Wellbutrin SR

Concurrent administration of WELLBUTRIN SR Tablets with agents that lower seizure threshold (e.g., antipsychotics, other antidepressants, theophylline, lithium, systemic steroids etc) should be undertaken only with extreme caution (see Warnings and Precautions). Low initial dosing and gradual dose increases should be employed.

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 and Precautions, Predisposing Risk Factors for Seizures).

Co-administration of bupropion with other 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.

(See Warnings and Precautions, Cardiovascular Effects.)

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 WELLBUTRIN SR to patients receiving either levodopa or amantadine concurrently should be undertaken with caution, using small initial doses and gradual dose increases.

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

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 WELLBUTRIN SR is contraindicated (see Contraindications).

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 and Precautions, Seizures). Patients receiving drugs used to reduce blood clots (such as either clopidogrel and/or ticlopidine) are likely to require dose adjustments of bupropion.

In vitro studies indicate that bupropion is primarily metabolized to hydroxybupropion by the CYP2B6 isoenzyme (see Action and Clinical Pharmacology, Pharmacokinetics). Therefore, the potential exists for a drug interaction between WELLBUTRIN SR and drugs that affect the CYP2B6 isoenzyme (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 WELLBUTRIN SR following concomitant administration with other drugs or alternatively, the effect of concomitant administration of WELLBUTRIN SR 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).

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 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 two-, five- and two-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.

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

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 WELLBUTRIN SR 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-erythrobupropion AUC (16%) and C_max (32%).

Given the variable pharmacokinetics of bupropion in patients with either mild or moderate hepatic impairment (Child-Pugh Grade A or B), treatment with WELLBUTRIN SR should be initiated at the lowest recommended dose. Maintenance dose may be adjusted according to clinical response and tolerance. Caution should be exercised as there is no clinical experience with WELLBUTRIN SR in hepatically impaired patients (see also Warnings and Precautions).

The usual recommended dose of sustained release bupropion hydrochloride is 100 to 150 mg/day given once daily. As with all antidepressants, the full antidepressant effect of WELLBUTRIN SR 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 one week. In order to minimize the risk of seizures (see Warnings and Precautions), single doses of WELLBUTRIN SR must not exceed 150 mg. Doses of WELLBUTRIN SR greater than 150 mg/day should be administered b.i.d. preferably with at least 8 hours between successive doses.

Patients should be advised to swallow WELLBUTRIN SR 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.

WELLBUTRIN SR should be taken at the same time each day and no more than the recommended dose should be taken each day. If the normal administration time has been missed, the dose should be skipped and administration resumed at the normal administration time of the following day.

No pharmacokinetic or therapeutic trials have been conducted to systematically investigate dose requirements in patients who are elderly or debilitated (see Warnings and 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 sustained release bupropion hydrochloride should be initiated at the lowest recommended dose (100 mg/day).

Given the risks associated with both peak bupropion levels and drug accumulation, WELLBUTRIN SR is not recommended for use in patients with severe hepatic impairment. However, should clinical judgement deem it necessary, the drug should be used only with extreme caution (see also Warnings and Precautions). The dose should not exceed 150 mg every day or every other day in these patients. Any theoretical dose reduction for this patient population based on the findings of the pharmacokinetic studies may result in toxic drug levels in these patients (see Action and Clinical Pharmacology and Warnings and Precautions).

WELLBUTRIN SR is not indicated for use in children under 18 years of age (see Indications and Clinical Use and Warnings and Precautions, Potential Association with Behavioural and Emotional Changes, Including Self-harm).

WELLBUTRIN SR should be used with caution in patients with renal impairment due to the potential for drug accumulation, and a reduced frequency and/or dose should be considered (see Action and Clinical Pharmacology and Warnings and Precautions).

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

Post-marketing reports indicate that some neonates exposed to WELLBUTRIN SR, SSRIs, or other newer antidepressants late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding (see Warnings and Precautions). When treating pregnant women with WELLBUTRIN SR during the third trimester, the physician should carefully consider the potential risks and benefits of treatment. The physician may consider tapering WELLBUTRIN SR in the third trimester.

Infrequent were abnormal liver function, bruxism, gastric reflux, gingivitis, glossitis, increased salivation, jaundice, mouth ulcers, stomatitis, and thirst. Rare was edema of tongue. Also observed were colitis, esophagitis, gastrointestinal hemorrhage, gum hemorrhage, hepatitis, intestinal perforation, liver damage, pancreatitis, and stomach ulcer.

