Bupropion

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 Error! Hyperlink reference not valid. , Warnings and Precautions (5.1) ] • Neuropsychiatric symptoms and suicide risk in smoking cessation treatment [see Error! Hyperlink reference not valid. , 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 Solco Healthcare US, LLC at 1-866-257-2597 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-per-day, and 400-mg-per-day groups, respectively, discontinued treatment due to adverse reactions. The specific adverse reactions leading to discontinuation in at least 1% of the 300-mg-per-day or 400-mg-per-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) Bupropion Hydrochloride Extended-release (SR) tablets 300 mg/day (n=376) Bupropion Hydrochloride Extended-release (SR) tablets 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 Bupropion Hydrochloride Extended-release (SR) tablets and at a rate at least twice the placebo rate are listed below for the 300- and 400-mg-per-day dose groups. Bupropion Hydrochloride Extended-release (SR) tablets 300 mg per day: Anorexia, dry mouth, rash, sweating, tinnitus, and tremor. Bupropion Hydrochloride Extended-release (SR) tablets 400 mg per 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 Body System/Adverse Reaction Bupropion Hydrochloride Extended-release (SR) tablets 300 mg/day (n = 376) Bupropion Hydrochloride Extended-release (SR) tablets 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% Increased cough 1% 2% 1% Skin Sweating 6% 5% 2% Rash 5% 4% 1% Pruritus 2% 4% 2% Urticaria 2% 1% 0% Special senses Tinnitus 6% 6% 2% Taste perversion 2% 4% — Blurred vision or diplopia 3% 2% 2% Urogenital Urinary frequency 2% 5% 2% Urinary urgency — 2% 0% Vaginal hemorrhage Incidence based on the number of female subjects. — Hyphen denotes adverse events occurring in greater than 0 but less than 0.5% of subjects. 0% 2% — Urinary tract infection 1% 0% — Other Adverse Reactions Observed During the Clinical Development of Bupropion: In addition to the adverse reactions noted above, the following adverse reactions have been reported in clinical trials with the sustained-release formulation of bupropion in depressed subjects and in nondepressed smokers, as well as in clinical trials with the immediate-release formulation of bupropion. Adverse reaction frequencies represent the proportion of subjects who experienced a treatment-emergent adverse reaction on at least one occasion in placebo-controlled trials for depression (n = 987) or smoking cessation (n = 1,013), or subjects who experienced an adverse reaction requiring discontinuation of treatment in an open-label surveillance trial with Bupropion Hydrochloride Extended-release (SR) tablets (n = 3,100). All treatment-emergent adverse reactions are included except those listed in Table 3, those listed in other safety-related sections of the prescribing information, those subsumed under COSTART terms that are either overly general or excessively specific so as to be uninformative, those not reasonably associated with the use of the drug, and those that were not serious and occurred in fewer than 2 subjects. Adverse reactions are further categorized by body system and listed in order of decreasing frequency according to the following definitions of frequency: Frequent adverse reactions are defined as those occurring in at least 1/100 subjects. Infrequent adverse reactions are those occurring in 1/100 to 1/1,000 subjects, while rare events are those occurring in less than 1/1,000 subjects. Body (General): Infrequent were chills, facial edema, and photosensitivity. Rare was malaise. Cardiovascular: Infrequent were postural hypotension, stroke, tachycardia, and vasodilation. Rare were syncope and myocardial infarction. Digestive: Infrequent were abnormal liver function, bruxism, gastric reflux, gingivitis, increased salivation, jaundice, mouth ulcers, stomatitis, and thirst. Rare was edema of tongue. Hemic and Lymphatic: Infrequent was ecchymosis. Metabolic and Nutritional: Infrequent were edema and peripheral edema. Musculoskeletal: Infrequent were leg cramps. Nervous System: Infrequent were abnormal coordination, decreased libido, depersonalization, dysphoria, emotional lability, hostility, hyperkinesia, hypertonia, hypesthesia, suicidal ideation, and vertigo. Rare were amnesia, ataxia, derealization, and hypomania. Respiratory: Rare was bronchospasm. Special Senses: Infrequent were accommodation abnormality and dry eye. Urogenital: Infrequent were impotence, polyuria, and prostate disorder. Changes in Body Weight: In placebo-controlled trials, subjects experienced weight gain or weight loss as shown in Table 4. Table 4. Incidence of Weight Gain and Weight Loss (≥5 lbs.) in Placebo-Controlled Trials Weight Change Bupropion Hydrochloride Extended-release (SR) tablets 300 mg/day (n = 339) Bupropion Hydrochloride Extended-release (SR) tablets 400 mg/day (n = 112) Placebo (n = 347) Gained >5 lbs 3% 2% 4% Lost >5 lbs 14% 19% 6% In clinical trials conducted with the immediate-release formulation of bupropion, 35% of subjects receiving tricyclic antidepressants gained weight, compared with 9% of subjects treated with the immediate-release formulation of bupropion. If weight loss is a major presenting sign of a patient’s depressive illness, the anorectic and/or weight-reducing potential of Bupropion Hydrochloride Extended-release (SR) tablets should be considered. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of Bupropion Hydrochloride Extended-release (SR) tablets and are not described elsewhere in the label. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Body (General): Arthralgia, myalgia, and fever with rash and other symptoms suggestive of delayed hypersensitivity. These symptoms may resemble serum sickness [see Warnings and Precautions (5.8)] . Cardiovascular: Complete atrioventricular block, extrasystoles, hypotension, hypertension (in some cases severe), phlebitis, and pulmonary embolism. Digestive: Colitis, esophagitis, gastrointestinal hemorrhage, gum hemorrhage, hepatitis, intestinal perforation, pancreatitis, and stomach ulcer. Endocrine: Hyperglycemia, hypoglycemia, hyponatremia, and syndrome of inappropriate antidiuretic hormone secretion. Hemic and Lymphatic: Anemia, leukocytosis, leukopenia, lymphadenopathy, pancytopenia, and thrombocytopenia. Altered PT and/or INR, infrequently associated with hemorrhagic or thrombotic complications, were observed when bupropion was coadministered with warfarin. Metabolic and Nutritional: Glycosuria. Musculoskeletal: Muscle rigidity/fever/rhabdomyolysis and muscle weakness. Nervous System: Abnormal electroencephalogram (EEG), aggression, akinesia, aphasia, coma, completed suicide, delirium, delusions, dysarthria, euphoria, extrapyramidal syndrome (dyskinesia, dystonia, hypokinesia, parkinsonism), hallucinations, increased libido, manic reaction, neuralgia, neuropathy, paranoid ideation, restlessness, suicide attempt, and unmasking tardive dyskinesia. Respiratory: Pneumonia. Skin: Alopecia, angioedema, exfoliative dermatitis, hirsutism, and Stevens-Johnson syndrome. Special Senses: Deafness, increased intraocular pressure, and mydriasis. Urogenital: Abnormal ejaculation, cystitis, dyspareunia, dysuria, gynecomastia, menopause, painful erection, salpingitis, urinary incontinence, urinary retention, and vaginitis.

