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bupropion hcl xl 300 mg tablet (generic wellbutrin xl)

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Uses

Major Depressive Disorder

Bupropion hydrochloride is used in the treatment of major depressive disorder. Efficacy of conventional bupropion tablets for long-term use (i.e., exceeding 6 weeks) as an antidepressant has not been established by controlled studies; if conventional or extended-release tablets of the drug are used for extended periods, the need for continued therapy should be reassessed periodically. Systematic evaluation of bupropion hydrochloride extended-release tablets has shown that antidepressant efficacy is maintained for periods of up to 44 weeks in patients receiving 150 mg twice daily.

Efficacy of bupropion for the management of major depression has been established by a controlled study of approximately 6 weeks' duration in an outpatient setting and by 2 controlled studies of approximately 4 weeks' duration in inpatient settings. Bupropion hydrochloride was administered as conventional tablets in these studies, and the dosage received by 78% of the patients in one of the studies of 4 week's duration was 450 mg or less daily, although the dosage was titratable to 600 mg daily. Efficacy of bupropion in these studies was demonstrated by improvement in total score on the Hamilton rating scale for depression (HAM-D), in item 1 of the HAM-D that measures depressed mood, and in the Clinical Global Impressions of Severity of Illness (CGI-S) scale. Patients received 300 or 450 mg daily of bupropion hydrochloride in the second study of 4 weeks' duration, which demonstrated efficacy only of the higher dosage, as indicated by improvement in total score on the HAM-D and in the CGI-S scale. However, in the study of 6 weeks' duration that evaluated the efficacy of 300 mg daily of bupropion hydrochloride, the drug was superior to placebo in improvement of total score on the HAM-D, which was the primary measure of efficacy. In addition, depressed mood, as measured by item 1 on the HAM-D, was improved in patients treated with bupropion. The drug also was superior to placebo in improvement of scores on the Montgomery-Asberg Depression Rating Scale, the CGI-S scale, and the Clinical Global Impressions of Improvement (CGI-I) scale. Although clinical studies specifically establishing the efficacy of extended-release tablets of bupropion in the management of major depression have not been performed to date, the extended-release, film-coated tablet (e.g., Wellbutrin SR) formulation of the drug has been shown to be bioequivalent at steady state to conventional tablets of bupropion, and antidepressant efficacy was maintained for up to 44 weeks in a placebo-controlled study. In addition, the extended-release tablet (Wellbutrin XL) has been shown to be bioequivalent to the conventional and the extended-release, film-coated tablets.(See Pharmacokinetics: Absorption.)

A major depressive episode is characterized principally by a relatively persistent depressed mood and/or loss of interest or pleasure in all or almost all activities; such symptoms differ from previous functioning and occur for most of the day nearly every day for at least 2 weeks. In addition, the episode may be manifested as a change in appetite, substantial weight loss or gain, a change in sleep, psychomotor agitation or retardation, fatigue or loss of energy, feelings of guilt or worthlessness, difficulty in thinking or concentrating, and/or suicidal ideation or attempts.

Clinical studies have shown that the antidepressant effect of usual dosages of bupropion in patients with moderate to severe depression is greater than that of placebo and comparable to that of usual dosages of tricyclic antidepressants, fluoxetine, or trazodone. Bupropion generally was not distinguishable from these antidepressant agents in measures of efficacy that included the HAM-D scale, the CGI-S scale, the CGI-I scale, and the Hamilton rating scale for anxiety (HAM-A). However, other antidepressants were associated with greater improvement on the HAM-D rating scale during some weeks of the evaluations principally because of the greater improvement in the sleep factor of this scale observed with tricyclic antidepressants or trazodone in comparison to bupropion.

Because of differences in the adverse effect profile between bupropion and tricyclic antidepressants, particularly less frequent anticholinergic effects, cardiovascular effects, antihistaminic effects, and weight gain with bupropion therapy, bupropion may be preferred for patients in whom such effects are not tolerated or are of potential concern. In a study that compared bupropion with doxepin, discontinuance of therapy because of adverse effects resulted mainly from anticholinergic effects, particularly drowsiness, in patients treated with doxepin but from a variety of adverse effects in patients treated with bupropion. After 13 weeks of therapy, patients who received doxepin had gained 2.73 kg while those who received bupropion had lost 1.36 kg. Orthostatic hypotension that required discontinuance of the antidepressant agent occurred with some frequency with imipramine but not with bupropion. In addition, in a large open study, 54% of patients who responded poorly to previous antidepressant therapy responded to bupropion therapy, and 63% of patients who poorly tolerated previous antidepressant therapy tolerated bupropion; 81% of patients who completed an initial 8-week treatment phase in this study elected to receive maintenance therapy with bupropion. Although the possibility of bupropion-induced seizures should be considered in weighing the benefits versus risks compared with alternative therapies, the risk of seizures appears to be within clinically acceptable parameters in patients without preexisting risk.(See Cautions: Nervous System Effects.)

Bupropion also may be preferable because of its minimal adverse effects and possibly beneficial effects on sexual functioning. Most men with depression who experienced sexual dysfunction (e.g., decreased libido, partial erectile failure) during therapy with another antidepressant (e.g., tricyclic antidepressant, maprotiline, trazodone, tranylcypromine) did not have such impairment with bupropion. In a study comparing the adverse sexual effects of bupropion with those of selective serotonin-reuptake inhibitors (i.e., fluoxetine, paroxetine, and sertraline), statistically significant increases in libido, sexual arousal, intensity of orgasm, and/or duration of orgasm were reported in most bupropion-treated patients compared with those reported before the onset of illness, while selective serotonin-reuptake inhibitor therapy significantly reduced these aspects of sexual functioning in most of the patients studied. In another study, dysfunctional orgasm resolved when antidepressant therapy was changed from fluoxetine to bupropion in most men and women who developed orgasm failure and/or delay with fluoxetine. Libido and satisfaction with overall sexual functioning also were improved with bupropion. Limited experience suggests that bupropion also may be useful in the management of sexual dysfunction associated with fluoxetine. Sexual dysfunction (e.g., decreased libido, erectile and orgasmic impairment) associated with fluoxetine was reported to respond to concomitant administration of 75 mg daily of bupropion hydrochloride.

Bupropion administered alone or concurrently with other antidepressant agents may be useful in patients with refractory depression. In the large-scale Sequenced Treatment Alternatives to Relieve Depression (STAR*D) effectiveness trial, patients with major depressive disorder who did not respond to or could not tolerate citalopram, a selective serotonin-reuptake inhibitor (SSRI), were randomized to switch to extended-release (''sustained-release'') bupropion, sertraline (another SSRI), or extended-release venlafaxine (a selective serotonin- and norepinephrine-reuptake inhibitor) as a second step of treatment (level 2). Remission rates as assessed by the 17-item Hamilton Rating Scale for Depression (HRSD-17) and the Quick Inventory of Depressive Symptomatology--Self Report (QIDS-SR-16) were approximately 21 and 26% for extended-release bupropion, 18 and 27% for sertraline, and 25 and 25% for extended-release venlafaxine therapy, respectively; response rates as assessed by the QIDS-SR-16 were 26%, 27%, and 28% for extended-release bupropion, sertraline, and extended-release venlafaxine therapy, respectively. These results suggest that after unsuccessful initial treatment of depressed patients with an SSRI, approximately 25% of patients will achieve remission after therapy is switched to another antidepressant, and either another SSRI (e.g., sertraline) or an agent from another class (e.g., bupropion, venlafaxine) may be reasonable alternative antidepressants in patients not responding to initial SSRI therapy.

In a second STAR*D level 2 trial, patients with major depressive disorder who did not respond to or could not tolerate SSRI therapy (citalopram) were randomized to receive either extended-release (''sustained-release'') bupropion or buspirone therapy in addition to citalopram. Although both extended-release bupropion and buspirone were found to produce similar remission rates, extended-release bupropion produced a greater reduction in the number and severity of symptoms and a lower rate of drug discontinuance than buspirone in this large-scale, effectiveness trial. These results suggest that augmentation of SSRI therapy with extended-release bupropion may be useful in some patients with refractory depression.

For further information on treatment of major depressive disorder and considerations in choosing the most appropriate antidepressant for a particular patient, including considerations related to patient tolerance, patient age, and cardiovascular, sedative, and suicidal risks, .

Seasonal Affective Disorder

Bupropion, as extended-release tablets (Wellbutrin XL), is used in the prevention of seasonal major depressive episodes in patients with a diagnosis of seasonal affective disorder (SAD; also referred to as winter depression). Seasonal affective disorder is characterized by recurrent major depressive episodes, most commonly occurring during the autumn and/or winter months. Episodes may last up to 6 months and typically begin in the autumn and remit in the springtime. Although patients with seasonal affective disorder may have depressive episodes during other times of the year, the number of seasonal episodes should substantially outnumber the number of nonseasonal episodes during the individual's lifetime for a diagnosis of seasonal affective disorder to be considered.

Efficacy of bupropion, as extended-release tablets, for the prevention of seasonal major depressive episodes associated with seasonal affective disorder has been established in 3 double-blind, placebo-controlled trials in adult outpatients with a history of major depressive disorder with an autumn-winter seasonal pattern (as defined by DSM-IV criteria). Bupropion therapy was initiated prior to symptom onset during the autumn (September to November), continued through the winter months, and discontinued following a 2-week tapering period beginning the first week of spring (the fourth week of March), which resulted in a treatment duration of approximately 4 to 6 months for the majority of patients. Patients were randomized to receive either placebo or 150 mg of bupropion as extended-release tablets (Wellbutrin XL) once daily for 1 week, then the dosage was titrated upward to 300 mg once daily. Patients judged by the investigator to be unlikely or unable to tolerate the 300-mg daily dosage were allowed to continue to receive 150 mg daily or to have their dosage reduced to 150 mg once daily; mean dosages in the 3 studies ranged from 257-280 mg once daily. In these 3 trials, a substantially higher percentage of patients receiving bupropion extended-release tablets were depression-free at the end of treatment compared with those receiving placebo (81.4 vs 69.7%, 87.2 vs 78.7%, and 84 vs 69%, respectively, for studies 1, 2, and 3, respectively); the depression-free rate for the 3 studies combined was 84.3% for extended-release bupropion tablets and 72% for placebo.

Smoking Cessation

Bupropion, as extended-release tablets, is used as an adjunct in the cessation of smoking. Such therapy may be combined with nicotine replacement therapy if necessary. However, the manufacturer states that before patients receive this combination of therapies, the labeling for both bupropion and nicotine should be consulted and recommends that patients who receive bupropion and nicotine concurrently be monitored for the development of hypertension related to such therapy.(See Cautions: Cardiovascular Effects.)

The US Public Health Service (USPHS) guideline for the treatment of tobacco use and dependence recommends bupropion (as extended-release tablets) as one of several first-line drugs that may reliably increase long-term smoking abstinence rates. Nicotine (tobacco) dependence is a chronic relapsing disorder that requires ongoing assessment and often repeated intervention. Because effective nicotine dependence therapies are available, every patient should be offered effective treatment, and those who are unwilling to attempt cessation should be provided at least brief interventions designed to increase their motivation to stop tobacco use. Delineated in the current USPHS guideline for the treatment of tobacco use and dependence are 5 brief strategies of intervention that can be provided by any clinician; these strategies consist of asking patients if they use tobacco, advising those who use tobacco to quit, assessing their willingness to quit, assisting those who attempt to quit, and arranging follow-up to prevent relapse. Also included in the USPHS guideline are recommendations for the use of pharmacotherapy in general, first-line drugs (i.e., extended-release bupropion, buccal [gum or lozenge] nicotine polacrilex, transdermal nicotine, nicotine nasal spray, nicotine oral inhaler, varenicline) that should be considered initially as part of treatment for tobacco dependence, unless contraindicated, and second-line drugs (i.e., clonidine, nortriptyline). Clinicians should encourage all patients attempting to quit smoking to use effective pharmacotherapy, except when contraindicated or in specific populations for which there is insufficient evidence of efficacy (e.g., pregnant women, smokeless tobacco users, light smokers [e.g., less than 10 cigarettes daily], adolescents). For additional information on smoking cessation, , and also consult the most current USPHS Clinical Practice Guideline on Treating Tobacco Use and Dependence available at http://www.ahrq.gov/professionals/clinicians-providers/guidelines-recommendations/index.html.

Bupropion (extended-release) may be particularly useful in patients greatly concerned about gaining weight after cessation of smoking since therapy with the drug has been shown to result in delay in such gain in weight. Nicotine dependence therapy with an antidepressant such as bupropion also may be particularly useful when a depressive disorder is included in the current or past history of patients attempting to quit smoking. Although it is not necessary to assess for possible comorbid psychiatric disorders prior to initiating therapy for nicotine dependence, awareness of such comorbidity is important in the assessment and treatment of nicotine-dependent patients since psychiatric disorders are common in this population, smoking cessation or nicotine withdrawal may exacerbate the comorbid condition, bupropion and varenicline therapy have been associated with worsening of preexisting psychiatric disorders in some cases, and patients with psychiatric comorbidities have an increased risk for relapse to smoking after a cessation attempt.