Adverse events commonly encountered during the clinical development of WELLBUTRIN SR (incidence of 5% or greater; and higher incidence in WELLBUTRIN SR-treated, than placebo-treated patients) were headache, constipation, dry mouth, nausea, dizziness, insomnia, tremor and tinnitus.

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

In placebo controlled studies of depression (987 patients treated with WELLBUTRIN SR, and 385 treated with placebo), adverse events caused discontinuation in 7% of WELLBUTRIN SR-treated patients and 3% of placebo-treated patients. The more common events leading to discontinuation of WELLBUTRIN SR included nervous system disturbances (2.2%), primarily agitation, anxiety and insomnia; skin disorders (1.9%), primarily rashes, pruritus, and urticaria; general body complaints (1.0%), primarily headaches, and digestive system disturbances (1.0%), primarily nausea. Two patients in WELLBUTRIN SR 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 WELLBUTRIN SR, 11% patients (361 out of 3100) discontinued treatment due to an adverse event. Adverse events leading to premature discontinuation in 1% or more of patients were: headache (1.1%), nausea (1.0%), and insomnia (1.0%). 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=1577) 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 WELLBUTRIN SR.

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

Rare was bronchospasm/dyspnea. Also observed was pneumonia and epistaxis.

Infrequent were chills, facial edema, musculoskeletal chest pain, and photosensitivity. Rare was malaise.

Adverse Event (%) Placebo-Controlled Studies: Treatment-Emergent Adverse Experiences Occurring in ≥1% of Patients in Any BUP SR Group for Studies 203, 205, and 212

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

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 WELLBUTRIN SR Tablets (n=3100). All treatment-emergent adverse events are included except those listed in Table 1, those events listed in other safety-related sections, 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 of major clinical importance are described in the Warnings and Precautions sections.

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 WELLBUTRIN SR is unknown.

Rare was maculopapular rash. Also observed were alopecia, hirsutism, angioedema, exfoliative dermatitis, erythema multiforme, and Stevens-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.

Also observed were arthritis, muscle rigidity/fever/ rhabdomyolysis and muscle weakness.

Infrequent were abnormal coordination, depersonalization, dysphoria, emotional lability, hostility, hyperkinesia, hypesthesia, suicidal ideation, and vertigo. Rare were amnesia, ataxia, derealization, and hypomania. Also observed were abnormal electroencephalogram (EEG), akinesia, aphasia, coma, delirium, dysarthria, dyskinesia, dystonia, euphoria, extrapyramidal syndrome, hallucinations, hypokinesia, increased libido, manic reaction, neuralgia, neuropathy, paranoid reaction, and unmasking tardive dyskinesia.

Post-marketing reports suggest that the reintroduction of WELLBUTRIN SR in patients who experienced a seizure is associated with a risk of seizure reoccurrence in some cases. Thus, patients should not restart WELLBUTRIN SR therapy if they have had a seizure on a bupropion formulation (WELLBUTRIN SR, WELLBUTRIN XL, or ZYBAN). See Warnings and Precautions.

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

The information included under Adverse Reactions is based on data from clinical trials with WELLBUTRIN SR (bupropion hydrochloride), the sustained release formulation of bupropion in the treatment of depression. Information on additional adverse events associated with the sustained release formulation of bupropion as well as the immediate release formulation of bupropion, is included in a separate subsection (see Events Observed During Development and Post-Marketing Experience of Bupropion with Other Formulations or Indications).

WELLBUTRIN SR 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.

Infrequent were edema and peripheral edema. Also observed was glycosuria.

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

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

WELLBUTRIN SR is not indicated for use in patients below the age of 18 years (see Warnings and Precautions, General, Potential Association with Behavioural and Emotional Changes, Including Self-harm).

WELLBUTRIN SR is indicated for the symptomatic relief of major depressive illness. The effectiveness of WELLBUTRIN SR in long-term use (greater than 8 weeks) has not been evaluated in controlled trials. Therefore, the physician who elects to use WELLBUTRIN SR for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient.

In the event of overdose, hospitalization 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 WELLBUTRIN SR, 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 center for additional information on the treatment of any overdose. Telephone numbers for certified poison control centers are listed in the Compendium of Pharmaceuticals and Specialties (CPS).

