Wellbutrin (Bupropion HCl)

WELLBUTRIN® SR

Glaxo Wellcome

Bupropion HCl

Antidepressant

Action And Clinical Pharmacology: Bupropion is an antidepressant of the aminoketone class. It is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors or other known antidepressant agents. Its structure closely resembles that of diethylpropion. It is related to the phenylethylamines.

The mechanism of bupropion’s antidepressant activity is unknown but appears to be mediated by noradrenergic (and possibly dopaminergic), rather than serotonergic mechanisms. Preclinical studies have shown that bupropion blocks noradrenalin (NA) reuptake and dopamine (DA) reuptake. Its major metabolite (hydroxybupropion), which in man is present at blood levels 10 to 20-fold higher than buproprion, blocks only NA reuptake.

In vitro, bupropion and its major metabolites had essentially no affinity for b-adrenergic, dopaminergic, GABA, benzodiazepine, 5HT1A, glycine and adenosine receptors, and only weakly inhibited a-adrenergic receptors in rat brain, a2-adrenergic, 5HT2, and muscarinic cholinergic receptors. High concentrations of bupropion and its major metabolites did not inhibit MAO-A or MAO-B activity. Bupropion and its major metabolites had no significant affinity for the 5HT transport system.

Pharmacokinetics: Absorption: Bupropion has not been administered i.v. to humans; therefore, the absolute bioavailability of Wellbutrin SR 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 Wellbutrin SR to healthy volunteers, peak plasma concentrations of bupropion are achieved within 3 hours. In 2 single-dose (150 mg) studies the mean peak concentration (Cmax) values were 91 and 143 ng/mL. At steady state, the mean Cmax following a 150 mg dose every 12 hours was 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 g/mL. The extent of protein binding of hydroxybupropion is similar to that of 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. There are 3 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. In preclinical tests used to predict antidepressant activity, it has been observed that hydroxybupropion is comparable in potency to bupropion, while the other metabolites are one half to one tenth as potent. This may be of clinical importance because the plasma concentrations of the metabolites are higher than those of bupropion.

In vitro results indicate that biotransformation of bupropion to hydroxybupropion is catalyzed primarily by CYP2B6, and to a much lesser extent by CYP1A2, 2A6, 2C9, 2E1 and 3A4 isozymes. Detectable levels of hydroxybupropion are not observed with CYP1A1 and CYP2D6 isozymes. Cytochrome P450 isoenzymes are not involved in the formation of threohydrobupropion. Following a single 150 mg dose of bupropion in humans, peak plasma concentrations of hydroxybupropion occur approximately 6 hours after administration. Peak plasma concentrations of hydroxybupropion are approximately 10 times the peak level of the parent drug at steady state. The AUC of hydroxybupropion at steady state is about 17-fold higher than that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of hydroxybupropion, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively.

Elimination: In 2 single-dose (150 mg) studies the mean (±% CV) apparent clearance (Cl/F) of bupropion was 135 (±20%) and 209 L/hr (±21%). Following chronic dosing of 150 mg of Wellbutrin SR every 12 hours for 14 days (n=34), the mean Cl/F at steady state was 160 L/h (±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 of 4-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%. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 150 to 300 mg/day.

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.

The disposition of buproprion following a single 200 mg oral dose was compared in 8 healthy volunteers and 8 weight- and age-matched volunteers with alcoholic liver disease. The half-life of hydroxybuproprion was significantly prolonged in subjects with alcoholic liver disease (32 hours versus 21 hours). The differences in half-life for bupropion and the other metabolites in the two patients groups were minimal.

In patients with renal or hepatic impairment, treatment should be initiated at reduced dosage (see Precautions and Dosage).

In a single dose study, there were no significant differences in the pharmacokinetics of bupropion or its major metabolites in smokers compared with nonsmokers.

The effects of age on the pharmacokinetics of bupropion and its metabolites have not been fully characterized (see Precautions and Dosage).

