Sunosi

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 CLINICAL STUDIES

14.1 Narcolepsy

The efficacy of SUNOSI in improving wakefulness and reducing excessive daytime sleepiness was demonstrated in a 12-week, multi-center, randomized, double-blind, placebo-controlled, parallel-group study (Study 1; NCT02348593) in adult patients with a diagnosis of narcolepsy according to the ICSD-3 or DSM-5 criteria.

Wakefulness and sleepiness were assessed using the Maintenance of Wakefulness Test (MWT) and the Epworth Sleepiness Scale (ESS). The MWT measures an individual’s ability to remain awake during the daytime in a darkened, quiet environment. Patients were instructed to remain awake for as long as possible during 40-minute test sessions, and sleep latency was determined as the mean number of minutes patients could remain awake in the first four test sessions. The ESS is an 8-item questionnaire by which patients rate their perceived likelihood of falling asleep during usual daily life activities. Change in overall symptom severity was assessed using the Patient Global Impression of Change (PGIc) scale. The PGIc is a 7-point patient-reported scale by which patients rate their symptom change since the beginning of the study. Responses range from “very much improved” to “very much worse.” The co-primary efficacy endpoints were change from baseline in MWT and ESS at Week 12. A pre-specified secondary endpoint was percentage of subjects reported as improved (minimally, much, or very much) at Week 12 by PGIc.

A total of 239 patients with narcolepsy were randomized to receive SUNOSI 75 mg, 150 mg, or 300 mg (two times the maximum recommended daily dose), or placebo once daily. Patients randomized to the 150-mg dose received 75 mg for the first 3 days before increasing to 150 mg.

Demographic and baseline disease characteristics were similar for the SUNOSI and placebo groups. Median age was 34 years (range 18 to 70 years), 65% were female, 80% were Caucasian, 14% were African American, and 3% were Asian. Approximately 51% of patients had cataplexy.

Compared to the placebo group, patients randomized to 150 mg SUNOSI showed statistically significant improvements on the MWT (treatment effect difference: 7.7 minutes, Table 6) and on the ESS (treatment effect difference: 3.8 points, Table 7) at Week 12. These effects were apparent at Week 1 and consistent with the results at Week 12. The change on percentage of subjects reported as improved by PGIc was also statistically significant compared with placebo. There were trends toward improvement in the SUNOSI 75-mg treatment group ; however, these changes were not statistically significant. There was no evidence of differential efficacy in patients with cataplexy and patients without cataplexy. Examination of subgroups by age, race, and sex did not suggest differences in response.

At Week 12, 150 mg of SUNOSI demonstrated improvements in wakefulness compared to placebo as assessed in test sessions 1 (approximately 1 hour post-dose) through 5 (approximately 9 hours post-dose) of the MWT . Nighttime sleep as measured with polysomnography was not affected by the use of SUNOSI in Study 1.

Figure 2: Maintenance of Wakefulness Test Improvements in Test Sessions 1 through 5 in Patients with Narcolepsy in Study 1 at Week 12

14.2 Obstructive Sleep Apnea (OSA)

The efficacy of SUNOSI in improving wakefulness and reducing excessive daytime sleepiness in patients with OSA was demonstrated in a 12-week multi-center, randomized, double-blind, placebo-controlled study (Study 2; NCT02348606) in adults diagnosed with OSA according to ICSD-3 criteria. The co-primary efficacy endpoints were change from baseline in MWT and ESS at Week 12; a pre-specified secondary endpoint was percentage of subjects reported as improved (minimally, much, or very much) at Week 12 by PGIc.

A total of 476 patients with OSA were randomized to receive SUNOSI 37.5 mg, 75 mg, 150 mg, or 300 mg (two times the maximum recommended daily dose), or placebo once daily. Patients randomized to the 150-mg dose received 75 mg for the first 3 days before increasing to 150 mg.

Demographic and baseline disease characteristics were similar for the SUNOSI and placebo groups. Median age was 55 years (range 20 to 75 years), 37% were female, 76% were Caucasian, 19% were African American, and 4% were Asian.

Compared to the placebo group, patients randomized to 37.5 mg, 75 mg, and 150 mg SUNOSI showed statistically significant improvements on the MWT (treatment effect difference: 4.5 minutes, 8.9 minutes, and 10.7 minutes respectively; Table 6) and ESS (treatment effect difference: 1.9 points, 1.7 points, and 4.5 points respectively; Table 7) at Week 12. These effects were apparent at Week 1 and consistent with the results at Week 12. The change on percentage of subjects reported as improved by PGIc was also statistically significant compared with placebo at the 75 mg and 150 mg doses. Examination of subgroups by age, race, and sex did not suggest differences in response.