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

11 DESCRIPTION Bupropion Hydrochloride Extended-release Tablets USP (SR), 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: Bupropion Hydrochloride Extended-release Tablets USP (SR) is supplied for oral administration as 100-mg (blue), 150-mg (purple), and 200-mg (pink), film-coated, sustained-release tablets. Each tablet contains the labeled amount of bupropion hydrochloride and the inactive ingredients: copovidone, glyceryl behenate, hydroxypropyl cellulose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polyvinyl alcohol, talc and titanium dioxide. In addition, the 100-mg tablet contains FD&C Blue No. 2 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 Iron Oxide Red. Meet USP Dissolution Test 19. Chemical Structure

2 DOSAGE AND ADMINISTRATION • Starting dose: 150 mg per 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 per day, given as 150 mg twice daily at an interval of at least 8 hours. ( 2.1 ) • Usual target dose: 300 mg per day as 150 mg twice daily. ( 2.1 ) • Maximum dose: 400 mg per day, given as 200 mg twice daily, for patients not responding to 300 mg per 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) ] . Bupropion Hydrochloride Extended-release (SR) tablets should be swallowed whole and not crushed, divided, or chewed. Bupropion Hydrochloride Extended-release (SR) tablets may be taken with or without food. The usual adult target dose for Bupropion Hydrochloride Extended-release (SR) tablets is 300 mg per day, given as 150 mg twice daily. Initiate dosing with 150 mg per day given as a single daily dose in the morning. After 3 days of dosing, the dose may be increased to the 300-mg-per-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 per 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 per 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 Bupropion Hydrochloride Extended-release (SR) tablets 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 Bupropion Hydrochloride Extended-release (SR) tablets is 100 mg per 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) , Error! Hyperlink reference not valid. ] . 2.3 Dose Adjustment in Patients with Renal Impairment Consider reducing the dose and/or frequency of Bupropion Hydrochloride Extended-release (SR) tablets in patients with renal impairment (Glomerular Filtration Rate less than 90 mL per min) [see Use in Specific Populations (8.6) , Error! Hyperlink reference not valid. ] . 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 Bupropion Hydrochloride Extended-release (SR) tablets. Conversely, at least 14 days should be allowed after stopping Bupropion Hydrochloride Extended-release (SR) tablets before starting an MAOI antidepressant [see Error! Hyperlink reference not valid. , Drug Interactions (7.6) ] . 2.5 Use of Bupropion Hydrochloride Extended-release (SR) Tablets with Reversible MAOIs Such as Linezolid or Methylene Blue Do not start Bupropion hydrochloride Extended-release (SR) tablets 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 Error! Hyperlink reference not valid. , Drug Interactions (7.6) ] . In some cases, a patient already receiving therapy with Bupropion Hydrochloride Extended-release (SR) tablets 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 blue treatment are judged to outweigh the risks of hypertensive reactions in a particular patient, Bupropion Hydrochloride Extended-release (SR) tablets should be stopped promptly, and linezolid or intravenous methylene blue can be administered. The patient should be monitored for 2 weeks or until 24 hours after the last dose of linezolid or intravenous methylene blue, whichever comes first. Therapy with Bupropion Hydrochloride Extended-release (SR) tablets may be resumed 24 hours after the last dose of linezolid or intravenous methylene blue. The risk of administering methylene blue by non-intravenous routes (such as oral tablets or by local injection) or in intravenous doses much lower than 1 mg per kg with Bupropion Hydrochloride Extended-release (SR) tablets is unclear. The clinician should, nevertheless, be aware of the possibility of a drug interaction with such use [see Error! Hyperlink reference not valid. , Drug Interactions (7.6) ] .

1 INDICATIONS AND USAGE Bupropion Hydrochloride Extended-release (SR) tablets are 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 Error! Hyperlink reference not valid. ] . The efficacy of Bupropion Hydrochloride Extended-release (SR) tablets in maintaining an antidepressant response for up to 44 weeks following 8 weeks of acute treatment was demonstrated in a placebo-controlled trial [see Error! Hyperlink reference not valid. ] . Bupropion Hydrochloride Extended-release (SR) tablets are an aminoketone antidepressant, indicated for the treatment of major depressive disorder (MDD). ( Error! Hyperlink reference not valid. )

9.2 Abuse Humans : Controlled clinical trials conducted in normal volunteers, in subjects with a history of multiple drug abuse, and in depressed subjects showed some increase in motor activity and agitation/excitement, often typical of central stimulant activity. In a population of individuals experienced with drugs of abuse, a single oral dose of 400 mg of bupropion produced mild amphetamine-like activity as compared with placebo on the Morphine-Benzedrine Subscale of the Addiction Research Center Inventories (ARCI) and a score greater than placebo but less than 15mg of the Schedule II stimulant dextroamphetamine on the Liking Scale of the ARCI. These scales measure general feelings of euphoria and drug liking which are often associated with abuse potential. Findings in clinical trials, however, are not known to reliably predict the abuse potential of drugs. Nonetheless, evidence from single-dose trials does suggest that the recommended daily dosage of bupropion when administered orally in divided doses is not likely to be significantly reinforcing to amphetamine or CNS stimulant abusers. However, higher doses (which could not be tested because of the risk of seizure) might be modestly attractive to those who abuse CNS stimulant drugs. Bupropion Hydrochloride Extended-release (SR) tablets are intended for oral use only. The inhalation of crushed tablets or injection of dissolved bupropion has been reported.. Seizures and/or cases of death have been reported when bupropion has been administered intranasally or by parenteral injection. Animals: Studies in rodents and primates demonstrated that bupropion exhibits some pharmacologic actions common to psychostimulants. In rodents, it has been shown to increase locomotor activity, elicit a mild stereotyped behavior response, and increase rates of responding in several schedule-controlled behavior paradigms. In primate models assessing the positive-reinforcing effects of psychoactive drugs, bupropion was self-administered intravenously. In rats, bupropion produced amphetamine-like and cocaine-like discriminative stimulus effects in drug discrimination paradigms used to characterize the subjective effects of psychoactive drugs.

