Bupropion

DESCRIPTION

Bupropion HCl, an antidepressant of the aminoketone class and a non-nicotine aid to smoking cessation, is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitor, or other known antidepressant agents. Its structure closely resembles that of diethylpropion; it is related to phenylethylamines. It is designated as (±)-1-(3-chlorophenyl)-2-[(1,1-dimethylethyl)amino]-1-propanone hydrochloride. The molecular weight is 276.2. The empirical formula is C₁₃H₁₈ClNO·HCl. Bupropion HCl powder is white, crystalline, and highly soluble in water. It has a bitter taste and produces the sensation of local anesthesia on the oral mucosa.

Immediate Release Tablets: Wellbutrin is supplied for oral administration as 75 mg (yellow-gold) and 100 mg (red) film-coated tablets. Each tablet contains the labeled amount of bupropion HCl and the inactive ingredients: 75 mg tablet: D&C yellow no. 10 lake, FD&C yellow no. 6 lake, hydroxypropyl cellulose, hydroxypropyl methylcellulose, microcrystalline cellulose, polyethylene glycol, talc, and titanium dioxide; 100 mg tablet: FD&C red no. 40 lake, FD&C yellow no. 6 lake, hydroxypropyl cellulose, hydroxypropyl methylcellulose, microcrystalline cellulose, polyethylene glycol, talc, and titanium dioxide.

Sustained Release Tablets: Wellbutrin SR: Wellbutrin SR tablets are supplied for oral administration as 100 mg (blue) and 150 mg (purple), film-coated, sustained-release tablets. Each tablet contains the labeled amount of bupropion HCl and the inactive ingredients: carnauba wax, cysteine hydrochloride, hydroxypropyl methylcellulose, magnesium stearate, microcrystalline cellulose, polythylene glycol, and titanium dioxide and is printed with edible black ink. In addition, the 100 mg tablet contains FD&C blue no.1 lake and polysorbate 80, and the 150 mg tablet contains FD&C blue no. 2 lake, FD&C red no. 40 lake, and polysorbate 80. Zyban: Zyban (bupropion HCl for smoking cessation) is supplied for oral administration as 150-mg (purple), film-coated, sustained-release tablets. Each tablet contains the labeled amount of bupropion HCl and the inactive ingredients carnuba wax, cysteine HCl, hydroxypropyl methylcellulose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80 and titanium dioxide and is printed with edible black ink. In addition, the 150-mg tablet contains FD&C blue no. 2 lake and FD&C red no. 40 lake.

CLINICAL PHARMACOLOGY

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 central nervous system (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. The mechanism of action of bupropion, as with other antidepressants, is unknown and the mechanism by which bupropion enhances the ability of patients to abstain from smoking is also unknown. However, it is presumed that this action is also mediated by nonadrenergic and/or dopaminergic mechanisms.

Pharmacokinetics

For the Immediate Release Tablet Only: Several of the known metabolites of bupropion are pharmacologically active, but their potency and toxicity relative to bupropion have not been fully characterized. However, because of their longer elimination half-lives, the plasma concentrations of at least two of the known metabolites can be expected, especially in chronic use, to be very much higher than the plasma concentration of bupropion. This is of potential clinical importance because factors or conditions altering metabolic capactiy (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 these active metabolites.

Furthermore, bupropion has been shown to induce its own metabolism in three animal species (mice, rats, and dogs) following subchronic administration. If induction also occurs in humans, the relative contribution of bupropion and its metabolites to the clinical effects of bupropion HCl may be changed in chronic use.

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, the erythro-amino diol of bupropion, and a morpholinol metabolite (formed from hydroxylation of the tert-butyl group of bupropion).

The morpholinol metabolite appears in the systemic circulation almost as rapidly as the parent drug following a single oral dose. Its peak level is three times the peak level of the parent drug; it has a half-life on the order of 24 hours; and its AUC to 0 to 60 hours is about 15 times that of bupropion.

