BUPROPION HYDROCHLORIDE

Bupropion hydrochloride extended-release tablets (XL), 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 (±)-2-(tert-Butylamino)-3'-chloropropiophenone hydrochloride. The molecular weight is 276.2. The empirical formula is C 13 H 18 ClNO·HCl. Bupropion hydrochloride 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: Bupropion hydrochloride extended-release tablets (XL) are supplied for oral administration of 450 mg of bupropion hydrochloride, USP as white to off-white extended-release tablets. Each film-coated tablet contains the labeled amount of bupropion hydrochloride, USP and the inactive ingredients: carboxymethyl cellulose sodium, colloidal silicon dioxide, hydrochloric acid, hydroxypropyl cellulose, hypromellose, magnesium stearate, methacrylic acid copolymer, polyethylene glycol 8000, polyethylene oxide, polyvinyl pyrrolidone and polyvinyl acetate blend, stearic acid, talc, titanium dioxide and triacetin. “BUP450” is printed on one side of the tablet with edible black ink. Structural Formula

Bupropion hydrochloride extended-release tablets (XL) 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 )] . The physician who elects to use bupropion hydrochloride extended-release tablets (XL) for extended periods should periodically reevaluate the long-term usefulness of the drug for the individual patient. Bupropion hydrochloride extended-release tablets (XL) are an aminoketone antidepressant indicated for the treatment of major depressive disorder (MDD) ( 1 ). The efficacy was established in two 4-week trials, one 6-week trial with bupropion immediate-release formulation, and one maintenance trial with bupropion sustained-release formulation, all in adults ( 14 ). Periodically re-evaluate long-term usefulness for the individual patient ( 1 ).

• Use one tablet (450 mg) once daily without regard to food ( 2.1 ). • Swallow the tablet whole. Do not chew, divide, or crush ( 2.1 ). • Do not initiate treatment with bupropion hydrochloride extended-release tablets (XL). Use another bupropion formulation for initial dose titration ( 2.2 ). • Can be used in patients who are receiving 300 mg/day of another bupropion formulation for at least 2 weeks, and require a dosage of 450 mg/day ( 2.2 ). • Patients who are currently being treated with other bupropion products at 450 mg/day can be switched to equivalent dose of bupropion hydrochloride extended-release tablets (XL) once daily ( 2.2 ). 2.1 General Instructions for Use One tablet (450 mg) of bupropion hydrochloride extended-release tablets (XL) should be taken once daily without regard to meals. Bupropion hydrochloride extended-release tablets (XL) should be swallowed whole and not crushed, divided, or chewed. 2.2 Initial Treatment with Bupropion Hydrochloride Extended-Release Tablets (XL) Do not initiate treatment with bupropion hydrochloride extended-release tablets (XL) because the 450 mg tablet is the only available dose formulation. Use another bupropion formulation for initial dose titration (referring to prescribing information of other bupropion products). Bupropion hydrochloride extended-release tablets (XL) can be used in patients who are receiving 300 mg/day of another bupropion formulation for at least 2 weeks, and require a dosage of 450 mg/day. Patients who are currently being treated with other bupropion products at 450 mg/day can be switched to an equivalent dose of bupropion hydrochloride extended-release tablets (XL) once daily. 2.3 Maintenance Treatment with Bupropion Hydrochloride Extended-Release Tablets (XL) It is generally agreed that acute episodes of depression require several months or longer of sustained antidepressant treatment beyond the response in the acute episode. It is unknown whether the 450 mg 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 To Discontinue Bupropion Hydrochloride Extended-Release Tablets (XL), Taper the Dose Because the 450 mg tablet is the only available dose formulation, use another bupropion formulation for tapering the dose prior to discontinuation (referring to prescribing information of other bupropion products). 2.5 Patients with Impaired Hepatic Function Because there is no lower dose strength for bupropion hydrochloride extended-release tablets (XL), bupropion hydrochloride extended-release tablets (XL) is not recommended in patients with hepatic impairment [see Use in Specific Populations ( 8.7 ) and Clinical Pharmacology ( 12.3 )] . 