9.1 Controlled Substance Bupropion is not a controlled substance.

9 DRUG ABUSE AND DEPENDENCE 9.1 Controlled Substance Bupropion is not a controlled substance. 9.2 Abuse Humans : Controlled clinical trials conducted in normal volunteers, in subjects with a history of multiple drug abuse, and in depressed subjects showed some increase in motor activity and agitation/excitement, often typical of central stimulant activity. In a population of individuals experienced with drugs of abuse, a single oral dose of 400 mg of bupropion produced mild amphetamine-like activity as compared with placebo on the Morphine-Benzedrine Subscale of the Addiction Research Center Inventories (ARCI) and a score greater than placebo but less than 15mg of the Schedule II stimulant dextroamphetamine on the Liking Scale of the ARCI. These scales measure general feelings of euphoria and drug liking which are often associated with abuse potential. Findings in clinical trials, however, are not known to reliably predict the abuse potential of drugs. Nonetheless, evidence from single-dose trials does suggest that the recommended daily dosage of bupropion when administered orally in divided doses is not likely to be significantly reinforcing to amphetamine or CNS stimulant abusers. However, higher doses (which could not be tested because of the risk of seizure) might be modestly attractive to those who abuse CNS stimulant drugs. Bupropion Hydrochloride Extended-release (SR) tablets are intended for oral use only. The inhalation of crushed tablets or injection of dissolved bupropion has been reported.. Seizures and/or cases of death have been reported when bupropion has been administered intranasally or by parenteral injection. Animals: Studies in rodents and primates demonstrated that bupropion exhibits some pharmacologic actions common to psychostimulants. In rodents, it has been shown to increase locomotor activity, elicit a mild stereotyped behavior response, and increase rates of responding in several schedule-controlled behavior paradigms. In primate models assessing the positive-reinforcing effects of psychoactive drugs, bupropion was self-administered intravenously. In rats, bupropion produced amphetamine-like and cocaine-like discriminative stimulus effects in drug discrimination paradigms used to characterize the subjective effects of psychoactive drugs.

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, sinus tachycardia, and ECG changes such as conduction disturbances (including QRS prolongation) or arrhythmias. 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. Telephone numbers for certified poison control centers are listed in the Physicians' Desk Reference (PDR). 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.

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 ) • Drugs that lower seizure threshold: Dose Bupropion Hydrochloride Extended-release (SR) tablets with caution. ( 5.3 , 7.3 ) • Digoxin: May decrease plasma digoxin levels. Monitor digoxin levels. ( 7.2) • Dopaminergic drugs (levodopa and amantadine): CNS toxicity can occur when used concomitantly with Bupropion Hydrochloride Extended-release (SR) tablets. ( 7.4 ) • MAOIs: Increased risk of hypertensive reactions can occur when used concomitantly with Bupropion Hydrochloride Extended-release (SR) tablets. ( 7.6 ) • Drug-laboratory test interactions: Bupropion Hydrochloride Extended-release (SR) tablets can cause false-positive urine test results for amphetamines. ( 7.7 ) 7.1 Potential for Other Drugs to Affect Bupropion Hydrochloride Extended-release (SR) Tablets Bupropion is primarily metabolized to hydroxybupropion by CYP2B6. Therefore, the potential exists for drug interactions between Bupropion Hydrochloride Extended-release (SR) tablets 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 Bupropion Hydrochloride Extended-release (SR) tablets may be necessary when coadministered with CYP2B6 inhibitors (e.g., ticlopidine or clopidogrel) [see Error! Hyperlink reference not valid. ] . Inducers of CYP2B6: Ritonavir, Lopinavir, and Efavirenz: Concomitant treatment with these drugs can decrease bupropion and hydroxybupropion exposure. Dosage increase of Bupropion Hydrochloride Extended-release (SR) tablets may be necessary when coadministered with ritonavir, lopinavir, or efavirenz [see Error! Hyperlink reference not valid. ] 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 Error! Hyperlink reference not valid. ] . 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 Bupropion Hydrochloride Extended-release (SR) Tablets to Affect Other Drugs Drugs Metabolized by CYP2D6: Bupropion and its metabolites (erythrohydrobupropion, threohydrobupropion, hydroxybupropion) are CYP2D6 inhibitors. Therefore, coadministration of Bupropion Hydrochloride Extended-release (SR) tablets 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 Bupropion Hydrochloride Extended-release (SR) tablets, 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 Bupropion Hydrochloride Extended-release (SR) tablets and such drugs may require increased doses of the drug [see Error! Hyperlink reference not valid. ] . Digoxin Coadministration of Bupropion Hydrochloride Extended-release (SR) tablets 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 caution when coadministering Bupropion Hydrochloride Extended-release (SR) tablets with other drugs that lower seizure threshold (e.g., other bupropion products, antipsychotics, antidepressants, theophylline, or systemic corticosteroids). Use low initial doses and increase the dose gradually [see Error! Hyperlink reference not valid. , Warnings and Precautions (5.3) ] . 7.4 Dopaminergic Drugs (Levodopa and Amantadine) Bupropion, levodopa, and amantadine have dopamine agonist effects. CNS toxicity has been reported when bupropion was coadministered with levodopa or amantadine. Adverse reactions have included restlessness, agitation, tremor, ataxia, gait disturbance, vertigo, and dizziness. It is presumed that the toxicity results from cumulative dopamine agonist effects. Use caution when administering Bupropion Hydrochloride Extended-release (SR) tablets concomitantly with these drugs. 7.5 Use with Alcohol In postmarketing experience, there have been rare reports of adverse neuropsychiatric events or reduced alcohol tolerance in patients who were drinking alcohol during treatment with Bupropion Hydrochloride Extended-release (SR) tablets. The consumption of alcohol during treatment with Bupropion Hydrochloride Extended-release (SR) tablets should be minimized or avoided. 7.6 MAO Inhibitors Bupropion inhibits the reuptake of dopamine and norepinephrine. Concomitant use of MAOIs and bupropion is contraindicated because there is an increased risk of hypertensive reactions if bupropion is used concomitantly with MAOIs. Studies in animals demonstrate that the acute toxicity of bupropion is enhanced by the MAO inhibitor phenelzine. At least 14 days should elapse between discontinuation of an MAOI intended to treat depression and initiation of treatment with Bupropion Hydrochloride Extended-release (SR) tablets. Conversely, at least 14 days should be allowed after stopping Bupropion Hydrochloride Extended-release (SR) tablets before starting an MAOI antidepressant [see Dosage and Administration (2.4 , 2.5) , Error! Hyperlink reference not valid. ] . 7.7 Drug-Laboratory Test Interactions False-positive urine immunoassay screening tests for amphetamines have been reported in patients taking bupropion. This is due to lack of specificity of some screening tests. False- positive test results may result even following discontinuation of bupropion therapy. Confirmatory tests, such as gas chromatography/mass spectrometry, will distinguish bupropion from amphetamines.