It should be considered that serious neuropsychiatric adverse effects (including but not limited to depression, suicidal ideation, suicide attempt, and completed suicide) have been reported during postmarketing experience in patients being treated with bupropion or varenicline (another smoking cessation drug).(See Neuropsychiatric Symptoms and Suicidality in Smoking Cessation Treatment under Cautions: Nervous System Effects and Cautions: Precautions and Contraindications.) The possible risk of serious adverse effects during bupropion therapy should always be weighed against the significant health benefits of its use for smoking cessation, including a reduction in the risk of developing pulmonary disease, cardiovascular disease, and cancer.

Patients should begin receiving bupropion while they are still smoking since steady-state plasma concentrations of the drug are not achieved until after about 1 week. A date on which patients quit smoking (cessation date) should be scheduled within the first 2 weeks of therapy with bupropion and generally should be set for the second week (e.g., day 8). Counseling and support are important interventions for patients to receive throughout therapy with bupropion and for a period after its discontinuance. Achievement of cessation of smoking and maintenance of abstinence are more likely with frequent follow-ups and the provision of support by the clinician and other health-care professionals. The importance of participation in behavioral therapies, counseling, and/or support services to which bupropion is adjunctive therapy should be discussed with the patient. The overall program of interventions to enable cessation of smoking should be reviewed by clinicians. The choice of adjunctive therapy (e.g., nicotine replacement, bupropion) should consider factors such as ease of administration, compliance, and potential adverse effects and risks.

Clinical Studies

The efficacy of bupropion, as extended-release tablets, as an adjunct in the cessation of smoking has been established in controlled studies of smokers of at least 15 cigarettes daily, who did not have an underlying depressive disorder. Patients were treated with bupropion in conjunction with individual counseling. Cessation of smoking was defined as total abstinence, as determined with patients' daily diaries and verified by measurement of expiratory carbon monoxide, during the fourth through seventh week of treatment. Treatment over 7 weeks with bupropion or placebo resulted in 1-year cessation of smoking in a greater proportion of patients treated with the drug at a dosage of 150 or 300 mg daily but not in those receiving 100 mg daily. Cessation of smoking was achieved at the end of 7 weeks of treatment in 36-44, 27-39, or 17-19% of patients who received 300 mg daily of bupropion hydrochloride, 150 mg daily of the drug, or placebo, respectively. Maintenance of abstinence was observed with bupropion hydrochloride at a dosage of 300 mg daily. At follow-up during the twelfth week, abstinence continued in 25-30 or 14% of patients who had received bupropion hydrochloride at 300 mg daily or placebo, respectively, and at follow-up during the twenty-sixth week, abstinence continued in 19-27 or 11-16% of patients who had received bupropion hydrochloride at 300 mg daily or placebo, respectively.

Treatment over 9 weeks with bupropion at a dosage of 300 mg daily, transdermal nicotine at a dosage of 21 mg/24 hours, the combination of 300 mg daily of bupropion and transdermal nicotine at 21 mg/24 hours, or placebo resulted in cessation of smoking in a greater proportion of patients treated with bupropion, transdermal nicotine, or the combination of bupropion and transdermal nicotine than in those receiving placebo. Cessation of smoking was achieved during weeks 4-7 in 49, 36, 58, or 23% of patients who received bupropion, transdermal nicotine, the combination of bupropion and transdermal nicotine, or placebo, respectively. At follow-up during the tenth week, abstinence was observed in 46, 32, 51, or 20% of patients who had received bupropion, transdermal nicotine, the combination of bupropion and transdermal nicotine, or placebo, respectively. Additionally, when these patients were assessed at 26 weeks, cessation of smoking continued to be observed in 30, 33, and 13% of patients who received bupropion, the combination of bupropion and transdermal nicotine, or placebo, respectively. A final assessment was performed at 52 weeks and abstinence continued to be observed in 23, 28, and 8% of patients who received bupropion, the combination of bupropion and nicotine, or placebo, respectively. The manufacturer states that because the comparisons between bupropion extended-release tablets, transdermal nicotine, or the combination of these products have not been replicated, these data should not be interpreted as demonstrating superiority of any individual treatment protocol.

Another clinical study also reviewed long-term maintenance treatment with bupropion. Patients received bupropion hydrochloride extended-release tablets at a dosage of 300 mg daily for 7 weeks; therapy was continued in the patients who achieved cessation of smoking at 7 weeks with either bupropion hydrochloride extended-release tablets or placebo. At 6-month follow-up, abstinence continued in 55% of patients receiving bupropion compared with 44% of patients who received placebo therapy.

The safety and efficacy of bupropion extended-release tablets as an adjunct in the cessation of smoking in patients with chronic obstructive pulmonary disease (COPD) was established in a clinical trial in adults with mild to moderate COPD (FEV1 at least 35%, FEV1/FVC 70% or less, and a diagnosis of chronic bronchitis, emphysema, and/or small airways disease). Treatment over a 12 week period with bupropion or placebo resulted in cessation of smoking during the final four weeks of the study in 22 or 12% of patients, respectively.

Since efficacy in clinical studies is influenced by the population selected, a lower rate of cessation of smoking is possible with use of bupropion in an unselected population. The reported cessation rates in patients receiving bupropion were similar in patients who had and had not previously received nicotine replacement therapy for the cessation of smoking. Withdrawal symptoms, especially irritability, frustration, anger, anxiety, difficulty concentrating, restlessness, and depressed mood or negative affect, were reduced with bupropion compared with placebo. Craving for cigarettes or urge to smoke appeared to be reduced with bupropion in comparison with placebo.

Obesity

Bipolar Disorder

Bupropion has been used for the treatment of bipolar depression (bipolar disorder, depressive episode). Lithium preferably or lamotrigine alternatively are considered first-line agents by the American Psychiatric Association (APA) for the treatment of acute depressive episode of bipolar disorder, and lamotrigine (if not used initially), bupropion, or paroxetine are considered second-line agents when first-line agents are ineffective or not tolerated. If bupropion was effective for the management of an acute depressive episode, including during the continuation phase, then maintenance therapy with the drug should be considered to prevent recurrences of major depressive episodes. In a comparative study, bupropion (mean dosage of 358 mg daily) was as effective as desipramine (mean dosage of 140 mg daily) in the management of depression in patients with bipolar disorder. Hypomania or mania occurred less frequently with bupropion than with desipramine in patients treated for up to 1 year with either drug and concomitant lithium, carbamazepine, or valproate sodium.

Because bupropion may be less likely than some other antidepressants to cause a switch to mania or rapid cycling in patients with bipolar disorder, many experts consider bupropion a preferred antidepressant for use in combination with a mood-stabilizing agent in patients with severe (nonpsychotic) depression that is unresponsive to therapy with mood-stabilizing agents alone. However, the possibility that manic attacks may be precipitated in patients with bipolar disorder who receive bupropion still must be considered. To reduce the risk of developing mania, antidepressants should not be used alone in patients with depression associated with bipolar disorder and the lowest effective dosage of the antidepressant should be used for the shortest time necessary.

For further information on the management of bipolar disorder,

Attention Deficit Hyperactivity Disorder

Bupropion has been used in a limited number of children with attention deficit hyperactivity disorder (ADHD). Although stimulants (e.g., methylphenidate, dextroamphetamine) usually are considered the drugs of first choice when pharmacotherapy is indicated as an adjunct to psychological, educational, social, and other remedial measures in the treatment of ADHD in children, some clinicians recommend use of bupropion or tricyclic antidepressants as second-line therapy when there has been no response to at least 2 stimulants or when the patient is intolerant of stimulants. In controlled studies, bupropion was more effective than placebo and comparably effective to methylphenidate. In addition, in a comparative study, bupropion hydrochloride (mean dosage of 3.3 mg/kg daily; range: 1.4-5.7 mg/kg daily) was comparably effective to methylphenidate hydrochloride (mean dosage of 31 mg daily; range: 20-60 mg daily) in overall improvement of symptoms, as evaluated with the Iowa-Conners Abbreviated Parent and Teacher Questionnaire, although a trend favoring methylphenidate was noted in almost all rating scales.

Bupropion also has been used in a limited number of adults with ADHD. In an uncontrolled study in adults, bupropion (mean dosage of 359 mg daily; range: 150-450 mg daily) administered for 6-8 weeks reduced the severity of signs and symptoms of attention deficit hyperactivity disorder, as evaluated with the Targeted Attention Deficit Disorder Symptoms Scale. Additional study and experience are needed to establish the role of antidepressants versus CNS stimulants in the treatment of this disorder.

For further information on management of ADHD,

Other Uses

Bupropion does not appear to be effective in the treatment of panic disorder and concomitant phobic disorder. However, the drug generally improves symptoms of panic and depression in patients with major depression who have superimposed panic symptoms.

Although bupropion has been used effectively in some patients with bulimia nervosa, the American Psychiatric Association (APA) states that the drug has been associated with seizures in purging bulimic patients and cautions against its use in the management of this disorder. For information on the use of antidepressants in the treatment of bulimia nervosa and other eating disorders, .

Dosage and Administration

Administration

Bupropion hydrochloride is administered orally. As conventional tablets, the drug usually is administered 3 times daily, preferably with 6 or more hours separating doses, or in the morning, at midday, and in the evening.

Bupropion hydrochloride extended-release tablets should be swallowed whole so that the slow drug-release characteristics are maintained. Patients should be instructed not to chew, divide, or crush the extended-release tablets. As extended-release, film-coated tablets (e.g., Wellbutrin SR, Zyban), bupropion hydrochloride usually is administered twice daily with an interval of at least 8 hours between doses. Extended-release tablets commercially available as Wellbutrin XL are administered once daily in the morning with an interval of at least 24 hours between doses. For patients who develop insomnia while receiving extended-release bupropion twice daily, taking the evening dose earlier (e.g., in the afternoon, but at least 8 hours after the morning dose) rather than at bedtime may provide some relief.

Bupropion therapy with conventional tablets usually is initiated with administration twice daily, in the morning and in the evening. As extended-release tablets, bupropion hydrochloride therapy usually is initiated with administration of a single daily dose in the morning.

A retrospective analysis of clinical experience suggests that the risk of seizures during bupropion therapy may be minimized by increasing dosages gradually, by not exceeding the recommended maximum daily dosage (400 mg as extended-release, film-coated tablets [e.g., Wellbutrin SR]) or 450 mg as conventional tablets or as extended-release tablets of Wellbutrin XL), and by administering the daily dosage in 2 divided doses with a maximum single dose of 200 mg (as extended-release tablets) or in 3 divided doses with a maximum single dose of 150 mg (as conventional tablets). Increasing the dosage gradually also lessens the occurrence of agitation, motor restlessness, and insomnia commonly experienced when bupropion therapy is initiated. If any of these adverse effects occur and are troublesome, temporarily reducing dosage or delaying any dosage increases may be useful.

Avoiding bedtime administration of the evening dose of bupropion may lessen the occurrence of insomnia (commonly experienced during initiation of bupropion therapy). Short-term administration of an intermediate- to long-acting sedative hypnotic also may be useful during the first week of therapy but thereafter generally is not needed.

Dosages exceeding 300 mg daily as conventional tablets are administered as divided doses that should not exceed 150 mg. Conventional tablets of 75 or 100 mg can be used to create the divided doses. If the components of a larger dosage include 4 whole conventional tablets of 100 mg, the divided doses are administered 4 times daily separated by 4 or more hours so that none of the doses exceed 150 mg. Dosages exceeding 150 mg daily as extended-release, film-coated tablets (e.g., Wellbutrin SR) should be administered as divided doses twice daily, preferably with 8 or more hours separating the doses.

Dosage

Dosage of bupropion hydrochloride is expressed in terms of the salt.

All patients receiving bupropion for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, or unusual changes in behavior, particularly during initial therapy or following any change (increase or decrease) in dosage. (See Clinical Worsening and Suicide Risk in Treating Psychiatric Disorders under Cautions: Nervous System Effects, and see also Cautions: Precautions and Contraindications.)

All patients receiving bupropion for smoking cessation should be monitored for serious neuropsychiatric symptoms or worsening of preexisting psychiatric illness. (See Neuropsychiatric Symptoms and Suicidality in Smoking Cessation Treatment under Cautions: Nervous System Effects, and see also Cautions: Precautions and Contraindications.)

Major Depressive Disorder

For the management of depressive disorder in adults, the recommended initial dosage of bupropion hydrochloride as conventional tablets is 100 mg twice daily. Alternatively, dosage also has been initiated at 75 mg 3 times daily. If no clinical improvement is apparent, dosage may be increased to 100 mg 3 times daily as conventional tablets after at least 3 days of therapy with the initial dosage. Bupropion hydrochloride dosages exceeding 300 mg daily should not be considered until several weeks of therapy at this dosage level have been completed since maximum effects of a given dosage of antidepressant, in general, may not be fully apparent until after 4 or more weeks of therapy. Beyond this time, if no clinical improvement is apparent, dosage of the conventional preparation may be increased to a maximum of 450 mg daily as divided doses not exceeding 150 mg each.

