Zyban 150 mg

Following oral administration of ZYBAN Tablets to healthy volunteers, peak plasma concentrations of bupropion are achieved within 3 hours. Food increased C_max and AUC of bupropion by 11% and 17%, respectively, indicating that there is no clinically significant food effect. In vitro tests indicate that bupropion is 84% bound to human albumin at plasma concentrations up to 200 µg/mL.

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 5 days.

Three active metabolites have been identified. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 150 to 300 mg/day. Plasma concentrations of the metabolites exceed those of the parent drug and may be clinically important.

The Nicotine Transdermal System (NTS) used in clinical trials did not appear to have effects on the pharmacokinetics of ZYBAN. Smokers and non-smokers appear to have similar pharmacokinetics of bupropion or its major metabolites.

The third study was a long-term relapse prevention trial conducted at five clinical centers. Patients in this study received open-label ZYBAN 300 mg/day for 7 weeks. Patients who quit smoking while receiving ZYBAN 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. Relapse was defined as the first cigarette smoked.

Results of this 1-year trial demonstrated statistically significantly less relapse to smoking for those patients taking ZYBAN compared to those taking placebo. The time for 50% of the patients to relapse to smoking was significantly longer for ZYBAN compared to placebo (32 weeks versus 20 weeks). Continuous abstinence rates were greater for those patients randomized to ZYBAN as compared to placebo through 6 months (P<0.05; 55% versus 44%). At 1 year, point prevalence abstinence rates only (abstinence from smoking for the 7 consecutive days preceding the clinic visit) were significantly higher for patients treated with ZYBAN compared to placebo-treated patients (P<0.01; 55% versus 42%).

Treatment with ZYBAN reduced some of the withdrawal symptoms compared to placebo: 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.

Of the approximately 6000 patients who participated in clinical trials with bupropion sustained-release tablets (depression and smoking cessation studies), 275 were 65 and over and 47 were 75 and over. In addition, several hundred patients 65 and over participated in clinical trials using the immediate-release formulation of bupropion (depression studies). No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

A single-dose pharmacokinetic study demonstrated that the disposition of bupropion and its metabolites in elderly subjects was similar to that of younger subjects; however, another single and multiple dose pharmacokinetic study has suggested that the elderly are at increased risk for accumulation of bupropion and its metabolites.

Bupropion is extensively metabolized in the liver to active metabolites, of which some are eliminated by the kidneys, while others are further metabolized before being excreted in urine. The risk of toxic reaction to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function (see Precautions, Renal Impairment and Dosage).

In vitro studies indicate that bupropion is primarily metabolized to hydroxybupropion by Cytochrome P450llB6 (CYP2B6) isoenzyme. Therefore the potential exists for a drug interaction between ZYBAN 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. Few systematic data have been collected on the metabolism of ZYBAN following concomitant administration with other drugs, or alternatively, the effect of concomitant administration of ZYBAN on the metabolism of other drugs.

Animal data indicate that bupropion may be an inducer of drug-metabolizing enzymes in humans. However, 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. Bupropion is extensively metabolized. The coadministration of other drugs may affect its clinical activity. Carbamazepine, phenobarbital and phenytoin may induce the metabolism of bupropion. The effects of concomitant administration of cimetidine on the pharmacokinetics of bupropion and its active metabolites were studied in 24 healthy young male volunteers. Following oral administration of two 150 mg ZYBAN tablets with and without a single dose of 800 mg of cimetidine, there were no clinically relevant differences in C_max, t_max, half-life, and clearance of bupropion or hydroxybupropion, but there was a small but statistically significant increase in the combined threohydro and erythropropion AUC (16%) and C_max (32%).

Drugs Metabolized by Cytochrome P450IID6 (CYP2D6): Many drugs, including most antidepressants (SSRIs, many tricyclics), beta-blockers, antiarrhythmics, and antipsychotics are metabolized by the CYP2D6 isoenzyme. Although bupropion is not metabolized by this isoenzyme, bupropion and hydroxybupropion are inhibitors of the CYP2D6 isoenzyme in vitro. In a study of 15 male subjects (ages 19 to 35 years) who were extensive metabolizers of the CYP2D6 isoenzyme, daily doses of bupropion given as 150 mg twice daily followed by a single dose of 50 mg desipramine increased the C_max, AUC, and t_1/2 of desipramine by an average of approximately 2-, 5- and 2-fold, respectively. The effect was present for at least 7 days after the last dose of bupropion. Concomitant use of bupropion with other drugs metabolized by CYP2D6 has not been formally studied.

