WELLBUTRIN

WELLBUTRIN SR is supplied for oral administration as 100‑mg (blue), 150‑mg (purple), and 200‑mg (light pink), film‑coated, sustained‑release tablets. Each tablet contains the labeled amount of bupropion hydrochloride and the inactive ingredients: carnauba wax, cysteine hydrochloride, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, and titanium dioxide and is printed with edible black ink. In addition, the 100‑mg tablet contains FD&C Blue No. 1 Lake, the 150‑mg tablet contains FD&C Blue No. 2 Lake and FD&C Red No. 40 Lake, and the 200‑mg tablet contains FD&C Red No. 40 Lake.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

The exact mechanism of the antidepressant action of bupropion is not known, but is presumed to be related to noradrenergic and/or dopaminergic mechanisms. Bupropion is a relatively weak inhibitor of the neuronal reuptake of norepinephrine and dopamine, and does not inhibit the reuptake of serotonin. Bupropion does not inhibit monoamine oxidase.

12.3 Pharmacokinetics

Bupropion is a racemic mixture. The pharmacological activity and pharmacokinetics of the individual enantiomers have not been studied. The mean elimination half‑life (±SD) of bupropion after chronic dosing is 21 (±9) hours, and steady-state plasma concentrations of bupropion are reached within 8 days.

Absorption: The absolute bioavailability of WELLBUTRIN SR in humans has not been determined because an intravenous formulation for human use is not available. However, it appears likely that only a small proportion of any orally administered dose reaches the systemic circulation intact. In rat and dog studies, the bioavailability of bupropion ranged from 5% to 20%.

In humans, following oral administration of WELLBUTRIN SR, peak plasma concentration (C_max) of bupropion is usually achieved within 3 hours.

In a trial comparing chronic dosing with WELLBUTRIN SR 150 mg twice daily to bupropion immediate‑release formulation 100 mg 3 times daily, the steady state C_max for bupropion after WELLBUTRIN SR administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both C_max and AUC. Thus, at steady state, WELLBUTRIN SR given twice daily, and the immediate‑release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites.

WELLBUTRIN SR can be taken with or without food. Bupropion C_max and AUC was increased by 11% to 35% and 16% to 19%, respectively, when WELLBUTRIN SR was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant.

Distribution: In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg/mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion; whereas, the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion.

Metabolism: Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert‑butyl group of bupropion, and the amino‑alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta‑chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion.

Following a single dose administration of WELLBUTRIN SR in humans, C_max of hydroxybupropion occurs approximately 6 hours post‑dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half‑life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half‑lives are longer, 33 (±10) and 37 (±13) hours, respectively, and steady‑state AUCs are 1.5 and 7 times that of bupropion, respectively.

Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day.

Elimination: 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. Only 0.5% of the oral dose was excreted as unchanged bupropion.

Population Subgroups: Factors or conditions altering metabolic capacity (e.g., liver disease, congestive heart failure [CHF], 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.

Renal Impairment: There is limited information on the pharmacokinetics of bupropion in patients with renal impairment. An inter-trial comparison between normal subjects and subjects with end-stage renal failure demonstrated that the parent drug C_max and AUC values were comparable in the 2 groups, whereas the hydroxybupropion and threohydrobupropion metabolites had a 2.3- and 2.8-fold increase, respectively, in AUC for subjects with end-stage renal failure. A second trial, comparing normal subjects and subjects with moderate‑to‑severe renal impairment (GFR 30.9 ± 10.8 mL/min), showed that after a single 150-mg dose of sustained-release bupropion, exposure to bupropion was approximately 2-fold higher in subjects with impaired renal function, while levels of the hydroxybupropion and threo/erythrohydrobupropion (combined) metabolites were similar in the 2 groups. Bupropion is extensively metabolized in the liver to active metabolites, which are further metabolized and subsequently excreted by the kidneys. The elimination of the major metabolites of bupropion may be reduced by impaired renal function. WELLBUTRIN SR should be used with caution in patients with renal impairment and a reduced frequency and/or dose should be considered [see Use in Specific Populations (8.6)].

Hepatic Impairment: The effect of hepatic impairment on the pharmacokinetics of bupropion was characterized in 2 single-dose trials, one in subjects with alcoholic liver disease and one in subjects with mild-to-severe cirrhosis. The first trial demonstrated that the half‑life of hydroxybupropion was significantly longer in 8 subjects with alcoholic liver disease than in 8 healthy volunteers (32 ± 14 hours versus 21 ± 5 hours, respectively). Although not statistically significant, the AUCs for bupropion and hydroxybupropion were more variable and tended to be greater (by 53% to 57%) in volunteers with alcoholic liver disease. The differences in half‑life for bupropion and the other metabolites in the 2 groups were minimal.