Experience in Clinical Trials: The effectiveness of bupropion in the treatment of moderate depression has been systematically evaluated at doses ranging from 50 to 400 mg/day in 3 multicentre, randomized, placebo-controlled, double-blind, parallel-group studies involving a total of 1 420 patients of whom 1 021 received active doses of the bupropion and 399 received placebo. Each study included a 1-week placebo lead-in phase to identify and exclude placebo responders, followed by an 8-week treatment phase.

The response to treatment was evaluated at regular intervals using the Hamilton Rating Scale for Depression (HAMD), Clinical Global Impressions Scales of Severity (CGI-S) and Improvement (CGI-I) Scale. Both the observed and the last observation carried forward (LOCF) values were analyzed.

In 1 study comparing fixed daily doses of either 150 mg once daily (n=121) or 300 mg as 150 mg twice daily (n=120) bupropion to placebo (n=121), the HAMD, CGI-S (change from baseline) and CGI-I scores for both bupropion groups at endpoint were statistically significantly superior to placebo. Both active treatment groups showed a similar magnitude of improvement during the trial.

In a second study patients received fixed daily doses of either 100 mg, 200 mg, 300 mg or 400 mg/day (given on a twice daily schedule) bupropion or placebo. The magnitude of the mean change scores were consistently greater for all active groups than placebo by day 21. At endpoint, scores in the 100 mg group were statistically significantly superior to placebo on all rating scales, while the higher dose groups followed a similar pattern but did not achieve statistical significance.

A third study compared 2 flexible doses; 50 to 150 mg/day (given once daily), and 100 to 300 mg/day (twice daily schedule) to placebo (n=approximately 150 patients per group). Patients began at the lowest dose in the range and were titrated to the highest tolerated dose in the range over a period of 7 days. Investigators had the option to titrate down when a higher dose was not well tolerated. The mean daily dose calculated from day 8 onwards was 144 mg in the 50 to 150 mg arm and 276 mg in the 100 to 300 mg arm, indicating that the vast majority of patients remained on the highest allowable dose in their respective groups for the duration of the study. Efficacy measures at endpoint for the 50 to 150 mg/day group were statistically significantly superior to placebo. The higher dose group followed a similar pattern but did not achieve statistical significance at endpoint. A combined endpoint analysis of all patients treated with bupropion in the trial, demonstrated statistically significant superiority on all efficacy measures compared to placebo.

In summary, patients receiving bupropion at doses of 100 to 150 mg/day in single or divided doses experienced improvement relative to placebo on the major indices of depression. Clinical response did not improve with increasing dose, indicating a flat dose-response relationship in the range of doses studied.

Indications And Clinical Uses: For the symptomatic relief of depressive illness. The effectiveness of bupropion in long-term use (more than 8 weeks) has not been systematically evaluated in controlled trials. Therefore, the physician who elects to use bupropion for extended periods should periodically reevaluate the long-term usefulness of the drug for the individual patient.

Contra-Indications: Patients receiving Zyban or any other medications that contain bupropion HCl because the incidence of seizure is dose dependent.

Seizures: Bupropion is contraindicated in patients with a seizure disorder.

Bulimia/Anorexia Nervosa: Bupropion is contraindicated in patients with a current or prior diagnosis of bulimia or anorexia nervosa because of a higher incidence of seizures (see Warnings) noted in patients treated for bulimia with the immediate release formulation of bupropion.

MAO Inhibitors: The concurrent administration of bupropion and MAO inhibitor is contraindicated. At least 14 days should elapse between discontinuation of an MAO inhibitor and initiation of treatment with bupropion. Treatment with a MAO inhibitor should not be started until 2 weeks after discontinuation of bupropion treatment.

Bupropion is contraindicated in patients with known hypersensitivity to bupropion or to any of the components of the formulation.

Manufacturers’ Warnings In Clinical States: Patients should be made aware that Wellbutrin SR contains the same active ingredient (bupropion HCl) as Zyban. Wellbutrin SR should not be administered to patients already receiving a product containing bupropion (see Contraindications).

