Wellbutrin SR/Wellbutrin XL

Bupropion hydrochloride.

Wellbutrin SR: Each tablet contains 150 mg of bupropion hydrochloride.
WELLBUTRIN SR (bupropion hydrochloride), an antidepressant of the aminoketone class, is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitor, or other known antidepressant agents. Its structure closely resembles that of diethylpropion; it is related to phenylethylamines. It is designated as (±)-1-(3-chlorophenyl)-2-[(1,1-dimethylethyl)amino]-1propanone hydrochloride. The molecular weight is 276.2. The molecular formula is C₁₃H₁₈ClNO•HCl. Bupropion hydrochloride powder is white, crystalline, and highly soluble in water. It has a bitter taste and produces the sensation of local anesthesia on the oral mucosa.
Excipients/Inactive Ingredients: Each tablet contains the inactive ingredients: microcrystalline cellulose, hypromellose, cysteine hydrochloride, magnesium stearate, carnauba wax and white color concentrate and is printed with edible black ink.

Pharmacotherapeutic Group: Other antidepressants. ATC Code: N06AX12.
Pharmacology: Pharmacodynamics: Wellbutrin SR: Mechanism of Action: The exact mechanism of the antidepressant action of bupropion is not known, but is presumed to be related to noradrenergic and/or dopaminergic mechanisms. Bupropion is a relatively weak inhibitor of the neuronal reuptake of norepinephrine and dopamine, and does not inhibit the reuptake of serotonin. Bupropion does not inhibit monoamine oxidase.
Clinical Studies: The efficacy of the immediate-release formulation of bupropion in the treatment of major depressive disorder was established in two 4-week, placebo-controlled trials in adult inpatients with MDD (Trials 1 and 2 in Table 1) and in one 6-week, placebo-controlled trial in adult outpatients with MDD (Trial 3 in Table 1). In the first trial, the dose range of bupropion was 300 mg to 600 mg per day administered in divided doses; 78% of subjects were treated with doses of 300 mg to 450 mg per day. This trial demonstrated the effectiveness of the immediate-release formulation of bupropion by the Hamilton Depression Rating Scale (HDRS) total score, the HDRS depressed mood item (Item 1), and the Clinical Global Impressions severity score (CGIS). The second trial included 2 doses of the immediate-release formulation of bupropion (300 and 450 mg per day) and placebo. This trial demonstrated the effectiveness of the immediate-release formulation of bupropion, but only at the 450-mg-per-day dose. The efficacy results were significant for the HDRS total score and the CGI-S score, but not for HDRS Item 1. In the third trial, outpatients were treated with 300 mg per day of the immediate-release formulation of bupropion. This trial demonstrated the efficacy of the immediate-release formulation of bupropion as measured by the HDRS total score, the HDRS Item 1, the Montgomery-Asberg Depression Rating Scale (MADRS), the CGI-S score, and the CGI-Improvement Scale (CGI-I) score. (See Table 1.)

Click on icon to see table/diagram/image

Although there are not as yet independent trials demonstrating the antidepressant effectiveness of the sustained-release formulation of bupropion, trials have demonstrated the bioequivalence of the immediate-release and sustained-release forms of bupropion under steady-state conditions, i.e., bupropion sustained-release 150 mg twice daily was shown to be bioequivalent to 100 mg 3 times daily of the immediate-release formulation of bupropion, with regard to both rate and extent of absorption, for parent drug and metabolites.
In a longer-term trial, outpatients meeting DSM-IV criteria for major depressive disorder, recurrent type, who had responded during an 8-week open trial on WELLBUTRIN SR (150 mg twice daily) were randomized to continuation of their same dose of WELLBUTRIN SR or placebo for up to 44 weeks of observation for relapse. Response during the open phase was defined as CGI Improvement score of 1 (very much improved) or 2 (much improved) for each of the final 3 weeks. Relapse during the double-blind phase was defined as the investigator's judgment that drug treatment was needed for worsening depressive symptoms. Patients receiving continued treatment with WELLBUTRIN SR experienced significantly lower relapse rates over the subsequent 44 weeks compared with those receiving placebo.
Wellbutrin XL: Mechanism of Action: Bupropion is a selective inhibitor of the neuronal re-uptake of catecholamines (noradrenaline and dopamine) with minimal effect on the re-uptake of indolamines (serotonin) and does not inhibit monoamine oxidase. While the mechanism of action of bupropion, as with other antidepressants is unknown, it is presumed that this action is mediated by noradrenergic and/or dopaminergic mechanisms.
Clinical Trials: Major Depressive Disorder (MDD): The efficacy of bupropion as a treatment for MDD was established with the immediate-release formulation of bupropion in two 4-week, placebo-controlled trials in adult inpatients and in one 6-week, placebo-controlled trial in adult outpatients. In the 1st study, patients were titrated in a bupropion dose range of 300-600 mg/day of the immediate-release formulation on a 3 times daily schedule; 78% of patients received maximum doses of ≤450 mg/day. This trial demonstrated the effectiveness of bupropion on the Hamilton Depression Rating Scale (HDRS) total score, the depressed mood item (item 1) from that scale, and the Clinical Global Impressions (CGI) severity score. A 2nd study included 2 fixed doses of the immediate-release formulation of bupropion (300 and 450 mg/day) and placebo. This trial demonstrated the effectiveness of bupropion, but only at the 450-mg/day dose of the immediate-release formulation; the results were positive for the HDRS total score and the CGI severity score, but not for HDRS item 1. In the 3rd study, outpatients received 300 mg/day of the immediate-release formulation of bupropion. This study demonstrated the effectiveness of bupropion on the HDRS total score, HDRS item 1, the Montgomery-Asberg Depression Rating Scale, the CGI severity score and the CGI improvement score.
In a longer-term study, outpatients meeting DSM-IV criteria for MDD, recurrent type, who had responded during an 8-week open trial on bupropion (150 mg twice daily of the sustained-release formulation) were randomized to continuation of their same dose of bupropion or placebo, for up to 44 weeks of observation for relapse. Response during the open phase was defined as CGI improvement score of 1 (very much improved) or 2 (much improved) for each of the final 3 weeks. Relapse during the double-blind phase was defined as the investigator's judgment that drug treatment was needed for worsening depressive symptoms. Patients receiving continued bupropion treatment experienced significantly lower relapse rates over the subsequent 44 weeks compared to those receiving placebo.
Although there are no independent trials demonstrating the antidepressant effectiveness of Wellbutrin XL, studies have demonstrated similar bioavailability of Wellbutrin XL to both the immediate-release formulation and to the sustained-release formulation of bupropion under steady-state conditions ie, Wellbutrin XL 300 mg once daily was shown to have bioavailability that was similar to that of 100 mg 3 times daily of the immediate-release formulation of bupropion and to that of 150 mg 2 times daily of the sustained-release formulation of bupropion, with regard to both peak plasma concentration (C_max) and extent of absorption, for parent drug and metabolites.
Seasonal Affective Disorder: The efficacy of Wellbutrin XL for the prevention of seasonal major depressive episodes associated with seasonal affective disorder was established in 3 double-blind, placebo-controlled trials in adult outpatients with a history of MDD with an autumn-winter seasonal pattern (as defined by DSM-IV criteria). Treatment was initiated prior to the onset of symptoms in the autumn (September to November) and was discontinued following a 2-week taper that began the 1st week of spring (4th week of March), resulting in a treatment duration of approximately 4-6 months for the majority of patients. At the start of the study, patients were randomized to receive placebo or Wellbutrin XL 150 mg once daily for 1 week, followed by up-titration to 300 mg once daily. Patients who were deemed by the investigator to be unlikely or unable to tolerate 300 mg once daily were allowed to remain on, or had their dose reduced to, 150 mg once daily. The mean Wellbutrin XL doses in the 3 studies ranged from 257-280 mg/day.
In these 3 trials, the percentage of patients who were depression-free at the end of treatment was significantly higher for Wellbutrin XL than for placebo: 81.4% versus 69.7%, 87.2% versus 78.7% and 84% versus 69% for study 1, 2 and 3, respectively; with a depression-free rate for the 3 studies combined of 84.3% versus 72%.
Pharmacokinetics: Wellbutrin SR: Bupropion is a racemic mixture. The pharmacological activity and pharmacokinetics of the individual enantiomers have not been studied. The mean elimination half-life (±SD) of bupropion after chronic dosing is 21 (±9) hours, and steady-state plasma concentrations of bupropion are reached within 8 days.
Absorption: The absolute bioavailability of WELLBUTRIN SR in humans has not been determined because an intravenous formulation for human use is not available. However, it appears likely that only a small proportion of any orally administered dose reaches the systemic circulation intact. In rat and dog studies, the bioavailability of bupropion ranged from 5% to 20%.
In humans, following oral administration of WELLBUTRIN SR, peak plasma concentration (C_max) of bupropion is usually achieved within 3 hours.
In a trial comparing chronic dosing with WELLBUTRIN SR 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state C_max for bupropion after WELLBUTRIN SR administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both C_max and AUC. Thus, at steady state, WELLBUTRIN SR given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites.
WELLBUTRIN SR can be taken with or without food. Bupropion C_max and AUC were increased by 11% to 35% and 16% to 19%, respectively, when WELLBUTRIN SR was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant.
Distribution: In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion; whereas, the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion.
Metabolism: Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion.
Following a single-dose administration of WELLBUTRIN SR in humans, C_max of hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33 (±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively.
Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day.
Elimination: Following oral administration of 200 mg of ¹⁴C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. Only 0.5% of the oral dose was excreted as unchanged bupropion.
Population Subgroups: Factors or conditions altering metabolic capacity (e.g., liver disease, congestive heart failure [CHF], age, concomitant medications, etc.) or elimination may be expected to influence the degree and extent of accumulation of the active metabolites of bupropion. The elimination of the major metabolites of bupropion may be affected by reduced renal or hepatic function because they are moderately polar compounds and are likely to undergo further metabolism or conjugation in the liver prior to urinary excretion.
Renal Impairment: There is limited information on the pharmacokinetics of bupropion in patients with renal impairment. An inter-trial comparison between normal subjects and subjects with end-stage renal failure demonstrated that the parent drug C_max and AUC values were comparable in the 2 groups, whereas the hydroxybupropion and threohydrobupropion metabolites had a 2.3 and 2.8-fold increase, respectively, in AUC for subjects with end-stage renal failure. A second trial, comparing normal subjects and subjects with moderate-to-severe renal impairment (GFR 30.9 ± 10.8 mL per min), showed that after a single 150-mg dose of sustained-release bupropion, exposure to bupropion was approximately 2-fold higher in subjects with impaired renal function, while levels of the hydroxybupropion and threo/erythrohydrobupropion (combined) metabolites were similar in the 2 groups. Bupropion is extensively metabolized in the liver to active metabolites, which are further metabolized and subsequently excreted by the kidneys. The elimination of the major metabolites of bupropion may be reduced by impaired renal function. WELLBUTRIN SR should be used with caution in patients with renal impairment and a reduced frequency and/or dose should be considered (see Renal Impairment under Precautions).
Hepatic Impairment: The effect of hepatic impairment on the pharmacokinetics of bupropion was characterized in 2 single-dose trials, one in subjects with alcoholic liver disease and one in subjects with mild-to-severe cirrhosis. The first trial demonstrated that the half-life of hydroxybupropion was significantly longer in 8 subjects with alcoholic liver disease than in 8 healthy volunteers (32 ± 14 hours versus 21 ± 5 hours, respectively). Although not statistically significant, the AUCs for bupropion and hydroxybupropion were more variable and tended to be greater (by 53% to 57%) in volunteers with alcoholic liver disease. The differences in half-life for bupropion and the other metabolites in the 2 groups were minimal.
The second trial demonstrated no statistically significant differences in the pharmacokinetics of bupropion and its active metabolites in 9 subjects with mild-to-moderate hepatic cirrhosis compared with 8 healthy volunteers. However, more variability was observed in some of the pharmacokinetic parameters for bupropion (AUC, C_max, and T_max) and its active metabolites (t_1/2) in subjects with mild-to-moderate hepatic cirrhosis. In subjects with severe hepatic cirrhosis, significant alterations in the pharmacokinetics of bupropion and its metabolites were seen (Table 2). (See Table 2.)