The second trial demonstrated no statistically significant differences in the pharmacokinetics of bupropion and its active metabolites in 9 subjects with mild-to-moderate hepatic cirrhosis compared with 8 healthy volunteers. However, more variability was observed in some of the pharmacokinetic parameters for bupropion (AUC, C_max, and T_max) and its active metabolites (t_½) in subjects with mild-to-moderate hepatic cirrhosis. In subjects with severe hepatic cirrhosis, significant alterations in the pharmacokinetics of bupropion and its metabolites were seen (Table 5).

Table 5. Pharmacokinetics of Bupropion and Metabolites in Patients With Severe Hepatic Cirrhosis: Ratio Relative to Healthy Matched Controls

^a = Difference.

Left Ventricular Dysfunction: During a chronic dosing trial with bupropion in 14 depressed subjects with left ventricular dysfunction (history of CHF or an enlarged heart on x-ray), there was no apparent effect on the pharmacokinetics of bupropion or its metabolites, compared with healthy volunteers.

Age: The effects of age on the pharmacokinetics of bupropion and its metabolites have not been fully characterized, but an exploration of steady‑state bupropion concentrations from several depression efficacy trials involving subjects dosed in a range of 300 to 750 mg per day, on a 3 times daily schedule, revealed no relationship between age (18 to 83 years) and plasma concentration of bupropion. A single‑dose pharmacokinetic trial 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 pharmacokinetics trial suggested that the elderly are at increased risk for accumulation of bupropion and its metabolites [see Use in Specific Populations (8.5)].

Gender: Pooled analysis of bupropion pharmacokinetic data from 90 healthy male and 90 healthy female volunteers revealed no sex‑related differences in the peak plasma concentrations of bupropion. The mean systemic exposure (AUC) was approximately 13% higher in male volunteers compared with female volunteers. The clinical significance of this finding is unknown.

Smokers: The effects of cigarette smoking on the pharmacokinetics of bupropion were studied in 34 healthy male and female volunteers; 17 were chronic cigarette smokers and 17 were nonsmokers. Following oral administration of a single 150‑mg dose of bupropion, there were no statistically significant differences in C_max, half-life, T_max, AUC, or clearance of bupropion or its active metabolites between smokers and nonsmokers.

Drug Interactions: Potential for Other Drugs to Affect WELLBUTRIN SR: In vitro studies indicate that bupropion is primarily metabolized to hydroxybupropion by CYP2B6. Therefore, the potential exists for drug interactions between WELLBUTRIN SR and drugs that are inhibitors or inducers of CYP2B6. In addition, in vitro studies suggest that paroxetine, sertraline, norfluoxetine, fluvoxamine, and nelfinavir inhibit the hydroxylation of bupropion.

Inhibitors of CYP2B6: Ticlopidine, Clopidogrel: In a trial in healthy male volunteers, clopidogrel 75 mg once daily or ticlopidine 250 mg twice daily increased exposures (C_max and AUC) of bupropion by 40% and 60% for clopidogrel, and by 38% and 85% for ticlopidine, respectively. The exposures (C_max and AUC) of hydroxybupropion were decreased 50% and 52%, respectively, by clopidogrel, and 78% and 84%, respectively, by ticlopidine. This effect is thought to be due to the inhibition of the CYP2B6-catalyzed bupropion hydroxylation.

Prasugrel: Prasugrel is a weak inhibitor of CYP2B6. In healthy subjects, prasugrel increased bupropion C_max and AUC values by 14% and 18%, respectively, and decreased C_max and AUC values of hydroxybupropion, an active metabolite of bupropion, by 32% and 24%, respectively.

Cimetidine: The threohydrobupropion metabolite of bupropion does not appear to be produced by cytochrome P450 enzymes. 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 bupropion 300 mg with and without cimetidine 800 mg, the pharmacokinetics of bupropion and hydroxybupropion were unaffected. However, there were 16% and 32% increases in the AUC and C_max, respectively, of the combined moieties of threohydrobupropion and erythrohydrobupropion.

Citalopram: Citalopram did not affect the pharmacokinetics of bupropion and its three metabolites.

Inducers of CYP2B6: Ritonavir and Lopinavir: In a healthy volunteer trial, ritonavir 100 mg twice daily reduced the AUC and C_max of bupropion by 22% and 21%, respectively. The exposure of the hydroxybupropion metabolite was decreased by 23%, the threohydrobupropion decreased by 38%, and the erythrohydrobupropion decreased by 48%.

In a second healthy volunteer trial, ritonavir 600 mg twice daily decreased the AUC and the C_max of bupropion by 66% and 62%, respectively. The exposure of the hydroxybupropion metabolite was decreased by 78%, the threohydrobupropion decreased by 50%, and the erythrohydrobupropion decreased by 68%.

In another healthy volunteer trial, lopinavir 400 mg/ritonavir 100 mg twice daily decreased bupropion AUC and C_max by 57%. The AUC and C_max of hydroxybupropion were decreased by 50% and 31%, respectively.

Efavirenz: In a trial in healthy volunteers, efavirenz 600 mg once daily for 2 weeks reduced the AUC and Cmax of bupropion by approximately 55% and 34%, respectively. The AUC of hydroxybupropion was unchanged, whereas Cmax of hydroxybupropion was increased by 50%.

Carbamazepine, Phenobarbital, Phenytoin: While not systematically studied, these drugs may induce the metabolism of bupropion.

Potential for WELLBUTRIN SR to Affect Other Drugs: Animal data indicated that bupropion may be an inducer of drug-metabolizing enzymes in humans. In one trial, following chronic administration of bupropion 100 mg three times daily to 8 healthy male volunteers for 14 days, there was no evidence of induction of its own metabolism. Nevertheless, there may be potential for clinically important alterations of blood levels of co-administered drugs.

Drugs Metabolized by CYP2D6: In vitro, bupropion and its metabolites (erythrohydrobupropion, threohydrobupropion, hydroxybupropion) are CYP2D6 inhibitors. In a clinical trial of 15 male subjects (ages 19 to 35 years) who were extensive metabolizers of CYP2D6, bupropion 300 mg per day followed by a single dose of 50 mg desipramine increased the C_max, 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.

Citalopram: Although citalopram is not primarily metabolized by CYP2D6, in one trial bupropion increased the C_max and AUC of citalopram by 30% and 40%, respectively.

Lamotrigine: Multiple oral doses of bupropion had no statistically significant effects on the single-dose pharmacokinetics of lamotrigine in 12 healthy volunteers.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Lifetime carcinogenicity studies were performed in rats and mice at bupropion doses up to 300 and 150 mg/kg/day, respectively. These doses are approximately 7 and 2 times the MRHD, respectively, on a mg/m² 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/m² basis); lower doses were not tested. The question of whether or not such lesions may be precursors of neoplasms of the liver is currently unresolved. Similar liver lesions were not seen in the mouse study, and no increase in malignant tumors of the liver and other organs was seen in either study.

Bupropion produced a positive response (2 to 3 times control mutation rate) in 2 of 5 strains in the Ames bacterial mutagenicity assay. Bupropion produced 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.

14 CLINICAL STUDIES

The efficacy of the immediate‑release formulation of bupropion in the treatment of major depressive disorder was established in two 4‑week, placebo‑controlled trials in adult inpatients with MDD (Trials 1 and 2 in Table 6) and in one 6‑week, placebo‑controlled trial in adult outpatients with MDD (Trial 3 in Table 6). In the first trial, the dose range of bupropion was 300 mg to 600 mg per day administered in divided doses; 78% of subjects were treated with doses of 300 mg to 450 mg per day. This trial demonstrated the effectiveness of the immediate‑release formulation of bupropion by the Hamilton Depression Rating Scale (HDRS) total score, the HDRS depressed mood item (item 1), and the Clinical Global Impressions severity score (CGI-S). The second trial included 2 doses of the immediate‑release formulation of bupropion (300 and 450 mg per day) and placebo. This trial demonstrated the effectiveness of the immediate‑release formulation of bupropion, but only at the 450‑mg-per-day dose. The efficacy results were significant for the HDRS total score and the CGI-S score, but not for HDRS item 1. In the third trial, outpatients were treated with 300 mg per day of the immediate‑release formulation of bupropion. This trial demonstrated the efficacy of the immediate‑release formulation of bupropion as measured by the HDRS total score, the HDRS item 1, the Montgomery‑Asberg Depression Rating Scale (MADRS), the CGI-S score, and the CGI-Improvement Scale (CGI-I) score.

Table 6. Efficacy of Immediate-Release Bupropion for the Treatment of Major Depressive Disorder

n: sample size; SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: unadjusted confidence interval included for doses that were demonstrated to be effective; NA: not available.

^aDifference (drug minus placebo) in least-squares estimates with respect to the primary efficacy parameter. For Trial 1, it refers to the mean score at the endpoint visit; for Trials 2 and 3, it refers to the mean change from baseline to the endpoint visit.

^bDoses that are demonstrated to be statistically significantly superior to placebo.

Although there are not as yet independent trials demonstrating the antidepressant effectiveness of the sustained‑release formulation of bupropion, trials have demonstrated the bioequivalence of the immediate‑release and sustained‑release forms of bupropion under steady‑state conditions, i.e., bupropion sustained‑release 150 mg twice daily was shown to be bioequivalent to 100 mg 3 times daily of the immediate‑release formulation of bupropion, with regard to both rate and extent of absorption, for parent drug and metabolites.

In a longer-term trial, outpatients meeting DSM-IV criteria for major depressive disorder, recurrent type, who had responded during an 8-week open trial on WELLBUTRIN SR (150 mg twice daily) were randomized to continuation of their same dose of WELLBUTRIN SR or placebo for up to 44 weeks of observation for relapse. Response during the open phase was defined as CGI Improvement score of 1 (very much improved) or 2 (much improved) for each of the final 3 weeks. Relapse during the double-blind phase was defined as the investigator’s judgment that drug treatment was needed for worsening depressive symptoms. Patients receiving continued treatment with WELLBUTRIN SR experienced significantly lower relapse rates over the subsequent 44 weeks compared with those receiving placebo.

16 HOW SUPPLIED/STORAGE AND HANDLING

WELLBUTRIN SR Sustained‑Release Tablets, 100 mg of bupropion hydrochloride, are blue, round, biconvex, film‑coated tablets printed with “WELLBUTRIN SR 100” in bottles of 60 (NDC 0173-0947-55) tablets.

WELLBUTRIN SR Sustained‑Release Tablets, 150 mg of bupropion hydrochloride, are purple, round, biconvex, film‑coated tablets printed with “WELLBUTRIN SR 150” in bottles of 60 (NDC 0173-0135-55) tablets.

WELLBUTRIN SR Sustained-Release Tablets, 200 mg of bupropion hydrochloride, are light pink, round, biconvex, film-coated tablets printed with “WELLBUTRIN SR 200” in bottles of 60 (NDC 0173-0722-00) tablets.

Store at room temperature, 20° to 25°C (68° to 77°F); excursions permitted between 15°C and 30°C (59°F and 86°F) [see USP Controlled Room Temperature]. Protect from light and moisture.

17 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Inform patients, their families, and their caregivers about the benefits and risks associated with treatment with WELLBUTRIN SR and counsel them in its appropriate use.

A patient Medication Guide about “Antidepressant Medicines, Depression and Other Serious Mental Illnesses, and Suicidal Thoughts or Actions,” “Quitting Smoking, Quit-Smoking Medications, Changes in Thinking and Behavior, Depression, and Suicidal Thoughts or Actions,” and “What Other Important Information Should I Know About WELLBUTRIN SR?” is available for WELLBUTRIN SR. Instruct patients, their families, and their caregivers to read the Medication Guide and assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. The complete text of the Medication Guide is reprinted at the end of this document.

Advise patients regarding the following issues and to alert their prescriber if these occur while taking WELLBUTRIN SR.

Suicidal Thoughts and Behaviors: Instruct patients, their families, and/or their caregivers to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal ideation, especially early during antidepressant treatment and when the dose is adjusted up or down. Advise families and caregivers of patients to observe for the emergence of such symptoms on a day-to-day basis, since changes may be abrupt. Such symptoms should be reported to the patient’s prescriber or healthcare professional, especially if they are severe, abrupt in onset, or were not part of the patient’s presenting symptoms. Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior and indicate a need for very close monitoring and possibly changes in the medication.

Neuropsychiatric Symptoms and Suicide Risk in Smoking Cessation Treatment: Although WELLBUTRIN SR is not indicated for smoking cessation treatment, it contains the same active ingredient as ZYBAN which is approved for this use. Advise patients, families and caregivers that quitting smoking, with or without ZYBAN, may trigger nicotine withdrawal symptoms (e.g., including depression or agitation), or worsen pre-existing psychiatric illness. Some patients have experienced changes in mood (including depression and mania), psychosis, hallucinations, paranoia, delusions, homicidal ideation, aggression, anxiety, and panic, as well as suicidal ideation, suicide attempt, and completed suicide when attempting to quit smoking while taking ZYBAN. If patients develop agitation, hostility, depressed mood, or changes in thinking or behavior that are not typical for them, or if patients develop suicidal ideation or behavior, they should be urged to report these symptoms to their healthcare provider immediately.

