AUVELITY

1 INDICATIONS AND USAGE 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 ( 1.1 ) the treatment of agitation associated with dementia due to Alzheimer’s disease ( 1.2 ) Limitations of Use: AUVELITY is not indicated as an as needed (“prn”) treatment for agitation associated with dementia due to Alzheimer’s disease (1.2). 1.1 Major Depressive Disorder AUVELITY is indicated for the treatment of major depressive disorder (MDD) in adults. 1.2 Agitation Associated with Dementia Due to Alzheimer’s Disease AUVELITY is indicated for the treatment of agitation associated with dementia due to Alzheimer’s disease. Limitations of Use: AUVELITY is not indicated as an as needed (“prn”) treatment for agitation associated with dementia due to Alzheimer’s disease [see Clinical Studies Section 14.2 ].

2 DOSAGE AND ADMINISTRATION 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. ( 2.1 ) For MDD, the starting dosage is AUVELITY 45 mg/105 mg once daily in the morning. On day 4, increase to the maximum recommended dosage of AUVELITY 45 mg/105 mg twice daily, separated by at least 8 hours. Do not exceed two doses within the same day. ( 2.2 ) For agitation associated with dementia due to Alzheimer’s disease, the starting dosage is AUVELITY 30 mg/105 mg once daily in the morning. On day 8, increase to AUVELITY 30 mg/105 mg twice daily, separated by at least 8 hours, based on tolerability. On day 15, increase to the maximum recommended dosage of AUVELITY 45 mg/105 mg twice daily, separated by at least 8 hours, based on tolerability. Do not exceed two doses within the same day. ( 2.3 ) Swallow tablets whole, do not crush, divide, or chew. ( 2.2 , 2.3 ) Moderate renal impairment: For patients with MDD or agitation associated with dementia due to Alzheimer’s disease, the maximum recommended dosage is one tablet of 45 mg/105 mg by mouth once daily in the morning. ( 2.4 , 8.6 ) CYP2D6 poor metabolizers: For patients with MDD or agitation associated with dementia due to Alzheimer’s disease, the maximum recommended dosage is one tablet of 45 mg/105 mg by mouth once daily in the morning. ( 2.6 , 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 [see Warnings and Precautions ( 5.3 )] . screen patients for a personal or family history of bipolar disorder, mania, or hypomania [see Warnings and Precautions ( 5.4 )] . screen patients to determine if they are receiving any other medications that contain bupropion or dextromethorphan [see Warnings and Precautions ( 5.2 , 5.5 , 5.8 )] . 2.2 Recommended Dosage for the Treatment of Major Depressive Disorder The recommended starting dosage ofis AUVELITY (45 mg of dextromethorphan hydrobromide and /105 mg of bupropion hydrochloride) is one tablet once daily in the morning. After 3 daysOn day 4, 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 [see Clinical Pharmacology ( 12.3 )] . Swallow tablets whole, do not crush, divide, or chew. 2.3 Recommended Dosage for Treatment of Agitation Associated with Dementia Due to Alzheimer’s Disease The recommended titration schedule is as follows: The recommended starting dose is AUVELITY 30 mg/105 mg once daily, in the morning. On day 8, increase to AUVELITY 30 mg/105 mg twice daily, given at least 8 hours apart, based on tolerability. On day 15, after starting AUVELITY, increase to the maximum recommended dosage of 45 mg/105 mg twice daily, given at least 8 hours apart, based on tolerability. Do not exceed two doses within the same day. Administer AUVELITY orally with or without food [see Clinical Pharmacology ( 12.3 )]. Swallow tablets whole, do not crush, divide, or chew. 2.4 Dosage Recommendations in Patients with Renal Impairment For patients with moderate renal impairment (eGFR 30 to 59 mL/minute/1.73 m²), the dosing recommendations for AUVELITY are as follows: For patients with MDD, the recommended starting and maximum dosage is 45 mg/105 mg once daily in the morning [see Use in Specific Populations ( 8.6 ), Clinical Pharmacology ( 12.3 )]. For patients with Agitation Associated with Dementia due to Alzheimer’s Disease, the recommended starting dosage is 30 mg/105 mg once daily in the morning. On day 8, increase to the maximum recommended dosage of 45 mg/105 mg once daily in the morning, based on tolerability [see Use in Specific Populations ( 8.6 ), Clinical Ph…

