Bupropion Hydrochloride

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 tablets USP are indicated for the treatment of major depressive disorder (MDD), as defined by the Diagnostic and Statistical Manual (DSM). The efficacy of bupropion hydrochloride tablets USP 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)] . Bupropion hydrochloride tablets USP are an aminoketone antidepressant, indicated for the treatment of major depressive disorder (MDD). (1)

2 DOSAGE AND ADMINISTRATION Starting dose: 200 mg per day given as 100 mg twice daily ( 2.1 ) General: Increase dose gradually to reduce seizure risk. ( 2.1 , 5.3) After 3 days, may increase the dose to 300 mg per day, given as 100 mg 3 times daily at an interval of at least 6 hours between doses. ( 2.1 ) Usual target dose: 300 mg per day as 100 mg 3 times daily. ( 2.1 ) Maximum dose: 450 mg per day given as 150 mg 3 times daily. ( 2.1 ) Periodically reassess the dose and need for maintenance treatment. (2.1 ) Moderate to severe hepatic impairment: 75 mg once daily. ( 2.2 , 8.7) Mild hepatic impairment: Consider reducing the dose and/or frequency of dosing. ( 2.2 , 8.7 ) Renal impairment: Consider reducing the dose and/or frequency. ( 2.3 , 8.6 ) 2.1 General Instructions for Use To minimize the risk of seizure, increase the dose gradually [see Warnings and Precautions (5.3 )] . Increases in dose should not exceed 100 mg per day in a 3-day period. Bupropion hydrochloride tablets should be swallowed whole and not crushed, divided, or chewed. Bupropion hydrochloride tablets may be taken with or without food. The recommended starting dose is 200 mg per day, given as 100 mg twice daily. After 3 days of dosing, the dose may be increased to 300 mg per day, given as 100 mg 3 times daily, with at least 6 hours between successive doses. Dosing above 300 mg per day may be accomplished using the 75- or 100-mg tablets. A maximum of 450 mg per day, given in divided doses of not more than 150 mg each, may be considered for patients who show no clinical improvement after several weeks of treatment at 300 mg per day. Administer the 100-mg tablet 4 times daily to not exceed the limit of 150 mg in a single dose. It is generally agreed that acute episodes of depression require several months or longer of antidepressant drug treatment beyond the response in the acute episode. It is unknown whether the dose of bupropion hydrochloride tablets needed for maintenance treatment is identical to the dose that provided an initial response. Periodically reassess the need for maintenance treatment and the appropriate dose for such treatment. 2.2 Dose Adjustment in Patients with Hepatic Impairment In patients with moderate to severe hepatic impairment (Child-Pugh score: 7 to 15), the maximum dose of bupropion hydrochloride tablets are 75 mg per day. In patients with mild hepatic impairment (Child-Pugh score: 5 to 6), consider reducing the dose and/or frequency of dosing [see Use in Specific Populations (8.7 ), Clinical Pharmacology ( 12.3 )] . 2.3 Dose Adjustment in Patients with Renal Impairment Consider reducing the dose and/or frequency of bupropion hydrochloride tablets 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 )] . 2.4 Switching a Patient to or from a Monoamine Oxidase Inhibitor (MAOI) Antidepressant At least 14 days should elapse between discontinuation of an MAOI intended to treat depression and initiation of therapy with bupropion hydrochloride tablets. Conversely, at least 14 days should be allowed after stopping bupropion hydrochloride tablets before starting an MAOI antidepressant [see Contraindications ( 4 ), Drug Interactions ( 7.6 )] . 2.5 Use of Bupropion Hydrochloride Tablets with Reversible MAOIs Such as Linezolid or Methylene Blue Do not start bupropion hydrochloride tablets in a patient who is being treated with a reversible MAOI such as linezolid or intravenous methylene blue. Drug interactions can increase the risk of hypertensive reactions. In a patient who requires more urgent treatment of a psychiatric condition, non-pharmacological interventions, including hospitalization, should be considered [see Contraindications ( 4 ), Drug Interactions ( 7.6 )] . In some cases, a patient already receiving therapy with bupropion hydrochloride tablets may require urgent treatment with linezolid or intravenous methylene blue. If accep …

