Bupropion Hydrochloride SR

6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the labeling: Suicidal thoughts and behaviors in adolescents and young adults [see Boxed Warning , W arnings and Precautions ( 5.1 )] Neuropsychiatric adverse events and suicide risk in smoking cessation treatment [see Warnings and Precautions ( 5.2 )] Seizure [see Warnings and Precautions ( 5.3 )] Hypertension [see Warnings and Precautions ( 5.4 )] Activation of mania or hypomania [see Warnings and Precautions ( 5.5 )] Psychosis and other neuropsychiatric 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 greater than or equal to 5% and greater than or equal to 1% more than placebo rate) are insomnia, rhinitis, dry mouth, dizziness, nervous disturbance, anxiety, nausea, constipation, and arthralgia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Teva at 1-888-838-2872 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. Ad v e r se Reactions Leading to Discontinuation of Treatment Adverse reactions were sufficiently troublesome to cause discontinuation of treatment in 8% of the 706 subjects treated with bupropion hydrochloride extended-release tablets (SR) and 5% of the 313 patients treated with placebo. The more common events leading to discontinuation of treatment with bupropion hydrochloride extended-release tablets (SR) included nervous system disturbances (3.4%), primarily tremors, and skin disorders (2.4%), primarily rashes. Commonly Observed Adverse Reactions The most commonly observed adverse reactions consistently associated with the use of bupropion hydrochloride extended-release tablets (SR) were dry mouth and insomnia. The incidence of dry mouth and insomnia may be related to the dose of bupropion hydrochloride extended-release tablets (SR). The occurrence of these adverse reactions may be minimized by reducing the dose of bupropion hydrochloride extended-release tablets (SR). In addition, insomnia may be minimized by avoiding bedtime doses. Adverse reactions reported in the dose-response and comparator trials are presented in Table 2 and Table 3, respectively. Reported adverse reactions were classified using a COSTART-based dictionary. Table 2. Adverse Reactions Reported by at Least 1% of Subjects and at a Greater Frequency than Placebo in the Dose-Response Trial Adverse Reaction Bupropion Hydrochloride Extended-Release Tablets (SR) 100 to 300 mg/day ( n = 461) % P lacebo ( n = 150) % Body (General) Neck pain 2 <1 Allergic reaction 1 0 Cardiovascular Hot flashes 1 0 Hypertension 1 <1 Digestive Dry mouth 11 5 Increased appetite 2 <1 Anorexia 1 <1 Musculoskeletal Arthralgia 4 3 Myalgia 2 1 Nervous system Insomnia 31 21 Dizziness 8 7 Tremor 2 1 Somnolence 2 1 Thinking abnormality 1 0 Respiratory Bronchitis 2 0 Skin Pruritus 3 <1 Rash 3 <1 Dry skin 2 0 Urticaria 1 0 Special senses Taste perversion 2 <1 Table 3. Adverse Reactions Reported by at Least 1% of Subjects on Active Treatment and at a Greater Frequency than Placebo in the Comparator Trial Adverse Experience (COSTART Term) Bupropion Hydrochloride Extended-Release Tablets (SR) 300 mg/day ( n = 243) % Nicotine Transdermal System (NTS) 21 mg/day (n = 243) % Bupropion Hydrochloride Extended-Release Tablets (SR) and NTS (n = 244) % Placebo (n = 159) % Body Abdominal pain 3 4 1 1 Accidental injury 2 2 1 1 Chest pain <1 1 3 1 Neck pain 2 1 <1 0 Facial edema <1 0 1 0 Cardiovascular Hypertension 1 <1 2 0 Palpitations 2 0 1 0 Digestive Nausea 9 7 11 4 Dry mouth 10 4 9 4 Constipation 8 4 9 3 Diarrhea 4 4 3 1 Anorexia 3 1 5 1 Mouth ulcer 2 1 1 1 Thirst <1 <1 2 0 Musculoskeletal Myalgia 4 3 5 3 Arthralgia 5 3 3 2 Nervous system Insomnia 40 28 45 18 Dream abnormality 5 18 13 3 Anxiety 8 6 9 6 Disturbed concentration 9 3 9 4 Dizziness 10 2 8 6 Nervousness 4 <1 2 2 Tremor 1 <1 2 0 Dysphoria <1 1 2 1 Respiratory Rhinitis 12 11 9 8 Increased cough 3 5 <1 1 Pharyngitis 3 2 3 0 Sinusitis 2 2 2 1 Dyspnea 1 0 2 1 Epistaxis 2 1 1 0 Skin Application site reaction a 11 17 15 7 Rash 4 3 3 2 Pruritus 3 1 5 1 Urticaria 2 0 2 0 Special senses Taste perversion 3 1 3 2 Tinnitus 1 0 <1 0 a Subjects randomized to bupropion hydrochloride extended-release tablets (SR) or placebo received placebo patches. Adverse reactions in a 1-year maintenance trial and a 12-week COPD trial with bupropion hydrochloride extended-release tablets (SR) were quantitatively and qualitatively similar to those observed in the dose-response and comparator trials. In the trial of patients without or with a history of psychiatric disorder, the most common adverse events in subjects treated with bupropion hydrochloride extended-release tablets (SR) were broadly similar to those observed in premarketing studies. Adverse events reported in greater than 10% of subjects treated with bupropion hydrochloride extended-release tablets (SR) in the entire study population were nausea, insomnia, and anxiety disorders. Additionally, the following psychiatric adverse events were reported in greater than 2% of patients in either treatment group (bupropion hydrochloride extended-release tablets (SR) vs. placebo) by cohort. For the non-psychiatric cohort, these adverse events were anxiety, nervousness, abnormal dreams, and insomnia. For the psychiatric cohort, these adverse events were agitation, anxiety, panic, abnormal dreams, insomnia, and crying. 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 sustained-release tablets (n = 3,100). All treatment-emergent adverse reactions are included except those listed in Tables 2 and 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. Bod y (General): Frequent were asthenia, fever, and headache. Infrequent were chills, inguinal hernia, and photosensitivity. Rare was malaise. Cardiovascular: Infrequent were flushing, migraine, postural hypotension, stroke, tachycardia, and vasodilation. Rare was syncope. Digestive: Frequent were dyspepsia and vomiting. Infrequent were abnormal liver function, bruxism, dysphagia, gastric reflux, gingivitis, jaundice, and stomatitis. Hemic and Lymphatic: Infrequent was ecchymosis. M e tabolic and Nutritional: Infrequent were edema and peripheral edema. M u sculoskeletal: Infrequent were leg cramps and twitching. Nervous System: Frequent were agitation, depression, and irritability. Infrequent were abnormal coordination, CNS stimulation, confusion, decreased libido, decreased memory, depersonalization, emotional lability, hostility, hyperkinesia, hypertonia, hypesthesia, paresthesia, suicidal ideation, and vertigo. Rare were amnesia, ataxia, derealization, and hypomania. Respiratory: Rare was bronchospasm. S kin: Frequent was sweating. Spe cial Senses: Frequent was blurred vision or diplopia. Infrequent were accommodation abnormality and dry eye. Urogenital: Frequent was urinary frequency. Infrequent were impotence, polyuria, and urinary urgency. 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of bupropion hydrochloride extended-release tablets (SR) 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 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 Cardiovascular disorder, complete atrioventricular block (AV) block, extrasystoles, hypotension, myocardial infarction, phlebitis, and pulmonary embolism. Digestive Colitis, esophagitis, gastrointestinal hemorrhage, gum hemorrhage, hepatitis, increased salivation, intestinal perforation, liver damage, pancreatitis, stomach ulcer, and stool abnormality. Endo crine Hyperglycemia, hypoglycemia, hyponatremia, and syndrome of inappropriate antidiuretic hormone secretion. Hemic and Lymphatic Anemia, leukocytosis, leukopenia, lymphadenopathy, pancytopenia, and thrombocytopenia. Altered prothrombin time (PT) and/or international normalized ratio (INR), infrequently associated with hemorrhagic or thrombotic complications, were observed when bupropion was coadministered with warfarin. M e tabolic and Nutritional Glycosuria. M u sculoskeletal Arthritis and 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. S kin Alopecia, angioedema, exfoliative dermatitis, hirsutism, and Stevens-Johnson syndrome. Spe cial Senses Deafness, increased intraocular pressure, and mydriasis. Urogenital Abnormal ejaculation, cystitis, dyspareunia, dysuria, gynecomastia, menopause, painful erection, prostate disorder, salpingitis, urinary incontinence, urinary retention, urinary tract disorder, and vaginitis.

