FDA Drug Class: Antidepressants; CNS, Miscellaneous
Brand Names: Wellbutrin; Wellbutrin SR; Zyban
Cost of Therapy: $239.24 (Depression; Tablet; 150 mg; 2/day; 90 days)
Bupropion HCl, an antidepressant of the aminoketone class and a non-nicotine aid to smoking cessation, is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitor, or other known antidepressant agents. Its structure closely resembles that of diethylpropion; it is related to phenylethylamines. It is (±)-1-(3-chlorophenyl)-2-((1,1-dimethylethyl)amino)-1-propanone hydrochloride. The molecular weight is 276.2. The empirical formula is C13H18ClNO·HCl. Bupropion HCl powder is white, crystalline, and highly soluble in water. It has a bitter taste and produces the sensation of local anesthesia on the oral mucosa.
Immediate Release Tablets: Wellbutrin is supplied for oral administration as 75 mg (yellow-gold) and 100 mg (red) film-coated tablets. Each tablet contains the labeled amount of bupropion HCl and the inactive ingredients: 75 mg tablet: D&C Yellow No. 10 Lake, FD&C Yellow No. 6 Lake, hydroxypropyl cellulose, hydroxypropyl methylcellulose, microcrystalline cellulose, polyethylene glycol, talc, and titanium dioxide; 100 mg tablet: FD&C Red No. 40 Lake, FD&C Yellow No. 6 Lake, hydroxypropyl cellulose, hydroxypropyl methylcellulose, microcrystalline cellulose, polyethylene glycol, talc, and titanium dioxide.
Sustained Release Tablets: Wellbutrin SR: Wellbutrin SR tablets are supplied for oral administration as 100 mg (blue) and 150 mg (purple), film-coated, sustained-release tablets. Each tablet contains the labeled amount of bupropion HCl and the inactive ingredients: carnauba wax, cysteine hydrochloride, hydroxypropyl methylcellulose, magnesium stearate, microcrystalline cellulose, polythylene glycol, and titanium dioxide and is printed with edible black ink. In addition, the 100 mg tablet contains FD&C Blue No.1 Lake and polysorbate 80, and the 150 mg tablet contains FD&C Blue No. 2 Lake, FD&C Red No. 40 Lake, and polysorbate 80. Zyban: Zyban (bupropion HCl for smoking cessation) is supplied for oral administration as 150-mg (purple), film-coated, sustained-release tablets. Each tablet contains the labeled amount of bupropion HCl and the inactive ingredients carnuba wax, cysteine HCl, hydroxypropyl methylcellulose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80 and titanium dioxide and is printed with edible black ink. In addition, the 150-mg table contains FD&C Blue No. 2 Lake and FD&C Red No. 40 Lake.
Immediate Release Tablets: The neurochemical mechanism of the antidepressant effect of bupropion is not known. Bupropion does not inhibit monoamine oxidase. Compared to classical tricyclic antidepressants, it is a weak blocker of the neuronal uptake of serotonin and norepinephrine; it also inhibits the neuronal re-uptake of dopamine to some extent. Bupropion produces dose-related CNS stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behavior tasks, and, at high doses, induction of mild stereotyped behavior.
Bupropion causes convulsions in rodents and dogs at doses approximately tenfold the dose recommended as the human antidepressant dose.
Sustained Release Tablets: Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine, serotonin, and dopamine, and does not inhibit monoamine oxidase. 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. The mechanism by which bupropion enhances the ability of patients to abstain from smoking is unknown. However, it is presumed that this action is also mediated by nonadrenergic and/or dopaminergic mechanisms.
Following oral administration of bupropion sustained release tablets 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 two 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 Cmax by 11% and the extent of absorption as defined by area under the plasma concentration-time curve (AUC) of bupropion by 17%. The mean time to peak concentration (tmax) was prolonged by 1 hour. This effect was of no clinical significance.
In vitro tests show that bupropion is 84% bound to human albumin at plasma 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 1950 L (20% CV).
Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion HCl excreted unchanged was only 0.5%, a finding documenting the extensive metabolism of bupropion.
The mean 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.