Click on icon to see table/diagram/image

Left Ventricular Dysfunction: During a chronic dosing trial with bupropion in 14 depressed subjects with left ventricular dysfunction (history of CHF or an enlarged heart on x-ray), there was no apparent effect on the pharmacokinetics of bupropion or its metabolites, compared with healthy volunteers.
Age: The effects of age on the pharmacokinetics of bupropion and its metabolites have not been fully characterized, but an exploration of steady-state bupropion concentrations from several depression efficacy trials involving subjects dosed in a range of 300 to 750 mg per day, on a 3 times-daily schedule, revealed no relationship between age (18 to 83 years) and plasma concentration of bupropion. A single-dose pharmacokinetic trial demonstrated that the disposition of bupropion and its metabolites in elderly subjects was similar to that of younger subjects. These data suggest there is no prominent effect of age on bupropion concentration; however, another single- and multiple-dose pharmacokinetics trial suggested that the elderly are at increased risk for accumulation of bupropion and its metabolites (see Use in Elderly under Precautions).
Gender: Pooled analysis of bupropion pharmacokinetic data from 90 healthy male and 90 healthy female volunteers revealed no sex-related differences in the peak plasma concentrations of bupropion. The mean systemic exposure (AUC) was approximately 13% higher in male volunteers compared with female volunteers. The clinical significance of this finding is unknown.
Smokers: The effects of cigarette smoking on the pharmacokinetics of bupropion were studied in 34 healthy male and female volunteers; 17 were chronic cigarette smokers and 17 were nonsmokers. Following oral administration of a single 150-mg dose of bupropion, there were no statistically significant differences in C_max, half-life, T_max, AUC, or clearance of bupropion or its active metabolites between smokers and nonsmokers.
Drug Interactions: Potential for Other Drugs to Affect WELLBUTRIN SR: In vitro studies indicate that bupropion is primarily metabolized to hydroxybupropion by CYP2B6. Therefore, the potential exists for drug interactions between WELLBUTRIN SR and drugs that are inhibitors or inducers of CYP2B6. In addition, in vitro studies suggest that paroxetine, sertraline, norfluoxetine, fluvoxamine, and nelfinavir inhibit the hydroxylation of bupropion.
Inhibitors of CYP2B6: Ticlopidine, Clopidogrel: In a trial in healthy male volunteers, clopidogrel 75 mg once daily or ticlopidine 250 mg twice daily increased exposures (C_max and AUC) of bupropion by 40% and 60% for clopidogrel, and by 38% and 85% for ticlopidine, respectively. The exposures (C_max and AUC) of hydroxybupropion were decreased 50% and 52%, respectively, by clopidogrel, and 78% and 84%, respectively, by ticlopidine. This effect is thought to be due to the inhibition of the CYP2B6-catalyzed bupropion hydroxylation.
Prasugrel: Prasugrel is a weak inhibitor of CYP2B6. In healthy subjects, prasugrel increased bupropion C_max and AUC values by 14% and 18%, respectively, and decreased C_max and AUC values of hydroxybupropion, an active metabolite of bupropion, by 32% and 24%, respectively.
Cimetidine: The threohydrobupropion metabolite of bupropion does not appear to be produced by cytochrome P450 enzymes. The effects of concomitant administration of cimetidine on the pharmacokinetics of bupropion and its active metabolites were studied in 24 healthy young male volunteers. Following oral administration of bupropion 300 mg with and without cimetidine 800 mg, the pharmacokinetics of bupropion and hydroxybupropion were unaffected. However, there were 16% and 32% increases in the AUC and C_max, respectively, of the combined moieties of threohydrobupropion and erythrohydrobupropion.
Citalopram: Citalopram did not affect the pharmacokinetics of bupropion and its three metabolites.
Inducers of CYP2B6: Ritonavir and Lopinavir: In a healthy volunteer trial, ritonavir 100 mg twice daily reduced the AUC and C_max of bupropion by 22% and 21%, respectively. The exposure of the hydroxybupropion metabolite was decreased by 23%, the threohydrobupropion decreased by 38%, and the erythrohydrobupropion decreased by 48%.
In a second healthy volunteer trial, ritonavir at a dose of 600 mg twice daily decreased the AUC and the C_max of bupropion by 66% and 62%, respectively. The exposure of the hydroxybupropion metabolite was decreased by 78%, the threohydrobupropion decreased by 50%, and the erythrohydrobupropion decreased by 68%.
In another healthy volunteer trial, lopinavir 400 mg/ritonavir 100 mg twice daily decreased bupropion AUC and C_max by 57%. The AUC and C_max of hydroxybupropion were decreased by 50% and 31%, respectively.
Efavirenz: In a trial in healthy volunteers, efavirenz 600 mg once daily for 2 weeks reduced the AUC and C_max of bupropion by approximately 55% and 34%, respectively. The AUC of hydroxybupropion was unchanged, whereas C_max of hydroxybupropion was increased by 50%.
Carbamazepine, Phenobarbital, Phenytoin: While not systematically studied, these drugs may induce the metabolism of bupropion.
Potential for WELLBUTRIN SR to Affect Other Drugs: Animal data indicated that bupropion may be an inducer of drug-metabolizing enzymes in humans. In one trial, following chronic administration of bupropion 100 mg three times daily to 8 healthy male volunteers for 14 days, there was no evidence of induction of its own metabolism. Nevertheless, there may be potential for clinically important alterations of blood levels of co-administered drugs.
Drugs Metabolized by CYP2D6: In vitro, bupropion and its metabolites (erythrohydrobupropion, threohydrobupropion, hydroxybupropion) are CYP2D6 inhibitors. In a clinical trial of 15 male subjects (ages 19 to 35 years) who were extensive metabolizers of CYP2D6, bupropion 300 mg per day followed by a single dose of 50 mg desipramine increased the C_max, AUC, and t_1/2 of desipramine by an average of approximately 2-, 5-, and 2-fold, respectively. The effect was present for at least 7 days after the last dose of bupropion. Concomitant use of bupropion with other drugs metabolized by CYP2D6 has not been formally studied.
Citalopram: Although citalopram is not primarily metabolized by CYP2D6, in one trial bupropion increased the C_max and AUC of citalopram by 30% and 40%, respectively.
Lamotrigine: Multiple oral doses of bupropion had no statistically significant effects on the single-dose pharmacokinetics of lamotrigine in 12 healthy volunteers.
Digoxin: Literature data showed that digoxin exposure was decreased when a single oral dose of 0.5-mg digoxin was administered 24 hours after a single oral dose of extended-release 150-mg bupropion in healthy volunteers.
Wellbutrin XL: Bupropion is a racemic mixture. The pharmacologic activity and pharmacokinetics of the individual enantiomers have not been studied. The mean elimination t_½ (±SD) of bupropion after chronic dosing is 21 (±9) hrs and steady-state plasma concentrations of bupropion are reached within 8 days.
In a study comparing 14-day dosing with Wellbutrin XL 300 mg once daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for C_max and AUC for bupropion and the 3 metabolites (hydroxybupropion, threohydrobupropion and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with Wellbutrin XL 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for C_max and AUC for bupropion and the 3 metabolites.
Absorption: Following oral administration of Wellbutrin XL to healthy volunteers, T_max of bupropion are approximately 5 hrs and food did not affect the C_max or AUC of bupropion.
Distribution: In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg/mL. The extent of protein-binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein-binding of the threohydrobupropion metabolite is about ½ that seen with bupropion.
Metabolism: Bupropion is extensively metabolized in humans. Three (3) metabolites have been shown to be active: Hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that cytochrome P450IIB6 (CYP2B6) is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P-450 isoenzymes are not involved in the formation of threohydrobupropion. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is ½ as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion.
Because bupropion is extensively metabolized, there is the potential for drug-drug interactions, particularly with those agents that are metabolized by or which inhibit/induce the cytochrome P450IIB6 (CYP2B6) isoenzyme eg, ritonavir or efavirenz. In a healthy volunteer study, ritonavir at a dose of 100 mg twice daily reduced the AUC and C_max of bupropion by 22% and 21%, respectively. The exposure of the hydroxybupropion metabolite was decreased by 23%, the threohydrobupropion decreased by 38% and the erythrohydrobupropion decreased by 48%.
In a 2nd healthy volunteer study, ritonavir at a dose of 600 mg twice daily decreased the AUC and the C_max of bupropion by 66% and 62%, respectively. The exposure of the hydroxybupropion metabolite was decreased by 78%, the threohydrobupropion decreased by 50% and the erythrohydrobupropion decreased by 68%.
In another healthy volunteer study, Kaletra (lopinavir 400 mg/ritonavir 100 mg twice daily) decreased bupropion AUC and C_max by 57%. The AUC and C_max of hydroxybupropion were decreased by 50% and 31%, respectively (see Precautions).
In a study in healthy volunteers, efavirenz 600 mg once daily for 2 weeks reduces the AUC and C_max of bupropion by approximately 55% and 34%, respectively. The AUC of hydroxybupropion was unchanged, whereas C_max of hydroxybupropion was increased by 50%.
Although bupropion is not metabolized by cytochrome P450IID6 (CYP2D6), there is the potential for drug-drug interactions when bupropion is co-administered with drugs metabolized by this isoenzyme (see Precautions).
In humans, C_max of hydroxybupropion occur approximately 7 hrs after administration of Wellbutrin XL. Following administration of Wellbutrin XL, C_max of hydroxybupropion are approximately 7 times the peak level of the parent drug at steady-state. The elimination t_½ of hydroxybupropion is approximately 20 (±5) hrs and its AUC at steady-state is about 13 times that of bupropion. The T_max for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination t_½ are longer, approximately 33 (±10) and 37 (±13) hrs, respectively and steady-state AUCs are 1.4 and 7 times that of bupropion, respectively.
Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300-450 mg/day.
Elimination: Following oral administration of 200 mg of ¹⁴C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and faeces, respectively. The fraction of the dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion.
Population Subgroups: Factors or conditions altering metabolic capacity [eg, liver disease, congestive heart failure (CHF), age, concomitant medications, etc] or elimination may be expected to influence the degree and extent of accumulation of the active metabolites of bupropion. The elimination of the major metabolites of bupropion may be affected by reduced renal or hepatic function because they are moderately polar compounds and are likely to undergo further metabolism or conjugation in the liver prior to urinary excretion.
Hepatic: The effect of hepatic impairment on the pharmacokinetics of bupropion was characterized in 2 single-dose studies, 1 in patients with alcoholic liver disease and 1 in patients with mild to severe cirrhosis. The 1st study showed that the t_½ of hydroxybupropion was significantly longer in 8 patients with alcoholic liver disease than in 8 healthy volunteers (32±14 hrs vs 21±5 hrs, respectively). Although not statistically significant, the AUCs for bupropion and hydroxybupropion were more variable and tended to be greater (by 53-57%) in patients with alcoholic liver disease. The differences in t_½ for bupropion and the other metabolites in the 2 patient groups were minimal.
The 2nd study showed no statistically significant differences in the pharmacokinetics of bupropion and its active metabolites in 9 patients with mild to moderate hepatic cirrhosis compared to 8 healthy volunteers. However, more variability was observed in some of the pharmacokinetic parameters for bupropion (AUC, C_max and T_max) and its active metabolites (t_½) in patients with mild to moderate hepatic cirrhosis. In addition, in patients with severe hepatic cirrhosis, the bupropion C_max and AUC were substantially increased (mean difference: by approximately 70% and 3-fold, respectively) and more variable when compared to values in healthy volunteers; the mean bupropion t_½ was also longer (29 hrs in patients with severe hepatic cirrhosis vs 19 hrs in healthy subjects). For the metabolite hydroxybupropion, the mean C_max was approximately 69% lower. For the combined amino-alcohol isomers threohydrobupropion and erythrohydrobupropion, the mean C_max was approximately 31% lower. The mean AUC increased by about 1½-fold for hydroxybupropion and about 2½-fold for threo/erythrohydrobupropion. The median T_max was observed 19 hrs later for hydroxybupropion and 31 hrs later for threo/erythrohydrobupropion. The mean t_½ for hydroxybupropion and threo/erythrohydrobupropion were increased 5-fold and 2-fold, respectively, in patients with severe hepatic cirrhosis compared to healthy volunteers (see Dosage & Administration, Warnings and Precautions).
Renal: There is limited information on the pharmacokinetics of bupropion in patients with renal impairment. An inter-study comparison between normal subjects and patients with end-stage renal failure demonstrated that the parent drug C_max and AUC values were comparable in the 2 groups, whereas the hydroxybupropion and threohydrobupropion metabolites had a 2.3- and 2.8-fold increase, respectively, in AUC for patients with end-stage renal failure. A 2nd study, comparing normal subjects and patients with moderate to severe renal impairment (GFR 30.9±10.8 mL/min) showed that exposure to a single 150 mg dose sustained-release bupropion was approximately 2-fold higher in patients with impaired renal function while levels of the hydroxybupropion and threo/erythrohydrobupropion (combined) metabolites were similar in the 2 groups. The elimination of bupropion and/or the major metabolites of bupropion may be reduced by impaired renal function (see Precautions).
Left Ventricular Dysfunction: During a chronic dosing study with bupropion in 14 depressed patients with left ventricular dysfunction (history of CHF or an enlarged heart on x-ray), no apparent effect on the pharmacokinetics of bupropion or its metabolites was revealed, compared to healthy volunteers.
Age: The effects of age on the pharmacokinetics of bupropion and its metabolites have not been fully characterized, but an exploration of steady-state bupropion concentrations from several depression efficacy studies involving patients dosed in a range of 300-750 mg/day, on a 3 times daily schedule, revealed no relationship between age (18-83 years) and plasma concentration of bupropion. A single-dose pharmacokinetic study demonstrated that the disposition of bupropion and its metabolites in elderly subjects was similar to that of younger subjects. These data suggest that there is no prominent effect of age on bupropion concentration; however, another pharmacokinetic study, single and multiple dose, has suggested that the elderly are at increased risk for accumulation of bupropion and its metabolites (see Precautions).
Gender: A single-dose study involving 12 healthy male and 12 healthy female volunteers revealed no sex-related differences in the pharmacokinetic parameters of bupropion.
Smokers: The effects of cigarette smoking on the pharmacokinetics of bupropion were studied in 34 healthy male and female volunteers; 17 were chronic cigarette smokers and 17 were nonsmokers. Following oral administration of a single 150-mg dose of bupropion, there was no statistically significant difference in C_max, t_½, T_max, AUC or clearance of bupropion or its active metabolites between smokers and nonsmokers.
Toxicology: Wellbutrin SR: Nonclinical Toxicology: Carcinogenesis, Mutagenesis, Impairment of Fertility: Lifetime carcinogenicity studies were performed in rats and mice at bupropion doses up to 300 and 150 mg per kg per day, respectively. These doses are approximately 7 and 2 times the MRHD, respectively, on a mg per m² basis. In the rat study there was an increase in nodular proliferative lesions of the liver at doses of 100 to 300 mg per kg per day (approximately 2 to 7 times the MRHD on a mg per m² basis); lower doses were not tested. The question of whether or not such lesions may be precursors of neoplasms of the liver is currently unresolved. Similar liver lesions were not seen in the mouse study, and no increase in malignant tumors of the liver and other organs was seen in either study.
Bupropion produced a positive response (2 to 3 times control mutation rate) in 2 of 5 strains in the Ames bacterial mutagenicity assay. Bupropion produced an increase in chromosomal aberrations in 1 of 3 in vivo rat bone marrow cytogenetic studies.
A fertility study in rats at doses up to 300 mg per kg per day revealed no evidence of impaired fertility.