4 CONTRAINDICATIONS Bupropion hydrochloride extended-release tablets (SR) are contraindicated in patients with a seizure disorder. Bupropion hydrochloride extended-release tablets (SR) 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 tablets (SR) 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 tablets (SR) or within 14 days of discontinuing treatment with bupropion hydrochloride extended-release tablets (SR) is contraindicated. There is an increased risk of hypertensive reactions when bupropion hydrochloride extended-release tablets (SR) are used concomitantly with MAOIs. The use of bupropion hydrochloride extended-release tablets (SR) within 14 days of discontinuing treatment with an MAOI is also contraindicated. Starting bupropion hydrochloride extended-release tablets (SR) in a patient treated with reversible MAOIs such as linezolid or intravenous methylene blue is contraindicated [see Dosage and Administration ( 2.8 ), Warnings and Precautions ( 5.4 ), Drug Interactions ( 7.6 )] . Bupropion hydrochloride extended-release tablets (SR) are contraindicated in patients with a known hypersensitivity to bupropion or other ingredients of bupropion hydrochloride extended-release tablets (SR). Anaphylactoid/anaphylactic reactions and Stevens-Johnson syndrome have been reported [see Warnings and Precautions ( 5.8 )] . Seizure disorder. ( 4 , 5.3 ) Current or prior diagnosis of bulimia or anorexia nervosa. ( 4 , 5.3 ) Abrupt discontinuation of alcohol, benzodiazepines, barbiturates, antiepileptic drugs. ( 4 , 5.3 ) Monoamine Oxidase Inhibitors (MAOIs): Do not use MAOIs intended to treat psychiatric disorders with bupropion hydrochloride extended-release tablets (SR) or within 14 days of stopping treatment with bupropion hydrochloride extended-release tablets (SR). Do not use bupropion hydrochloride extended-release tablets (SR) within 14 days of stopping an MAOI intended to treat psychiatric disorders. In addition, do not start bupropion hydrochloride extended-release tablets (SR) in a patient who is being treated with linezolid or intravenous methylene blue. ( 4 , 7.6 ) Known hypersensitivity to bupropion or other ingredients of bupropion hydrochloride extended-release tablets (SR). ( 4 , 5.8 )

11 DESCRIPTION Bupropion Hydrochloride Extended-Release Tablets, USP (SR) are a non-nicotine aid to smoking cessation. Bupropion Hydrochloride Extended-Release Tablets, USP (SR) are chemically unrelated to nicotine or other agents currently used in the treatment of nicotine addiction. Initially developed and marketed as an antidepressant (WELLBUTRIN ® [bupropion hydrochloride] tablets and WELLBUTRIN SR ® [bupropion hydrochloride] sustained-release tablets), Bupropion Hydrochloride Extended-Release Tablets, USP (SR) are also 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) are supplied for oral administration as 150 mg white to off-white, film-coated, sustained-release tablets. Each tablet contains the labeled amount of bupropion hydrochloride, USP and the inactive ingredients: hydroxypropyl cellulose, microcrystalline cellulose, colloidal silicon dioxide, stearic acid, magnesium stearate, and diluted hydrochloric acid. The film-coating contains lactose monohydrate, hydroxypropyl cellulose, titanium dioxide, and polyethylene glycol. USP Dissolution Test Pending. bupropion hydrochloride chemical structure

2 DOSAGE AND ADMINISTRATION Starting dose: 150 mg per day for first 3 days. ( 2.1 ) General: Increase dose gradually to reduce seizure risk. ( 2.1 , 5.3 ) Begin dosing one week before quit day. ( 2.1 ) After 3 days, increase the dose to 300 mg per day, given as 150 mg twice daily at an interval of at least 8 hours. ( 2.1 ) May be used with a nicotine transdermal system. ( 2.5 ) Moderate to severe hepatic impairment: 150 mg every other day. ( 2.6 , 8.7 ) Mild hepatic impairment: Consider reducing the dose and/or frequency of dosing. ( 2.6 , 8.7 ) Renal impairment: Consider reducing the dose and/or frequency. ( 2.7 , 8.6 ) 2.1 Usual Dosage Treatment with bupropion hydrochloride extended-release tablets (SR) should be initiated before the patient’s planned quit day, while the patient is still smoking, because it takes approximately 1 week of treatment to achieve steady-state blood levels of bupropion. The patient should set a “target quit date” within the first 2 weeks of treatment with bupropion hydrochloride extended-release tablets (SR). Dosing To minimize the risk of seizure: Begin dosing with one 150 mg tablet per day for 3 days. Increase dose to 300 mg per day given as one 150 mg tablet twice each day with an interval of at least 8 hours between each dose. Do not exceed 300 mg per day. Bupropion hydrochloride extended-release tablets (SR) should be swallowed whole and not crushed, divided, or chewed, as this may lead to an increased risk of adverse effects including seizures [see Warnings and Precautions ( 5.3 )] . Bupropion hydrochloride extended-release tablets (SR) may be taken with or without food [see Clinical Pharmacology ( 12.3 )] . 2.2 Duration of Treatment Treatment with bupropion hydrochloride extended-release tablets (SR) should be continued for 7 to 12 weeks. If the patient has not quit smoking after 7 to 12 weeks, it is unlikely that he or she will quit during that attempt so treatment with bupropion hydrochloride extended-release tablets (SR) should probably be discontinued and the treatment plan reassessed. The goal of therapy with bupropion hydrochloride extended-release tablets (SR) is complete abstinence. Discuss discontinuing treatment with bupropion hydrochloride extended-release tablets (SR) after 12 weeks if the patient feels ready but consider whether the patient may benefit from ongoing treatment. Patients who successfully quit after 12 weeks of treatment but do not feel ready to discontinue treatment should be considered for ongoing therapy with bupropion hydrochloride extended-release tablets (SR); longer treatment should be guided by the relative benefits and risks for individual patients. It is important that patients continue to receive counseling and support throughout treatment with bupropion hydrochloride extended-release tablets (SR) and for a period of time thereafter. 2.3 Individualization of Therapy Patients are more likely to quit smoking and remain abstinent if they are seen frequently and receive support from their physicians or other healthcare professionals. It is important to ensure that patients read the instructions provided to them and have their questions answered. Physicians should review the patient’s overall smoking cessation program that includes treatment with bupropion hydrochloride extended-release tablets (SR). Patients should be advised of the importance of participating in the behavioral interventions, counseling, and/or support services to be used in conjunction with bupropion hydrochloride extended-release tablets (SR) [see Medication Guide ] . Patients who fail to quit smoking during an attempt may benefit from interventions to improve their chances for success on subsequent attempts. Patients who are unsuccessful should be evaluated to determine why they failed. A new quit attempt should be encouraged when factors that contributed to failure can be eliminated or reduced, and conditions are more favorable. 2.4 Maintenance Tobacco dependence is a chronic condition. Some patients may need ongoing treatment. Whether to continue treatment with bupropion hydrochloride extended-release tablets (SR) for periods longer than 12 weeks for smoking cessation must be determined for individual patients. 2.5 Combination Treatment with Bupropion Hydrochloride Extended-Release Tablets (SR) and a Nicotine Transdermal System (NTS) Combination treatment with bupropion hydrochloride extended-release tablets (SR) and NTS may be prescribed for smoking cessation. The prescriber should review the complete prescribing information for both bupropion hydrochloride extended-release tablets (SR) and NTS before using combination treatment [see Clinical Studies ( 14 )]. Monitoring for treatment-emergent hypertension in patients treated with the combination of bupropion hydrochloride extended-release tablets (SR) and NTS is recommended. 2.6 Dose Adjustment in Patients with Hepatic Impairment In patients with moderate to severe hepatic impairment (Child-Pugh score: 7 to 15), the maximum dose should not exceed 150 mg every other day. In patients with mild hepatic impairment (Child-Pugh score: 5 to 6), consider reducing the dose and/or frequency of dosing [see Use in Specific Populations ( 8.7 ), Clinical Pharmacology ( 12.3 )] . 2.7 Dose Adjustment in Patients with Renal Impairment Consider reducing the dose and/or frequency of bupropion hydrochloride extended-release tablets (SR) in patients with renal impairment (Glomerular Filtration Rate less than 90 mL per min) [see Use in Specific Populations ( 8.6 ), Clinical Pharmacology ( 12.3 )] . 2.8 Use of Bupropion Hydrochloride Extended-Release Tablets (SR) with Reversible MAOIs Such as Linezolid or Methylene Blue Do not start bupropion hydrochloride extended-release tablets (SR) in a patient who is being treated with a reversible MAOI such as linezolid or intravenous methylene blue. Drug interactions can increase the risk of hypertensive reactions [see Contraindications ( 4 ), Drug Interactions ( 7.6 )] . In some cases, a patient already receiving therapy with bupropion hydrochloride extended-release tablets (SR) may require urgent treatment with linezolid or intravenous methylene blue. If acceptable alternatives to linezolid or intravenous methylene blue treatment are not available and the potential benefits of linezolid or intravenous methylene blue treatment are judged to outweigh the risks of hypertensive reactions in a particular patient, bupropion hydrochloride extended-release tablets (SR) 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 tablets (SR) 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 tablets (SR) is unclear. The clinician should, nevertheless, be aware of the possibility of a drug interaction with such use [see Contraindications ( 4 ), Drug Interactions ( 7.6 )] .