In addition to those events reported under Adverse Reactions, overdose has resulted in symptoms including drowsiness, loss of consciousness and ECG changes such as conduction disturbances (including QRS prolongation) or arrhythmias. Three overdoses with WELLBUTRIN SR (bupropion hydrochloride) occurred during clinical trials. One patient ingested 3000 mg of WELLBUTRIN SR tablets and vomited quickly after the overdose; the patient experienced blurred vision and lightheadedness. A second patient ingested a “handful” of WELLBUTRIN SR tablets and experienced confusion, lethargy, nausea, jitteriness, and seizure. A third patient ingested 3600 mg of WELLBUTRIN SR 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 4200 mg and recovered without significant sequelae. Another patient who ingested 9000 mg of WELLBUTRIN 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 WELLBUTRIN, 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 WELLBUTRIN alone included hallucinations, loss of consciousness, and sinus tachycardia. Fever, muscle rigidity, rhabdomyolysis, hypotension, stupor, coma, and respiratory failure have been reported when WELLBUTRIN was part of multiple drug overdoses.

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

The possibility of a suicide attempt in seriously depressed patients is inherent to the illness and may persist until significant remission occurs. Patients with depression may experience worsening of their depressive symptoms and/or the emergence of suicidal ideation and behaviours (suicidality) whether or not they are taking antidepressant medications. As improvement may not occur during the first few weeks or more of treatment, patients should be closely monitored for clinical worsening (including development of new symptoms) and suicidality, especially at the beginning of a course of treatment, or at the time of dosage changes, either increases or decreases. Close supervision of high risk patients should accompany initial drug therapy, and consideration should be given to the need for hospitalization. (See Warnings and Precautions, Potential Association with Behavioural and Emotional Changes, Including Self-harm.)

It should be noted that a causal role for SSRIs and other newer antidepressants in inducing self-harm or harm to others has not been established.

In order to reduce the risk of overdose, prescriptions for WELLBUTRIN SR (bupropion hydrochloride) should be written for the smallest number of tablets consistent with good patient management.

There are clinical trial and post-marketing reports with SSRIs and other newer antidepressants, in both pediatrics and adults, of severe agitation-type adverse events coupled with self-harm or harm to others. The agitation-type events include: akathisia, agitation, disinhibition, emotional lability, hostility, aggression, depersonalization. In some cases, the events occurred within several weeks of starting treatment.

Rigorous clinical monitoring for suicidal ideation or other indicators of potential for suicidal behaviour is advised in patients of all ages given an antidepressant drug. This includes monitoring for agitation-type emotional and behavioural changes.

Recent analyses of placebo-controlled clinical trial safety databases from SSRIs and other newer antidepressants suggests that use of these drugs in patients under the age of 18 may be associated with behavioural and emotional changes, including an increased risk of suicidal ideation and behaviour over that of placebo.

Pregnancy, Labour and Delivery: There are no adequate and well-controlled studies of WELLBUTRIN SR in pregnant women. WELLBUTRIN SR should thus not be used during pregnancy unless the potential benefit is judged to outweigh the potential risk.

Post-marketing reports indicate that some neonates exposed to SSRIs (Selective Serotonin Reuptake Inhibitors), or other newer antidepressants, such as WELLBUTRIN SR, 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 antidepressants, or, possibly, a drug discontinuation syndrome. When treating a pregnant woman with WELLBUTRIN SR during the third trimester, the physician should carefully consider the potential risks and benefits of treatment. (See Dosage and Administration.)

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 on the lowest recommended dose. Bupropion is not recommended for patients with severe hepatic impairment (see Warnings and Precautions, and also Dosage and Administration). All patients with hepatic impairment should be closely monitored for possible adverse effects that could indicate high drug and metabolite levels (see Action and Clinical Pharmacology; Warnings and Precautions and Dosage and Administration).

Bupropion is extensively metabolized in the liver to active metabolites, which are largely further metabolised before being excreted by the kidneys. WELLBUTRIN SR treatment of patients with renal impairment should be initiated at a reduced dosage regimen, as 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.

In clinical trials WELLBUTRIN SR was associated with dose-related weight loss. In eight week controlled trials mean weight loss for trial completers was 0.1 kg for placebo, 0.8 kg for WELLBUTRIN SR 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 anorectic and/or weight reducing effect of bupropion hydrochloride should be considered.