Plasma and urinary metabolites so far identified include biotransformation products formed via reduction of the carbonyl group and/or hydroxylation of the tert-butyl group of bupropion. Four basic metabolites have been identified. They are the erythro- and threo-amino alcohols of bupropion (erythrohydrobupropion and threohydrobupropion), the erythro-amino diol of bupropion, and a morpholinol metabolite (hydroxybupropion, formed from hydroxylation of the tert-butyl group of bupropion). These metabolites of bupropion are pharmacologically active, but their potency and toxicity relative to bupropion have not been fully characterized. They may be of clinical importance because the plasma concentrations of the metabolites are higher than those of bupropion.
Following a single dose in humans, peak plasma concentrations of the morpholinol metabolite (hydroxybupropion) occur approximately 6 hours after administration of bupropion HCl sustained release tablets. Peak plasma concentrations of the morpholinol metabolite are approximately 10 times the peak level of the parent drug at steady state with bupropion HCl sustained release tablets. The elimination half-life of the morpholinol metabolite is approximately 20 (±5) hours, and its AUC at steady state is about 17 times that of bupropion.
The times to peak concentrations for the erythro- and threo-amino alcohol metabolites (erythrohydrobuprobion and threohydrobupropion) are similar to that of the morpholinol metabolite. However, their elimination half-lives are longer, 33 (±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion.
The erythro-amino diol metabolite generally cannot be detected in the systematic circulation following a single oral dose of the parent drug.
In a study comparing chronic dosing with bupropion HCl sustained release tablets 150 mg twice a day to the immediate release formulation of bupropion at 100 mg three times a day, peak plasma concentrations of bupropion at steady state for bupropion HCl sustained release tablets were approximately 85% of those achieved with the immediate-release formulation. There was equivalence for both peak plasma concentration and AUCs for all three of the detectable bupropion metabolites. Thus, at steady state, bupropion sustained release tablets and the immediate-release formulation are essentially bioequivalent for both bupropion and the three quantitatively important metabolites.
Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg/day.
Bupropion is a racemic mixture. The pharmacologic activity and pharmacokinetics of the individual enantiomers have not been studied. Bupropion follows biphasic pharmacokinetics best described by a two-compartment model. The terminal phase has a mean half-life (±% CV) of about 21 hours (±20%), while the distribution phase has a mean half-life of 3 to 4 hours.
Bupropion has not bełen administered intravenously to humans; therefore, the absolute bioavailability of bupropion sustained-release tablets in humans has not been determined. In rat and dog studies, the bioavailability of bupropion ranged from 5% to 20%.
Bupropion is extensively metabolized in humans. There are three active metabolites: hydroxybupropion and the amino-alcohol isomers threohydrobupropion and erythrohydrobupropion, which are formed via hydroxylation of the tert-butyl group of bupropion and/or reduction of the carbonyl group. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potenticity and toxicity of the metabolites relative to bupropion have not been fully characterized; however, it has been demonstrated in mice that hydroxybupropion is comparable in potency to bupropion, while the other metabolites are one tenth to one half as potent. This may be of clinical importance because the plasma concentrations of the metabolites are higher than those of bupropion. In vitro findings suggest that cytochrome P450 2B6 (CYP2B6) is the principle isoenzyme involved in the formation of hydroxybupropion, which cytochrome P450 isoenzymes are not involved in the formation of threohydrobupropion.
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 disposition of bupropion following a single 200-mg oral dose was compared in eight healthy volunteers and eight weight- and age-matched volunteers with alcoholic liver disease. The half-life of the morpholinol metabolite (hydroxybupropion) was significantly prolonged in subjects with alcoholic liver disease (32 hours (±41%) versus 21 hours (±23%)). The differences in half-life for bupropion and the other metabolites in the two patient groups were minimal.
Renal: The effect of renal disease on the pharmacokinetics of bupropion has not been studied. The elimination of the major metabolites of bupropion may be affected by reduced renal function.
Left Ventricular Dysfunction: During a chronic dosing study with bupropion in 14 depressed patients with left ventricular dysfunction (history of congestive heart failure or an enlarged heart on x-ray), there was substantial interpatient variability (twofold to fivefold) in the trough steady-state concentrations of bupropion and the morpholinol and threo-amino alcohol metabolites. This variability was in the same range of the variability observed in healthy volunteers (threefold to eightfold). In addition, the steady-state plasma concentrations of these metabolites were 10 to 100 times the steady-state concentrations of the parent drug.