Severe Allergic Reactions: Educate patients on the symptoms of hypersensitivity and to discontinue WELLBUTRIN SR if they have a severe allergic reaction.

Seizure: Instruct patients to discontinue and not restart WELLBUTRIN SR if they experience a seizure while on treatment. Advise patients that the excessive use or abrupt discontinuation of alcohol, benzodiazepines, antiepileptic drugs, or sedatives/hypnotics can increase the risk of seizure. Advise patients to minimize or avoid use of alcohol.

As the dose is increased during initial titration to doses above 150 mg per day, instruct patients to take WELLBUTRIN SR in 2 divided doses, preferably with at least 8 hours between successive doses, to minimize the risk of seizures.

Bupropion-Containing Products: Educate patients that WELLBUTRIN SR contains the same active ingredient (bupropion hydrochloride) found in ZYBAN, which is 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 (such as WELLBUTRIN^®, the immediate-release formulation and WELLBUTRIN XL^® or FORFIVO XL™, the extended-release formulations, and APLENZIN^®, the extended-release formulation of bupropion hydrobromide). In addition, there are a number of generic bupropion HCl products for the immediate-, sustained-, and extended-release formulations.

Potential for Cognitive and Motor Impairment: Advise patients that any CNS‑active drug like WELLBUTRIN SR may impair their ability to perform tasks requiring judgment or motor and cognitive skills. Advise patients that until they are reasonably certain that WELLBUTRIN SR does not adversely affect their performance, they should refrain from driving an automobile or operating complex, hazardous machinery. WELLBUTRIN SR may lead to decreased alcohol tolerance.

Concomitant Medications: Counsel patients to notify their healthcare provider if they are taking or plan to take any prescription or over‑the‑counter drugs because WELLBUTRIN SR Sustained-Release Tablets and other drugs may affect each others’ metabolisms.

Pregnancy: Advise patients to notify their healthcare provider if they become pregnant or intend to become pregnant during therapy.

Precautions for Nursing Mothers: Advise patients that WELLBUTRIN SR is present in human milk in small amounts.

Storage Information: Instruct patients to store WELLBUTRIN SR at room temperature, between 59°F and 86°F (15°C to 30°C) and keep the tablets dry and out of the light.

Administration Information: Instruct patients to swallow WELLBUTRIN SR Tablets whole so that the release rate is not altered. Do not chew, divide, or crush tablets; they are designed to slowly release drug in the body. When patients take more than 150 mg per day, instruct them to take WELLBUTRIN SR in 2 doses at least 8 hours apart, to minimize the risk of seizures. Instruct patients if they miss a dose, not to take an extra tablet to make up for the missed dose and to take the next tablet at the regular time because of the dose-related risk of seizure. Instruct patients that WELLBUTRIN SR Tablets may have an odor. WELLBUTRIN SR can be taken with or without food.

WELLBUTRIN, WELLBUTRIN SR, WELLBUTRIN XL, and ZYBAN are registered trademarks of the GSK group of companies. The other brands listed are trademarks of their respective owners and are not trademarks of the GSK group of companies. The makers of these brands are not affiliated with and do not endorse the GSK group of companies or its products.

GlaxoSmithKline

Research Triangle Park, NC 27709

©2014, the GSK group of companies. All rights reserved.

WLS:11PI

Medication Guide

WELLBUTRIN^® SR (WELL byu-trin)

(bupropion hydrochloride) Sustained‑Release Tablets

Read this Medication Guide carefully before you start taking WELLBUTRIN SR and each time you get a refill. There may be new information. This information does not take the place of talking with your healthcare provider about your medical condition or your treatment. If you have any questions about WELLBUTRIN SR, ask your healthcare provider or pharmacist.

IMPORTANT: Be sure to read the three sections of this Medication Guide. The first section is about the risk of suicidal thoughts and actions with antidepressant medicines; the second section is about the risk of changes in thinking and behavior, depression and suicidal thoughts or actions with medicines used to quit smoking; and the third section is entitled “What Other Important Information Should I Know About WELLBUTRIN SR?”

Antidepressant Medicines, Depression and Other Serious Mental Illnesses, and Suicidal Thoughts or Actions

This section of the Medication Guide is only about the risk of suicidal thoughts and actions with antidepressant medicines. Talk to your healthcare provider or your family member’s healthcare provider about:

• •all risks and benefits of treatment with antidepressant medicines
• •all treatment choices for depression or other serious mental illness

What is the most important information I should know about antidepressant medicines, depression and other serious mental illnesses, and suicidal thoughts or actions?

• •Antidepressant medicines may increase suicidal thoughts or actions in some children, teenagers, or young adults within the first few months of treatment.
• •Depression or other serious mental illnesses are the most important causes of suicidal thoughts and actions. Some people may have a particularly high risk of having suicidal thoughts or actions. These include people who have (or have a family history of) bipolar illness (also called manic-depressive illness) or suicidal thoughts or actions.
• •How can I watch for and try to prevent suicidal thoughts and actions in myself or a family member?
• •Pay close attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or feelings. This is very important when an antidepressant medicine is started or when the dose is changed.
• •Call your healthcare provider right away to report new or sudden changes in mood, behavior, thoughts, or feelings.
• •Keep all follow-up visits with your healthcare provider as scheduled. Call the healthcare provider between visits as needed, especially if you have concerns about symptoms.

Call your healthcare provider right away if you or your family member has any of the following symptoms, especially if they are new, worse, or worry you:

What else do I need to know about antidepressant medicines?

• •Never stop an antidepressant medicine without first talking to a healthcare provider. Stopping an antidepressant medicine suddenly can cause other symptoms.
• • Antidepressants are medicines used to treat depression and other illnesses. It is important to discuss all the risks of treating depression and also the risks of not treating it. Patients and their families or other caregivers should discuss all treatment choices with the healthcare provider, not just the use of antidepressants.
• • Antidepressant medicines have other side effects. Talk to the healthcare provider about the side effects of the medicine prescribed for you or your family member.
• • Antidepressant medicines can interact with other medicines. Know all of the medicines that you or your family member takes. Keep a list of all medicines to show the healthcare provider. Do not start new medicines without first checking with your healthcare provider.

It is not known if WELLBUTRIN SR is safe and effective in children under the age of 18.

Quitting Smoking, Quit-Smoking Medications, Changes in Thinking and Behavior, Depression, and Suicidal Thoughts or Actions

This section of the Medication Guide is only about the risk of changes in thinking and behavior, depression and suicidal thoughts or actions with drugs used to quit smoking.

Although WELLBUTRIN SR is not a treatment for quitting smoking, it contains the same active ingredient (bupropion hydrochloride) as ZYBAN^® which is used to help patients quit smoking.

Some people have had changes in behavior, hostility, agitation, depression, suicidal thoughts or actions while taking bupropion to help them quit smoking. These symptoms can develop during treatment with bupropion or after stopping treatment with bupropion.

If you, your family member, or your caregiver notice agitation, hostility, depression, or changes in thinking or behavior that are not typical for you, or you have any of the following symptoms, stop taking bupropion and call your healthcare provider right away:

When you try to quit smoking, with or without bupropion, you may have symptoms that may be due to nicotine withdrawal, including urge to smoke, depressed mood, trouble sleeping, irritability, frustration, anger, feeling anxious, difficulty concentrating, restlessness, decreased heart rate, and increased appetite or weight gain. Some people have even experienced suicidal thoughts when trying to quit smoking without medication. Sometimes quitting smoking can lead to worsening of mental health problems that you already have, such as depression.

Before taking bupropion, tell your healthcare provider if you have ever had depression or other mental illnesses. You should also tell your healthcare provider about any symptoms you had during other times you tried to quit smoking, with or without bupropion.

What Other Important Information Should I Know About WELLBUTRIN SR?

• •Seizures: There is a chance of having a seizure (convulsion, fit) with WELLBUTRIN SR, especially in people:
  • •with certain medical problems.
  • •who take certain medicines.

The chance of having seizures increases with higher doses of WELLBUTRIN SR. For more information, see the sections “Who should not take WELLBUTRIN SR?” and “What should I tell my healthcare provider before taking WELLBUTRIN SR?” Tell your healthcare provider about all of your medical conditions and all the medicines you take. Do not take any other medicines while you are taking WELLBUTRIN SR unless your healthcare provider has said it is okay to take them.

If you have a seizure while taking WELLBUTRIN SR, stop taking the tablets and call your healthcare provider right away. Do not take WELLBUTRIN SR again if you have a seizure.

• • High blood pressure (hypertension). Some people get high blood pressure, that can be severe, while taking WELLBUTRIN SR. The chance of high blood pressure may be higher if you also use nicotine replacement therapy (such as a nicotine patch) to help you stop smoking.
• • Manic episodes. Some people may have periods of mania while taking WELLBUTRIN SR, including:
  • •Greatly increased energy
  • •Severe trouble sleeping
  • •Racing thoughts
  • •Reckless behavior
  • •Unusually grand ideas
  • •Excessive happiness or irritability
  • •Talking more or faster than usual

If you have any of the above symptoms of mania, call your healthcare provider.

• • Unusual thoughts or behaviors. Some patients have unusual thoughts or behaviors while taking WELLBUTRIN, including delusions (believe you are someone else), hallucinations (seeing or hearing things that are not there), paranoia (feeling that people are against you), or feeling confused. If this happens to you, call your healthcare provider.
• •Severe allergic reactions. Some people can have severe allergic reactions to WELLBUTRIN SR. Stop taking WELLBUTRIN SR and call your healthcare provider right away if you get a rash, itching, hives, fever, swollen lymph glands, painful sores in the mouth or around the eyes, swelling of the lips or tongue, chest pain, or have trouble breathing. These could be signs of a serious allergic reaction.

What is WELLBUTRIN SR?

WELLBUTRIN SR is a prescription medicine used to treat adults with a certain type of depression called major depressive disorder.

Who should not take WELLBUTRIN SR?

Do not take WELLBUTRIN SR if you

• •have or had a seizure disorder or epilepsy.
• •have or had an eating disorder such as anorexia nervosa or bulimia.
• •are taking any other medicines that contain bupropion, ZYBAN (used to help people stop smoking) APLENZIN^®, FORFIVO XL^™, WELLBUTRIN^®, or WELLBUTRIN XL^®. Bupropion is the same active ingredient that is in WELLBUTRIN SR.
• •drink a lot of alcohol and abruptly stop drinking, or use medicines called sedatives (these make you sleepy), benzodiazepines, or anti-seizure medicines, and you stop using them all of a sudden.
• •take a monoamine oxidase inhibitor (MAOI). Ask your healthcare provider or pharmacist if you are not sure if you take an MAOI, including the antibiotic linezolid.
  • •do not take an MAOI within 2 weeks of stopping WELLBUTRIN SR unless directed to do so by your healthcare provider.
  • •do not start WELLBUTRIN SR if you stopped taking an MAOI in the last 2 weeks unless directed to do so by your healthcare provider.
• •are allergic to the active ingredient in WELLBUTRIN SR, bupropion, or to any of the inactive ingredients. See the end of this Medication Guide for a complete list of ingredients in WELLBUTRIN SR.

What should I tell my healthcare provider before taking WELLBUTRIN SR?

•  Tell your healthcare provider if you have ever had depression, suicidal thoughts or actions, or other mental health problems. See “Antidepressant Medicines, Depression and Other Serious Mental Illnesses, and Suicidal Thoughts or Actions.”

Tell your healthcare provider about your other medical conditions including if you:

• •have liver problems, especially cirrhosis of the liver.
• •have kidney problems.
• •have, or have had, an eating disorder, such as anorexia nervosa or bulimia.
• •have had a head injury.
• •have had a seizure (convulsion, fit).
• •have a tumor in your nervous system (brain or spine).
• •have had a heart attack, heart problems, or high blood pressure.
• •are a diabetic taking insulin or other medicines to control your blood sugar.
• •drink alcohol.
• •abuse prescription medicines or street drugs.
• •are pregnant or plan to become pregnant.
• •are breastfeeding. WELLBUTRIN passes into your milk in small amounts.

Tell your healthcare provider about all the medicines you take, including prescription, over-the-counter medicines, vitamins, and herbal supplements. Many medicines increase your chances of having seizures or other serious side effects if you take them while you are taking WELLBUTRIN SR.

How should I take WELLBUTRIN SR?

• •Take WELLBUTRIN SR exactly as prescribed by your healthcare provider.
• • Swallow WELLBUTRIN SR Tablets whole. Do not chew, cut, or crush WELLBUTRIN SR Tablets. If you do, the medicine will be released into your body too quickly. If this happens you may be more likely to get side effects including seizures. Tell your healthcare provider if you cannot swallow tablets.
• •Take WELLBUTRIN SR at the same time each day.
• •Take your doses of WELLBUTRIN SR at least 8 hours apart.
• •You may take WELLBUTRIN SR with or without food.
• •If you miss a dose, do not take an extra dose to make up for the dose you missed. Wait and take your next dose at the regular time. This is very important. Too much WELLBUTRIN SR can increase your chance of having a seizure.
• •If you take too much WELLBUTRIN SR, or overdose, call your local emergency room or poison control center right away.
• •Do not take any other medicines while taking WELLBUTRIN SR unless your healthcare provider has told you it is okay.
• •If you are taking WELLBUTRIN SR for the treatment of major depressive disorder, it may take several weeks for you to feel that WELLBUTRIN SR is working. Once you feel better, it is important to keep taking WELLBUTRIN SR exactly as directed by your healthcare provider. Call your healthcare provider if you do not feel WELLBUTRIN SR is working for you.
• •Do not change your dose or stop taking WELLBUTRIN SR without talking with your healthcare provider first.

What should I avoid while taking WELLBUTRIN SR?

• •Limit or avoid using alcohol during treatment with WELLBUTRIN SR. If you usually drink a lot of alcohol, talk with your healthcare provider before suddenly stopping. If you suddenly stop drinking alcohol, you may increase your chance of having seizures.
• •Do not drive a car or use heavy machinery until you know how WELLBUTRIN SR affects you. WELLBUTRIN SR can affect your ability to do these things safely.

What are possible side effects of WELLBUTRIN SR?

See “What Other Important Information Should I Know About WELLBUTRIN SR?”

WELLBUTRIN SR can cause serious side effects.

The most common side effects of WELLBUTRIN SR include:

• •Headache
• •Dry mouth
• •Nausea
• •Trouble sleeping
• •Dizziness
• •Sore throat
• •Constipation

If you have nausea, take your medicine with food. If you have trouble sleeping, do not take your medicine too close to bedtime.

Tell your healthcare provider right away about any side effects that bother you.

These are not all the possible side effects of WELLBUTRIN SR. For more information, ask your healthcare provider or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1‑800-FDA-1088.

You may also report side effects to GlaxoSmithKline at 1-888-825-5249.

How should I store WELLBUTRIN SR?

• •Store WELLBUTRIN SR at room temperature between 59°F and 86°F (15°C to 30°C).
• •Keep WELLBUTRIN SR dry and out of the light.
• •WELLBUTRIN SR Tablets may have an odor.

Keep WELLBUTRIN SR and all medicines out of the reach of children.

General Information about WELLBUTRIN SR.

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use WELLBUTRIN SR for a condition for which it was not prescribed. Do not give WELLBUTRIN SR to other people, even if they have the same symptoms you have. It may harm them.

If you take a urine drug screening test, WELLBUTRIN SR may make the test result positive for amphetamines. If you tell the person giving you the drug screening test that you are taking WELLBUTRIN SR, they can do a more specific drug screening test that should not have this problem.

This Medication Guide summarizes important information about WELLBUTRIN SR. If you would like more information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about WELLBUTRIN SR that is written for healthcare professionals.

For more information about WELLBUTRIN SR, go to www.wellbutrin.com or call 1-888-825-5249.

What are the ingredients in WELLBUTRIN SR?

Active ingredient: bupropion hydrochloride.

Inactive ingredients: carnauba wax, cysteine hydrochloride, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, and titanium dioxide. In addition, the 100‑mg tablet contains FD&C Blue No. 1 Lake, the 150‑mg tablet contains FD&C Blue No. 2 Lake and FD&C Red No. 40 Lake, and the 200‑mg tablet contains FD&C Red No. 40 Lake. The tablets are printed with edible black ink.

This Medication Guide has been approved by the U.S. Food and Drug Administration.

WELLBUTRIN, WELLBUTRIN SR, WELLBUTRIN XL, and ZYBAN are registered trademarks of the GSK group of companies. The other brands listed are trademarks of their respective owners and are not trademarks of the GSK group of companies. The makers of these brands are not affiliated with and do not endorse the GSK group of companies or its products.

GlaxoSmithKline

Research Triangle Park, NC 27709

©2014, the GSK group of companies. All rights reserved.

April 2014

WLS: 10MG

Package/Label Display Panel

NDC 0173-0135-55

Wellbutrin SR^®

(bupropionHCl)

Sustained-Release Tablets

Twice-A-Day

(After Initial Titration)

150 mg

60 Tablets

R_x only

Each sustained-release tablet contains 150 mg bupropion HCl.

WARNING: Do not use with other medicines that contain bupropion HCl.

Federal Law requires dispensing of Wellbutrin SR^® with the Medication Guide under this label.

See prescribing information for dosage information.

Store at controlled room temperature, 20^o to 25^oC (68^o to 77^oF) [see USP].

GlaxoSmithKline

Research Triangle Park, NC 27709

Made in Germany

10000000119766 Rev. 9/13