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 Bupropion Hydrochloride Extended-release (SR) tablets 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 Bupropion Hydrochloride Extended-release (SR) tablets, peak plasma concentration (C max ) of bupropion is usually achieved within 3 hours. In a trial comparing chronic dosing with Bupropion Hydrochloride Extended-release (SR) tablets 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after Bupropion Hydrochloride Extended-release (SR) tablets 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, Bupropion Hydrochloride Extended-release (SR) tablets 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. Bupropion Hydrochloride Extended-release (SR) tablets can be taken with or without food. Bupropion C max and AUC were increased by 11% to 35% and 16% to 19%, respectively, when Bupropion Hydrochloride Extended-release (SR) tablets were 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 per 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 Bupropion Hydrochloride Extended-release (SR) tablets 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 14 C-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 per m), 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. Bupropion Hydrochloride Extended-release (SR) tablets 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 (t½) 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 C max AUC t ½ T max = Difference. Bupropion 1.69 3.12 1.43 0.5 h Hydroxybupropion 0.31 1.28 3.88 19 h Threo/erythrohydrobupropion amino alcohol 0.69 2.48 1.96 20 h 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 Error! Hyperlink reference not valid. ] . 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 Bupropion Hydrochloride Extended-release (SR) Tablets: In vitro studies indicate that bupropion is primarily metabolized to hydroxybupropion by CYP2B6. Therefore, the potential exists for drug interactions between Bupropion Hydrochloride Extended-release (SR) tablets 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 at a dose of 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 C max of bupropion by approximately 55% and 34%, respectively. The AUC of hydroxybupropion was unchanged, whereas C max of hydroxybupropion was increased by 50%. Carbamazepine, Phenobarbital, Phenytoin : While not systematically studied, these drugs may induce the metabolism of bupropion. Potential for Bupropion Hydrochloride Extended-release (SR) Tablets 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 t 1/2 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. Digoxin : Literature data showed that digoxin exposure was decreased when a single oral dose of 0.5-mg digoxin was administered 24 hours after a single oral dose of extended-release 150-mg bupropion in healthy volunteers.

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 Bupropion Hydrochloride Extended-release (SR) tablets 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 Bupropion Hydrochloride Extended-release (SR) tablets, peak plasma concentration (C max ) of bupropion is usually achieved within 3 hours. In a trial comparing chronic dosing with Bupropion Hydrochloride Extended-release (SR) tablets 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after Bupropion Hydrochloride Extended-release (SR) tablets 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, Bupropion Hydrochloride Extended-release (SR) tablets 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. Bupropion Hydrochloride Extended-release (SR) tablets can be taken with or without food. Bupropion C max and AUC were increased by 11% to 35% and 16% to 19%, respectively, when Bupropion Hydrochloride Extended-release (SR) tablets were 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 per 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 Bupropion Hydrochloride Extended-release (SR) tablets 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 14 C-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 per m), 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. Bupropion Hydrochloride Extended-release (SR) tablets 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 (t½) 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 C max AUC t ½ T max = Difference. Bupropion 1.69 3.12 1.43 0.5 h Hydroxybupropion 0.31 1.28 3.88 19 h Threo/erythrohydrobupropion amino alcohol 0.69 2.48 1.96 20 h 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 Error! Hyperlink reference not valid. ] . 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 Bupropion Hydrochloride Extended-release (SR) Tablets: In vitro studies indicate that bupropion is primarily metabolized to hydroxybupropion by CYP2B6. Therefore, the potential exists for drug interactions between Bupropion Hydrochloride Extended-release (SR) tablets 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 at a dose of 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 C max of bupropion by approximately 55% and 34%, respectively. The AUC of hydroxybupropion was unchanged, whereas C max of hydroxybupropion was increased by 50%. Carbamazepine, Phenobarbital, Phenytoin : While not systematically studied, these drugs may induce the metabolism of bupropion. Potential for Bupropion Hydrochloride Extended-release (SR) Tablets 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 t 1/2 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. Digoxin : Literature data showed that digoxin exposure was decreased when a single oral dose of 0.5-mg digoxin was administered 24 hours after a single oral dose of extended-release 150-mg bupropion in healthy volunteers.

20220401

2

3 DOSAGE FORMS AND STRENGTHS • 100 mg – blue, round, biconvex, film-coated, extended-release (SR) tablets debossed with “S” on one side and “522” on the other. • 150 mg – purple, round, biconvex, film-coated, extended-release (SR) tablets debossed with “S” on one side and “525” on the other. • 200 mg –pink, round, biconvex, film-coated, extended-release (SR) tablets debossed with “S” on one side and “527” on the other. • Tablets: 100 mg, 150 mg, 200 mg. ( Error! Hyperlink reference not valid. )

bupropion bupropion hydrochloride BUPROPION HYDROCHLORIDE BUPROPION COPOVIDONE K25-31 GLYCERYL DIBEHENATE HYDROXYPROPYL CELLULOSE (1600000 WAMW) MAGNESIUM STEARATE MICROCRYSTALLINE CELLULOSE POLYETHYLENE GLYCOL, UNSPECIFIED POLYVINYL ALCOHOL, UNSPECIFIED TALC TITANIUM DIOXIDE FD&C BLUE NO. 2 FD&C RED NO. 40 S;525

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 per kg per day, respectively. These doses are approximately 7 and 2 times the MRHD, respectively, on a mg per 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 per kg per day (approximately 2 to 7 times the MRHD on a mg per 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 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 per kg per day revealed no evidence of impaired fertility.

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 per kg per day, respectively. These doses are approximately 7 and 2 times the MRHD, respectively, on a mg per 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 per kg per day (approximately 2 to 7 times the MRHD on a mg per 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 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 per kg per day revealed no evidence of impaired fertility.

ANDA202304

Bupropion

bupropion hydrochloride

71205-565

HUMAN PRESCRIPTION DRUG

ORAL

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL - 150 mg Label NDC 71205-565-60 Twice-A-Day (After Initial Titration) BuPROPion Hydrochloride Extended-release (SR) Tablets, USP 150 mg WARNING: Do not use in combination with ZYBAN ® or any other medicines that contain bupropion HCl. PHARMACIST: Dispense the Medication Guide provided separately to each patient. 60 Tablets R x only 71205-565-60

RECENT MAJOR CHANGES Boxed Warning 05/2017 Warnings and Precautions, Neuropsychiatric Adverse 05/2017 Events and Suicide Risk in Smoking Cessation Treatment ( 5.2 )

Trademarks are owned by or licensed to the GSK group of companies. The other brands listed are trademarks of their respective owners. You may report side effects to Solco Healthcare US LLC. at 1-866-257-2597 or FDA at 1-800-FDA-1088. Manufactured by: Zhejiang Huahai Pharmaceutical Co., Ltd. Xunqiao, Linhai, Zhejiang 317024, China Distributed by: Solco Healthcare US, LLC Cranbury, NJ 08512, USA Repackaged by: Proficient Rx LP Thousand Oaks, CA 91320

