APLENZIN

APLENZIN ® (bupropion hydrobromide), an antidepressant of the aminoketone class, is chemically unrelated to tricyclic, tetracyclic, selective serotonin reuptake inhibitor, or other known antidepressant agents. Its structure closely resembles that of diethylpropion; it is related to phenylethylamines. It is designated as (±)-2-(tert-butylamino)-3’-chloropropiophenone hydrobromide. The molecular weight is 320.6. The molecular formula is C 13 H 18 ClNO•HBr. Bupropion hydrobromide powder is white or almost white, crystalline, and soluble in water. It has a bitter taste and produces the sensation of local anesthesia on the oral mucosa. The structural formula is: APLENZIN tablets are supplied for oral administration as 174 mg, 348 mg, and 522 mg white to off-white extended-release tablets. Each tablet contains the labeled amount of bupropion hydrobromide and the inactive ingredients: ethylcellulose, glyceryl dibehenate, polyvinyl alcohol, polyethylene glycol, povidone, and dibutyl sebacate. Carnauba wax is included in the 174 mg and 348 mg strengths. The tablets are printed with edible black ink. The insoluble shell of the extended-release tablet may remain intact during gastrointestinal transit and is eliminated in the feces. chemical structure

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

General • Increase dose gradually to reduce seizure risk. ( 2.1 , 5.3 ) Major Depressive Disorder • Starting dose: 174 mg once daily (equivalent to 150 mg bupropion HCl). Usual target dose: 348 mg once daily (equivalent to 300 mg bupropion HCl). ( 2.3 ) • After 4 days, may increase the dose to 348 mg once daily. ( 2.3 ) Seasonal Affective Disorder • Initiate treatment in the autumn prior to onset of seasonal depressive symptoms. ( 2.4 ) • Starting dose: 174 mg once daily (equivalent to 150 mg bupropion HCl). Usual target dose: 348 mg once daily (equivalent to 300 mg bupropion HCl). ( 2.4 ) • After one week, may increase the dose to 348 mg once daily. ( 2.4 ) • Continue treatment through the winter season. ( 2.4 ) Hepatic Impairment • Moderate to severe hepatic impairment: Maximum dose 174 mg every other day ( 2.6 ) • Mild hepatic impairment: Consider reducing the dose and/or frequency of dosing. ( 2.2 , 2.6 , 8.7 ) Renal Impairment • Consider reducing the dose and/or frequency of dosing. ( 2.2 , 2.7 , 8.6 ) 2.1 General Instructions for Use To minimize the risk of seizure, increase the dose gradually [see Warnings and Precautions (5.3) ]. APLENZIN should be swallowed whole and not crushed, divided, or chewed. APLENZIN should be administered in the morning and may be taken with or without regard to meals. 2.2 Equivalent Daily Doses of APLENZIN (Bupropion hydrobromide) and Bupropion hydrochloride See Table 1 for equivalent daily doses of APLENZIN (bupropion hydrobromide) and bupropion hydrochloride. Table 1: Equivalent Daily Doses of APLENZIN (Bupropion hydrobromide) and Bupropion hydrochloride APLENZIN (Bupropion hydrobromide) Bupropion hydrochloride 522 mg 450 mg 348 mg 300 mg 174 mg 150 mg 2.3 Dosage for Major Depressive Disorder (MDD) The recommended starting dose for MDD is 174 mg once daily in the morning. After 4 days of dosing, the dose may be increased to the target dose of 348 mg once daily in the morning. It is generally agreed that acute episodes of depression require several months or longer of antidepressant treatment beyond the response in the acute episode. It is unknown whether the APLENZIN dose needed for maintenance treatment is identical to the dose that provided an initial response. Periodically reassess the need for maintenance treatment and the appropriate dose for such treatment. 