2.6 Patients with Impaired Renal Function Because there is no lower dose strength for bupropion hydrochloride extended-release tablets (XL), bupropion hydrochloride extended-release tablets (XL) is not recommended in patients with renal impairment [see Use in Specific Populations ( 8.6 ) and Clinical Pharmacology ( 12.3 )] . 2.7 Switching a Patient To or From a Monoamine Oxidase Inhibitor (MAOI) Antidepressant At least 14 days should elapse between discontinuation of an MAOI intended to treat depression and initiation of therapy with bupropion hydrochloride extended-release tablets (XL). Conversely, at least 14 days should be allowed after stopping bupropion hydrochloride extended-release tablets (XL) before starting an MAOI antidepressant [see Contraindications ( 4 ) and Drug Interactions ( 7.6 )] . 2.8 Use of Bupropion Hydrochloride Extended-Release Tablets (XL) with Reversible MAOIs Such as Linezolid or Methylene Blue Do not start bupropion hydrochloride extended-release tablets (XL) 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, nonpharmacological interventions, including hospitalization, should be considered [see Contraindications ( 4 )] . In some cases, a patient already receiving therapy with bupropion hydrochloride extended-release tablets (XL) 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 (XL) 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 (XL) may be resumed 24 hours after the last dose of linezolid or intravenous methylene blue. The risk of administering methylene blue by nonintravenous routes (such as oral tablets or by local injection) or in intravenous doses much lower than 1 mg/kg with bupropion hydrochloride extended-release tablets (XL) 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 )] .

• Bupropion hydrochloride extended-release tablets (XL) are contraindicated in patients with a seizure disorder [see Warnings and Precautions ( 5.3 )] . • Bupropion hydrochloride extended-release tablets (XL) are contraindicated in patients treated currently with other bupropion products because the incidence of seizure is dose dependent [see Warnings and Precautions ( 5.3 )] . • Bupropion hydrochloride extended-release tablets (XL) are contraindicated in patients with a current or prior diagnosis of bulimia or anorexia nervosa because a higher incidence of seizures was observed in such patients treated with bupropion [see Warnings and Precautions ( 5.3 )] . • Bupropion hydrochloride extended-release tablets (XL) are 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 bupropion hydrochloride extended-release tablets (XL) or within 14 days of discontinuing treatment with bupropion hydrochloride extended-release tablets (XL) is contraindicated. There is an increased risk of hypertensive reactions when bupropion hydrochloride extended-release tablets (XL) are used concomitantly with MAOIs. The use of bupropion hydrochloride extended-release tablets (XL) within 14 days of discontinuing treatment with an MAOI is also contraindicated. Starting bupropion hydrochloride extended-release tablets (XL) 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 ), and Drug Interactions ( 7.6 )] . • Bupropion hydrochloride extended-release tablets (XL) are contraindicated in patients with known hypersensitivity to bupropion or the other ingredients of bupropion hydrochloride extended-release tablets (XL). Anaphylactoid/anaphylactic reactions and Stevens-Johnson syndrome have been reported [see Warnings and Precautions ( 5.8 )] . • Seizure disorder ( 4 , 5.3 ) • Current use of other bupropion products ( 4 , 5.3 ) • Current or prior diagnosis of bulimia or anorexia nervosa ( 4 , 5.3 ) • Abrupt discontinuation of alcohol, benzodiazepines, barbiturates, or antiepileptic drugs ( 4 , 5.3 ) • Monoamine Oxidase Inhibitors (MAOIs): Do not use MAOIs intended to treat psychiatric disorders with bupropion hydrochloride extended-release tablets (XL) or within 14 days of stopping treatment with bupropion hydrochloride extended-release tablets (XL). Do not use bupropion hydrochloride extended-release tablets (XL) within 14 days of stopping an MAOI intended to treat psychiatric disorders. In addition, do not start bupropion hydrochloride extended-release tablets (XL) 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 (XL) ( 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 times 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 Alvogen, Inc. at 1-866-770-3024 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 clinical 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 hydrochloride sustained-release (300 and 400 mg/day) and at a rate at least twice the placebo rate are listed below. 