Bupropion hydrochloride dosage as conventional tablets should not be increased by more than 100 mg daily every 3 days. Such cautious adjustment of dosage is particularly important in lessening the risk of bupropion-induced seizures. If clinical improvement is not apparent after an appropriate trial of 450 mg daily as conventional tablets, the drug should be discontinued since further increases may be associated with an unacceptable risk of toxicity.

If extended-release, film-coated tablets of bupropion hydrochloride (e.g., Wellbutrin SR) are used for the management of depression in adults, the recommended initial dosage is 150 mg once daily given as a single dose. If the initial dosage is tolerated adequately, it may be increased to the target dosage of 150 mg twice daily (with at least 8 hours between doses) as early as the fourth day of therapy. However, the full therapeutic effect of a given dosage may not be apparent for 4 weeks or longer, and caution is recommended when increasing dosages to minimize the risk of bupropion-induced seizures. For patients not exhibiting clinical improvement with 300 mg daily, dosage of the extended-release, film-coated tablets may be increased to 400 mg daily, given as divided doses of 200 mg twice daily (with at least 8 hours between doses). Dosages exceeding 400 mg daily as extended-release, film-coated tablets are not recommended.

Alternatively, for management of depression in adults, extended-release tablets of bupropion hydrochloride (Wellbutrin XL) may be used. The recommended initial adult dosage of Wellbutrin XL extended-release tablets is 150 mg given as a single dose once daily in the morning. If the initial dosage is tolerated adequately, the dosage may be increased to the target dosage of 300 mg once daily given as a single dose as early as the fourth day of therapy. However, the full therapeutic effect of a given dosage may not be apparent for 4 weeks or longer, and caution is recommended when increasing dosages to minimize the risk of bupropion-induced seizures. At least 24 hours should elapse between successive doses. For patients not exhibiting clinical improvement with a dosage of 300 mg daily, the dosage may be increased to 450 mg once daily as a single dose. Dosages exceeding 450 mg daily as Wellbutrin XL extended-release tablets are not recommended.

If therapy is to be switched from conventional bupropion (e.g., Wellbutrin) or from the extended-release, film-coated tablets (e.g., Wellbutrin SR) to the once-daily Wellbutrin XL extended-release tablets, the same total daily dosage should be given when possible, but as a single daily dose.

Although the optimum duration of bupropion hydrochloride therapy has not been established, acute depressive episodes are thought to require several months or longer of sustained antidepressant therapy. In addition, some clinicians recommend that long-term antidepressant therapy be considered in certain patients at risk for recurrence of depressive episodes (such as those with highly recurrent unipolar depression). Whether the dosage of bupropion required to induce remission is identical to the dosage needed to maintain and/or sustain euthymia is unknown. Systematic evaluation of bupropion hydrochloride extended-release, film-coated tablets (Wellbutrin SR) has shown that antidepressant efficacy is maintained for periods of up to 44 weeks in patients receiving 150 mg twice daily. Efficacy of bupropion hydrochloride conventional tablets beyond 6 weeks has not been established systematically in controlled studies. The usefulness of the drug in patients receiving prolonged therapy with conventional or extended-release tablets should be reevaluated periodically.

Seasonal Affective Disorder

For the prevention of seasonal major depressive episodes associated with seasonal affective disorder in adults, therapy with extended-release tablets of bupropion hydrochloride (Wellbutrin XL) generally is initiated in the autumn prior to the onset of depressive symptoms; treatment should continue through the winter season and should be tapered and discontinued in the early spring. The timing of initiation and duration of treatment should be individualized based on the patient's historical pattern of seasonal major depressive episodes. Patients whose seasonal depressive episodes are infrequent or not associated with clinically important impairment generally should not be treated prophylactically.

The recommended initial adult dosage of bupropion hydrochloride, as extended-release tablets (Wellbutrin XL), is 150 mg once daily in the morning. If the 150-mg once-daily dosage is adequately tolerated, the dosage may be increased to 300 mg once daily after 1 week. If the 300-mg once daily dosage is not adequately tolerated, the dosage may be reduced to 150 mg once daily. The usual target dosage is 300 mg given once daily in the morning. For patients receiving 300 mg of bupropion hydrochloride as extended-release tablets during the autumn-winter season, the dosage should be tapered to 150 mg once daily for 2 weeks prior to discontinuance. Dosages exceeding 300 mg daily as extended-release tablets have not been studied for prevention of episodes of seasonal major depression.

Smoking Cessation

For use in adults as an adjunct in smoking cessation, the initial dosage of bupropion hydrochloride, as extended-release tablets, is 150 mg daily for the first 3 days of therapy. The dosage subsequently is increased in most patients to the usual recommended dosage of 150 mg twice daily, which also is the maximum recommended dosage. Dosages exceeding 300 mg daily should not be used for smoking cessation because of the risk of seizures. Because steady-state plasma concentrations of the drug are not achieved for about 1 week, bupropion therapy for smoking cessation should be initiated 1-2 weeks prior to discontinuance of cigarette smoking. Patients should continue to receive bupropion hydrochloride for 7-12 weeks; the need for more prolonged therapy should be individualized depending on benefits and risks to the patient. Discontinuance of therapy does not require that the dosage be tapered.

For some patients, it may be appropriate to continue pharmacotherapy with bupropion for smoking cessation for periods longer than usually recommended since nicotine dependence is a chronic condition. Use of bupropion hydrochloride as an adjunct in smoking cessation has been studied systematically as maintenance therapy at 150 mg twice daily for up to 6 months. The decision to continue therapy beyond 12 weeks for smoking cessation must be individualized. Although weaning should be encouraged for all smoking cessation pharmacotherapies, continued use of such therapy is clearly preferable to a return to smoking with respect to health consequences.

Patients have received the combination of bupropion, as extended-release tablets, and transdermal nicotine. Patients treated with this combination have been started on bupropion hydrochloride at a dosage of 150 mg daily, while they were still smoking. After 3 days, the dosage of bupropion hydrochloride was increased to 150 mg twice daily. Patients received concomitant transdermal nicotine therapy at a dosage of 21 mg/24 hours after about 1 week of therapy with bupropion, when the date scheduled for patients to stop smoking was reached. The dosage of transdermal nicotine was tapered to 14 and 7 mg/24 hours during the eighth and ninth weeks of therapy, respectively.

Complete smoking abstinence is the goal of therapy with bupropion hydrochloride. Cessation of smoking is unlikely in patients who do not show substantial progress toward abstinence after receiving bupropion hydrochloride for 7 weeks, so such therapy probably should be discontinued at that time in these patients. Unsuccessful patients may benefit from interventions to enhance the possibility for success on the next attempt. Such patients should be evaluated to determine why failure occurred, and another attempt to quit smoking should be encouraged by a more favorable context that includes elimination or reduction of the factors responsible for failure.

Depression Associated With Bipolar Disorder

While comparative efficacy of various dosages in the usual range have not been established in the management of depression associated with bipolar disorder, some experts recommend that dosages of antidepressants, including bupropion, be titrated to levels comparable to those used in the treatment of unipolar depression. In clinical studies in patients with depression associated with bipolar disorder, bupropion hydrochloride has been given in a dosage of 75-400 mg daily in conjunction with a mood-stabilizing agent (e.g., carbamazepine, lithium, valproate). Antidepressants should be used in these patients for the shortest time necessary.

Attention Deficit Hyperactivity Disorder

For the treatment of attention deficit hyperactivity disorder (ADHD) in adults, bupropion hydrochloride therapy has been initiated with a dosage of 150 mg daily as conventional tablets. Dosage was then titrated to a maximum daily dosage of 450 mg as conventional tablets.

Although safety and efficacy of bupropion hydrochloride in pediatric patients younger than 18 years of age have not been established, if bupropion is used for the treatment of ADHD in children, some experts recommend that those weighing 20 kg or more receive an initial dosage of 1 mg/kg daily in 2-3 divided doses. This initial dosage should be given for the first 3 days of therapy, then dosage should be titrated up to 3 mg/kg daily in 2-3 divided doses by day 7 and up to 6 mg/kg daily in 2-3 divided doses or 300 mg (whichever is smaller) by the third week of therapy. Alternatively, some experts suggest that pediatric patients with ADHD receive bupropion hydrochloride beginning with an initial dosage of 37.5 mg or 50 mg twice daily with dosage titration over 2 weeks up to a maximum dosage of 250 mg daily (300-400 mg daily in adolescents). Up to 4 weeks of bupropion therapy may be necessary to attain maximum effects of the drug. Pediatric dosage for ADHD generally has ranged from 50-100 mg 3 times daily. If extended-release tablets are used for ADHD, the pediatric dosage generally has ranged from 100-150 mg twice daily.

Dosage in Renal and Hepatic Impairment

Bupropion should be used with caution in patients with renal impairment, and a reduction in dosage and/or frequency of administration should be considered. Although bupropion is extensively metabolized in the liver to active metabolites, its active metabolites are renally excreted and may accumulate to a greater extent in patients with renal impairment than in those with normal renal function.(See Pharmacokinetics.) Therefore, patients with renal impairment should be closely monitored for possible adverse effects (e.g., seizures) that could indicate higher than recommended drug or metabolite concentration and necessitate a reduction in dose and/or frequency of administration of bupropion. Based on limited pharmacokinetic data obtained in a single-dose study, some clinicians suggest that patients undergoing hemodialysis should receive 150 mg of bupropion hydrochloride as extended-release tablets every 3 days instead of daily for smoking cessation; a multiple-dose study is needed to confirm these findings.(See Pharmacokinetics: Elimination.)

Because substantial increases in peak plasma bupropion concentrations and accumulation of the drug may occur in patients with severe hepatic cirrhosis, bupropion should be used with extreme caution in these patients. Dosage of the drug in these patients should not exceed 75 mg once daily as conventional tablets, 100 mg once daily or 150 mg every other day as extended-release, film-coated tablets (e.g., Wellbutrin SR), or 150 mg every other day as Wellbutrin XL extended-release tablets or Zyban extended-release, film-coated tablets. The drug should also be used with caution in patients with hepatic impairment (including mild to moderate hepatic cirrhosis) and a reduction in dose and/or frequency of administration of bupropion should be considered in these patients.

Cautions

Bupropion generally is well tolerated. Common adverse effects of the drug include agitation, dry mouth, insomnia, headache/migraine, nausea/vomiting, constipation, and tremor. Discontinuance of bupropion therapy was required in about 10% of patients and healthy individuals who participated in clinical trials with conventional tablets during the drug's initial development, principally secondary to adverse neuropsychiatric (mainly agitation and abnormal mental status), GI (mainly nausea and vomiting), neurologic (mainly seizures, headaches, and sleep disturbances), and dermatologic (mainly rashes) effects in 3, 2.1, 1.7, and 1.4% of patients, respectively. However, these adverse effects often occurred at dosages exceeding the daily dosages currently recommended for major depression.

The incidences of most adverse effects in controlled trials were reported for bupropion hydrochloride dosages ranging from 300-600 mg daily for 3-4 weeks as conventional tablets, and often such effects were reported regardless of whether any attempt was made to attribute them to therapy. While the manufacturer's labeling includes comparative incidences for patients receiving placebo, reporting apparently similar incidences between bupropion and placebo groups for many of the effects, no information is provided on whether significant differences in the incidences of adverse effects exist between the groups. Because of the nature and conditions of reporting these effects in clinical trials, the incidences may not predict precisely the likelihood of encountering adverse reactions under usual medical practice where patient characteristics and other factors differ from those prevailing in the trials. In one report of several placebo-controlled trials, only dry mouth was found to occur with an incidence significantly greater than that reported for placebo, occurring in 13.1% more of patients receiving bupropion than placebo, and other adverse effects occurring at incidences that exceeded those for placebo by at least 3% included syncope/dizziness, constipation, tremor, nausea/vomiting, blurred vision, excitement/agitation, and increased motor activity.

In patients receiving 300 mg daily of bupropion hydrochloride extended-release, film-coated tablets (as Wellbutrin SR), anorexia, dry mouth, rash, sweating, tinnitus, and tremor were reported in 5% or more of patients and at least twice as often as in patients receiving placebo in clinical trials. Abdominal pain, agitation, anxiety, dizziness, dry mouth, insomnia, myalgia, nausea, palpitation, pharyngitis, sweating, tinnitus, and urinary frequency were reported in 5% or more of patients receiving 400 mg daily (as Wellbutrin SR) and at least twice as often as in patients receiving placebo in clinical trials.