2.4 Dosage for Seasonal Affective Disorder (SAD) The recommended starting dose for SAD is 174 mg once daily. After 7 days of dosing, the dose may be increased to the target dose of 348 mg once daily in the morning. Doses above 300 mg of bupropion HCl extended-release (equivalent to APLENZIN 348 mg) were not assessed in the SAD trials. For the prevention of seasonal MDD episodes associated with SAD, initiate APLENZIN in the autumn, prior to the onset of depressive symptoms. Continue treatment through the winter season. Taper and discontinue APLENZIN in early spring. For patients treated with 348 mg per day, decrease the dose to 174 mg once daily before discontinuing APLENZIN. Individualize the timing of initiation, and duration of treatment should be individualized, based on the patient’s historical pattern of seasonal MDD episodes. 2.5 To Discontinue APLENZIN, Taper the Dose When discontinuing treatment in patients treated with APLENZIN 348 mg once daily, decrease the dose to 174 mg once daily prior to discontinuation. 2.6 Dosage Adjustment in Patients with Hepatic Impairment In patients with moderate to severe hepatic impairment (Child-Pugh score: 7 to 15), the maximum dose is 174 mg every other day. In patients with mild hepatic impairment (Child-Pugh score: 5 to 6), consider reducing the dose and/or frequency of dosing [see Use in Specific Populations (8.7) and Clinical Pharmacology (12.3) ]. 2.7 Dosage Adjustment in Patients with Renal Impairment Consider reducing the dose and/or frequency of APLENZIN in patients with renal impairment (glomerular filtration rate less than 90 mL/min) [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3) ] . 2.8 Switching a Patient to or from a Monoamine Oxidase Inhibitor (MAOI) Antidepressant At least 14 days should elapse between discontinuation of an MAOI intended to treat depression and initiation of therapy with APLENZIN. Conversely, at least 14 days should be allowed after stopping APLENZIN before starting an MAOI antidepressant [see Contraindications (4) and Drug Interactions (7.6) ] . 2.9 Use of APLENZIN with Reversible MAOIs such as Linezolid or Methylene Blue Do not start APLENZIN in a patient who is being treated with a reversible MAOI such as linezolid or intravenous methylene blue. Drug interactions can increase 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) ] . In some cases, a patient already receiving APLENZIN therapy 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, APLENZIN 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 APLENZIN 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 APLENZIN is unclear. The clinician should, nevertheless, be aware of the possibility of a drug interaction with such use [see Contraindications (4) and Drug Interactions (7.6)] .

• APLENZIN is contraindicated in patients with a seizure disorder. • APLENZIN is contraindicated in patients with a current or prior diagnosis of bulimia or anorexia nervosa as a higher incidence of seizures was observed in such patients treated with APLENZIN [see Warnings and Precautions (5.3) ]. • APLENZIN is contraindicated in patients undergoing abrupt discontinuation of alcohol, benzodiazepines, barbiturates, and antiepileptic drugs [see Warnings and Precautions (5.3) and Drug Interactions (7.3) ]. • The use of MAOIs (intended to treat psychiatric disorders) concomitantly with APLENZIN or within 14 days of discontinuing treatment with APLENZIN is contraindicated. There is an increased risk of hypertensive reactions when APLENZIN is used concomitantly with MAOIs. The use of APLENZIN within 14 days of discontinuing treatment with an MAOI is also contraindicated. Starting APLENZIN in a patient treated with reversible MAOIs such as linezolid or intravenous methylene blue is contraindicated [see Dosage and Administration ( 2.5 , 2.6 , 2.9 ), Warnings and Precautions (5.4) , and Drug Interactions (7.6) ]. • APLENZIN is contraindicated in patients with known hypersensitivity to bupropion or other ingredients of APLENZIN. 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 APLENZIN or within 14 days of stopping an MAOI intended to treat psychiatric disorders. In addition, do not start APLENZIN in a patient who is being treated with linezolid or intravenous methylene blue. ( 4 , 7.6 ) • Known hypersensitivity to bupropion or other ingredients of APLENZIN. ( 4 , 5.8 )

