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Zyban (Bupropion Hydrochloride) - Description and Clinical Pharmacology

 
 



DESCRIPTION

ZYBAN (bupropion hydrochloride) Sustained-Release Tablets are a non-nicotine aid to smoking cessation. ZYBAN is chemically unrelated to nicotine or other agents currently used in the treatment of nicotine addiction. Initially developed and marketed as an antidepressant (WELLBUTRIN® [bupropion hydrochloride] Tablets and WELLBUTRIN SR® [bupropion hydrochloride] Sustained-Release Tablets), ZYBAN is also 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 (±)-1-(3-chlorophenyl)-2-[(1,1-dimethylethyl)amino]-1-propanone 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.

ZYBAN is supplied for oral administration as 150-mg (purple), film-coated, sustained-release tablets. Each tablet contains the labeled amount of bupropion hydrochloride and the inactive ingredients carnauba wax, cysteine hydrochloride, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80 and titanium dioxide and is printed with edible black ink. In addition, the 150-mg tablet contains FD&C Blue No. 2 Lake and FD&C Red No. 40 Lake.

CLINICAL PHARMACOLOGY

Pharmacodynamics:   Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine, serotonin, and dopamine, and does not inhibit monoamine oxidase. The mechanism by which ZYBAN enhances the ability of patients to abstain from smoking is unknown. However, it is presumed that this action is mediated by noradrenergic and/or dopaminergic mechanisms.

Pharmacokinetics:   Bupropion is a racemic mixture. The pharmacologic activity and pharmacokinetics of the individual enantiomers have not been studied. Bupropion follows biphasic pharmacokinetics best described by a 2-compartment model. The terminal phase has a mean half-life (±%CV) of about 21 hours (±20%), while the distribution phase has a mean half-life of 3 to 4 hours.

Absorption:   Bupropion has not been administered intravenously to humans; therefore, the absolute bioavailability of ZYBAN Sustained-Release Tablets in humans has not been determined. In rat and dog studies, the bioavailability of bupropion ranged from 5% to 20%.

Following oral administration of ZYBAN to healthy volunteers, peak plasma concentrations of bupropion are achieved within 3 hours. The mean peak concentration (Cmax) values were 91 and 143 ng/mL from 2 single-dose (150-mg) studies. At steady state, the mean Cmax following a 150-mg dose every 12 hours is 136 ng/mL.

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

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 half that seen with bupropion. The volume of distribution (Vss/F) estimated from a single 150-mg dose given to 17 subjects is 1,950 L (20% CV).

Metabolism:   Bupropion is extensively metabolized in humans. Three 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 P450 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 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 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 the cytochrome P450IIB6 (CYP2B6) isoenzyme. Although bupropion is not metabolized by cytochrome P450IID6 (CYP2D6), there is the potential for drug-drug interactions when bupropion is co-administered with drugs metabolized by this isoenzyme (see PRECAUTIONS: Drug Interactions).

Following a single dose in humans, peak plasma concentrations of hydroxybupropion occur approximately 6 hours after administration of ZYBAN Tablets. Peak plasma concentrations of hydroxybupropion are 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/day.

Elimination:   The mean (±%CV) apparent clearance (Cl/F) estimated from 2 single-dose (150-mg) studies are 135 (±20%) and 209 L/hr (±21%). Following chronic dosing of 150 mg of ZYBAN every 12 hours for 14 days (n=34), the mean Cl/F at steady state was 160 L/hr (±23%). The mean elimination half-life of bupropion estimated from a series of studies is approximately 21 hours. Estimates of the half-lives of the metabolites determined from a multiple-dose study were 20 hours (±25%) for hydroxybupropion, 37 hours (±35%) for threohydrobupropion, and 33 hours (±30%) for erythrohydrobupropion. Steady-state plasma concentrations of bupropion and metabolites are reached within 5 and 8 days, respectively.

Following oral administration of 200 mg of14 C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. The fraction of the oral dose of bupropion excreted unchanged was only 0.5%.

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 was no statistically significant difference in Cmax, half-life, Tmax, AUC, or clearance of bupropion or its major metabolites between smokers and nonsmokers.

In a study comparing the treatment combination of ZYBAN and nicotine transdermal system (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.

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

Hepatic:   The effect of hepatic impairment on the pharmacokinetics of bupropion was characterized in 2 single-dose studies, one in patients with alcoholic liver disease and one in patients with mild to severe cirrhosis.

The first study showed that the half-life of hydroxybupropion was significantly longer in 8 patients 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 patients with alcoholic liver disease. The differences in half-life for bupropion and the other metabolites in the 2 patient groups were minimal.

The second study showed that there were 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, Cmax, and Tmax) and its active metabolites (t½ ) in patients with mild to moderate hepatic cirrhosis. In addition, in patients with severe hepatic cirrhosis, the bupropion Cmax 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 half-life was also longer (29 hours in patients with severe hepatic cirrhosis vs. 19 hours in healthy subjects). For the metabolites hydroxybupropion, the mean Cmax was approximately 69% lower.

For the combined amino-alcohol isomers threohydrobupropion and erythrohydrobupropion, the mean Cmax was approximately 31% lower. The mean AUC increased by 28% for hydroxybupropion and 50% for threo/erythrohydrobupropion.