Bupropion therapy was discontinued by 9% of patients with seasonal affective disorder receiving bupropion hydrochloride extended-release tablets (as Wellbutrin XL) in clinical studies, compared with 5% of patients receiving placebo. Adverse effects leading to discontinuance of bupropion in at least 1% of patients and at a rate that was numerically greater than that reported with placebo included insomnia and headache, which resulted in discontinuance in 2 and 1%, respectively, of those receiving bupropion, compared with less than 1% of those receiving placebo. Constipation and flatulence were reported in 5% or more of patients and at least twice as often as in patients receiving placebo in controlled clinical trials.

In patients receiving bupropion as an adjunct in the cessation of smoking, the most commonly observed adverse effects consistently associated with the drug were dry mouth and insomnia. These adverse effects may be related in incidence to dosage so reduction of the dosage may minimize their occurrence; however, dosages less than 150 mg daily may not be effective.(See Uses: Smoking Cessation.) Although headache was a commonly reported effect, the incidences between placebo and various bupropion dosages were comparable. Therapy was discontinued in 8% of patients commonly because of neurologic (mainly tremors) or dermatologic (mainly rashes) effects, which resulted in discontinuance in 3.4 or 2.4% of patients, respectively. Other common reasons for discontinuing therapy included headache and urticaria. In 2 studies of patients receiving bupropion therapy as an adjunct for cessation of smoking, one in patients with mild to moderate chronic obstructive pulmonary disease (COPD) for 12 weeks and another that evaluated long-term administration of bupropion therapy (up to 1 year), the incidence and nature of the adverse effects reported were similar to those reported in previous studies.

Nervous System Effects

Seizures

One of the potentially most serious adverse effects of bupropion is reduction in the seizure threshold. However, despite the potential seriousness of this effect, seizures remain a relatively uncommon adverse effect of bupropion therapy, particularly when currently recommended dosages for depression are not exceeded and underlying predisposing factors are not present.

Seizures reportedly occurred in about 1% or more of patients overall receiving bupropion as conventional tablets, many of whom had predisposing factors; however, the risk appears to be strongly associated with predisposing factors and with dosage, with seizures occurring in only approximately 0.4% of patients receiving dosages not exceeding 450 mg daily of bupropion as conventional tablets. Seizures reportedly occurred in about 0.1% of patients treated with the extended-release, film-coated tablets of bupropion hydrochloride (as Wellbutrin SR) at dosages of 100-300 mg daily. Whether this lower incidence of seizures is related to administration of the extended-release preparation or to lower dosages is not known, although since most observed seizures reportedly occurred during steady state, a pertinent consideration in the estimation of incidence is that the extended-release and conventional tablets are bioequivalent in terms of both the rate and extent of absorption of drug at steady state. The maximum dosages recommended for the extended-release, film-coated tablets (e.g., Wellbutrin SR), extended-release tablets (Wellbutrin XL), and conventional tablets are close at 400, 450, and 450 mg daily, respectively, and result in the same incidence of seizures, about 0.4%.

Of approximately 2400 patients who participated in early clinical trials with bupropion as conventional tablets, 25 patients developed seizures. The incidence of seizures was 2.8%, 2.3%, or 0.3%, respectively, in patients treated with dosages of 600-900, 600, or 450 mg and lower daily as conventional tablets. In a prospective study of the incidence of seizures in approximately 3200 patients treated with dosages up to 450 mg daily of bupropion, the total incidence of seizures was 0.1 or 0.4% for patients treated for 8 weeks or longer with dosages up to 300 mg daily as extended-release tablets (as Wellbutrin SR) or 300-450 mg daily as conventional tablets, respectively, but most patients experiencing seizures had a predisposing factor (e.g., seizure or head trauma history, current seizure disorder, concomitant use of drugs that lower the seizure threshold). The manufacturer warns that this risk of 0.4% may be up to 4 times that of other currently available antidepressants, including bupropion as extended-release tablets administered at dosages not exceeding 300 mg daily (at a dosage of 400 mg daily, the risk is the same); however, the relative risk of seizures with antidepressant agents is not clearly defined and can be affected by a number of factors, including dosage and dosing schedule, concomitantly administered drugs, age, and underlying predisposing factors (e.g., seizure history). In addition, most patients in this prospective study received the maximum dosage of 450 mg daily. Seizures often occurred during the early phase of bupropion therapy and sometimes occurred several weeks after establishment of dosage. Although one study reported that age did not influence the risk of seizures, this study did not adequately control for potentially confounding risk factors, and it has been suggested that the risk of seizures may decrease with advancing age.

Other Nervous System Effects

Many other adverse nervous system effects of bupropion occur more commonly than seizures. Agitation, insomnia, and anxiety occurred in about 32, 19, and 6% of patients, respectively, receiving bupropion. These adverse effects and restlessness occur, to some extent, in a substantial number of patients, particularly at the beginning of bupropion therapy. Such adverse effects required treatment with sedative/hypnotic drugs in some patients in clinical trials in major depressive disorder, while discontinuance of bupropion was required in about 2% of patients treated with conventional tablets of bupropion and in about 1 or 3% of patients treated with extended-release, film-coated tablets (as Wellbutrin SR) of the drug at 300 or 400 mg daily, respectively, in these studies. A limited number of patients with insomnia derived improvement in sleep with concomitant administration of a low dosage of trazodone hydrochloride (e.g., 100 mg daily). Impairment in sleep quality and asthenia each occurred in about 4% of patients receiving bupropion, and fatigue occurred in about 5% of patients. In patients receiving extended-release, film-coated tablets of bupropion hydrochloride (as Wellbutrin SR), agitation occurred in 3 or 9%, insomnia occurred in 11 or 16%, and anxiety occurred in 5 or 6% with 300 or 400 mg daily, respectively. In patients receiving extended-release tablets of bupropion hydrochloride (as Wellbutrin XL) for seasonal affective disorder, agitation occurred in 2%, anxiety occurred in 7%, and insomnia occurred in 20% at a dosage of 150-300 mg daily. In patients receiving bupropion hydrochloride as an adjunct in smoking cessation, insomnia occurred in 29 or 35% of patients receiving 150 or 300 mg daily, respectively, and discontinuance of therapy was required in 0.6% of patients. Insomnia occurred in 40 or 45% of patients receiving 300 mg daily of bupropion hydrochloride alone or in combination with transdermal nicotine in a dosage of 21 mg/24 hours, respectively, and discontinuance of therapy was required in 0.8% of patients who received bupropion alone. Avoidance of administering bupropion at bedtime or reducing the dosage, if necessary, may minimize insomnia. Anxiety occurred in about 11 or 5-8% of patients receiving placebo or bupropion, respectively, as an adjunct in smoking cessation.

A variety of neuropsychiatric manifestations reportedly have emerged in patients receiving bupropion. However, because of the uncontrolled nature of many studies with the drug, it is not possible to provide a precise estimate of the risk of such effects imposed by bupropion therapy. Confusion and delusions occurred in about 8 and 1% of patients, respectively, receiving bupropion. In several cases, these and other adverse neuropsychiatric effects, such as hallucinations, psychosis, disturbance in concentration, and paranoid ideation, reportedly abated when bupropion dosage was reduced, although discontinuance of the drug may be necessary. In clinical trials, administration of bupropion as an adjunct in smoking cessation or placebo resulted in a generally comparable incidence of adverse neuropsychiatric effects in smokers without a depressive disorder. However, in postmarketing experience, patients receiving bupropion for smoking cessation have reported similar types of neuropsychiatric symptoms as those reported by patients in clinical trials of bupropion for depression. (See Neuropsychiatric Symptoms and Suicidality in Smoking Cessation Treatment and see also Clinical Worsening and Suicide Risk in Treating Psychiatric Disorders under Cautions: Nervous System Effects, and see Cautions: Precautions and Contraindications.)

Headache/migraine occurred in up to about 26% of patients receiving bupropion, and dizziness (which may be secondary to cardiovascular effects), tremor, and sedation occurred in 22, 21, and 20% of patients, respectively. Akinesia/bradykinesia occurred in about 8% of patients receiving the drug. Hostility, nervousness, and sensory disturbance occurred in about 6, 5, and 4% of patients, respectively. Disturbed concentration, somnolence, irritability, and a decrease in memory occurred in about 3% of patients. Adverse nervous system effects reportedly occurring in about 1-2% of patients include akathisia, pseudoparkinsonism, euphoria, paresthesia, and CNS stimulation. Therapy with bupropion as an adjunct in smoking cessation resulted in dizziness, disturbed concentration, dream abnormalities, or nervousness in up to about 10, 9, 5, or 4% of patients, respectively. Tremor and somnolence each occurred in up to about 2% of patients receiving bupropion as an adjunct in smoking cessation, and abnormality in thinking occurred in about 1% of patients.

Mania/hypomania reportedly occurred in up to 1% or more of patients receiving bupropion, but a causal relationship to the drug has not been established. Limited data suggest that in comparison to tricyclic antidepressants or fluoxetine, mania associated with bupropion is less severe, as indicated by the Clinical Global Impression severity rating. Therapy with bupropion as an adjunct in smoking cessation has not resulted in precipitation of mania in smokers without a depressive disorder.

Psychosis reportedly occurred in less than 1% of patients receiving bupropion, but a causal relationship to the drug has not been established. Exacerbation of psychotic behavior in patients with schizoaffective disorder, depressed type also has been reported, and catatonia, manifested as mutism, waxy flexibility, staring, rigidity, withdrawal, refusal to eat, and negativism, also has been reported in patients receiving the drug. Therapy with bupropion as an adjunct in smoking cessation has not resulted in activation of psychosis in smokers without a depressive disorder.

In at least one patient who was receiving bupropion for smoking cessation (300 mg daily), extreme irritability, restlessness, anger, anxiety, and cravings occurred soon after cigarettes were withdrawn. Within 2 days after discontinuing bupropion and initiating transdermal nicotine replacement therapy, these manifestations resolved.

Ataxia/incoordination, myoclonus, dyskinesia, dystonia, and depression occurred in 1% or more of patients receiving bupropion; however, a causal relationship to the drug has not been established. Adverse nervous system effects occurring in less than 1% of bupropion-treated patients include vertigo, dysarthria, hyperkinesia, hypesthesia, hypertonia, memory impairment, depersonalization, dysphoria, mood instability, labile emotions, paranoia, and formal thought disorder; however, a causal relationship to the drug has not been established. Rarely reported adverse nervous system effects for which a causal relationship has not been established include EEG abnormalities, abnormal neurologic exam, neuropathy, impaired attention, amnesia, neuralgia, sciatica, derealization, aggression, and aphasia. Coma, delirium, dream abnormalities, akinesia, hypokinesia, extrapyramidal syndrome, and unmasking of tardive dyskinesia also have been reported, although a causal relationship to bupropion has not been established. Exacerbation of tics in patients with attention-deficit hyperactivity disorder and coexistent Tourette's syndrome has been reported, but such exacerbation also has been observed with stimulants (e.g., amphetamine, methylphenidate) in such patients.

Clinical Worsening and Suicide Risk in Treating Psychiatric Disorders

Suicidal ideation has emerged rarely in patients receiving bupropion. Suicide also is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. However, there has been a long-standing concern that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment. Pooled analyses of short-term, placebo-controlled studies of antidepressants (i.e., selective serotonin-reuptake inhibitors and other antidepressants) have shown an increased risk of suicidality in children, adolescents, and young adults (18-24 years of age) with major depressive disorder and other psychiatric disorders. An increased suicidality risk was not demonstrated with antidepressants compared with placebo in adults older than 24 years of age, and a reduced risk was observed in adults 65 years of age or older. It is currently unknown whether the suicidality risk extends to longer-term use (i.e., beyond several months); however, there is substantial evidence from placebo-controlled maintenance trials in adults with major depressive disorder that antidepressants can delay the recurrence of depression. The US Food and Drug Administration (FDA) recommends that all patients being treated with antidepressants for any indication be appropriately monitored and closely observed for clinical worsening, suicidality, and unusual changes in behavior, particularly during initiation of therapy (i.e., the first few months) and during periods of dosage adjustments.(See Cautions: Precautions and Contraindications and see Cautions: Pediatric Precautions.)