The following adverse reactions are discussed in greater detail in other sections of the labeling: • Suicidal thoughts and behaviors in children, adolescents, and young adults [see Warnings and Precautions (5.1) ] • Neuropsychiatric adverse events and suicide risk in smoking cessation treatment [see Warnings and Precautions (5.2) ] • Seizure [see Warnings and Precautions (5.3) ] • Hypertension [see Warnings and Precautions (5.4) ] • Activation of mania or hypomania [see Warnings and Precautions (5.5 )] • Psychosis and other neuropsychiatric events [see Warnings and Precautions (5.6) ] • Angle-closure glaucoma [see Warnings and Precautions (5.7) ] • Hypersensitivity reactions [see Warnings and Precautions (5.8) ] Most common adverse reactions are (incidence ≥5%; ≥2× placebo rate): dry mouth, nausea, insomnia, dizziness, pharyngitis, abdominal pain, agitation, anxiety, tremor, palpitation, sweating, tinnitus, myalgia, anorexia, urinary frequency, rash. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Bausch Health US, LLC at 1-800-321-4576 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Commonly Observed Adverse Reactions in Controlled Clinical Trials of Sustained-Release Bupropion Hydrochloride Adverse reactions that occurred in at least 5% of patients treated with bupropion HCl sustained-release (300 mg and 400 mg per day) and at a rate at least twice the placebo rate are listed below. 300 mg/day of bupropion HCl sustained-release (equivalent to APLENZIN 348 mg/day): anorexia, dry mouth, rash, sweating, tinnitus, and tremor. 400 mg/day of bupropion HCl sustained-release (equivalent to APLENZIN 464 mg/day): abdominal pain, agitation, anxiety, dizziness, dry mouth, insomnia, myalgia, nausea, palpitation, pharyngitis, sweating, tinnitus, and urinary frequency. APLENZIN is bioequivalent to bupropion HCl extended-release, which has been demonstrated to have similar bioavailability both to the immediate-release formulation of bupropion and to the sustained-release formulation of bupropion. The information included under this subsection and under subsection 6.2 is based primarily on data from controlled clinical trials with the sustained-release and extended-release formulations of bupropion hydrochloride. Major Depressive Disorder Adverse Reactions Leading to Discontinuation of Treatment with Bupropion HCl Immediate-Release, Bupropion HCl Sustained-Release, and Bupropion HCl Extended-Release in Major Depressive Disorder Trials In placebo-controlled clinical trials with bupropion HCl sustained-release, 4%, 9%, and 11% of the placebo, 300 mg/day and 400 mg/day groups, respectively, discontinued treatment because of adverse reactions. The specific adverse reactions leading to discontinuation in at least 1% of the 300 mg/day or 400 mg/day groups and at a rate at least twice the placebo rate are listed in Table 3 . Table 3: Treatment Discontinuation Due to Adverse Reactions in Placebo-Controlled Trials in MDD Adverse Reaction Term Placebo (n=385) Bupropion HCl Sustained-Release 300 mg/day Equivalent to 348 mg/day bupropion HBr (n=376) Bupropion HCl Sustained-Release 400 mg/day Equivalent to 464 mg/day bupropion HBr (n=114) Rash 0.0% 2.4% 0.9% Nausea 0.3% 0.8% 1.8% Agitation 0.3% 0.3% 1.8% Migraine 0.3% 0.0% 1.8% In clinical trials with bupropion HCl immediate-release, 10% of patients and volunteers discontinued due to an adverse reaction. Reactions resulting in discontinuation (in addition to those listed above for the sustained-release formulation) included vomiting, seizures, and sleep disturbances. Adverse Reactions Occurring at an Incidence of >1% in