WELLBUTRIN

1 INDICATIONS AND USAGE Wellbutrin XL is an aminoketone antidepressant, indicated for: • treatment of major depressive disorder (MDD) ( 1.1 ) • prevention of seasonal affective disorder (SAD) ( 1.2 ) 1.1 Major Depressive Disorder (MDD) Wellbutrin XL ® (bupropion hydrochloride extended-release) tablets is indicated for the treatment of major depressive disorder (MDD), as defined by the Diagnostic and Statistical Manual (DSM). The efficacy of the immediate-release formulation of bupropion was established in two 4-week controlled inpatient trials and one 6-week controlled outpatient trial of adult patients with MDD. The efficacy of the sustained-release formulation of bupropion in the maintenance treatment of MDD was established in a long-term (up to 44 weeks), placebo-controlled trial in patients who had responded to bupropion in an 8-week study of acute treatment [ see Clinical Studies (14.1) ]. 1.2 Seasonal Affective Disorder (SAD) Wellbutrin XL is indicated for the prevention of seasonal major depressive episodes in patients with a diagnosis of seasonal affective disorder (SAD). The efficacy of bupropion hydrochloride extended-release tablets in the prevention of seasonal major depressive episodes was established in 3 placebo-controlled trials in adult outpatients with a history of MDD with an autumn-winter seasonal pattern as defined in the DSM [ see Clinical Studies (14.2) ].

2 DOSAGE AND ADMINISTRATION General • Increase dose gradually to reduce seizure risk. ( 2.1 , 5.3 ) • Periodically reassess the dose and need for maintenance treatment. ( 2.2 ) Major Depressive Disorder • Starting dose: 150 mg once daily. Usual target dose: 300 mg once daily ( 2.2 ) • After 4 days, may increase the dose to 300 mg once daily. ( 2.2 ) Seasonal Affective Disorder • Initiate treatment in the autumn prior to onset of seasonal depressive symptoms. ( 2.3 ) • Starting dose: 150 mg once daily. Usual target dose: 300 mg once daily. ( 2.3 ) • After one week, may increase the dose to 300 mg once daily. ( 2.3 ) • Continue treatment through the winter season. ( 2.3 ) Hepatic Impairment • Moderate to severe hepatic impairment: 150 mg every other day ( 2.6 ) • Mild hepatic impairment: Consider reducing the dose and/or frequency of dosing. ( 2.6 , 8.7 ) Renal Impairment • Consider reducing the dose and/or frequency of dosing. ( 2.7 , 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 XL should be swallowed whole and not crushed, divided, or chewed. Wellbutrin XL should be administered in the morning and may be taken with or without food. 2.2 Dosage for Major Depressive Disorder (MDD) The recommended starting dose for MDD is 150 mg once daily in the morning. After 4 days of dosing, the dose may be increased to the target dose of 300 mg once daily in the morning. It is generally agreed that acute episodes of depression require several months or longer of antidepressant treatment beyond the response in the acute episode. It is unknown whether the Wellbutrin XL dose 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. 2.3 Dosage for Seasonal Affective Disorder (SAD) The recommended starting dose for SAD is 150 mg once daily. After 7 days of dosing, the dose may be increased to the target dose of 300 mg once daily in the morning. Doses above 300 mg of bupropion hydrochloride extended-release were not assessed in the SAD trials. For the prevention of seasonal MDD episodes associated with SAD, initiate Wellbutrin XL in the autumn, prior to the onset of depressive symptoms. Continue treatment through the winter season. Taper and discontinue Wellbutrin XL in early spring. For patients treated with 300 mg per day, decrease the dose to 150 mg once daily before discontinuing Wellbutrin XL. Individualize the timing of initiation, and duration of treatment should be individualized, based on the patient’s historical pattern of seasonal MDD episodes. 2.4 Switching Patients from WELLBUTRIN Tablets or from WELLBUTRIN SR Sustained-Release Tablets When switching patients from WELLBUTRIN Tablets to Wellbutrin XL or from WELLBUTRIN SR Sustained-Release Tablets to Wellbutrin XL, give the same total daily dose when possible. 2.5 To Discontinue Wellbutrin XL, Taper the Dose When discontinuing treatment in patients treated with Wellbutrin XL 300 mg once daily, decrease the dose to 150 mg once daily prior to discontinuation. 2.6 Dosage Adjustment in Patients with Hepatic Impairment In patients with moderate to severe hepatic impairment (Child-Pugh score: 7 to 15), the maximum dose is 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) and Clinical Pharmacology (12.3) ]. 2.7 Dose Adjustment in Patients with Renal Impairment Consider reducing the dose and/or frequency of Wellbutrin XL in patients with renal impairment (glomerular filtration rate less than 90 mL/min) [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3) ] . 2.8 Switching a Patient to or from a Monoamine Oxidase Inhibitor (MAOI) Antidepressant At least 14 days should elapse between discontinuation of an …

