupropion sustained release tablets should begin at 150 mg/day given as a sinle daily dose in the morning. If the 150 mg initial dose is adequately tolerated, an increase to the 300 mg/day target dose, given as 150 mg twice daily, may be made as early as day 4 of dosing. There should be an interval of at least 8 hours between successive doses.

Immediate Release: Increases in dose should not exceed 100 mg/day in a 3-day period. No single dose of bupropion HCl should exceed 150 mg. Bupropion HCl should be administered three times daily, preferably with at least 6 hours between successive doses.

The usual adult dose is 300 mg/day, given three times daily. Dosing should begin at 200 mg/day given as 100 mg twice daily. Based on clinical response, this dose may be increased to 300 mg/day, given as 100 mg twice daily, no sooner than 3 days after the beginning of therapy. See TABLE 9

Maintenance: The lowest dose that maintains remission is recommended. Although it is not known how long the patient should remain on bupropion HCl, it is generally recognized that acute episodes of depression require several months or longer of antidepressant drug treatment.

Usual Dosage for Adults: The recommended and maximum dose of bupropion sustained release tablets for smoking cessation is 300 mg/day, given as 150 mg twice daily. Dosing should begin at 150 mg/day given every day for the first 3 days, followed by a dose increase for most patients to the recommended usual dose of 300 mg/day. There should be an interval of at least 8 hours between successive doses. Doses above 300 mg/day should not be used (see WARNINGS). Treatment with bupropion sustained release tablets should be initiated while the patient is still smoking , since approximately 1 week of treatment is required to achieve steady-state blood levels of bupropion. Patients should set a "target quit date" within the first 2 weeks of treatment with bupropion, generally in the second week. Treatment with bupropion should be continued for 7 to 12 weeks; duration of treatment should be based on the relative benefits and risks for individual patients. If a patient has not made significant progress toward abstinence by the seventh week of therapy with bupropion, it is unlikely that he or she will quit during that attempt, and treatment should probably be discontinued. Dose tapering of bupropion is not required when discontinuing treatment. It is important that patients continue to receive counseling and support throughout treatment with bupropion, and for a period of time thereafter.

Individualization of Therapy: Patients are more likely to quit smoking and remain abstinent if they are seen frequently and receive support from their physicians or other health care professionals. It is important to ensure that patients read the instructions provided to them and have their questions answered. Physicians should review the patient's overall smoking cessation program that includes treatment with bupropion. Patients should be advised of the importance of participating in the behavioral interventions, counseling, and/or support services to be used in conjunction with bupropion. See information for patients at the end of the package insert.

The goal of therapy with bupropion is complete abstinence. If a patient has not made significant progress towards abstinence by the seventh week of therapy with bupropion, it is unlikely that he or she will quit during that attempt, and treatment should be discontinued.

Patients who fail to quit smoking during an attempt may benefit from interventions to improve their chances for success on subsequent attempts. Patinets who are unsuccessful should be evaluated to determine why they failed. A new quit attempt should be encouraged when factors that contributed to failure can be eliminated or reduced, and conditions are more favorable.

Maintenance: Although clinical data are not available regarding the long-term use (>12 weeks) of bupropion for smoking cessation, bupropion has been used for longer periods of time in the treatment of depression. Whether to continue treatment with bupropion for periods longer than 12 weeks for smoking cessation must be determined for individual patients.

Combination Treatment with Bupropion and a Nicotine Transdermal System (NTS): Combination treatment with bupropion and NTS may be prescribed for smoking cessation. The prescriber should review the complete prescribing information for both bupropion and NTS before using combination treatment. See also CLINICAL STUDIES for methods and dosing used in the bupropion and NTS combination trial. Monitoring for treatment-emergent hypertension in patients treated with the combination of bupropion and NTS is recommended.

PATIENT PACKAGE INSERT:

HOW SUPPLIED:

Wellbutrin immediate release tablets are supplied as 75 mg (yellow-gold) round, biconvex tablets printed "Wellbutrin" and "75"; and 100 mg (red) round, biconvex tablets printed "Wellbutrin" and "100".
Store at 15° to 25°C (59° to 77°F). Protect from light and moisture.
Wellbutrin SR Sustained Release Tablets, 100 mg of bupropion HCl, are blue, round, biconvex, film-coated tablets printed with "WELLBUTRIN SR 100".
Wellbutrin SR Sustained Release Tablets, 150 mg of bupropion HCl, are purple, round, biconvex, film-coated tablets printed with "WELLBUTRIN SR 150".
Zyban Sustained Release Tablets, 150 mg of bupropion HCl, are purple, round, biconvex, film-coated tablets printed with "ZYBAN 150".
Storage: Store at controlled room temperature, 20° to 25°C (68° to 77°F) [see USP]. Dispense in a tight, light-resistant container.