Age: The effects of age on the pharmacokinetics of bupropion and its metabolites have not been fully characterized, but an exploration of steady-state bupropion concentrations from several efficacy studies involving patients dosed in a range of 300 to 750 mg/day, on a three-times daily schedule, revealed no relationship between age (18 to 83 years) and plasma concentration of bupropion. These data suggest there is no prominent effect of age on bupropion concentration (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.
The efficacy of the immediate-release formulation of bupropion as a treatment for depression was established in two 4-week, placebo-controlled trials in adult inpatients with depression and in one 6-week, placebo-controlled trial in adult outpatients with depression. In the first study, patients were titrated in a bupropion dose range of 300 to 600 mg/day on a three times daily schedule; 78% of patients received maximum doses of 450 mg/day or less. This trial demonstrated the effectiveness of the immediate-release formulation of bupropion on the Hamilton Depresssion Rating Scale (HDRS) total score, the depressed mood item (i.e., 1) from that scale, and the Clinical Global Impressions (CGI) severity score. A second study included two fixed doses of the immediate-release formulation of bupropion (300 and 450 mg/day) and placebo. This trial demonstrated the effectiveness of the immediate-release formulation of bupropion, but only at 450-mg/day dose; the results were positive for the HDRS total score and the CGI severity score, but not for HDRS item 1. In the third study, outpatients received 300 mg/day of the immediate-release formulation of bupropion. This study demonstrated the effectiveness of the immediate-release formulation of bupropion on the HDRS total score, HDRS item 1, the Montgomery-Asberg Depression Rating Scale, the CGI severity score, and the CGI improvement score.
Although there are not as yet independent trials demonstrating the antidepressant effectiveness of the sustained-release formulation of bupropion, studies have demonstrated the bioequivalence of the immediate-release and sustained-release forms of bupropion under steasy state conditions, i.e., bupropion sustained-release 150 mg twice daily was shown to be bioequivalent to the 100 mg, three-times daily dose of the immediate-release formulation of bupropion, with regard to both rate and extent of absorption, for parent drug and metabolites.
The efficacy of bupropion as an aid to smoking cessation was demonstrated in two placebo-controlled, double-blind trials in nondepressed chronic cigarette smokers (n=1508, >=15 cigarettes per day). In these studies, bupropion was used in conjuction with individual smoking cessation counseling.
The first study was a dose-response trial conducted at three clinical centers. Patients in this study were treated for 7 weeks with one of three doses of bupropion sustained elease tablets (100, 150, or 300 mg/day) or placebo; quitting was defined as total abstinene during the last 4 weeks of treatment (weeks 4 through 7). Abstinence was determined by patient daily diaries and verified by carbon monoxide levels in expired air.
Results of this dose-response trial with bupropion sustained release tablets demonstrated a dose-dependent increase in the percentage of patients able to achieve 4-week abstinence (weeks 4 through 7). Treatment with bupropion sustained release tablets at both 150 and 300 mg/day was significantly more effective than placebo in this study.
TABLE 1 presents quit rates over time in the multicenter trial by treatment group. The quit rates are the proportions of all persons initially enrolled (i.e., intent to treat analysis) who abstained from week 4 of the study through the specified week. Treatment with bupropion sustained release tablets (150 or 300 mg/day) was more effective than placebo in helping patients achieve 4-week abstinence. In addition, treatment with bupropion sustained release tablets (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.
| Abstinence From Week 4 Through Specified Week | Placebo (n=151) (95% Cl) | Bupropion SR 100 mg/day (n=153) (95% Cl) | Bupropion SR 150 mg/day (n=153) (95% Cl) | Bupropion SR 300 mg/day (n=156) (95% Cl) |
| 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) |
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* Significantly different than placebo (P<=0.05). | ||||
The second study was a comparative trial conducted at four clinical centers. Four treatments were evaluated: bupropion sustained release tablets, 300 mg/day, nicotine transdermal system (NTS) 21 mg/day, combination of bupropion sustained release tablets 300 mg/day plus NTS 21 mg/day, and placebo. Patients were treated for 9 weeks. Treatment with bupropion sustained release tablets was initiated at 150 mg/day while the patient was still smoking and was increased after 3 days to 300 mg/day given as 150 mg twice daily. NTS 21 mg/day was added to treatment with bupropion sustained release tablets after approximately 1 week when the patient reached the target quit date. During weeks 8 and 9 f the study, NTS was tapered to 14 and 7 mg/day, respectively. Quitting, defined as total abstinence during weeks 4 through 7, was determined by patient daily diaries and verified by expired air carbon monoxide levels.