3 DOSAGE FORMS AND STRENGTHS Wellbutrin XL extended-release tablets, 150 mg of bupropion hydrochloride, are creamy-white to pale yellow, round tablets imprinted with “Wellbutrin XL 150” in black ink on one side and the other side plain. Wellbutrin XL extended-release tablets, 300 mg of bupropion hydrochloride, are creamy-white to pale yellow, round tablets imprinted with “Wellbutrin XL 300” in black ink on one side and the other side plain. Extended-release tablets: 150 mg, 300 mg ( 3 )

4 CONTRAINDICATIONS • Wellbutrin XL is contraindicated in patients with seizure disorder. • Wellbutrin XL 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 Wellbutrin XL [ see Warnings and Precautions (5.3) ]. • Wellbutrin XL is contraindicated in patients undergoing abrupt discontinuation of alcohol, benzodiazepines, barbiturates, and antiepileptic drugs [see Warnings and Precautions (5.3) and Drug Interactions (7.3) ] . • The use of MAOIs (intended to treat psychiatric disorders) concomitantly with Wellbutrin XL or within 14 days of discontinuing treatment with Wellbutrin XL is contraindicated. There is an increased risk of hypertensive reactions when Wellbutrin XL is used concomitantly with MAOIs. The use of Wellbutrin XL within 14 days of discontinuing treatment with an MAOI is also contraindicated. Starting Wellbutrin XL in a patient treated with reversible MAOIs such as linezolid or intravenous methylene blue is contraindicated [see Dosage and Administration (2.9) , Warnings and Precautions (5.4) and Drug Interactions (7.6) ] . • Wellbutrin XL is contraindicated in patients with known hypersensitivity to bupropion or other ingredients of Wellbutrin XL. 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 XL or within 14 days of stopping treatment with Wellbutrin XL. Do not use Wellbutrin XL within 14 days of stopping an MAOI intended to treat psychiatric disorders. In addition, do not start Wellbutrin XL 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 XL ( 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 children, adolescents, and young adults [see Warnings and Precautions (5.1) ] • Neuropsychiatric adverse events 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 events [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 are (incidence ≥5%; ≥2× placebo rate): dry mouth, nausea, insomnia, dizziness, pharyngitis, abdominal pain, agitation, anxiety, tremor, palpitation, sweating, tinnitus, myalgia, anorexia, urinary frequency, rash. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Bausch Health US, LLC at 1-800-321-4576 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 to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Commonly Observed Adverse Reactions in Controlled Clinical Trials of Sustained-Release Bupropion Hydrochloride Adverse reactions that occurred in at least 5% of patients treated with bupropion HCl sustained-release (300 mg and 400 mg per day) and at a rate at least twice the placebo rate are listed below. 300 mg/day of bupropion HCl sustained-release: anorexia, dry mouth, rash, sweating, tinnitus, and tremor. 400 mg/day of bupropion HCl sustained-release: abdominal pain, agitation, anxiety, dizziness, dry mouth, insomnia, myalgia, nausea, palpitation, pharyngitis, sweating, tinnitus, and urinary frequency. Wellbutrin XL has been demonstrated to have similar bioavailability both to the immediate-release and sustained-release formulations of bupropion. The information included under this subsection and under subsection 6.2 is based primarily on data from controlled clinical trials with the sustained-release and extended-release formulations of bupropion hydrochloride. Major Depressive Disorder Adverse Reactions Leading to Discontinuation of Treatment with Bupropion HCl Immediate-Release, Bupropion HCl Sustained-Release, and Bupropion HCl Extended-Release in Major Depressive Disorder Trials In placebo-controlled clinical trials with bupropion HCl sustained-release, 4%, 9%, and 11% of the placebo, 300 mg/day and 400 mg/day groups, respectively, discontinued treatment because of 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 Discontinuation Due to Adverse Reactions in Placebo-Controlled Trials in MDD Adverse Reaction Term Placebo (n=385) Bupropion HCl Sustained-Release 300 mg/day (n=376) Bupropion HCl Sustained-Release 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% In clinical trials with bupropion HCl immediate-release, 10% of patients and volunteers discontinued due to an adverse reaction. Reactions resulting in discontinuation (in addition to those listed above for the sustained-release formulation) included vomiting, seizures, and sleep disturbances. Adverse Reactions Occurring at an Incidence of >1% in Patients Treated with Bupropion HCl Immediate-Release or Bupropion HCl Sustained-Release in MDD Table 3 summarizes the adverse reactions that occurred in placebo-controlled trials in patients treated with bupropion HCl sustained-release 300 mg/day and 400 mg/day. These include reactions that occurred …