Seizures: Data for bupropion tablets revealed a seizure incidence of approximately 0.1% (3 of 3 100 patients followed prospectively) in patients treated at the recommended dose range of 100 to 300 mg/day. The incidence of seizures increased to 0.4% (4/1 000), above the recommended dose, at 400 mg/day. Data for the immediate-release buproprion revealed a seizure incidence of approximately 0.4% (13 of 3 200 patients followed prospectively) in patients treated at doses of 300 to 450 mg/day. Additional data accumulated for the immediate-release formulation of buproprion suggests that the estimated seizure incidence increases almost 10-fold between 450 and 600 mg/day. Given the wide variability among individuals and their capacity to metabolize and eliminate drugs, the disproportionate increase in seizure incidence with dose incrementation calls for caution in dosing.

The risk of seizure occurring with bupropion use appears to be associated with the presence of predisposing risk factors. Therefore caution should be used when treating patients with predisposing factors which increase the risk of seizures, including: history of head trauma or prior seizure; CNS tumor; excessive use of alcohol; abrupt withdrawal from alcohol, benzodiazepines or other sedatives; addiction to opiates, cocaine, or stimulants; use of concomitant medications that lower seizure threshold (e.g., antipsychotics, antidepressants, lithium, theophylline or systemic steroids); use of over-the-counter stimulants or anorectics; diabetes treated with oral hypoglycemics or insulin.

The risk of seizure may be minimized if the total daily dose of bupropion does not exceed 300 mg (the maximum recommended dose), and no single dose of bupropion exceeds 150 mg, in order to avoid high peak concentrations of buproprion and/or its metabolites.

Precautions: Suicide: The possibility of a suicide attempt in seriously depressed patients is inherent to the illness and may persist until significant remission occurs. Close supervision of high risk patients should accompany initial drug therapy, and consideration should be given to the need for hospitalization. In order to reduce the risk of overdose, prescriptions for bupropion should be written for the smallest number of tablets consistent with good patient management.

Allergic Reactions: Anaphylactoid reactions characterized by symptoms such as pruritus, urticaria, angioedema, and dyspnea requiring medical treatment have been reported in clinical trials with bupropion at a rate of 1 to 3 per thousand. In addition, there have been rare spontaneous postmarketing reports of erythema multiforme, Stevens-Johnson syndrome, and anaphylactic shock associated with bupropion.

In uncontrolled and controlled clinical trials, skin disorders, primarily rashes, pruritus and urticaria, led to discontinuation of 1.5% and 1.9 %, respectively of bupropion-treated subjects.

Agitation and Insomnia: In placebo-controlled trials, patients receiving bupropion tablets experienced an increased incidence of agitation, anxiety, and insomnia relative to those receiving placebo (see Adverse Effects). These symptoms were sometimes of sufficient magnitude to require discontinuation of bupropion, or concurrent treatment with sedative/hypnotic drugs.

Psychosis, Confusion, and Other Neuropsychiatric Phenomena: 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 abated upon dose reduction and/or withdrawal of treatment.

Activation of Psychosis and/or Mania: Antidepressants can precipitate manic episodes in bipolar patients during the depressed phase of their illness and may activate latent psychosis in other susceptible patients. Bupropion is expected to pose similar risks.

Altered Appetite and Weight: In clinical trials bupropion was associated with dose-related weight loss. In 8-week controlled trials mean weight loss for trial completers was 0.1 kg for placebo, 0.8 kg for bupropion 100 mg/day, 1.4 kg at 150 mg/day, and 2.3 kg at 300 mg/day. If weight loss is a major presenting sign of a patient’s depressive illness, the potential anoretic and/or weight reducing effect of bupropion should be considered.

Cardiovascular Disease: There is no clinical experience establishing the safety of bupropion in patients with a recent history of myocardial infarction or unstable heart disease. In a study of depressed inpatients with stable congestive heart failure, bupropion was associated with a rise in supine blood pressure, resulting in discontinuation of 2 patients for exacerbation of baseline hypertension.

Hepatic or Renal Disease: Because bupropion 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 the lowest recommended dose (see Dosage) as bupropion and its metabolites may accumulate in such patients to a greater extent than usual (See Pharmacology, Pharmacokinetics).

Occupational Hazards: Any psychoactive drug may impair judgment, thinking or motor skills. Therefore patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that the drug treatment does not affect their performance adversely.

