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 )

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 )

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.

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. […]

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.

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

8.2 Lactation Risk Summary Available data from a lactation study in 6 women indicate that solriamfetol is present in human milk. The daily infant dose is 0.112 mg/kg (based on nominal infant weight of 6 kg) and the relative infant dose (RID) is approximately 5.5% of the maternal weight-adjusted dosage (see Data) . Data are insufficient to determine effects of solriamfetol on a breastfed infant or its effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for SUNOSI and any potential adverse effects on the breastfed infant from SUNOSI or from the underlying maternal condition. Clinical Considerations Monitor infants exposed to SUNOSI for signs of agitation, insomnia, and reduced weight gain. Data A single-dose milk and plasma lactation study was conducted in 6 healthy adult lactating women who were between 10 days and 52 weeks postpartum and were administered a single oral 150 mg dose of SUNOSI. The cumulative median amount excreted in breast milk was 0.67 mg over 72 hours, which is about 5.5% of the maternal dose on a weight-adjusted basis. Of the total amount of solriamfetol excreted in breast milk over 72 hours, approximately 78% and 98% were excreted by 8 and 24 hours, respectively, with an apparent mean elimination half-life in breast milk of about 5 hours.

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

8.5 Geriatric Use 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 )].

8.6 Renal Impairment Dosage adjustment is not required for patients with mild renal impairment (eGFR 60-89 mL/min/1.73 m 2 ). Dosage adjustment is recommended for patients with moderate to severe renal impairment (eGFR 15-59 mL/min/1.73 m 2 ). SUNOSI is not recommended for patients with end stage renal disease (eGFR <15 mL/min/1.73 m 2 ) [see Dosage and Administration ( 2.5 ), Warnings and Precautions ( 5.1 , 5.2 ), Clinical Pharmacology ( 12.3 )].

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).