300 mg/day of bupropion hydrochloride sustained-release: anorexia, dry mouth, rash, sweating, tinnitus, and tremor. 400 mg/day of bupropion hydrochloride sustained-release: abdominal pain, agitation, anxiety, dizziness, dry mouth, insomnia, myalgia, nausea, palpitation, pharyngitis, sweating, tinnitus, and urinary frequency. Bupropion hydrochloride extended-release tablets (XL) is bioequivalent to three 150 mg tablets of WELLBUTRIN XL ® , which has been demonstrated to have similar bioavailability both to the immediate-release and the sustained-release formulations 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 Hydrochloride Immediate-release, Bupropion Hydrochloride Sustained-release, and Bupropion Hydrochloride Extended-release Formulations in Major Depressive Disorder Trials In placebo-controlled clinical trials with bupropion hydrochloride 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 2. Table 2. Treatment Discontinuation Due to Adverse Reactions in Placebo-controlled Trials in Major Depressive Disorder Adverse Reaction Term Placebo (N = 385) Bupropion Hydrochloride Sustained-release 300 mg/day (N = 376) Bupropion Hydrochloride Sustained-release 400 mg/day (N = 114) Rash 0.0% 2.4% 0.9% Nausea 0.3% 0.8% 1.8% Agitation 0.3% 0.3% 1.8% Migraine 0.3% 0.0% 1.8% In clinical trials with bupropion hydrochloride 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 Hydrochloride Immediate-release or Bupropion Hydrochloride Sustained-release Formulations in Major Depressive Disorder Trials Table 3 summarizes the adverse reactions that occurred in placebo-controlled trials in patients treated with bupropion hydrochloride sustained-release at 300 mg/day and 400 mg/day. These include reactions that occurred in either the 300 mg/day or 400 mg/day group at an incidence of 1% or more and were more frequent than in the placebo group. Table 3. Adverse Reactions in Placebo-controlled Trials for Major Depressive Disorder a = Incidence based on the number of female patients. — = Denotes adverse reactions occurring in greater than 0 but less than 0.5% of patients. Body System/Adverse Reaction Placebo (N = 385) Bupropion Hydrochloride Sustained-release 300 mg/day (N = 376) Bupropion Hydrochloride Sustained-release 400 mg/day (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 — 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 a — 0% 2% Urinary tract infection — 1% 0% The following additional adverse reactions occurred in controlled trials of bupropion hydrochloride immediate-release (300 to 600 mg/day) at an incidence of at least 1% more frequently than in the placebo group: cardiac arrhythmia (5% vs 4%), hypertension (4% vs 2%), hypotension (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%). Changes in Body Weight Table 4 presents the incidence of body weight changes (≥ 5 lbs) in the short-term MDD trials using bupropion hydrochloride sustained-release. There was a dose-related decrease in body weight. Table 4. Incidence of Weight Gain or Weight Loss (≥ 5 lbs) in Placebo-controlled Trials of Bupropion Hydrochloride Sustained-release Tablets for Major Depressive Disorder Weight Change Placebo (N = 347) Bupropion Hydrochloride Sustained-release 300 mg/day (N = 339) Bupropion Hydrochloride Sustained-release 400 mg/day (N = 112) Gained > 5 lbs 4% 3% 2% Lost > 5 lbs 6% 14% 19% 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of bupropion hydrochloride. 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, hypertension, stroke, vasodilation, syncope, complete atrioventricular block, extrasystoles, myocardial infarction, phlebitis, and pulmonary embolism. 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, and unmasking tardive dyskinesia. Respiratory: bronchospasm and pneumonia. Skin: maculopapular rash, alopecia, angioedema, exfoliative dermatitis, and hirsutism. 