At Week 12, 37.5 mg, 75 mg, and 150 mg of SUNOSI all demonstrated improvements in wakefulness compared to placebo as assessed in test sessions 1 (approximately 1 hour post-dose) through 5 (approximately 9 hours post-dose) of the MWT . Nighttime sleep as measured with polysomnography was not affected by the use of SUNOSI in Study 2. Patients’ compliance with a primary OSA therapy device was similar across the placebo and SUNOSI treatment groups at baseline, and did not change during the 12-week study period in any treatment group.

Figure 3: Maintenance of Wakefulness Test Improvements in Test Sessions 1 through 5 in Patients with OSA in Study 2 at Week 12

Table 6: Efficacy Results for Maintenance of Wakefulness Test (minutes) in Patients with Narcolepsy (Study 1) and OSA (Study 2)

SD = standard deviation; SE = standard error; LS Mean = least square mean; CI = confidence interval Maximum possible MWT score is 40 minutes. A positive change represents improvement. Difference from Placebo = LS Mean Difference between change from baseline between active drug and placebo. * Dose that was statistically significantly superior to placebo after adjusting for multiplicity.
Indication/ Study	Treatment Group (N)	Baseline Mean (SD)	LS Mean Change from Baseline at Week 12 (SE)	Difference from Placebo (95% CI)
Narcolepsy STUDY 1	Placebo (58)	6.2 (5.7)	2.1 (1.3)	-
	SUNOSI 75 mg (59)	7.5 (5.4)	4.7 (1.3)	2.6 (-1.0, 6.3)
	SUNOSI 150 mg* (55)	7.9 (5.7)	9.8 (1.3)	7.7 (4.0, 11.3)
OSA STUDY 2	Placebo (114)	12.6 (7.1)	0.2 (1.0)	-
	SUNOSI 37.5 mg* (56)	13.6 (8.1)	4.7 (1.4)	4.5 (1.2, 7.9)
	SUNOSI 75 mg* (58)	12.4 (6.9)	9.1 (1.4)	8.9 (5.6, 12.4)
	SUNOSI 150 mg* (116)	12.5 (7.2)	11.0 (1.0)	10.7 (8.1, 13.4)

Table 7: Efficacy Results for Epworth Sleepiness Scale in Patients with Narcolepsy (Study 1) and OSA (Study 2)

SD = standard deviation; SE = standard error; LS Mean = least square mean; CI = confidence interval Scores range from 0 to 24 with higher scores indicating more severe sleepiness. A negative change represents improvement. Difference from placebo = LS mean difference between change from baseline between SUNOSI and placebo. * Dose that was statistically significantly superior to placebo after adjusting for multiplicity.
Indication/ Study	Treatment Groups (N)	Baseline Score Mean (SD)	LS Mean Change from Baseline at Week 12 (SE)	Difference from Placebo (95% CI)
Narcolepsy STUDY 1	Placebo (58)	17.3 (2.9)	-1.6 (0.7)	-
	SUNOSI 75 mg (59)	17.3 (3.5)	-3.8 (0.7)	-2.2 (-4.0, -0.3)
	SUNOSI 150 mg* (55)	17.0 (3.6)	-5.4 (0.7)	-3.8 (-5.6, -2.0)
OSA STUDY 2	Placebo (114)	15.6 (3.3)	-3.3 (0.5)	-
	SUNOSI 37.5 mg* (56)	15.1 (3.5)	-5.1 (0.6)	-1.9 (-3.4, -0.3)
	SUNOSI 75 mg* (58)	15.0 (3.5)	-5.0 (0.6)	-1.7 (-3.2, -0.2)
	SUNOSI 150 mg* (116)	15.1 (3.4)	-7.7 (0.4)	-4.5 (-5.7, -3.2)

14.3 Maintenance of Efficacy in Narcolepsy and OSA

The maintenance of effect of SUNOSI in improving wakefulness and reducing excessive daytime sleepiness in patients with narcolepsy and OSA was assessed in two randomized-withdrawal, placebo-controlled studies, Study 3 and Study 4 .) and Study 4 (NCT02348632).

Study 3 was a 6-week, multi-center, double-blind, placebo-controlled, randomized-withdrawal study in 174 adult patients with a diagnosis of OSA. The co-primary efficacy endpoints were change from the beginning to the end of the randomized withdrawal period in MWT and ESS. During a 2-week, open-label titration phase, patients were started on SUNOSI 75 mg once daily, and were titrated to the maximum tolerable dose between 75 mg and 300 mg per day (two times the maximum recommended daily dose). Patients were continued on this dose for a 2-week stable-dose phase. At the end of the stable-dose phase, 124 patients who reported “much” or “very much” improvement on the PGIc and who showed improvements on the MWT and ESS entered a double-blind withdrawal phase and were randomized 1:1 to either continue SUNOSI at the dose received in the stable-dose phase or switch to placebo. Compared to patients who remained on SUNOSI, patients randomized to placebo experienced statistically significant worsening of sleepiness as measured by the MWT and ESS .