Coadministration of Thioridazine Contraindicated: Administration of the antipsychotic thioridazine alone produces prolongation of the QTc interval, which is associated with serious ventricular arrhythmias such as torsades de pointes, and sudden death. As this effect appears to be dose-related, it is anticipated that risk increases with inhibition of thioridazine metabolism. An in-vivo study suggests that drugs which inhibit CYP2D6 will elevate plasma levels of thioridazine. Therefore concomitant use of thioridazine with ZYBAN is contraindicated (see Contraindications).

Coadministration of Other Drugs Metabolized by CYP2D6 Isoenzyme: Coadministration of bupropion with drugs that are metabolized by CYP2D6 isoenzyme including certain antidepressants (e.g., nortriptyline, imipramine, desipramine, paroxetine, fluoxetine, sertraline), antipsychotics (e.g., haloperidol, risperidone, ), beta-blockers (e.g., metoprolol), and Type 1C antiarrhythmics (e.g., propafenone, flecainide), should be approached with caution and should be initiated at the lower end of the dose range of the concomitant medication. If bupropion is added to the treatment regimen of a patient already receiving a drug metabolized by CYP2D6, the need to decrease the dose of the original medication should be considered, particularly for those concomitant medications with a narrow therapeutic index.

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 sustained release tablets with and without 800 mg of cimetidine. A single dose of cimetidine had no effect on single dose pharmacokinetic parameter estimates for bupropion, or hydroxybupropion, but caused a small statistically significant increase in the combined threohydro and erythrobupropion AUC (16%) and C_max (32%).

Levodopa and Amantadine: Limited clinical data suggest a higher incidence of neuropsychiatric adverse experiences, such as confusion, agitation and delirium, in patients receiving bupropion concurrently with either levodopa or amantadine. Tremor, ataxia and dizziness were also reported. Administration of ZYBAN to patients receiving either levodopa or amantadine concurrently should be undertaken with caution, using small initial doses and gradual dose increases.

Clopidogrel and Ticlopidine: Both clopidogrel and ticlopidine have been shown to significantly inhibit CYP2B6-catalysed bupropion hydroxylation. The mean area under the plasma concentration-time curve (AUC) of hydroxybupropion was reduced by 52% by clopidogrel and by 84% by ticlopidine. The AUC of bupropion was increased by 60% with clopidogrel and by 85% with ticlopidine. Therefore, concomitant administration of bupropion and either clopidogrel or ticlopidine may result in increased plasma concentrations of bupropion and reduced concentrations of hydroxybupropion. This may affect the efficacy of bupropion and may also increase the risk of concentration-dependent adverse events of bupropion, such as seizures (see Warnings, Seizures). Patients receiving drugs used to reduce blood clots (such as either clopidogrel and/or ticlopidine) are likely to require dose adjustments of bupropion.

Use of ZYBAN with Drugs that Predispose Patients to Seizures: Concurrent administration of ZYBAN with agents (e.g., antipsychotics, antidepressants, theophylline, lithium, amantadine, systemic steroids, etc.) that lower seizure threshold should be undertaken only with extreme caution (see Warnings). Low initial dosing and gradual dose increases should be employed.

Use of ZYBAN with other Drugs with CNS activity: The risks of bupropion in combination with other CNS-active drugs have not been systematically evaluated. Consequently, caution is advised if the concomitant administration of ZYBAN and such drugs is required.

Nicotine Transdermal System: See Precautions, Cardiovascular Effects.

Smoking Cessation: Physiological changes resulting from smoking cessation itself, with or without treatment with ZYBAN, may alter the pharmacokinetics of some concomitant medications, which may require dosage adjustment.

Alcohol Interactions: In post-marketing experience, there have been reports of adverse neuropsychiatric events or, reduced alcohol tolerance, in patients who were drinking alcohol during treatment with bupropion. Rarely, reports of fatal outcomes with this combination have been received, however a causal relationship has not been established. The consumption of alcohol during treatment with bupropion should be avoided (also see Warnings, Predisposing Risk Factor for Seizures).