Patients Treated with Bupropion HCl Immediate-Release or Bupropion HCl Sustained-Release in MDD Table 4 summarizes the adverse reactions that occurred in placebo-controlled trials in patients treated with bupropion HCl sustained-release 300 mg/day and 400 mg/day. These include reactions that occurred in either the 300 mg or 400 mg group at an incidence of 1% or more and were more frequent than in the placebo group. Table 4: Adverse Reactions in Placebo-Controlled Trials in Patients with MDD Body System/Adverse Reaction Placebo (n=385) Bupropion HCl Sustained-Release 300 mg/day Equivalent to 348 mg/day bupropion HBr (n=376) Bupropion HCl Sustained-Release 400 mg/day Equivalent to 464 mg/day bupropion HBr (n=114) Body (General) Headache 23% 26% 25% Infection 6% 8% 9% Abdominal pain 2% 3% 9% Asthenia 2% 2% 4% Chest pain 1% 3% 4% Pain 2% 2% 3% Fever — Hyphen denotes adverse reactions occurring in greater than 0 but less than 0.5% of patients 1% 2% Cardiovascular Palpitation 2% 2% 6% Flushing — 1% 4% Migraine 1% 1% 4% Hot flashes 1% 1% 3% Digestive Dry mouth 7% 17% 24% Nausea 8% 13% 18% Constipation 7% 10% 5% Diarrhea 6% 5% 7% Anorexia 2% 5% 3% Vomiting 2% 4% 2% Dysphagia 0% 0% 2% Musculoskeletal Myalgia 3% 2% 6% Arthralgia 1% 1% 4% Arthritis 0% 0% 2% Twitch — 1% 2% Nervous System Insomnia 6% 11% 16% Dizziness 5% 7% 11% Agitation 2% 3% 9% Anxiety 3% 5% 6% Tremor 1% 6% 3% Nervousness 3% 5% 3% Somnolence 2% 2% 3% Irritability 2% 3% 2% Memory decreased 1% — 3% Paresthesia 1% 1% 2% Central nervous system stimulation 1% 2% 1% Respiratory Pharyngitis 2% 3% 11% Sinusitis 2% 3% 1% Increased cough 1% 1% 2% Skin Sweating 2% 6% 5% Rash 1% 5% 4% Pruritus 2% 2% 4% Urticaria 0% 2% 1% Special Senses Tinnitus 2% 6% 6% Taste perversion — 2% 4% Blurred vision or diplopia 2% 3% 2% Urogenital Urinary frequency 2% 2% 5% Urinary urgency 0% — 2% Vaginal hemorrhage Incidence based on the number of female patients. — 0% 2% Urinary tract infection — 1% 0% The following additional adverse reactions occurred in controlled trials of bupropion HCl immediate-release (300 to 600 mg per day) at an incidence of at least 1% more frequently than in the placebo group were: cardiac arrhythmia (5% vs. 4%), hypertension (4% vs. 2%), hypotension (3% vs. 2%), tachycardia (11% vs. 9%), appetite increased (4% vs. 2%), dyspepsia (3% vs. 2%), menstrual complaints (5% vs. 1%), akathisia (2% vs. 1%), impaired sleep quality (4% vs. 2%), sensory disturbance (4% vs. 3%), confusion (8% vs. 5%), decreased libido (3% vs. 2%), hostility (6% vs. 4%), auditory disturbance (5% vs. 3%), and gustatory disturbance (3% vs. 1%). Seasonal Affective Disorder In placebo-controlled clinical trials in SAD, 9% of patients treated with bupropion HCl extended-release and 5% of patients treated with placebo discontinued treatment because of adverse reactions. The adverse reactions leading to discontinuation in at least 1% of patients treated with bupropion and at a rate numerically greater than the placebo rate were insomnia (2% vs. <1%) and headache (1% vs. <1%). Table 5 summarizes the adverse reactions that occurred in patients treated with bupropion HCl extended-release for up to approximately 6 months in 3 placebo-controlled trials. These include reactions that occurred at an incidence of 2% or more and were more frequent than in the placebo group. Table 5: Adverse Reactions in Placebo-Controlled Trials in Patients with SAD System Organ Class/ Preferred Term Placebo (n=511) Bupropion HCl Extended-Release (n=537) Gastrointestinal Disorder Dry mouth 15% 26% Nausea 8% 13% Constipation 2% 9% Flatulence 3% 6% Abdominal pain <1% 2% Nervous System Disorders Headache 26% 34% Dizziness 5% 6% Tremor <1% 3% Infections and Infestations Nasopharyngitis 12% 13% Upper respiratory tract infection 8% 9% Sinusitis 4% 5% Psychiatric Disorders Insomnia 13% 20% Anxiety 5% 7% Abnormal dreams 2% 3% Agitation <1% 