AUVELITY is a combination of dextromethorphan hydrobromide, an uncompetitive NMDA receptor antagonist and sigma-1 receptor agonist, and bupropion hydrochloride, an aminoketone and CYP450 2D6 inhibitor. The chemical name of dextromethorphan hydrobromide is morphinan, 3- methoxy-17-methyl-, (9α, 13α, 14α), hydrobromide monohydrate. Dextromethorphan hydrobromide has the empirical formula C 18 H 25 NO•HBr•H 2 O and a molecular weight of 370.33 (271.4 dextromethorphan base). The structural formula is: Dextromethorphan hydrobromide powder is white or almost white, crystalline, and sparingly soluble in water. The chemical name of bupropion hydrochloride is:(±)-1-(3-chlorophenyl)-2-[(1,1-dimethylethyl)amino]-1­propanone hydrochloride. Bupropion hydrochloride has the empirical formula C 13 H 18 ClNO•HCl and a molecular weight of 276.2 (239.74 bupropion base). The structural formula is: Bupropion hydrochloride powder is white and highly soluble in water. AUVELITY is for oral administration and is available as round bilayer tablets. Each tablet contains 45 mg dextromethorphan hydrobromide (equivalent to 32.98 mg dextromethorphan base) in an immediate-release formulation and 105 mg bupropion hydrochloride (equivalent to 91.14 mg bupropion base) in an extended-release formulation. Each tablet contains the following inactive ingredients: carbomer homopolymer, colloidal silicon dioxide, crospovidone, glyceryl monocaprylocaprate, l-cysteine hydrochloride monohydrate, magnesium stearate, microcrystalline cellulose, polyvinyl alcohol, red iron oxide, sodium lauryl sulfate, stearic acid, talc, titanium dioxide, and yellow iron oxide. Structural Formula - Dextromethorphan Hydrobromide Structural Formula - Bupropion Hydrochloride

AUVELITY is indicated for the treatment of major depressive disorder (MDD) in adults. AUVELITY is a combination of dextromethorphan, an uncompetitive N -methyl D -aspartate (NMDA) receptor antagonist and sigma-1 receptor agonist, and bupropion, an aminoketone and CYP450 2D6 inhibitor, indicated for the treatment of major depressive disorder (MDD) in adults.

AUVELITY extended-release tablets contain 45 mg dextromethorphan hydrobromide and 105 mg bupropion hydrochloride. The tablets are beige and round with “45/105” debossed on one side. Extended-release tablets: 45 mg/105 mg dextromethorphan hydrobromide/ bupropion hydrochloride.

Prior to initiating treatment with AUVELITY: assess blood pressure; screen patients for history of bipolar disorder, mania, or hypomania; and determine if patients are receiving any other medications that contain bupropion or dextromethorphan. Starting dosage is one tablet once daily in the morning. After 3 days, increase to the maximum recommended dosage of one tablet twice daily, separated by at least 8 hours. Do not exceed two doses within the same day. Swallow tablets whole, do not crush, divide, or chew. Moderate renal impairment: One tablet by mouth once daily in the morning. CYP2D6 poor metabolizers: One tablet by mouth once daily in the morning. ( 2.5 , 8.8 , 12.3 ) 2.1 Important Recommendations Prior to Initiating and During Treatment with AUVELITY Prior to initiating and during treatment with AUVELITY: assess blood pressure and monitor periodically during treatment . screen patients for a personal or family history of bipolar disorder, mania, or hypomania . screen patients to determine if they are receiving any other medications that contain bupropion or dextromethorphan

Recommended Dosage for the Treatment of Major Depressive Disorder The recommended starting dosage of AUVELITY (45 mg of dextromethorphan hydrobromide and 105 mg of bupropion hydrochloride) is one tablet once daily in the morning. After 3 days, increase to the maximum recommended dosage of one tablet twice daily, given at least 8 hours apart. Do not exceed two doses within the same day. Administer AUVELITY orally with or without food . Swallow tablets whole, do not crush, divide, or chew