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

Bupropion and its metabolites are secreted in human milk. Because of the potential for serious adverse reactions in nursing infants from ZYBAN, 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.

Clinical trials with ZYBAN did not include individuals under the age of 18. Therefore, the safety and efficacy in a pediatric smoking population have not been established.

Allergic Reactions: Anaphylactoid/anaphylactic reactions characterized by symptoms such as pruritus, urticaria, angioedema, and dyspnea have been reported at a rate of one to three per thousand in clinical trials. In addition, there have been rare spontaneous postmarketing reports of erythema multiforme, Stevens Johnson syndrome, and anaphylactic shock associated with bupropion. A patient should stop taking ZYBAN and consult a doctor if experiencing allergic or anaphylactoid/anaphylactic reactions (e.g., skin rash, pruritus, hives, chest pain, edema, and shortness of breath) during treatment.

Arthralgia, myalgia and fever have also been reported in association with rash and other symptoms suggestive of delayed hypersensitivity. These symptoms may resemble serum sickness.

Bupropion should be discontinued immediately if any hypersensitivity reactions are experienced. Symptoms of hypersensitivity should be treated in accordance with established medical practice. Clinicians should be aware that symptoms may persist beyond the discontinuation of bupropion, and clinical management should be provided accordingly. In post-market experience, there have been reports of hypersensitivity reactions in patients who consumed alcohol while taking bupropion. As the contribution of alcohol to these reactions has been established, patients should avoid alcohol when they are taking bupropion (see Alcohol Interaction).

Conditions that Predispose Patients to Seizures: To reduce the risk of seizures, ZYBAN is contraindicated in patients with specific conditions (see Contraindications), while extreme caution is recommended with other conditions (see Warnings).

Insomnia: In the dose response smoking cessation trial, 29% of patients treated with 150 mg/day of ZYBAN (bupropion hydrochloride) and 35% of patients treated with 300 mg/day of ZYBAN experienced insomnia, compared to 21% of placebo treated patients. Symptoms were sufficiently severe to require discontinuation of treatment in 0.6% of patients treated with ZYBAN and none of the patients treated with placebo.

In the comparative trial, 40% of the patients treated with 300 mg/day of ZYBAN, 28% of the patients treated with 21 mg/day of nicotine transdermal system (NTS), and 45% of the patients treated with the combination of ZYBAN and NTS experienced insomnia compared to 18% of placebo treated patients. Symptoms were sufficiently severe to require discontinuation of treatment in 0.8% of patients treated with ZYBAN 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.

Agitation-type emotional and behavioural changes: Agitation-type changes are reported for ZYBAN, and monitoring for these indicators of potential suicidal behaviour is advised in patients of all ages given a newer antidepressant drug, including bupropion (see Warnings, Potential Association with the Occurrence of Behavioural and Emotional Changes, Including Self-Harm).

When reported in patients undergoing a smoking cessation attempt, such changes may be a symptom of nicotine withdrawal, along with depressed mood and related symptoms such as difficulty concentrating and anxiety.

Psychosis, Confusion, and Other Neuropsychiatric Phenomena: In clinical trials with ZYBAN conducted in nondepressed smokers, the incidence of neuropsychiatric side effects was generally comparable to placebo. Depressed patients treated with bupropion in depression trials have been reported to show a variety of neuropsychiatric signs and symptoms including delusions, hallucinations, psychosis, concentration disturbance, paranoia, and confusion. In some cases, these symptoms abated upon dose reduction and/or withdrawal of treatment.

Activation of Psychosis and/or Mania: Antidepressants can precipitate manic episodes in bipolar disorder patients during the depressed phase of their illness and may activate latent psychosis in other susceptible individuals. The sustained release formulation of bupropion is expected to pose similar risks. There were no reports of activation of psychosis or mania in clinical trials with ZYBAN conducted in nondepressed smokers.

Changes in Body Weight: Weight gain is a well-known side effect of smoking cessation and may either impede initiation of a quit attempt or precipitate relapse.

Treatment: In clinical trials where treatment was for 7 to 12 weeks, a trend for lower body weight gain in subjects treated with bupropion as compared to those treated with placebo was noted. This trend was not maintained. One year after bupropion discontinuation, a trend to lower body weight gain in patients previously treated with placebo was detected.

Maintenance: In the study of up to 1 year's treatment duration, patients treated with ZYBAN demonstrated significantly less weight gain (p≤0.05) than those patients treated with placebo throughout the study (3.6 kg vs 5.9 kg, respectively, at Week 52).

Cardiovascular Effects: In clinical practice, hypertension, in some cases severe, requiring acute treatment, has been reported in patients receiving bupropion alone and in combination with nicotine replacement therapy. These events have been observed in both patients with and without evidence of preexisting hypertension.

Data from a comparative study of ZYBAN, nicotine transdermal system (NTS), the combination of sustained-release bupropion plus NTS, and placebo as an aid to smoking cessation suggest a higher incidence of treatment-emergent hypertension in patients treated with the combination of ZYBAN and NTS. In this study, 6.1% of patients treated with the combination of ZYBAN and NTS had treatment-emergent hypertension compared to 2.5%, 1.6% and 3.1% of patients treated with ZYBAN, NTS, and placebo, respectively. The majority of these patients had evidence of preexisting hypertension. Three patients (1.2%) treated with the combination of ZYBAN and NTS and one patient (0.4%) treated with NTS had study medication discontinued due to hypertension compared to none of the patients treated with ZYBAN or placebo. Monitoring of blood pressure is recommended in patients who receive the combination of bupropion and nicotine replacement.

There is no clinical experience establishing the safety of ZYBAN in patients with a recent history of myocardial infarction or unstable heart disease. Therefore, care should be exercised if it is used in these groups. Bupropion was well tolerated in depressed patients who had previously developed orthostatic hypotension while receiving tricyclic antidepressants, and was also generally well tolerated in a group of 36 depressed inpatients with stable heart failure. However, bupropion was associated with a rise in supine blood pressure in the study of patients with stable heart failure, resulting in discontinuation of treatment in two patients for exacerbation of baseline hypertension.

Renal Impairment: There is no clinical experience establishing the safety of ZYBAN in patients with renal impairment. Bupropion is extensively metabolized in the liver to active metabolites, which are largely further metabolized before being excreted by the kidneys. ZYBAN should be used with caution in patients with renal impairment and a reduced frequency of dosing should be considered as bupropion and its metabolites may accumulate in such patients to a greater extent than usual. The patient should be closely monitored for possible adverse effects (e.g., insomnia, dry mouth, seizures) that could indicate high drug or metabolite levels.

Hepatic Impairment: Based on the variability reported for individual pharmacokinetic (PK) values of patients with mild hepatic impairment in a single dose pharmacokinetic study, patients with mild or moderate hepatic impairment should be initiated at 100 mg/day of bupropion. Bupropion is not recommended for patients with severe hepatic impairment (see Warnings and Dosage).

All patients with hepatic impairment should be closely monitored for possible adverse effects (e.g., insomnia, dry mouth, seizures) that could indicate high drug and metabolite levels (see Warnings and Dosage).

Teratogenic Effects: Teratology studies have been performed at doses up to 450 mg/kg in rats (approximately 14 times the MRHD on a mg/m² basis) and at doses up to 150 mg/kg in rabbits (approximately 10 times the MRHD on a mg/m² basis). There is no evidence of impaired fertility or harm to the fetus due to bupropion. There are no 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. Pregnant smokers should be encouraged to attempt cessation using educational and behavioral interventions before pharmacological approaches are used.

Third Trimester: Postmarketing reports indicate that some neonates exposed to ZYBAN, SSRIs (Selective Serotonin Reuptake Inhibitors), or other newer anti-depressants late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. Such complications can arise immediately upon delivery. Reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying. The frequency of symptoms may vary with each drug. These features are consistent with either a direct toxic effect of SSRIs and other newer anti-depressants, or, possibly, a drug discontinuation syndrome. When treating a pregnant woman with ZYBAN during the third trimester, the physician should carefully consider the potential risks and benefits of treatment (see Dosage).

Labor and Delivery: The effect of ZYBAN on labor and delivery in humans is unknown.

Frequent was sweating. Infrequent was acne and dry skin. Rare was maculopapular rash. Also observed were alopecia, angioedema, erythema multiforme, exfoliative dermatitis, hirsutism, and Steven-Johnson syndrome. Arthralgia, myalgia and fever have also been reported in association with rash and other symptoms suggestive of delayed hypersensitivity. These symptoms may resemble serum sickness.

Frequent were agitation, depression, and irritability. Infrequent were abnormal coordination, CNS stimulation, confusion, decreased libido, decreased memory, depersonalization, emotional lability, hostility, hyperkinesia, hypertonia, hypesthesia, paresthesia, suicidal ideation and vertigo. Rare were amnesia, ataxia, derealization, hypomania and seizure. Also observed were abnormal electroencephalogram (EEG), akinesia, aphasia, coma, delirium, delusions, dysarthria, dyskinesia, dystonia, euphoria, extrapyramidal syndrome, hallucinations, hypokinesia, increased libido, manic reaction, neuralgia, neuropathy, paranoid reaction, and unmasking tardive dyskinesia.

Infrequent were leg cramps and twitching. Also observed were arthritis and muscle rigidity/fever/rhabdomyolysis, and muscle weakness.

In the relapse prevention study of up to 1 year in duration, ZYBAN was well tolerated. Adverse events were quantitatively and qualitatively similar to those observed in the dose-response and comparative trials.

Other Events Observed During the Clinical Development and Postmarketing Experience of Bupropion: Postmarketing reports suggest that the reintroduction of ZYBAN in patients who experienced a seizure is associated with a risk of seizure reoccurrence in some cases. Thus, patients should not restart ZYBAN therapy if they have had a seizure on either bupropion formulation (ZYBAN, WELLBUTRIN XL, or WELLBUTRIN SR). (See Warnings.)

In addition to the events noted above, the following events have been reported in clinical trials and postmarketing experience with the sustained-release formulation of bupropion in depressed patients and in nondepressed smokers, as well as in clinical trials and postmarketing clinical experience with the immediate-release formulation of bupropion.

Adverse events for which frequencies are provided below occurred in clinical trials with bupropion sustained release. The frequencies represent the proportion of patients who experienced a treatment emergent adverse event on at least one occasion in placebo controlled studies for depression (n=987) or smoking cessation (n=1013), or patients who experienced an adverse event requiring discontinuation of treatment in an open label surveillance study with bupropion sustained release tablets (n=3100). All treatment emergent adverse events are included except those listed in Table 3 and Table 4, those events listed in other safety related sections of the monograph, those adverse events subsumed under COSTART terms that are either overly general or excessively specific so as to be uninformative, those events not reasonably associated with the use of the drug, and those events that were not serious and occurred in fewer than two patients.

Events are further categorized by body system and listed in order of decreasing frequency according to the following definitions of frequency: Frequent adverse events are defined as those occurring in at least 1/100 patients. Infrequent adverse events are those occurring in 1/100 to 1/1000 patients, while rare events are those occurring in less than 1/1000 patients.

Adverse events for which frequencies are not provided occurred in clinical trials or postmarketing experience with bupropion. Only those adverse events not previously listed for sustained release bupropion are included. The extent to which these events may be associated with ZYBAN is unknown.

Frequent were dyspepsia, flatulence, and vomiting. Infrequent were abnormal liver function, bruxism, dysphagia, gastric reflux, gingivitis, glossitis, jaundice, and stomatitis. Rare was edema of tongue. Also observed were colitis, esophagitis, gastrointestinal hemorrhage, gum hemorrhage, hepatitis, increased salivation, intestinal perforation, liver damage, pancreatitis, stomach ulcer, and stool abnormality.

Frequent was urinary frequency. Infrequent were impotence, polyuria, and urinary urgency. Also observed were abnormal ejaculation, cystitis, dyspareunia, dysuria, gynecomastia, menopause, painful erection, prostate disorder, salpingitis, urinary incontinence, urinary retention, urinary tract disorder, and vaginitis.

ZYBAN (bupropion hydrochloride) is likely to have a low abuse potential.

Frequent was amblyopia. Infrequent were accommodation abnormality and dry eye. Also observed were deafness, diplopia and mydriasis.

Also observed were hyperglycemia, hypoglycemia and syndrome of inappropriate antidiuretic hormone.

Infrequent were edema, increased weight, and peripheral edema. Also observed was glycosuria.

Rare was bronchospasm. Also observed was pneumonia.

Frequent were asthenia, fever, and headache. Infrequent were back pain, chills, inguinal hernia, musculoskeletal chest pain, pain, and photosensitivity. Rare was malaise.

Infrequent was ecchymosis. Also observed were anemia, leukocytosis, leukopenia, lymphadenopathy, pancytopenia, and thrombocytopenia.