1 INDICATIONS AND USAGE Bupropion hydrochloride extended-release tablets (SR) are indicated as an aid to smoking cessation treatment. Bupropion hydrochloride extended-release tablets (SR) are an aminoketone agent indicated as an aid to smoking cessation treatment. ( 1 )

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 15 mg 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 tablets (SR) 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. An imals 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. The possibility that bupropion may induce dependence should be kept in mind when evaluating the desirability of including the drug in smoking cessation programs of individual patients.

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 15 mg 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 tablets (SR) 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. An imals 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. The possibility that bupropion may induce dependence should be kept in mind when evaluating the desirability of including the drug in smoking cessation programs of individual patients.

10 OVERDOSAGE 10.1 Human Overdose Experience Overdoses of up to 30 grams or more of bupropion have been reported. Seizure was reported in approximately one-third of all cases. Other serious reactions reported with overdoses of bupropion alone included hallucinations, loss of consciousness, mental status changes, sinus tachycardia, ECG changes such as conduction disturbances (including QRS prolongation) or arrhythmias, clonus, myoclonus, and hyperreflexia. Fever, muscle rigidity, rhabdomyolysis, hypotension, stupor, coma, and respiratory failure have been reported mainly when bupropion was part of multiple drug overdoses. Although most patients recovered without sequelae, deaths associated with overdoses of bupropion alone have been reported in patients ingesting large doses of the drug. Multiple uncontrolled seizures, bradycardia, cardiac failure, and cardiac arrest prior to death were reported in these patients. 10.2 Overdosage Management Consult a Certified Poison Control Center for up–to-date guidance and advice. 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 ) Digoxin: May decrease plasma digoxin levels. Monitor digoxin levels. ( 7.2 ) Drugs that lower seizure threshold: Dose bupropion hydrochloride extended-release tablets (SR) with caution. ( 5.3 , 7.3 ) Dopaminergic drugs (levodopa and amantadine): Central nervous system (CNS) toxicity can occur when used concomitantly with bupropion hydrochloride extended-release tablets (SR). ( 7.4 ) MAOIs: Increased risk of hypertensive reactions can occur when used concomitantly with bupropion hydrochloride extended-release tablets (SR). ( 7.6 ) Drug-laboratory test interactions: Bupropion hydrochloride extended-release tablets (SR) can cause false-positive urine test results for amphetamines. ( 7.8 ) 7.1 Potential for Other Drugs to Affect Bupropion Hydrochloride Extended-Release Tablets (SR) Bupropion is primarily metabolized to hydroxybupropion by CYP2B6. Therefore, the potential exists for drug interactions between bupropion hydrochloride extended-release tablets (SR) and drugs that are inhibitors or inducers of CYP2B6. Inhibitors of CYP2B6 Ticlopidine and Clopidogrel: Concomitant treatment with these drugs can increase bupropion exposure but decrease hydroxybupropion exposure. Based on clinical response, dosage adjustment of bupropion hydrochloride extended-release tablets (SR) may be necessary when coadministered with CYP2B6 inhibitors (e.g., ticlopidine or clopidogrel) [see Clinical Pharmacology ( 12.3 )] . Inducers of CYP2B6 Ritonavir, Lopinavir, and Efavirenz : Concomitant treatment with these drugs can decrease bupropion and hydroxybupropion exposure. Dosage increase of bupropion hydrochloride extended-release tablets (SR) may be necessary when coadministered with ritonavir, lopinavir, or efavirenz [see Clinical Pharmacology ( 12.3 )] but should not exceed the maximum recommended dose. Carbamazepine, Phenobarbital, Phenytoin: While not systematically studied, these drugs may induce the metabolism of bupropion and may decrease bupropion exposure [see Clinical Pharmacology ( 12.3 )] . If bupropion is used concomitantly with a CYP inducer, it may be necessary to increase the dose of bupropion, but the maximum recommended dose should not be exceeded. 7.2 Potential for Bupropion Hydrochloride Extended-Release Tablets (SR) 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 tablets (SR) with drugs that are metabolized by CYP2D6 can increase the exposures of drugs that are substrates of CYP2D6. Such drugs include certain antidepressants (e.g., venlafaxine, nortriptyline, imipramine, desipramine, paroxetine, fluoxetine, and sertraline), antipsychotics (e.g., haloperidol, risperidone, thioridazine), beta-blockers (e.g., metoprolol), and Type 1C antiarrhythmics (e.g., propafenone and flecainide). When used concomitantly with bupropion hydrochloride extended-release tablets (SR), it may be necessary to decrease the dose of these CYP2D6 substrates, particularly for drugs with a narrow therapeutic index. Drugs that require metabolic activation by CYP2D6 to be effective (e.g., tamoxifen) theoretically could have reduced efficacy when administered concomitantly with inhibitors of CYP2D6 such as bupropion. Patients treated concomitantly with bupropion hydrochloride extended-release tablets (SR) and such drugs may require increased doses of the drug [see Clinical Pharmacology ( 12.3 )] . Digoxin Coadministration of bupropion hydrochloride extended-release tablets (SR) with digoxin may decrease plasma digoxin levels. Monitor plasma digoxin levels in patients treated concomitantly with bupropion hydrochloride extended-release tablets (SR) and digoxin [see Clinical Pharmacology ( 12.3 )] . 7.3 Drugs that Lower Seizure Threshold Use extreme caution when coadministering bupropion hydrochloride extended-release tablets (SR) 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 Contraindications ( 4 ), 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 tablets (SR) 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 tablets (SR). The consumption of alcohol during treatment with bupropion hydrochloride extended-release tablets (SR) 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 and initiation of treatment with bupropion hydrochloride extended-release tablets (SR). Conversely, at least 14 days should be allowed after stopping bupropion hydrochloride extended-release tablets (SR) before starting an MAOI intended to treat psychiatric disorders [see Dosage and Administration ( 2.8 ), Contraindications ( 4 )] . 7.7 Smoking Cessation Physiological changes resulting from smoking cessation, with or without treatment with bupropion hydrochloride extended-release tablets (SR), may alter the pharmacokinetics or pharmacodynamics of certain drugs (e.g., theophylline, warfarin, insulin) for which dosage adjustment may be necessary. 7.8 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 by which bupropion hydrochloride extended-release tablets (SR) enhances the ability of patients to abstain from smoking 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. Ab sorption The absolute bioavailability of bupropion hydrochloride extended-release tablets (SR) in humans has not been determined because an intravenous formulation for human use is not available. However, it appears likely that only a small proportion of any orally administered dose reaches the systemic circulation intact. In rat and dog studies, the bioavailability of bupropion ranged from 5% to 20%. In humans, following oral administration of bupropion hydrochloride extended-release tablets (SR), peak plasma concentration (C max ) of bupropion is usually achieved within 3 hours. Bupropion hydrochloride extended-release tablets (SR) 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 tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Distribution In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg 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. M e tabolism 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 tablets (SR) in humans, C max of hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33 (±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. E limination 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. Specific Populations 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. Patients with 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 min), showed that after a single 150 mg dose of sustained-release bupropion, exposure to bupropion was approximately 2-fold higher in subjects with impaired renal function while levels of the hydroxybupropion and threo/erythrohydrobupropion (combined) metabolites were similar in the 2 groups. Bupropion is extensively metabolized in the liver to active metabolites, which are further metabolized and subsequently excreted by the kidneys. The elimination of the major metabolites of bupropion may be reduced by impaired renal function. Bupropion hydrochloride extended-release tablets (SR) should be used with caution in patients with renal impairment and a reduced frequency and/or dose should be considered [see Use in Specific Populations ( 8.6 )]. Patients with 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 8 subjects with severe hepatic cirrhosis, significant alterations in the pharmacokinetics of bupropion and its metabolites were seen (Table 4). Table 4. Pharmacokinetics of Bupropion and Metabolites in Patients with Severe Hepatic Cirrhosis: Ratio Relative to Healthy Matched Controls C max AUC t ½ T max a 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 a Difference. S m o kers: 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 hydrochloride extended-release tablets (SR), there were no statistically significant differences in C max , half-life, T max , AUC, or clearance of bupropion or its major metabolites between smokers and nonsmokers. In a trial comparing the treatment combination of bupropion hydrochloride extended-release tablets (SR) and NTS versus bupropion hydrochloride extended-release tablets (SR) alone, no statistically significant differences were observed between the 2 treatment groups of combination bupropion hydrochloride extended-release tablets (SR) and NTS (n = 197) and bupropion hydrochloride extended-release tablets (SR) alone (n = 193) in the plasma concentrations of bupropion or its active metabolites at Weeks 3 and 6. Patients with Le ft Ventricular Dysfunction: During a chronic dosing trial with bupropion in 14 depressed subjects with left ventricular dysfunction (history of CHF or an enlarged heart on x-ray), there was no apparent effect on the pharmacokinetics of bupropion or its metabolites, compared with healthy volunteers. Age : The effects of age on the pharmacokinetics of bupropion and its metabolites have not been fully characterized, but an exploration of steady-state bupropion concentrations from several depression efficacy trials involving subjects dosed in a range of 300 to 750 mg per day, on a 3-times-daily schedule, revealed no relationship between age (18 to 83 years) and plasma concentration of bupropion. A single-dose pharmacokinetic trial demonstrated that the disposition of bupropion and its metabolites in elderly subjects was similar to that of younger subjects. These data suggest there is no prominent effect of age on bupropion concentration; however, another single- and multiple-dose pharmacokinetics trial suggested that the elderly are at increased risk for accumulation of bupropion and its metabolites [see Use in Specific Populations ( 8.5 )] . Male and Female Patients: 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. Drug Interaction Studies Potential for Other Drugs to Affect Bupropion Hydrochloride Extended-Release Tablets (SR): 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 tablets (SR) and drugs that are inhibitors or inducers of CYP2B6. In addition, in vitro studies suggest that paroxetine, sertraline, norfluoxetine, fluvoxamine, and nelfinavir inhibit the hydroxylation of bupropion. Inhibitors of CYP2B6: Ticlopidine, Clopidogrel: In a trial in healthy male volunteers, clopidogrel 75 mg once daily or ticlopidine 250 mg twice daily increased exposures (C max and AUC) of bupropion by 40% and 60% for clopidogrel, and by 38% and 85% for ticlopidine, respectively. The exposures (C max and AUC) of hydroxybupropion were decreased 50% and 52%, respectively, by clopidogrel, and 78% and 84%, respectively, by ticlopidine. This effect is thought to be due to the inhibition of the CYP2B6-catalyzed bupropion hydroxylation. P r a sugrel: 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 3 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. E favirenz: 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. Po tential for Bupropion Hydrochloride Extended-Release Tablets (SR) to Affect Other Drugs Animal data indicated that bupropion may be an inducer of drug-metabolizing enzymes in humans. In one trial, following chronic administration of bupropion 100 mg three times daily to 8 healthy male volunteers for 14 days, there was no evidence of induction of its own metabolism. Nevertheless, there may be potential for clinically important alterations of blood levels of coadministered 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. La m o trigine: 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 by which bupropion hydrochloride extended-release tablets (SR) enhances the ability of patients to abstain from smoking 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. Ab sorption The absolute bioavailability of bupropion hydrochloride extended-release tablets (SR) in humans has not been determined because an intravenous formulation for human use is not available. However, it appears likely that only a small proportion of any orally administered dose reaches the systemic circulation intact. In rat and dog studies, the bioavailability of bupropion ranged from 5% to 20%. In humans, following oral administration of bupropion hydrochloride extended-release tablets (SR), peak plasma concentration (C max ) of bupropion is usually achieved within 3 hours. Bupropion hydrochloride extended-release tablets (SR) 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 tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Distribution In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg 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. M e tabolism 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 tablets (SR) in humans, C max of hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33 (±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. E limination 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. Specific Populations 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. Patients with 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 min), showed that after a single 150 mg dose of sustained-release bupropion, exposure to bupropion was approximately 2-fold higher in subjects with impaired renal function while levels of the hydroxybupropion and threo/erythrohydrobupropion (combined) metabolites were similar in the 2 groups. Bupropion is extensively metabolized in the liver to active metabolites, which are further metabolized and subsequently excreted by the kidneys. The elimination of the major metabolites of bupropion may be reduced by impaired renal function. Bupropion hydrochloride extended-release tablets (SR) should be used with caution in patients with renal impairment and a reduced frequency and/or dose should be considered [see Use in Specific Populations ( 8.6 )]. Patients with 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 8 subjects with severe hepatic cirrhosis, significant alterations in the pharmacokinetics of bupropion and its metabolites were seen (Table 4). Table 4. Pharmacokinetics of Bupropion and Metabolites in Patients with Severe Hepatic Cirrhosis: Ratio Relative to Healthy Matched Controls C max AUC t ½ T max a 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 a Difference. S m o kers: 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 hydrochloride extended-release tablets (SR), there were no statistically significant differences in C max , half-life, T max , AUC, or clearance of bupropion or its major metabolites between smokers and nonsmokers. In a trial comparing the treatment combination of bupropion hydrochloride extended-release tablets (SR) and NTS versus bupropion hydrochloride extended-release tablets (SR) alone, no statistically significant differences were observed between the 2 treatment groups of combination bupropion hydrochloride extended-release tablets (SR) and NTS (n = 197) and bupropion hydrochloride extended-release tablets (SR) alone (n = 193) in the plasma concentrations of bupropion or its active metabolites at Weeks 3 and 6. Patients with Le ft Ventricular Dysfunction: During a chronic dosing trial with bupropion in 14 depressed subjects with left ventricular dysfunction (history of CHF or an enlarged heart on x-ray), there was no apparent effect on the pharmacokinetics of bupropion or its metabolites, compared with healthy volunteers. Age : The effects of age on the pharmacokinetics of bupropion and its metabolites have not been fully characterized, but an exploration of steady-state bupropion concentrations from several depression efficacy trials involving subjects dosed in a range of 300 to 750 mg per day, on a 3-times-daily schedule, revealed no relationship between age (18 to 83 years) and plasma concentration of bupropion. A single-dose pharmacokinetic trial demonstrated that the disposition of bupropion and its metabolites in elderly subjects was similar to that of younger subjects. These data suggest there is no prominent effect of age on bupropion concentration; however, another single- and multiple-dose pharmacokinetics trial suggested that the elderly are at increased risk for accumulation of bupropion and its metabolites [see Use in Specific Populations ( 8.5 )] . Male and Female Patients: 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. Drug Interaction Studies Potential for Other Drugs to Affect Bupropion Hydrochloride Extended-Release Tablets (SR): 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 tablets (SR) and drugs that are inhibitors or inducers of CYP2B6. In addition, in vitro studies suggest that paroxetine, sertraline, norfluoxetine, fluvoxamine, and nelfinavir inhibit the hydroxylation of bupropion. Inhibitors of CYP2B6: Ticlopidine, Clopidogrel: In a trial in healthy male volunteers, clopidogrel 75 mg once daily or ticlopidine 250 mg twice daily increased exposures (C max and AUC) of bupropion by 40% and 60% for clopidogrel, and by 38% and 85% for ticlopidine, respectively. The exposures (C max and AUC) of hydroxybupropion were decreased 50% and 52%, respectively, by clopidogrel, and 78% and 84%, respectively, by ticlopidine. This effect is thought to be due to the inhibition of the CYP2B6-catalyzed bupropion hydroxylation. P r a sugrel: 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 3 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. E favirenz: 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. Po tential for Bupropion Hydrochloride Extended-Release Tablets (SR) to Affect Other Drugs Animal data indicated that bupropion may be an inducer of drug-metabolizing enzymes in humans. In one trial, following chronic administration of bupropion 100 mg three times daily to 8 healthy male volunteers for 14 days, there was no evidence of induction of its own metabolism. Nevertheless, there may be potential for clinically important alterations of blood levels of coadministered 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. La m o trigine: 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.