Pregnancy , Labor and Delivery: There are no adequate and well-controlled studies of bupropion in pregnant women. Bupropion should thus not be used during pregnancy unless the potential benefit is judged to outweigh the potential risk. To monitor fetal outcomes of pregnant women exposed to bupropion, Glaxo Wellcome Inc. maintains a Bupropion Pregnancy Registry. Health care providers are encouraged to register patients by calling (800) 722-9292, ext. 39441.

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 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.

Children: The safety and effectiveness of bupropion in individuals under 18 years old have not been established.

Geriatrics: There is limited experience with bupropion in the elderly. 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.

Drug Interactions: Cytochrome P450 2B6: In vitro studies indicate that bupropion is primarily metabolized to hydroxybupropion by the CYP2B6 isoenzyme (see Pharmacology, Pharmacokinetics). Therefore, the potential exists for a drug interaction between bupropion and drugs that affect the CYP2B6 isoenzyme metabolism (e.g., orphenadrine and cyclophosphamide). The threohydrobupropion metabolite of bupropion does not appear to be produced by the cytochrome P450 isoenzymes. No systematic 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.

Following chronic administration of bupropion, 100 mg t.i.d. to 8 healthy male volunteers for 14 days, there was no evidence of induction of its own metabolism.

Because bupropion is extensively metabolized, the coadministration of other drugs may affect its clinical activity. In particular, certain drugs may induce the metabolism of bupropion (e.g., carbamazepine, phenobarbital, phenytoin).

MAO Inhibitors: Studies in animals demonstrate that the acute toxicity of bupropion is enhanced by the MAO inhibitor, phenelzine (see Contraindications).

Cimetidine: The effects of concomitant administration of cimetidine on the pharmacokinetics of bupropion and its active metabolites were examined in a crossover study in 24 healthy young male volunteers, following oral administration of two 150 mg bupropion tablets with and without 800 mg of cimetidine. A single dose of cimetidine had no effect on single dose pharmacokinetic parameter estimates for buproprion, or hydroxybupropion, but caused a small statistically significant increase in the combined threohydro and erythrobupropion AUC (16%) and Cmax (32%).

Levodopa: Limited clinical data suggest a higher incidence of adverse experiences in patients receiving concurrent administration of the sustained- and immediate-release formulations of bupropion and L-dopa. Administration of bupropion sustained release to patients receiving L-dopa concurrently should be undertaken with caution, using small initial doses and gradual dose increases.

Other Drugs with CNS Activity: The risk of using bupropion in combination with other CNS-active drugs has not been systematically evaluated. Consequently, caution is advised if the concomitant administration of bupropion and such drugs is required.

Transdermal Nicotine: Monitoring for treatment-emergent hypertension is recommended in patients receiving a combination of sustained-release bupropion and transdermal nicotine.

Adverse Reactions: The information included is based on data from clinical trials with the sustained release formulation of bupropion. Information on additional adverse events associated with the immediate release formulation of bupropion is included in a separate subsection (see Events Observed During Development and Postmarketing Experience with the Immediate Release Formulation of Bupropion).

Adverse Events Associated with Discontinuation of Treatment: In placebo controlled studies of depression (987 patients treated with bupropion, and 385 treated with placebo), adverse events caused discontinuation in 7% of bupropion treated patients and 3% of placebo-treated patients. The more common events leading to discontinuation of bupropion included nervous system disturbances (2.2%), primarily agitation, anxiety and insomnia; skin disorders (1.9%), primarily rashes, pruritus, and urticaria ; general body complaints (1%), primarily headaches, and digestive system disturbances (1%), primarily nausea. Two patients in bupropion treatment groups discontinued due to hallucinations (auditory or visual). The rates of premature discontinuation due to an adverse event were dose-related in these studies.

In an open label, uncontrolled (acute treatment and continuation) study of bupropion, 11% patients (361 out of 3 100) discontinued treatment due to an adverse event. Adverse events leading to premature discontinuation in 1% or more of patients were: headache (1.1%), nausea (1%), and insomnia (1%). Adverse events leading to premature discontinuation in 0.5 to 1% of patients were: anxiety (0.8%), rash (0.8%), agitation (0.7%), irritability (0.5%), and dizziness (0.5%). In those patients (n=1 577) who went into the continuation phase after 8 weeks of treatment, 6 (0.4%) discontinued due to alopecia. Because this study was uncontrolled, it is not possible to reliably assess the causal relationship of these events to treatment with bupropion.