5 WARNINGS AND PRECAUTIONS Seizure: Risk is dose-related. Discontinue if seizure occurs. ( 4 , 5.2 ) Increased Blood Pressure and Hypertension: AUVELITY can increase blood pressure and cause hypertension. Assess blood pressure before initiating treatment and monitor periodically during treatment. ( 5.3 ) Activation of Mania or Hypomania: Screen patients for bipolar disorder. ( 5.4 ) Psychosis and Other Neuropsychiatric Reactions: Instruct patients to contact a healthcare provider if such reactions occur. ( 5.5 ) Angle-Closure Glaucoma: Angle-closure glaucoma has occurred in patients with untreated anatomically narrow angles treated with antidepressants. ( 5.6 ) Dizziness: AUVELITY may cause dizziness. Take precautions to reduce falls and use caution when operating machinery. ( 5.7 ) Serotonin Syndrome: Use of AUVELITY with selective serotonin reuptake inhibitors (SSRIs) or tricyclic antidepressants increases the risk. Discontinue if occurs. ( 5.8 , 7.1 ) 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 ) Hyponatremia: Can occur in association with SIADH. ( 5.10 ) 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. 5.2 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/…

4 CONTRAINDICATIONS AUVELITY is contraindicated in patients: with a seizure disorder [see Warnings and Precautions ( 5.2 )] . with a current or prior diagnosis of bulimia or anorexia nervosa as a higher incidence of seizures was observed in such patients treated with the immediate-release formulation of bupropion [see Warnings and Precautions ( 5.2 )] . undergoing abrupt discontinuation of alcohol, benzodiazepines, barbiturates, and antiepileptic drugs [see Warnings and Precautions ( 5.2 ), Drug Interactions ( 7.1 )] . taking, or within 14 days of stopping, MAOIs due to the risk of serious and possibly fatal drug interactions, including hypertensive crisis and serotonin syndrome [see Dosage and Administration ( 2.7 ), Warnings and Precautions ( 5.8 ), Drug Interactions ( 7.1 )] . Starting AUVELITY in a patient treated with reversible MAOIs such as linezolid or intravenous methylene blue is contraindicated. with known hypersensitivity to bupropion, dextromethorphan, or other components of AUVELITY. Anaphylactoid/anaphylactic reactions and Stevens-Johnson syndrome have been reported with bupropion. Arthralgia, myalgia, fever with rash, and other serum sickness-like symptoms suggestive of delayed hypersensitivity have also been reported with bupropion [see Adverse Reactions ( 6.2 )] . Seizure disorder. ( 4 ) Current or prior diagnosis of bulimia or anorexia nervosa. ( 4 ) Abrupt discontinuation of alcohol, benzodiazepines, barbiturates, and antiepileptic drugs. ( 4 ) Use with an MAOI or within 14 days of stopping treatment with AUVELITY. Do not use AUVELITY within 14 days of discontinuing an MAOI. ( 4 ) Known hypersensitivity to bupropion, dextromethorphan, or other components of AUVELITY. ( 4 )

7 DRUG INTERACTIONS Strong CYP2D6 inhibitors: For patients with MDD or agitation associated with dementia due to Alzheimer’s disease, maximum recommended dosage is one tablet of 45 mg dextromethorphan hydrobromide/105 mg bupropion hydrochloride by mouth once daily in the morning. ( 2.5 , 7.1 ) Strong CYP2B6 inducers: Avoid use. ( 7.1 ) CYP2D6 Substrates: Increases the exposures of drugs that are substrates of CYP2D6. ( 7.1 ) Digoxin: May decrease plasma digoxin levels. Monitor digoxin levels. ( 7.1 ) Drugs that lower seizure threshold: Coadministration may increase risk of seizure. ( 7.1 ) Dopaminergic drugs: Central Nervous System (CNS) toxicity can occur with concomitant use. ( 7.1 ) Drug-laboratory test interactions: AUVELITY can cause false-positive urine test results for amphetamines. ( 7.2 ) 7.1 Drugs Having Clinically Important Interactions with AUVELITY Table 4: 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 [see Dosage and Administration ( 2.7 ), Contraindications ( 4 ), Warnings and Precautions ( 5.3 , 5.8 )] 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 [see Dosage and Administration ( 2.1 ), Warnings and Precautions ( 5.8 )] . 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 [see Warnings and Precautions ( 5.2 )] . 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 [see Dosage and Administration ( 2.5 )] . 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 [see Clinical Pharmacology ( 12.3 )] . 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 …