Wellbutrin SR: WELLBUTRIN SR is indicated for the treatment of major depressive disorder (MDD), as defined by the Diagnostic and Statistical Manual (DSM).
The efficacy of bupropion in the treatment of a major depressive episode was established in two 4-week controlled in-patient trials and in one 6-week controlled out-patient trial of adult subjects with MDD (see Pharmacology: Pharmacodynamics: Clinical Studies under Actions).
The efficacy of WELLBUTRIN SR in maintaining an antidepressant response for up to 44 weeks following 8 weeks of acute treatment was demonstrated in a placebo-controlled trial (see Pharmacology: Pharmacodynamics: Clinical Studies under Actions).
Wellbutrin XL: Depression/Major Depressive Disorder (MDD): Wellbutrin XL is indicated for the treatment of MDD.
The efficacy of bupropion in the treatment of depression or a major depressive episode was established in two 4-week controlled trials of depressed inpatients and in one 6-week controlled trial of outpatients whose diagnoses corresponded most closely to the major depression category of the APA Diagnostic and Statistical Manual (DSM) (see Pharmacology: Pharmacodynamics: Clinical Trials under Actions).
A major depressive episode (DSM-IV) implies the presence of depressed mood or loss of interest or pleasure; in addition, at least 5 of the following symptoms have been present during the same 2-week period and represent a change from previous functioning: Depressed mood, markedly diminished interest or pleasure in usual activities, significant change in weight and/or appetite, insomnia or hypersomnia, psychomotor agitation or retardation, increased fatigue, feelings of guilt or worthlessness, slowed thinking or impaired concentration, a suicide attempt or suicidal ideation.
The efficacy of bupropion in maintaining an antidepressant response for up to 44 weeks following 8 weeks of acute treatment was demonstrated in a placebo-controlled trial with the sustained-release formulation of bupropion (see Pharmacology: Pharmacodynamics: Clinical Trials under Actions). Nevertheless, the physician who elects to use Wellbutrin XL for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient.
Seasonal Affective Disorder: Wellbutrin XL is indicated for the prevention of seasonal major depressive episodes in patients with a diagnosis of seasonal affective disorder.
The efficacy of Wellbutrin XL for the prevention of seasonal major depressive episodes was established in 3 controlled trials of adult outpatients with a history of MDD with an autumn-winter seasonal pattern as defined by DSM of Mental Disorders, 4th edition (DSM-IV) criteria (see Pharmacology: Pharmacodynamics: Clinical Trials under Actions).
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 in duration, typically beginning in the autumn and remitting in the springtime. Although patients with seasonal affective disorder may have depressive episodes during other times of the year, the diagnosis of seasonal affective disorder requires that the number of seasonal episodes substantially outnumber the number of nonseasonal episodes during the individual's lifetime.

Wellbutrin SR: General Instructions for Use: To minimize the risk of seizure, increase the dose gradually (see Seizures under Precautions). WELLBUTRIN SR should be swallowed whole and not crushed, divided, or chewed. WELLBUTRIN SR may be taken with or without food.
The usual adult target dose for WELLBUTRIN SR is 300 mg/day, given as 150 mg twice daily. Initiate dosing with 150 mg/day given as a single daily dose in the morning. After 3 days of dosing, the dose may be increased to the 300 mg/day target dose, given as 150 mg twice daily. There should be an interval of at least 8 hours between successive doses.
Increasing the Dosage Above 300 mg/day: As with other antidepressants, the full antidepressant effect of WELLBUTRIN SR Tablets may not be evident until 4 weeks of treatment or longer. An increase in dosage to the maximum of 400 mg/day, given as 200mg twice daily, may be considered for patients in whom no clinical improvement is noted after several weeks of treatment at 300 mg/day.
It is generally agreed that acute episodes of depression require several months or longer of antidepressant drug treatment beyond response in the acute episode. It is unknown whether the dose of WELLBUTRIN SR needed for maintenance treatment is identical to the dose that provided an initial response. Periodically reassessed to determine the need for maintenance treatment and the appropriate dose for such treatment.
Dose Adjustment for Patients with Hepatic Impairment: In patients with moderate to severe hepatic impairment (Child-Pugh score: 7 to 15), the maximum dose of WELLBUTRIN SR is 150 mg every other day. In patients with mild hepatic impairment (Child-Pugh score: 5 to 6), consider reducing the dose and/or frequency of dosing (see Hepatic Impairment under Precautions and Pharmacology: Pharmacokinetics: Population Subgroups: Hepatic Impairment under Actions).
Dose Adjustment for Patients with Renal Impairment: Consider reducing the dose and/or frequency of WELLBUTRIN SR in patients with renal impairment (Glomerular Filtration Rate less than 90 ml per min) (see Renal Impairment under Precautions and Pharmacology: Pharmacokinetics: Population Subgroups: Renal Impairment under Actions).
Switching a patient to or from a Monoamine Oxidase Inhibitor (MAOI) Antidepressant: At least 14 days should elapse between discontinuation of an MAOI intended to treat depression and initiation of therapy with WELLBUTRIN SR. Conversely, at least 14 days should be allowed after stopping WELLBUTRIN SR before starting an MAOI antidepressant (see Contraindications and Interactions).
Use of WELLBUTRIN SR with reversible MAOIs such as Linezolid or Methylene Blue: Do not start WELLBUTRIN SR in a patient who is being treated with a reversible MAOI such as linezolid or intravenous methylene blue. Drug interactions can increase the risk of hypertensive reactions. In a patient who requires more urgent treatment of a psychiatric condition, non-pharmacological interventions, including hospitalization, should be considered (see Contraindications and Interactions).
In some cases, a patient already receiving therapy with WELLBUTRIN SR may require urgent treatment with linezolid or intravenous methylene blue. If acceptable alternatives to linezolid or intravenous methylene blue treatment are not available and the potential benefits of linezolid or intravenous methylene blue treatment are judged to outweigh the risks of hypertensive reactions in a particular patient, WELLBUTRIN SR should be stopped promptly, and linezolid or intravenous methylene blue can be administered. The patient should be monitored for 2 weeks or until 24 hours after the last dose of linezolid or intravenous methylene blue, whichever comes first. Therapy with WELLBUTRIN SR may be resumed 24 hours after the last dose of linezolid or intravenous methylene blue.
The risk of administering methylene blue by non-intravenous routes (such as oral tablets or by local injection) or in intravenous doses much lower than 1 mg per kg with WELLBUTRIN SR is unclear. The clinician should, nevertheless, be aware of the possibility of a drug interaction with such use (see Contraindications and Interactions).
Wellbutrin XL: General Dosing Considerations: It is particularly important to administer Wellbutrin XL tablets in a manner most likely to minimize the risk of seizure (see Warnings and Precautions). Gradual escalation in dosage is also important if agitation, motor restlessness and insomnia, often seen during the initial days of treatment, are to be minimized. If necessary, these effects may be managed by temporary reduction of dose or the short-term administration of an intermediate to long-acting sedative hypnotic. A sedative hypnotic usually is not required beyond the 1st week of treatment. In Wellbutrin SR, insomnia is a very common adverse event which is often transient. Insomnia may also be minimized by avoiding bedtime doses. If distressing, untoward effects supervene, dose escalation should be stopped. Wellbutrin XL should be swallowed whole and not crushed, divided or chewed as this may lead to an increased risk of adverse effects including seizures.
Wellbutrin XL may be taken without regard to meals.
Adults: Depression/Major Depressive Disorder (MDD): Initial Treatment: The usual adult target dose is 300 mg/day, given as 150 mg twice daily (for Wellbutrin SR) or once daily in the morning (for Wellbutrin XL). Dosing with Wellbutrin SR/XL should begin at 150 mg/day given as a single daily dose in the morning. If the 150 mg initial dose is adequately tolerated, an increase to the 300 mg/day target dose, given as 150 mg twice daily, may be made as early as day 4 of dosing. There should be an interval of at least 8 hrs between successive doses.
Increasing the Dosage >300 mg/day: As with other antidepressants, the full antidepressant effect of Wellbutrin SR/XL may not be evident until 4 weeks of treatment or longer.
An increase in dosage to the maximum of 450 mg/day, given as a single dose, may be considered for patients in whom no clinical improvement is noted after several weeks of treatment at 300 mg/day.
Maintenance Treatment: It is generally agreed that acute episodes of depression require several months or longer of sustained pharmacological therapy beyond response to the acute episode.
It is unknown whether or not the dose of Wellbutrin XL needed for maintenance treatment is identical to the dose needed to achieve an initial response. Patients should be periodically reassessed to determine the need for maintenance treatment and the appropriate dose for such treatment.
Seasonal Affective Disorder: For the prevention of seasonal major depressive episodes associated with seasonal affective disorder, Wellbutrin XL should generally be 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 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 significant impairment should not generally be treated prophylactically.
Dosing with Wellbutrin XL should begin at 150 mg/day given as a single daily dose in the morning. If the 150-mg initial dose is adequately tolerated, the dose of Wellbutrin XL should be increased to the 300-mg/day dose after 1 week. If the 300-mg dose is not adequately tolerated, the dose can be reduced to 150 mg/day. The usual adult target dose for Wellbutrin XL is 300 mg/day, given once daily in the morning.
For patients taking 300 mg/day during the autumn-winter season, the dose should be tapered to 150 mg/day for 2 weeks prior to discontinuation.
Doses of Wellbutrin XL >300 mg/day have not been studied for the prevention of seasonal major depressive episodes.
Switching Patients from Wellbutrin Tablets or from Wellbutrin SR Sustained-Release Tablets: When switching patients from Wellbutrin tablets to Wellbutrin XL or from Wellbutrin SR sustained-release tablets to Wellbutrin XL, give the same total daily dose when possible. Patients who are currently being treated with Wellbutrin tablets at 300 mg/day (for example, 100 mg 3 times a day) may be switched to Wellbutrin XL 300 mg once daily. Patients who are currently being treated with Wellbutrin SR sustained-release tablets at 300 mg/day (for example, 150 mg twice daily) may be switched to Wellbutrin XL 300 mg once daily.
Hepatic Impairment: Wellbutrin XL should be used with extreme caution in patients with severe hepatic cirrhosis. The dose should not exceed 150 mg every other day in these patients. Wellbutrin SR/XL should be used with caution in patients with hepatic impairment (including mild to moderate hepatic cirrhosis) and a reduced frequency and/or dose should be considered in patients with mild to moderate hepatic cirrhosis (see Pharmacology under Actions, Warnings and Precautions).
Renal Impairment: Wellbutrin XL should be used with caution in patients with renal impairment. Wellbutrin SR should be initiated at a reduced frequency and/or dose (see Precautions). A reduced frequency and/or dose of Wellbutrin XL should be considered (see Pharmacology under Actions and Precautions).

Human Overdose Experience: Overdoses of up to 30 grams or more of bupropion have been reported. Seizure was reported in approximately one-third of all cases. Other serious reactions reported with overdoses of bupropion alone included hallucinations, loss of consciousness, sinus tachycardia, and ECG changes such as conduction disturbances (including QRS prolongation) or arrhythmias. Fever, muscle rigidity, rhabdomyolysis, hypotension, stupor, coma, and respiratory failure have been reported mainly when bupropion was part of multiple drug overdoses.
Although most patients recovered without sequelae, deaths associated with overdoses of bupropion alone have been reported in patients ingesting large doses of the drug. Multiple uncontrolled seizures, bradycardia, cardiac failure, and cardiac arrest prior to death were reported in these patients.
Overdosage Management: Wellbutrin SR: There are no known antidotes for bupropion. In case of an overdose, provide supportive care, including close medical supervision and monitoring. Consider the possibility of multiple drug overdose. Ensure an adequate airway, oxygenation, and ventilation. Monitor cardiac rhythm and vital signs. Induction of emesis is not recommended.
Wellbutrin XL: Ensure an adequate airway, oxygenation and ventilation. Monitor cardiac rhythm and vital signs. Electroencephalogram (EEG) monitoring is also recommended for the first 48 hrs post-ingestion. General supportive and symptomatic measures are also recommended. Induction of emesis is not recommended.
Activated charcoal should be administered. There is no experience with the use of forced diuresis, dialysis, hemoperfusion or exchange transfusion in the management of bupropion overdoses. No specific antidotes for bupropion are known.
Due to the dose-related risk of seizures with Wellbutrin XL, hospitalization following suspected overdose should be considered. Based on studies in animals, it is recommended that seizures be treated with IV benzodiazepine administration and other supportive measures, as appropriate.
In managing overdosage, consider the possibility of multiple drug involvement. The physician should consider contacting a poison control center for additional information on the treatment of any overdose.