In this study, patient treated with either bupropion sustained release tablets or NTS achieved greater 4-week abstinence rates than patients treated with placebo. In addition, patients treated with the combination of bupropion sustained release tablets and NTS achieved higher abstinence rates than patients treated with either of the individual active treatments alone, although only the comparison with NTS achieved statistical significance.
TABLE 2 presents quit rates over time by treatment group for the comparative trial. Both bupropion sustained release tablets and NTS were more effective than placebo in helping patients maintain abstinence through week 10 of the study. The treatmetn combination of bupropion sustained release tablets and NTS displayed the highest rates of continuous abstinence throughout the study.
| Abstinence From Week 4 Through Specified Week | Placebo (n=160) (95% Cl) | Nicotine Transdermal System (NTS) 21 mg/day (n=244) (95% Cl) | Bupropion SR 300 mg/day (n=244) (95% Cl) | Bupropion SR 300 mg/day and NTS 21 mg/day (n=245) (95% Cl) |
| Week 7 (4-week quit) | 23% (17-30) | 36%* (30-42) | 49%* | 58%* |
| Week 10 | 20% (14-26) | 32%* (26-37) | 46%* | 51%* |
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* P<=0.01 versus placebo. | ||||
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Quit rates in clinical trials are influenced by the population selected. Quit rates in an unselected population may be lower than the above rates.
Treatment with bupropion sustained release tablets reduced withdrawal symptoms compared to placebo. Reductions on the following withdrawal symptoms were most pronounced: irritability, frustration, or anger; anxiety; difficulty concentrating; restlessness; and depressed mood or negative affect. Depending on the study and the measure used, treatment with bupropion sustained release tablets showed evidence of reduction in craving for cigarettes or urge to smoke compared to placebo.
Bupropion HCl is indicated for the treatment of depression.
A physician considering bupropion SR tablets for the management of a patient s first episode of depression should be aware that the drug may cause generalized seizures in a dose-dependent manner with an approximate incidence of 0.4% (4/1,000) at the upper end of the recommended dose range, i.e., 400 mg/day, and an incidence of 0.1% (1/1,000) at a bupropion dose of 300 mg/day. Bupropion s seizure incidence at the 400-mg/day dose may exceed that of other marketied antidepressants and doses of bupropion sustained release tablets up to 300 mg/day by as much as fourfold. This relative risk is only an approximate estimate because no direct comparative studies have been conducted (see WARNINGS).
The efficacy of bupropion in the treatment of depression was established in two 4-week controlled trials of depressed inpatients and in one 6-week controlled trial of depressed outpatients whose diagnoses corresponded most closely to the Major Depression category of the APA Diagnostic and Statistical Manual (DSM) (see CLINICAL PHARMACOLOGY.)
A major depressive episode (DSM-IV) implies the presence of 1) depressed mood or 2) loss of interest or pleasure; in addition, at least five of the following symptoms have been present during the same 2-week period and represent a change from previous functioning: depressed mood, markedly diminished interest or pleasure in usual activities, significant change in weight and/or appetite, insomnia or hypersomia, psychomotor agitation or retardation, increased fatigue, feeling of guilt or worthlessness, slowed thinking or impaired concentration, a suicide attempt or suicidal ideation.
Effectiveness of bupropion in long-term use (more than 6 weeks) has not been systematically evaluated in controlled trials. Therefore, the physician who elects to use bupropion sustained release tablets for extended periods should periodically reevaluate the long-term usefulness of the drug for the individual patient.
Bupropion is indiced as a smoking cessation treatment.
Bupropion HCl is contraindicated in patients with a seizure disorder.
Buproprion HCl is contraindicated in patients treated with an other medications that contain bupropion because the incidence of seizure is dose-dependent.
Bupropion HCl is also contraindicated in patients with a current or prior diagnosis of bulimia or anorexia nervosa because of a higher incidence of seizures noted in such patients treated with bupropion HCl immediate-relase formulation.
The concurrent administration of bupropion HCl and a monoamine oxidase (MAO) inhibitor is contraindicated. At least 14 days should elapse between discontinuation of an MAO inhibitor and initiation of treatment with bupropion HCl.
Bupropion HCl is contraindicated in patients who have shown an allergic response to bupropion or the other ingredients contained in the formulations.
Patients should be made aware that Wellbutrin SR (bupropion HCl used to treat depression) contains the same active ingredient found in Zyban (bupropion HCl used as an aid for to smoking cessation treatment) and that Wellbutrin SR should not be used in combination with Zyban, or any other medications that contain bupropion.
At doses of up to 300 mg/day, the incidence of seizures is approximately 0.1% (1/1000) but increases to approximately 0.4% (4/1000) at the recommended dose (for treatment of depression) of 400 mg/day of the sustained-release formulation or 450 mg/day of the immediate-release formulation. The risk of seizure also appears to be strongly associated with the presence of predisposing factors.
Immediate Release Formulation: Data for the immediate release bupropion revealed a seizure incidence of approximately 0.4% (i.e., 13 of 3200 patients followed propectively) in patients treated at doses in a range of 300 to 450 mg/day. The 450 mg/day upper limit of this dose range is close to the currently recommended maximum dose (for treatment of depression) of 400 mg/day for bupropion sustained release tablets. The seizure incidence (0.4%) may exceed that of other marketed antidepressants and doses of bupropion sustained release tablets up to 300 mg/day by as much as fourfold. This relative risk is only an approximate estimate because no direct comparative studies have been conducted.
Additional data accumulated for the immediate release formulation of bupropion suggested that the estimated seizure incidence increases almost tenfold between 450 and 600 mg/day, which is twice the usual adult target dose and one-half the maximum recommended daily dose (400 mg) of bupropion sustained release tablets. Given the wide variability among individuals and their capacity to metabolize and eliminate drugs, this disproportionate increase in seizure incidence with dose incrementation calls for caution in dosing.
Sustained Release Formulations: Data for bupropion sustained release tablets revealed a seizure incidence of approximately 0.1% (i.e., 3 of 3100 patients followed propspectively) in patients treated at doses in a range of 100 to 300 mg/day. It is not possible to know if the lower seizure incidence observed in this study involving the sustained-release formulation of bupropion resulted from the different formulation or the lower dose used. However, the immediate-release and sustained-release formulations are bioequivalent regarding both rate and extent of absorption during steady-state, the most pertinent condition to estimating seizure incidence since most observed seizures occur under steady-state conditions.
Risk Factors: The risk of seizure is also related to patient factors, clinical situations, and concomitant medications, which must be considered in selection of patients for therapy with bupropion HCl.
Patient factors: Predisposing factors that may increase the risk of seizure with bupropion use inclue history of head trauma or prior seizure, central nervous system (CNS) tumor, and concomitant medications that lower seizure threshold.
Clinical situations: Circumstances associated with an increased seizure risk include, among others, excessive use of alcohol; abrupt withdrawal from alcohol or other sedatives; addiction to opiates, cocaine, or stimulants; use of over-the-counter stimulants and anorectics; and diabetes treated with oral hypoglycemics or insulin.
Concomitant medications: Many medications (e.g., antipsychotics, antidepressants, theophylline, systemic steroids) and treatment regimens (e.g., abrupt discontinuation of benzodiazepines) are known to lower seizure threshold.
Recommendations for Reducing the Risk of Seizure with the Sustained Release Formulation: Retrospective analysis of clinical experience gained during the development of bupropion suggests that the risk of seizure may be minimized if
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.
Agitation and Insomnia: Patients in placebo-controlled trials with bupropion sustained release tablets experienced agitation, anxiety, and insomnia as shown in TABLE 3.
| Adverse Event Term | Bupropion SR 300 mg/day (n=376) | Bupropion SR 400 mg/day (n=114) | Placebo (n=385) |
| Agitation | 3% | 9% | 2% |
| Anxiety | 5% | 6% | 3% |
| Insomnia | 11% | 16% | 6% |
In clinical studies of both the immediate and sustained release formulations of bupropion HCl, these symptoms were sometimes of sufficient magnitude to require treatment with sedative/hypnotic drugs.
Symptoms were sufficiently severe to require discontinuation of treatment in 1% and 2.6% of patients treated with 300 and 400 mg/day, respectively, of bupropion sustained release tablets and 0.8% of patients treated with placebo.
Immediate Release Tablets: In approximately 2% of patients, symptoms were sufficiently severe to require discontinuation of treatment with bupropion HCl.
Bupropion HCl for Smoking Cessation: In the dose-responsive smoking cessation trial, 29% of patients treated with 150 mg/day of bupropion sustained release tablets and 35% of patients treated with 300 mg/day of bupropion sustained release tablets experience insomnia, compared to 21% of placebo-treated patients. Symptoms were sufficiently severe to require discontinuation of treatment in 0.6% of patients treated with bupropion HCl and none of the patients treated with placebo.
In the comparative trial, 40% of the patients treated with 300 mg/day of bupropion sustained release tablets, 28% of the patients treated with 21 mg/day of NTS, and 45% of the patients treated with the combination of bupropion sustained release tablets and NTS experienced insomnia compared with 18% of placebo-treated patients. Symptoms were sufficiently severe to require discontinuation of treatment in 0.8% of patients treated with bupropion HCl and none of the patients in the other three treatment groups.
Insomnia may be minimized by avoiding bedtime doses and, if necessary, reduction in dose.
Pyschosis, Confusion, and Other Neuropyschiatric Phenomena: Depressed patients treated with an immediate-release formulation of bupropion or with the sustained release tablets have been reported to show a variety of neuropsychiatric signs and symptoms, including delusions, hallucinations, pyschosis, concentration disturbance, paranoia, and confusion. In some cases, these symptoms abated upon dose reduction and/or withdrawal of treatment. In clinical trials with bupropion sustained release tablets conducted in nondepressed smokers, the incidence of neuropsychiatric side effects was generally comparable to placebo.
Activation of Psychosis and/or Mania: Antidepressants can precipitate manic episodes in bipolar disorder patients during the depressed phase of their illness and may activate latent pyschosis in other susceptible patients. Bupropion sustained release formulation is expected to pose similar risks. There were no reports of activation of psychosis or mania in clinical trials with bupropion sustained release formulation conducted in nondepressed smokers.
Altered Appetite and Weight: In placebo-controlled studies with the sustained release tablets, patients experienced weight gain or weight loss as shown in TABLE 4.
| Weight Change | Bupropion Sustained Release 300 mg/day (n=339) | Bupropion Sustained Release 400 mg/day (n=112) | Placebo (n=347) |
| Gained >5 lbs | 3% | 2% | 4% |
| Lost >5 lbs | 14% | 19% | 6% |
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 bupropion sustained release tablets should be considered.
A weight loss of greater than 5 pounds occurred in 28% of bupropion HCl patients. This incidence is approximately double that seen in comparable patients treated with tricyclics or placebo.
Suicide: The possibility of a suicide attempt is inherent in depression an›d may persist until significant remission occurs. Accordingly, prescriptions for bupropion HCl should be written for the smallest number of tablets consistent with good patient management.
Allergic Reactions: Anaphylactoid reactions characterized by symptoms such apruritis, urticaria, angioedema, and dyspnea requiring medical treatment have been reported in clinical trials with bupropion. In addition, there have been rare spontaneous postmarketing reports of erythema multiforme, Stevens-Johnson syndrome, and anaphylactic shock associated with bupropion.
Use in Patients With Systemic Illness: There is no clinical experience establishing the safety of bupropion sustained release tablets in patients with a recent history of myocardial infarction or unstable heart disease. Therefore, care should be exercised if it is used in these groups. Bupropion was well tolerated in 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 congestive heart failure (CHF). However, bupropion was associated with a rise in supine blood pressure in the study of patients with CHF, resulting is discontinuation of two patients for exacerbation of baseline hypertension.
Because bupropion HCl and its metabolites are almost completely excreted through the kidney and metabolites are likely to undergo conjugation in the liver prior to urinary excretion, treatment of patients with renal or hepatic impairment should be initiated at reduced dosage as bupropion and its metabolites may accumulate in such patients to a greater extent than usual. The patient should be closely monitored for possible toxic effects of elevated blood and tissue levels of drug and metabolites.
In the comparative trial of bupropion as an aid to smoking cessation, 6.1% of patients treated with the combination of bupropion sustained release tablets and NTS had treatment-emergent hypertension compared to 2.5%, 1.6%, and 3.1% of patients treated with bupropion HCl, NTS, and placebo respectively. The majority of these patients had evidence of preexisting hypertension. Three patients (1.2%) treated with the combination of bupropion and NTS and one patient (0.4%) treated with NTS had study medication discontinued due to hypertension compared to non of the patients treated with bupropion or placebo. Monitoring for treatment-emergent hypertension is recommended in patients receiving the combination of bupropion sustained release tablets and NTS.
Patients should be made aware that Zyban, used as an aid to smoking cessation, contains the same active ingredient found in Wellbutrin and Wellbutrin SR used to treat depression and that Zyban should not be used in conjunction with Wellbutrin, Wellbutrin SR, or any other medications that contain bupropion HCl.
Information for Patients Using Bupropion Sustained Release Tablets as an Aid to Smoking Cessation: See patient information leaflet at the end of this monograph. Physicians are advised to review the leaflet with their patients.
There are no specific laboratory tests recommended.
Lifetime carcinogenicity studies were performed in rats and mice at doses up to 300 and 150 mg/kg per day, respectively. These doses are approximately seven and two times the maximum recommended dose (MRHD) for depression treatment, respectively, and ten and two times the MRHD for smoking cessation, respectively, on a mg/m2 basis. In the rat study there was an increase in nodular proliferation lesions of the liver at doses of 100 to 300 mg/kg per day (approximately two to seven times the MRHD for depression treatment and three to ten times the MRHD for smoking cessation on a mg/m2 basis): lower doses were not tested. The question of whether or not such lesions may be precursors of neoplasms of the liver is currently unresolved. Similar liver lesions were not seen in the mouse study, and no increase in malignant tumors of the liver and other organs was seen in either study.
Bupropion produced a positive response (two to three times control mutation rate) in two of five strains in the Ames bacterial mutagenicity test and an increase in chromosomal aberrations in one of three in vivo rat bone marrow cytogenetic studies.
A fertility study in rats at doses up to 300 mg/kg revealed no evidence of impaired fertility.
Teratology studies have been performed at doses up to 450 mg/kg in rats, and at doses up to 150 mg/kg in rabbits (approximately 7 to 11 and 7 times the MRHD for depression treatment, and 14 and 10 times the MRHD for smoking cessation, respectively, on a mg/m2 basis), and have revealed no evidence of harm to the fetus due to bupropion. There are adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.
The effect of bupropion sustained release tablets on labor and delivery in humans is unknown.
Like many other drugs, bupropion and its metabolites are secreted in human milk. Because of the potential for serious adverse reactions in nursing infants from bupropion, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
The safety and effectiveness of bupropion sustained release tablets in pediatric patients below 18 years of age have not been established. Clinical trials with bupropion HCl for smoking cessation did not include individuals under the age of 18. Therefore, the safety and efficacy in a pediatric smoking population have not been established. The immediate release formulation of bupropion was studied in 104 pediatric patients (age range, 6 to 16) in clinical trials of the drug for other indications. Although generally well tolerated, the limited exposure is insufficient to assess the safety of bupropion in pediatric patients.
In general, older patients are known to metabolize drugs more slowly and to be more sensitive to the anticholinergic, sedative, and cardiovascular side effects of antidepressant drugs. A single-dose pharmacokinetic study demonstrated that the disposition of bupropion and its metabolites in elderly subjects was similar to that of younger subjects (see CLINICAL PHARMACOLOGY.) Of the approximately 5600 patients who participated in clinical trials with bupropion sustained release tablets (depression and smoking cessation studies), 303 were 60 to 69 years old and 88 were 70 years of age or older. The experience with patients 60 years of age or older was similar to that in younger patients.
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