Dosage Recommendations in Patients with Renal Impairment The recommended dosage of AUVELITY for patients with moderate renal impairment (eGFR 30 to 59 mL/minute/1.73 m 2 ) is one tablet once daily in the morning

Dosage Recommendations for Concomitant Use with Strong CYP2D6 Inhibitors The recommended dosage of AUVELITY when co-administered with strong CYP2D6 inhibitors is one tablet once daily in the morning

Dosage Recommendations for Known CYP2D6 Poor Metabolizers (PMs) The recommended dosage for patients known to be poor CYP2D6 metabolizers is one tablet once daily in the morning

Switching a Patient to or from a Monoamine Oxidase Inhibitor (MAOI) Antidepressant At least 14 days must elapse between discontinuation of an MAOI intended to treat depression and initiation of therapy with AUVELITY. Conversely, at least 14 days must be allowed after stopping AUVELITY before starting an MAOI antidepressant .

Seizure: Risk is dose-related. Discontinue if seizure occurs. Increased Blood Pressure and Hypertension: AUVELITY can increase blood pressure and cause hypertension. Assess blood pressure before initiating treatment and monitor periodically during treatment. Activation of Mania or Hypomania: Screen patients for bipolar disorder. Psychosis and Other Neuropsychiatric Reactions: Instruct patients to contact a healthcare provider if such reactions occur. Angle-Closure Glaucoma: Angle-closure glaucoma has occurred in patients with untreated anatomically narrow angles treated with antidepressants. Dizziness: AUVELITY may cause dizziness. Take precautions to reduce falls and use caution when operating machinery. Serotonin Syndrome: Use of AUVELITY with selective serotonin reuptake inhibitors (SSRIs) or tricyclic antidepressants increases the risk. Discontinue if occurs. Embryo-fetal Toxicity: May cause fetal harm. Advise pregnant females of the potential risk to a fetus. Discontinue treatment in pregnant females and use alternative treatment for females who are planning to become pregnant. ( 5.9 , 8.1 , 8.3 ) 5.1 Suicidal Thoughts and Behaviors in Adolescents and Young Adults In pooled analyses of placebo-controlled trials of antidepressant drugs (SSRIs and other antidepressant classes) that included approximately 77,000 adult patients and 4,500 pediatric patients, the incidence of suicidal thoughts and behaviors in antidepressant-treated patients age 24 years and younger was greater than in placebo-treated patients. There was considerable variation in risk of suicidal thoughts and behaviors among drugs, but there was an increased risk identified in young patients for most drugs studied. There were differences in absolute risk of suicidal thoughts and behaviors across the different indications, with the highest incidence in patients with MDD. The drug-placebo differences in the number of cases of suicidal thoughts and behaviors per 1000 patients treated are provided in Table 1. Table 1: Risk Differences of the Number of Patients of Suicidal Thoughts and Behavior in the Pooled Placebo-Controlled Trials of Antidepressants in Pediatric* and Adult Patients *AUVELITY is not approved for use in pediatric patients. Age Range Drug-Placebo Difference in Number of Patients of Suicidal Thoughts or Behaviors per 1000 Patients Treated Increases Compared to Placebo <18 years old 14 additional patients 18-24 years old 5 additional patients Decreases Compared to Placebo 25-64 years old 1 fewer patient ≥65 years old 6 fewer patients It is unknown whether the risk of suicidal thoughts and behaviors in children, adolescents, and young adults extends to longer-term use, i.e., beyond four months. However, there is substantial evidence from placebo-controlled maintenance studies in adults with MDD that antidepressants delay the recurrence of depression and that depression itself is a risk factor for suicidal thoughts and behaviors. Monitor all antidepressant-treated patients for any indication for clinical worsening and emergence of suicidal thoughts and behaviors, especially during the initial few months of drug therapy, and at times of dosage changes. Counsel family members or caregivers of patients to monitor for changes in behavior and to alert the healthcare provider. Consider changing the therapeutic regimen, including possibly discontinuing AUVELITY, in patients whose depression is persistently worse, or who are experiencing emergent suicidal thoughts or behaviors

