Solriamfetol

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 )] .

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 disorders : cough Skin and subcutaneous tissue disorders : hyperhidrosis General disorders and administration site conditions : feeling jittery, thirst, chest discomfort, chest pain Investigations : weight decreased OSA population: Psychiatric disorders : bruxism, restlessness Nervous system disorders : disturbance in attention, tremor Respiratory, thoracic and mediastinal disorders : cough, dyspnea Gastrointestinal disorders : constipation, vomiting Investigations : weight decreased Dose-Dependent Adverse Reactions In the 12-week placebo-controlled clinical trials that compared doses of 37.5 mg, 75 mg, and 150 mg daily of SUNOSI to placebo, the following adverse reactions were dose-related: headache, nausea, decreased appetite, anxiety, diarrhea, and dry mouth ( Table 3 ). Table 3: Dose-Dependent Adverse Reactions ≥ 2% in Patients Treated with SUNOSI and Greater than Placebo in Pooled 12-Week Placebo-Controlled Clinical Trials in Narcolepsy and OSA * In OSA only. ** “Headache” includes headache, tension headache, and head discomfort. “Nausea” includes nausea and vomiting. Placebo N = 226 (%) SUNOSI 37.5 mg N = 58* (%) SUNOSI 75 mg N = 120 (%) SUNOSI 150 mg N = 218 (%) Headache** 8 7 9 13 Nausea** 5 7 5 9 Decreased appetite 1 2 7 8 Anxiety 1 2 3 7 Dry mouth 2 2 3 4 Diarrhea 2 2 4 5 Adverse Reactions Resulting in Discontinuation of Treatment In the 12-week placebo-controlled clinical trials, 11 of the 396 patients (3%) who received SUNOSI discontinued because of an adverse reaction compared to 1 of the 226 patients (< 1%) who received placebo. The adverse reactions resulting in discontinuation that occurred in more than one SUNOSI-treated patient and at a higher rate than placebo were: anxiety (2/396; < 1%), palpitations (2/396; < 1%), and restlessness (2/396; < 1%). Increases in Blood Pressure and Heart Rate SUNOSI’s effects on blood pressure and heart rate are summarized below. Table 4 shows maximum mean changes in blood pressure and heart rate recorded at sessions where the Maintenance of Wakefulness Test (MWT) was administered [see Clinical Studies ( 14 )] . Table 5 summarizes 24-hour ambulatory blood pressure monitoring (ABPM) and ambulatory heart rate monitoring performed in the outpatient setting. Table 4: Maximal Mean Changes in Blood Pressure and Heart Rate Assessed at MWT Sessions from Baseline through Week 12: Mean (95% CI)* SBP = systolic blood pressure; DBP = diastolic blood pressure; HR = heart rate * For study weeks 1, 4, and 12, SBP, DBP, and HR were assessed pre-dose and every 1-2 hours for 10 hours after test drug administration. For all time points at all visits, the mean change from baseline was calculated, by indication and dose, for all patients with a valid assessment. The table shows, by indication and dose, the mean changes from baseline for the week and time point with the maximal change in SBP, DBP, and HR. ** The maximum recommended daily dose is 150 mg. Dosages above 150 mg daily do not confer increased effectiveness sufficient to outweigh dose-related adverse reactions. Placebo SUNOSI 37.5 mg SUNOSI 75 mg SUNOSI 150 mg SUNOSI 300 mg ** Narcolepsy STUDY 1 n 52 - 51 49 53 SBP 3.5 (0.7, 6.4) 3.1 (0.1, 6.0) 4.9 (1.7, 8.2) 6.8 (3.2, 10.3) n 23 - 47 49 53 DBP 1.8 (-1.8, 5.5) 2.2 (0.2, 4.1) 4.2 (2.0, 6.5) 4.2 (1.5, 6.9) n 48 - 26 49 53 HR 2.3 (-0.1, 4.7) 3.7 (0.4, 6.9) 4.9 (2.3, 7.6) 6.5 (3.9, 9.0) OSA STUDY 2 n 35 17 54 103 35 SBP 1.7 (-1.4, 4.9) 4.6 (-1.1, 10.2) 3.8 (1.2, 6.4) 2.4 (0.4, 4.4) 4.5 (1.1, 7.9) n 99 17 17 107 91 DBP 1.4 (-0.1, 2.9) 1.9 (-2.3, 6.0) 3.2 (-0.9, 7.3) 1.8 (0.4, 3.2) 3.3 (1.8, 4.8) n 106 17 51 102 91 HR 1.7 (0.1, 3.3) 1.9 (-1.9, 5.7) 3.3 (0.6, 6.0) 2.9 (1.4, 4.4) 4.5 (3.0, 6.0) Table 5: Blood Pressure and Heart Rate by 24-hour Ambulatory Monitoring: Mean Change (95% CI) from Baseline at Week 8 SBP = systolic blood pressure; DBP = diastolic blood pressure; HR = heart rate * Number of patients who had at least 50% valid ABPM readings. ** The maximum recommended daily dose is 150 mg. Dosages above 150 mg daily do not confer increased effectiveness sufficient to outweigh dose-related adverse reactions. Placebo SUNOSI 37.5 mg SUNOSI 75 mg SUNOSI 150 mg SUNOSI 300 mg ** Narcolepsy STUDY 1 n* 46 44 44 40 SBP -0.4 (-3.1, 2.4) - 1.6 (-0.4, 3.5) -0.5 (-2.1, 1.1) 2.4 (0.5, 4.3) DBP -0.2 (-1.9, 1.6) - 1.0 (-0.4, 2.5) 0.8 (-0.4, 2.0) 3.0 (1.4, 4.5) HR 0.0 (-1.9, 2.0) - 0.2 (-2.1, 2.4) 1.0 (-1.2, 3.2) 4.8 (2.3, 7.2) OSA STUDY 2 n* 92 43 49 96 84 SBP -0.2 (-1.8, 1.4) 1.8 (-1.1, 4.6) 2.6 (0.02, 5.3) -0.2 (-2.0, 1.6) 2.8 (-0.1, 5.8) DBP 0.2 (-0.9, 1.3) 1.4 (-0.4, 3.2) 1.5 (-0.04, 3.1) -0.1 (-1.1, 1.0) 2.4 (0.5, 4.4) HR -0.4 (-1.7, 0.9) 0.4 (-1.4, 2.2) 1.0 (-0.9, 2.81) 1.7 (0.5, 2.9) 1.6 (0.3, 2.9) 6.2 Postmarketing Experience The following adverse reactions have been reported during post-approval use of SUNOSI. 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: Immune system disorders : Hypersensitivity (rash erythematous, rash [unspecified], and urticaria).