Wellbutrin SR: WELLBUTRIN SR is contraindicated in patients with a seizure disorder.
WELLBUTRIN SR is contraindicated in patients undergoing abrupt discontinuation of alcohol, benzodiazepines, barbiturates and antiepileptic drugs (see Precautions and Interactions).
WELLBUTRIN SR is contraindicated in patients with a current or previous diagnosis of bulimia or anorexia nervosa as a higher incidence of seizures was seen in such patients treated with the immediate release formulation of bupropion (see Precautions).
The use of MAOIs (intended to treat psychiatric disorders) concomitantly with WELLBUTRIN SR or within 14 days of discontinuing treatment with WELLBUTRIN SR is contraindicated. There is an increased risk of hypertensive reactions when WELLBUTRIN SR is used concomitantly with MAOIs. The use of WELLBUTRIN SR within 14 days of discontinuing treatment with an MAOI is also contraindicated. Starting WELLBUTRIN SR in a patient treated with reversible MAOI such as linezolid or intravenous methylene blue is contraindicated (see Dosage & Administration, Precautions, and Interactions).
WELLBUTRIN SR is contraindicated in patients with known hypersensitivity to bupropion or other ingredients of WELLBUTRIN SR. Anaphylactoid / anaphylactic reactions and Stevens-Johnson syndrome have been reported (see Precautions).
Wellbutrin XL: Hypersensitivity to bupropion or to any of the other components of Wellbutrin XL.
Patients with a seizure disorder; undergoing abrupt discontinuation of alcohol or sedatives; currently being treated with any other preparation containing bupropion, as the incidence of seizures is dose-dependent; with a current or previous diagnosis of bulimia or anorexia nervosa, as a higher incidence of seizures was seen in this patient population when bupropion was administered.
Concomitant use of Wellbutrin XL and monoamine oxidase inhibitors (MAOIs) is contraindicated. At least 14 days should elapse between discontinuation of irreversible MAOIs and initiation of treatment with Wellbutrin XL.

Wellbutrin XL: Clinical Worsening and Suicide Risk in Treating Psychiatric Disorders: Patients with MDD, both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a long-standing concern, however, 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 trials of antidepressant drugs [selective serotonin reuptake inhibitors (SSRIs) and others] showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents and young adults (18-24 years) with MDD and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction with antidepressants compared to placebo in adults ≥65 years.
The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive compulsive disorder (OCD) or other psychiatric disorders included a total of 24 short-term trials of 9 antidepressant drugs in over 4,400 patients. The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied. There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk differences (drug vs placebo), however, were relatively stable within age strata and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1,000 patients treated) are provided in Table 3. (See Table 3.)

Click on icon to see table/diagram/image

No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but the number was not sufficient to reach any conclusion about drug effect on suicide.
It is unknown whether the suicidality risk extends to longer-term use ie, beyond several months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with depression that the use of antidepressants can delay the recurrence of depression.
All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality and unusual changes in behavior, especially during the initial few months of a course of drug therapy or at times of dose changes, either increases or decreases.
The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania and mania, have been reported in adult and pediatric patients being treated with antidepressants for MDD as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms 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.
Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset or were not part of the patient's presenting symptoms.
Families and caregivers of patients being treated with antidepressants for MDD or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior and the other symptoms described previously, as well as the emergence of suicidality, and to report such symptoms immediately to healthcare providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for Wellbutrin XL should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose.
Neuropsychiatric Symptoms and Suicide Risk in Smoking Cessation Treatment: Wellbutrin SR and Wellbutrin XL are not approved for smoking cessation treatment, but bupropion under the name Zyban is approved for this use. Serious neuropsychiatric symptoms have been reported in patients taking bupropion for smoking cessation (see Adverse Reactions). These have included 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. Some reported cases may have been complicated by the symptoms of nicotine withdrawal in patients who stopped smoking. Depressed mood may be a symptom of nicotine withdrawal. Depression, rarely including suicidal ideation, has been reported in smokers undergoing a smoking cessation attempt without medication. However, some of these symptoms have occurred in patients taking bupropion who continued to smoke. When symptoms were reported, most were during bupropion treatment, but some were following discontinuation of bupropion therapy.
These events have occurred in patients with and without preexisting psychiatric disease; some have experienced worsening of their psychiatric illnesses. All patients being treated with bupropion as part of smoking cessation treatment should be observed for neuropsychiatric symptoms or worsening of preexisting psychiatric illness.
Patients with serious psychiatric illness eg, schizophrenia, bipolar disorder and MDD did not participate in the premarketing studies of Zyban.
Advise patients and caregivers that the patient using bupropion for smoking cessation should stop taking bupropion and contact a healthcare provider immediately if agitation, depressed mood or changes in behavior or thinking that are not typical for the patient are observed, or if the patient develops suicidal ideation or suicidal behavior. In many post-marketing cases, resolution of symptoms after discontinuation of Zyban was reported, although in some cases the symptoms persisted, therefore, ongoing monitoring and supportive care should be provided until symptoms resolve.
The risks of using bupropion for smoking cessation should be weighed against the benefits of its use. Zyban has been demonstrated to increase the likelihood of abstinence from smoking for as long as 6 months compared to treatment with placebo. The health benefits of quitting smoking are immediate and substantial.
Screening Patients for Bipolar Disorder: A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described above represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder and depression. It should be noted that Wellbutrin XL is not approved for use in treating bipolar depression.
Bupropion-Containing Products: Patients should be made aware that Wellbutrin XL contains the same active ingredient found in Zyban, used as an aid to smoking cessation treatment, and that Wellbutrin XL should not be used in combination with Zyban or any other medications that contain bupropion eg, Wellbutrin SR or Wellbutrin, the immediate-release formulation.
Information for Patients: Patients should be advised that taking Wellbutrin XL can cause mild pupillary dilation, which in susceptible individuals, can lead to an episode of angle closure glaucoma. Preexisting glaucoma is almost always open-angle glaucoma because angle closure glaucoma, when diagnosed, can be treated definitively with iridectomy. Open-angle glaucoma is not a risk factor for angle closure glaucoma. Patients may wish to be examined to determine whether they are susceptible to angle closure and have a prophylactic procedure (eg, iridectomy), if they are susceptible.
Seizures: Bupropion is associated with a dose-related risk of seizures. The risk of seizures is also related to patient factors, clinical situations and concomitant medications, which must be considered in selection of patients for therapy with Wellbutrin XL. Wellbutrin XL should be discontinued and not restarted in patients who experience a seizure while on treatment.
As Wellbutrin XL is bioequivalent to both the immediate-release formulation of bupropion and to the sustained-release formulation of bupropion, the seizure incidence with Wellbutrin XL, while not formally evaluated in clinical trials, may be similar to that presented below for the immediate-release and sustained-release formulations of bupropion.
Dose: At doses up to 300 mg/day of the sustained-release formulation of Wellbutrin SR, the incidence of seizure is approximately 0.1% (1/1,000).
Data for the immediate-release formulation of bupropion revealed a seizure incidence of approximately 0.4% (ie, 13 of 3,200 patients followed prospectively) in patients treated at doses in a range of 300-450 mg/day. This seizure incidence (0.4%) may exceed that of some other marketed antidepressants.
Additional data accumulated for the immediate-release formulation of bupropion suggested that the estimated seizure incidence increases almost 10-fold between 450 and 600 mg/day. The 600-mg dose is twice the usual adult dose and 1¹/₃ the maximum recommended daily dose (450 mg) of Wellbutrin XL. This disproportionate increase in seizure incidence with dose incrementation calls for caution in dosing.
Patient Factors: Predisposing factors that may increase the risk of seizure with bupropion use include history of head trauma or prior seizure, central nervous system tumor, the presence of severe hepatic cirrhosis and concomitant medications that lower seizure threshold.
Clinical Situations: Circumstances associated with an increased seizure risk include, among others, excessive use of alcohol or sedatives (including benzodiazepines); addiction to opiates, cocaine or stimulants; use of over-the-counter stimulants and anorectics; and diabetes treated with oral hypoglycemics or insulin.
Concomitant Medications: Many medications (eg, antipsychotics, antidepressants, theophylline, systemic steroids) are known to lower seizure threshold.
Recommendations for Reducing the Risk of Seizure: Retrospective analysis of clinical experience gained during the development of bupropion suggests that the risk of seizure may be minimized if the total daily dose of Wellbutrin XL does not exceed 450 mg; and if the rate of incrementation of dose is gradual.
Wellbutrin XL should be administered with extreme caution to patients with a history of seizure, cranial trauma or other predisposition(s) toward seizure or patients treated with other agents (eg, antipsychotics, other antidepressants, theophylline, systemic steroids, etc) that lower seizure threshold.
Hepatic Impairment: Wellbutrin XL should be used with extreme caution in patients with severe hepatic cirrhosis. In these patients, a reduced frequency and/or dose is required as peak bupropion as well as AUC levels are substantially increased and accumulation is likely to occur in such patients to a greater extent than usual. The dose should not exceed 150 mg every other day in these patients (see Pharmacology under Actions, Dosage & Administration and Precautions).
Angle-Closure Glaucoma: The pupillary dilation that occurs following use of many antidepressant drugs including Wellbutrin XL may trigger an angle closure attack in a patient with anatomically narrow angles who does not have a patent iridectomy.
Potential for Hepatotoxicity: In rats receiving large doses of bupropion chronically, there was an increase in incidence of hepatic hyperplastic nodules and hepatocellular hypertrophy. In dogs receiving large doses of bupropion chronically, various histologic changes were seen in the liver and laboratory tests suggesting mild hepatocellular injury were noted.

Wellbutrin SR: Suicidal thoughts and behaviours in children, adolescents and young adults: Patients with MDD, both adult and paediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behaviour (suicidality) or unusual changes in behaviour, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. 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 trials of antidepressant drugs (selective serotonin reuptake inhibitors [SSRIs] and others) show that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18 to 24) with MDD and other psychiatric disorders. Short-term clinical trials did not show an increase in the risk of suicidality with antidepressants compared with placebo in adults beyond age 24; there was a reduction with antidepressants compared with placebo in adults aged 65 and older.
The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9 antidepressant drugs in over 4,400 subjects. The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 subjects. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger subjects for almost all drugs studied. There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk differences (drug vs. placebo), however, were relatively stable within age strata and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1,000 subjects treated) are provided in Table 4. (See Table 4.)