The threo-amino alcohol metabolite has a plasma concentration-time profile similar to that of the morpholinol metabolite. The erythro-amino alcohol and the erythro-amino diol metabolites generally cannot be detected in the systemic circulation following a single oral dose of the parent drug. The morpholinol and the threo-amino alcohol metabolites have been found to be half as potent as bupropion in animal screening tests for antidepressant drugs.

For the Sustained Release Tablet Only: 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.

Absorption

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%.

Following oral administration of bupropion sustained release tablets to healthy volunteers, peak plasma concentrations of bupropion are achieved within 3 hours (2 hours for the immediate release formulation). The mean peak concentration (C_max) values for the sustained release tablets 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.

Distribution

In vitro tests wshow that bupropion is 80% or more bound to human albumin at plasma concentrations up to 800 mcmol/L (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 for the sustained release tablets (V_ss/F) estimated from a single 150-mg dose given to 17 subjects is 1950 L (20% CV).

Metabolism

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 potency 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.

Because bupropion is extensively metabolized, there is the potential for drug-drug interactions, particularly with those agents that are metabolized by the cytochrome P450IIB6 (CYP2B6) isoenzyme. Although bupropion is not metabolized by cytochrome P450IID6 (CYP2D6), there is the potential for drug-drug interactions when bupropion is co-administered with drugs metabolozied by this isoenzyme (see DRUG INTERACTIONS).

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 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.

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.

Elimination

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 (±% CV) apparent clearance (CI/F) estimated from two single-dose (150-mg) studies are 135 (±20%) and 209 L/hr (±21%). Following chronic dosing of 150 mg of bupropion HCl sustained release tablets every 12 hours for 14 days (n=34), the mean CI/F at steady state was 160 L/hr (±23%). The mean elimination half-life of bupropion estimated from a series of studies is approximately 21 hours. Estimates of the half-lives of the metabolites determined from a multiple-dose study were 20 hours (±25%) for hydroxybupropion, 37 hours (±35%) for threohydrobupropion, and 33 hours (±30%) for erythrohydrobupropion. Steady-state plasma concentrations of bupropion and metabolites are reached within 5 and 8 days, respectively.

Special Populations

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: For the Sustained Release Tablets Only: 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. For the Immediate Release Tablets Only: The effect of other diseases states and altered organ function on the metabolism and/or elimination of bupropion has not been studied in detail. However, 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 conjugation in the liver prior to urinary excretion. The preliminary results of a comparative single-dose pharmacokinetic study in normal versus cirrhotic patients indicated that half-lives of the metabolites were prolonged by cirrhosis and that the metabolites accumulated to levels two to three times those in normals.

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. A single-dose pharmacokinetic study demonstrated that the disposition of bupropion and its metabolites in elderly subjects was similar to that of younger subjects. These data suggest there is no prominent effect of age on bupropion concentration; 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 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.

Smokers: The effects of cigarette smoking on the pharmacokinetics of bupropion were studied in 34 healthy male and female volunteers; 17 were chronic cigarette smokers and 17 were nonsmokers. Following oral administration of a single 150-mg dose of bupropion, there was no statistically significant difference in C_max, half-life, t_max, AUC, or clearance of bupropion or its active metabolites between smokers and nonsmokers.

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 (item 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 steady 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.

Smoking Cessation

The efficacy of bupropion HCl as an aid to smoking cessation was demonstrated in two placebo-controlled, double-blind trials in nondepressed chronic cigarette smokers (n=1508, ³15 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 HCl (100, 150, or 300 mg/day) or placebo; quitting was defined as total abstinence 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 HCl demonstrated a dose-dependent increase in the percentage of patients able to achieve 4-week abstinence (weeks 4 through 7). Treatment with bupropion HCl 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 HCl (150 or 300 mg/day) was more effective than placebo in helping patients achieve 4-week abstinence. In addition, treatment with bupropion HCl (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.