12.3 Pharmacokinetics Solriamfetol exhibits linear kinetics over the dose range of 42 to 1008 mg (approximately 0.28 to 6.7 times the maximum recommended dosage). Steady state is reached in 3 days, and once‑daily administration is expected to result in minimal accumulation (1.06 times single‑dose exposure). Absorption The oral bioavailability of solriamfetol is approximately 95%. Peak plasma concentration of solriamfetol occurs at a median T max of 2 hours (range 1.25 to 3.0 hours) post-dose under fasted conditions. Effect of Food Ingestion of solriamfetol with a high-fat meal resulted in minimal change in C max and AUC inf ; however, a delay of approximately 1 hour in T max was observed. Distribution The apparent volume of distribution of solriamfetol is approximately 199 L. Plasma protein binding ranged from 13.3% to 19.4% over solriamfetol concentration range of 0.059 to 10.1 mcg/mL in human plasma. The mean blood‑to‑plasma concentration ratio ranged from 1.16 to 1.29. Elimination Solriamfetol exhibits first‑order elimination after oral administration. The apparent mean elimination half‑life is about 7.1 hours. Metabolism Solriamfetol is minimally metabolized in humans. Excretion Approximately 95% of the dose was recovered in urine as unchanged solriamfetol, and 1% or less of the dose was recovered as the minor inactive metabolite N‑acetyl solriamfetol in a mass balance study. Renal clearance (18.2 L/h) represented the majority of apparent total clearance (19.5 L/h). Active tubular secretion is likely involved in the renal elimination of the parent drug. Specific Populations Population PK analysis indicated that age, gender, and race do not have clinically relevant effects on the pharmacokinetics of solriamfetol. No dose adjustments were made in clinical studies that enrolled patients ages 65 and above. Patients with Renal Impairment Exposures to solriamfetol in patients with renal impairment compared to subjects with normal renal function (eGFR ≥ 90 mL/min/1.73 m 2 ) are summarized in Figure 1. The half‑life of solriamfetol was increased approximately 1.2‑, 1.9‑, and 3.9‑fold in patients with mild (eGFR 60‑89 mL/min/1.73 m 2 ), moderate (eGFR 30–59 mL/min/1.73 m 2 ), or severe (eGFR <30 mL/min/1.73 m 2 ) renal impairment, respectively. Exposure (AUC) and half-life of solriamfetol was significantly increased in patients with ESRD (eGFR <15 mL/min/1.73 m 2 ) [see Use in Specific Populations ( 8.6 )] . An average of 21% of solriamfetol was removed by hemodialysis. In general, median T max values were not affected by renal impairment. Figure 1: Effect of Renal Impairment on Solriamfetol Pharmacokinetics Drug Interaction Studies In Vitro Studies CYP and UGT Enzymes : Solriamfetol was minimally metabolized in vitro . Solriamfetol is not an inhibitor of CYPs 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, or 3A4. It does not induce CYP1A2, 2B6, 3A4, or UGT1A1 enzymes at clinically relevant concentrations. Transporter Systems : Solriamfetol is a low-avidity substrate of OCT2, MATE1, OCTN1, and OCTN2. Solriamfetol is a weak inhibitor of OCT2 (IC 50 of 146 μM) and MATE1 (IC 50 of 211 μM), and is not an inhibitor of OCT1, MATE2-K, OCTN1, or OCTN2. Solriamfetol does not appear to be a substrate or inhibitor of P-gp, BCRP, OATP1B1, OATP1B3, OAT1, or OAT3. Based on in vitro data, clinically significant PK drug interactions with major CYPs and transporters are not expected in patients taking SUNOSI. Figure 1