Solriamfetol

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 )

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 )] .

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 )

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 )

5 WARNINGS AND PRECAUTIONS Blood Pressure and Heart Rate Increases : Measure heart rate and blood pressure prior to initiating and periodically throughout treatment. Control hypertension before and during therapy. Avoid use in patients with unstable cardiovascular disease, serious heart arrhythmias, or other serious heart problems. ( 5.1 ) Psychiatric Symptoms : Use caution in treating patients with a history of psychosis or bipolar disorders. Consider dose reduction or discontinuation of SUNOSI if psychiatric symptoms develop. ( 5.2 )

5.1 Blood Pressure and Heart Rate Increases SUNOSI increases systolic blood pressure, diastolic blood pressure, and heart rate in a dose-dependent fashion [see Adverse Reactions ( 6.1 )] . Epidemiological data show that chronic elevations in blood pressure increase the risk of major adverse cardiovascular events (MACE), including stroke, heart attack, and cardiovascular death. The magnitude of the increase in absolute risk is dependent on the increase in blood pressure and the underlying risk of MACE in the population being treated. Many patients with narcolepsy and OSA have multiple risk factors for MACE, including hypertension, diabetes, hyperlipidemia, and high body mass index (BMI). Assess blood pressure and control hypertension before initiating treatment with SUNOSI. Monitor blood pressure regularly during treatment and treat new-onset hypertension and exacerbations of pre-existing hypertension. Exercise caution when treating patients at higher risk of MACE, particularly patients with known cardiovascular and cerebrovascular disease, pre-existing hypertension, and patients with advanced age. Use caution with other drugs that increase blood pressure and heart rate [see Drug Interactions ( 7.2 )] . Periodically reassess the need for continued treatment with SUNOSI. If a patient experiences increases in blood pressure or heart rate that cannot be managed with dose reduction of SUNOSI or other appropriate medical intervention, consider discontinuation of SUNOSI. Patients with moderate or severe renal impairment may be at a higher risk of increases in blood pressure and heart rate because of the prolonged half-life of SUNOSI [see Dosage and Administration ( 2.5 ), Clinical Pharmacology ( 12.3 )] .

5.2 Psychiatric Symptoms Psychiatric adverse reactions have been observed in clinical trials with SUNOSI, including anxiety, insomnia, and irritability [see Adverse Reactions ( 6.1 )] . SUNOSI has not been evaluated in patients with psychosis or bipolar disorders. Exercise caution when treating patients with SUNOSI who have a history of psychosis or bipolar disorders. Patients with moderate or severe renal impairment may be at a higher risk of psychiatric symptoms because of the prolonged half-life of SUNOSI [see Dosage and Administration ( 2.5 ), Clinical Pharmacology ( 12.3 )] . Patients treated with SUNOSI should be observed for the possible emergence or exacerbation of psychiatric symptoms. If psychiatric symptoms develop in association with the administration of SUNOSI, consider dose reduction or discontinuation of SUNOSI.

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.

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.

9.1 Controlled Substance SUNOSI contains solriamfetol, a Schedule IV controlled substance.

9.2 Abuse SUNOSI has potential for abuse. Abuse is the intentional non-therapeutic use of a drug, even once, to achieve a desired psychological or physiological effect. The abuse potential of SUNOSI 300 mg, 600 mg, and 1200 mg (two, four, and eight times the maximum recommended dose, respectively) was assessed relative to phentermine, 45 mg and 90 mg, (a Schedule IV controlled substance) in a human abuse potential study in individuals experienced with the recreational use of stimulants. Results from this clinical study demonstrated that SUNOSI produced Drug Liking scores similar to or lower than phentermine. In this crossover study, elevated mood was reported by 2.4% of placebo-treated subjects, 8 to 24% of SUNOSI-treated subjects, and 10 to 18% of phentermine-treated subjects. A ‘feeling of relaxation’ was reported in 5% of placebo-treated subjects, 5 to 19% of SUNOSI-treated subjects and 15 to 20% of phentermine-treated subjects. Physicians should carefully evaluate patients for a recent history of drug abuse, especially those with a history of stimulant (e.g., methylphenidate, amphetamine, or cocaine) or alcohol abuse, and follow such patients closely, observing them for signs of misuse or abuse of SUNOSI (e.g., incrementation of doses, drug-seeking behavior).

9.3 Dependence In a long-term safety and maintenance of efficacy study, the effects of abrupt discontinuation of SUNOSI were evaluated following at least 6 months of SUNOSI use in patients with narcolepsy or OSA. The effects of abrupt discontinuation of SUNOSI were also evaluated during the two-week safety follow-up periods in the Phase 3 studies. There was no evidence that abrupt discontinuation of SUNOSI resulted in a consistent pattern of adverse events in individual subjects that was suggestive of physical dependence or withdrawal.