Neuropsychiatric Symptoms and Suicidality in Smoking Cessation Treatment

Serious neuropsychiatric symptoms, including changes in mood (including depression and mania), psychosis, hallucinations, paranoia, delusions, homicidal ideation, hostility, agitation, aggression, anxiety, and panic as well as suicidal ideation, suicide attempt, and completed suicide, have been reported during postmarketing experience in patients receiving bupropion or varenicline for smoking cessation. Such events have occurred in patients with or without preexisting psychiatric disease, and some patients experienced worsening of their psychiatric illness. While some of the cases may have been confounded by symptoms of nicotine withdrawal typically seen in individuals who have stopped smoking, these effects also were observed in patients who continued to smoke. As a postmarketing requirement to further assess the neuropsychiatric safety of bupropion and varenicline, the manufacturers conducted a large, randomized, double-blind, placebo- and active-controlled study (EAGLES) in more than 8000 smokers with or without a history of psychiatric disorders. Patients were stratified into a nonpsychiatric or psychiatric cohort and randomized to receive varenicline (1 mg twice daily), extended-release bupropion (150 mg twice daily), transdermal nicotine (21 mg/day with taper), or placebo; treatment was continued for a total of 12 weeks and patients were followed for an additional 12 weeks posttreatment. In this study, use of varenicline or bupropion was not associated with an increased risk of clinically important psychiatric events (as assessed by a composite safety end point of anxiety, depression, feeling abnormal, hostility, agitation, aggression, delusions, hallucinations, homicidal ideation, mania, panic, paranoia, psychosis, suicidal ideation, and suicidal behavior or completed suicide) compared with nicotine replacement therapy or placebo. However, patients with a psychiatric disorder were more likely than those without such a disorder to experience a clinically important neuropsychiatric event. In the psychiatric cohort, clinically important neuropsychiatric events occurred in 12.2, 11.8, or 9.8% of patients receiving varenicline, bupropion, or nicotine, respectively, and these event rates were greater for each of the active treatments compared with placebo (9.5%). In the nonpsychiatric cohort, such events occurred in approximately 3% of patients across treatment groups. Serious neuropsychiatric events, including those requiring hospitalization, were reported in less than 1% of patients with or without a psychiatric history in all treatment groups; one completed suicide occurred in a placebo-treated patient in the nonpsychiatric cohort.(See Cautions: Precautions and Contraindications.)

Metabolic Effects

Weight loss exceeding 2.27 kg occurred in about 28% of patients receiving bupropion as conventional tablets. Such weight loss occurred in about 23% of patients who were heavier than normal body weight at baseline compared with about 10% of those who were lighter than normal body weight at baseline. Patients with weight loss symptomatic of a major depressive episode were not affected differently from patients without weight loss at baseline. In patients receiving extended-release, film-coated tablets of bupropion hydrochloride (as Wellbutrin SR) for major depressive disorder, weight loss exceeding 2.27 kg occurred in about 14 or 19% with dosages of 300 or 400 mg daily, respectively. In patients receiving extended-release tablets of bupropion hydrochloride (as Wellbutrin XL) for seasonal affective disorder, weight loss exceeding 2.27 kg occurred in about 23% with dosages of 150-300 mg daily.

Weight gain occurred in about 14% of patients receiving bupropion as conventional tablets. A gain of at least 2.27 kg occurred in 6 or 9% of patients who were overweight or underweight, respectively, at baseline. In patients receiving extended-release, film-coated tablets of bupropion hydrochloride (as Wellbutrin SR) for major depressive disorder, weight gain exceeding 2.27 kg occurred in about 3 or 2% with dosages of 300 or 400 mg daily, respectively. In patients receiving extended-release tablets of bupropion hydrochloride (as Wellbutrin XL) for seasonal affective disorder, weight gain exceeding 2.27 kg occurred in about 11% with dosages of 150-300 mg daily.

Although most smokers who quit smoking gain weight, bupropion appears to be effective in delaying postcessation weight gain and therefore may be particularly useful in patients greatly concerned about gaining weight after cessation of smoking. However, once bupropion therapy is discontinued, the quitting smoker on average will gain an amount of weight that is about the same as if they had not used the drug. In patients receiving bupropion for smoking cessation, weight gain from baseline was inversely related to dose at the end of treatment in patients who abstained from smoking, with gains averaging 2.3 kg in those receiving 100 or 150 mg of the drug daily and 1.5 kg in those receiving 300 mg daily; weight gain was 2.9 kg in those receiving placebo. However, in those who remained abstinent from smoking 25 weeks after discontinuance of bupropion, weight gain was not dose related, averaging 6.6, 4.4, or 4.5 kg at dosages of 100, 150, or 300 mg daily and 5.5 kg for placebo.

Cardiovascular Effects

Tachycardia occurred in up to 11% of patients receiving bupropion, and cardiac arrhythmias occurred in 5% of patients. Palpitations occurred in up to about 6% of patients receiving bupropion. Hypertension, chest pain, and flushing each occurred in about 4% of patients receiving the drug. Hypotension and syncope occurred in 3 and 1% of patients, respectively. Orthostatic hypotension also has been reported. Dizziness, possibly secondary to cardiovascular effects, has been reported commonly in patients receiving bupropion.(See Cautions: Nervous System Effects.) Bupropion generally was well tolerated in a limited number of inpatients with depression and stable congestive heart failure, although an increase in supine blood pressure was associated with the drug that resulted in discontinuance of therapy in some patients because of exacerbation of hypertension present at baseline.

In patients receiving the drugs as adjunctive therapy in smoking cessation, 300 mg daily of bupropion hydrochloride alone or combined with transdermal nicotine in a dosage of 21 mg/24 hours, hypertension emergent to either treatment was observed in 2.5 or 6.1% of patients, respectively, most of whom had evidence of preexisting hypertension. Therapy was discontinued because of hypertension in 1.2% of patients who received the combination of bupropion and transdermal nicotine. Palpitations, hypertension, or chest pain occurred in about 2, 1, or less than 1% of patients, respectively, receiving bupropion as an adjunct in smoking cessation. In some cases, the hypertension reported was severe. (See Cautions: Precautions and Contraindications.)

ECG abnormalities (e.g., premature beats, nonspecific ST-T wave changes) occurred in less than 1% of patients receiving bupropion, although a causal relationship to the drug has not been established. Pallor, phlebitis, and myocardial infarction occurred rarely, but these adverse effects also have not been definitely attributed to the drug. Third-degree heart block also has been reported.

Edema occurred in 1% or more of patients receiving bupropion but has not been definitely attributed to the drug. Peripheral edema occurred in less than 1% of patients receiving bupropion, and facial edema occurred rarely. Therapy with bupropion as an adjunct in smoking cessation resulted in facial edema in less than 1% of patients. In a patient with preexisting cardiomyopathy and hypertension who had received bupropion hydrochloride (300 mg daily) for smoking cessation, cardiac and pulmonary arrest occurred 4 days after completing therapy, and the patient died 9 days later. The safety of bupropion for smoking cessation in patients with underlying coronary heart disease remains to be established.

GI Effects

Dry mouth and constipation occurred in up to about 28 and 26% of patients, respectively, receiving bupropion, and the possibility exists that such effects may result from adverse nervous system effects; however, the anticholinergic activity of the drug reportedly is substantially less than that of tricyclic antidepressants. Nausea/vomiting occurred in up to about 23% of patients. Although anorexia occurred in up to about 18% of patients receiving the drug, an increase in appetite was reported in up to about 4% of patients. Abdominal pain occurred in up to about 9% of patients receiving bupropion. Diarrhea occurred in up to about 7% of patients and dyspepsia, increased salivation, and gustatory disturbance each occurred in up to about 3% of patients receiving bupropion. Dysphagia occurred in up to about 2% of patients receiving bupropion. Mouth ulcer occurred in 2% of patients receiving bupropion as an adjunct in smoking cessation.

Stomatitis has been reported in 1% or more of patients receiving bupropion, but has not been definitely attributed to the drug. Thirst disturbance, gum irritation, and oral edema were reported in less than 1% of patients receiving the drug, but a causal relationship also has not been established. Rectal complaints, colitis, GI bleeding, intestinal perforation, stomach ulcer, gingivitis, lingual edema, glossitis, and esophagitis have occurred rarely but have not been definitely attributed to bupropion.

Dermatologic and Sensitivity Reactions

Excessive sweating occurred in up to about 22% of patients receiving bupropion. Rash, pruritus, and urticaria occurred in up to about 8, 4, and 2% of patients, respectively. Cutaneous temperature disturbance occurred in about 2% of patients receiving the drug. Nonspecific rashes occurred in 1% or more of patients receiving bupropion, and alopecia, photosensitivity, and dry skin have occurred in less than 1% of patients receiving the drug, but these effects have not been definitely attributed to bupropion. Although a causal relationship has not been established, a change in hair color, hirsutism, maculopapular rash, and acne have been reported rarely, and Stevens-Johnson syndrome, angioedema, exfoliative dermatitis, and ecchymosis also have been reported. Symptoms resembling serum sickness, including arthralgia, myalgia, and fever with rash and other symptoms suggestive of delayed hypersensitivity, have been reported in association with bupropion. Anaphylactoid reactions (e.g., pruritus, urticaria, angioedema, dyspnea) that required medical management occurred rarely in patients receiving bupropion; other concomitantly administered drugs may have confounded attributing these effects to bupropion. Application site reaction occurred in 15% of patients receiving bupropion combined with transdermal nicotine as adjunctive therapy in the cessation of smoking. Dry skin or allergic reaction occurred in about 2 or 1% of patients receiving bupropion as an adjunct in smoking cessation.

Ocular and Otic Effects

Blurred vision occurred in about 15% of patients receiving bupropion. Amblyopia occurred in up to about 3% of patients receiving bupropion. Adverse ocular effects reported in less than 1% of bupropion-treated patients include visual disturbance, accommodation abnormality, dry eye, increased intraocular pressure, and mydriasis; however, a causal relationship to the drug has not been established. Diplopia also has occurred but has not been definitely attributed to bupropion.

Tinnitus occurred in up to about 6% of patients receiving bupropion. Auditory disturbance occurred in 5% of patients receiving the drug. Deafness has occurred but has not definitely been attributed to bupropion.

Musculoskeletal Effects

Myalgia and arthralgia occurred in up to about 6 and 5%, respectively, of patients receiving bupropion. Arthritis and muscle spasm or twitch occurred in up to about 3 and 2% of patients, respectively, receiving the drug. Musculoskeletal chest pain has been reported rarely in less than 1% of patients receiving bupropion. Leg cramps, muscle weakness, and muscle rigidity/fever/rhabdomyolysis also have been reported, although a causal relationship also has not been established. Neck pain occurred in 2% of patients receiving bupropion as an adjunct in smoking cessation.

Respiratory Effects

Pharyngitis occurred in up to about 11% of patients receiving bupropion. Upper respiratory complaints occurred in about 5% of patients receiving bupropion. Sinusitis and an increase in coughing each occurred in up to about 3% of patients receiving bupropion. Although a causal relationship has not been established, bronchitis and shortness of breath/dyspnea each have occurred in less than 1% of patients receiving bupropion, and respiratory rate or rhythm disorder, bronchospasm, pneumonia, and pulmonary embolism have occurred rarely. Therapy with bupropion as an adjunct in smoking cessation resulted in rhinitis, bronchitis, or dyspnea in 12, 2, or 1% of patients, respectively.

Genitourinary Effects

Menstrual complaints occurred in about 5% of patients receiving bupropion, and impotence and decreased libido each occurred in about 3% of patients. Urinary frequency, urgency, and retention occurred in up to about 5, 2, and 2% of patients, respectively, receiving the drug. Vaginal hemorrhage occurred in up to about 2% of female patients receiving bupropion. Urinary tract infection occurred in up to about 1% of patients receiving bupropion. Nocturia, increased libido, and a decrease in sexual function have occurred in 1% or more of patients receiving bupropion, although a casual relationship to the drug has not been established. Although not definitely attributed to the drug, vaginal irritation, vaginitis, testicular swelling, polyuria, painful erection, retarded ejaculation, and frigidity have been reported in less than 1% of bupropion-treated patients, and dysuria, enuresis, urinary incontinence, glycosuria, menopause, ovarian disorder, salpingitis, pelvic infection, cystitis, dyspareunia, and painful or abnormal ejaculation have occurred rarely. Clitoral priapism and sexual arousal prolonged to about 24 hours reportedly occurred in at least one female receiving bupropion; she previously had experienced anorgasmia while receiving sertraline. Substantial increases in libido, level of sexual arousal, and intensity and duration of orgasm also have been reported in some bupropion-treated patients.

Other Adverse Effects

Infection occurred in up to about 9% of patients receiving bupropion. Hot flashes and pain each occurred in up to about 3% of patients receiving the drug. Fever/chills occurred in up to about 2% of patients receiving bupropion. Accidental injury or epistaxis each occurred in about 2% of patients receiving bupropion as an adjunct in smoking cessation.

Flu-like symptoms occurred in 1% or more of patients receiving bupropion but have not been definitely attributed to the drug. Although a causal relationship also has not been established, gynecomastia, abnormal liver function test results, liver damage/jaundice, toothache, and bruxism have been reported in less than 1% of bupropion-treated patients, and hormone concentration change, lymphadenopathy, anemia, pancytopenia, epistaxis, body odor, surgically related pain, drug reaction, malaise, and overdose have occurred rarely in patients receiving the drug. Syndrome of inappropriate antidiuretic hormone secretion (SIADH), hyperglycemia, hypoglycemia, hepatitis, thrombocytopenia, leukocytosis, and leukopenia also have been reported, although these adverse effects have not been definitely attributed to bupropion. Eosinophilia has also been reported. In addition, altered prothrombin time and/or international normalized ratio (INR), which have been infrequently associated with hemorrhagic or thrombotic complications, has been reported when bupropion and warfarin were administered concomitantly.