The second study was a comparative trial conducted at four clinical centers. Four treatments were evaluated: bupropion HCl sustained release tablets, 300 mg/day, nicotine transdermal system (NTS) 21 mg/day, combination of bupropion HCl sustained release tablets 300 mg/day plus NTS 21 mg/day, and placebo. Patients were treated for 9 weeks. Treatment with bupropion HCl sustained release tablets was initiated at 150 mg/day while the patient was still smoking and was increased after 3 days to 300 mg/day given as 150 mg twice daily. NTS 21 mg/day was added to treatment with bupropion HCl sustained release tablets after approximately 1 week when the patient reached the target quit date. During weeks 8 and 9 of the study, NTS was tapered to 14 and 7 mg/day, respectively. Quitting, defined as total abstinence during weeks 4 through 7, was determined by patient daily diaries and verified by expired air carbon monoxide levels.

In this study, patient treated with either bupropion HCl sustained release tablets or NTS achieved greater 4-week abstinence rates than patients treated with placebo. In addition, patients treated with the combination of bupropion HCl sustained release tablets and NTS achieved higher abstinence rates than patients treated with either of the individual active treatments alone, although only the comparison with NTS achieved statistical significance.

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

Quit rates in clinical trials are influenced by the population selected. Quit rates in an unselected population may be lower than the above rates.

Treatment with bupropion HCl sustained release tablets reduced withdrawal symptoms compared to placebo. Reductions on the following withdrawal symptoms were most pronounced: irritability, frustration, or anger; anxiety; difficulty concentrating; restlessness; and depressed mood or negative affect. Depending on the study and the measure used, treatment with bupropion HCl sustained release tablets showed evidence of reduction in craving for cigarettes or urge to smoke compared to placebo.

INDICATIONS

Sustained Release and Immediate Release Tablets: Treatment for Depression

Bupropion HCl is indicated for the treatment of depression.

The efficacy of bupropion HCl 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 for the sustained release tablets (two trials of approximately 3 weeks' duration in depressed patients and one of approximately 6 weeks' duration in depressed outpatients) whose diagnoses corresponded most closely to the Major Depression category of the APA Diagnostic and Statistical Manual (DSM) III (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 or decrease in sex drive, 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.

Additional Information for the Immediate Release Tablets: A physician considering bupropion HCl sustained release 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% (4/1000). This incidence of seizures may exceed that of other marketed antidepressants by as much as fourfold. This relative risk is only an approximate estimate because no direct comparative studies have been conducted (see WARNINGS).

Sustained Release Tablets: Treatment for Smoking Cessation

Bupropion is indicated as a smoking cessation treatment.

DOSAGE AND ADMINISTRATION

General Dosing Considerations: It is particularly important to administer bupropion HCl 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.

Treatment of Depression

Initial Treatment

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 single 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 3 times daily, no sooner than 3 days after beginning therapy. (See TABLE 10.)

Increasing the Dosage Above 300 mg/day: As with other antidepressants, the full antidepressant effect of bupropion HCl may not be evident until 4 weeks of treatment or longer. An increase in dosage to the maximum of 400 mg/day, given as 200 mg twice daily, (450 mg/day for the immediate release, given as in doses not more than 150 mg each) may be considered for patients in whom no clinical improvement is noted after several weeks of treatment at 300 mg/day. For the Immediate Release Tablets Only: Dosing above 300 mg/day may be accomplished using the 75 or 100 mg tablets. The 100 mg tablet must be administered 4 times daily with at least 4 hours between successive doses, in order to not exceed the limit of 150 mg in a single dose. Bupropion HCl should be discontinued in patients who do not demonstrate an adequate response after an appropriate period of treatment at 450 mg/day.

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.

Treatment for Smoking Cessation

Usual Dosage for Adults: The recommended and maximum dose of bupropion HCl 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 HCl 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 HCl, generally in the second week. Treatment with bupropion HCl 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 HCl, 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 HCl. 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 HCl. See information for patients at the end of the package insert.

The goal of therapy with bupropion HCl is complete abstinence. If a patient has not made significant progress towards abstinence by the seventh week of therapy with bupropion HCl, 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 HCl for periods longer than 12 weeks for smoking cessation must be determined for individual patients.