Seizure Bupropion, a component of AUVELITY, can cause seizure. The risk of seizure with bupropion is dose-related. When a bupropion hydrochloride (HCl) sustained-release tablet was dosed up to 300 mg per day (approximately 1.5 times the maximum recommended daily dosage of AUVELITY), the incidence of seizure was approximately 0.1% (1/1,000) and increased to approximately 0.4% (4/1,000) at the maximum recommended dosage for the sustained-release tablet of 400 mg per day (approximately 2 times the maximum recommended daily dosage of AUVELITY). The risk of seizures is also related to patient factors, clinical situations, and concomitant medications that lower the seizure threshold. Consider these risks before initiating treatment with AUVELITY. AUVELITY is contraindicated in patients with a seizure disorder, current or prior diagnosis of anorexia nervosa or bulimia, or undergoing abrupt discontinuation of alcohol, benzodiazepines, barbiturates, and antiepileptic drugs . The following conditions can also increase the risk of seizure: severe head injury; arteriovenous malformation; CNS tumor or CNS infection; severe stroke; concomitant use of other medications that lower the seizure threshold (e.g., other bupropion products, antipsychotics, tricyclic antidepressants, theophylline, and systemic corticosteroids); metabolic disorders (e.g., hypoglycemia, hyponatremia, severe hepatic impairment, and hypoxia); use of illicit drugs (e.g., cocaine); or abuse or misuse of prescription drugs such as CNS stimulants. Additional predisposing conditions include diabetes mellitus treated with oral hypoglycemic drugs or insulin; use of anorectic drugs; and excessive use of alcohol, benzodiazepines, sedative/hypnotics, or opiates. Because the risk of seizure with bupropion is dose-related, screen patients for use of other bupropion-containing products prior to initiating AUVELITY . If concomitant use of AUVELITY with other bupropion-containing products is clinically warranted, inform patients of the risk. Discontinue AUVELITY and do not restart treatment if the patient experiences a seizure

Increased Blood Pressure and Hypertension AUVELITY contains bupropion, which can cause elevated blood pressure and hypertension. The risk of hypertension is increased if AUVELITY is used concomitantly with MAOIs or other drugs that increase dopaminergic or noradrenergic activity . Data from a comparative trial of a sustained-release tablet formulation of bupropion HCl, nicotine transdermal system (NTS), the combination of sustained-release bupropion plus NTS, and placebo as an aid to smoking cessation suggest a higher incidence of hypertension in patients treated with the combination of sustained-release bupropion and NTS. In this trial, 6.1% of subjects treated with the combination of sustained-release bupropion and NTS had hypertension compared with 2.5%, 1.6%, and 3.1% of subjects treated with sustained-release bupropion, NTS, and placebo, respectively. The majority of these subjects had evidence of pre-existing hypertension. Three subjects (1.2%) treated with the combination of sustained-release bupropion and NTS and 1 subject (0.4%) treated with NTS had study medication discontinued due to hypertension compared with none of the subjects treated with sustained-release bupropion or placebo. Monitor blood pressure in patients who receive the combination of bupropion and nicotine replacement. In a clinical trial of an immediate-release bupropion tablet formulation in MDD subjects with stable congestive heart failure (N=36), bupropion was associated with an exacerbation of pre-existing hypertension in 2 subjects, leading to discontinuation of bupropion treatment. There are no controlled trials assessing the safety of bupropion in patients with a recent history of myocardial infarction or unstable cardiac disease. Assess blood pressure prior to initiating treatment, and periodically monitor blood pressure during treatment with AUVELITY