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 Bupropion Hydrochloride Extended-release (SR) tablets 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 Bupropion Hydrochloride Extended-release (SR) Tablets?” is available for Bupropion Hydrochloride Extended-release (SR) tablets. 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 Bupropion Hydrochloride Extended-release (SR) tablets. 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 Adverse Events and Suicide Risk in Smoking Cessation Treatment: Although Bupropion Hydrochloride Extended-release (SR) tablets are not indicated for smoking cessation treatment, it contains the same active ingredient as ZYBAN ® which is approved for this use. Inform patients that some patients have experienced changes in mood (including depression and mania), psychosis, hallucinations, paranoia, delusions, homicidal ideation, aggression, hostility, agitation, anxiety, and panic, as well as suicidal ideation and suicide when attempting to quit smoking while taking bupropion. Instruct patients to discontinue bupropion and contact a healthcare professional if they experience such symptoms [see Warnings and Precautions ( 5.2 ), Adverse Reactions ( 6.2 )]. Severe Allergic Reactions: Educate patients on the symptoms of hypersensitivity and to discontinue Bupropion Hydrochloride Extended-release (SR) tablets if they have a severe allergic reaction. Seizure: Instruct patients to discontinue and not restart Bupropion Hydrochloride Extended-release (SR) tablets 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 Bupropion Hydrochloride Extended-release (SR) tablets in 2 divided doses, preferably with at least 8 hours between successive doses, to minimize the risk of seizures. Angle-Closure Glaucoma: Patients should be advised that taking Bupropion Hydrochloride Extended-release (SR) tablets can cause mild pupillary dilation, which in susceptible individuals, can lead to an episode of angle-closure glaucoma. Pre-existing glaucoma is almost always open-angle glaucoma because angle-closure glaucoma, when diagnosed, can be treated definitively with iridectomy. Open-angle glaucoma is not a risk factor for angle-closure glaucoma. Patients may wish to be examined to determine whether they are susceptible to angle closure, and have a prophylactic procedure (e.g., iridectomy), if they are susceptible [see Error! Hyperlink reference not valid. ] . Bupropion-Containing Products: Educate patients that Bupropion Hydrochloride Extended-release (SR) tablets contain the same active ingredient (bupropion hydrochloride) found in ZYBAN, which is used as an aid to smoking cessation treatment, and that Bupropion Hydrochloride Extended-release (SR) tablets should not be used in combination with ZYBAN or any other medications that contain bupropion (such as WELLBUTRIN, the immediate-release formulation and Bupropion hydrochloride extended-release (XL) tablets 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 Bupropion Hydrochloride Extended-release (SR) tablets may impair their ability to perform tasks requiring judgment or motor and cognitive skills. Advise patients that until they are reasonably certain that Bupropion Hydrochloride Extended-release (SR) tablets do not adversely affect their performance, they should refrain from driving an automobile or operating complex, hazardous machinery. Bupropion Hydrochloride Extended-release (SR) tablets 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 Bupropion Hydrochloride Extended-release (SR) 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 Bupropion Hydrochloride is present in human milk in small amounts. Storage Information: Store at 20°C to 25°C (68°F to 77°F) [see USP Controlled Room Temperature]. Keep the tablets dry and out of the light. Administration Information: Instruct patients to swallow Bupropion Hydrochloride Extended-release (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 Bupropion Hydrochloride Extended-release (SR) tablets 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 Bupropion Hydrochloride Extended-release (SR) tablets may have an odor. Bupropion Hydrochloride Extended-release (SR) tablets can be taken with or without food.