20230321

46

3 DOSAGE FORMS AND STRENGTHS 150 mg – white to off-white, round, unscored, film-coated tablets, with " WPI " over " 867 " on one side. Tablets: 150 mg. ( 3 )

Bupropion Hydrochloride SR bupropion hydrochloride BUPROPION HYDROCHLORIDE BUPROPION HYDROXYPROPYL CELLULOSE (160000 WAMW) MICROCRYSTALLINE CELLULOSE 101 SILICON DIOXIDE STEARIC ACID MAGNESIUM STEARATE HYDROCHLORIC ACID LACTOSE MONOHYDRATE HYDROXYPROPYL CELLULOSE, UNSPECIFIED TITANIUM DIOXIDE POLYETHYLENE GLYCOL 400 white to off-white WPI;867

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 10 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 3 to 10 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 10 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 3 to 10 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.

ANDA079094

Bupropion Hydrochloride SR

bupropion hydrochloride

0591-3543

HUMAN PRESCRIPTION DRUG

ORAL

PRINCIPAL DISPLAY PANEL NDC 0591-3543-60 Twice-A-Day (After Initial Titration) BuPROPion HCl Extended-Release Tablets, USP (SR) 150mg WARNING: Do not use in combination with Wellbutrin ® ,Wellbutrin SR ® , Wellbutrin XL ® or any other medicines that contain bupropion hydrochloride. Federal Law requires dispensing of BuPROPion HCl Extended Release Tablets, USP (SR) with the Medication Guide. 60 Tablets Rx Only 1 1

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling ( Medication Guide ). 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 [see Boxed Warning , Warnings and Precautions ( 5.1 )] . Neuropsychiatric Adverse Events and Suicide Risk in Smoking Cessation Treatment 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 hydrochloride extended-release tablets (SR). Instruct patients to discontinue bupropion hydrochloride extended-release tablets (SR) and contact a healthcare professional if they experience such symptoms [see Warnings and Precautions ( 5.2 ), Adverse Reactions ( 6.2 )] . Se v e r e Allergic Reactions Educate patients on the symptoms of hypersensitivity and to discontinue bupropion hydrochloride extended-release tablets (SR) if they have a severe allergic reaction to bupropion hydrochloride extended-release tablets (SR). Se izure Instruct patients to discontinue bupropion hydrochloride extended-release tablets (SR) and not restart it 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. Angle-Closure Glaucoma Patients should be advised that taking bupropion hydrochloride extended-release tablets (SR) 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 Warnings and Precautions ( 5.7 )] . Bup ro p ion-Containing Products Educate patients that bupropion hydrochloride extended-release tablets (SR) contains the same active ingredient (bupropion hydrochloride) found in WELLBUTRIN ® , WELLBUTRIN SR ® , and WELLBUTRIN XL ® , which are used to treat depression and that bupropion hydrochloride extended-release tablets (SR) should not be used in conjunction with any other medications that contain bupropion (such as WELLBUTRIN ® , the immediate-release formulation; WELLBUTRIN SR ® , the sustained-release formulation; WELLBUTRIN XL ® or FORFIVO XL ® , the extended-release formulations; and APLENZIN ® , the extended-release formulation of bupropion hydrobromide). In addition, there are a number of generic bupropion HCl products for the immediate-, sustained-, and extended-release formulations. Po tential for Cognitive and Motor Impairment Advise patients that any CNS-active drug like bupropion hydrochloride extended-release tablets (SR) 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 tablets (SR) does not adversely affect their performance, they should refrain from driving an automobile or operating complex, hazardous machinery. Bupropion hydrochloride extended-release tablets (SR) may lead to decreased alcohol tolerance. Concomitant Medications Counsel patients to notify their healthcare provider if they are taking or plan to take any prescription or over-the-counter drugs because bupropion hydrochloride extended-release tablets (SR) and other drugs may affect each others’ metabolisms. P r e g nan cy Advise patients to notify their healthcare provider if they become pregnant or intend to become pregnant during therapy. P r e cautions for Nursing Mothers Advise patients that bupropion hydrochloride extended-release (SR) is present in human milk in small amounts. S torage Information Instruct patients to store bupropion hydrochloride extended-release tablets (SR) at room temperature, between 68°F and 77°F (20°C to 25°C) and keep the tablets dry and out of the light. Ad m i n istration Information Instruct patients to swallow bupropion hydrochloride extended-release tablets (SR) 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 tablets (SR) in 2 doses at least 8 hours apart, to minimize the risk of seizures. Instruct patients if they miss a dose, not to take an extra tablet to make up for the missed dose and to take the next tablet at the regular time because of the dose-related risk of seizure. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Advise patients that bupropion hydrochloride extended-release tablets (SR) may have an odor. Brands listed are the trademarks of their respective owners. Dispense with Medication Guide available at: www.tevausa.com/medguides Manufactured For: Teva Pharmaceuticals Parsippany, NJ 07054 Rev. C 3/2023