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 Inhibitors: Ticlopidine or clopidogrel may increase bupropion exposure. Coadministration of bupropion hydrochloride extended-release tablets (XL) with ticlopidine or clopidogrel is not recommended ( 7.1 ). • CYP2B6 Inducers: Dose increase may be necessary if coadministered with CYP2B6 inducers (e.g., ritonavir, lopinavir, efavirenz, carbamazepine, phenobarbital, and phenytoin) based on clinical exposure, but should not exceed the maximum recommended dose ( 7.1 ). • Drugs Metabolized by CYP2D6: Bupropion inhibits CYP2D6 and can increase concentrations of: antidepressants (e.g., venlafaxine, nortriptyline, imipramine, desipramine, paroxetine, fluoxetine, sertraline), antipsychotics (e.g., haloperidol, risperidone, thioridazine), beta-blockers (e.g., metoprolol), and Type 1C antiarrhythmics (e.g., propafenone, flecainide). Consider dose reduction when using with bupropion ( 7.2 ). • Drugs That Lower Seizure Threshold: Dose bupropion hydrochloride extended-release tablets (XL) with extreme caution ( 5.3 , 7.3 ). • Dopaminergic Drugs (levodopa and amantadine): CNS toxicity can occur when used concomitantly with bupropion hydrochloride extended-release tablets (XL) ( 7.4 ). • MAOIs: Increased risk of hypertensive reactions can occur when used concomitantly with bupropion hydrochloride extended-release tablets (XL) ( 7.6 ). • Drug-Laboratory Test Interactions: Bupropion hydrochloride extended-release tablets (XL) can cause false-positive urine test results for amphetamines ( 7.7 ). 7.1 Potential for Other Drugs to Affect Bupropion Hydrochloride Extended-Release Tablets (XL) Bupropion is primarily metabolized to hydroxybupropion by CYP2B6. Therefore, the potential exists for drug interactions between bupropion hydrochloride extended-release tablets (XL) 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. Coadministration of bupropion hydrochloride extended-release tablets (XL) with ticlopidine or clopidogrel is not recommended [see Clinical Pharmacology ( 12.3 )] . Inducers of CYP2B6 Ritonavir, Lopinavir, and Efavirenz: Concomitant treatment with these drugs can decrease bupropion and hydroxybupropion exposure. Patients receiving any of these drugs with bupropion may need increased doses of bupropion, but the maximum recommended dose of bupropion should not be exceeded [see Clinical Pharmacology ( 12.3 )] . Carbamazepine, Phenobarbital, and Phenytoin: Although not systematically 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 Bupropion Hydrochloride Extended-Release Tablets (XL) to Affect Other Drugs Drugs Metabolized by CYP2D6 Bupropion and its metabolites (erythrohydrobupropion, threohydrobupropion, and hydroxybupropion) are CYP2D6 inhibitors. Therefore, coadministration of bupropion with drugs that are metabolized by CYP2D6 can increase the exposures of drugs that are substrates of CYP2D6. Such drugs include 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 bupropion, 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 (XL) and such drugs may require increased doses of the drug [see Clinical Pharmacology ( 12.3 )] . 7.3 Drugs that Lower Seizure Threshold Because there is no lower strength for bupropion hydrochloride extended-release tablets (XL), concurrent administration of bupropion hydrochloride extended-release tablets (XL) and agents that lower the seizure threshold (e.g., other bupropion products, antipsychotics, antidepressants, theophylline, or systemic corticosteroids) should be undertaken only with extreme caution [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. Because there is no lower strength for bupropion hydrochloride extended-release tablets (XL), administration of bupropion hydrochloride extended-release tablets (XL) to patients receiving either levodopa or amantadine concurrently should be undertaken with caution. 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. Alcohol increased the release rate of bupropion hydrochloride extended-release tablets (XL) in vitro . The consumption of alcohol during treatment with bupropion hydrochloride extended-release tablets (XL) should be avoided. 7.6 Monoamine Oxidase Inhibitors (MAOIs) 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 MAOI phenelzine. At least 14 days should elapse between discontinuation of an MAOI intended to treat depression and initiation of treatment with bupropion hydrochloride extended-release tablets (XL). Conversely, at least 14 days should be allowed after stopping bupropion hydrochloride extended-release tablets (XL) before starting an MAOI antidepressant [see Dosage and Administration ( 2.7 , 2.8 ) 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.