2% Musculoskeletal and Connective Tissue Disorders Myalgia 2% 3% Pain in extremity 2% 3% Respiratory, Thoracic, and Mediastinal Disorders Cough 3% 4% General Disorders and Administration Site Conditions Feeling jittery 2% 3% Skin and Subcutaneous Tissue Disorders Rash 2% 3% Metabolism and Nutrition Disorders Decreased appetite 1% 4% Reproductive System and Breast Disorders Dysmenorrhea <1% 2% Ear and Labyrinth Disorders Tinnitus <1% 3% Vascular Disorders Hypertension 0% 2% Changes in Body Weight Table 6 presents the incidence of body weight changes (≥5 lbs) in the short-term MDD trials using bupropion HCl sustained-release. There was a dose-related decrease in body weight. Table 6: Incidence of Weight Gain or Weight Loss (≥5 lbs) in MDD Trials Using Bupropion HCl Sustained-Release Weight Change Bupropion HCl Sustained-Release 300 mg/day Equivalent to 348 mg/day bupropion HBr (n=339) Bupropion HCl Sustained-Release 400 mg/day Equivalent to 464 mg/day bupropion HBr (n=112) Placebo (n=347) Gained >5 lbs 3% 2% 4% Lost >5 lbs 14% 19% 6% Table 7 presents the incidence of body weight changes (≥5 lbs) in the 3 SAD trials using bupropion HCl extended-release. A higher proportion of subjects in the bupropion group (23%) had a weight loss ≥5 lbs, compared to the placebo group (11%). These were relatively long-term trials (up to 6 months). Table 7: Incidence of Weight Gain or Weight Loss (≥5 lbs) in SAD Trials Using Bupropion HCl Extended-Release Weight Change Bupropion HCl Extended-Release 150 to 300 mg/day (n=537) Placebo (n=511) Gained >5 lbs 11% 21% Lost >5 lbs 23% 11% 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of APLENZIN. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Body (General) Chills, facial edema, edema, peripheral edema, musculoskeletal chest pain, photosensitivity, and malaise. Cardiovascular Postural hypotension, stroke, vasodilation, syncope, complete atrioventricular block, extrasystoles, myocardial infarction, phlebitis, pulmonary embolism, and Brugada pattern/syndrome. Digestive Abnormal liver function, bruxism, gastric reflux, gingivitis, glossitis, increased salivation, jaundice, mouth ulcers, stomatitis, thirst, edema of tongue, colitis, esophagitis, gastrointestinal hemorrhage, gum hemorrhage, hepatitis, intestinal perforation, liver damage, pancreatitis, and stomach ulcer. Endocrine Hyperglycemia, hypoglycemia, and syndrome of inappropriate antidiuretic hormone secretion. Hemic and Lymphatic Ecchymosis, anemia, leukocytosis, leukopenia, lymphadenopathy, pancytopenia, and thrombocytopenia. Altered PT and/or INR, associated with hemorrhagic or thrombotic complications, were observed when bupropion was coadministered with warfarin. Metabolic and Nutritional Glycosuria. Musculoskeletal Leg cramps, fever/rhabdomyolysis, and muscle weakness. Nervous System Abnormal coordination, depersonalization, emotional lability, hyperkinesia, hypertonia, hypesthesia, vertigo, amnesia, ataxia, derealization, abnormal electroencephalogram (EEG), aggression, akinesia, aphasia, coma, dysarthria, dyskinesia, dystonia, euphoria, extrapyramidal syndrome, hypokinesia, increased libido, neuralgia, neuropathy, paranoid ideation, restlessness, suicide attempt, unmasking tardive dyskinesia and aseptic meningitis. Respiratory Bronchospasm and pneumonia. Skin and Subcutaneous Tissue Disorders Maculopapular rash, alopecia, angioedema, exfoliative dermatitis, hirsutism, acute generalized exanthematous pustulosis and drug reaction with eosinophilia and systemic symptoms (DRESS). Special Senses Accommodation abnormality, dry eye, deafness, increased intraocular pressure, angle-closure glaucoma, and mydriasis. Urogenital Impotence, polyuria, prostate disorder, abnormal ejaculation, cystitis, dyspareunia, dysuria, gynecomastia, menopause, painful erection, salpingitis, urinary incontinence, urinary retention, and vaginitis.