Click on icon to see table/diagram/image

No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but the number was not sufficient to reach any conclusion about drug effect on suicide.
It is 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 depression that the use of antidepressants can delay the recurrence of depression.
All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases.
The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms 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.
Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient's presenting symptoms.
Families and caregivers of patients being treated with antidepressants for MDD or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described previously, as well as the emergence of suicidality, and to report such symptoms immediately to healthcare providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for WELLBUTRIN SR should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose.
Neuropsychiatric Adverse Events and Suicide Risk in Smoking Cessation Treatment: WELLBUTRIN SR is not approved for smoking cessation treatment; however, it contains the same active ingredient as the smoking cessation medication ZYBAN. Serious neuropsychiatric adverse events have been reported in patients taking bupropion for smoking cessation. These postmarketing reports have included changes in mood (including depression and mania), psychosis, hallucinations, paranoia, delusions, homicidal ideation, aggression, hostility, agitation, anxiety, and panic, as well as suicidal ideation, suicide attempt, and completed suicide (see Adverse Reactions). Some patients who stopped smoking may have been experiencing symptoms of nicotine withdrawal, including depressed mood. Depression, rarely including suicidal ideation, has been reported in smokers undergoing a smoking cessation attempt without medication. However, some of these adverse events occurred in patients taking bupropion who continued to smoke.
Neuropsychiatric adverse events occurred in patients without and with pre-existing psychiatric disease; some patients experienced worsening of their psychiatric illnesses. Observe patients for the occurrence of neuropsychiatric adverse events. Advise patients and caregivers that the patient should stop taking WELLBUTRIN and contact a healthcare provider immediately if agitation, depressed mood, or changes in behavior or thinking that are not typical for the patient are observed, or if the patient develops suicidal ideation or suicidal behavior. In many postmarketing cases, resolution of symptoms after discontinuation of bupropion was reported. However, the symptoms persisted in some cases; therefore, ongoing monitoring and supportive care should be provided until symptoms resolve.
Seizures: WELLBUTRIN SR can cause seizure. The risk of seizure is dose-related. The dose should not exceed 400 mg/day. Increase the dose gradually. Discontinue WELLBUTRIN SR and do not restart treatment if the patient experiences a seizure.
The risk of seizures is also related to patient factors, clinical situations, and concomitant medications that lower the seizure threshold. Consider these risks before initiating treatment with WELLBUTRIN SR. WELLBUTRIN SR is contraindicated in patients with a seizure disorder, current or prior diagnosis of anorexia nervosa or bulimia, or undergoing abrupt discontinuation of alcohol, benzodiazepines, barbiturates, and antiepileptic drugs (see Contraindications and Interactions). The following conditions can also increase the risk of seizure: severe head injury; arteriovenous malformation; CNS tumor or CNS infection; severe stroke; concomitant use of other medications that lower the seizure threshold (e.g. other bupropion products, antipsychotics, tricyclic antidepressants, theophylline, and systemic corticosteroids); metabolic disorders (e.g. hypoglycemia, hyponatremia, severe hepatic impairment, and hypoxia); use of illicit drugs (e.g. cocaine); or abuse or misuse of prescription drugs such as CNS stimulants. Additional predisposing conditions include diabetes mellitus treated with oral hypoglycemic drugs or insulin; use of anorectic drugs; and excessive use of alcohol, benzodiazepines, sedative/hypnotics or opiates.
Incidence of seizure with Bupropion Use: When WELLBUTRIN SR is dosed up to 300 mg/day, the incidence of seizure is approximately 0.1% (1/1000) and increases to approximately 0.4% (4/1000) at the maximum recommended dose of 400 mg/day.
The risk of seizures can be reduced if the dose of WELLBUTRIN SR does not exceed 400 mg/day, given as 200 mg twice daily and the titration rate is gradual.
Hypertension: Treatment with WELLBUTRIN SR can result in elevated blood pressure and hypertension. Assess blood pressure before initiating treatment with WELLBUTRIN SR, and monitor periodically during treatment. The risk of hypertension is increased if WELLBUTRIN SR is used concomitantly with MAOIs or other drugs that increase dopaminergic or noradrenergic activity (see Contraindications).
Data from a comparative trial of the sustained-release formulation of bupropion HCl, nicotine transdermal system (NTS), the combination of sustained-release bupropion plus NTS, and placebo as an aid to smoking cessation suggest a higher incidence of treatment-emergent hypertension in patients treated with the combination of sustained-release bupropion and NTS. In this trial, 6.1% of subjects treated with the combination of sustained-release bupropion and NTS had treatment-emergent hypertension compared with 2.5%, 1.6%, and 3.1% of subjects treated with sustained-release bupropion, NTS, and placebo, respectively. The majority of these subjects had evidence of pre-existing hypertension. Three subjects (1.2%) treated with the combination of sustained-release bupropion and NTS and 1 subject (0.4%) treated with NTS had study medication discontinued due to hypertension compared with none of the subjects treated with sustained-release bupropion or placebo. Monitoring of blood pressure is recommended in patients who receive the combination of bupropion and nicotine replacement.
In a clinical trial of bupropion immediate-release in MDD subjects with stable congestive heart failure (N = 36), bupropion was associated with an exacerbation of pre-existing hypertension in 2 subjects, leading to discontinuation of bupropion treatment. There are no controlled trials assessing the safety of bupropion in patients with a recent history of myocardial infarction or unstable cardiac disease.
Activation of Mania/Hypomania: Antidepressant treatment can precipitate a manic, mixed, or hypomanic manic episode. The risk appears to be increased in patients with bipolar disorder or who have risk factors for bipolar disorder. Prior to initiating WELLBUTRIN SR, screen patients for a history of bipolar disorder and the presence of risk factors for bipolar disorder (e.g. family history of bipolar disorder, suicide, or depression). WELLBUTRIN SR is not approved for use in treating bipolar depression.
Psychosis and Other Neuropsychiatric Reactions: Depressed patients treated with WELLBUTRIN SR have had a variety of neuropsychiatric signs and symptoms, including delusions, hallucinations, psychosis, concentration disturbance, paranoia, and confusion. Some of these patients had a diagnosis of bipolar disorder. In some cases, these symptoms abated upon dose reduction and/or withdrawal of treatment. Instruct patients to contact a healthcare professional if such reactions occur.
Angle-Closure Glaucoma: The pupillary dilation that occurs following use of many antidepressant drugs including WELLBUTRIN SR may trigger an angle-closure attack in a patient with anatomically narrow angles who does not have a patent iridectomy.
Hypersensitivity reactions: Anaphylactoid/anaphylactic reactions have occurred during clinical trials with bupropion. Reactions have been characterized by pruritus, urticaria, angioedema, and dyspnea requiring medical treatment. In addition, there have been rare, spontaneous postmarketing reports of erythema multiforme, Stevens-Johnson syndrome, and anaphylactic shock associated with bupropion. Instruct patients to discontinue WELLBUTRIN SR and consult a healthcare provider if they develop an allergic or anaphylactoid/anaphylactic reaction (e.g., skin rash, pruritus, hives, chest pain, edema, and shortness of breath) during treatment.
There are reports of arthralgia, myalgia, fever with rash and other serum sickness-like symptoms suggestive of delayed hypersensitivity.
Renal Impairment: Consider a reduced dose and/or dosing frequency of WELLBUTRIN SR in patients with renal impairment (Glomerular Filtration Rate: less than 90 mL per min). Bupropion and its metabolites are cleared renally and may accumulate in such patients to a greater extent than usual. Monitor closely for adverse reactions that could indicate high bupropion or metabolite exposures (see Dosage & Administration and Pharmacology: Pharmacokinetics: Population Subgroups: Renal Impairment under Actions).
Hepatic Impairment: In patients with moderate to severe hepatic impairment (Child-Pugh score: 7 to 15), the maximum dose of WELLBUTRIN SR is 100 mg per day or 150 mg every other day. In patients with mild hepatic impairment (Child-Pugh score: 5 to 6), consider reducing the dose and/or frequency of dosing (see Dosage & Administration and Pharmacology: Pharmacokinetics: Population Subgroups: Hepatic Impairment under Actions).
Drug Abuse and Dependence: Abuse: Humans: Controlled clinical trials conducted in normal volunteers, in subjects with a history of multiple drug abuse, and in depressed subjects showed some increase in motor activity and agitation/excitement, often typical of central stimulant activity.
In a population of individuals experienced with drugs of abuse, a single oral dose of 400 mg of bupropion produced mild amphetamine-like activity as compared with placebo on the Morphine-Benzedrine Subscale of the Addiction Research Center Inventories (ARCI) and a score greater than placebo but less than 15 mg of the Schedule II stimulant dextroamphetamine on the Liking Scale of the ARCI. These scales measure general feelings of euphoria and drug liking which are often associated with abuse potential.
Findings in clinical trials, however, are not known to reliably predict the abuse potential of drugs. Nonetheless, evidence from single-dose trials does suggest that the recommended daily dosage of bupropion when administered orally in divided doses is not likely to be significantly reinforcing to amphetamine or CNS stimulant abusers. However, higher doses (which could not be tested because of the risk of seizure) might be modestly attractive to those who abuse CNS stimulant drugs.
WELLBUTRIN SR is intended for oral use only. The inhalation of crushed tablets or injection of dissolved bupropion has been reported. Seizures and/or cases of death have been reported when bupropion has been administered intranasally or by parenteral injection.
Animals: Studies in rodents and primates demonstrated that bupropion exhibits some pharmacologic actions common to psychostimulants. In rodents, it has been shown to increase locomotor activity, elicit a mild stereotyped behavior response, and increase rates of responding in several schedule-controlled behavior paradigms. In primate models assessing the positive-reinforcing effects of psychoactive drugs, bupropion was self-administered intravenously. In rats, bupropion produced amphetamine-like and cocaine-like discriminative stimulus effects in drug discrimination paradigms used to characterize the subjective effects of psychoactive drugs.
Use in Children: Safety and effectiveness in the pediatric population have not been established.
Use in Elderly: Of the approximately 6,000 subjects who participated in clinical trials with bupropion sustained-release tablets (depression and smoking cessation trials), 275 were aged ≥65 years and 47 were aged ≥75 years. In addition, several hundred subjects aged ≥65 years participated in clinical trials using the immediate-release formulation of bupropion (depression trials). No overall differences in safety or effectiveness were observed between these subjects and younger subjects. Reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.
Bupropion is extensively metabolized in the liver to active metabolites, which are further metabolized and excreted by the kidneys. The risk of adverse reactions may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, it may be necessary to consider this factor in dose selection; it may be useful to monitor renal function (see Dosage & Administration and Pharmacology: Pharmacokinetics: Population Subgroups: Age under Actions).
Wellbutrin XL: General: Agitation and Insomnia: Increased restlessness, agitation, anxiety and insomnia, especially shortly after initiation of treatment, have been associated with treatment with bupropion. In 3 placebo-controlled clinical trials of seasonal affective disorder with Wellbutrin XL, the incidence of agitation, anxiety and insomnia are shown in Table 5. (See Table 5.)

Click on icon to see table/diagram/image

Patients in placebo-controlled trials of MDD with Wellbutrin SR, the sustained-release formulation of bupropion, experienced agitation, anxiety and insomnia as shown in Table 6. (See Table 6.)

Click on icon to see table/diagram/image

In clinical studies of MDD, these symptoms were sometimes of sufficient magnitude to require treatment with sedative/hypnotic drugs.
Symptoms in these studies were sufficiently severe to require discontinuation of treatment in 1% and 2.6% of patients treated with 300 and 400 mg/day, respectively, of bupropion sustained-release tablets and 0.8% of patients treated with placebo.
Psychosis, Confusion and Other Neuropsychiatric Phenomena: Depressed patients treated with bupropion have been reported to show a variety of neuropsychiatric signs and symptoms, including delusions, hallucinations, psychosis, concentration disturbance, paranoia and confusion. In some cases, these symptoms abated upon dose reduction and/or withdrawal of treatment.
Activation of Psychosis and/or Mania: Antidepressants can precipitate manic episodes in bipolar disorder patients during the depressed phase of their illness and may activate latent psychosis in other susceptible patients. Wellbutrin XL is expected to pose similar risks.
Altered Appetite and Weight: In 3 placebo-controlled clinical trials of seasonal affective disorder with Wellbutrin XL, the percentage of patients with weight gain or weight loss are shown in Table 7. (See Table 7.)

Click on icon to see table/diagram/image

In placebo-controlled studies of MDD using Wellbutrin SR, the sustained-release formulation of bupropion, patients experienced weight gain or weight loss as shown in Table 8. (See Table 8.)