Activation of Mania or Hypomania Antidepressant treatment can precipitate a manic, mixed, or hypomanic manic episode. The risk appears to be increased in patients with bipolar disorder or who have risk factors for bipolar disorder. Prior to initiating AUVELITY, screen patients for a history of bipolar disorder and the presence of risk factors for bipolar disorder (e.g., family history of bipolar disorder, suicide, or depression) . AUVELITY is not approved for use in treating bipolar depression

Psychosis and Other Neuropsychiatric Reactions AUVELITY contains bupropion. Depressed patients treated with bupropion have had a variety of neuropsychiatric signs and symptoms, including delusions, hallucinations, psychosis, concentration disturbance, paranoia, and confusion. Some of these patients had a diagnosis of bipolar disorder. In some cases, these symptoms abated upon dose reduction and/or withdrawal of treatment. AUVELITY contains dextromethorphan. Dextromethorphan overdose can cause toxic psychosis, stupor, coma, and hyperexcitability . Because the risks of neuropsychiatric reactions are dose-related, screen patients for use of other bupropion- or dextromethorphan-containing products prior to initiating AUVELITY. If concomitant use of AUVELITY with other bupropion- or dextromethorphan-containing products is clinically warranted, monitor patients for neuropsychiatric reactions and instruct patients to contact a healthcare provider if such reactions occur

Angle-Closure Glaucoma The pupillary dilation that occurs following use of many antidepressant drugs including bupropion, a component of AUVELITY, may trigger an angle closure attack in a patient with anatomically narrow angles who does not have a patent iridectomy. Avoid use of antidepressants, including AUVELITY, in patients with untreated anatomically narrow angles

Dizziness AUVELITY may cause dizziness . In controlled studies of AUVELITY, 14% of patients receiving AUVELITY and 6% of patients on placebo experienced dizziness. Take precautions to reduce the risk of falls, particularly for patients with motor impairment affecting gait or those with a history of falls. Caution patients about operating hazardous machinery, including motor vehicles, until they are reasonably certain that AUVELITY therapy does not affect them adversely

Serotonin Syndrome AUVELITY contains dextromethorphan. Concomitant use of AUVELITY with SSRIs or tricyclic antidepressants may cause serotonin syndrome, a potentially life-threatening condition with changes including altered mental status, hypertension, restlessness, myoclonus, hyperthermia, hyperreflexia, diaphoresis, shivering, and tremor . The concomitant use of AUVELITY with MAOIs is contraindicated. In addition, do not initiate AUVELITY in a patient being treated with MAOIs such as linezolid or intravenous methylene blue. If it is necessary to initiate treatment with an MAOI such as linezolid or intravenous methylene blue in a patient taking AUVELITY discontinue AUVELITY before initiating treatment with the MAOI . Prior to initiating AUVELITY, screen patients for use of other dextromethorphan-containing products . If concomitant use of AUVELITY with other serotonergic drugs is clinically warranted, inform patients of the increased risk for serotonin syndrome and monitor for symptoms. Discontinue AUVELITY and/or concomitant serotonergic drug immediately if the above symptoms occur, and initiate supportive symptomatic treatment

Embryo-fetal Toxicity Based on animal studies, AUVELITY may cause fetal harm when administered during pregnancy. In developmental toxicity studies in rats and rabbits, when a combination of dextromethorphan/quinidine was given to pregnant animals, fetal malformations (rabbits) and embryolethality were demonstrated in offspring. Neurotoxicity findings were observed in juvenile rats treated with a combination of dextromethorphan/quinidine on postnatal day (PND) 7, which corresponds to the third trimester of gestation through the first few months of life and may extend through the first three years of life in humans. The separate effect of dextromethorphan on developmental toxicity at the recommended clinical dose is unclear. Discontinue treatment in pregnant females and advise the patient about the potential risk to a fetus. Use alternative treatment for females who are planning to become pregnant .