Incidence of Commonly Observed Adverse Events in Controlled Clinical Trials: Adverse events commonly encountered during the clinical development of bupropion (incidence of 5% or greater; and higher incidence in bupropion-treated, than placebo-treated patients) were headache, constipation, dry mouth, nausea, dizziness, insomnia, tremor and tinnitus.

Adverse Events Occurring at an Incidence of 1% or More Among Patients Treated with Bupropion in Placebo Controlled Trials: Table I enumerates treatment-emergent adverse events that occurred at an incidence of 1% or more and were more frequent than in the placebo group in patients participating in placebo-controlled clinical trials. Reported adverse events were classified using a COSTART-based Dictionary.

Events Observed During Development and Postmarketing Experience with the Immediate-Release Formulation of Bupropion: The following adverse events have been reported in clinical trials and postmarketing clinical experience with the immediate-release formulation of bupropion. The extent to which these events may be associated with the sustained-release tablet, is unknown.

Body (General): altered hormone level, body odor, flu syndrome.

Cardiovascular: complete AV block, abnormal ECG, pulmonary embolism, extrasystoles, myocardial infarction, pallor, phlebitis.

Digestive: colitis, esophagitis, gingivitis, gastrointestinal hemorrhage, hepatitis, intestinal perforation, liver damage, rectal disorder, increased salivation, stomach ulcer, toothache.

Endocrine: syndrome of inappropriate antidiuretic hormone.

Hemic and Lymphatic: anemia, leukocytosis, leukopenia, lymphadenopathy, pancytopenia.

Metabolic and Nutritional: glycosuria.

Musculoskeletal: arthritis, muscle rigidity/fever/rhabdomyolysis.

Nervous System: akinesia, aphasia, coma, delirium, delusions, dysarthria, dyskinesia, tardive dyskinesia, dystonia, abnormal EEG, labile emotions, euphoria, extrapyramidal syndrome, hypokinesia, decreased libido, increased libido, manic reaction, neuralgia, neuropathy, paranoid reaction, suicidal ideation.

Respiratory: bronchitis, dyspnea, epistaxis, pneumonia, respiratory disorder.

Skin: acne, angioedema, exfoliative dermatitis, hair discoloration, hirsutism, Stevens-Johnson syndrome.

Special Senses: deafness, diplopia, mydriasis.

Urogenital: cystitis, dyspareunia, dysuria, abnormal ejaculation, gynecomastia, urinary incontinence, menopause, ovarian disorder, penis disorder, salpingitis, testis disorder, urinary retention, vaginitis.

Drug Abuse and Dependence: Bupropion is likely to have a low abuse potential. There have been few reported cases of drug dependence and withdrawal symptoms associated with the immediate-release formulation of bupropion. In human studies of abuse liability, individuals experienced with drugs of abuse reported that bupropion produced a feeling of euphoria and desirability. In these a single dose of 400 mg (1.33 times the recommended daily dose) of the immediate-release formulation of bupropion produced mild amphetamine-like effects compared to placebo on the Morphine-Benzedrine Subscale of the Addiction Research Center Inventories (ARCI), which is indicative of euphorigenic properties and a score intermediate between placebo and amphetamine on the Liking Scale of the ARCI. Higher doses could not be tested because of the risk of seizure.

Symptoms And Treatment Of Overdose: Symptoms and Treatment: Human Overdose Experience: Three overdoses with bupropion occurred during clinical trials. One patient ingested 3 000 mg of bupropion and vomited quickly after the overdose; the patient experienced lightheadedness. A second patient ingested a “handful” of bupropion and experienced confusion, lethargy, nausea, jitteriness and seizure. A third patient ingested 3 600 mg of bupropion tablets and a bottle of wine; the patient experienced nausea, visual hallucinations and “grogginess”. None of the patients experienced further sequelae.