MEDICATION GUIDE Dispense with Medication Guide available at: www.tevausa.com/medguides MEDICATION GUIDE BuPROPion Hydrochloride ( bue proe' pee on hye" droe klor' ide) Extended-Release Tablets (SR) IMPORTANT: Be sure to read the three sections of this Medication Guide. The first section is about the risk of changes in thinking and behavior, depression and suicidal thoughts or actions with medicines used to quit smoking; the second section is about the risk of suicidal thoughts and actions with antidepressant medicines; and the third section is entitled “What Other Important Information Should I Know About Bupropion Hydrochloride Extended-Release Tablets (SR)?” 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 member’s 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 hydrochloride extended-release tablets (SR), 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 effects while taking bupropion hydrochloride extended-release tablets (SR) to help them quit smoking, including: New or worse mental health problems, such as changes in behavior or thinking, aggression, hostility, agitation, depression, suicidal thoughts or actions. Some people had these symptoms when they began taking bupropion hydrochloride extended-release tablets (SR), and others developed them after several weeks of treatment, or after stopping bupropion hydrochloride extended-release tablets (SR). These symptoms happened more often in people who had a history of mental health problems before taking bupropion hydrochloride extended-release tablets (SR) than in people without a history of mental health problems. Stop taking bupropion hydrochloride extended-release tablets (SR) and call your healthcare provider right away if you, your family, or caregiver notices any of these symptoms. Work with your healthcare provider to decide whether you should continue to take bupropion hydrochloride extended-release tablets (SR). In many people, these symptoms went away after stopping bupropion hydrochloride extended-release tablets (SR), but in some people symptoms continued after stopping bupropion hydrochloride extended-release tablets (SR). It is important for you to follow-up with your healthcare provider until your symptoms go away. Before taking bupropion hydrochloride extended-release tablets (SR), 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 hydrochloride extended-release tablets (SR). Antidepressant Medicines, Depression and Other Serious Mental Illnesses, and Suicidal Thoughts or Actions Although bupropion hydrochloride extended-release tablets (SR) are not a treatment for depression, it contains bupropion, the same active ingredient as the antidepressant medications WELLBUTRIN ® , WELLBUTRIN SR ® , and WELLBUTRIN XL ® . 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? 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 trouble sleeping (insomnia) attempts to commit suicide new or worse irritability new or worse depression acting aggressive, being angry, or violent new or worse anxiety acting on dangerous impulses feeling very agitated or restless an extreme increase in activity and talking (mania) panic attacks 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 tablets (SR) are safe and effective in children under the age of 18. What Other Important Information Should I Know About Bupropion Hydrochloride Extended-Release Tablets (SR)? Seizures: There is a chance of having a seizure (convulsion, fit) with bupropion hydrochloride extended-release tablets (SR), 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 tablets (SR). For more information, see the sections “Who should not take bupropion hydrochloride extended-release tablets (SR)?” and “What should I tell my healthcare provider before taking bupropion hydrochloride extended-release tablets (SR)?” Tell your healthcare provider about all of your medical conditions and all the medicines you take. Do not take any other medicines while you are taking bupropion hydrochloride extended-release tablets (SR) unless your healthcare provider has said it is okay to take them. If you have a seizure while taking bupropion hydrochloride extended-release tablets (SR), stop taking the tablets and call your healthcare provider right away. Do not take bupropion hydrochloride extended-release tablets (SR) again if you have a seizure. High blood pressure (hypertension). Some people get high blood pressure that can be severe, while taking bupropion hydrochloride extended-release tablets (SR). The chance of high blood pressure may be higher if you also use nicotine replacement therapy (such as a nicotine patch) to help you stop smoking (see the section of this Medication Guide called “How should I take bupropion hydrochloride extended-release tablets (SR)?”). Manic episodes. Some people may have periods of mania while taking bupropion hydrochloride extended-release tablets (SR), including: Greatly increased energy Severe trouble sleeping Racing thoughts Reckless behavior Unusually grand ideas Excessive happiness or irritability Talking more or faster than usual If you have any of the above symptoms of mania, call your healthcare provider. Unusual thoughts or behaviors. Some patients have unusual thoughts or behaviors while taking bupropion hydrochloride extended-release tablets (SR), 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 tablets (SR). Stop taking bupropion hydrochloride extended-release tablets (SR) and call your healthcare provider right away if you get a rash, itching, hives, fever, swollen lymph glands, painful sores in the mouth or around the eyes, swelling of the lips or tongue, chest pain, or have trouble breathing. These could be signs of a serious allergic reaction. What are bupropion hydrochloride extended-release tablets (SR)? Bupropion hydrochloride extended-release tablets (SR) are a prescription medicine to help people quit smoking. Bupropion hydrochloride extended-release tablets (SR) should be used with a patient support program. It is important to participate in the behavioral program, counseling, or other support program your healthcare professional recommends. Quitting smoking can lower your chances of having lung disease, heart disease, or getting certain types of cancer that are related to smoking. Who should not take bupropion hydrochloride extended-release tablets (SR)? Do not take bupropion hydrochloride extended-release tablets (SR) if you : have or had a seizure disorder or epilepsy. have or had an eating disorder such as anorexia nervosa or bulimia. are taking any other medicines that contain bupropion, including WELLBUTRIN ® , WELLBUTRIN SR ® , WELLBUTRIN XL ® , APLENZIN ® , or FORFIVO XL ® . Bupropion is the same active ingredient that is in bupropion hydrochloride extended-release tablets (SR). drink a lot of alcohol and abruptly stop drinking, or take medicines called sedatives (these make you sleepy), benzodiazepines, or anti-seizure medicines, and you stop taking 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 tablets (SR) unless directed to do so by your healthcare provider. do not start bupropion hydrochloride extended-release tablets (SR) if you stopped taking an MAOI in the last 2 weeks unless directed to do so by your healthcare provider. are allergic to the active ingredient in bupropion hydrochloride extended-release tablets (SR), 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 tablets (SR). What should I tell my healthcare provider before taking bupropion hydrochloride extended-release tablets (SR)? Tell your healthcare provider if you have ever had depression, suicidal thoughts or actions, 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 hydrochloride extended-release tablets (SR). See “Quitting Smoking, Quit-Smoking Medications, Changes in Thinking and Behavior, Depression, 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 extended-release (SR) 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 tablets (SR). How should I take bupropion hydrochloride extended-release tablets (SR)? Start bupropion hydrochloride extended-release tablets (SR) before you stop smoking to give bupropion hydrochloride extended-release tablets (SR) time to build up in your body. It takes about 1 week for bupropion hydrochloride extended-release tablets (SR) to start working. Pick a date to stop smoking that is during the second week you are taking bupropion hydrochloride extended‑release tablets (SR). Take bupropion hydrochloride extended-release tablets (SR) exactly as prescribed by your healthcare provider. Do not change your dose or stop taking bupropion hydrochloride extended-release tablets (SR) without talking with your healthcare provider first. Bupropion hydrochloride extended-release tablets (SR) are usually taken for 7 to 12 weeks. Your healthcare provider may decide to prescribe bupropion hydrochloride extended-release tablets (SR) for longer than 12 weeks to help you stop smoking. Follow your healthcare provider’s instructions. Swallow bupropion hydrochloride extended-release tablets (SR) whole. Do not chew, cut, or crush bupropion hydrochloride extended-release tablets (SR). 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 tablets (SR) may have an odor. This is normal. Take your doses of bupropion hydrochloride extended-release tablets (SR) at least 8 hours apart. You may take bupropion hydrochloride extended-release tablets (SR) with or without food. It is not dangerous to smoke and take bupropion hydrochloride extended-release tablets (SR) at the same time. But, you will lower your chance of breaking your smoking habit if you smoke after the date you set to stop smoking. You may use bupropion hydrochloride extended-release tablets (SR) and nicotine patches (a type of nicotine replacement therapy) at the same time, following the precautions below. You should only use bupropion hydrochloride extended-release tablets (SR) and nicotine patches together under the care of your healthcare provider. Using bupropion hydrochloride extended-release tablets (SR) and nicotine patches together may raise your blood pressure, and sometimes this can be severe. Tell your healthcare provider if you plan to use nicotine patches. Your healthcare provider should check your blood pressure regularly if you use nicotine patches with bupropion hydrochloride extended-release tablets (SR) to help you quit smoking. 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 many bupropion hydrochloride extended-release tablets (SR) can increase your chance of having a seizure. If you take too many bupropion hydrochloride extended-release tablets (SR), 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 tablets (SR) unless your healthcare provider has told you it is okay. What should I avoid while taking bupropion hydrochloride extended-release tablets (SR)? Limit or avoid using alcohol during treatment with bupropion hydrochloride extended-release tablets (SR). If you usually drink a lot of alcohol, talk with your healthcare provider before suddenly stopping. If you suddenly stop drinking alcohol, you may increase your chance of having seizures. Do not drive a car or use heavy machinery until you know how bupropion hydrochloride extended-release tablets (SR) affects you. Bupropion hydrochloride extended-release tablets (SR) can affect your ability to do these things safely. What are possible side effects of bupropion hydrochloride extended-release tablets (SR)? Bupropion hydrochloride extended-release tablets (SR) can cause serious side effects. See the sections at the beginning of this Medication Guide for information about serious side effects of bupropion hydrochloride extended-release tablets (SR). The most common side effects of bupropion hydrochloride extended-release tablets (SR) include: trouble sleeping feeling anxious stuffy nose nausea dry mouth constipation dizziness joint aches If you have trouble sleeping, do not take bupropion hydrochloride extended-release tablets (SR) 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 tablets (SR). For more information, ask your healthcare provider or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. You may also report side effects to Teva at 1-888-838-2872. How should I store bupropion hydrochloride extended-release tablets (SR)? Store bupropion hydrochloride extended-release tablets (SR) at room temperature between 68°F and 77°F (20°C to 25°C). Keep bupropion hydrochloride extended-release tablets (SR) dry and out of the light. Keep bupropion hydrochloride extended-release tablets (SR) and all medicines out of the reach of children. General information about the safe and effective use of bupropion hydrochloride extended-release tablets (SR) Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use bupropion hydrochloride extended-release tablets (SR) for a condition for which it was not prescribed. Do not give bupropion hydrochloride extended-release tablets (SR) to other people, even if they have the same symptoms you have. It may harm them. If you take a urine drug screening test, bupropion hydrochloride extended-release tablets (SR) 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 tablets (SR), 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 tablets (SR). 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 tablets (SR) that is written for health professionals. For more information about bupropion hydrochloride extended-release tablets (SR), call 1-888-838-2872. What are the ingredients in bupropion hydrochloride extended-release tablets (SR)? Active ingredient: bupropion hydrochloride. Inactive ingredients: hydroxypropyl cellulose, microcrystalline cellulose, colloidal silicon dioxide, stearic acid, magnesium stearate, and diluted hydrochloric acid. The film-coating contains lactose monohydrate, hydroxypropyl cellulose, titanium dioxide, and polyethylene glycol. Brands listed are the trademarks of their respective owners. Manufactured For: Teva Pharmaceuticals, Parsippany, NJ 07054 This Medication Guide has been approved by the U.S. Food and Drug Administration. Rev. C 3/2023