Strong CYP2D6 inhibitors: Recommended dosage is one tablet by mouth once daily in the morning. Strong CYP2B6 inducers: Avoid use. CYP2D6 Substrates: Increases the exposures of drugs that are substrates of CYP2D6. Digoxin: May decrease plasma digoxin levels. Monitor digoxin levels. Drugs that lower seizure threshold: Coadministration may increase risk of seizure. Dopaminergic drugs: Central Nervous System (CNS) toxicity can occur with concomitant use. Drug-laboratory test interactions: AUVELITY can cause false-positive urine test results for amphetamines

Drugs Having Clinically Important Interactions with AUVELITY Table 3: Clinically Important Drug Interactions with AUVELITY Monoamine Oxidase Inhibitors (MAOIs) Clinical Impact Concomitant use of AUVELITY with MAOIs increases the risk of hypertensive crisis and serotonin syndrome. Intervention AUVELITY is contraindicated in patients taking MAOIs (including MAOIs such as linezolid or intravenous methylene blue) or in patients who have taken MAOIs within the preceding 14 days. Allow at least 14 days after stopping AUVELITY before starting an MAOI Serotonergic Drugs Clinical Impact Concomitant use of AUVELITY with other serotonergic drugs increases the risk of serotonin syndrome. Intervention Monitor for symptoms of serotonin syndrome when AUVELITY is used concomitantly with other drugs that may affect the serotonergic neurotransmitter systems. If serotonin syndrome occurs, consider discontinuation of AUVELITY and/or concomitant serotonergic drug . Drugs that Lower Seizure Threshold Clinical Impact AUVELITY contains bupropion which can cause seizure. Co-administration with other drugs that lower seizure threshold may increase risk of seizure. Intervention Use caution when administering AUVELITY concomitantly with drugs that lower the seizure threshold . Discontinue AUVELITY and do not restart treatment if the patient experiences a seizure. Strong Inhibitors of CYP2D6 Clinical Impact Concomitant use of AUVELITY with strong CYP2D6 inhibitors increases plasma concentrations of dextromethorphan. Intervention Dosage adjustment is necessary when AUVELITY is co-administered with strong inhibitors of CYP2D6 . Monitor patients for adverse reactions potentially attributable to dextromethorphan, such as somnolence and dizziness. Strong Inducers of CYP2B6 Clinical Impact Concomitant use of AUVELITY with strong CYP2B6 inducers decreases plasma concentrations of dextromethorphan and bupropion and may decrease efficacy of AUVELITY . Intervention Avoid co-administration of AUVELITY with strong inducers of CYP2B6. Consider alternatives to strong CYP2B6 inducers if needed. Drugs Metabolized by CYP2D6 Clinical Impact CYP2D6 Substrates Coadministration of AUVELITY with drugs that are metabolized by CYP2D6 can increase the exposures of drugs that are substrates of CYP2D6. Drugs that Require Metabolic Activation by CYP2D6 Drugs that require metabolic activation by CYP2D6 to be effective could have reduced efficacy when administered concomitantly with AUVELITY. Intervention CYP2D6 Substrates When used concomitantly with AUVELITY, it may be necessary to decrease the dose of CYP2D6 substrates, particularly for drugs with a narrow therapeutic index. Drugs that Require Metabolic Activation by CYP2D6 Patients treated concomitantly with AUVELITY may require increased doses of drugs that require activation by CYP2D6 to be effective. Digoxin Clinical Impact Coadministration of AUVELITY with digoxin may decrease plasma digoxin levels. Intervention Monitor plasma digoxin levels in patients treated concomitantly with AUVELITY and digoxin . Dopaminergic Drugs Clinical Impact CNS toxicity was reported when bupropion was co-administered with levodopa or amantadine. Adverse reactions include restlessness, agitation, tremor, ataxia, gait disturbance, vertigo, and dizziness. Intervention Use caution when administering AUVELITY concomitantly with dopaminergic drugs. Alcohol Clinical Impact AUVELITY contains bupropion which can increase adverse neuropsychiatric events or reduce alcohol tolerance. Intervention Consumption of alcohol should be minimized or avoided during treatment with AUVELITY

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.