MEDICATION GUIDE Bupropion Hydrochloride Extended-release (SR) Tablets, USP (bue-PROE-pee-on HYE-droe-KLOR-ide) 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 Bupropion Hydrochloride Extended-release (SR) Tablets? 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. What is the most important information I should know about antidepressant medicines, depression and other serious mental illnesses, and suicidal thoughts or actions? What is the most important information I should know about antidepressant medicines, depression and other serious mental illnesses, and suicidal thoughts or actions? 1. Antidepressant medicines may increase suicidal thoughts or actions in some children, teenagers, or young adults within the first few months of treatment. 2. 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. 3. 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: • thoughts about suicide or dying • attempts to commit suicide • new or worse depression • new or worse anxiety • feeling very agitated or restless • panic attacks • trouble sleeping (insomnia) • new or worse irritability • acting aggressive, being angry, or violent • acting on dangerous impulses • an extreme increase in activity and talking (mania) • other unusual changes in behavior or mood 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 Bupropion Hydrochloride Extended-release (SR) tablets are 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. Talk to your healthcare provider or your family members healthcare provider about: • all risks and benefits of quit-smoking medicines • all treatment choices for quitting smoking 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 • frustration • restlessness • depressed mood • anger • decreased heart rate • trouble sleeping • feeling anxious • increased appetite • irritability • difficulty concentrating • 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. Some people have had serious side effect while taking bupropion to help them quit smoking, including: New or worse mental health problems, such as changes in behavior or thinking, aggression, hostility, agitation, depression, or suicidal thoughts or actions. Some people had these symptoms when they began taking bupropion, and others developed them after several weeks of treatment, or after stopping bupropion. These symptoms happened more often in people who had a history of mental health problems before taking bupropion than in people without a history of mental health problems. Stop taking Bupropion Hydrochloride Extended-release (SR) tablets and call your healthcare provider right away if you, your family, or caregiver notice any of these symptoms. Work with your healthcare provider to decide whether you should continue to take Bupropion Hydrochloride Extended-release (SR) tablets. In many people, these symptoms went away after stopping Bupropion Hydrochloride Extended-release (SR) tablets, but in some people symptoms continued after stopping Bupropion Hydrochloride Extended-release (SR) tablets. It is important for you to follow-up with your healthcare provider until your symptoms go away. Before taking Bupropion Hydrochloride Extended-release (SR) tablets, tell your healthcare provider if you have ever had depression or other mental health problems. 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 Bupropion Hydrochloride Extended-release (SR) Tablets? • Seizures: There is a chance of having a seizure (convulsion, fit) with Bupropion Hydrochloride Extended-release (SR) tablets, especially in people: • with certain medical problems. • who take certain medicines. The chance of having seizures increases with higher doses of Bupropion Hydrochloride Extended-release (SR) tablets. For more information, see the sections Who should not take Bupropion Hydrochloride Extended-release (SR) tablets? and What should I tell my healthcare provider before taking Bupropion Hydrochloride Extended-release (SR) tablets? 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 Bupropion Hydrochloride Extended-release (SR) tablets unless your healthcare provider has said it is okay to take them. 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 Bupropion hydrochloride, 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. • Visual problems. • eye pain • changes in vision • swelling or redness in or around the eye Only some people are at risk for these problems. You may want to undergo an eye examination to see if you are at risk and receive preventative treatment if you are. • Severe allergic reactions. Some people can have severe allergic reactions to Bupropion Hydrochloride Extended-release (SR) tablets. Stop taking Bupropion Hydrochloride Extended-release (SR) tablets 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 are Bupropion Hydrochloride Extended-release (SR) tablets? Bupropion Hydrochloride Extended-release (SR) tablets are a prescription medicine used to treat adults with a certain type of depression called major depressive disorder. Who should not take Bupropion Hydrochloride Extended-release (SR) tablets? Do not take Bupropion Hydrochloride Extended-release (SR) tablets 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), WELLBUTRIN (bupropion hydrochloride tablets), Bupropion hydrochloride extended-release (XL) tablets, APLENZIN, or FORFIVO XL. Bupropion is the same active ingredient that is in Bupropion Hydrochloride Extended-release (SR) tablets. • 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 Bupropion Hydrochloride Extended-release (SR) tablets unless directed to do so by your healthcare provider. • do not start Bupropion Hydrochloride Extended-release (SR) tablets 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 Bupropion Hydrochloride Extended-release (SR) tablets, bupropion, or to any of the inactive ingredients. See the end of this Medication Guide for a complete list of ingredients in Bupropion Hydrochloride Extended-release (SR) tablets. What should I tell my healthcare provider before taking Bupropion Hydrochloride Extended-release (SR) tablets? 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. Bupropion hydrochloride 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 Bupropion Hydrochloride Extended-release (SR) tablets. How should I take Bupropion Hydrochloride Extended-release (SR) tablets? • Take Bupropion Hydrochloride Extended-release (SR) tablets exactly as prescribed by your healthcare provider. Do not change your dose or stop taking Bupropion Hydrochloride Extended-release (SR) tablets without talking to your healthcare provider first. • Swallow Bupropion Hydrochloride Extended-release (SR) tablets whole. Do not chew, cut, or crush Bupropion Hydrochloride Extended-release (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. • Bupropion Hydrochloride Extended-release (SR) tablets may have an odor. This is normal. • Take Bupropion Hydrochloride Extended-release (SR) tablets at the same time each day. • Take your doses of Bupropion Hydrochloride Extended-release (SR) tablets at least 8 hours apart. • You may take Bupropion Hydrochloride Extended-release (SR) tablets 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 Bupropion Hydrochloride Extended-release (SR) tablets can increase your chance of having a seizure. • If you take too much Bupropion Hydrochloride Extended-release (SR) tablets, or overdose, call your local emergency room or poison control center right away. • Do not take any other medicines while taking Bupropion Hydrochloride Extended-release (SR) tablets unless your healthcare provider has told you it is okay. • If you are taking Bupropion Hydrochloride Extended-release (SR) tablets for the treatment of major depressive disorder, it may take several weeks for you to feel that Bupropion Hydrochloride Extended-release (SR) tablets are working. Once you feel better, it is important to keep taking Bupropion Hydrochloride Extended-release (SR) tablets exactly as directed by your healthcare provider. Call your healthcare provider if you do not feel Bupropion Hydrochloride Extended-release (SR) tablets are working for you. What should I avoid while taking Bupropion Hydrochloride Extended-release (SR) tablets? • Limit or avoid using alcohol during treatment with Bupropion Hydrochloride Extended-release (SR) tablets. 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 Bupropion Hydrochloride Extended-release (SR) tablets affect you. Bupropion Hydrochloride Extended-release (SR) tablets can affect your ability to do these things safely. What are possible side effects of Bupropion Hydrochloride Extended-release (SR) tablets? Bupropion Hydrochloride Extended-release (SR) tablets can cause serious side effects. See the sections at the beginning of this Medication Guide for information about serious side effects of Bupropion Hydrochloride. The most common side effects of Bupropion Hydrochloride Extended-release (SR) tablets 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 Bupropion Hydrochloride Extended-release (SR) tablets. For more information, ask your healthcare provider or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to Solco Healthcare US, LLC at 1-866-257-2597 or FDA at 1-800-FDA-1088. How should I store Bupropion Hydrochloride Extended-release (SR) tablets • Store Bupropion Hydrochloride Extended-release (SR) tablets at room temperature between 68°F and 77°F (20°C to 25°C). • Keep Bupropion Hydrochloride Extended-release (SR) tablets dry and out of the light. Keep Bupropion Hydrochloride Extended-release (SR) tablets and all medicines out of the reach of children. General Information about the safe and effective use of Bupropion Hydrochloride Extended-release (SR) Tablets. Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use Bupropion Hydrochloride Extended-release (SR) tablets for a condition for which it was not prescribed. Do not give Bupropion Hydrochloride Extended-release (SR) tablets to other people, even if they have the same symptoms you have. It may harm them. If you take a urine drug screening test, Bupropion Hydrochloride Extended-release (SR) tablets may make the test result positive for amphetamines. If you tell the person giving you the drug screening test that you are taking Bupropion Hydrochloride Extended-release (SR) tablets, they can do a more specific drug screening test that should not have this problem. This Medication Guide summarizes important information about Bupropion Hydrochloride Extended-release (SR) tablets. If you would like more information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about Bupropion Hydrochloride Extended-release (SR) tablets that is written for healthcare professionals. For more information about Bupropion Hydrochloride Extended-release (SR) tablets, call Solco Healthcare US, LLC at 1-866-257-2597. What are the ingredients in Bupropion Hydrochloride Extended-release (SR) tablets? Active ingredient: bupropion hydrochloride. Inactive ingredients: copovidone, glyceryl behenate, hydroxypropyl cellulose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polyvinyl alcohol, talc and titanium dioxide. In addition, the 100-mg tablet contains FD&C Blue No. 2 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 Iron Oxide Red. Trademarks are owned by or licensed to the GSK group of companies. The other brands listed are trademarks of their respective owners. Manufactured by: Zhejiang Huahai Pharmaceutical Co., Ltd. Xunqiao, Linhai, Zhejiang 317024, China Distributed by: Solco Healthcare US, LLC Cranbury, NJ 08512, USA Repackaged by: Proficient Rx LP Thousand Oaks, CA 91320 This Medication Guide has been approved by the U.S. Food and Drug Administration Revised: 09/2017 17098-05

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. Trial Number Treatment Group Primary Efficacy Measure: HDRS Mean Baseline Score (SD) LS Mean Score at Endpoint Visit (SE) Placebo-subtracted Difference Difference (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. (95% CI) Trial 1 Immediate-Release Bupropion 300-600 mg/day Doses that are demonstrated to be statistically significantly superior to placebo. (n = 48) 28.5 (5.1) 14.9 (1.3) -4.7 (-8.8, -0.6) Placebo (n = 27) 29.3 (7.0) 19.6 (1.6) -- Mean Baseline Score (SD) LS Mean Change from Baseline (SE) Placebo-subtracted Difference (95% CI) Trial 2 Immediate-Release Bupropion 300 mg/day (n = 36) 32.4 (5.9) -15.5 (1.7) -4.1 Immediate-Release Bupropion 450 mg/day (n = 34) 34.8 (4.6) -17.4 (1.7) -5.9 (-10.5, -1.4) Placebo (n = 39) 32.9 (5.4) -11.5 (1.6) -- Trial 3 Immediate-Release Bupropion 300 mg/dayb (n = 110) 26.5 (4.3) -12.0 (NA) -3.9 (-5.7, -1.0) Placebo (n = 106) 27.0 (3.5) -8.7 (NA) -- 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 Bupropion Hydrochloride Extended-release (SR) tablets (150 mg twice daily) were randomized to continuation of their same dose of Bupropion Hydrochloride Extended-release (SR) tablets 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 Bupropion Hydrochloride Extended-release (SR) tablets experienced significantly lower relapse rates over the subsequent 44 weeks compared with those receiving placebo.

