BUPROPION HYDROCHLORIDE (SR)

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

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

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 p …

3 DOSAGE FORMS AND STRENGTHS 100 mg – blue, round, biconvex, film-coated extended -release tablets debossed with ‘IG’ on one side and ‘484’ on the other side. 150 mg – Purple, round, biconvex, film-coated extended -release tablets debossed with ‘IG’ on one side and ‘485’ on the other side. 200 mg – Pink, round, biconvex, film-coated extended -release tablets debossed with ‘IG’ on one side and ‘486’ on the other side. Tablets: 100 mg, 150 mg, 200 mg. ( 3 )

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 ( 2.4 , 2.5 ), Warnings and Precautions ( 5.4 ), Drug Interactions ( 7.6 )]. Bupropion hydrochloride extended-release tablets (SR) are contraindicated in patients with 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 )

6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the labeling: Suicidal thoughts and behaviors in adolescents and young adults [see Boxed Warning , Warnings and Precautions (5.1) ] Neuropsychiatric 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 ≥5% and ≥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 Dr. Reddy’s Laboratories Inc., at 1-888-375-3784 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Adverse Reactions Leading to Discontinuation of Treatment 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) % Placebo (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 a Subjects randomized to bupropion hydrochloride extended-release tablets (SR) or placebo received placebo patches. 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 …

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 …

8 USE IN SPECIFIC POPULATIONS Pregnancy: Use only if benefit outweighs potential risk to the fetus. ( 8.1 ) 8.1 Pregnancy Pregnancy Category C Risk Summary Data from epidemiological studies of pregnant women exposed to bupropion in the first trimester indicate no increased risk of congenital malformations overall. All pregnancies, regardless of drug exposure, have a background rate of 2% to 4% for major malformations, and 15% to 20% for pregnancy loss. No clear evidence of teratogenic activity was found in reproductive developmental studies conducted in rats and rabbits; however, in rabbits, slightly increased incidences of fetal malformations and skeletal variations were observed at doses approximately equal to the maximum recommended human dose (MRHD) and greater and decreased fetal weights were seen at doses twice the MRHD and greater. Bupropion hydrochloride extended-release tablets (SR) should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Clinical Considerations Consider the risks of untreated depression when discontinuing or changing treatment with antidepressant medications during pregnancy and postpartum. Human Data Data from the international bupropion Pregnancy Registry (675 first trimester exposures) and a retrospective cohort study using the United Healthcare database (1,213 first trimester exposures) did not show an increased risk for malformations overall. No increased risk for cardiovascular malformations overall has been observed after bupropion exposure during the first trimester. The prospectively observed rate of cardiovascular malformations in pregnancies with exposure to bupropion in the first trimester from the international Pregnancy Registry was 1.3% (9 cardiovascular malformations/675 first-trimester maternal bupropion exposures), which is similar to the background rate of cardiovascular malformations (approximately 1%). Data from the United Healthcare database and a case-control study (6,853 infants with cardiovascular malformations and 5,763 with non-cardiovascular malformations) from the National Birth Defects Prevention Study (NBDPS) did not show an increased risk for cardiovascular malformations overall after bupropion exposure during the first trimester. Study findings on bupropion exposure during the first trimester and risk for left ventricular outflow tract obstruction (LVOTO) are inconsistent and do not allow conclusions regarding a possible association. The United Healthcare database lacked sufficient power to evaluate this association; the NBDPS found increased risk for LVOTO (n = 10; adjusted OR = 2.6; 95% CI: 1.2, 5.7), and the Slone Epidemiology case control study did not find increased risk for LVOTO. Study findings on bupropion exposure during the first trimester and risk for ventricular septal defect (VSD) are inconsistent and do not allow conclusions regarding a possible association. The Slone Epidemiology Study found an increased risk for VSD following first trimester maternal bupropion exposure (n = 17; adjusted OR = 2.5; 95% CI: 1.3, 5.0) but did not find increased risk for any other cardiovascular malformations studied (including LVOTO as above). The NBDPS and United Healthcare database study did not find an association between first trimester maternal bupropion exposure and VSD. For the findings of LVOTO and VSD, the studies were limited by the small number of exposed cases, inconsistent findings among studies, and the potential for chance findings from multiple comparisons in case control studies. Animal Data In studies conducted in rats and rabbits, bupropion was administered orally during the period of organogenesis at doses of up to 450 and 150 mg per kg per day, respectively (approximately 11 and 7 times the MRHD, respectively, on a mg per m2 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 o …

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.

11 DESCRIPTION Bupropion hydrochloride extended-release tablets, USP (SR) are a non-nicotine aid to smoking cessation. Bupropion is 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) is 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 USP is white powder, and soluble in 0.1N Hydrochloric acid, in alcohol (96.0%) and 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 (purple), film-coated, sustained-release tablets. Each tablet contains the labeled amount of bupropion hydrochloride USP and the inactive ingredients: copovidone, cysteine hydrochloride, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, titanium dioxide, FD&C Blue No.2 Lake and FD&C Red No. 40 Lake. In addition, flavoring agent contains dextrose, ethyl alcohol, gum arabic, propylene glycol and silicon dioxide. Bupropion hydrochloride extended-release tablets, USP (SR) meets USP dissolution Test 2. Chemical Structure

10 OVERDOSAGE 10.1 Human Overdose Experience Overdoses of up to 30 grams or more of bupropion have been reported. Seizure was reported in approximately one-third of all cases. Other serious reactions reported with overdoses of bupropion alone included hallucinations, loss of consciousness, sinus tachycardia, and ECG changes such as conduction disturbances (including QRS prolongation) or arrhythmias. Fever, muscle rigidity, rhabdomyolysis, hypotension, stupor, coma, and respiratory failure have been reported mainly when bupropion was part of multiple drug overdoses. Although most patients recovered without sequelae, deaths associated with overdoses of bupropion alone have been reported in patients ingesting large doses of the drug. Multiple uncontrolled seizures, bradycardia, cardiac failure, and cardiac arrest prior to death were reported in these patients. 10.2 Overdosage Management Consult a Certified Poison Control Center for up-to-date guidance and advice. Telephone numbers for certified poison control centers are listed in the Physician’s 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.

16 HOW SUPPLIED/STORAGE AND HANDLING Bupropion hydrochloride extended-release tablets, USP (SR), 100 mg, are blue, round, biconvex, film-coated tablets debossed with “IG” on one side and “484” on other side in bottles of 30 ( NDC 69097-877-02), 60 ( NDC 69097-877-03), 100 ( NDC 69097-877-07) and 500 ( NDC 69097-877-12). Bupropion hydrochloride extended-release tablets, USP (SR), 150 mg are purple, round, biconvex, film-coated tablets debossed with “IG” on one side and “485” on other side in bottles of 30 ( NDC 69097-878-02), 60 ( NDC 69097-878-03), 100 ( NDC 69097-878-07) and 500 ( NDC 69097-878-12). Bupropion hydrochloride extended-release tablets, USP (SR), 200 mg, are pink, round, biconvex, film-coated tablets debossed with “IG” on one side and “486” on other side in bottles of 30 ( NDC 69097-879-02), 60 ( NDC 69097-879-03), 100 ( NDC 69097-879-07) and 500 ( NDC 69097-879-12). Store Bupropion hydrochloride extended-release tablets, USP (SR) at 20° to 25°C (68°F to 77°F) [see USP Controlled Room Temperature]. Dispense in a tight-light resistant container as defined in the USP.