8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antidepressants, including AUVELITY, during pregnancy. Healthcare providers are encouraged to register patients by contacting the National Pregnancy Registry for Antidepressants at 1-866-961-2388 or online at: https://womensmentalhealth.org/research/pregnancyregistry/antidepressants/ . Risk Summary Based on animal studies, AUVELITY may cause fetal harm when administered during pregnancy. AUVELITY is not recommended during pregnancy. If a female becomes pregnant while being treated with AUVELITY, discontinue treatment and counsel the patient about the potential risk to a fetus [see Warnings and Precautions ( 5.9 )] . In oral studies conducted in rats and rabbits, a combination of dextromethorphan/quinidine demonstrated developmental toxicity, including fetal malformations (rabbits) and embryolethality, when given to pregnant animals. When bupropion alone was administered to pregnant rats during organogenesis, there was no evidence of fetal malformations at doses up to approximately 21 times the maximum recommended human dose (MRHD) of 210 mg/day. When bupropion alone was given to pregnant rabbits during organogenesis, non-dose–related increases in incidence of fetal malformations, and skeletal variations were observed at doses approximately 2 to 5 times the MRHD and greater. Decreased fetal weights were seen at bupropion doses approximately 5 times the MRHD and greater. 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. Based on these findings, AUVELITY may cause fetal harm when administered to pregnant women (see Data ) . The available clinical data on the use of AUVELITY during pregnancy is insufficient to evaluate for a drug-associated risk of major birth malformations, miscarriage, or other adverse maternal or fetal outcomes. However, there are available data on one of the individual components of AUVELITY, bupropion. 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 ) . The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. 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 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 Bupropion 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 o…

6 ADVERSE REACTIONS The following adverse reactions are discussed in more detail in other sections of the labeling: Suicidal Thoughts and Behaviors in Adolescents and Young Adults [see Warnings and Precautions ( 5.1 )] Seizure [see Warnings and Precautions ( 5.2 )] Increased Blood Pressure and Hypertension [see Warnings and Precautions ( 5.3 )] Activation of Mania or Hypomania [see Warnings and Precautions ( 5.4 )] Psychosis and Other Neuropsychiatric Reactions [see Warnings and Precautions ( 5.5 )] Angle-closure Glaucoma [see Warnings and Precautions ( 5.6 )] Dizziness [see Warnings and Precautions ( 5.7 )] Serotonin Syndrome [see Warnings and Precautions ( 5.8 )] Embryo-fetal Toxicity [see Warnings and Precautions ( 5.9 )] Hyponatremia [see Warnings and Precautions ( 5.10 )] MDD: Most common adverse reactions (≥5% and more than twice as frequently as placebo): dizziness, headache, diarrhea, somnolence, dry mouth, sexual dysfunction, and hyperhidrosis. (6.1) Agitation associated with dementia due to Alzheimer’s disease: Most common adverse reactions (≥5% and more than twice as frequently as placebo): dizziness and dyspepsia. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Axsome Therapeutics at 1-800-484-1672 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. AUVELITY has been evaluated for safety in 2,550 adult patients who participated in multiple-dose clinical trials for major depressive disorder, agitation associated with dementia due to Alzheimers disease, or another indication. Among them, 918 patients were treated with AUVELITY for at least 6 months, and 251 patients were treated with AUVELITY for at least 1 year. Major Depressive Disorder The data below are based on the 6-week, placebo-controlled study in which either AUVELITY (n=162) or placebo (n=164) was administered twice daily to patients with MDD (Study 1). Demographics of the patients who participated in this study are summarized in Clinical Studies [see Clinical Studies (Section 14.1 )]. Adverse Reactions Leading to Discontinuation In the 6-week placebo-controlled study, 4% of patients treated with AUVELITY and 0% of placebo-treated patients discontinued participation due to adverse reactions. The adverse reaction that led to study discontinuation in 1% of patients treated with AUVELITY was anxiety (2%). Most Common Adverse Reactions In the 6-week placebo-controlled clinical study, the most common (incidence 5% for AUVELITY and more than twice as frequently as placebo) adverse reactions were dizziness (16%), headache (8%), diarrhea (7%), somnolence (7%), dry mouth (6%), sexual dysfunction (6%), and hyperhidrosis (5%). Table 2 shows the incidence of adverse reactions that occurred in 2% of patients treated with AUVELITY and more frequently than in patients treated with placebo in Study 1. Table 2: Adverse Reactions Occurring in ≥2% of Adult Patients with MDD Treated with AUVELITY and More Frequently than in Patients Treated with Placebo in a 6-Week Placebo-Controlled Study (Study 1) a Sexual dysfunction includes orgasm abnormal, erectile dysfunction, libido decreased, anorgasmia b Fatigue includes fatigue, lethargy c Paraesthesia includes paraesthesia, hypoaesthesia Adverse Reaction AUVELITY (N=162) % Placebo (N=164) % Dizziness 16 6 Nausea 13 9 Headache 8 4 Diarrhea 7 3 Somnolence 7 3 Dry mouth 6 2 Sexual dysfunction a 6 0 Hyperhidrosis 5 0 Anxiety 4 1 Constipation 4 2 Decreased appetite 4 1 Insomnia 4 2 Arthralgia 3 0 Fatigue b 3 2 Paraesthesia c 3 0 Vision blurred 3 0 Agitation Associated with Dementia Due to Alzheimers Disease The data below are based on the 5-week, placebo-controlled, parallel-group study in which either AUVELITY (n=159) or placebo (n=1…