Click on icon to see table/diagram/image

In studies conducted with the immediate-release formulation of bupropion, 35% of patients receiving tricyclic antidepressants gained weight, compared to 9% of patients treated with the immediate-release formulation of bupropion. If weight loss is a major presenting sign of a patient's depressive illness, the anorectic and/or weight-reducing potential of Wellbutrin XL should be considered.
Allergic Reactions: Anaphylactoid/anaphylactic reactions characterized by symptoms eg, pruritus, urticaria, angioedema and dyspnea requiring medical treatment have been reported in clinical trials with bupropion. In addition, there have been rare spontaneous post-marketing reports of erythema multiforme, Stevens-Johnson syndrome and anaphylactic shock associated with bupropion. A patient should stop taking Wellbutrin XL and consult a physician if experiencing allergic or anaphylactoid/anaphylactic reactions (eg, skin rash, pruritus, hives, chest pain, edema and shortness of breath) during treatment.
Arthralgia, myalgia and fever with rash and other symptoms suggestive of delayed hypersensitivity have been reported in association with bupropion. These symptoms may resemble serum sickness.
Cardiovascular Effects: In clinical practice, hypertension, in some cases severe, requiring acute treatment, has been reported in patients receiving bupropion alone and in combination with nicotine replacement therapy. These events have been observed in both patients with and without evidence of preexisting hypertension.
Data from a comparative study of the sustained-release formulation of bupropion (Zyban sustained-release tablets), NTS, the combination of sustained-release bupropion plus NTS and placebo as an aid to smoking cessation suggest a higher incidence of treatment-emergent hypertension in patients treated with the combination of sustained-release bupropion and NTS. In this study, 6.1% of patients treated with the combination of sustained-release bupropion and NTS had treatment-emergent hypertension compared to 2.5%, 1.6% and 3.1% of patients treated with sustained-release bupropion, NTS, and placebo, respectively. The majority of these patients had evidence of preexisting hypertension. Three patients (1.2%) treated with the combination of Zyban and NTS and 1 patient (0.4%) treated with NTS had study medication discontinued due to hypertension compared to none of the patients treated with Zyban or placebo. Monitoring of blood pressure is recommended in patients who receive the combination of bupropion and nicotine replacement. There is no clinical experience establishing the safety of Wellbutrin XL in patients with a recent history of myocardial infarction or unstable heart disease. Therefore, care should be exercised if it is used in these groups. Bupropion was well tolerated in depressed patients who had previously developed orthostatic hypotension while receiving tricyclic antidepressants, and was also generally well tolerated in a group of 36 depressed inpatients with stable CHF. However, bupropion was associated with a rise in supine blood pressure in the study of patients with CHF, resulting in discontinuation of treatment in 2 patients for exacerbation of baseline hypertension.
Hepatic Impairment: Wellbutrin XL should be used with extreme caution in patients with severe hepatic cirrhosis. In these patients, a reduced frequency and/or dose is required. Wellbutrin XL should be used with caution in patients with hepatic impairment (including mild to moderate hepatic cirrhosis) and reduced frequency and/or dose should be considered in patients with mild to moderate hepatic cirrhosis.
All patients with hepatic impairment should be closely monitored for possible adverse effects that could indicate high drug and metabolite levels (see Pharmacology under Actions, Dosage & Administration and Warnings).
Renal Impairment: There is limited information on the pharmacokinetics of bupropion in patients with renal impairment. An inter-study comparison between normal subjects and patients with end-stage renal failure demonstrated that the parent drug C_max and AUC values were comparable in the 2 groups, whereas the hydroxybupropion and threohydrobupropion metabolites had a 2.3- and 2.8-fold increase, respectively, in AUC for patients with end-stage renal failure. A 2nd study, comparing normal subjects and patients with moderate to severe renal impairment (GFR 30.9±10.8 mL/min) showed that exposure to a single 150 mg dose of sustained-release bupropion was approximately 2-fold higher in patients with impaired renal function while levels of the hydroxybupropion and threo/erythrohydrobupropion (combined) metabolites were similar in the 2 groups. Bupropion is extensively metabolized in the liver to active metabolites, which are further metabolized and subsequently excreted by the kidneys.
Wellbutrin XL should be used with caution in patients with renal impairment and a reduced frequency and/or dose should be considered as bupropion and the metabolites of bupropion may accumulate in such patients to a greater extent than usual. The patient should be closely monitored for possible adverse effects that could indicate high drug or metabolite levels.
Information for Patients: Prescribers or other health professionals should inform patients, their families and their caregivers about the benefits and risks associated with treatment with Wellbutrin XL and should counsel them in its appropriate use.
Patients should be advised of the following issues and asked to alert the prescriber if these occur while taking Wellbutrin XL.
Clinical Worsening and Suicide Risk: Patients, their families and their caregivers should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other unusual changes in behavior, worsening of depression and suicidal ideation, especially early during antidepressant treatment and when the dose is adjusted up or down. Families and caregivers of patients should be advised to look for the emergence of such symptoms on a day-to-day basis, since changes may be abrupt. Such symptoms should be reported to the patient's prescriber or health professional, especially if they are severe, abrupt in onset or were not part of the patient's presenting symptoms. Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior and indicate a need for very close monitoring and possibly changes in the medication.
Neuropsychiatric Symptoms and Suicide Risk in Smoking Cessation Treatment: Although Wellbutrin XL is not indicated for smoking cessation treatment, it contains the same active ingredient as Zyban which is approved for this use. Patients should be informed that quitting smoking, with or without Zyban, may be associated with nicotine withdrawal symptoms (including depression or agitation) or exacerbation of preexisting psychiatric illness. Furthermore, some patients have experienced changes in mood (including depression and mania), psychosis, hallucinations, paranoia, delusions, homicidal ideation, aggression, anxiety and panic, as well as suicidal ideation, suicide attempt and completed suicide when attempting to quit smoking while taking Zyban. If patients develop agitation, hostility, depressed mood or changes in thinking or behavior that are not typical for them, or if patients develop suicidal ideation or behavior, they should be urged to report these symptoms to their healthcare provider immediately.
Patients should be made aware that Wellbutrin XL contains the same active ingredient found in Zyban, used as an aid to smoking cessation treatment and that Wellbutrin XL should not be used in combination with Zyban or any other medications that contain bupropion hydrochloride (eg, Wellbutrin SR, the sustained-release formulation, and Wellbutrin, the immediate-release formulation).
Patients should be told that Wellbutrin XL should be discontinued and not restarted if they experience a seizure while on treatment.
Patients should be told that any central nervous system-active drug like Wellbutrin XL may impair the ability to perform tasks requiring judgment or motor and cognitive skills. Consequently, until they are reasonably certain that Wellbutrin XL do not adversely affect their performance, they should refrain from driving an automobile or operating complex, hazardous machinery.
Patients should be told that the excessive use or abrupt discontinuation of alcohol or sedatives (including benzodiazepines) may alter the seizure threshold. Some patients have reported lower alcohol tolerance during treatment with Wellbutrin XL. Patients should be advised that the consumption of alcohol should be minimized or avoided.
Patients should be advised to inform physicians if they are taking or plan to take any prescription or over-the-counter drugs. Concern is warranted because Wellbutrin XL and other drugs may affect each other's metabolism.
Patients should be advised to notify physicians if they become pregnant or intend to become pregnant during therapy.
Patients should be advised to swallow Wellbutrin XL whole so that the release rate is not altered. Do not chew, divide or crush tablets.
Patients should be advised that they may notice in their stool something that looks like a tablet. This is normal. The medication in Wellbutrin XL is contained in a non-absorbable shell that has been specially designed to slowly release drug in the body. When this process is completed, the empty shell is eliminated from the body.
Laboratory Tests: There are no specific laboratory tests recommended.
Drug Abuse and Dependence: Controlled Substance Class: Bupropion is not a controlled substance.
Humans: Controlled clinical studies of bupropion (immediate-release formulation) conducted in normal volunteers, in subjects with a history of multiple drug abuse and in depressed patients showed some increase in motor activity and agitation/excitement.
In a population of individuals experienced with drugs of abuse, a single dose of bupropion 400 mg produced mild amphetamine-like activity as compared to placebo on the Morphine-Benzedrine Subscale of the Addiction Research Center Inventories (ARCI) and a score intermediate between placebo and amphetamine on the Liking Scale of the ARCI. These scales measure general feelings of euphoria and drug desirability.
Findings in clinical trials, however, are not known to reliably predict the abuse potential of drugs. Nonetheless, evidence from single-dose studies does suggest that the recommended daily dosage of bupropion when administered in divided doses is not likely to be especially reinforcing to amphetamine or stimulant abusers. However, higher doses that could not be tested because of the risk of seizure might be modestly attractive to those who abuse stimulant drugs.
Animals: Studies in rodents and primates have shown that bupropion exhibits some pharmacologic actions common to psychostimulants. In rodents, it has been shown to increase locomotor activity, elicit a mild stereotyped behavioral response and increase rates of responding in several schedule-controlled behavior paradigms. In primate models to assess the positive reinforcing effects of psychoactive drugs, bupropion was self-administered IV. In rats, bupropion produced amphetamine-like and cocaine-like discriminative stimulus effects in drug discrimination paradigms used to characterize the subjective effects of psychoactive drugs.
Carcinogenesis, Mutagenesis, Impairment of Fertility: Lifetime carcinogenicity studies were performed in rats and mice at doses up to 300 and 150 mg/kg/day, respectively. These doses are approximately 7 and 2 times the maximum recommended human dose (MRHD), respectively, on a mg/m² basis. In the rat study, there was an increase in nodular proliferative lesions of the liver at doses of 100-300 mg/kg/day (approximately 2-7 times the MRHD on a mg/m² basis); lower doses were not tested. The question of whether or not such lesions may be precursors of neoplasms of the liver is currently unresolved. Similar liver lesions were not seen in the mouse study, and no increase in malignant tumors of the liver and other organs was seen in either study.
Bupropion produced a positive response (2-3 times control mutation rate) in 2 of 5 strains in the Ames bacterial mutagenicity test and an increase in chromosomal aberrations in 1 of 3 in vivo rat bone marrow cytogenetic studies.
A fertility study in rats at doses up to 300 mg/kg/day revealed no evidence of impaired fertility.
Use in children: Safety and effectiveness in the pediatric population have not been established (see Clinical Worsening and Suicide Risk under Warnings). Anyone considering the use of Wellbutrin XL in a child or adolescent must balance the potential risks with the clinical need.
Use in the elderly: Of the approximately 6,000 patients who participated in clinical trials with bupropion sustained-release tablets (depression and smoking cessation studies), 275 were ≥65 years old and 47 were ≥75 years old. In addition, several hundred patients ≥65 years participated in clinical trials using the immediate-release formulation of bupropion (depression studies). No overall differences in safety or effectiveness were observed between these subjects and younger subjects. Reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.
A single-dose pharmacokinetic study demonstrated that the disposition of bupropion and its metabolites in elderly subjects was similar to that of younger subjects; however, another pharmacokinetic study, single and multiple dose, has suggested that the elderly are at increased risk for accumulation of bupropion and its metabolites (see Pharmacology under Actions).
Bupropion is extensively metabolized in the liver to active metabolites, which are further metabolized and excreted by the kidneys. The risk of toxic reaction to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection and it may be useful to monitor renal function (see Dosage & Administration and Precautions).

Wellbutrin SR: Pregnancy: The prescribing physician will need to weigh the option of alternative treatments in women who are pregnant or are planning to become pregnant and should only prescribe bupropion if the expected benefits are greater than the potential risks.
Some epidemiological studies of pregnancy outcomes following maternal exposure to bupropion in the first trimester have reported an association with increased risk of some congenital cardiovascular malformations. These findings are not consistent across studies.
Risk Summary: Data from epidemiological studies of pregnant women exposed to bupropion in the first trimester indicate no increased risk of congenital malformations overall. All pregnancies, regardless of drug exposure, have a background rate of 2% to 4% for major malformations, and 15% to 20% for pregnancy loss. No clear evidence of teratogenic activity was found in reproductive developmental studies conducted in rats and rabbits; however, in rabbits, slightly increased incidences of fetal malformations and skeletal variations were observed at doses approximately equal to the maximum recommended human dose (MRHD) and greater and decreased fetal weights were seen at doses twice the MRHD and greater. WELLBUTRIN SR should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Clinical Considerations: Consider the risks of untreated depression when discontinuing or changing treatment with antidepressant medications during pregnancy and postpartum.
Human Data: Data from the international bupropion Pregnancy Registry (675 first trimester exposures) and a retrospective cohort study using the United Healthcare database (1,213 first trimester exposures) did not show an increased risk for malformations overall.
No increased risk for cardiovascular malformations overall has been observed after bupropion exposure during the first trimester. The prospectively observed rate of cardiovascular malformations in pregnancies with exposure to bupropion in the first trimester from the international Pregnancy Registry was 1.3% (9 cardiovascular malformations/675 first-trimester maternal bupropion exposures), which is similar to the background rate of cardiovascular malformations (approximately 1%). Data from the United Healthcare database and a case-control study (6,853 infants with cardiovascular malformations and 5,763 with non-cardiovascular malformations) from the National Birth Defects Prevention Study (NBDPS) did not show an increased risk for cardiovascular malformations overall after bupropion exposure during the first trimester.
Study findings on bupropion exposure during the first trimester and risk for left ventricular outflow tract obstruction (LVOTO) are inconsistent and do not allow conclusions regarding a possible association. The United Healthcare database lacked sufficient power to evaluate this association; the NBDPS found increased risk for LVOTO (n = 10; adjusted OR = 2.6; 95% CI: 1.2, 5.7), and the Slone Epidemiology case control study did not find increased risk for LVOTO.
Study findings on bupropion exposure during the first trimester and risk for ventricular septal defect (VSD) are inconsistent and do not allow conclusions regarding a possible association. The Slone Epidemiology Study found an increased risk for VSD following first trimester maternal bupropion exposure (n = 17; adjusted OR = 2.5; 95% CI: 1.3, 5.0) but did not find increased risk for any other cardiovascular malformations studied (including LVOTO as previously mentioned). The NBDPS and United Healthcare database study did not find an association between first trimester maternal bupropion exposure and VSD.
For the findings of LVOTO and VSD, the studies were limited by the small number of exposed cases, inconsistent findings among studies, and the potential for chance findings from multiple comparisons in case control studies.
Animal Data: In studies conducted in rats and rabbits, bupropion was administered orally during the period of organogenesis at doses of up to 450 and 150 mg per kg per day, respectively (approximately 11 and 7 times the MRHD, respectively, on a mg per m² basis). No clear evidence of teratogenic activity was found in either species; however, in rabbits, slightly increased incidences of fetal malformations and skeletal variations were observed at the lowest dose tested (25 mg per kg per day, approximately equal to the MRHD on a mg per m² basis) and greater. Decreased fetal weights were observed at 50 mg per kg and greater.
When rats were administered bupropion at oral doses of up to 300 mg per kg per day (approximately 7 times the MRHD on a mg per m² basis) prior to mating and throughout pregnancy and lactation, there were no apparent adverse effects on offspring development.
Nursing Mothers: Bupropion and its metabolites are present in human milk. In a lactation study of 10 women, levels of orally dosed bupropion and its active metabolites were measured in expressed milk. The average daily infant exposure (assuming 150 mL per kg daily consumption) to bupropion and its active metabolites was 2% of the maternal weight-adjusted dose. Exercise caution when WELLBUTRIN SR is administered to a nursing woman.
Wellbutrin XL: Use in pregnancy: Teratogenic Effects: Pregnancy Category C: In studies conducted in rats and rabbits, bupropion was administered orally at doses up to 450 and 150 mg/kg/day, respectively (approximately 11 and 7 times the MRHD, respectively, on a mg/m² basis), during the period of organogenesis. No clear evidence of teratogenic activity was found in either species; however, in rabbits, slightly increased incidences of fetal malformations and skeletal variations were observed at the lowest dose tested (25 mg/kg/day, approximately equal to the MRHD on a mg/m² basis) and greater. Decreased fetal weights were seen at ≥50 mg/kg.
When rats were administered bupropion at oral doses of up to 300 mg/kg/day (approximately 7 times the MRHD on a mg/m² basis) prior to mating and throughout pregnancy and lactation, there were no apparent adverse effects on offspring development.
One (1) study has been conducted in pregnant women. This retrospective, managed-care database study assessed the risk of congenital malformations overall, and cardiovascular malformations specifically, following exposure to bupropion in the 1st trimester compared to the risk of these malformations following exposure to other antidepressants in the 1st trimester and bupropion outside of the 1st trimester. This study included 7,005 infants with antidepressant exposure during pregnancy, 1,213 of whom were exposed to bupropion in the 1st trimester. The study showed no greater risk for congenital malformations overall, or cardiovascular malformations specifically, following 1st trimester bupropion exposure compared to exposure to all other antidepressants in the 1st trimester or bupropion outside of the 1st trimester. The results of this study have not been corroborated. Wellbutrin XL should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
In a retrospective, case-control analysis using data from the National Birth Defects Prevention Study, there were 12,383 case infants and 5,869 control infants. A statistically significant association was observed between the occurrence of a left outflow tract heart defect in the infant and self-reported maternal bupropion use in early pregnancy (n=10; adjusted OR=2.6; 95% CI 1.2, 5.7). No association was observed between maternal bupropion use and any other type of cardiac defect or with all categories of heart defects combined.
A further case-control analysis of data from the Slone Epidemiology Center Birth Defects Study included 7,913 infant cases of cardiac defects and 8,611 controls. This found no statistically significant increase of left outflow tract heart defects with maternal bupropion use (n=2; adjusted OR=0.4; 95% CI 0.1, 1.6). However, a statistically significant association was observed for ventricular septal defects (n=17; adjusted OR=2.5; 95% CI 1.3, 5) following the use of bupropion alone during the 1st trimester.
Labor and Delivery: The effect of Wellbutrin XL on labor and delivery in humans is unknown.
Use in lactation: Like many other drugs, bupropion and its metabolites are secreted in human milk. Because of the potential for serious adverse reactions in nursing infants from Wellbutrin XL, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Wellbutrin SR: The following adverse reactions are discussed in greater detail in Precautions: Suicidal thoughts and behaviours in adolescents and young adults; Neuropsychiatric symptoms and suicide risk in smoking cessation treatment; Seizure; Hypertension; Activation of mania or hypomania; Psychosis and other neuropsychiatric reactions; Angle-closure glaucoma; Hypersensitivity reactions.
Clinical Trials Experience: Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
Adverse Reactions Leading to Discontinuation of Treatment: In placebo-controlled clinical trials, 4%, 9%, and 11% of the placebo, 300-mg-per-day, and 400-mg-per-day groups, respectively, discontinued treatment due to adverse reactions. The specific adverse reactions leading to discontinuation in at least 1% of the 300-mg-per-day or 400-mg-per-day groups and at a rate at least twice the placebo rate are listed in Table 9. (See Table 9.)