14 CLINICAL STUDIES The efficacy of bupropion hydrochloride extended-release tablets (SR) as an aid to smoking cessation was demonstrated in 3 placebo-controlled, double-blind trials in nondepressed chronic cigarette smokers (n = 1,940, greater than or equal to 15 cigarettes per day). In these trials, bupropion hydrochloride extended-release tablets (SR) were used in conjunction with individual smoking cessation counseling. The first trial was a dose-response trial conducted at 3 clinical centers. Subjects in this trial were treated for 7 weeks with 1 of 3 doses of bupropion hydrochloride extended-release tablets (SR) (100, 150, or 300 mg per day) or placebo; quitting was defined as total abstinence during the last 4 weeks of treatment (Weeks 4 through 7). Abstinence was determined by subject daily diaries and verified by carbon monoxide levels in expired air. Results of this dose-response trial with bupropion hydrochloride extended-release tablets (SR) demonstrated a dose-dependent increase in the percentage of subjects able to achieve 4-week abstinence (Weeks 4 through 7). Treatment with bupropion hydrochloride extended-release tablets (SR) at both 150 and 300 mg per day was significantly more effective than placebo in this trial. Table 5 presents quit rates over time in the multicenter trial by treatment group. The quit rates are the proportions of all subjects initially enrolled (i.e., intent-to-treat analysis) who abstained from Week 4 of the trial through the specified week. Treatment with bupropion hydrochloride extended-release tablets (SR) (150 or 300 mg per day) was more effective than placebo in helping subjects achieve 4-week abstinence. In addition, treatment with bupropion hydrochloride extended-release tablets (SR) (7 weeks at 300 mg per day) was more effective than placebo in helping subjects maintain continuous abstinence through Week 26 (6 months) of the trial. Table 5. Dose-Response Trial: Quit Rates by Treatment Group Abstinence from Week 4 through Specified Week Treatment Groups Placebo (n = 151) % (95% CI) Bupropion Hydrochloride Extended-Release Tablets (SR) 100 mg/day ( n = 153) % (95% CI) Bupropion Hydrochloride Extended-Release Tablets (SR) 150 mg/day ( n = 153) % (95% CI) Bupropion Hydrochloride Extended-Release Tablets (SR) 300 mg/day ( n = 156) % (95% CI) Week 7 (4-week quit) 17% (11 to 23) 22% (15 to 28) 27% a (20 to 35) 36% a (28 to 43) Week 12 14% (8 to 19) 20% (13 to 26) 20% (14 to 27) 25% a (18 to 32) Week 26 11% (6 to 16) 16% (11 to 22) 18% (12 to 24) 19% a (13 to 25) a Significantly different from placebo ( P ≤0.05). The second trial was a comparator trial conducted at 4 clinical centers. Four treatments were evaluated: bupropion hydrochloride extended-release tablets (SR) 300 mg per day, nicotine transdermal system (NTS) 21 mg per day, combination of bupropion hydrochloride extended-release tablets (SR) 300 mg per day plus NTS 21 mg per day, and placebo. Subjects were treated for 9 weeks. Treatment with bupropion hydrochloride extended-release tablets (SR) was initiated at 150 mg per day while the subject was still smoking and was increased after 3 days to 300 mg per day given as 150 mg twice daily. NTS 21 mg per day was added to treatment with bupropion hydrochloride extended-release tablets (SR) after approximately 1 week when the subject reached the target quit date. During Weeks 8 and 9 of the trial, NTS was tapered to 14 and 7 mg per day, respectively. Quitting, defined as total abstinence during Weeks 4 through 7, was determined by subject daily diaries and verified by expired air carbon monoxide levels. In this trial, subjects treated with any of the 3 treatments achieved greater 4-week abstinence rates than subjects treated with placebo. Table 6 presents quit rates over time by treatment group for the comparator trial. Table 6. Comparator Trial: Quit Rates by Treatment Group Abstinence from Week 4 through Specified Week Treatment Groups Placebo (n = 160) % (95% CI) Nicotine Transdermal System (NTS) 21 mg/day (n = 244) % (95% CI) Bupropion Hydrochloride Extended-Release Tablets (SR) 300 mg/day ( n = 244) % (95% CI) Bupropion Hydrochloride Extended-Release Tablets (SR) 300 mg/day and NTS 21 mg/day ( n = 245) % (95% CI) Week 7 (4-week quit) 23% (17 to 30) 36% (30 to 42) 49% (43 to 56) 58% (51 to 64) Week 10 20% (14 to 26) 32% (26 to 37) 46% (39 to 52) 51% (45 to 58) When subjects in this trial were followed out to 1 year, the superiority of bupropion hydrochloride extended-release tablets (SR) and the combination of bupropion hydrochloride extended-release tablets (SR) and NTS over placebo in helping them to achieve abstinence from smoking was maintained. The continuous abstinence rate was 30% (95% CI: 24 to 35) in the subjects treated with bupropion hydrochloride extended-release tablets (SR) and 33% (95% CI: 27 to 39) for subjects treated with the combination at 26 weeks compared with 13% (95% CI: 7 to 18) in the placebo group. At 52 weeks, the continuous abstinence rate was 23% (95% CI: 18 to 28) in the subjects treated with bupropion hydrochloride extended-release tablets (SR) and 28% (95% CI: 23 to 34) for subjects treated with the combination, compared with 8% (95% CI: 3 to 12) in the placebo group. Although the treatment combination of bupropion hydrochloride extended-release tablets (SR) and NTS displayed the highest rates of continuous abstinence throughout the trial, the quit rates for the combination were not significantly higher ( P >0.05) than for bupropion hydrochloride extended-release tablets (SR) alone. The comparisons between bupropion hydrochloride extended-release tablets (SR), NTS, and combination treatment in this trial have not been replicated, and, therefore should not be interpreted as demonstrating the superiority of any of the active treatment arms over any other. The third trial was a long-term maintenance trial conducted at 5 clinical centers. Subjects in this trial received open-label bupropion hydrochloride extended-release tablets (SR) 300 mg per day for 7 weeks. Subjects who quit smoking while receiving bupropion hydrochloride extended-release tablets (SR) (n = 432) were then randomized to bupropion hydrochloride extended-release tablets (SR) 300 mg per day or placebo for a total trial duration of 1 year. Abstinence from smoking was determined by subject self-report and verified by expired air carbon monoxide levels. This trial demonstrated that at 6 months, continuous abstinence rates were significantly higher for subjects continuing to receive bupropion hydrochloride extended-release tablets (SR) than for those switched to placebo ( P <0.05; 55% versus 44%). Quit rates in clinical trials are influenced by the population selected. Quit rates in an unselected population may be lower than the above rates. Quit rates for bupropion hydrochloride extended-release tablets (SR) were similar in subjects with and without prior quit attempts using nicotine replacement therapy. Treatment with bupropion hydrochloride extended-release tablets (SR) reduced withdrawal symptoms compared with placebo. Reductions on the following withdrawal symptoms were most pronounced: irritability, frustration, or anger; anxiety; difficulty concentrating; restlessness; and depressed mood or negative affect. Depending on the trial and the measure used, treatment with bupropion hydrochloride extended-release tablets (SR) showed evidence of reduction in craving for cigarettes or urge to smoke compared with placebo. Use in Patients with Chronic Obstructive Pulmonary Disease (COPD) Bupropion hydrochloride extended-release tablets (SR) were evaluated in a randomized, double-blind, comparator trial of 404 subjects with mild-to­-moderate COPD defined as FEV 1 greater than or equal to 35%, FEV 1 /FVC less than or equal to 70%, and a diagnosis of chronic bronchitis, emphysema, and/or small airways disease. Subjects aged 36 to 76 years were randomized to bupropion hydrochloride extended-release tablets (SR) 300 mg per day (n = 204) or placebo (n = 200) and treated for 12 weeks. Treatment with bupropion hydrochloride extended-release tablets (SR) was initiated at 150 mg per day for 3 days while the subject was still smoking and increased to 150 mg twice daily for the remaining treatment period. Abstinence from smoking was determined by subject daily diaries and verified by carbon monoxide levels in expired air. Quitters were defined as subjects who were abstinent during the last 4 weeks of treatment. Table 7 shows quit rates in the COPD Trial. Table 7. COPD Trial: Quit Rates by Treatment Group 4-Week Abstinence Period Treatment Groups Placebo (n = 200) % (95% CI) Bupropion Hydrochloride Extended-Release Tablets (SR) 300 mg/day ( n = 204) % (95% CI) Weeks 9 through 12 12% (8 to 16) 22% a (17 to 27) a Significantly different from placebo ( P <0.05). Postmarketing Neuropsychiatric Safety Outcome Trial Bupropion hydrochloride extended-release tablets (SR) were evaluated in a randomized, double-blind, active-and placebo-controlled trial that included subjects without a history of psychiatric disorder (non-psychiatric cohort, n = 3,912) and subjects with a history of psychiatric disorder (psychiatric cohort, n = 4003). Subjects aged 18 to 75 years, smoking 10 or more cigarettes per day were randomized 1:1:1:1 to bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily, varenicline 1 mg twice daily, nicotine replacement therapy patch (NRT) 21 mg per day with taper or placebo for a treatment period of 12 weeks; they were then followed for another 12 weeks post-treatment [see Warnings and Precautions ( 5.2 )]. A composite safety endpoint intended to capture clinically significant neuropsychiatric (NPS) adverse events including the following NPS adverse events: anxiety, depression, feeling abnormal, hostility, agitation, aggression, delusions, hallucinations, homicidal ideation, mania, panic, paranoia, psychosis, irritability, suicidal ideation, suicidal behavior, or completed suicide. The use of bupropion hydrochloride extended-release tablets (SR), varenicline, and NRT in the non-psychiatric cohort was not associated with an increased risk of clinically significant NPS adverse events compared with placebo (Table 8). Table 8. Number of Patients with Clinically Significant or Serious NPS Adverse Events by Treatment Group among Patients without a History of Psychiatric Disorder Treatment Group Bupropion Hydrochloride Extended-Release Tablets (SR) (n = 968) n (%) Varenicline (n = 975) n (%) NRT (n = 987) n (%) Placebo (n = 982) n (%) Clinically significant NPS 34 (3.5) 30 (3.1) 33 (3.3) 40 (4.1) Serious NPS 5 (0.5) 1 (0.1) 1 (0.1) 4 (0.4) Psychiatric hospitalizations 2 (0.2) 1 (0.1) 0 (0.0) 1 (0.1) There were more clinically significant NPS adverse events reported in patients in the psychiatric cohort in each treatment group compared with the non-psychiatric cohort (Table 9). The incidence of events in the composite endpoint was higher for each of the active treatments compared with placebo: Risk Differences (RDs) (95% CI) vs. placebo were 2.2 % (-0.5, 4.9) for bupropion hydrochloride extended-release tablets (SR); 2.7% (-0.05, 5.4) for varenicline, and 0.4% (-2.2, 3.0) for NRT transdermal nicotine. Table 9. Number of Patients with Clinically Significant or Serious NPS Adverse Events by Treatment Group among Patients with a History of Psychiatric Disorder Treatment Group Bupropion Hydrochloride Extended-Release Tablets (SR) (n = 1,004) n (%) Varenicline (n = 1,007) n (%) NRT (n = 995) n (%) Placebo (n = 997) n (%) Clinically significant NPS 118 (11.8) 123 (12.2) 98 (9.8) 95 (9.5) Serious NPS 8 (0.8) 6 (0.6) 4 (0.4) 6 (0.6) Psychiatric hospitalizations 8 (0.8) 5 (0.5) 4 (0.4) 2 (0.2) There was one completed suicide, which occurred during treatment in a patient treated with placebo in the non-psychiatric cohort. There were no completed suicides reported in the psychiatric cohort. In both cohorts, subjects treated with bupropion hydrochloride extended-release tablets (SR) had a superior rate of CO-confirmed abstinence during Weeks 9 through 12 and 9 through 24 compared with subjects treated with placebo. Table 10: Continuous Abstinence (95% Confidence Interval), Study in Patients with or without a History of Psychiatric Disorder Bupropion Hydrochloride Extended-Release Tablets (SR) 150 mg Twice Daily Varenicline 1 mg Twice Daily NRT 21 mg/day with Taper Placebo Weeks 9 through 12 Non-Psychiatric Cohort 26% (23%, 29%) 38% (35%, 41%) 26% (24%, 29%) 14% (12%, 16%) Psychiatric Cohort 19% (17%, 22%) 29% (26%, 32%) 20% (18%, 23%) 11% (10%, 14%) Weeks 9 through 24 Non-Psychiatric Cohort 19% (16%, 21%) 25% (23%, 28%) 18% (16%, 21%) 11% (9%, 13%) Psychiatric Cohort 14% (12%, 16%) 18% (16%, 21%) 13% (11%, 15%) 8% (7%, 10%)