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 for maternal and developmental toxicity is approximately 2 times the MRHD based on mg/m 2 body surface area.

Safety and effectiveness in pediatric patients have not been established. Clinical studies of SUNOSI in pediatric patients have not been conducted.

Of the total number of patients in the narcolepsy and OSA clinical studies treated with SUNOSI, 13% (123/930) were 65 years of age or over. No clinically meaningful differences in safety or effectiveness were observed between elderly and younger patients. Solriamfetol is predominantly eliminated by the kidney. Because elderly patients are more likely to have decreased renal function, dosing may need to be adjusted based on eGFR in these patients. Consideration should be given to the use of lower doses and close monitoring in this population [see Dosage and Administration ( 2.5 )].

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

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).

Solriamfetol binds to the dopamine transporter and norepinephrine transporter with low affinity (Ki=14.2 µM and 3.7 µM, respectively), and inhibits the reuptake of dopamine and norepinephrine with low potency (IC 50 =2.9 μM and 4.4 μM, respectively). Solriamfetol has no appreciable binding affinity for the serotonin transporter (Ki=81.5 µM) and does not inhibit serotonin reuptake (IC 50 > 100 μM). Solriamfetol has no appreciable binding affinity to dopamine, serotonin, norepinephrine, GABA, adenosine, histamine, orexin, benzodiazepine, muscarinic acetylcholine, or nicotinic acetylcholine receptors. Cardiac Electrophysiology The effect of solriamfetol 300 mg and 900 mg (twice and six times the maximum recommended dose, respectively) on the QTc interval was evaluated in a randomized, double-blind, placebo-, and positive-controlled (moxifloxacin 400 mg), 4-period, crossover study in 60 healthy subjects. A large increase in heart rate was observed in both solriamfetol treatment groups (mean change from baseline in HR of 21 and 27 bpm in the 300 and 900 mg groups, respectively, compared with 8 bpm in the placebo group). These heart rate effects impact the interpretability of the QTc effects, particularly in the 900 mg group. In this study, solriamfetol 300 mg did not prolong the QTcF interval to a clinically relevant extent.

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

, Mutagenesis, Impairment of Fertility Carcinogenesis Solriamfetol did not increase the incidence of tumors in rats or mice treated orally for up to 101 and 104 weeks at 35, 80, and 200 mg/kg/day (rat), and 20, 65, and 200 mg/kg/day (mouse), respectively. These doses are approximately 2, 6, and 18 times (rat), and 0.4, 2.6, and 7 times (mouse) the MRHD based on AUC. Mutagenesis Solriamfetol was not mutagenic in the in vitro bacterial reverse mutation (Ames) assay or clastogenic in the in vitro mammalian chromosomal aberration assay or in the in vivo mouse bone marrow micronucleus assay. Impairment of Fertility Solriamfetol did not affect fertility or sperm parameters when administered orally to male rats for 8 weeks at doses of 35 and 110 mg/kg/day, which are approximately 2 and 7 times the MRHD, based on mg/m 2 body surface area. At 350 mg/kg/day, which is approximately 22 times the MRHD based on mg/m 2 body surface area, solriamfetol decreased sperm count and sperm concentration without affecting fertility. Solriamfetol did not affect fertility when administered orally to female rats for 2 weeks premating, during mating, and through gestation day 7 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.

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide). Potential for Abuse and Dependence Advise patients that SUNOSI is a federally controlled substance because it has the potential to be abused [see Drug Abuse and Dependence ( 9 )] . Advise patients to keep their medication in a secure place and to dispose of unused SUNOSI as recommended in the Medication Guide. Primary OSA Therapy Use Inform patients that SUNOSI is not indicated to treat the airway obstruction in OSA and they should use a primary OSA therapy, such as CPAP, as prescribed to treat the underlying obstruction [see Indications and Usage ( 1 )] . SUNOSI is not a substitute for primary OSA therapy. Blood Pressure and Heart Rate Increases Instruct patients that SUNOSI can cause elevations of their blood pressure and pulse rate and that they should be monitored for such effects [see Warnings and Precautions ( 5.1 )] . Psychiatric Symptoms Instruct patients to contact their healthcare provider if they experience, anxiety, insomnia, irritability, agitation, or signs of psychosis or bipolar disorders [see Warnings and Precautions ( 5.2 )] . Lactation Advise breastfeeding patients using SUNOSI to monitor infants for signs of agitation, insomnia, and reduced weight [see Use in Specific Populations ( 8.2 )] . For more information, visit www.SUNOSI.com Distributed by: Axsome Therapeutics, Inc. New York, NY 10007 For patent information: www.axsome.com/IP © 2023 Axsome Therapeutics, Inc. SUN-USPI-004.000-20230630

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).