Click on icon to see table/diagram/image

Commonly Observed Adverse Reactions: Adverse reactions from Table 10 occurring in at least 5% of subjects treated with WELLBUTRIN SR and at a rate at least twice the placebo rate are listed as follows for the 300- and 400-mg-per-day dose groups.
WELLBUTRIN SR 300 mg per day: Anorexia, dry mouth, rash, sweating, tinnitus, and tremor.
WELLBUTRIN SR 400 mg per day: Abdominal pain, agitation, anxiety, dizziness, dry mouth, insomnia, myalgia, nausea, palpitation, pharyngitis, sweating, tinnitus, and urinary frequency.
Adverse reactions reported in placebo-controlled trials are presented in Table 10. Reported adverse reactions were classified using a COSTART-based Dictionary. (See Table 10.)

Click on icon to see table/diagram/image

Other Adverse Reactions Observed during the Clinical Development of Bupropion: In addition to the adverse reactions noted previously, the following adverse reactions have been reported in clinical trials with the sustained-release formulation of bupropion in depressed subjects and in nondepressed smokers, as well as in clinical trials with the immediate-release formulation of bupropion.
Adverse reaction frequencies represent the proportion of subjects who experienced a treatment-emergent adverse reaction on at least one occasion in placebo-controlled trials for depression (n = 987) or smoking cessation (n = 1,013), or subjects who experienced an adverse reaction requiring discontinuation of treatment in an open-label surveillance trial with WELLBUTRIN SR (n = 3,100). All treatment-emergent adverse reactions are included except those listed in Table 10, those listed in other safety-related sections of the prescribing information, those subsumed under COSTART terms that are either overly general or excessively specific so as to be uninformative, those not reasonably associated with the use of the drug, and those that were not serious and occurred in fewer than 2 subjects.
Adverse reactions are further categorized by body system and listed in order of decreasing frequency according to the following definitions of frequency: Frequent adverse reactions are defined as those occurring in at least 1/100 subjects. Infrequent adverse reactions are those occurring in 1/100 to 1/1,000 subjects, while rare events are those occurring in less than 1/1,000 subjects.
Body (General): Infrequent were chills, facial edema and photosensitivity. Rare was malaise.
Cardiovascular: Infrequent were postural hypotension, stroke, tachycardia and vasodilation. Rare were syncope and myocardial infarction.
Digestive: Infrequent were abnormal liver function, bruxism, gastric reflux, gingivitis, increased salivation, jaundice, mouth ulcers, stomatitis, and thirst. Rare was edema of tongue.
Hemic and Lymphatic: Infrequent was ecchymosis.
Metabolic and Nutritional: Infrequent were edema and peripheral edema.
Musculoskeletal: Infrequent were leg cramps.
Nervous System: Infrequent were abnormal coordination, decreased libido, depersonalization, dysphoria, emotional lability, hostility, hyperkinesia, hypertonia, hypesthesia, suicidal ideation, and vertigo. Rare were amnesia, ataxia, derealization, and hypomania.
Respiratory: Rare was bronchospasm.
Special Senses: Infrequent were accommodation abnormality and dry eye.
Urogenital: Infrequent were impotence, polyuria, and prostate disorder.
Changes in Body Weight: In placebo-controlled trials, subjects experienced weight gain or weight loss as shown in Table 11. (See Table 11.)

Click on icon to see table/diagram/image

In clinical trials conducted with the immediate-release formulation of bupropion, 35% of subjects receiving tricyclic antidepressants gained weight, compared with 9% of subjects treated with the immediate-release formulation of bupropion. If weight loss is a major presenting sign of a patient's depressive illness, the anorectic and/or weight-reducing potential of WELLBUTRIN SR should be considered.
Postmarketing Experience: The following adverse reactions have been identified during post-approval use of WELLBUTRIN SR and are not described elsewhere in the label. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Body (General): Arthralgia, myalgia, and fever with rash and other symptoms suggestive of delayed hypersensitivity. These symptoms may resemble serum sickness (see Precautions).
Cardiovascular: Complete atrioventricular block, extrasystoles, hypotension, hypertension (in some cases severe), phlebitis, and pulmonary embolism.
Digestive: Colitis, esophagitis, gastrointestinal hemorrhage, gum hemorrhage, hepatitis, intestinal perforation, pancreatitis, and stomach ulcer.
Endocrine: Hyperglycemia, hypoglycemia, hyponatremia, and syndrome of inappropriate antidiuretic hormone secretion.
Hemic and Lymphatic: Anemia, leukocytosis, leukopenia, lymphadenopathy, pancytopenia, and thrombocytopenia. Altered PT and/or INR, infrequently associated with hemorrhagic or thrombotic complications, were observed when bupropion was coadministered with warfarin.
Metabolic and Nutritional: Glycosuria.
Musculoskeletal: Muscle rigidity/fever/rhabdomyolysis and muscle weakness.
Nervous System: Abnormal electroencephalogram (EEG), aggression, akinesia, aphasia, coma, completed suicide, delirium, delusions, dysarthria, euphoria, extrapyramidal syndrome (dyskinesia, dystonia, hypokinesia, parkinsonism), hallucinations, increased libido, manic reaction, neuralgia, neuropathy, paranoid ideation, restlessness, suicide attempt, and unmasking tardive dyskinesia.
Respiratory: Pneumonia.
Skin: Alopecia, angioedema, exfoliative dermatitis, hirsutism and Stevens-Johnson syndrome.
Special Senses: Deafness, increased intraocular pressure and mydriasis.
Urogenital: Abnormal ejaculation, cystitis, dyspareunia, dysuria, gynecomastia, menopause, painful erection, salpingitis, urinary incontinence, urinary retention and vaginitis.
Wellbutrin XL: Major Depressive Disorder: Wellbutrin XL has been demonstrated to have similar bioavailability both to the immediate-release formulation of bupropion and to the sustained-release formulation of bupropion (see Pharmacology under Actions). The information included under this subsection is based primarily on data from controlled clinical trials with Wellbutrin SR, the sustained-release formulation of bupropion.
Adverse Events Leading to Discontinuation of Treatment With Wellbutrin or Wellbutrin SR: In placebo-controlled clinical trials, 9% and 11% of patients treated with 300 and 400 mg/day, respectively, of the sustained-release formulation of bupropion and 4% of patients treated with placebo discontinued treatment due to adverse events. The specific adverse events in these trials that led to discontinuation in at least 1% of patients treated with either 300 mg/day or 400 mg/day of Wellbutrin SR and at a rate at least twice the placebo rate are listed in Table 12. (See Table 12.)

Click on icon to see table/diagram/image

In clinical trials with the immediate-release formulation of bupropion, 10% of patients and volunteers discontinued due to an adverse event. Events resulting in discontinuation, in addition to those listed previously for the sustained-release formulation of bupropion, include vomiting, seizures and sleep disturbances.
Adverse Events Occurring at an Incidence of ≥1% Among Patients Treated With Wellbutrin or Wellbutrin SR: Table 13 enumerates treatment-emergent adverse events that occurred among patients treated with 300 and 400 mg/day of the sustained-release formulation of bupropion and with placebo in controlled trials. Events that occurred in either the 300- or 400-mg/day group at an incidence of ≥1% and were more frequent than in the placebo group are included. Reported adverse events were classified using a COSTART-based dictionary.
Accurate estimates of the incidence of adverse events associated with the use of any drug are difficult to obtain. Estimates are influenced by drug dose, detection technique, setting, physician judgments, etc. The figures cited cannot be used to predict precisely the incidence of untoward events in the course of usual medical practice where patient characteristics and other factors differ from those that prevailed in the clinical trials. These incidence figures also cannot be compared with those obtained from other clinical studies involving related drug products as each group of drug trials is conducted under a different set of conditions.
Finally, it is important to emphasize that the tabulation does not reflect the relative severity and/or clinical importance of the events. A better perspective on the serious adverse events associated with the use of bupropion is provided in the Warnings and Precautions sections. (See Table 13.)

Click on icon to see table/diagram/image

Additional events to those listed in Table 13 that occurred at an incidence of at least 1% in controlled clinical trials of the immediate-release formulation of bupropion (300-600 mg/day) and that were numerically more frequent than placebo were: Cardiac arrhythmias (5% vs 4%), hypertension (4% vs 2%), hypotension (3% vs 2%), tachycardia (11% vs 9%), appetite increase (4% vs 2%), dyspepsia (3% vs 2%), menstrual complaints (5% vs 1%), akathisia (2% vs 1%), impaired sleep quality (4% vs 2%), sensory disturbance (4% vs 3%), confusion (8% vs 5%), decreased libido (3% vs 2%), hostility (6% vs 4%), auditory disturbance (5% vs 3%) and gustatory disturbance (3% vs 1%).
Incidence of Commonly Observed Adverse Events in Controlled Clinical Trials: Adverse events from Table 13 occurring in at least 5% of patients treated with the sustained-release formulation of bupropion and at a rate at least twice the placebo rate are listed as follows for the 300- and 400-mg/day dose groups.
Wellbutrin SR 300 mg/day: Anorexia, dry mouth, rash, sweating, tinnitus and tremor.
Wellbutrin SR 400 mg/day: Abdominal pain, agitation, anxiety, dizziness, dry mouth, insomnia, myalgia, nausea, palpitation, pharyngitis, sweating, tinnitus and urinary frequency.
Seasonal Affective Disorder: Adverse Events Leading to Discontinuation of Treatment with Wellbutrin XL: In placebo-controlled clinical trials, 9% of patients treated with Wellbutrin XL and 5% of patients treated with placebo discontinued treatment due to adverse events. The adverse events in these trials that led to discontinuation in at least 1% of patients treated with Wellbutrin XL and at a rate numerically greater than the placebo rate are insomnia (2% vs <1%) and headache (1% vs <1%).
Adverse Events Occurring at an Incidence of ≥2% Among Patients Treated With Wellbutrin XL: Table 14 enumerates treatment-emergent adverse events that occurred among patients treated with Wellbutrin XL for up to approximately 6 months in 3 placebo-controlled trials. Events that occurred at an incidence of ≥2% and were more frequent than in the placebo group are included. Reported adverse events were classified using a MedDRA-based dictionary.
Accurate estimates of the incidence of adverse events associated with the use of any drug are difficult to obtain. Estimates are influenced by drug dose, detection technique, setting, physician judgments, etc. The figures cited cannot be used to predict precisely the incidence of untoward events in the course of usual medical practice where patient characteristics and other factors differ from those that prevailed in the clinical trials. These incidence figures also cannot be compared with those obtained from other clinical studies involving related drug products as each group of drug trials is conducted under a different set of conditions; eg, different patient populations, different treatment durations.
Finally, it is important to emphasize that the tabulation does not reflect the relative severity and/or clinical importance of the events. A better perspective on the serious adverse events associated with the use of bupropion is provided in the Warnings and Precautions sections. (See Table 14.)

Click on icon to see table/diagram/image

Incidence of Commonly Observed Adverse Events in Controlled Clinical Trials: Adverse events from Table 14 that occurred in at least 5% of patients treated with Wellbutrin XL and at a rate at least twice the placebo rate were constipation and flatulence.
Adverse Events During Taper or Following Discontinuation of Wellbutrin XL: Adverse events with onset during the 2 weeks following down-titration of Wellbutrin XL from 300 mg/day to 150 mg/day were reported by 14% of patients compared to 18% of patients who continued on placebo.
Adverse events with onset during the 2 weeks following discontinuation of Wellbutrin XL were reported by 9% of patients compared with 12% of patients following discontinuation of placebo.
Other Events Observed During the Clinical Development and Post-Marketing Experience of Bupropion: In addition to the adverse events noted previously, the following events have been reported in clinical trials and post-marketing experience with the sustained-release formulation of bupropion in depressed patients and in nondepressed smokers, as well as in clinical trials and post-marketing clinical experience with the immediate-release formulation of bupropion.
Adverse events for which frequencies are provided as follows occurred in clinical trials with the sustained-release formulation of bupropion. The frequencies represent the proportion of patients who experienced a treatment-emergent adverse event on at least 1 occasion in placebo-controlled studies for depression (n=987) or smoking cessation (n=1,013) or patients who experienced an adverse event requiring discontinuation of treatment in an open-label surveillance study with the sustained-release formulation of bupropion (n=3,100). All treatment-emergent adverse events are included except those listed in Tables 5, 6, 7, 8, 12, 13 and 14, those events listed in other safety-related sections, those adverse events subsumed under COSTART terms that are either overly general or excessively specific so as to be uninformative, those events not reasonably associated with the use of the drug and those events that were not serious and occurred in fewer than 2 patients. Events of major clinical importance are described in the Warnings and Precautions sections.
Events are further categorized by body system and listed in order of decreasing frequency according to the following definitions of frequency: Frequent adverse events are defined as those occurring in at least 1/100 patients. Infrequent adverse events are those occurring in 1/100 to 1/1,000 patients, while rare events are those occurring in <1/1,000 patients.
Adverse events for which frequencies are not provided occurred in clinical trials or post-marketing experience with bupropion. Only those adverse events not previously listed for sustained-release bupropion are included. The extent to which these events may be associated with Wellbutrin XL is unknown.
Body (General): Infrequent were chills, facial edema, musculoskeletal chest pain and photosensitivity. Rare was malaise. Also observed were arthralgia, myalgia and fever with rash and other symptoms suggestive of delayed hypersensitivity. These symptoms may resemble serum sickness (see Precautions).
Cardiovascular: Infrequent were postural hypotension, stroke, tachycardia and vasodilation. Rare was syncope. Also observed were complete atrioventricular block, extrasystoles, hypotension, hypertension (in some cases severe, see Precautions), myocardial infarction, phlebitis and pulmonary embolism.
Digestive: Infrequent were abnormal liver function, bruxism, gastric reflux, gingivitis, glossitis, increased salivation, jaundice, mouth ulcers, stomatitis and thirst. Rare was edema of tongue. Also observed were colitis, esophagitis, gastrointestinal hemorrhage, gum hemorrhage, hepatitis, intestinal perforation, liver damage, pancreatitis and stomach ulcer.
Endocrine: Also observed were hyperglycemia, hypoglycemia and syndrome of inappropriate antidiuretic hormone (SIADH).
Hemic and Lymphatic: Infrequent was ecchymosis. Also observed were anemia, leukocytosis, leukopenia, lymphadenopathy, pancytopenia and thrombocytopenia. Altered prothrombin time (PT) and/or international normalized ratio (INR), infrequently associated with hemorrhagic or thrombotic complications, were observed when bupropion was co-administered with warfarin.
Metabolic and Nutritional: Infrequent were edema and peripheral edema. Also observed was glycosuria.
Musculoskeletal: Infrequent were leg cramps. Also observed were muscle rigidity/fever/rhabdomyolysis and muscle weakness.
Nervous System: Infrequent were abnormal coordination, decreased libido, depersonalization, dysphoria, emotional lability, hostility, hyperkinesia, hypertonia, hypesthesia, suicidal ideation and vertigo. Rare were amnesia, ataxia, derealization and hypomania. Also observed were abnormal EEG, aggression, akinesia, aphasia, coma, delirium, delusions, dysarthria, dyskinesia, dystonia, euphoria, extrapyramidal syndrome, hallucinations, hypokinesia, increased libido, manic reaction, neuralgia, neuropathy, paranoid ideation, restlessness and unmasking tardive dyskinesia.
Respiratory: Rare was bronchospasm. Also observed was pneumonia.
Skin: Rare was maculopapular rash. Also observed were alopecia, angioedema, exfoliative dermatitis and hirsutism.
Special Senses: Infrequent were accommodation abnormality and dry eye. Also observed were deafness, diplopia, increased intraocular pressure and mydriasis.
Urogenital: Infrequent were impotence, polyuria and prostate disorder. Also observed were abnormal ejaculation, cystitis, dyspareunia, dysuria, gynecomastia, menopause, painful erection, salpingitis, urinary incontinence, urinary retention and vaginitis.