The median Tmax was observed 19 hours later for hydroxybupropion and 21 hours later for threo/erythrohydrobupropion. The mean half-lives for hydroxybupropion and threo/erythrohydrobupropion were increased 2- and 4-fold, respectively, in patients with severe hepatic cirrhosis compared to healthy volunteers (see WARNINGS, PRECAUTIONS, and DOSAGE AND ADMINISTRATION).

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

Left Ventricular Dysfunction:   During a chronic dosing study with bupropion in 14 depressed patients with left ventricular dysfunction (history of congestive heart failure [CHF] or an enlarged heart on x-ray), no apparent effect on the pharmacokinetics of bupropion or its metabolites, compared to healthy normal volunteers, was revealed.

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 to 750 mg/day, on a 3 times a day schedule, revealed no relationship between age (18 to 83 years) and plasma concentration of bupropion. A single-dose pharmacokinetic study demonstrated that the disposition of bupropion and its metabolites in elderly subjects was similar to that of younger subjects. These data suggest there is no prominent effect of age on bupropion concentration; however, another pharmacokinetic study, single and multiple dose, has suggested that the elderly are at increased risk for accumulation of bupropion and its metabolites (see PRECAUTIONS: Geriatric Use).

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

CLINICAL TRIALS

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, >/=15 cigarettes per day). In these studies, ZYBAN was used in conjunction with individual smoking cessation counseling.

The first study was a dose-response trial conducted at 3 clinical centers. Patients in this study were treated for 7 weeks with 1 of 3 doses of ZYBAN (100, 150, or 300 mg/day) or placebo; quitting was defined as total abstinence during the last 4 weeks of treatment (weeks 4 through 7). Abstinence was determined by patient daily diaries and verified by carbon monoxide levels in expired air.

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

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

Table 1. Dose-Response Trial: Quit Rates by Treatment Group
Treatment Groups
Abstinence From
Week 4 Through
Specified Week
Placebo
(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%
(11-23)
22%
(15-28)
27% *
(20-35)
36% *
(28-43)
Week 12 14%
(8-19)
20%
(13-26)
20%
(14-27)
25% *
(18-32)
Week 26 11%
(6-16)
16%
(11-22)
18%
(12-24)
19% *
(13-25)
* Significantly different from placebo (p </=0.05).

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

Table 2 presents quit rates over time by treatment group for the comparative trial.

Table 2. Comparative Trial: Quit Rates by Treatment Group
Treatment Groups
Abstinence From
Week 4 Through
Specified Week
Placebo
(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%
(17-30)
36%
(30-42)
49%
(43-56)
58%
(51-64)
Week 10 20%
(14-26)
32%
(26-37)
46%
(39-52)
51%
(45-58)

When patients in this study were followed out to one year, the superiority of ZYBAN and the combination of ZYBAN and NTS over placebo in helping patients to achieve abstinence from smoking was maintained. The continuous abstinence rate was 30% (95% CI 24-35) in the ZYBAN treated patients, and 33% (95% CI 27-39) for patients treated with the combination at 26 weeks compared with 13% (95% CI 7-18) in the placebo group. At 52 weeks, the continuous abstinence rate was 23% (95% CI 18-28) in the ZYBAN treated patients, and 28% (95% CI 23-34) for patients treated with the combination, compared with 8% (95% CI 3-12) in the placebo group. Although the treatment combination of ZYBAN and NTS displayed the highest rates of continuous abstinence throughout the study, 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 study 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 study was a long-term maintenance trial conducted at 5 clinical centers. Patients in this study received open-label ZYBAN 300 mg/day for 7 weeks. Patients who quit smoking while receiving ZYBAN (n = 432) were then randomized to ZYBAN 300 mg/day or placebo for a total study duration of 1 year. Abstinence from smoking was determined by patient self-report and verified by expired air carbon monoxide levels. This trial demonstrated that at 6 months, continuous abstinence rates were significantly higher for patients 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 patients with and without prior quit attempts using nicotine replacement therapy.

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

Use In Patients With Chronic Obstructive Pulmonary Disease (COPD):   ZYBAN was evaluated in a randomized,double-blind, comparative study of 404 patients with mild-to-moderate COPD, defined as FEV1>/=35%, FEV1/FVC </=70% and a diagnosis of chronic bronchitis, emphysema and/or small airways disease. Patients aged 36 to 76 years were randomized to ZYBAN 300 mg/day (n = 204) or placebo (n = 200) and treated for 12 weeks. Treatment with ZYBAN was initiated at 150 mg/day for 3 days while the patient was still smoking and increased to 150 mg twice daily for the remaining treatment period. Abstinence from smoking was determined by patient daily diaries and verified by carbon monoxide levels in expired air. Quitters are defined as subjects who were abstinent during the last 4 weeks of treatment. Table 3 shows quit rates in the COPD Trial.

Table 3. COPD Trial: Quit Rates by Treatment Group
  Treatment Groups
4-Week Abstinence Period Placebo
(n = 200)
%
(95% CI)
ZYBAN
300 mg/day
(n = 204)
%
(95% CI)
Weeks 9 through 12 12%
(8-16)
22% *
(17-27)
*Significantly different from placebo (p <0.05).

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