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 exposure, 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 ) • Drugs that lower seizure threshold: Dose Wellbutrin XL with caution. ( 5.3 , 7.3 ) • Dopaminergic Drugs (levodopa and amantadine): CNS toxicity can occur when used concomitantly with Wellbutrin XL. ( 7.4 ) • MAOIs: Increased risk of hypertensive reactions can occur when used concomitantly with Wellbutrin XL. ( 7.6 ) • Drug-laboratory test interactions: Wellbutrin XL can cause false-positive urine test results for amphetamines. ( 7.7 ) 7.1 Potential for Other Drugs to Affect Wellbutrin XL Bupropion is primarily metabolized to hydroxybupropion by CYP2B6. Therefore, the potential exists for drug interactions between Wellbutrin XL and drugs that are inhibitors or inducers of CYP2B6. Inhibitors of CYP2B6 Ticlopidine and Clopidogrel: Concomitant treatment with these drugs can increase bupropion exposures but decrease hydroxybupropion exposure. Based on clinical response, dosage adjustment of Wellbutrin XL 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 XL may be necessary when coadministered with ritonavir, lopinavir, or efavirenz but should not exceed the maximum recommended dose [ see Clinical Pharmacology (12.3) ]. Carbamazepine, Phenobarbital, Phenytoin: While not systemically studied, these drugs may induce 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 XL to Affect Other Drugs Drugs Metabolized by CYP2D6 Bupropion and its metabolites (erythrohydrobupropion, threohydrobupropion, hydroxybupropion) are CYP2D6 inhibitors. Therefore, coadministration of Wellbutrin XL 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, and thioridazine), beta-blockers (e.g., metoprolol), and Type 1C antiarrhythmics (e.g., propafenone, and flecainide). When used concomitantly with Wellbutrin XL, 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 XL and such drugs may require increased doses of the drug [ see Clinical Pharmacology (12.3) ]. 7.3 Drugs That Lower Seizure Threshold Use extreme caution when coadministering Wellbutrin XL with other drugs that lower the seizure threshold (e.g., other bupropion products, antipsychotics, antidepressants, theophylline, or systemic corticosteroids). Use low initial doses of Wellbutrin XL and increase the dose gradually [ see Warnings and Precautions (5.3 …

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to 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/clinical-and-research-programs/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 (see Clinical Considerations). When bupropion was administered to pregnant rats during organogenesis, there was no evidence of fetal malformations at doses up to approximately 10 times the maximum recommended human dose (MRHD) of 450 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 are unknown for the indicated population. All pregnancies have a background rate of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and 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 has a limited number of exposed cases with cardiovascular malformations, and a case-controlled study (6,853 infants with cardiovascular malformations and 5,753 with non-cardiovascular malformations) 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 left ventricular outflow tract obstruction (LVOTO) are inconsistent and do not allow conclusions regarding possible association. The United Healthcare database lacked sufficient power to evaluate this association; the NBDPS found increased risk for LVOTO (n = 10; adjusted odds ratio (OR) = 2.6; 95% CI 1.2, 5.7), and the Slone Epidemiolo …

12.1 Mechanism of Action The mechanism of action of bupropion is unknown, as is the case with other antidepressants. However, it is presumed that this action is mediated by noradrenergic and/or dopaminergic mechanisms. Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine and does not inhibit monoamine oxidase or the reuptake of serotonin.

11 DESCRIPTION Wellbutrin XL (bupropion hydrochloride), an antidepressant of the aminoketone class, is chemically unrelated to tricyclic, tetracyclic, selective serotonin reuptake inhibitor, or other known antidepressant agents. Its structure closely resembles that of diethylpropion; it is related to phenylethylamines. It is designated as (±)-1-(3-chorophenyl)-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 XL tablets are supplied for oral administration as 150 mg and 300 mg creamy-white to pale yellow extended-release tablets. Each tablet contains the labeled amount of bupropion hydrochloride and the inactive ingredients: ethylcellulose, glyceryl dibehenate, methacrylic acid copolymer dispersion, polyvinyl alcohol, polyethylene glycol, povidone, silicon dioxide, and triethyl citrate. The tablets are printed with edible black ink. The insoluble shell of the extended-release tablet may remain intact during gastrointestinal transit and is eliminated in the feces. chemstructure

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 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.

16 HOW SUPPLIED/STORAGE AND HANDLING Wellbutrin XL extended-release tablets are supplied as: NDC Strength Quantity Description 0187‐0730‐30 150 mg bottle of 30 tablets Creamy white to pale yellow round tablets imprinted with “Wellbutrin XL 150” in black ink on one side and the other side plain. 0187‐0730‐90 150 mg bottle of 90 tablets Creamy white to pale yellow round tablets imprinted with “Wellbutrin XL 150” in black ink on one side and the other side plain. 0187‐0731‐30 300 mg bottle of 30 tablets Creamy white to pale yellow round tablets imprinted with “Wellbutrin XL 300” in black ink on one side and the other side plain. Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. Wellbutrin XL tablets may have an odor.