Wellbutrin SR - Warnings & Precautions

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 preexisting hypertension.

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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 WELLBUTRIN SR Tablets in patients with a recent history of myocardial infarction or unstable heart disease. Therefore, care should be exercised if it is used in these groups. Bupropion was well tolerated in depressed patients who had previously WELLBUTRIN SR ® (bupropion hydrochloride) Sustained-Release Tablets antidepressants, and was also generally well tolerated in a group of 36 depressed inpatients with stable congestive heart failure (CHF). However, bupropion was associated with a rise in supine blood pressure in the study of patients with CHF, resulting in discontinuation of treatment in 2 patients for exacerbation of baseline hypertension.

Hepatic Impairment

WELLBUTRIN SR should be used with extreme caution in patients with severe hepatic cirrhosis. In these patients, a reduced frequency and/ or dose is required.

WELLBUTRIN SR should be used with caution in patients with hepatic impairment (including mild to moderate hepatic cirrhosis) and reduced frequency and/ or dose should be considered in patients with mild to moderate hepatic cirrhosis. All patients with hepatic impairment should be closely monitored for possible adverse effects that could indicate high drug and metabolite levels (see CLINICAL PHARMACOLOGY, WARNINGS, and DOSAGE AND ADMINISTRATION).

Renal Impairment

No studies have been conducted in patients with renal impairment. Bupropion is extensively metabolized in the liver to active metabolites, which are further metabolized and subsequently excreted by the kidneys. WELLBUTRIN SR should be used with caution in patients with renal impairment and a reduced frequency and/ or dose 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 that could indicate high drug or metabolite levels.

Information for Patients:

See the tear-off leaflet at the end of this labeling for Patient Information. Patients should be made aware that WELLBUTRIN SR contains the same active ingredient found in ZYBAN, used as an aid to smoking cessation treatment, and that WELLBUTRIN SR should not be used in combination with ZYBAN or any other medications that contain bupropion hydrochloride. Physicians are advised to discuss the following issues with patients: As dose is increased during initial titration to doses above 150 mg/ day, patients should be instructed to take WELLBUTRIN SR Tablets in 2 divided doses, preferably with at least 8 hours between successive doses, to minimize the risk of seizures.

Patients should be told that WELLBUTRIN SR should be discontinued and not restarted if they experience a seizure while on treatment.

Patients should be told that any CNS-active drug like WELLBUTRIN SR Tablets may impair their ability to perform tasks requiring judgment or motor and cognitive skills. Consequently, until they are reasonably certain that WELLBUTRIN SR Tablets do not adversely affect their performance, they should refrain from driving an automobile or operating complex, hazardous machinery. Patients should be told that the excessive use or abrupt discontinuation of alcohol or sedatives (including benzodiazepines) may alter the seizure threshold. Some patients have reported lower alcohol tolerance during treatment with WELLBUTRIN SR. Patients should be advised that the consumption of alcohol should be minimized or avoided.

Patients should be advised to inform their physicians if they are taking or plan to take any prescription or over-the-counter drugs. Concern is warranted because WELLBUTRIN SR Tablets and other drugs may affect each other's metabolism. Patients should be advised to notify their physicians if they become pregnant or intend to become pregnant during therapy.

WELLBUTRIN SR ® (bupropion hydrochloride) Sustained-Release Tablets

Patients should be advised to swallow WELLBUTRIN SR Tablets whole so that the release rate is not altered. Do not chew, divide, or crush tablets.

Laboratory Tests

There are no specific laboratory tests recommended.

Drug Interactions

Few systemic 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. Because bupropion is extensively metabolized, the coadministration of other drugs may affect its clinical activity. In vitro studies indicate that bupropion is primarily metabolized to hydroxybupropion by the CYP2B6 isoenzyme. 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. 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 WELLBUTRIN SR Tablets with and without 800 mg of cimetidine, the pharmacokinetics of bupropion and hydroxybupropion were unaffected. However, there were 16% and 32% increases in the AUC and Cmax, respectively, of the combined moieties of threohydrobupropion and erythrohydrobupropion.