Anaphylactoid/anaphylactic 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 1-3 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, lead to discontinuation of 1.5% and 1.9%, respectively of bupropion-treated subjects. A patient should stop taking WELLBUTRIN SR 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 Drug Interactions, Alcohol Interactions).

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 (see Action and Clinical Pharmacology, Pharmacokinetics).

Bupropion is extensively metabolized in the liver to active metabolites, of which some are eliminated by the kidney, 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 Warnings and Precautions, Hepatic Impairment or Renal Impairment).

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.

Patients treated with WELLBUTRIN SR 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.

Patients should be made aware that WELLBUTRIN SR contains the same active ingredient (bupropion hydrochloride) as ZYBAN and WELLBUTRIN XL. WELLBUTRIN SR should not be administered to patients already receiving a product containing bupropion hydrochloride (see Contraindications).

Data for WELLBUTRIN SR Tablets revealed a seizure incidence of approximately 0.1% (3 of 3100 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% (4/1000), above the recommended dose, at 400 mg/day. Data for the immediate release bupropion 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 bupropion suggests that the estimated seizure incidence increases almost tenfold 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.

Antidepressants can precipitate manic episodes in bipolar patients during the depressed phase of their illness and may activate latent psychosis in other susceptible patients. WELLBUTRIN SR is expected to pose similar risks.

WELLBUTRIN SR is not indicated for use in patients below the age of 18 years (see Warnings and Precautions, Potential Association with Behavioural and Emotional Changes, Including Self-harm). See also Indications and Clinical Use, Pediatrics (<18 years of age) and Dosage and Administration, Special Patient Populations, Pediatrics.

Any psychoactive drug may impair judgement, 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.

The risk of seizure occurring with bupropion use appears to be associated with the presence of predisposing risk factors. Therefore extreme caution should be used when treating patients with predisposing factors which increase the risk of seizures, including: history of head trauma or prior seizure; central nervous system (CNS) tumour; the presence of severe hepatic impairment; excessive use of alcohol; addiction to opiates, cocaine, or stimulants; use of concomitant medications that lower seizure threshold, including but not limited to: antipsychotics, antidepressants, lithium, amantadine, theophylline, systemic steroids, quinolone antibiotics, and anti-malarials; use of over-the-counter stimulants or anorectics; diabetes treated with oral hypoglycemics or insulin.

The above group of risk factors, including medications, should not be considered exhaustive; for each patient, all potential predisposing factors must be carefully considered.

In Order to Minimize the Risk of Seizure: The total daily dose of WELLBUTRIN SR must not exceed 300 mg (the maximum recommended dose); no single dose of WELLBUTRIN SR may exceed 150 mg, in order to avoid high peak concentrations of bupropion and/or its metabolites.

If a Seizure Occurs: Patients should be warned that if they experience a seizure while taking WELLBUTRIN SR, they should contact their doctor or be taken to a hospital emergency ward immediately, and should stop taking WELLBUTRIN SR. Treatment should not be restarted if a patient has experienced a seizure while taking WELLBUTRIN SR, WELLBUTRIN XL or ZYBAN.

In placebo controlled trials patients receiving WELLBUTRIN SR Tablets experienced an increased incidence of insomnia and anxiety relative to those receiving placebo (see Adverse Reactions and Warnings and Precautions, Potential Association with Behavioural and Emotional Changes, Including Self-harm). These symptoms were sometimes of sufficient magnitude to require discontinuation of WELLBUTRIN SR, or concurrent treatment with sedative/hypnotic drugs. Insomnia may be minimized by avoiding bedtime doses and, if necessary, reduction in dose.

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 WELLBUTRIN SR, 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.

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 pre-existing hypertension.

Data from a comparative study of the sustained-release formulation of bupropion (ZYBAN Sustained-Release Tablets), 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 sustained-release bupropion and NTS. In this study, 6.1% of patients treated with the combination of sustained- release bupropion and NTS had treatment-emergent hypertension compared to 2.5%, 1.6%, and 3.1% of patients treated with sustained-release bupropion, NTS, and placebo, respectively. The majority of these patients had evidence of pre-existing 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 bupropion 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. In a study of depressed inpatients with stable heart failure, bupropion was associated with a rise in supine blood pressure, resulting in discontinuation of two patients for exacerbation of baseline hypertension.