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

HOW SUPPLIED

Wellbutrin Immediate Release Tablets: The 75 mg tablets are yellow-gold, round, biconvex tablets printed with "Wellbutrin 75". The 100 mg tablets are red, round, biconvex tablets printed with "Wellbutrin 100".

Wellbutrin SR Sustained Release Tablets: The 100 mg tablets are blue, round, biconvex, film-coated tablets printed with “WELLBUTRIN SR 100”. The 150 mg tablets are purple, round, biconvex, film-coated tablets printed with “WELLBUTRIN SR 150”.

Zyban Sustained Release Tablets: The 150 mg tablets are purple, round, biconvex, film-coated tablets printed with "ZYBAN 150".

Storage: Store at controlled room temperature, 20-25°C (68-77°F) The immediate release tablet can be stored at temperatures as low as 15°C (59°F). Dispense in a tight, light-resistant container as defined in the USP.

PRODUCT LISTING

SIDE EFFECTS

(See WARNINGS and PRECAUTIONS).

For Bupropion HCl Sustained Release Tablets for Depression

The information included under the Incidence in Controlled Trials section is primarily based on data from controlled clinical trials with bupropion HCl sustained release tablets. Information on additional adverse events associated with the sustained-release formulation of bupropion in smoking cessation trials, as well as immediate-release formulation of bupropion, is included in a separate section (see Other Events Observed During the Clinical Development and Postmarketing Experience of Bupropion).

Incidence in Controlled Trials With Bupropion Sustained Release Tablets for Treatment of Depression:

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 HCl 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 HCl 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 HCl 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 HCl sustained release tablets is provided in WARNINGS and PRECAUTIONS.

Incidence of Commonly Observed Adverse Events in Controlled Clinical Trials: Adverse events from TABLE 6 occurring in at least 5% of patients treated with bupropion HCl 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 HCl Sustained Release 300 mg/day: Anorexia, dry mouth, rash, sweating, tinnitus, and tremor.
Bupropion HCl Sustained Release 400 mg/day: Abdominal pain, agitation, anxiety, dizziness, dry mouth, insomnia, myalgia, nausea, palpitation, pharyngitis, sweating, tinnitus, and urinary frequency.

For Bupropion HCl for Smoking Cessation

The information included under the

SIDE EFFECTS

Incidence of Adverse Reactions in Controlled Trials of Bupropion Sustained Release Tablets for Smoking Cessation: This information included under

SIDE EFFECTS

Adverse Events Associated with Discontinuation of Treatment: Adverse events were sufficiently troublesome to cause discontinuation of treatment in 8% of the 706 patients treated with bupropion HCl sustained release tablets and 5% of the 313 patients treated with placebo. The more common events leading to discontinuation of treatment with bupropion HCl 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 5 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 HCl. The occurrence of these adverse events may be minimized by reducing the dose of bupropion HCl. 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 HCl 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 HCl 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 HCl , NTS, or the combination of bupropion HCl and NTS compared to those treated with placebo. Reported adverse events were classified using a COSTART-based dictionary.

For Bupropion HCl for Immediate Release

Adverse events commonly encountered in patients treated with bupropion HCl are agitation, dry mouth, insomnia, headache/migraine, nausea/vomiting, constipation, and tremor.

Adverse events were suficiently troublesome to cause discontinuation of treatment with bupropion HCl in approximately 10% of the 2400 patients and volunteers who participated in clinical trials during the product's initial development. The more common events causing discontinuation include neuropsychiatric disturbances (3.0%), primarily agitation and abnormalities in mental status; gastrointestinal disturbances (2.1%), primarily nausea and vomiting; neurological disturbances (1.7%), primarily seizures, headaches, and sleep disturbances; and dermatologic problems (1.4%), primarily rashes. It is important to note, however, that many of these events occurred at doses that exceed the recommended daily dose.