8.5 Geriatric Use Of the approximately 6,000 subjects who participated in clinical trials with bupropion sustained-release tablets (depression and smoking cessation trials), 275 were aged ≥65 years and 47 were aged ≥75 years. In addition, several hundred subjects aged ≥65 years participated in clinical trials using the immediate-release formulation of bupropion (depression trials). No overall differences in safety or effectiveness were observed between these subjects and younger subjects. 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. Bupropion is extensively metabolized in the liver to active metabolites, which are further metabolized and excreted by the kidneys. The risk of adverse reactions may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, it may be necessary to consider this factor in dose selection; it may be useful to monitor renal function [see Dosage and Administration (2.3) , Use in Specific Populations (8.6) , Error! Hyperlink reference not valid. ] .

8.3 Nursing Mothers Bupropion and its metabolites are present in human milk. In a lactation study of 10 women, levels of orally dosed bupropion and its active metabolites were measured in expressed milk. The average daily infant exposure (assuming 150 mL per kg daily consumption) to bupropion and its active metabolites was 2% of the maternal weight-adjusted dose. Exercise caution when Bupropion Hydrochloride Extended-release (SR) tablets are administered to a nursing woman.

8.4 Pediatric Use Safety and effectiveness in the pediatric population have not been established [see Error! Hyperlink reference not valid. , Warnings and Precautions (5.1) ].

8.1 Pregnancy Pregnancy Category C Risk Summary: Data from epidemiological studies of pregnant women exposed to bupropion in the first trimester indicate no increased risk of congenital malformations overall. All pregnancies, regardless of drug exposure, have a background rate of 2% to 4% for major malformations, and 15% to 20% for pregnancy loss. No clear evidence of teratogenic activity was found in reproductive developmental studies conducted in rats and rabbits; however, in rabbits, slightly increased incidences of fetal malformations and skeletal variations were observed at doses approximately equal to the maximum recommended human dose (MRHD) and greater and decreased fetal weights were seen at doses twice the MRHD and greater. Bupropion Hydrochloride Extended-release (SR) tablets should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Clinical Considerations: Consider the risks of untreated depression when discontinuing or changing treatment with antidepressant medications during pregnancy and postpartum. 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. 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 and a case-control study (6,853 infants with cardiovascular malformations and 5,763 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 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: 1.2, 5.7), and the Slone Epidemiology case control study did not find increased risk for LVOTO. Study findings on bupropion exposure during the first trimester and risk for ventricular septal defect (VSD) are inconsistent and do not allow conclusions regarding a possible association. The Slone Epidemiology Study found an increased risk for VSD following first trimester maternal bupropion exposure (n = 17; adjusted OR = 2.5; 95% CI: 1.3, 5.0) but did not find increased risk for any other cardiovascular malformations studied (including LVOTO as above). The NBDPS and United Healthcare database study did not find an association between first trimester maternal bupropion exposure and VSD. For the findings of LVOTO and VSD, the studies were limited by the small number of exposed cases, inconsistent findings among studies, and the potential for chance findings from multiple comparisons in case control studies. Animal Data: In studies conducted in rats and rabbits, bupropion was administered orally during the period of organogenesis at doses of up to 450 and 150 mg per kg per day, respectively (approximately 11 and 7 times the MRHD, respectively, on a mg per m 2 basis). No clear evidence of teratogenic activity was found in either species; however, in rabbits, slightly increased incidences of fetal malformations and skeletal variations were observed at the lowest dose tested (25 mg per kg per day, approximately equal to the MRHD on a mg per m 2 basis) and greater. Decreased fetal weights were observed at 50 mg per kg and greater. When rats were administered bupropion at oral doses of up to 300 mg per kg per day (approximately 7 times the MRHD on a mg per m 2 basis) prior to mating and throughout pregnancy and lactation, there were no apparent adverse effects on offspring development. When rats were administered bupropion at oral doses of up to 300 mg/kg/day (approximately 7 times the MRHD on a mg/m 2 basis) prior to mating and throughout pregnancy and lactation, there were no apparent adverse effects on offspring development.

Pregnancy Category C Risk Summary: Data from epidemiological studies of pregnant women exposed to bupropion in the first trimester indicate no increased risk of congenital malformations overall. All pregnancies, regardless of drug exposure, have a background rate of 2% to 4% for major malformations, and 15% to 20% for pregnancy loss. No clear evidence of teratogenic activity was found in reproductive developmental studies conducted in rats and rabbits; however, in rabbits, slightly increased incidences of fetal malformations and skeletal variations were observed at doses approximately equal to the maximum recommended human dose (MRHD) and greater and decreased fetal weights were seen at doses twice the MRHD and greater. Bupropion Hydrochloride Extended-release (SR) tablets should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Clinical Considerations: Consider the risks of untreated depression when discontinuing or changing treatment with antidepressant medications during pregnancy and postpartum. 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. 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 and a case-control study (6,853 infants with cardiovascular malformations and 5,763 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 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: 1.2, 5.7), and the Slone Epidemiology case control study did not find increased risk for LVOTO. Study findings on bupropion exposure during the first trimester and risk for ventricular septal defect (VSD) are inconsistent and do not allow conclusions regarding a possible association. The Slone Epidemiology Study found an increased risk for VSD following first trimester maternal bupropion exposure (n = 17; adjusted OR = 2.5; 95% CI: 1.3, 5.0) but did not find increased risk for any other cardiovascular malformations studied (including LVOTO as above). The NBDPS and United Healthcare database study did not find an association between first trimester maternal bupropion exposure and VSD. For the findings of LVOTO and VSD, the studies were limited by the small number of exposed cases, inconsistent findings among studies, and the potential for chance findings from multiple comparisons in case control studies. Animal Data: In studies conducted in rats and rabbits, bupropion was administered orally during the period of organogenesis at doses of up to 450 and 150 mg per kg per day, respectively (approximately 11 and 7 times the MRHD, respectively, on a mg per m 2 basis). No clear evidence of teratogenic activity was found in either species; however, in rabbits, slightly increased incidences of fetal malformations and skeletal variations were observed at the lowest dose tested (25 mg per kg per day, approximately equal to the MRHD on a mg per m 2 basis) and greater. Decreased fetal weights were observed at 50 mg per kg and greater. When rats were administered bupropion at oral doses of up to 300 mg per kg per day (approximately 7 times the MRHD on a mg per m 2 basis) prior to mating and throughout pregnancy and lactation, there were no apparent adverse effects on offspring development. When rats were administered bupropion at oral doses of up to 300 mg/kg/day (approximately 7 times the MRHD on a mg/m 2 basis) prior to mating and throughout pregnancy and lactation, there were no apparent adverse effects on offspring development.