• CYP2B6 inducers: Dose increase may be necessary if coadministered with CYP2B6 inducers (e.g., ritonavir, lopinavir, efavirenz, carbamazepine, phenobarbital, phenytoin) based on clinical exposure, but should not exceed the maximum dose. ( 7.1 ) • Drugs metabolized by CYP2D6: Bupropion inhibits CYP2D6 and can increase concentrations of: antidepressants (e.g., venlafaxine, nortriptyline, imipramine, desipramine, paroxetine, fluoxetine, sertraline), antipsychotics (e.g., haloperidol, risperidone, thioridazine), beta-blockers (e.g., metoprolol), and Type 1C antiarrhythmics (e.g., propafenone, flecainide). Consider dose reduction when using with bupropion. ( 7.2 ) • Drugs that lower seizure threshold: Dose APLENZIN with caution. ( 5.3 , 7.3 ) • Dopaminergic Drugs (levodopa and amantadine): CNS toxicity can occur when used concomitantly with APLENZIN. ( 7.4 ) • MAOIs: Increased risk of hypertensive reactions can occur when used concomitantly with APLENZIN. ( 7.6 ) • Drug-laboratory test interactions: APLENZIN can cause false-positive urine test results for amphetamines. ( 7.7 ) 7.1 Potential for Other Drugs to Affect APLENZIN Bupropion is primarily metabolized to hydroxybupropion by CYP2B6. Therefore, the potential exists for drug interactions between APLENZIN and drugs that are inhibitors or inducers of CYP2B6. Inhibitors of CYP2B6 Ticlopidine and Clopidogrel: Concomitant treatment with these drugs can increase bupropion exposures but decrease hydroxybupropion exposure. Based on clinical response, dosage adjustment of APLENZIN 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 APLENZIN may be necessary when coadministered with ritonavir, lopinavir, or efavirenz but should not exceed the maximum recommended dose [see Clinical Pharmacology (12.3) ]. Carbamazepine, Phenobarbital, Phenytoin: While not systemically studied, these drugs may induce metabolism of bupropion and may decrease bupropion exposure [see Clinical Pharmacology (12.3) ] . If bupropion is used concomitantly with a CYP inducer, it may be necessary to increase the dose of bupropion, but the maximum recommended dose should not be exceeded. 7.2 Potential for APLENZIN to Affect Other Drugs Drugs Metabolized by CYP2D6 Bupropion and its metabolites (erythrohydrobupropion, threohydrobupropion, hydroxybupropion) are CYP2D6 inhibitors. Therefore, coadministration of APLENZIN with drugs that are metabolized by CYP2D6 can increase the exposures of drugs that are substrates of CYP2D6. Such drugs include certain antidepressants (e.g., venlafaxine, nortriptyline, imipramine, desipramine, paroxetine, fluoxetine, and sertraline), antipsychotics (e.g., haloperidol, risperidone, and thioridazine), beta-blockers (e.g., metoprolol), and Type 1C antiarrhythmics (e.g., propafenone, and flecainide). When used concomitantly with APLENZIN, 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 APLENZIN and such drugs may require increased doses of the drug [see Clinical Pharmacology (12.3) ]. 7.3 Drugs That Lower Seizure Threshold Use extreme caution when coadministering APLENZIN with other drugs that lower the seizure threshold (e.g., other bupropion products, antipsychotics, antidepressants, theophylline, or systemic corticosteroids). Use low initial doses of APLENZIN and increase the dose gradually [see 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 APLENZIN 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 APLENZIN. The consumption of alcohol during treatment with APLENZIN should be minimized or avoided. 7.6 MAO Inhibitors Bupropion inhibits the reuptake of dopamine and norepinephrine. Concomitant use of MAOIs and bupropion is contraindicated because there is an increased risk of hypertensive reactions if bupropion is used concomitantly with MAOIs. Studies in animals demonstrate that the acute toxicity of bupropion is enhanced by the MAO inhibitor phenelzine. At least 14 days should elapse between discontinuation of an MAOI intended to treat depression and initiation of treatment with APLENZIN. Conversely, at least 14 days should be allowed after stopping APLENZIN before starting an MAOI antidepressant [see Dosage and Administration ( 2.8 , 2.9 ) and Contraindications (4) ]. 7.7 Drug-Laboratory Test Interactions False-positive urine immunoassay screening tests for amphetamines have been reported in patients taking bupropion. This is due to lack of specificity of some screening tests. False-positive test results may result even following discontinuation of bupropion therapy. Confirmatory tests, such as gas chromatography/mass spectrometry, will distinguish bupropion from amphetamines.

Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature].