SUNOSI

1 INDICATIONS AND USAGE SUNOSI is indicated to improve wakefulness in adult patients with excessive daytime sleepiness associated with narcolepsy or obstructive sleep apnea (OSA) [see Clinical Studies ( 14 )] . Limitations of Use SUNOSI is not indicated to treat the underlying airway obstruction in OSA. Ensure that the underlying airway obstruction is treated (e.g., with continuous positive airway pressure (CPAP)) for at least one month prior to initiating SUNOSI for excessive daytime sleepiness. Modalities to treat the underlying airway obstruction should be continued during treatment with SUNOSI. SUNOSI is not a substitute for these modalities. SUNOSI is a dopamine and norepinephrine reuptake inhibitor (DNRI) indicated to improve wakefulness in adult patients with excessive daytime sleepiness associated with narcolepsy or obstructive sleep apnea (OSA). ( 1 ) Limitations of Use SUNOSI is not indicated to treat the underlying airway obstruction in OSA. Ensure that the underlying airway obstruction is treated (e.g., with continuous positive airway pressure (CPAP)) for at least one month prior to initiating SUNOSI for excessive daytime sleepiness. Modalities to treat the underlying airway obstruction should be continued during treatment with SUNOSI. SUNOSI is not a substitute for these modalities. ( 1 )

2 DOSAGE AND ADMINISTRATION Administer once daily upon awakening. Avoid administration within 9 hours of planned bedtime because of the potential to interfere with sleep. ( 2.2 ) Starting dose for patients with narcolepsy: 75 mg once daily. ( 2.3 ) Starting dose for patients with OSA: 37.5 mg once daily. ( 2.4 ) Dose may be increased at intervals of at least 3 days. ( 2.3 , 2.4 ) Maximum dose is 150 mg once daily. ( 2.3 , 2.4 ) Renal impairment ( 2.5 , 8.6 , 12.3 ): Moderate impairment: Starting dose is 37.5 mg once daily. May increase to 75 mg once daily after at least 7 days. Severe impairment: Starting dose and maximum dose is 37.5 mg once daily. End stage renal disease (ESRD): Not recommended. 2.1 Important Considerations Prior to Initiating Treatment Prior to initiating treatment with SUNOSI, ensure blood pressure is adequately controlled [see Warnings and Precautions ( 5.1 )] . 2.2 General Administration Instructions Administer SUNOSI orally upon awakening with or without food. Avoid taking SUNOSI within 9 hours of planned bedtime because of the potential to interfere with sleep if taken too late in the day. SUNOSI 75 mg tablets are functionally scored tablets that can be split in half (37.5 mg) at the score line. 2.3 Dosage in Narcolepsy Initiate SUNOSI at 75 mg once daily in adults with narcolepsy. The recommended dose range for SUNOSI is 75 mg to 150 mg once daily. Based on efficacy and tolerability, the dosage of SUNOSI may be doubled at intervals of at least 3 days. The maximum recommended dose is 150 mg once daily. Dosages above 150 mg daily do not confer increased effectiveness sufficient to outweigh dose-related adverse reactions [see Warnings and Precautions ( 5.1 )] . 2.4 Dosage in OSA Initiate SUNOSI at 37.5 mg once daily in adults with OSA. The recommended dosage range for SUNOSI is 37.5 mg to 150 mg once daily. Based on efficacy and tolerability, the dosage of SUNOSI may be doubled at intervals of at least 3 days. The maximum recommended dosage is 150 mg once daily. Dosages above 150 mg daily do not confer increased effectiveness sufficient to outweigh dose-related adverse reactions [see Warnings and Precautions ( 5.1 )] . 2.5 Dosage Recommendations in Patients with Renal Impairment Moderate renal impairment (eGFR 30-59 mL/min/1.73 m 2 ) : Initiate dosing at 37.5 mg once daily. Based on efficacy and tolerability, dose may be increased to a maximum of 75 mg once daily after at least 7 days [see Use in Specific Populations ( 8.6 ), Clinical Pharmacology ( 12.3 )] . Severe renal impairment (eGFR 15-29 mL/min/1.73 m 2 ) : Administer 37.5 mg once daily. The maximum recommended daily dose is 37.5 mg [see Use in Specific Populations ( 8.6 ), Clinical Pharmacology ( 12.3 )] . End Stage Renal Disease (eGFR <15 mL/min/1.73 m 2 ) : SUNOSI is not recommended for use in patients with ESRD [see Use in Specific Populations ( 8.6 ), Clinical Pharmacology ( 12.3 )] .