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 judgments, etc. Consequently, the table below is presented soley to indicate the relative frequency of adverse events reported in representative controlled clinical studies conducted to evaluate the safety and efficacy of bupropion HCl under relatively similar conditions of daily dosage (300 to 600 mg), setting, and duration (3 to 4 weeks). 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 must differ from those which 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 HCl is provided in WARNINGS and PRECAUTIONS.

Other Events Observed During the Clinical Development and Postmarketing Experience of Bupropion Sustained Release Tablets for Depression and Smoking Cessation

In addition to the adverse events already noted, the following events have been reported in clinical trials and postmarketing experience with the sustained-release formulation of bupropion in depressed patients and in nondepressed smokers, as well as in clinical trials and postmarketing clinical experience with the immediate-release formulation of bupropion.

Adverse events for which frequencies are provided below occurred in clinical trials with bupropion sustained-release. 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 HCl sustained release tablets (n=3100). All treatment-emergent adverse events are included except those listed in TABLE 3, TABLE 4, TABLE 5, TABLE 6, TABLE 7 and TABLE 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.

Adverse events for which frequencies are not provided occurred in clinical trials or postmarketing experience with bupropion. Only those adverse events not previously listed for sustained-release bupropion are included. The extent to which these events may be associated with bupropion HCl is unknown.

For Bupropion HCl Sustained Release Tablets for Depression

Body (General): Infrequent: Chills, facial edema, musculoskeletal chest pain, and photosensitivity. Rare: Malaise.

Cardiovascular: Infrequent: Postural hypotension, stroke, tachycardia, and vasodilation. Rare: Syncope. Also observed were complete atrioventricular block, extrasystoles, hypotension, myocardial infarction, phlebitis, and pulmonary embolism.

Digestive: Infrequent: Abnormal liver function, bruxism, gastric reflux, gingivitis, glossitis, increased salivation, jaundice, mouth ulcers, stomatitis, and thirst. Rare: Edema of tongue. Also observed were colitis, esophagitis, gastrintestinal hemorrhage, gum hemorrhage, hepatitis, intestinal perforation, liver damage, pancreatitis, and stomach ulcer.

Endocrine: Also observed were hyperglycemia, hypoglycemia, and syndrome of inappropriate antidiuretic hormone.

Hemic and Lymphatic: Infrequent: Ecchymosis. Also observed were anemia, leukocytosis, leukopenia, lymphadenopathy, pancytopenia, and thrombocytopenia.

Metabolic and Nutrional: Infrequent: Edema, increased and peripheral edema. Also observed was glycosuria.

Musculoskeletal: Infrequent: Leg cramps. Also observed were muscle rigidity/fever/rhabdomyolysis and muscle weakness.

Nervous system: Infrequent: Abnormal coordination, decreased libido, depersonalization, dysphoria, emotional labity, hostility, hyperkinesia, hypertonia, hypesthesia, suicidal ideation, and vertigo. Rare: Amnesia, ataxia, derealization, and hypomania. Also observed were abnormal electroencephalogram (EEG), hypokinesia, increased libido, manic reaction, neuralgia, neuropathy, paranoid reaction, and unmasking tardive dyskinesia.

Respiratory: Rare: Bronchospasm. Also observed was pneumonia.

Skin: Rare: Maculopapular rash. Also observed were alopecia, angioedema, exfoliative dermatitis, and hirsutism.

Special Senses: Infrequent: Accomodation abnormality and dry eye. Also observed were deafness, diplopia, and mydriasis.

Urogenital: Infrequent: Impotence, polyuria, and prostate disorder. Also observed were abnormal ejaculation, cycstitis, dyspareunia, dysuria, gynecomastia, menopause, painful erection, salpingitis, urinary incontinence, urinary retention, and vaginitis.

For Bupropion HCl Sustained Release Tablets for Smoking Cessation

Body (General): Frequent: Asthenia, fever, and headache. Infrequent: Back pain, chills, inguinal hernia, musculskeletal chest pain, pain, and photosensivity. Rare: Malaise.

Cardiovascular: Infrequent: Flushing, migraine, postural hypotension, stroke, tachycardia, and vasodilation. Rare: Syncope. Also observed were cardiovascular disorder, complete AV block, extrasystoles, hypotension, myocardial infarction, phlebitis, and pulmonary embolism.

Digestive: Frequent: Dyspepsia, flatulence, and vomiting. Infrequent: Abnormal liver function, bruxism, dysphagia, gastric reflux, gingivitis, glossitis, jaundice, stomatitis. Rare: Edema of tongue. Also observed were colitis, esophagitis, gastrointestinal hemorrhage, gum hemorrhage, hepatitis, increased salivation, intestinal perforation, liver damage, pancreatitis, stomach ulcer, and stool abnormality.

Endocrine: Also observed were hyperglycemia, hypoglycemia, and syndrome of inappropriate antidiuretic hormone.

Hemic and Lymphatic: Infrequent: Ecchymosis. Also observed were anemia, leukocytosis, leukopenia, lymphadenopathy, pancytopenia, and thrombocytopenia.

Metabolic and Nutrional: Infrequent: Edema, increased weight, and peripheral edema. Also observed was glycosuria.

Musculoskeletal: Infrequent: Leg cramps and twitching. Also observed were arthritis and muscle rigidty/fever/rhabdomyolysis, and muscle weakness.

Nervous system: Frequent: Agitation, depression, and irritability. Infrequent: Abnormal coordination, CNS stimulation, confusion, decreased libido, decreased memory, depersonalization, emotional labity, hostility, hyperkinesia, hypertonia, hypesthesia, paresthesia, suicidal ideation, and vertigo. Rare: Amnesia, ataxia, derealization, and hypomania. Also observed were abnormal electroencephalogram (EEG) , akinesia, aphasia, coma delirium, delusions, dysarthria, dyskinesia, dystonia, euphoria, extrapyramidal syndrome, hypokinesia, increased libido, manic reaction, neuralgia, neuropathy, paranoid reaction, and unmasking tardive dyskinesia.

Respiratory: Rare: Bronchospasm. Also observed was pneumonia.

Skin: Frequent: Sweating. Infrequent: Acne and dry skin. Rare: Maculopapular rash. Also observed were alopecia, angioedema, exfoliative dermatitis, and hirsutism.

Special Senses: Frequent: Amblyopia. Infrequent: Accomodation abnormality and dry eye. Also observed were deafness, diplopia, and mydriasis.

Urogenital: Frequent: Urinary frequency. Infrequent: Impotence, polyuria, and urinary urgency. Also observed were abnormal ejaculation, cystitis, dyspareunia, dysuria, gynecomastia, menopause, painful erection, prostate disorder, salpingitis, urinary incontinence, urinary retention, urinary tract disorder, and vaginitis.

Other Events Observed During the Development of the Immediate Release Formulation of Bupropion

The conditions and duration of exposure to bupropion HCl varied greatly, and a substantial proportion of the experience was gained in open and uncontrolled clinical settings. During this experience, numerous adverse events were reported; however, without appropriate controls, it is impossible to determine with certainty which events were or were not caused by bupropion HCl. The following enumeration is organized by organ system and describes events in terms of their relative frequency of reporting in the data base. Events of major clinical importance are also described in WARNINGS and PRECAUTIONS.

The following definitions of frequency are used: 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.

Cardiovascular: Frequent: Edema. Infrequent: Chest pain, electrocardiogram (ECG) abnormalities (premature beats and nonspecific ST-T changes), and shortness of breath/dyspnea. Rare: Flushing, pallor, phlebitis, and mycocardial infarction.

Dermatologic: Frequent: Nonspecific rashes. Infrequent: Alopecia and dry skin.Rare: Change in hair color, hirsutism, and acne.

Endocrine: Infrequent: Dysphagia, thirst disturbance, and liver damage/jaundice. Rare: Rectal complaints, colitis, gastrointestinal bleeding, intestinal perforation, and stomach ulcer.

Genitourinary: Frequent: Nocturia. Infrequent: Vaginal irritation, testicular swelling, urinary tract infection, painful erection, and retarded ejaculation. Rare: Dysuria, enuresis, urinary incontinence, menopause, ovarian disorder, pelvic infection, cystitis, dyspareunia, and painful ejaculation.

Hematologic/Oncologic: Rare: Lymphadenopathy, anemia, and pancytopenia.

Musculoskeletal: Rare: Musculoskeletal chest pain.

Neurological: (See WARNINGS.) Frequent: Ataxia/incoordination, seizure, myoclonus, dyskinesia, and dystonia. Infrequent: Mydriasis, vertigo, and dysarthria. Rare: Electroencephalogram (EEG) abnormality, abnormal neurological exam, impaired attention, sciatica, and aphasia.

Neuropsychiatric: (See PRECAUTIONS.) Frequent: Mania/hypomania, increased libido, hallucinations, decrease in sexual function, and depression. Infrequent: Memory impairment, depersonalization, psychosis, dysphoria, mood instability, paranoia, formal thought disorder, and frigidity. Rare: Suicidal ideation.

Oral Complaints: Frequent: Stomatitis. Infrequent: Toothache, bruxism, gum irritation, and oral edema. Rare: Glossitis.

Respiratory: Infrequent: Bronchitis and shortness of breath/dyspnea.Rare: Epistaxis, rate or rhythm disorder, pneumonia, and pulmonary embolism.

Special Senses: Infrequent: Visual disturbance. Rare: Diplopia.

Nonspecific: Frequent: Flu-like symptoms. Infrequent: Nonspecific pain. Rare: Body odor, surgically related pain, infection, medication reaction, and overdose.

Postintroduction Reports

Voluntary reports of adverse events temporally associated with bupropion that have been received since marekt introduction and which may have no causal relationship with the drug include the following:

Cardiovascular: Orthostatic hypotension and third degree heart block.

Endocrine: Syndrome of inappropriate antiduretic hormone secretion, hyperglycemia, and hypoglycemia.

Gastrointestinal: Esophagitis, hepatitis, and liver damage.

Hemic and Lymphatic: Ecchymosis, leukocytosis, leukopenia, and thrombocytopenia.

Musculoskeletal: Arthralgia, myalgia, rigidity/fever/rhabdomyolysis, and muscle weakness.

Nervous: Coma, delirium, dream abnormalities,paresthesia, and unmasking of tardive dyskinesia.

Skin: Stevens-Johnson syndrome, angioedema, exfoliative dermatitis, and urticaria.

Special Senses: Tinnitus.

DRUG ABUSE AND DEPENDENCE

Controlled Substance Class: Bupropion is not a controlled substance.

Humans

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. There have been few reported cases of drug dependence and withdrawal symptions associated with the immediated release form of bupropion.

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 Inventories (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 reliably. Nonetheless, evidence from single-dose studies does 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.

Animals

Studies in rodents and primates have shown that bupropion exhibits some pharmacological actions common to psychostimulants. In rodents, it has been shown to increase locomotor activity, elicit a mild, stereotyped behavior response and increase rates of responding in several schedule-controlled behavior paradigms. In primate models to assess the positive reinforcing effects of psychoactive drugs, bupropion was self-administered intravenously. In rats, bupropion produced amphetamine-like and cocaine-like discriminative stimulus effects in drug discrimination paradigms used to characterize the subjective effects of psychoactive drugs.

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.

DRUG INTERACTIONS

In vitro studies indicate that bupropion is primarily metabolized to the morpholinol metabolite (hydroxybupropion) by the cytochrome P450IIB6 (CYP2B6) isoenzyme. Therefore, the potential exists for a drug interaction between bupropion HCl and drugs that affect the CYP2B6 isoenzyme (e.g., orphenadrine and cyclophosphamide). The threohydrobupropion metabolite of bupropion does not appear to be produced by the cytochrome P450 iosenzyme.

Animal data indicated that bupropion may be an inducer of drug-metabolized enzymes in humans. This may be of potential clinical importance because the blood levels of coadministered drugs may be altered. However, following chronic administration of bupropion, 100 mg three times daily to 8 healthy male volunteers for 14 days, there was no evidence of induction of its own metabolism. Because bupropion is extensively metabolized, the coadministration of other drugs may affect its clinical activity. In particular, certain drugs may induce the metabolism of bupropion (e.g., carbamazepine, phenobarbital, phenytoin), while other drugs may inhibit the metabolism of bupropion (e.g., cimetidine). The effects of concomitant administration of cimetidine on the pharmacokinetics of bupropion and its active metabolites were studied in 24 healthy young male volunteers. Following oral administration of two 150-mg bupropion HCl sustained release tablets with and without 800 mg of cimetidine, the pharmacokinetics of bupropion and hydroxybupropion were unaffected. However, there were 16% and 32% increases in the AUC and C_max, respectively, of the combined moieties of threohydrobupropion and erythrohydrobupropion.

Drugs Metabolized by Cytochrome P450IID6 (CYP2D6): Many drugs, including most antidepressants (SSRIs, many tricyclics), beta-blockers, antiarrhythmics, and antipsychotics are metabolized by the CYP2D6 isoenzyme. Although bupropion is not metabolized by this isoenzyme, bupropion and hydroxybupropion are inhibitors of the CYP2D6 isoenzyme in vitro. In a study of 15 males subjects (ages 19 to 35 years) who were extensive metabolizers of the CYP2D6 isoenzyme, daily doses of bupropion given as 150 mg twice daily followed by a single dose of 50 mg desipramine increased the C_max, AUC, and T_½ of desipramine by an average of approximately two-, five-and twofold, respectively. The effect was present for at least 7 days after the last dose of bupropion. Comcomitant use of bupropion with other drugs metabolized by CYP2D6 has not been formally studied.

Therefore, co-adminstration of bupropion with drugs that are metabolized by CYP2D6 isoenzyme including certain antidepressants (e.g., nortriptyline, imipramine, desipramine, paroxetine, fluoxetine, sertraline), antipsychotics (e.g., haloperidol, risperidone, thioridazine), beta-blockers (e.g., metoprolol), and Type 1C antiarrhythmics (e.g., propafenone, flecanide), should be approached with caution and should be initiated at the lower end of the dose range of the concomitant medication. If bupropion is added to the treatment regimen of a patient already receiving a drug metabolized by CYP2D6, the need to decrease the dose of the original medication should be considered, particularly for those concomitant medications with a narrow therapeutic index.

MAO Inhibitors: Studies in animals demonstrate that the acute toxicity of bupropion is enhanced by the MAO inhibitor phenelzine (see CONTRAINDICATIONS.)

Levodopa: Limited clinical data suggest a higher incidence of adverse experiences in patients receiving concurrent administration of bupropion HCl and levodopa. Administration of bupropion HCl to patients receiving levodopa concurrently should be undertaken with caution, using small initial doses and gradual dose increases.

Drugs That Lower Seizure Threshold: Concurrent administration of bupropion HCl and agents (e.g., antipyschotics, other antidepressants, theophyllinem systemic steroids, etc.) or treatment regimens (e.g., 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.

Smoking Cessation: Physiological changes resulting from smoking cessation itself, with or without treatment with bupropion HCl, may alter the pharmacokinetics of some concomitant medications, which may require dosage adjustment.

Nicotine Transdermal System: Data from a comparative study of the sustained-release formulation of bupropion, nicotine transdermal system (NTS), the combination of sustained-release bupropion plus NTS, and placebo as an aid to smoking cessation suggest a higher incidence of treatment-emergent hypertension in patients treated with the combination of bupropion and NTS. In this study, 6.1% of patients treated with the combination of bupropion and NTS had treatment-emergent hypertension compared to 2.5%, 1.6%, and 3.1% of patients treated with bupropion, NTS, and placebo, respectively. Monitoring for treatment-emergent hypertension is recommended in patients receiving the combination of bupropion and NTS.

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.

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 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. 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).