WELLBUTRIN

1 INDICATIONS AND USAGE WELLBUTRIN SR (bupropion hydrochloride) is indicated for the treatment of major depressive disorder (MDD), as defined by the Diagnostic and Statistical Manual (DSM). The efficacy of bupropion in the treatment of a major depressive episode was established in two 4-week controlled inpatient trials and one 6-week controlled outpatient trial of adult subjects with MDD [see Clinical Studies ( 14 )] . The efficacy of WELLBUTRIN SR in maintaining an antidepressant response for up to 44 weeks following 8 weeks of acute treatment was demonstrated in a placebo‐controlled trial [see Clinical Studies ( 14 )] . WELLBUTRIN SR is an aminoketone antidepressant, indicated for the treatment of major depressive disorder (MDD). ( 1 )

2 DOSAGE AND ADMINISTRATION • Starting dose: 150 mg/day. ( 2.1 ) • General: Increase dose gradually to reduce seizure risk. ( 2.1 , 5.3 ) • After 3 days, may increase the dose to 300 mg/day, given as 150 mg twice daily at an interval of at least 8 hours. ( 2.1 ) • Usual target dose: 300 mg/day as 150 mg twice daily. ( 2.1 ) • Maximum dose: 400 mg/day, given as 200 mg twice daily, for patients not responding to 300 mg/day. ( 2.1 ) • Periodically reassess the dose and need for maintenance treatment. ( 2.1 ) • Moderate to severe hepatic impairment: 100 mg daily or 150 mg every other day. ( 2.2 , 8.7 ) • Mild hepatic impairment: Consider reducing the dose and/or frequency of dosing. ( 2.2 , 8.7 ) • Renal impairment: Consider reducing the dose and/or frequency. ( 2.3 , 8.6 ) 2.1 General Instructions for Use To minimize the risk of seizure, increase the dose gradually [see Warnings and Precautions ( 5.3 )] . WELLBUTRIN SR tablets should be swallowed whole and not crushed, divided, or chewed. WELLBUTRIN SR may be taken with or without food. The usual adult target dose for WELLBUTRIN SR is 300 mg/day, given as 150 mg twice daily. Initiate dosing with 150 mg/day given as a single daily dose in the morning. After 3 days of dosing, the dose may be increased to the 300-mg/day target dose, given as 150 mg twice daily. There should be an interval of at least 8 hours between successive doses. A maximum of 400 mg/day, given as 200 mg twice daily, may be considered for patients in whom no clinical improvement is noted after several weeks of treatment at 300 mg/day. To avoid high peak concentrations of bupropion and/or its metabolites, do not exceed 200 mg in any single dose. It is generally agreed that acute episodes of depression require several months or longer of antidepressant drug treatment beyond the response in the acute episode. It is unknown whether the dose of WELLBUTRIN SR needed for maintenance treatment is identical to the dose that provided an initial response. Periodically reassess the need for maintenance treatment and the appropriate dose for such treatment. 2.2 Dose Adjustment in Patients with Hepatic Impairment In patients with moderate to severe hepatic impairment (Child-Pugh score: 7 to 15), the maximum dose of WELLBUTRIN SR is 100 mg/day or 150 mg every other day. In patients with mild hepatic impairment (Child-Pugh score: 5 to 6), consider reducing the dose and/or frequency of dosing [see Use in Specific Populations ( 8.7 ), Clinical Pharmacology ( 12.3 )]. 2.3 Dose Adjustment in Patients with Renal Impairment Consider reducing the dose and/or frequency of WELLBUTRIN SR in patients with renal impairment (Glomerular Filtration Rate [GFR] less than 90 mL/min) [see Use in Specific Populations ( 8.6 ), Clinical Pharmacology ( 12.3 )] . 2.4 Switching a Patient to or from a Monoamine Oxidase Inhibitor (MAOI) Antidepressant At least 14 days should elapse between discontinuation of an MAOI intended to treat depression and initiation of therapy with WELLBUTRIN SR. Conversely, at least 14 days should be allowed after stopping WELLBUTRIN SR before starting an MAOI antidepressant [see Contraindications ( 4 ), Drug Interactions ( 7.6 )] . 2.5 Use of WELLBUTRIN SR with Reversible MAOIs Such as Linezolid or Methylene Blue Do not start WELLBUTRIN SR in a patient who is being treated with a reversible MAOI such as linezolid or intravenous methylene blue. Drug interactions can increase the risk of hypertensive reactions. In a patient who requires more urgent treatment of a psychiatric condition, non-pharmacological interventions, including hospitalization, should be considered [see Contraindications ( 4 ), Drug Interactions ( 7.6 )] . In some cases, a patient already receiving therapy with WELLBUTRIN SR may require urgent treatment with linezolid or intravenous methylene blue. If acceptable alternatives to linezolid or intravenous methylene blue treatment are not available and the potential benefits of linezolid or intravenous methylene b …

3 DOSAGE FORMS AND STRENGTHS • 100 mg – blue, round, biconvex, film‐coated, sustained-release tablets printed with “WELLBUTRIN SR 100”. • 150 mg – purple, round, biconvex, film‐coated, sustained-release tablets printed with “WELLBUTRIN SR 150”. • 200 mg – light pink, round, biconvex, film-coated, sustained-release tablets printed with “WELLBUTRIN SR 200”. Tablets: 100 mg, 150 mg, 200 mg. ( 3 )

4 CONTRAINDICATIONS • WELLBUTRIN SR is contraindicated in patients with a seizure disorder. • WELLBUTRIN SR is contraindicated in patients with a current or prior diagnosis of bulimia or anorexia nervosa as a higher incidence of seizures was observed in such patients treated with the immediate‐release formulation of bupropion [see Warnings and Precautions ( 5.3 )]. • WELLBUTRIN SR is contraindicated in patients undergoing abrupt discontinuation of alcohol, benzodiazepines, barbiturates, and antiepileptic drugs [see Warnings and Precautions ( 5.3 ), Drug Interactions ( 7.3 )] . • The use of MAOIs (intended to treat psychiatric disorders) concomitantly with WELLBUTRIN SR or within 14 days of discontinuing treatment with WELLBUTRIN SR is contraindicated. There is an increased risk of hypertensive reactions when WELLBUTRIN SR is used concomitantly with MAOIs. The use of WELLBUTRIN SR within 14 days of discontinuing treatment with an MAOI is also contraindicated. Starting WELLBUTRIN SR in a patient treated with reversible MAOIs such as linezolid or intravenous methylene blue is contraindicated [see Dosage and Administration ( 2.4 , 2.5 ), Warnings and Precautions ( 5.4 ), Drug Interactions ( 7.6 )] . • WELLBUTRIN SR is contraindicated in patients with known hypersensitivity to bupropion or other ingredients of WELLBUTRIN SR. Anaphylactoid/anaphylactic reactions and Stevens-Johnson syndrome have been reported [see Warnings and Precautions ( 5.8 )]. • Seizure disorder. ( 4 , 5.3 ) • Current or prior diagnosis of bulimia or anorexia nervosa. ( 4 , 5.3 ) • Abrupt discontinuation of alcohol, benzodiazepines, barbiturates, antiepileptic drugs. ( 4 , 5.3 ) • Monoamine Oxidase Inhibitors (MAOIs): Do not use MAOIs intended to treat psychiatric disorders with WELLBUTRIN SR or within 14 days of stopping treatment with WELLBUTRIN SR. Do not use WELLBUTRIN SR within 14 days of stopping an MAOI intended to treat psychiatric disorders. In addition, do not start WELLBUTRIN SR in a patient who is being treated with linezolid or intravenous methylene blue. ( 4 , 7.6 ) • Known hypersensitivity to bupropion or other ingredients of WELLBUTRIN SR. ( 4 , 5.8 )

6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the labeling: • Suicidal thoughts and behaviors in adolescents and young adults [see Boxed Warning, Warnings and Precautions ( 5.1 )] • Neuropsychiatric symptoms and suicide risk in smoking cessation treatment [see Warnings and Precautions ( 5.2 )] • Seizure [see Warnings and Precautions ( 5.3 )] • Hypertension [see Warnings and Precautions ( 5.4 )] • Activation of mania or hypomania [see Warnings and Precautions ( 5.5 )] • Psychosis and other neuropsychiatric reactions [see Warnings and Precautions ( 5.6 )] • Angle-closure glaucoma [see Warnings and Precautions ( 5.7 )] • Hypersensitivity reactions [see Warnings and Precautions ( 5.8 )] Most common adverse reactions (incidence ≥5% and ≥2% more than placebo rate) are: headache, dry mouth, nausea, insomnia, dizziness, pharyngitis, constipation, agitation, anxiety, abdominal pain, tinnitus, tremor, palpitation, myalgia, sweating, rash, and anorexia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact GlaxoSmithKline at 1-888-825-5249 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Adverse Reactions Leading to Discontinuation of Treatment In placebo‐controlled clinical trials, 4%, 9%, and 11% of the placebo, 300‐mg/day, and 400‐mg/day groups, respectively, discontinued treatment due to adverse reactions. The specific adverse reactions leading to discontinuation in at least 1% of the 300‐mg/day or 400‐mg/day groups and at a rate at least twice the placebo rate are listed in Table 2 . Table 2. Treatment Discontinuations Due to Adverse Reactions in Placebo-Controlled Trials Adverse Reaction Placebo (n = 385) WELLBUTRIN SR 300 mg/day (n = 376) WELLBUTRIN SR 400 mg/day (n = 114) Rash 0.0% 2.4% 0.9% Nausea 0.3% 0.8% 1.8% Agitation 0.3% 0.3% 1.8% Migraine 0.3% 0.0% 1.8% Commonly Observed Adverse Reactions Adverse reactions from Table 3 occurring in at least 5% of subjects treated with WELLBUTRIN SR and at a rate at least twice the placebo rate are listed below for the 300- and 400‐mg/day dose groups. WELLBUTRIN SR 300 mg/day: Anorexia, dry mouth, rash, sweating, tinnitus, and tremor. WELLBUTRIN SR 400 mg/day: Abdominal pain, agitation, anxiety, dizziness, dry mouth, insomnia, myalgia, nausea, palpitation, pharyngitis, sweating, tinnitus, and urinary frequency. Adverse reactions reported in placebo-controlled trials are presented in Table 3. Reported adverse reactions were classified using a COSTART‐based Dictionary. Table 3. Adverse Reactions Reported by at Least 1% of Subjects and at a Greater Frequency than Placebo in Controlled Clinical Trials a Incidence based on the number of female subjects. — Hyphen denotes adverse events occurring in greater than 0 but less than 0.5% of subjects. Body System/ Adverse Reaction WELLBUTRIN SR 300 mg/day (n = 376) WELLBUTRIN SR 400 mg/day (n = 114) Placebo (n = 385) Body (general) Headache 26% 25% 23% Infection 8% 9% 6% Abdominal pain 3% 9% 2% Asthenia 2% 4% 2% Chest pain 3% 4% 1% Pain 2% 3% 2% Fever 1% 2% — Cardiovascular Palpitation 2% 6% 2% Flushing 1% 4% — Migraine 1% 4% 1% Hot flashes 1% 3% 1% Digestive Dry mouth 17% 24% 7% Nausea 13% 18% 8% Constipation 10% 5% 7% Diarrhea 5% 7% 6% Anorexia 5% 3% 2% Vomiting 4% 2% 2% Dysphagia 0% 2% 0% Musculoskeletal Myalgia 2% 6% 3% Arthralgia 1% 4% 1% Arthritis 0% 2% 0% Twitch 1% 2% — Nervous system Insomnia 11% 16% 6% Dizziness 7% 11% 5% Agitation 3% 9% 2% Anxiety 5% 6% 3% Tremor 6% 3% 1% Nervousness 5% 3% 3% Somnolence 2% 3% 2% Irritability 3% 2% 2% Memory decreased — 3% 1% Paresthesia 1% 2% 1% Central nervous system stimulation 2% 1% 1% Respiratory Pharyngitis 3% 11% 2% Sinusitis 3% 1% 2% Increas …

7 DRUG INTERACTIONS • CYP2B6 inducers: Dose increase may be necessary if coadministered with CYP2B6 inducers (e.g., ritonavir, lopinavir, efavirenz, carbamazepine, phenobarbital, and phenytoin) based on clinical response, but should not exceed the maximum recommended dose. ( 7.1 ) • Drugs metabolized by CYP2D6: Bupropion inhibits CYP2D6 and can increase concentrations of: antidepressants (e.g., venlafaxine, 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). Consider dose reduction when using with bupropion. ( 7.2 ) • Digoxin: May decrease plasma digoxin levels. Monitor digoxin levels. ( 7.2 ) • Drugs that lower seizure threshold: Dose WELLBUTRIN SR with caution. ( 5.3 , 7.3 ) • Dopaminergic drugs (levodopa and amantadine): CNS toxicity can occur when used concomitantly with WELLBUTRIN SR. ( 7.4 ) • MAOIs: Increased risk of hypertensive reactions can occur when used concomitantly with WELLBUTRIN SR. ( 7.6 ) • Drug-laboratory test interactions: WELLBUTRIN SR can cause false-positive urine test results for amphetamines. ( 7.7 ) 7.1 Potential for Other Drugs to Affect WELLBUTRIN SR 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. Inhibitors of CYP2B6 Ticlopidine and Clopidogrel: Concomitant treatment with these drugs can increase bupropion exposure but decrease hydroxybupropion exposure. Based on clinical response, dosage adjustment of WELLBUTRIN SR may be necessary when coadministered with CYP2B6 inhibitors (e.g., ticlopidine or clopidogrel) [see Clinical Pharmacology ( 12.3 )] . Inducers of CYP2B6 Ritonavir, Lopinavir, and Efavirenz : Concomitant treatment with these drugs can decrease bupropion and hydroxybupropion exposure. Dosage increase of WELLBUTRIN SR may be necessary when coadministered with ritonavir, lopinavir, or efavirenz [see Clinical Pharmacology ( 12.3 )] but should not exceed the maximum recommended dose. Carbamazepine, Phenobarbital, Phenytoin: While not systematically studied, these drugs may induce the metabolism of bupropion and may decrease bupropion exposure [see Clinical Pharmacology ( 12.3 )] . If bupropion is used concomitantly with a CYP inducer, it may be necessary to increase the dose of bupropion, but the maximum recommended dose should not be exceeded. 7.2 Potential for WELLBUTRIN SR to Affect Other Drugs Drugs Metabolized by CYP2D6 Bupropion and its metabolites (erythrohydrobupropion, threohydrobupropion, hydroxybupropion) are CYP2D6 inhibitors. Therefore, coadministration of WELLBUTRIN SR with drugs that are metabolized by CYP2D6 can increase the exposures of drugs that are substrates of CYP2D6. Such drugs include certain antidepressants (e.g., venlafaxine, nortriptyline, imipramine, desipramine, paroxetine, fluoxetine, and sertraline), antipsychotics (e.g., haloperidol, risperidone, thioridazine), beta-blockers (e.g., metoprolol), and Type 1C antiarrhythmics (e.g., propafenone and flecainide). When used concomitantly with WELLBUTRIN SR, it may be necessary to decrease the dose of these CYP2D6 substrates, particularly for drugs with a narrow therapeutic index. Drugs that require metabolic activation by CYP2D6 to be effective (e.g., tamoxifen) theoretically could have reduced efficacy when administered concomitantly with inhibitors of CYP2D6 such as bupropion. Patients treated concomitantly with WELLBUTRIN SR and such drugs may require increased doses of the drug [ see Clinical Pharmacology ( 12.3 )] . Digoxin Coadministration of WELLBUTRIN SR with digoxin may decrease plasma digoxin levels. Monitor plasma digoxin levels in patients treated concomitantly with WELLBUTRIN SR and digoxin [see Clinical Pharmacology ( 12.3 )] . 7.3 Drugs that Lower Seizure Threshold Use extreme c …

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Exposure Registry There is an independent pregnancy exposure registry that monitors pregnancy outcomes in women exposed to any antidepressants during pregnancy. Healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for Antidepressants at 1-844-405-6185 or visiting online at https://womensmentalhealth.org/research/pregnancyregistry/antidepressants/. Risk Summary Data from epidemiological studies of pregnant women exposed to bupropion in the first trimester have not identified an increased risk of congenital malformations overall (see Data) . There are risks to the mother associated with untreated depression in pregnancy (see Clinical Considerations). When bupropion was administered to pregnant rats during organogenesis, there was no evidence of fetal malformations at doses up to approximately 11 times the maximum recommended human dose (MRHD) of 400 mg/day. When given to pregnant rabbits during organogenesis, non-dose–related increases in incidence of fetal malformations, and skeletal variations were observed at doses approximately equal to the MRHD and greater. Decreased fetal weights were seen at doses twice the MRHD and greater (see Animal Data) . The estimated background risk for major birth defects and miscarriage is unknown for the indicated population. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and of miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk: A prospective, longitudinal study followed 201 pregnant women with a history of major depressive disorder who were euthymic and taking antidepressants during pregnancy at the beginning of pregnancy. The women who discontinued antidepressants during pregnancy were more likely to experience a relapse of major depression than women who continued antidepressants. Consider the risks to the mother of untreated depression and potential effects on the fetus when discontinuing or changing treatment with antidepressant medications during pregnancy and postpartum. Data Human Data: Data from the international bupropion Pregnancy Registry (675 first trimester exposures) and a retrospective cohort study using the United Healthcare database (1,213 first trimester exposures) did not show an increased risk for malformations overall. The Registry was not designed or powered to evaluate specific defects but suggested a possible increase in cardiac malformations. No increased risk for cardiovascular malformations overall has been observed after bupropion exposure during the first trimester. The prospectively observed rate of cardiovascular malformations in pregnancies with exposure to bupropion in the first trimester from the international Pregnancy Registry was 1.3% (9 cardiovascular malformations/675 first trimester maternal bupropion exposures), which is similar to the background rate of cardiovascular malformations (approximately 1%). Data from the United Healthcare database, which had a limited number of exposed cases with cardiovascular malformations, and a case-control study (6,853 infants with cardiovascular malformations and 5,763 with non-cardiovascular malformations) of self-reported bupropion use from the National Birth Defects Prevention Study (NBDPS) did not show an increased risk for cardiovascular malformations overall after bupropion exposure during the first trimester. Study findings on bupropion exposure during the first trimester and risk for left ventricular outflow tract obstruction (LVOTO) are inconsistent and do not allow conclusions regarding a possible association. The United Healthcare database lacked sufficient power to evaluate this association; the NBDPS found increased risk for LVOTO (n = 10; adjusted OR = 2.6; 95% CI: 1 …

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.

11 DESCRIPTION WELLBUTRIN SR (bupropion hydrochloride), an antidepressant of the aminoketone class, is chemically unrelated to tricyclic, tetracyclic, selective serotonin re‐uptake inhibitor, or other known antidepressant agents. Its structure closely resembles that of diethylpropion; it is related to phenylethylamines. It is designated as (±)-1-(3-chlorophenyl)-2-[(1,1-dimethylethyl)amino]-1-propanone hydrochloride. The molecular weight is 276.2. The molecular formula is C 13 H 18 ClNO•HCl. Bupropion hydrochloride powder is white, crystalline, and highly soluble in water. It has a bitter taste and produces the sensation of local anesthesia on the oral mucosa. The structural formula is: 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. buproprion hydrochloride chemical structure

10 OVERDOSAGE 10.1 Human Overdose Experience Overdoses of up to 30 grams or more of bupropion have been reported. Seizure was reported in approximately one-third of all cases. Other serious reactions reported with overdoses of bupropion alone included hallucinations, loss of consciousness, mental status changes, sinus tachycardia, ECG changes such as conduction disturbances (including QRS prolongation) or arrhythmias, clonus, myoclonus, and hyperreflexia. Fever, muscle rigidity, rhabdomyolysis, hypotension, stupor, coma, and respiratory failure have been reported mainly when bupropion was part of multiple drug overdoses. Although most patients recovered without sequelae, deaths associated with overdoses of bupropion alone have been reported in patients ingesting large doses of the drug. Multiple uncontrolled seizures, bradycardia, cardiac failure, and cardiac arrest prior to death were reported in these patients. 10.2 Overdosage Management Consult a Certified Poison Control Center for up-to-date guidance and advice. Call 1-800-222-1222 or refer to www.poison.org. There are no known antidotes for bupropion. In case of an overdose, provide supportive care, including close medical supervision and monitoring. Consider the possibility of multiple drug overdose. Ensure an adequate airway, oxygenation, and ventilation. Monitor cardiac rhythm and vital signs. Induction of emesis is not recommended.

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.