Infrequent were flushing, migraine, postural hypotension, stroke, tachycardia, and vasodilation. Rare was syncope. Also observed were cardiovascular disorder, complete AV block, extrasystoles, hypotension, hypertension (in some cases severe, see Precautions, Cardiovascular Effects), myocardial infarction, phlebitis, and pulmonary embolism.

In addition to those events reported under Adverse Effects, overdose has resulted in symptoms including drowsiness, loss of consciousness and ECG changes such as conduction disturbances (including QRS prolongation) or arrhythmias.

There has been very limited experience with overdosage of the sustained-release formulation of bupropion; three such cases were reported during clinical trials in depressed patients. One patient ingested 3000 mg of bupropion sustained-release tablets and vomited quickly after the overdose; the patient experienced blurred vision and lightheadedness. A second patient ingested a “handful” of bupropion sustained-release tablets and experienced confusion, lethargy, nausea, jitteriness, and seizure. A third patient ingested 3600 mg of bupropion sustained-release tablets and a bottle of wine; the patient experienced nausea, visual hallucinations, and “grogginess”. None of the patients experienced further sequelae.

There has been extensive experience with overdosages of the immediate-release formulation of bupropion. Thirteen overdoses occurred during clinical trials in depressed patients. Twelve patients ingested 850 to 4200 mg and recovered without significant sequelae. Another patient who ingested 9000 mg of immediate-release bupropion 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 the immediate-release formulation 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 the immediate-release formulation of bupropion was part of multiple drug overdoses.

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

In the event of overdose, hospitalisation is advised. Ensure an adequate airway, oxygenation, and ventilation. Monitor cardiac rhythm (ECG) and vital signs. EEG monitoring is also recommended for the first 48 hours post-ingestion. General supportive and symptomatic measures are also recommended. Induction of emesis is not recommended. Gastric lavage with a large-bore orogastric tube with appropriate airway protection, if needed, may be indicated if performed soon after ingestion or in symptomatic patients.

Activated charcoal should be administered. There is no experience with the use of forced diuresis, dialysis, hemoperfusion, or exchange transfusion in the management of bupropion overdoses. No specific antidotes for bupropion are known.

Due to the dose-related risk of seizures with ZYBAN, hospitalization following suspected overdose should be considered. Based on studies in animals, it is recommended that seizures be treated with intravenous benzodiazepine administration and other supportive measures, as appropriate.

In managing overdosage, consider the possibility of multiple drug involvement. The physician should consider contacting a Poison Control Centre for additional information on the treatment of any overdose. Telephone numbers for certified Poison Control Centres are listed in the Compendium of Pharmaceuticals and Specialties (CPS).

The recommended and maximum dose of ZYBAN (bupropion hydrochloride) is 300 mg/day, given as 150 mg twice daily. Dosing should begin at 150 mg once daily for the first 3 days, followed by a dose increase to the recommended usual dose of 300 mg/day as necessary. There should be an interval of at least 8 hours between successive doses. In order to minimize the risk of seizures (see Warnings), single doses of ZYBAN must not exceed 150 mg and doses above 300 mg/day must not be used (see Warnings).

Treatment with ZYBAN should be initiated while the patient is still smoking, since approximately 1 week of treatment is required to achieve steady state blood levels of bupropion. Patients should set a “target quit date” within the first 2 weeks of treatment with ZYBAN, generally in the second week. Treatment with ZYBAN should be continued for 7 to 12 weeks; duration of treatment should be based on the relative benefits and risks for individual patients. If a patient has not made significant progress towards abstinence by the seventh week of therapy with ZYBAN, it is unlikely that he or she will quit during that attempt, and treatment should probably be discontinued. Dose tapering of ZYBAN is not required when discontinuing treatment. It is important that patients continue to receive counseling and support throughout treatment with ZYBAN, and for a period of time thereafter.

Maintenance: Nicotine dependence is a chronic condition. Many patients attempting to quit smoking experience multiple relapses. Systematic evaluation of ZYBAN 300 mg/day for the prevention of relapse demonstrated that treatment for up to 1 year was well tolerated and efficacious in preventing relapse (see Pharmacology). Whether to continue treatment with ZYBAN for periods longer than 12 weeks must be determined for individual patients.

Patients should be advised to swallow ZYBAN 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.