Wellbutrin SR: Potential for other drugs to affect WELLBUTRIN SR: Bupropion is primarily metabolized to hydroxbupropion by CYP2B6. Therefore, the potential exists for drug interactions between WELLBUTRIN SR and drugs that are inhibitors or inducers of CYP2B6.
Inhibitors of CYP2B6: Ticlopidine and Clopidogrel: Concomitant treatment with these drugs can increase bupropion exposure but decrease hydroxybupropion exposure. Based on clinical response, dosage adjustment of WELLBUTRIN SR may be necessary when coadministered with CYP2B6 inhibitors (e.g. ticlopidine or clopidogrel) (see Pharmacology: Pharmacokinetics: Drug Interactions under Actions).
Inducers of CYP2B6: Ritonavir, Lopinavir and Efavirenz: Concomitant treatment with these drugs can decrease bupropion and hydroxybupropion exposure. Dosage increase of WELLBUTRIN SR may be necessary when coadministered with ritonavir, lopinarvir or efavirenz (see Pharmacology: Pharmacokinetics: Drug Interactions under Actions) but should not exceed the maximum recommended dose.
Carbamazepine, Phenobarbital, Phenytoin: While not systematically studied, these drugs may induce the metabolism of bupropion and may decrease bupropion exposure (see Pharmacology: Pharmacokinetics: Drug Interactions under Actions). If bupropion is used concomitantly with a CYP inducer, it may be necessary to increase the dose of bupropion, but the maximum recommended dose should not be exceeded.
Potential for WELLBUTRIN SR to affect other drugs: Drugs metabolized by CYP2D6: Bupropion and its metabolites (erythrohydrobupropion, threohydrobupropion, hydrobupropion) are CYP2D6 inhibitors. Therefore, coadministration of WELLBUTRIN SR with drugs that are metabolized by CYP2D6 can increase the exposures of drugs that are substrates of CYP2D6. Such drugs include certain antidepressants (e.g. venlafaxine, nortriptyline, imipramine, desipramine, paroxetine, fluoxetine, and sertraline), antipsychotics (e.g. haloperidol, risperidone, thioridazine), beta-blockers (e.g. metoprolol), and Type 1C antiarrhythmics (e.g. propafenone and flecainide). When used concomitantly with WELLBUTRIN SR, it may be necessary to decrease the dose of these CYP2D6 substrates, particularly for drugs with a narrow therapeutic index.
Drugs that require metabolic activation by CYP2D6 to be effective (e.g. tamoxifen) theoretically could have reduced efficacy when administered concomitantly with inhibitors of CYP2D6 such as bupropion. Patients treated concomitantly with WELLBUTRIN SR and such drugs may require increased doses of the drug (see Pharmacology: Pharmacokinetics: Drug Interactions under Actions).
Digoxin: Coadministration of WELLBUTRIN SR with digoxin may decrease plasma digoxin levels. Monitor plasma digoxin levels in patients treated concomitantly with WELLBUTRIN SR and digoxin (see Pharmacology: Pharmacokinetics: Drug Interactions under Actions).
Drugs that lower seizure threshold: Use extreme caution when coadministering WELLBUTRIN SR with other drugs that lower seizure threshold (e.g. other bupropion products, antipsychotics, antidepressants, theophylline or systemic corticosteroids). Use low initial doses and increase the dose gradually (see Contraindications and Precautions).
Dopaminergic Drugs (Levodopa and Amantadine): Bupropion, levodopa, and amantadine have dopamine agonist effects. CNS toxicity has been reported when bupropion was coadministered with levodopa or amantadine. Adverse reactions have included restlessness, agitation, tremor, ataxia, gait disturbance, vertigo, and dizziness. It is presumed that the toxicity results from cumulative dopamine agonist effects. Use caution when administering WELLBUTRIN SR concomitantly with these drugs.
Use with alcohol: In postmarketing experience, there have been rare reports of adverse neuropsychiatric events or reduced alcohol tolerance in patients who were drinking alcohol during treatment with WELLBUTRIN SR. The consumption of alcohol during treatment with WELLBUTRIN SR should be minimized or avoided.
MAO Inhibitors: Bupropion inhibits the reuptake of dopamine and norepinephrine. Concomitant use of MAOIs and bupropion is contraindicated because there is an increased risk of hypertensive reactions if bupropion is used concomitantly with MAOIs. Studies in animals demonstrate that the acute toxicity of bupropion is enhanced by the MAO inhibitor phenelzine. At least 14 days should elapse between discontinuation of an MAOI intended to treat depression and initiation of treatment with WELLBUTRIN SR. Conversely, at least 14 days should be allowed after stopping WELLBUTRIN SR before starting an MAOI antidepressant (see Dosage & Administration and Contraindications).
Drug-Laboratory Test Interactions: False-positive urine immunoassay screening tests for amphetamines have been reported in patients taking bupropion. This is due to lack of specificity of some screening tests. False-positive test results may result even following discontinuation of bupropion therapy. Confirmatory tests, such as gas chromatography/mass spectrometry, will distinguish bupropion from amphetamines.
Wellbutrin XL: Few systemic data have been collected on the metabolism of bupropion following concomitant administration with other drugs or, alternatively, the effect of concomitant administration of bupropion on the metabolism of other drugs.
Because bupropion is extensively metabolized, the co-administration of other drugs may affect its clinical activity. In vitro studies indicate that bupropion is primarily metabolized to hydroxybupropion by the CYP2B6 isoenzyme. Therefore, the potential exists for a drug interaction between Wellbutrin XL and drugs that are substrates of or inhibitors/inducers of the CYP2B6 isoenzyme (eg, orphenadrine, thiotepa, cyclophosphamide, ticlopidine and clopidogrel). In addition, in vitro studies suggest that paroxetine, sertraline, norfluoxetine and fluvoxamine as well as nelfinavir and efavirenz inhibit the hydroxylation of bupropion. No clinical studies have been performed to evaluate this finding. The threohydrobupropion metabolite of bupropion does not appear to be produced by the cytochrome P-450 isoenzymes. The effects of concomitant administration of cimetidine on the pharmacokinetics of bupropion and its active metabolites were studied in 24 healthy young male volunteers. Following oral administration of two 150-mg tablets of the sustained-release formulation of bupropion with and without cimetidine 800 mg, the pharmacokinetics of bupropion and hydroxybupropion were unaffected. However, there were 16% and 32% increases in the AUC and C_max, respectively, of the combined moieties of threohydrobupropion and erythrohydrobupropion.
In a series of studies in healthy volunteers, ritonavir (100 mg twice daily or 600 mg twice daily) or ritonavir 100 mg plus lopinavir (Kaletra) 400 mg twice daily reduced the exposure of bupropion and its major metabolites in a dose-dependent manner by approximately 20-80%. Similarly, efavirenz 600 mg once daily for 2 weeks reduced the exposure of bupropion by approximately 55%. This effect of ritonavir, Kaletra and efavirenz is thought to be due to the induction of bupropion metabolism. Patients receiving any of these drugs with bupropion may need increased doses of bupropion, but the maximum recommended dose of bupropion should not be exceeded (see Pharmacology under Actions).
While not systematically studied, certain drugs may induce the metabolism of bupropion (eg, carbamazepine, phenobarbital, phenytoin).
Multiple oral doses of bupropion had no statistically significant effects on the single dose pharmacokinetics of lamotrigine in 12 healthy volunteers.
Animal data indicated that bupropion may be an inducer of drug-metabolizing enzymes in humans. In 1 study, following chronic administration of bupropion, 100 mg 3 times daily to 8 healthy male volunteers for 14 days, there was no evidence of induction of its own metabolism. Nevertheless, there may be the potential for clinically important alterations of blood levels of co-administered drugs.
Drugs Metabolized By Cytochrome P450IID6 (CYP2D6): Many drugs, including most antidepressants (SSRIs, many tricyclics), β-blockers, antiarrhythmics and antipsychotics are metabolized by the CYP2D6 isoenzyme. Although bupropion is not metabolized by this isoenzyme, bupropion and hydroxybupropion are inhibitors of CYP2D6 isoenzyme in vitro. In a study of 15 male subjects (ages 19-35 years) who were extensive metabolizers of the CYP2D6 isoenzyme, daily doses of bupropion given as 150 mg twice daily followed by a single dose of desipramine 50 mg increased the C_max, AUC and t_½ of desipramine by an average of approximately 2-, 5- and 2-fold, respectively. The effect was present for at least 7 days after the last dose of bupropion. Concomitant use of bupropion with other drugs metabolized by CYP2D6 has not been formally studied.
Therefore, co-administration of bupropion with drugs that are metabolized by CYP2D6 isoenzyme including certain antidepressants (eg, nortriptyline, imipramine, desipramine, paroxetine, fluoxetine, sertraline), antipsychotics (eg, haloperidol, risperidone, thioridazine), β-blockers (eg, metoprolol) and type 1C antiarrhythmics (eg, propafenone, flecainide), should be approached with caution and should be initiated at the lower end of the dose range of the concomitant medication. If bupropion is added to the treatment regimen of a patient already receiving a drug metabolized by CYP2D6, the need to decrease the dose of the original medication should be considered, particularly for those concomitant medications with a narrow therapeutic index.
Drugs which require metabolic activation by CYP2D6 in order to be effective (eg, tamoxifen) theorectically could have reduced efficacy when administered concomitantly with inhibitors of CYP2D6 eg, bupropion.
Although citalopram is not primarily metabolized by CYP2D6, in 1 study, bupropion increased the C_max and AUC of citalopram by 30% and 40%, respectively. Citalopram did not affect the pharmacokinetics of bupropion and its 3 metabolites.
Monoamine Oxidase (MAO) Inhibitors: Studies in animals demonstrate that the acute toxicity of bupropion is enhanced by the MAO inhibitor phenelzine (see Contraindications).
Levodopa and Amantadine: Limited clinical data suggest a higher incidence of adverse experiences in patients receiving bupropion concurrently with either levodopa or amantadine. Administration of Wellbutrin XL to patients receiving either levodopa or amantadine concurrently should be undertaken with caution, using small initial doses and gradual dose increases.
Drugs that Lower Seizure Threshold: Concurrent administration of Wellbutrin XL and agents (eg, antipsychotics, other antidepressants, theophylline, systemic steroids, etc) that lower seizure threshold should be undertaken only with extreme caution (see Warnings). Low initial dosing and gradual dose increases should be employed.
Nicotine Transdermal System (NTS): See Precautions.
Alcohol: In post-marketing experience, there have been rare reports of adverse neuropsychiatric events or reduced alcohol tolerance in patients who were drinking alcohol during treatment with bupropion. The consumption of alcohol during treatment with Wellbutrin XL should be minimized or avoided (see Contraindications).
Drug-Laboratory Test Interactions: False-positive urine immunoassay screening tests for amphetamines have been reported in patients taking bupropion. This is due to lack of specificity of some screening tests. False-positive test results may result even following discontinuation of bupropion therapy. Confirmatory tests eg, gas chromatography/mass spectrometry, will distinguish bupropion from amphetamines.
Serotonergic psychiatric drugs should not be started in a patient receiving linezolid. Wait until 24 hrs after the last dose of linezolid before starting the serotonergic psychiatric drugs.

Antidepressants

N06AX12 - bupropion ; Belongs to the class of other antidepressants.

P₁S₁S₃