While not systematically studied, certain drugs may induce the metabolism of bupropion (e. g., carbamazepine, phenobarbital, phenytoin). Animal data indicated that bupropion may be an inducer of drug-metabolizing enzymes in humans. In one study, following chronic administration of bupropion, 100 mg 3 times daily to 8 healthy male volunteers for 14 days, there was no evidence of induction of its own metabolism.

Nevertheless, there may be the potential for clinically important alterations of blood levels of coadministered drugs. 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 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 Cmax, AUC, and t1/ 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. Therefore, co-administration 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, thioridazine), 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.

WELLBUTRIN SR ® (bupropion hydrochloride) Sustained-Release Tablets

MAO Inhibitors

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

Levodopa and Amantadine: Limited clinical data suggest a higher incidence of adverse experiences in patients receiving bupropion concurrently with either levodopa or amantadine.

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

Drugs That Lower Seizure Threshold:

Concurrent administration of WELLBUTRIN SR Tablets and agents (e. g., antipsychotics, other antidepressants, theophylline, 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. Nicotine Transdermal System: (see PRECAUTIONS: Cardiovascular Effects).

Alcohol:

In post-marketing experience, there have been rare reports of adverse neuropsychiatric events or reduced alcohol tolerance in patients who were drinking alcohol during treatment with WELLBUTRIN SR. The consumption of alcohol during treatment with WELLBUTRIN SR should be minimized or avoided (also see CONTRAINDICATIONS).

Carcinogenesis, Mutagenesis, Impairment of Fertility

Lifetime carcinogenicity studies were performed in rats and mice at doses up to 300 and 150 mg/ kg/ day, respectively. These doses are approximately 7 and 2 times the maximum recommended human dose (MRHD), respectively, on a mg/ m 2 basis. In the rat study there was an increase in nodular proliferative lesions of the liver at doses of 100 to 300 mg/ kg/ day (approximately 2 to 7 times the MRHD on a mg/ m 2 basis); lower doses were not tested. The question of whether or not such lesions may be precursors of neoplasms of the liver is currently unresolved. Similar liver lesions were not seen in the mouse study, and no increase in malignant tumors of the liver and other organs was seen in either study. Bupropion produced a positive response (2 to 3 times control mutation rate) in 2 of 5 strains in the Ames bacterial mutagenicity test and an increase in chromosomal aberrations in 1 of 3 in vivo rat bone marrow cytogenetic studies.

A fertility study in rats at doses up to 300 mg/ kg/ day revealed no evidence of impaired fertility.

Pregnancy

Teratogenic Effects

Pregnancy Category B

Teratology studies have been performed at doses up to 450 mg/ kg in rats, and at doses up to 150 mg/ kg in rabbits (approximately 7 to 11 and 7 times the MRHD, respectively, on a mg/ m 2 basis), and have revealed no evidence of 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. To monitor fetal outcomes of pregnant women exposed to WELLBUTRIN SR, GlaxoSmithKline maintains a Bupropion Pregnancy Registry. Health care providers are encouraged to register patients by calling (800) 336-2176.

Labor and Delivery:

The effect of WELLBUTRIN SR Tablets on labor and delivery in humans is unknown.

Nursing Mothers:

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 Tablets, 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.

WELLBUTRIN SR ® (bupropion hydrochloride) Sustained-Release Tablets

Pediatric Use

The safety and effectiveness of WELLBUTRIN SR Tablets in pediatric patients below 18 years old have not been established. The immediate-release formulation of bupropion was studied in 104 pediatric patients (age range, 6 to 16) in clinical trials of the drug for other indications. Although generally well tolerated, the limited exposure is insufficient to assess the safety of bupropion in pediatric patients.

Geriatric Use

Of the approximately 6,000 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 pharmacokinetic study, single and multiple dose, has suggested that the elderly are at increased risk for accumulation of bupropion and its metabolites (see CLINICAL PHARMACOLOGY). Bupropion is extensively metabolized in the liver to active metabolites, which are further metabolized and excreted by the kidneys. 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 AND ADMINISTRATION).