3 DOSAGE FORMS AND STRENGTHS Bupropion Hydrochloride Tablets, USP are available containing 75 mg or 100 mg of bupropion hydrochloride, USP. The 75 mg tablets are a peach, film-coated, round, biconvex, beveled edge tablet debossed with 75 on one side of the tablet and B on the other side. The 100 mg tablets are a light blue, film-coated, round, biconvex, beveled edge tablet debossed with 100 on one side of the tablet and B on the other side. Tablets: 75 mg and 100 mg. ( 3 )

4 CONTRAINDICATIONS • Bupropion hydrochloride tablets are contraindicated in patients with a seizure disorder. • Bupropion hydrochloride tablets are contraindicated in patients with a current or prior diagnosis of bulimia or anorexia nervosa as a higher incidence of seizures was observed in such patients treated with bupropion hydrochloride tablets [ see Warnings and Precautions ( 5.3 ) ]. • Bupropion hydrochloride tablets are contraindicated in patients undergoing abrupt discontinuation of alcohol, benzodiazepines, barbiturates, and antiepileptic drugs [ see Warnings and Precautions ( 5.3 ), Drug Interactions ( 7.3 ) ]. • The use of MAOIs (intended to treat psychiatric disorders) concomitantly with bupropion hydrochloride tablets or within 14 days of discontinuing treatment with bupropion hydrochloride tablets are contraindicated. There is an increased risk of hypertensive reactions when bupropion hydrochloride tablets are used concomitantly with MAOIs. The use of bupropion hydrochloride tablets within 14 days of discontinuing treatment with an MAOI is also contraindicated. Starting bupropion hydrochloride tablets in a patient treated with reversible MAOIs such as linezolid or intravenous methylene blue is contraindicated [ see Dosage and Administration ( 2.4 , 2.5 ), Warnings and Precautions ( 5.4 ), Drug Interactions ( 7.6 ) ]. • Bupropion hydrochloride tablets are contraindicated in patients with known hypersensitivity to bupropion or other ingredients of bupropion hydrochloride tablets. 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 tablets or within 14 days of stopping treatment with bupropion hydrochloride tablets. Do not use bupropion hydrochloride tablets within 14 days of stopping an MAOI intended to treat psychiatric disorders. In addition, do not start bupropion hydrochloride tablets 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 tablets. ( 4 , 5.8 )

6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the labeling: • Suicidal thoughts and behaviors in adolescents and young adults [ see Boxed Warning , Warnings and Precautions (5.1) ] • Neuropsychiatric symptoms and suicide risk in smoking cessation treatment [see Warnings and Precautions (5.2) ] • Seizure [ see Warnings and Precautions (5.3) ] • Hypertension [see Warnings and Precautions (5.4)] • Activation of mania or hypomania [ see Warnings and Precautions (5.5) ] • Psychosis and other neuropsychiatric reactions [ see Warnings and Precautions (5.6) ] • Angle-closure glaucoma [ see Warnings and Precautions (5.7) ] • Hypersensitivity reactions [ see Warnings and Precautions (5.8) ] Most common adverse reactions (incidence ≥5% and ≥1% more than placebo rate) are: agitation, dry mouth, constipation, headache /migraine, nausea/vomiting, dizziness, excessive sweating, tremor, insomnia, blurred vision, tachycardia, confusion, rash, hostility, cardiac arrhythmias, and auditory disturbance. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact to Cadila Pharmaceuticals Limited at 1-202-355-9785 (Fax 1-202-355-9784) 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 with bupropion hydrochloride tablets in approximately 10% of the 2,400 subjects and healthy volunteers who participated in clinical trials during the product’s initial development. The more common events causing discontinuation include neuropsychiatric disturbances (3.0%), primarily agitation and abnormalities in mental status; gastrointestinal disturbances (2.1%), primarily nausea and vomiting; neurological disturbances (1.7%), primarily seizures, headaches, and sleep disturbances; and dermatologic problems (1.4%), primarily rashes. It is important to note, however, that many of these events occurred at doses that exceed the recommended daily dose. Commonly Observed Adverse Reactions Adverse reactions commonly encountered in subjects treated with bupropion hydrochloride tablets are agitation, dry mouth, insomnia, headache/migraine, nausea/vomiting, constipation, tremor, dizziness, excessive sweating, blurred vision, tachycardia, confusion, rash, hostility, cardiac arrhythmia, and auditory disturbance. Table 2 summarizes the adverse reactions that occurred in placebo-controlled trials at an incidence of at least 1% of subjects receiving bupropion hydrochloride tablets and more frequently in these subjects than in the placebo group. Table 2. Adverse Reactions Reported by at Least 1% of Subjects and at a Greater Frequency than Placebo in Controlled Clinical Trials Adverse Reaction Bupropion (n=323) % Placebo (n=185) % Cardiovascular Cardiac arrhythmias 5.3 4.3 Dizziness 22.3 16.2 Hypertension 4.3 1.6 Hypotension 2.5 2.2 Palpitations 3.7 2.2 Syncope 1.2 0.5 Tachycardia 10.8 8.6 Dermatologic Pruritus 2.2 0.0 Rash 8.0 6.5 Gastrointestinal Appetite increase 3.7 2.2 Constipation 26.0 17.3 Dyspepsia 3.1 2.2 Nausea/vomiting 22.9 18.9 Genitourinary Impotence 3.4 3.1 Menstrual complaints 4.7 1.1 Urinary frequency 2.5 2.2 Musculoskeletal Arthritis 3.1 2.7 Neurological Akathisia 1.5 1.1 Cutaneous temperature disturbance 1.9 1.6 Dry mouth 27.6 18.4 Excessive sweating 22.3 14.6 Headache/Migraine 25.7 22.2 Impaired sleep quality 4.0 1.6 Insomia 18.6 15.7 Sedation 19.8 19.5 Sensory disturbance 4.0 3.2 Tremor 21.1 7.6 Neuropsychiatric Agitation 31.9 22.2 Anxiety 3.1 1.1 Confusion 8.4 4.9 Decreased libido 3.1 1.6 Delusions 1.2 1.1 Euphoria 1.2 0.5 Hostility 5.6 3.8 Nonspecific Fever/chills 1.2 0 …

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 tablets with caution. ( 5.3 , 7.3 ) Dopaminergic drugs (levodopa and amantadine): CNS toxicity can occur when used concomitantly with bupropion hydrochloride tablets. ( 7.4 ) MAOIs: Increased risk of hypertensive reactions can occur when used concomitantly with bupropion hydrochloride tablets. ( 7.6 ) Drug-laboratory test interactions: Bupropion hydrochloride tablets can cause false-positive urine test results for amphetamines. ( 7.7 ) See 17 for PATIENT COUNSELING INFORMATION and MEDICATION GUIDE. 7.1 Potential for Other Drugs to Affect Bupropion Hydrochloride Tablets Bupropion is primarily metabolized to hydroxybupropion by CYP2B6. Therefore, the potential exists for drug interactions between bupropion hydrochloride tablets and drugs that are inhibitors or inducers of CYP2B6. Inhibitors of CYP2B6 Ticlopidine and Clopidogrel : Concomitant treatment with these drugs can increase bupropion exposure but decrease hydroxybupropion exposure. Based on clinical response, dosage adjustment of bupropion hydrochloride tablets 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 tablets 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 Tablets to Affect Other Drugs Drugs Metabolized by CYP2D6 Bupropion and its metabolites (erythrohydrobupropion, threohydrobupropion, hydroxybupropion) are CYP2D6 inhibitors. Therefore, coadministration of bupropion hydrochloride tablets with drugs that are metabolized by CYP2D6 can increase the exposures of drugs that are substrates of CYP2D6. Such drugs include certain antidepressants (e.g., venlafaxine, nortriptyline, imipramine, desipramine, paroxetine, fluoxetine, and sertraline), antipsychotics (e.g., haloperidol, risperidone, thioridazine), beta-blockers (e.g., metoprolol), and Type 1C antiarrhythmics (e.g., propafenone and flecainide). When used concomitantly with bupropion hydrochloride tablets, it may be necessary to decrease the dose of these CYP2D6 substrates, particularly for drugs with a narrow therapeutic index. Drugs that require metabolic activation by CYP2D6 to be effective (e.g., tamoxifen) theoretically could have reduced efficacy when administered concomitantly with inhibitors of CYP2D6 such as bupropion. Patients treated concomitantly with bupropion hydrochloride tablets and such drugs may require increased doses of the drug [see Clinical Pharmacology ( 12.3 )]. Digoxin Coa …

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Exposure Registry There is an independent pregnancy exposure registry that monitors pregnancy outcomes in women exposed to any antidepressants during pregnancy. Healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for Antidepressants at 1-844-405-6185 or visiting online at https://womensmentalhealth.org/research/pregnancyregistry/antidepressants/ Risk Summary Data from epidemiological studies of pregnant women exposed to bupropion in the first trimester have not identified an increased risk of congenital malformations overall (see Data) . There are risks to the mother associated with untreated depression in pregnancy (see Clinical Considerations) . When bupropion was administered to pregnant rats during organogenesis, there was no evidence of fetal malformations at doses up to approximately 10 times the maximum recommended human dose (MRHD) of 450 mg/day. When given to pregnant rabbits during organogenesis, non-dose–related increases in incidence of fetal malformations and skeletal variations were observed at doses approximately equal to the MRHD and greater. Decreased fetal weights were seen at doses twice the MRHD and greater (see Animal Data) . The estimated background risk for major birth defects and miscarriage is unknown for the indicated population. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and of miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk: A prospective, longitudinal study followed 201 pregnant women with a history of major depressive disorder who were euthymic and taking antidepressants during pregnancy at the beginning of pregnancy. The women who discontinued antidepressants during pregnancy were more likely to experience a relapse of major depression than women who continued antidepressants. Consider the risks to the mother of untreated depression and potential effects on the fetus when discontinuing or changing treatment with antidepressant medications during pregnancy and postpartum. Data Human Data: Data from the international bupropion Pregnancy Registry (675 first- trimester exposures) and a retrospective cohort study using the United Healthcare database (1,213 first trimester exposures) did not show an increased risk for malformations overall. The Registry was not designed or powered to evaluate specific defects but suggested a possible increase in cardiac malformations. No increased risk for cardiovascular malformations overall has been observed after bupropion exposure during the first trimester. The prospectively observed rate of cardiovascular malformations in pregnancies with exposure to bupropion in the first trimester from the international Pregnancy Registry was 1.3% (9 cardiovascular malformations/675 first-trimester maternal bupropion exposures), which is similar to the background rate of cardiovascular malformations (approximately 1%). Data from the United Healthcare database, which had a limited number of exposed cases with cardiovascular malformations, and a case-control study (6,853 infants with cardiovascular malformations and 5,763 with non-cardiovascular malformations) of self-reported bupropion use from the National Birth Defects Prevention Study (NBDPS) did not show an increased risk for cardiovascular malformations overall after bupropion exposure during the first trimester. Study findings on bupropion exposure during the first trimester and risk for left ventricular outflow tract obstruction (LVOTO) are inconsistent and do not allow conclusions regarding a possible association. The United Healthcare database lacked sufficient power to evaluate this association; the NBDPS found increased risk for LVOTO (n = 10; adjusted OR = 2.6; 95% CI: 1 …

12.1 Mechanism of Action The exact mechanism of the antidepressant action of bupropion is not known, but is presumed to be related to noradrenergic and/or dopaminergic mechanisms. Bupropion is a relatively weak inhibitor of the neuronal reuptake of norepinephrine and dopamine, and does not inhibit the reuptake of serotonin. Bupropion does not inhibit monoamine oxidase.