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

The first study involved 8 subjects with alcoholic liver disease, and 8 healthy matched controls. While mean AUC values were not significantly different, individual AUC values for both the parent drug bupropion and the primary metabolite hydroxybupropion were more variable in subjects with alcoholic liver disease, and increased by approximately 50% over those of healthy volunteers. The mean half-life of the primary metabolite hydroxybupropion was significantly longer by approximately 40% in subjects with alcoholic liver disease than in healthy volunteers (32±14 hours versus 21±5 hours, respectively). For all other pharmacokinetic values, for both parent drug and metabolites, there were minimal differences between the two groups.

The second study involved 17 subjects with hepatic impairment (n=9 mild/Grade A child-Pugh rating; n=8 severe/Grade C Child-Pugh rating) and 8 healthy matched controls. In the severe group, the mean value for bupropion AUC was increased threefold over control values, with mean clearance decreased proportionately. Mean C_max and plasma half-life were increased by approximately 70% and 40% respectively. For the primary metabolites, mean AUC was increased by approximately 30%-50%, with mean clearance decreased proportionately. Mean C_max was lower by approximately 30% to 70%, and mean plasma half life increased threefold.

In the mild group, while mean values were not statistically increased from those of controls, the variability in the pharmacokinetic values was higher in the subjects with impairment; a sub-group of 1 to 3 subjects (dependent on pharmacokinetic parameter examined) showed individual values which were in the range of the severely impaired subjects. For the primary metabolites, the differences between groups in pharmacokinetic parameters were minimal.

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

The effects of age on the pharmacokinetics of bupropion and its metabolites have not been fully characterized, but an exploration of steady state bupropion concentrations from several depression efficacy studies involving patients dosed in a range of 300 to 750 mg/day, on a three times a day schedule, revealed no relationship between age (18 to 83 years) and plasma concentration of bupropion. A single-dose pharmacokinetic study demonstrated that the disposition of bupropion and its metabolites in elderly subjects was similar to that of younger subjects. These data suggest there is no prominent effect of age on bupropion concentration: however, another single and multiple dose pharmacokinetic study, has suggested that the elderly are at increased risk for accumulation of bupropion and its metabolites (see Warnings and Precautions and Dosage and Administration).

In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 µg/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 (V_ss/F) estimated from a single 150 mg dose given to 17 subjects is 1950 L (20% CV).

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.

Bupropion has not been administered intravenously 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 two single-dose (150 mg) studies the mean peak concentration (C_max) values were 91 and 143 ng/mL. At steady state, the mean C_max following a 150 mg dose every 12 hours was 136 ng/mL.

Three studies in healthy volunteers suggest that exposure to bupropion may be increased when sustained release bupropion tablets are taken with food. When taken following food, peak plasma concentration of bupropion (C_max) increased by 11%, 16% and 35% in three studies. The overall exposure to bupropion (AUC) increased by 17%, 17% and 19% in these three studies.

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 norepinephrine (NE) reuptake and dopamine (DA) reuptake. Its major metabolite (hydroxybupropion), which in man is present at blood levels 10-20-fold higher than bupropion, blocks only NE reuptake.

The non-serotonergic mechanism of action of bupropion likely contributes to a distinct side effect profile that includes low rates of sexual dysfunction and somnolence.

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

The influence of race (Asian, Black and Caucasian) on the pharmacokinetics of bupropion (bupropion hydrochloride immediate release tablets) was evaluated based on dose normalized data pooled from five healthy volunteer studies. A comparison of pharmacokinetic parameter values did not detect any important differences in race with respect to AUC (p=0.5564) and C_max (p=0.8184).

In two single-dose (150 mg) studies the mean (±% CV) apparent clearance (Cl/F) of bupropion was 135 (±20%) and 209 L/h (±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 ¹⁴C-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.

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. 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.

Because bupropion is extensively metabolized, there is the potential for drug-drug interactions, particularly with those agents that are metabolized by the CYP2B6 isoenzyme. Although bupropion is not metabolized by CYP2D6, there is the potential for drug-drug interactions when bupropion is co-administered with drugs metabolized by this isoenzyme (see Drug Interactions).

In vitro, bupropion and its major metabolites had essentially no affinity for β-adrenergic, dopaminergic, GABA, benzodiazepine, 5HT1A, glycine and adenosine receptors, and only weakly inhibited α-adrenergic receptors in rat brain, α2-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.

The pharmacokinetics of WELLBUTRIN SR in individuals under 18 years old has not been evaluated.