The information included in the remainder of this section is based on the clinical experience with overdosage of the immediate release formulation of bupropion. Thirteen overdoses occurred during clinical trials. Twelve patients ingested 850 to 4 200 mg and recovered without significant sequelae. Another patient who ingested 9 000 mg of bupropion immediate release and 300 mg of tranylcypromine experienced a grand mal seizure and recovered without further sequelae.

Since introduction, overdoses of up to 17 500 mg of the immediate release formulation 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 and sinus tachycardia. Fever, muscle rigidity, rhabdomyolysis, hypotension, stupor, coma and respiratory failure have been reported when bupropion was part of multiple drug overdoses.

Although most patients recovered without sequelae, deaths associated with overdoses of bupropion alone have been reported rarely in patients ingesting massive doses of bupropion immediate release tablets. Multiple uncontrolled seizures, bradycardia, cardiac failure, and cardiac arrest prior to death were reported in these patients.

Management of Overdose: Following suspected overdose, hospitalization is advised. If the patient is conscious, vomiting should be induced by syrup of ipecac. Activated charcoal also may be administered every 6 hours during the first 12 hours after ingestion. Baseline laboratory values should be obtained. ECG and EEG monitoring also are recommended for the next 48 hours. Adequate fluid intake should be provided.

If the patient is stuporous, comatose, or convulsing, airway intubation is recommended prior to undertaking gastric lavage. Although there is little clinical experience with lavage following an overdose of bupropion immediate release and none with bupropion sustained release, it is likely to be of benefit within the first 12 hours after ingestion since absorption of the drug may not yet be complete.

While diuresis, dialysis, or hemoperfusion are sometimes used to treat overdosage, there is no experience with their use in the management of overdoses of bupropion sustained release. Because diffusion of bupropion and its metabolites from tissue to plasma may be slow, dialysis may be of minimal benefit.

Based on studies in animals, it is recommended that seizures be treated with an i.v. benzodiazepine preparation and other supportive measures, as appropriate.

Further information about the treatment of overdoses may be available from a poison control center.

Dosage And Administration: The usual recommended dose is 100 to 150 mg/day given once daily. As with all antidepressants, the full antidepressant effect may not be evident until several weeks of treatment. In patients who are not responding to a dose of 150 mg/day the dose may be increased up to a maximum of 300 mg/day. Dose increases should occur at intervals of at least 1 week. In order to minimize the risk of seizures (see Warnings), single doses of bupropion should not exceed 150 mg. Doses greater than 150 mg/day should be administered b.i.d, preferably with at least 8 hours between successive doses.

Geriatrics, Debilitated, Hepatic, and Renal Impairment: In subjects with hepatic impairment limited pharmacokinetic data demonstrates a prolonged half-life of hydroxybupropion (see Pharmacology). No pharmacokinetic or therapeutic trials have been conducted to systematically investigate dose requirements in patients who are elderly, debilitated or renally impaired (see Precautions). As such patients may have reduced clearance of bupropion and its metabolites, and/or increased sensitivity to the side effects of CNS active drugs, treatment with bupropion should be initiated at the lowest recommended dose (100 mg/day).

Patients should be advised to swallow bupropion sustained release tablets whole with fluids, and not to chew, divide, crush or otherwise tamper with the tablets in any way that might affect the release rate of bupropion.

Availability And Storage: 100 mg: Each blue, round, biconvex, film-coated, sustained-release tablet, printed WELLBUTRIN SR 100″, contains: bupropion HCl 100 mg. Nonmedicinal ingredients: carnauba wax, cysteine hydrochloride, edible black ink, FD&C Blue No. 1 Lake, hydroxypropylcellulose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80 and titanium dioxide. Bottles of 60.

150 mg: Each purple, round, biconvex, film-coated, sustained-release tablet, printed WELLBUTRIN SR 150″, contains: bupropion HCl 150 mg. Nonmedicinal ingredients: carnauba wax, cysteine hydrochloride, edible black ink, FD&C Blue No. 2 Lake, FD&C Red No. 40 Lake, hydroxypropyl methylcellulose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80 and titanium dioxide. Bottles of 60.

Store between 15 and 25°C away from direct sunlight.

WELLBUTRIN® SR Glaxo Wellcome Bupropion HCl Antidepressant

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