Precautions and Contraindications

Worsening of depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior may occur in both adult and pediatric (see Cautions: Pediatric Precautions) patients with major depressive disorder or other psychiatric disorders, whether or not they are taking antidepressants. This risk may persist until clinically important remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. However, there has been a long-standing concern that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment. Pooled analyses of short-term, placebo-controlled studies of antidepressants (i.e., selective serotonin-reuptake inhibitors and other antidepressants) have shown an increased risk of suicidality in children, adolescents, and young adults (18-24 years of age) with major depressive disorder and other psychiatric disorders. An increased suicidality risk was not demonstrated with antidepressants compared with placebo in adults older than 24 years of age, and a reduced risk was observed in adults 65 years of age or older. It is currently unknown whether the suicidality risk extends to longer-term use (i.e., beyond several months); however, there is substantial evidence from placebo-controlled maintenance trials in adults with major depressive disorder that antidepressants can delay the recurrence of depression.

FDA recommends that all patients being treated with antidepressants for any indication be appropriately monitored and closely observed for clinical worsening, suicidality, and unusual changes in behavior, particularly during initiation of therapy (i.e., the first few months) and during periods of dosage adjustments. Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, also should be advised to monitor patients on a daily basis for the emergence of agitation, irritability, or unusual changes in behavior, as well as the emergence of suicidality, and to report such symptoms immediately to a health-care provider.

Although a causal relationship between the emergence of symptoms such as anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia, hypomania, and/or mania and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality. Consequently, consideration should be given to changing the therapeutic regimen or discontinuing therapy in patients whose depression is persistently worse or in patients experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, particularly if such manifestations are severe, abrupt in onset, or were not part of the patient's presenting symptoms. FDA also recommends that the drugs be prescribed in the smallest quantity consistent with good patient management, in order to reduce the risk of overdosage.

It is generally believed (though not established in controlled trials) that treating a major depressive episode with an antidepressant alone may increase the likelihood of precipitating a mixed or manic episode in patients at risk for bipolar disorder. Therefore, patients should be adequately screened for bipolar disorder prior to initiating treatment with an antidepressant; such screening should include a detailed psychiatric history (e.g., family history of suicide, bipolar disorder, and depression). Bupropion is not approved for use in treating bipolar depression.

Serious neuropsychiatric symptoms, including changes in mood (including depression and mania), psychosis, hallucinations, paranoia, delusions, homicidal ideation, hostility, agitation, aggression, anxiety, and panic as well as suicidal ideation, suicide attempt, and completed suicide, have been reported in patients receiving bupropion or varenicline for smoking cessation.(See Neuropsychiatric Symptoms and Suicidality in Smoking Cessation Treatment under Cautions: Nervous System Effects.) Patients receiving bupropion for smoking cessation should be informed that it is not unusual to experience symptoms such as irritability, anxiety, depressed mood, and difficulty sleeping while withdrawing from nicotine. Patients with serious psychiatric illness (e.g., schizophrenia, bipolar disorder, major depressive disorder) should also be advised that they may experience an exacerbation of their illness when withdrawing from nicotine, regardless of whether they are receiving bupropion therapy. Before initiating therapy with bupropion for smoking cessation, patients should inform their clinicians about any previous psychiatric history and about any symptoms they experienced during previous attempts at smoking cessation, with or without bupropion.

Based on findings from a large randomized controlled postmarketing study indicating that the risk of serious neuropsychiatric effects with bupropion and varenicline is lower than previously thought, FDA has removed the associated boxed warning that was included in the approved labeling for these drugs. Results of the study also confirmed the benefits of these smoking cessation therapies, which were observed regardless of whether patients had a history of psychiatric illness. Although the risk remains, particularly in individuals with current or past psychiatric illnesses (e.g., depression, anxiety disorder, schizophrenia), patients generally do not experience serious consequences such as hospitalization and, therefore, the benefits of smoking cessation (e.g., reduction in the risk of developing pulmonary disease, cardiovascular disease, or certain types of cancer) continue to outweigh the risks of these drugs. The health benefits of smoking cessation are immediate and substantial.

Patients receiving bupropion for smoking cessation should be monitored for neuropsychiatric symptoms or for worsening of preexisting psychiatric conditions. Patients who experience agitation, hostility, depressed mood, or changes in behavior or thinking that are not typical for the patient or who develop suicidal ideation or suicidal behavior should discontinue bupropion therapy and immediately contact a clinician. Although resolution of symptoms after bupropion discontinuance was reported in many postmarketing reports, manifestations persisted in some cases. Therefore, ongoing patient monitoring and supportive care should be provided until symptoms resolve.

Hypertension (sometimes severe) has been reported in patients with or without evidence of preexisting hypertension who were receiving bupropion alone or in combination with nicotine replacement therapy. Bupropion should be used cautiously in patients with cardiovascular disease as the safety of bupropion in patients with a recent history of myocardial infarction or unstable heart disease has not been established because of a lack of clinical experience. However, patients who developed orthostatic hypotension with tricyclic antidepressants have tolerated bupropion well. Since hypertension occurred with the combination of bupropion and transdermal nicotine as adjunctive therapy in smoking cessation, monitoring for hypertension as an adverse effect is recommended in recipients of such concurrent therapy.(See Cautions: Cardiovascular Effects.)

Bupropion should be used with extreme caution in patients with severe hepatic impairment and the dosing interval should be increased and/or the dosage reduced. Bupropion also should be used with caution in patients with mild to moderate hepatic impairment and consideration should be given to increasing the dosing interval. (See Dosage and Administration: Dosage.) Bupropion is extensively metabolized in the liver, and pharmacokinetics of the drug and its metabolites may be altered in patients with hepatic impairment. Patients with hepatic impairment who receive bupropion should be closely monitored for adverse effects that could indicate higher than recommended drug or metabolite concentrations.

Limited information is available on the pharmacokinetics of bupropion in patients with renal impairment. An interstudy comparison between healthy individuals and patients with end-stage renal failure demonstrated that the peak concentrations and AUC values for the parent drug were comparable in the 2 groups of patients; however, the AUC values of the hydroxybupropion and threohydrobupropion metabolites were increased 2.3- and 2.8-fold, respectively, in patients with end-stage renal failure. Bupropion should be used with caution in patients with renal impairment because of potential increased accumulation of the drug and its active metabolites, which principally are excreted in urine. A reduction in dosage and/or frequency of administration of bupropion should be considered in patients with renal impairment, and the patients should be closely monitored for adverse effects (e.g., seizures) that could indicate higher than recommended drug or metabolite concentrations.

Patients should be informed that since alcohol may alter the seizure threshold, minimal drinking is advisable while abstinence is optimal during bupropion therapy. Additionally, patients should be informed that if they discontinue alcohol or sedatives (e.g., benzodiazepines) abruptly during bupropion therapy, there is an increased risk of seizures. Patients also should be cautioned that bupropion may impair their ability to perform activities requiring mental alertness or physical coordination (operating machinery, driving a motor vehicle) and to avoid such activities until they experience how the drug affects them. Counseling about bupropion as an adjunct in smoking cessation should include review of information provided by the manufacturer for patients. Ensuring that patients read the instructions provided and answering their questions are important. Patients should be warned that preparations of bupropion for use as an adjunct in smoking cessation (e.g., Zyban) contain the same drug as preparations of bupropion for use in the treatment of psychiatric disorders (e.g., various Wellbutrin formulations) and that they should not receive such preparations concurrently.

Patients should be advised to discontinue taking bupropion and to consult a clinician if they experience allergic, anaphylactoid or anaphylactic symptoms (e.g., skin rash, pruritus, hives, chest pain, edema, shortness of breath) during treatment with the drug. Anaphylactic or anaphylactoid reactions with symptoms including pruritus, urticaria, angioedema, and dyspnea have occurred in clinical trials of bupropion. Also, rare reports of erythema multiforme, Stevens-Johnson syndrome, and anaphylactic shock associated with use of bupropion have occurred.

Patients receiving bupropion should be advised to notify their clinician if they are taking or plan to take nonprescription (over-the-counter) or prescription drugs. The metabolism of bupropion and other drugs might be affected by such concomitant use.

Because bupropion therapy has been associated with weight loss exceeding 2.27 kg at twice the incidence with tricyclic antidepressants or placebo in comparable patients and because fewer patients gained weight with bupropion than with tricyclic antidepressants (9 versus 35%), such effects should be considered in patients whose depression includes weight loss as a major manifestation.

As with other antidepressants, the possibility should be considered that bupropion may precipitate manic attacks in patients with bipolar disorder. Another consideration is that in other susceptible patients the drug may activate latent psychosis.

The hepatotoxic potential, if any, of bupropion in humans is unclear. Hepatic hyperplastic nodules and hepatocellular hypertrophy were increased in incidence in rats chronically administered large doses of bupropion, and various histologic changes in the liver and mild hepatocellular injury suggested by laboratory tests occurred in dogs chronically administered large doses of the drug. However, despite scattered abnormalities in liver function test results observed during clinical trials with bupropion, there currently is no clinical evidence that the drug is a hepatotoxin in humans.

The manufacturer states that the incidence of seizures during therapy with bupropion administered as conventional tablets has been estimated to exceed, by as much as fourfold (e.g., 0.4 versus 0.1%), that observed during therapy with other currently available antidepressants, including bupropion hydrochloride as extended-release, film-coated tablets (e.g., Wellbutrin SR) administered at dosages not exceeding 300 mg daily. However, the relative risk of seizures with various antidepressants, including bupropion, has not been clearly defined. In addition, the incidence of seizures at dosages of 400 mg daily as extended-release, film-coated tablets (e.g., Wellbutrin SR) reportedly increases to 0.4%.(See Seizures under Cautions: Nervous System Effects.) The risk of seizures may be higher with sudden and large increases in dosage. Estimations of the incidence of seizures increase almost tenfold with dosages between 450-600 mg daily. Because of this disproportionate increase in the incidence of seizures and in consideration of interindividual variability in the metabolism and elimination of drugs, bupropion dosage should be titrated cautiously. While many seizures occurred early in the course of therapy, some seizures have occurred after several weeks of fixed dosage bupropion therapy. The manufacturer states that bupropion should be discontinued and not restarted in patients who experience a seizure during bupropion therapy.

Besides dose, factors that are predispositions to the development of seizures (e.g., history of head trauma or prior seizure, CNS tumor, the presence of severe hepatic cirrhosis, concomitant drugs that lower seizure threshold) appear to be strongly associated with the risk of seizures with bupropion. Presence of such predisposing factors characterized approximately one-half of the patients affected with a seizure. In addition, the patient's clinical situation may be characterized by circumstances that are associated with an increase in the risk of seizures (e.g., diabetes mellitus treated with oral antidiabetic agents or insulin, excessive use of alcohol or sedatives [e.g., benzodiazepines], abrupt withdrawal from alcohol or other sedatives, use of over-the-counter stimulants and anorexigenic agents, addiction to opiate agonists, cocaine, or stimulants). Bupropion should be used with extreme caution in patients with a history of seizure, cranial trauma, or other relevant factors or who are receiving other drugs (e.g., antipsychotics, other antidepressants, theophylline, systemic corticosteroids) or therapeutic regimens (e.g., abrupt discontinuance of a benzodiazepine) that lower the seizure threshold.

For patients being treated with bupropion for psychiatric disorders other than nicotine dependence, minimization of the risk of seizures may be possible with measures that were retrospectively identified, including gradual dosage escalation and restriction of the total dosage to 400 mg daily as extended-release, film-coated tablets (e.g., Wellbutrin SR) or 450 mg daily as extended-release tablets (Wellbutrin XL) or as conventional tablets. In addition, administration of the daily dose in 3 divided doses each not exceeding 150 mg is recommended when the conventional tablets are used or in 2 divided doses each not exceeding 200 mg when extended-release, film-coated tablets (e.g., Wellbutrin SR) are used to avoid high peak concentrations of bupropion and/or its metabolites. For patients receiving bupropion for smoking cessation, such measures for minimizing the risk of seizures include restriction of the total dosage to 300 mg daily, administration of the daily dose recommended for most patients (i.e., 300 mg daily) in divided doses (i.e., 150 mg twice daily), and restriction of each dose to 150 mg so that high peak concentrations of bupropion and/or its metabolites are avoided. The decision to use bupropion as an adjunct in smoking cessation must involve consideration of whether the patient is at risk for seizures through the presence of factors that are predispositions to the development of seizures, drugs already being taken, or clinical situation of the patient. The dosage of bupropion as an adjunct in smoking cessation should not exceed 300 mg daily because the risk of seizures associated with the drug depends on dose. If patients experience a seizure while receiving bupropion for smoking cessation, the drug should be discontinued and should not be restarted.