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 greater than or equal to 65 years and 47 were aged greater than or equal to 75 years. In addition, several hundred subjects aged greater than or equal to 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 ( 2.7 ), Use in Specific Populations ( 8.6 ), Clinical Pharmacology ( 12.3 )] .

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 tablets (SR) are administered to a nursing woman.

8.4 Pediatric Use Safety and effectiveness in the pediatric population have not been established [see Boxed Warning , Warnings and Precautions ( 5.1 )].

8.1 Pregnancy 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 2 times the maximum recommended human dose (MRHD) and greater and decreased fetal weights were seen at doses three times the MRHD and greater. Bupropion hydrochloride extended-release tablets (SR) should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Clinical Considerations Pregnant smokers should be encouraged to attempt cessation using educational and behavioral interventions before pharmacological approaches are used. Data Human Data: Data from the international bupropion Pregnancy Registry (675 first trimester exposures) and a retrospective cohort study using the United Healthcare database (1,213 first trimester exposures) did not show an increased risk for malformations overall. 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. An imal 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 15 and 10 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 2 times 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 10 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.

8 USE IN SPECIFIC POPULATIONS Pregnancy: Use only if benefit outweighs potential risk to the fetus. ( 8.1 ) 8.1 Pregnancy 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 2 times the maximum recommended human dose (MRHD) and greater and decreased fetal weights were seen at doses three times the MRHD and greater. Bupropion hydrochloride extended-release tablets (SR) should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Clinical Considerations Pregnant smokers should be encouraged to attempt cessation using educational and behavioral interventions before pharmacological approaches are used. Data Human Data: Data from the international bupropion Pregnancy Registry (675 first trimester exposures) and a retrospective cohort study using the United Healthcare database (1,213 first trimester exposures) did not show an increased risk for malformations overall. 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. An imal 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 15 and 10 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 2 times 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 10 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. 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 tablets (SR) are administered to a nursing woman. 8.4 Pediatric Use Safety and effectiveness in the pediatric population have not been established [see Boxed Warning , 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 greater than or equal to 65 years and 47 were aged greater than or equal to 75 years. In addition, several hundred subjects aged greater than or equal to 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 ( 2.7 ), Use in Specific Populations ( 8.6 ), Clinical Pharmacology ( 12.3 )] . 8.6 Renal Impairment Consider a reduced dose and/or dosing frequency of bupropion hydrochloride extended-release tablets (SR) 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 ( 2.7 ), Clinical Pharmacology ( 12.3 )] . 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 tablets (SR) is 150 mg every other day. In patients with mild hepatic impairment (Child-Pugh score: 5 to 6), consider reducing the dose and/or frequency of dosing [see Dosage and Administration ( 2.6 ), Clinical Pharmacology ( 12.3 )] .

16 HOW SUPPLIED/STORAGE AND HANDLING Bupropion Hydrochloride Extended-Release Tablets, USP (SR) 150 mg of bupropion hydrochloride, USP are white to off-white, round, unscored, film-coated tablets imprinted with "WPI" over "867" on one side and supplied in bottles of 60 tablets (NDC 0591-3543-60) and the Starter Pack containing 1 bottle of 60 tablets (NDC 0591-3543-76). Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature]. Protect from light and moisture.

WARNING: SUICIDAL THOUGHTS AND BEHAVIORS S UICIDALITY AND ANTIDEPRESSANT DRUGS Although bupropion hydrochloride extended-release tablets (SR) are not indicated for treatment of depression, it contains the same active ingredient as the antidepressant medications WELLBUTRIN ® , WELLBUTRIN S R ® , and WELLBUTRIN XL ® . 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 )] . 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 )