3 DOSAGE FORMS AND STRENGTHS SUNOSI 75 mg – (75 mg solriamfetol equivalent to 89.3 mg of the hydrochloride salt) dark yellow oblong tablet with "75" debossed on one side and a functional score line on the opposite side. SUNOSI 150 mg – (150 mg solriamfetol equivalent to 178.5 mg of the hydrochloride salt) yellow oblong tablet with "150" debossed on one side. Tablets: 75 mg (functionally scored) and 150 mg. ( 3 )

4 CONTRAINDICATIONS SUNOSI is contraindicated in patients receiving concomitant treatment with monoamine oxidase (MAO) inhibitors, or within 14 days following discontinuation of monoamine oxidase inhibitor, because of the risk of hypertensive reaction [see Drug Interactions ( 7.1 )] . Concurrent treatment with a monoamine oxidase inhibitor (MAOI) or use of an MAOI within the preceding 14 days. ( 4 )

6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the label: Blood Pressure and Heart Rate Increases [see Warnings and Precautions ( 5.1 )] Psychiatric Symptoms [see Warnings and Precautions ( 5.2 )] Most common adverse reactions (≥ 5% and greater than placebo): headache, nausea, decreased appetite, insomnia, and anxiety. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Axsome Therapeutics, Inc. 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 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. The safety of SUNOSI has been evaluated in 930 patients (ages 18 to 75 years) with narcolepsy or OSA. Among these patients, 396 were treated with SUNOSI in the 12-week placebo-controlled trials at doses of 37.5 mg (OSA only), 75 mg, and 150 mg once daily. Information provided below is based on the pooled 12-week placebo-controlled studies in patients with narcolepsy or OSA. Most Common Adverse Reactions The most common adverse reactions (incidence ≥ 5% and greater than placebo) reported more frequently with the use of SUNOSI than placebo in either the narcolepsy or OSA populations were headache, nausea, decreased appetite, anxiety, and insomnia. Table 1 presents the adverse reactions that occurred at a rate of ≥ 2% and more frequently in SUNOSI-treated patients than in placebo-treated patients in the narcolepsy population. Table 1: Adverse Reactions ≥ 2% in Patients Treated with SUNOSI and Greater than Placebo in Pooled 12-Week Placebo-Controlled Clinical Trials in Narcolepsy (75 mg and 150 mg) * “Insomnia” includes insomnia, initial insomnia, middle insomnia, and terminal insomnia. “Anxiety” includes anxiety, nervousness, and panic attack. “Headache” includes headache, tension headache, and head discomfort. “Nausea” includes nausea and vomiting. Narcolepsy System Organ Class Placebo N = 108 (%) SUNOSI N = 161 (%) Metabolism and Nutrition Disorders Decreased appetite 1 9 Psychiatric Disorders Insomnia* Anxiety* 4 1 5 6 Nervous System Disorders Headache* 7 16 Cardiac Disorders Palpitations 1 2 Gastrointestinal Disorders Nausea* Dry mouth Constipation 4 2 1 7 4 3 Table 2 presents the adverse reactions that occurred at a rate of ≥ 2% and more frequently in SUNOSI-treated patients than in placebo-treated patients in the OSA population. Table 2: Adverse Reactions ≥ 2% in Patients Treated with SUNOSI and Greater than Placebo in Pooled 12-Week Placebo-Controlled Clinical Trials in OSA (37.5 mg, 75 mg, and 150 mg) * “Anxiety” includes anxiety, nervousness, and panic attack. “Nausea” includes nausea and vomiting. “Abdominal pain” includes abdominal pain, abdominal pain upper, and abdominal discomfort. OSA System Organ Class Placebo N = 118 (%) SUNOSI N = 235 (%) Metabolism and Nutrition Disorders Decreased appetite 1 6 Psychiatric Disorders Anxiety* Irritability 1 0 4 3 Nervous System Disorders Dizziness 1 2 Cardiac Disorders Palpitations 0 3 Gastrointestinal Disorders Nausea* Diarrhea Abdominal pain* Dry mouth 6 1 2 2 8 4 3 3 General Disorders and Administration Site Conditions Feeling jittery Chest discomfort 0 0 3 2 Skin and Subcutaneous Tissue Disorders Hyperhidrosis 0 2 Other Adverse Reactions Observed During the Premarketing Evaluation of SUNOSI Other adverse reactions of < 2% incidence but greater than placebo are shown below. The following list does not include adverse reactions: 1) already listed in previous tables or elsewhere in the labeling, 2) for which a drug cause was remote, 3) which were so general as to be uninformative, or 4) which were not considered to have clinically significant implications. Narcolepsy population: Psychiatric disorders : agitation, bruxism, irritability Respiratory, thoracic and mediastinal d …

