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Mechanism Of Action
The exact mechanism by which ZYBAN enhances the ability of patients to abstain from smoking 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.
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.
The absolute bioavailability of ZYBAN 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 ZYBAN, peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours.
ZYBAN can be taken with or without food. Bupropion Cmax and AUC was increased by 11% to 35%, and 16% to 19%, respectively, when ZYBAN was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant.
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.
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 ZYBAN in humans, Cmax 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.
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.
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 Cmax 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. ZYBAN should be used with caution in patients with renal impairment and a reduced frequency and/or dose should be considered [see Use in Specific Populations].
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, Cmax, and Tmax) and its active metabolites (t½) in subjects with mild–to-moderate hepatic cirrhosis. In 8 subjects with severe hepatic cirrhosis, significant alterations in the pharmacokinetics of bupropion and its metabolites were seen (Table 4).
Table 4: Pharmacokinetics of Bupropion and Metabolites
in Patients with Severe Hepatic Cirrhosis: Ratio Relative to Healthy Matched
|Threo/erythrohydrobupropi on amino alcohol||0.69||2.48||1.96||20 h|
|a = Difference.|
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 ZYBAN, there were no statistically significant differences in Cmax, half-life, Tmax, AUC, or clearance of bupropion or its major metabolites between smokers and nonsmokers.
In a trial comparing the treatment combination of ZYBAN and NTS versus ZYBAN alone, no statistically significant differences were observed between the 2 treatment groups of combination ZYBAN and NTS (n = 197) and ZYBAN alone (n = 193) in the plasma concentrations of bupropion or its active metabolites at Weeks 3 and 6.
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 Specific Populations].
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.
Potential for Other Drugs to Affect ZYBAN: In vitro studies indicate that bupropion is primarily metabolized to hydroxybupropion by CYP2B6. Therefore, the potential exists for drug interactions between ZYBAN 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 (Cmax and AUC) of bupropion by 40% and 60% for clopidogrel, and by 38% and 85% for ticlopidine, respectively. The exposures (Cmax 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 Cmax and AUC values by 14% and 18%, respectively, and decreased Cmax 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 Cmax, respectively, of the combined moieties of threohydrobupropion and erythrohydrobupropion.
Citalopram: Citalopram did not affect the pharmacokinetics of bupropion and its 3 metabolites.
Inducers of CYP2B6: Ritonavir and Lopinavir: In a healthy volunteer trial, ritonavir 100 mg twice daily reduced the AUC and Cmax 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 Cmax 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 Cmax by 57%. The AUC and Cmax 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 Cmax of bupropion by approximately 55% and 34%, respectively.
The AUC of hydroxybupropion was unchanged, whereas Cmax of hydroxybupropion was increased by 50%.
Carbamazepine, Phenobarbital, Phenytoin: While not systematically studied, these drugs may induce the metabolism of bupropion.
Potential for ZYBAN 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 Cmax, AUC, and t½ 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 Cmax 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.
The efficacy of ZYBAN as an aid to smoking cessation was demonstrated in 3 placebo-controlled, double-blind trials in nondepressed chronic cigarette smokers (n = 1,940, greater than or equal to 15 cigarettes per day). In these trials, ZYBAN was used in conjunction with individual smoking cessation counseling.
The first trial was a dose-response trial conducted at 3 clinical centers. Subjects in this trial were treated for 7 weeks with 1 of 3 doses of ZYBAN (100, 150, or 300 mg per day) or placebo; quitting was defined as total abstinence during the last 4 weeks of treatment (Weeks 4 through 7). Abstinence was determined by subject daily diaries and verified by carbon monoxide levels in expired air.
Results of this dose-response trial with ZYBAN demonstrated a dose-dependent increase in the percentage of subjects able to achieve 4-week abstinence (Weeks 4 through 7). Treatment with ZYBAN at both 150 and 300 mg per day was significantly more effective than placebo in this trial.
Table 5 presents quit rates over time in the multicenter trial by treatment group. The quit rates are the proportions of all subjects initially enrolled (i.e., intent–to-treat analysis) who abstained from Week 4 of the trial through the specified week. Treatment with ZYBAN (150 or 300 mg per day) was more effective than placebo in helping subjects achieve 4-week abstinence. In addition, treatment with ZYBAN (7 weeks at 300 mg per day) was more effective than placebo in helping subjects maintain continuous abstinence through Week 26 (6 months) of the trial.
Table 5: Dose-response
Trial: Quit Rates by Treatment Group
|Abstinence from Week 4 through Specified Week||Treatment Groups|
(n = 151) % (95% CI)
|ZYBAN 100 mg/day
(n = 153) % (95% CI)
|ZYBAN 150 mg/day
(n = 153) % (95% CI)
|ZYBAN 300 mg/day
(n = 156) % (95% CI)
|Week 7 (4-week quit)||17%
|a Significantly different from placebo (P ≤ 0.05).|
The second trial was a comparator trial conducted at 4 clinical centers. Four treatments were evaluated: ZYBAN 300 mg per day, nicotine transdermal system (NTS) 21 mg per day, combination of ZYBAN 300 mg per day plus NTS 21 mg per day, and placebo. Subjects were treated for 9 weeks. Treatment with ZYBAN was initiated at 150 mg per day while the subject was still smoking and was increased after 3 days to 300 mg per day given as 150 mg twice daily. NTS 21 mg per day was added to treatment with ZYBAN after approximately 1 week when the subject reached the target quit date. During Weeks 8 and 9 of the trial, NTS was tapered to 14 and 7 mg per day, respectively. Quitting, defined as total abstinence during Weeks 4 through 7, was determined by subject daily diaries and verified by expired air carbon monoxide levels. In this trial, subjects treated with any of the 3 treatments achieved greater 4-week abstinence rates than subjects treated with placebo.
Table 6 presents quit rates over time by treatment group for the comparator trial.
Table 6: Comparator Trial: Quit Rates by Treatment Group
|Abstinence from Week 4 through Specified Week||Treatment Groups|
(n = 160) % (95% CI)
|Nicotine Transdermal System (NTS) 21 mg/day
(n = 244) % (95% CI)
|ZYBAN 300 mg/day
(n = 244) % (95% CI)
|ZYBAN 300 mg/day and NTS 21 mg/day
(n = 245) % (95% CI)
|Week 7 (4-week quit)||23%
When subjects in this trial were followed out to 1 year, the superiority of ZYBAN and the combination of ZYBAN and NTS over placebo in helping them to achieve abstinence from smoking was maintained. The continuous abstinence rate was 30% (95% CI: 24 to 35) in the subjects treated with ZYBAN and 33% (95% CI: 27 to 39) for subjects treated with the combination at 26 weeks compared with 13% (95% CI: 7 to 18) in the placebo group. At 52 weeks, the continuous abstinence rate was 23% (95% CI: 18 to 28) in the subjects treated with ZYBAN and 28% (95% CI: 23 to 34) for subjects treated with the combination, compared with 8% (95% CI: 3 to 12) in the placebo group. Although the treatment combination of ZYBAN and NTS displayed the highest rates of continuous abstinence throughout the trial, the quit rates for the combination were not significantly higher (P > 0.05) than for ZYBAN alone.
The comparisons between ZYBAN, NTS, and combination treatment in this trial have not been replicated, and, therefore should not be interpreted as demonstrating the superiority of any of the active treatment arms over any other.
The third trial was a long-term maintenance trial conducted at 5 clinical centers. Subjects in this trial received open-label ZYBAN 300 mg per day for 7 weeks. Subjects who quit smoking while receiving ZYBAN (n = 432) were then randomized to ZYBAN 300 mg per day or placebo for a total trial duration of 1 year. Abstinence from smoking was determined by subject self-report and verified by expired air carbon monoxide levels. This trial demonstrated that at 6 months, continuous abstinence rates were significantly higher for subjects continuing to receive ZYBAN than for those switched to placebo (P < 0.05; 55% versus 44%).
Quit rates in clinical trials are influenced by the population selected. Quit rates in an unselected population may be lower than the above rates. Quit rates for ZYBAN were similar in subjects with and without prior quit attempts using nicotine replacement therapy.
Treatment with ZYBAN reduced withdrawal symptoms compared with placebo. Reductions on the following withdrawal symptoms were most pronounced: irritability, frustration, or anger; anxiety; difficulty concentrating; restlessness; and depressed mood or negative affect. Depending on the trial and the measure used, treatment with ZYBAN showed evidence of reduction in craving for cigarettes or urge to smoke compared with placebo.
Use in Patients with Chronic Obstructive Pulmonary Disease (COPD)
ZYBAN was evaluated in a randomized, double-blind, comparator trial of 404 subjects with mild–to-moderate COPD defined as FEV1 greater than or equal to 35%, FEV1/FVC less than or equal to 70%, and a diagnosis of chronic bronchitis, emphysema, and/or small airways disease. Subjects aged 36 to 76 years were randomized to ZYBAN 300 mg per day (n = 204) or placebo (n = 200) and treated for 12 weeks. Treatment with ZYBAN was initiated at 150 mg per day for 3 days while the subject was still smoking and increased to 150 mg twice daily for the remaining treatment period. Abstinence from smoking was determined by subject daily diaries and verified by carbon monoxide levels in expired air. Quitters were defined as subjects who were abstinent during the last 4 weeks of treatment. Table 7 shows quit rates in the COPD Trial.
Table 7: COPD Trial: Quit Rates by Treatment Group
|4-Week Abstinence Period||Treatment Groups|
(n = 200) % (95% CI)
|ZYBAN 300 mg/day
(n = 204) % (95% CI)
|Weeks 9 through 12||12%
|a Significantly different from placebo (P < 0.05).|
Last reviewed on RxList: 1/11/2016
This monograph has been modified to include the generic and brand name in many instances.
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