Bupropion is contraindicated in patients with a seizure disorder. Concurrent use of any bupropion-containing medication also is contraindicated in patients already receiving any other bupropion-containing formulation (e.g., Wellbutrin, Wellbutrin SR, Wellbutrin XL, Zyban) because the incidence of seizures is dose dependent. Current or past diagnosis of bulimia or anorexia nervosa also contraindicates bupropion therapy because of the increased incidence of seizures observed in patients with bulimia treated with conventional bupropion tablets. Bupropion is contraindicated in patients undergoing abrupt discontinuance of alcohol or sedatives (including benzodiazepines). Bupropion therapy also is contraindicated in patients currently receiving, or having recently received (i.e., within 2 weeks), monoamine oxidase (MAO) inhibitor therapy and in patients with known hypersensitivity to the drug or to any other component in the formulation.

Pediatric Precautions

Safety and efficacy of bupropion in children younger than 18 years of age have not been established. However, the drug has been used in a limited number of children 7-16 years of age with attention deficit hyperactivity disorder (ADHD) without unusual adverse effect, and use of the antidepressant currently is included in recommendations of the American Academy of Pediatrics (AAP) as possible second-line therapy for the treatment of this condition as directed by clinicians familiar with its use.

The US Public Health Service (USPHS) Guideline for the treatment of tobacco use and dependence states that there is insufficient evidence to support the effectiveness of extended-release bupropion in promoting long-term smoking abstinence rates in adolescents.

FDA warns that antidepressants increase the risk of suicidal thinking and behavior (suicidality) in children and adolescents with major depressive disorder and other psychiatric disorders. The risk of suicidality for these drugs was identified in a pooled analysis of data from a total of 24 short-term (4-16 weeks), placebo-controlled studies of 9 antidepressants (i.e., bupropion, citalopram, fluoxetine, fluvoxamine, mirtazapine, nefazodone, paroxetine, sertraline, venlafaxine) in over 4400 children and adolescents with major depressive disorder, obsessive-compulsive disorder (OCD), or other psychiatric disorders. The analysis revealed a greater risk of adverse events representing suicidal behavior or thinking (suicidality) during the first few months of treatment in pediatric patients receiving antidepressants than in those receiving placebo. However, a more recent meta-analysis of 27 placebo-controlled trials of 9 antidepressants (SSRIs and others) in patients younger than 19 years of age with major depressive disorder, OCD, or non-OCD anxiety disorders suggests that the benefits of antidepressant therapy in treating these conditions may outweigh the risks of suicidal behavior or suicidal ideation. No suicides occurred in these pediatric trials.

The risk of suicidality in FDA's pooled analysis differed across the different psychiatric indications, with the highest incidence observed in the major depressive disorder studies. In addition, although there was considerable variation in risk among the antidepressants, a tendency toward an increase in suicidality risk in younger patients was found for almost all drugs studied. It is currently unknown whether the suicidality risk in pediatric patients extends to longer-term use (i.e., beyond several months).

As a result of this analysis and public discussion of the issue, FDA has directed manufacturers of all antidepressants to add a boxed warning to the labeling of their products to alert clinicians of this suicidality risk in children, adolescents, and young adults and to recommend appropriate monitoring and close observation of patients receiving these agents.(See Cautions: Precautions and Contraindications.) The drugs that are the focus of the revised labeling are all drugs included in the general class of antidepressants, including those that have not been studied in controlled clinical trials in pediatric patients, since the available data are not adequate to exclude any single antidepressant from an increased risk. In addition to the boxed warning and other information in professional labeling on antidepressants, FDA currently recommends that a patient medication guide explaining the risks associated with the drugs be provided to the patient each time the drugs are dispensed.

Anyone considering the use of bupropion in a child or adolescent for any clinical use must balance the potential risk of therapy with the clinical need.

For information on serious neuropsychiatric effects in patients receiving bupropion for smoking cessation, see Neuropsychiatric Symptoms and Suicidality in Smoking Cessation Treatment under Cautions: Nervous System Effects, and see also Cautions: Precautions and Contraindications.

Geriatric Precautions

Bupropion has not been evaluated systematically in geriatric patients. The adverse effect profile in several hundred patients at least 60 years old who participated in clinical trials did not differ from that in younger patients. However, geriatric patients generally metabolize drugs slower and are more sensitive to the anticholinergic, sedative, and cardiovascular adverse effects of antidepressants. In addition, the effects of age on the pharmacokinetics of bupropion and it metabolites have not been fully elucidated. Although a single-dose pharmacokinetic study demonstrated that the disposition of bupropion and its metabolites was similar in geriatric and younger individuals, another pharmacokinetic study has suggested that geriatric patients are at increased risk for accumulation of bupropion and its metabolites following administration of single and multiple doses of the drug.(See Pharmacokinetics.)

Of the approximately 6000 patients studied in clinical trials of extended-release bupropion for smoking cessation or depression, 275 were 65 years of age or older, while 47 were 75 years of age and older. In addition, several hundred patients 65 years of age and older participated in clinical studies using conventional tablets of the drug for depression. Although no overall differences in efficacy or safety were observed between geriatric and younger patients, and other clinical experience revealed no evidence of age-related differences, the possibility that some older patients may exhibit increased sensitivity to the drug cannot be ruled out. In general, smoking cessation interventions that have been shown to be effective in the general population also have been shown to be effective in adults 50 years of age and older.

In pooled data analyses, a reduced risk of suicidality was observed in adults 65 years of age or older with antidepressant therapy compared with placebo.(See Cautions: Precautions and Contraindications.)

Mutagenicity and Carcinogenicity

Bupropion exhibited mutagenic activity in the Salmonella microbial mutagen (Ames) test system; the mutation rate was 2-3 times control in 2 of 5 strains. An increase in chromosomal aberrations was observed in one of 3 in vivo cytogenetic studies conducted with the bone marrow of rats.

In lifetime carcinogenicity studies of rats or mice receiving bupropion hydrochloride dosages of 100-300 (about 2-7 times the maximum dosage in mg/m recommended in humans) or 150 mg/kg daily (about 2 times the maximum dosage in mg/m recommended in humans), respectively, an increase in nodular proliferative lesions of the liver was observed in rats but not in mice. The relationship of these lesions to the development of neoplasms of the liver is unclear. An increase in malignant tumors of the liver and other organs was not observed in either rats or mice.

Pregnancy, Fertility, and Lactation

Pregnancy

In studies performed in rats and rabbits, bupropion was administered orally in dosages up to 450 and 150 mg/kg daily, respectively (equivalent to 11 and 7 times the maximum recommended human dosage [MRHD] as an antidepressant on a mg/m basis, respectively, or 14 and 10 times the MRHD for smoking cessation on a mg/m basis, respectively) during the period of organogenesis. Although no clear evidence of teratogenic activity was found in either species, slightly increased incidences of fetal malformations and skeletal variations were observed in rabbits receiving the lowest dosage tested (25 mg/kg daily, which is approximately equivalent to the antidepressant MRHD and twice the MRHD for smoking cessation on a mg/m basis) and higher dosages. Decreased fetal weights were observed at dosages of 50 mg/kg daily and at higher dosages.

In rats receiving oral dosages of bupropion of up to 300 mg/kg daily (approximately 7 or 10 times the MRHD on a mg/m basis as an antidepressant or for smoking cessation, respectively) prior to mating and throughout pregnancy and lactation, there were no apparent adverse effects on offspring development.

One study evaluating the teratogenic potential of bupropion in humans has been conducted. This retrospective, managed-care database study assessed the risk of congenital malformations overall and cardiovascular malformations specifically following bupropion exposure in the first trimester compared with the risk of such malformations following exposure to other antidepressants in the first trimester and bupropion outside of the first trimester. This study included 7,005 infants exposed to antidepressants in utero; 1,213 of these infants were exposed to bupropion during the first trimester. The study demonstrated no increased risk for congenital malformations overall or cardiovascular malformations specifically following first-trimester bupropion exposure compared with exposure to all other antidepressants in the first trimester or bupropion outside of the first trimester. The results of this study have not been corroborated.

The effect of bupropion on labor and delivery is not known.

Bupropion should be used during pregnancy only when the potential benefits justify the potential risks to the fetus. Women should be advised to notify their physician if they are or plan to become pregnant.

To monitor fetal outcomes of pregnant women exposed to bupropion in the US, the manufacturer maintains a Bupropion Pregnancy Registry. Clinicians are encouraged to register patients by calling 800-336-2176.

Fertility

A fertility study in rats using oral bupropion hydrochloride dosages of up to 300 mg/kg daily did not reveal evidence of impaired fertility.

Lactation

Bupropion, hydroxybupropion, and the threo-amino alcohol metabolite are distributed into milk. Limited data indicate that milk concentrations of the drug exceed concurrent plasma concentrations by as much as severalfold. Concentrations in milk of hydroxybupropion are about 10% of, and concentrations of the threo-amino alcohol metabolite are moderately higher than, the respective concurrent plasma concentrations. Bupropion, hydroxybupropion, the threo-amino alcohol, and the erythro-amino alcohol were not detected in the plasma of an infant 3.7 hours after breast-feeding that was done 9.5 hours after the mother received her last dose of the drug for the day. Because data are limited and because of the potential for adverse effects in nursing infants, a decision should be made as to whether to discontinue nursing or bupropion, taking into account the importance of the drug to the woman and the potential for serious adverse reactions to the drug in nursing infants.

Drug Interactions

Smoking Cessation

Smoking, via enzyme induction, can increase the metabolism of some drugs. Cessation of smoking, with or without adjunctive use of bupropion, may alter the pharmacokinetics of and response to various drugs that the patient also may be taking, thereby possibly necessitating adjustment of dosage.

Hepatic Microsomal Enzyme Induction

Data from animal studies suggest that bupropion may be an inducer of hepatic microsomal enzymes, which may have potential pharmacokinetic and clinical consequences in patients receiving bupropion concomitantly with drugs that depend on the microsomal enzyme system for metabolism. The possibility of an interaction between other drugs and bupropion (which is extensively metabolized) that might affect its metabolism and clinical effects also should be considered. Particular caution should be observed when bupropion is administered concomitantly with drugs that may induce its metabolism (e.g., carbamazepine, phenobarbital, phenytoin) or that may inhibit its metabolism (e.g., cimetidine).

Drugs that are substrates of or that inhibit the cytochrome P-450 (CYP) 2B6 isoenzyme (e.g., cyclophosphamide, orphenadrine, thiotepa) have the potential to interact with bupropion since in vitro studies indicate that metabolism of bupropion to hydroxybupropion (morpholinol) is principally via this isoenzyme. In addition, in vitro studies suggest that fluvoxamine, norfluoxetine (the principal metabolite of fluoxetine), paroxetine, and sertraline as well as efavirenz, nelfinavir, and ritonavir may inhibit the hydroxylation of bupropion. The threohydrobupropion metabolite of bupropion does not appear to be produced by the CYP isoenzymes.

Concomitant administration of bupropion and cimetidine resulted in 16% increases in the 24-hour area under the combined plasma concentration-time curve (AUC) and 32% increases in combined peak plasma concentration of the erythro- and threo-amino metabolites of bupropion. However, the pharmacokinetics of bupropion and hydroxybupropion were not affected.

Concomitant administration of bupropion and carbamazepine resulted in decreases in the peak plasma concentration of bupropion and in the 24-hour area under the plasma concentration-time curve (AUC) by 87 and 90%, respectively; the peak plasma concentration and 24-hour AUC of the metabolite, hydroxybupropion, were increased by 71 and 50%, respectively. In contrast, concomitant administration of bupropion and valproate sodium resulted only in an increase by 94% in 24-hour AUC of hydroxybupropion.

Steady-state bupropion did not substantially affect the pharmacokinetics of a single dose of lamotrigine in healthy individuals.

Limited data indicate that bupropion decreases the clearance of imipramine and its metabolite, desipramine, when the drugs are used concomitantly. Plasma concentrations of imipramine and desipramine were about fourfold higher with concomitant use of bupropion and imipramine than with imipramine alone. The mechanism of this interaction currently is not known, but it was suggested that studies be performed to determine whether specific cytochrome P-450 isoenzymes (e.g., CYP2D6) are involved. Pending further accumulation of data, caution should be exercised if bupropion and drugs that are metabolized by the CYP2D6 isoenzyme, including certain antidepressants (e.g., nortriptyline, imipramine, desipramine, paroxetine, fluoxetine, sertraline), antipsychotic agents (e.g., haloperidol, risperidone, thioridazine), β-adrenergic blocking agents (e.g., metoprolol), and class IC antiarrhythmic agents (e.g., propafenone, flecainide), are used concomitantly. When drugs that are metabolized by CYP2D6 are added to existing bupropion therapy or if bupropion is added to the treatment regimen of a patient already receiving one of these drugs, a reduction in dosages of the drugs that are metabolized by CYP2D6 should be considered, particularly for those with a narrow therapeutic index.

Monoamine Oxidase Inhibitors

Evidence from animal studies suggests that concomitant administration of bupropion and monoamine oxidase (MAO) inhibitors is potentially hazardous. In animals, phenelzine enhanced the acute toxicity of bupropion, as indicated by an increase in mortality and a decrease in time to death. The manufacturer states that concurrent administration of bupropion and MAO inhibitors is contraindicated and that at least 2 weeks elapse following discontinuance of an MAO inhibitor prior to initiation of bupropion therapy.