7 DRUG INTERACTIONS Drugs that Increase Blood Pressure and/or Heart Rate and Dopaminergic Drugs : Use caution when co-administering with SUNOSI. ( 7.2 , 7.3 ) 7.1 Monoamine Oxidase (MAO) Inhibitors Do not administer SUNOSI concomitantly with MAOIs or within 14 days after discontinuing MAOI treatment. Concomitant use of MAO inhibitors and noradrenergic drugs may increase the risk of a hypertensive reaction. Potential outcomes include death, stroke, myocardial infarction, aortic dissection, ophthalmological complications, eclampsia, pulmonary edema, and renal failure [see Contraindications ( 4 )]. 7.2 Drugs that Increase Blood Pressure and/or Heart Rate Concomitant use of SUNOSI with other drugs that increase blood pressure and/or heart rate has not been evaluated, and such combinations should be used with caution [see Warnings and Precautions ( 5.1 )]. 7.3 Dopaminergic Drugs Dopaminergic drugs that increase levels of dopamine or that bind directly to dopamine receptors might result in pharmacodynamic interactions with SUNOSI. Interactions with dopaminergic drugs have not been evaluated with SUNOSI. Use caution when concomitantly administering dopaminergic drugs with SUNOSI.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to SUNOSI during pregnancy. Healthcare providers are encouraged to register pregnant patients, or pregnant women may enroll themselves in the registry by calling 1-877-283-6220 or contacting the company at www.SunosiPregnancyRegistry.com . Risk Summary Available data from case reports are not sufficient to determine drug-associated risks of major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal reproductive studies, oral administration of solriamfetol during organogenesis caused maternal and fetal toxicities in rats and rabbits at doses ≥ 4 and 5 times and was teratogenic at doses 19 and ≥ 5 times, respectively, the maximum recommended human dose (MRHD) of 150 mg based on mg/m 2 body surface area. Oral administration of solriamfetol to pregnant rats during pregnancy and lactation at doses ≥ 7 times the MRHD based on mg/m 2 body surface area resulted in maternal toxicity and adverse effects on fertility, growth, and development in offspring (see Data ). 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 risks of major birth defects and miscarriage in clinically recognized pregnancies are 2% to 4% and 15% to 20%, respectively. Data Animal Data Solriamfetol was administered orally to pregnant rats during the period of organogenesis at 15, 67, and 295 mg/kg/day, which are approximately 1, 4, and 19 times the MRHD based on mg/m 2 body surface area. Solriamfetol at ≥ 4 times the MRHD caused maternal toxicity that included hyperactivity, significant decreases in body weight, weight gain, and food consumption. Fetal toxicity at these maternally toxic doses included increased incidence of early resorption and post-implantation loss, and decreased fetal weight. Solriamfetol was teratogenic at 19 times the MRHD; it increased the incidence of fetal malformations that included severe sternebrae mal-alignment, hindlimb rotation, bent limb bones, and situs inversus. This dose was also maternally toxic. The no-adverse-effect level for malformation is 4 times and for maternal and embryofetal toxicity is approximately 1 times the MRHD based on mg/m 2 body surface area. Solriamfetol was administered orally to pregnant rabbits during the period of organogenesis at 17, 38, and 76 mg/kg/day, which are approximately 2, 5, and 10 times the MRHD based on mg/m 2 body surface area. Solriamfetol at 10 times the MRHD caused maternal toxicity of body weight loss and decreased food consumption. Solriamfetol was teratogenic at ≥ 5 times the MRHD, it caused fetal skeletal malformation (slight-to-moderate sternebrae mal-alignment) and decreased fetal weight. The no-adverse-effect level for malformation and fetal toxicity is approximately 2 times and for maternal toxicity is approximately 5 times the MRHD based on mg/m 2 body surface area. Solriamfetol was administered orally to pregnant rats during the period of organogenesis from gestation day 7 through lactation day 20 post-partum, at 35, 110, and 350 mg/kg/day, which are approximately 2, 7, and 22 times the MRHD based on mg/m 2 body surface area. At ≥ 7 times the MRHD, solriamfetol caused maternal toxicity that included decreased body weight gain, decreased food consumption, and hyperpnea. At these maternally toxic doses, fetal toxicity included increased incidence of stillbirth, postnatal pup mortality, and decreased pup weight. Developmental toxicity in offspring after lactation day 20 included decreased body weight, decreased weight gain, and delayed sexual maturation. Mating and fertility of offspring were decreased at maternal doses 22 times the MRHD without affecting learning and memory. The no-adverse-effect level …