8 USE IN SPECIFIC POPULATIONS Pregnancy: Use only if benefit outweighs potential risk to the fetus. ( Error! Hyperlink reference not valid. ) 8.1 Pregnancy Pregnancy Category C Risk Summary: Data from epidemiological studies of pregnant women exposed to bupropion in the first trimester indicate no increased risk of congenital malformations overall. All pregnancies, regardless of drug exposure, have a background rate of 2% to 4% for major malformations, and 15% to 20% for pregnancy loss. No clear evidence of teratogenic activity was found in reproductive developmental studies conducted in rats and rabbits; however, in rabbits, slightly increased incidences of fetal malformations and skeletal variations were observed at doses approximately equal to the maximum recommended human dose (MRHD) and greater and decreased fetal weights were seen at doses twice the MRHD and greater. Bupropion Hydrochloride Extended-release (SR) tablets should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Clinical Considerations: Consider the risks of untreated depression when discontinuing or changing treatment with antidepressant medications during pregnancy and postpartum. 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. 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 and a case-control study (6,853 infants with cardiovascular malformations and 5,763 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 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: 1.2, 5.7), and the Slone Epidemiology case control study did not find increased risk for LVOTO. Study findings on bupropion exposure during the first trimester and risk for ventricular septal defect (VSD) are inconsistent and do not allow conclusions regarding a possible association. The Slone Epidemiology Study found an increased risk for VSD following first trimester maternal bupropion exposure (n = 17; adjusted OR = 2.5; 95% CI: 1.3, 5.0) but did not find increased risk for any other cardiovascular malformations studied (including LVOTO as above). The NBDPS and United Healthcare database study did not find an association between first trimester maternal bupropion exposure and VSD. For the findings of LVOTO and VSD, the studies were limited by the small number of exposed cases, inconsistent findings among studies, and the potential for chance findings from multiple comparisons in case control studies. Animal Data: In studies conducted in rats and rabbits, bupropion was administered orally during the period of organogenesis at doses of up to 450 and 150 mg per kg per day, respectively (approximately 11 and 7 times the MRHD, respectively, on a mg per m 2 basis). No clear evidence of teratogenic activity was found in either species; however, in rabbits, slightly increased incidences of fetal malformations and skeletal variations were observed at the lowest dose tested (25 mg per kg per day, approximately equal to the MRHD on a mg per m 2 basis) and greater. Decreased fetal weights were observed at 50 mg per kg and greater. When rats were administered bupropion at oral doses of up to 300 mg per kg per day (approximately 7 times the MRHD on a mg per m 2 basis) prior to mating and throughout pregnancy and lactation, there were no apparent adverse effects on offspring development. When rats were administered bupropion at oral doses of up to 300 mg/kg/day (approximately 7 times the MRHD on a mg/m 2 basis) prior to mating and throughout pregnancy and lactation, there were no apparent adverse effects on offspring development. 8.3 Nursing Mothers Bupropion and its metabolites are present in human milk. In a lactation study of 10 women, levels of orally dosed bupropion and its active metabolites were measured in expressed milk. The average daily infant exposure (assuming 150 mL per kg daily consumption) to bupropion and its active metabolites was 2% of the maternal weight-adjusted dose. Exercise caution when Bupropion Hydrochloride Extended-release (SR) tablets are administered to a nursing woman. 8.4 Pediatric Use Safety and effectiveness in the pediatric population have not been established [see Error! Hyperlink reference not valid. , Warnings and Precautions (5.1) ]. 8.5 Geriatric Use Of the approximately 6,000 subjects who participated in clinical trials with bupropion sustained-release tablets (depression and smoking cessation trials), 275 were aged ≥65 years and 47 were aged ≥75 years. In addition, several hundred subjects aged ≥65 years participated in clinical trials using the immediate-release formulation of bupropion (depression trials). No overall differences in safety or effectiveness were observed between these subjects and younger subjects. 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. Bupropion is extensively metabolized in the liver to active metabolites, which are further metabolized and excreted by the kidneys. The risk of adverse reactions may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, it may be necessary to consider this factor in dose selection; it may be useful to monitor renal function [see Dosage and Administration (2.3) , Use in Specific Populations (8.6) , Error! Hyperlink reference not valid. ] . 8.6 Renal Impairment Consider a reduced dose and/or dosing frequency of Bupropion Hydrochloride Extended-release (SR) tablets in patients with renal impairment (Glomerular Filtration Rate: less than 90 mL per min). Bupropion and its metabolites are cleared renally and may accumulate in such patients to a greater extent than usual. Monitor closely for adverse reactions that could indicate high bupropion or metabolite exposures [see Dosage and Administration (2.3) , Error! Hyperlink reference not valid. ] . 8.7 Hepatic Impairment In patients with moderate to severe hepatic impairment (Child-Pugh score: 7 to 15), the maximum dose of Bupropion Hydrochloride Extended-release (SR) tablets is 100 mg per 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 Dosage and Administration (2.2) , Error! Hyperlink reference not valid. ] .

16 HOW SUPPLIED/STORAGE AND HANDLING Bupropion Hydrochloride Extended-release Tablets USP (SR), 150 mg of bupropion hydrochloride, are purple, round, biconvex, film-coated tablets debossed with “S” on one side and “525” on the other. Bottles of 30 NDC # 71205-565-30 Bottles of 60 NDC # 71205-565-60 Bottles of 90 NDC # 71205-565-90 Store at 20°C to 25°C (68°F to 77°F) [see USP Controlled Room Temperature]. Protect from light and moisture.

WARNING: SUICIDAL THOUGHTS AND BEHAVIORS See full prescribing information for complete boxed warning. • Increased risk of suicidal thinking and behavior in children, adolescents and young adults taking antidepressants. ( 5.1 ) • Monitor for worsening and emergence of suicidal thoughts and behaviors. ( 5.1 ) WARNING: SUICIDALITY AND ANTIDEPRESSANT DRUGS Antidepressants increased the risk of suicidal thoughts and behavior in children, adolescents, and young adults in short-term trials. These trials did not show an increase in the risk of suicidal thoughts and behavior with antidepressant use in subjects over age 24; there was a reduction in risk with antidepressant use in subjects aged 65 and older [see Warnings and Precautions (5.1) ] . In patients of all ages who are started on antidepressant therapy, monitor closely for worsening, and for emergence of suicidal thoughts and behaviors. Advise families and caregivers of the need for close observation and communication with the prescriber [see Warnings and Precautions (5.1) ] .