Levodopa and Amantadine

A limited number of patients with parkinsonian syndrome treated with either amantadine or levodopa appeared to have a high incidence of adverse effects (e.g., nausea and vomiting, excitement and restlessness, postural tremor) when bupropion was used concurrently. Caution should be exercised if bupropion therapy is initiated in a patient receiving levodopa or amantadine, including use of low initial dosage and increasing the dosage gradually in small increments.

Alcohol

Adverse neuropsychiatric events or reduced alcohol tolerance have been reported rarely in patients who ingested alcohol during bupropion therapy. Because of concerns that excessive use of alcohol or abrupt withdrawal from alcohol may be associated with an increased risk of seizures during bupropion therapy, patients receiving the drug should be advised to minimize or, if possible, avoid alcohol consumption.

Concurrent administration of single doses of bupropion and alcohol did not result in alteration of blood alcohol concentrations, plasma bupropion concentrations, or other pharmacokinetic variables in healthy individuals, indicating that there is no pharmacokinetic interaction between bupropion and alcohol.

Drugs Affecting the Seizure Threshold

Extreme caution should be observed with concurrent administration of bupropion and drugs (e.g., other antidepressants, antipsychotic agents, theophylline, systemic corticosteroids) or treatment regimens (e.g., abrupt discontinuance of benzodiazepines) that lower the seizure threshold. Therapy should be initiated with low doses and dosage should be increased gradually.

Benzodiazepines

Concurrent administration of single doses of bupropion and diazepam to healthy individuals did not result in potentiation of the mental impairment induced by diazepam. The impairment of performance on the auditory vigilance test observed with diazepam alone was absent with the combination of diazepam and bupropion. Individuals did not feel more drowsy with the combination of diazepam and bupropion than with placebo or bupropion alone but subjective assessment indicated an increase in drowsiness with diazepam alone.

Electroconvulsive Therapy

Administration of bupropion in conjunction with electroconvulsive therapy (ECT) was reported to result in an increase in the duration of motor and EEG seizures associated with ECT in at least one patient. However, such an effect was absent in 2 other patients who received the drug at the same dosage concomitantly with ECT, and some clinicians suggest that ECT can be performed safely 48 hours after discontinuance of bupropion.

Nicotine

The manufacturer states that patients can receive bupropion concomitantly with transdermal nicotine therapy if indicated for smoking cessation. In a clinical study, concurrent use of bupropion extended-release tablets and nicotine transdermal systems resulted in similar plasma concentrations of bupropion and its active metabolites compared with patients receiving only bupropion extended-release tablets. However, the manufacturer reported a possible increased risk of hypertension during combined use (see Cautions: Cardiovascular Effects), and the possibility of treatment-emergent hypertension should be considered when bupropion is used concomitantly with nicotine replacement therapy.

Warfarin

Concomitant use of bupropion with warfarin has resulted in altered prothrombin time/international normalized ratio (INR) that has been rarely associated with hemorrhagic or thrombotic complications.

Pharmacokinetics

Absorption

Bupropion hydrochloride appears to be well absorbed from the GI tract following oral administration. The oral bioavailability of bupropion in humans has not been elucidated because a preparation for IV administration is not available. However, the relative proportion of an oral dose reaching systemic circulation unchanged appears likely to be small. In animals, the oral bioavailability of bupropion varies from 5-20%. Food does not appear to affect substantially the peak plasma concentration or area under the plasma concentration-time curve of bupropion achieved with extended-release tablets of the drug; these measures reportedly were increased with food by 11 or 17%, respectively.

Peak plasma bupropion concentrations usually occur within 2 or 3 hours after oral administration of the conventional or extended-release, film-coated tablets (Wellbutrin SR, Zyban), respectively, to healthy individuals. Plasma bupropion concentrations following administration of single oral doses of 100-250 mg and with chronic administration of up to 450 mg daily are proportional to dose. Steady-state plasma concentrations of bupropion are achieved within 8 days. During chronic administration of bupropion hydrochloride as conventional or extended-release, film-coated tablets at a dosage of 100 mg 3 times daily or 150 mg twice daily, respectively, peak plasma concentrations of the drug at steady state with extended-release tablets were about 85% of measurements for the conventional tablets. Equivalence in area under the plasma concentration-time curve (AUC) of bupropion was shown for the formulations, which demonstrated that at steady state the conventional and extended-release tablets are essentially bioequivalent. The drug exhibits linear pharmacokinetics during chronic administration of bupropion hydrochloride dosages of 300-450 mg daily.

The relationship between plasma concentrations of bupropion and its metabolites and the therapeutic and/or toxic effects of the drug has not been clearly established. Limited data suggest a curvilinear relationship between plasma concentrations of bupropion or its metabolites and antidepressant response.

Distribution

Bupropion is at least 80% bound to human albumin at in vitro plasma concentrations of up to 200 mcg/mL.

Bupropion, hydroxybupropion, and the threo-amino alcohol metabolite are distributed into milk. Limited data indicate that milk concentrations of the drug exceed concurrent plasma concentrations by as much as severalfold. Concentrations in milk of hydroxybupropion are about 10% of, and concentrations of the threo-amino alcohol metabolite are moderately higher than, the respective concurrent plasma concentrations. However, bupropion, hydroxybupropion, the threo-amino alcohol, and the erythro-amino alcohol were not detected in the plasma of a nursing infant 3.7 hours after breast-feeding, which was done 9.5 hours after the mother received her last dose of the drug for the day.

Elimination

Plasma concentrations of bupropion decline in a biphasic manner. A decline to approximately 30% of the peak plasma bupropion concentration is observed 6 hours after administration of a single oral dose of the drug. The half-life of bupropion in the terminal phase (t½β) averages about 14 hours (range: 8-24 hours) following single doses; with multiple dosing, t½β reportedly averages 21 hours (range: 8-39 hours). In a limited number of geriatric patients with a major depressive episode, the t½β of bupropion averaged about 34 hours after a single oral dose of the drug.

Bupropion appears to be metabolized extensively, probably in the liver. The 3 active metabolites that have been identified are formed through reduction of the carbonyl group and/or hydroxylation. The basic metabolites identified include the erythro- and threo-amino alcohols of bupropion, and a morpholinol metabolite. The amino-alcohol isomers threohydrobupropion and erythrohydrobupropion are formed by reduction of the carbonyl group of bupropion, and the morpholinol metabolite, hydroxybupropion, is formed by hydroxylation of the tert-butyl group of bupropion. The metabolites of bupropion exhibit linear pharmacokinetics during chronic administration of the drug at dosages of 300-450 mg daily.

Following a single oral dose of bupropion as conventional tablets, hydroxybupropion and bupropion are detectable in systemic circulation with nearly similar rapidity, although the metabolite's peak plasma concentration and area under the plasma concentration-time curve (AUC) from 0-60 hours are higher by 3 and 15 times, respectively. The half-life of hydroxybupropion is about 24 hours. In a limited number of geriatric patients with a major depressive episode, the apparent half-life of hydroxybupropion averaged about 34 hours after a single oral dose of the drug. Hydroxybupropion and the threo-amino alcohol have similar plasma concentration-time profiles, whereas the erythro-amino alcohol and the erythro-amino diol generally cannot be detected in systemic circulation following a single oral dose of bupropion. Animal screening tests for antidepressant agents showed that hydroxybupropion is half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are fivefold less potent than bupropion. Hydroxybupropion was approximately equipotent to bupropion in other tests in animals.

Following a single oral dose of bupropion hydrochloride as extended-release, film-coated tablets (e.g., Wellbutrin SR, Zyban), peak plasma concentrations of hydroxybupropion occur in about 6 hours. The metabolite's peak plasma concentration achieved with extended-release tablets is about 10 times higher than the peak plasma concentration of bupropion achieved with this dosage form. At steady state, the AUC is 17 times greater for hydroxybupropion than for bupropion with extended-release tablets. The half-life of hydroxybupropion is about 20 hours. With extended-release tablets, peak plasma concentrations of the erythro- and threo-amino alcohols occur at about the same time as for hydroxybupropion, although these metabolites have longer half-lives of 33 and 37 hours, respectively. At steady state, the AUCs are 1.5 and 7 times greater for the erythro- and threo-amino alcohols, respectively, than for bupropion.

During chronic administration of bupropion hydrochloride as the conventional or extended-release, film-coated tablets (e.g., Wellbutrin SR, Zyban), equivalence between these formulations was shown for the peak plasma concentration and AUC of hydroxybupropion, the erythro-amino alcohol, and the threo-amino alcohol, which demonstrated that at steady state the conventional and extended-release tablets are essentially bioequivalent for these metabolites.

Although several of the identified metabolites are pharmacologically active, the contribution of these metabolites to the therapeutic and/or toxic effects of bupropion is not fully known. The longer half-lives of at least two known metabolites is a potential clinical consideration because of the expectation of very much higher plasma concentrations of the metabolites than of bupropion, especially with chronic administration. Factors or conditions (e.g., liver disease, congestive heart failure, age, concomitant drugs) that affect metabolism or elimination would be expected to alter the degree and extent of accumulation of these metabolites. The extent to which the clinical effects of bupropion are related to the parent drug or to the metabolites also could be altered with chronic administration if bupropion induces its own metabolism in humans. In animals, bupropion induced its own metabolism following subchronic administration, although such an effect was not evident in healthy individuals receiving up to 450 mg daily of the drug over 14 days.

Approximately 87 and 10% of an orally administered, radiolabeled dose of bupropion are excreted in urine and feces, respectively. Unchanged drug comprised 0.5% of the dose excreted.

The effect of age on the plasma concentrations of bupropion and its metabolites has not been fully elucidated; however, data from studies of efficacy suggest that plasma concentrations of bupropion are not affected substantially by age. Evaluation of plasma concentrations of bupropion at steady state that were obtained from these studies in which patients who were 18-83 years in age received 300-750 mg of the drug in 3 divided doses daily did not identify a relationship between age and plasma concentration of bupropion. However, in a limited number of patients 63-76 years of age with a major depressive episode, the ratio of the AUC for combined metabolites (i.e., hydroxybupropion, the erythro- and threo-amino alcohols of bupropion) to that for bupropion after about 10 days of therapy was greater than twice that after a single dose of the drug. Differences in the pharmacokinetics of bupropion related to gender were not identified in a study of healthy males and females who received a single dose of the drug. Limited data suggest that accumulation of the metabolites of bupropion occurs with multiple doses of the drug.

Because bupropion is extensively metabolized by the liver, hepatic impairment can affect elimination of the drug. In a single-dose study in patients with alcoholic liver disease, the half-life of hydroxybupropion was substantially increased to a mean of 32 hours compared with 21 hours in healthy individuals. In addition, the AUC values and other pharmacokinetic parameters were reported to be more variable for bupropion and its active metabolites in the patients with mild to moderate hepatic impairment, although the differences were not found to be significant. The pharmacokinetics of bupropion also have been studied in patients with severe hepatic impairment. The peak plasma concentration and elimination half-life of bupropion were substantially increased by 70 and 40%, respectively, and AUC increased threefold in these patients compared with healthy individuals. Additionally, the AUC and elimination half-life of the metabolites of bupropion also were increased, but the peak plasma concentration was decreased in patients with severe hepatic impairment compared with healthy individuals. Therefore, the manufacturer recommends that bupropion be administered with caution and less frequently in patients with hepatic impairment.(See Cautions: Precautions and Contraindications and see Dosage and Administration: Dosage in Renal and Hepatic Impairment.)

Limited data are available on the pharmacokinetics of bupropion in patients with renal impairment. Elimination of the principal active metabolites of bupropion may be reduced by impaired renal function. An interstudy comparison between healthy individuals and patients with end-stage renal failure who received a single oral dose of 150 mg of bupropion hydrochloride administered as an extended-release (''sustained-action''), film-coated tablet (Zyban) demonstrated that the peak concentrations and AUC values for the parent drug were comparable in the 2 groups of patients; however, the AUC values of the hydroxybupropion and threohydrobupropion metabolites were increased 2.3- and 2.8-fold, respectively, in patients with end-stage renal failure.(See Cautions: Precautions and Contraindications and see Dosage and Administration: Dosage in Renal and Hepatic Impairment.)

In patients with left ventricular dysfunction (e.g., history of congestive heart failure, radiographic evidence of enlarged heart) who received chronic dosing of bupropion, substantial interindividual variability (e.g., twofold to fivefold) characterized trough steady-state plasma concentrations of bupropion, hydroxybupropion, and the threo-amino alcohol, although such variability was observed to a similar extent (e.g., threefold to eightfold) in healthy individuals. Steady-state plasma concentrations of the metabolites were 10-100 times greater than those for bupropion.

Whether other diseases affect metabolism and/or elimination of bupropion is unclear.

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