12.1 Mechanism of Action The mechanism of action of solriamfetol to improve wakefulness in patients with excessive daytime sleepiness associated with narcolepsy or obstructive sleep apnea is unclear. However, its efficacy could be mediated through its activity as a dopamine and norepinephrine reuptake inhibitor (DNRI).

11 DESCRIPTION SUNOSI contains solriamfetol, a dopamine and norepinephrine reuptake inhibitor (DNRI). Solriamfetol is a phenylalanine derivative with the systematic name ( R )-2-amino-3-phenylpropylcarbamate hydrochloride. The molecular formula is C 10 H 15 N 2 O 2 Cl, and the molecular weight is 230.69. The chemical structure is: Solriamfetol hydrochloride is a white to off-white solid that is freely soluble in water. SUNOSI tablets are intended for oral administration. Each 75 mg SUNOSI film-coated tablet contains 75 mg solriamfetol (equivalent to 89.3 mg solriamfetol hydrochloride). Each 150 mg SUNOSI film-coated tablet contains 150 mg solriamfetol (equivalent to 178.5 mg solriamfetol hydrochloride). The inactive ingredients are hydroxypropyl cellulose and magnesium stearate. In addition, the film coating contains: iron oxide yellow, polyethylene glycol, polyvinyl alcohol, talc, and titanium dioxide. Chemical Structure

10 OVERDOSAGE A specific reversal agent for SUNOSI is not available. Hemodialysis removed approximately 21% of a 75 mg dose in end stage renal disease patients. Overdoses should be managed with primarily supportive care, including cardiovascular monitoring. Consult with a Certified Poison Control Center at 1-800-222-1222 for latest recommendations.

16 HOW SUPPLIED / STORAGE AND HANDLING How Supplied SUNOSI is packaged in 30-count white, high density polyethylene (HDPE) bottles. SUNOSI tablets, 75 mg - dark yellow oblong tablet with "75" debossed on one side and a functional score line on the opposite side. NDC 81968-350-01: Bottles of 30 with child-resistant closure SUNOSI tablets, 150 mg - yellow oblong tablet with "150" debossed on one side. NDC 81968-351-01: Bottles of 30 with child-resistant closure Storage Store SUNOSI at 20 to 25°C (68°to 77°F); excursions permitted between 15°to 30°C (59°to 86°F) (see USP controlled room temperature).