11 DESCRIPTION Bupropion hydrochloride tablets, USP an antidepressant of the aminoketone class, is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitor, or other known antidepressant agents. Its structure closely resembles that of diethylpropion; it is related to phenylethylamines. It is designated as (±)-1-(3-chlorophenyl)-2-[(1,1-dimethylethyl)amino]-1-propanone hydrochloride. The molecular weight is 276.2. The molecular formula is C 13 H 18 ClNO•HCl. Bupropion hydrochloride, USP powder is white or almost white crystalline powder, and freely soluble in water, soluble in alcohol and 0.1N HCl. It has a bitter taste and produces the sensation of local anesthesia on the oral mucosa. The structural formula is: Bupropion hydrochloride tablets, USP are supplied for oral administration as 75-mg (peach) and 100-mg (light blue) film-coated tablets. Each tablet contains the labeled amount of bupropion hydrochloride, USP and the inactive ingredients: anhydrous lactose, colloidal silicon dioxide, crospovidone, hydrochloric acid, hypromellose, microcrystalline cellulose, polydextrose, polyethylene glycol, stearic acid 50, titanium dioxide and triacetin. The 75 mg tablets also contain red iron oxide and yellow iron oxide and the 100 mg tablets also contain FD&C Blue #2/Indigo Carmine Aluminum Lake and FD&C Yellow #6/Sunset Yellow FCF Aluminum Lake. CHEMICAL STRUCTURE

10 OVERDOSAGE 10.1 Human Overdose Experience Overdoses of up to 30 grams or more of bupropion have been reported. Seizure was reported in approximately one-third of all cases. Other serious reactions reported with overdoses of bupropion alone included hallucinations, loss of consciousness, mental status changes, sinus tachycardia, ECG changes such as conduction disturbances (including QRS prolongation) or arrhythmias, clonus, myoclonus, and hyperreflexia. Fever, muscle rigidity, rhabdomyolysis, hypotension, stupor, coma, and respiratory failure have been reported mainly when bupropion was part of multiple drug overdoses. Although most patients recovered without sequelae, deaths associated with overdoses of bupropion alone have been reported in patients ingesting large doses of the drug. Multiple uncontrolled seizures, bradycardia, cardiac failure, and cardiac arrest prior to death were reported in these patients. 10.2 Overdosage Management Consult a Certified Poison Control Center for up-to-date guidance and advice. 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 tablets, USP 75 mg are available for oral administration as orange, round, unscored, film coated tablets, imprinted "APO" on one side and "BU" over "75" on the other side. They are supplied as follows: Cartons of 100 film coated tablets (10 film coated tablets each blister pack x 10), NDC 0904-6635-61 Bupropion hydrochloride tablets, USP 100 mg are available for oral administration as purple, round, unscored, film coated tablets, imprinted "APO" on one side and "BUP" over "100" on the other side. They are supplied as follows: Cartons of 100 film coated tablets (10 film coated tablets each blister pack x 10), NDC 0904-6636-61 WARNING: These Unit Dose packages are not child resistant and are Intended for Institutional Use Only. Keep this and all drugs out of the reach of children. Store at 20oC to 25oC (68oF to 77oF); excursions permitted from 15oC to 30oC (59oF to 86oF) [see USP Controlled Room Temperature]. Protect from moisture. Store in a tight, light resistant container [see USP].