Study 4 was a 52-week, open-label study in 638 patients with either narcolepsy or OSA who had completed a prior trial. During a 2-week, open-label titration phase, patients were started on SUNOSI 75 mg once daily, and were titrated to the maximum tolerable dose between 75 mg and 300 mg per day (two times the maximum recommended daily dose). Patients remained on this dose during a subsequent open-label treatment period of either 38 (for patients previously enrolled in Study 1 or Study 2) or 50 (all others) weeks. A 2-week randomized-withdrawal period was incorporated into the study. After 6 months of stable-dose treatment, 282 patients (79 with narcolepsy; 203 with OSA) entered the randomized-withdrawal period. Patients were randomized 1:1 to either continue to receive SUNOSI at the dose received in the maintenance phase or to switch to placebo. The primary efficacy endpoint was change from the beginning to the end of the randomized-withdrawal period in ESS. Compared to patients who remained on SUNOSI, patients randomized to placebo experienced statistically significant worsening of sleepiness as measured by the ESS .

Table 8: Efficacy Results from Randomized Withdrawal Studies in Patients with Narcolepsy and OSA in Studies 3 and 4

SD = standard deviation; SE = standard error; LS Mean = least square mean; CI = confidence interval For MWT, maximum possible score is 40 minutes; negative changes indicate worsening. For ESS, scores range from 0 to 24; positive changes indicate worsening. * Statistically significantly superior to placebo after adjusting for multiplicity.
Indication/ Study	Endpoint	Treatment Groups (N)	Beginning of Randomized Withdrawal Period (Baseline) Mean (SD)	LS Mean Change from Baseline (SE)	Difference from Placebo (95% CI)
OSA STUDY 3	MWT (minutes)	Placebo (62)	29.0 (9.9)	-12.1 (1.3)
		SUNOSI* (60)	31.7 (9.2)	-1.0 (1.4)	11.2 (7.8, 14.6)
	ESS Score	Placebo (62)	5.9 (3.8)	4.5 (0.7)
		SUNOSI* (60)	6.4 (4.4)	-0.1 (0.7)	-4.6 (-6.4, -2.8)
OSA and Narcolepsy STUDY 4	ESS Score	Placebo (141)	7.8 (5.0)	5.3 (0.4)
		SUNOSI* (139)	7.3 (5.3)	1.6 (0.4)	-3.7 (-4.8, -2.7)

)]

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.

• Administer once daily upon awakening. Avoid administration within 9 hours of planned bedtime because of the potential to interfere with sleep. (
  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.
  )
• Starting dose for patients with narcolepsy: 75 mg once daily. (
  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 ]

  .
  )
• Starting dose for patients with OSA: 37.5 mg once daily. (
  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 ]

  .
  )
• Dose may be increased at intervals of at least 3 days. (
  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 ]

  .
  ,
  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 ]

  .
  )
• Maximum dose is 150 mg once daily. (
  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 ]

  .
  ,
  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 ]

  .
  )
• Renal impairment (
  2.5 Dosage Recommendations in Patients with Renal Impairment

  Moderate renal impairment (eGFR 30-59 mL/min/1.73 m²)

  : 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 , Clinical Pharmacology ]

  .

  Severe renal impairment (eGFR 15-29 mL/min/1.73 m²)

  : Administer 37.5 mg once daily. The maximum recommended daily dose is 37.5 mg

  [see Use in Specific Populations , Clinical Pharmacology ]

  .

  End Stage Renal Disease (eGFR <15 mL/min/1.73 m²)

  : SUNOSI is not recommended for use in patients with ESRD

  [see Use in Specific Populations , Clinical Pharmacology ]

  .
  ,
  8.6 Renal Impairment

  Dosage adjustment is not required for patients with mild renal impairment (eGFR 60-89 mL/min/1.73 m²). Dosage adjustment is recommended for patients with moderate to severe renal impairment (eGFR 15-59 mL/min/1.73 m²). SUNOSI is not recommended for patients with end stage renal disease (eGFR <15 mL/min/1.73 m²)

  [see Dosage and Administration , Warnings and Precautions , Clinical Pharmacology ].
  ,
  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_maxof 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_maxand AUC_inf; however, a delay of approximately 1 hour in T_maxwas 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 m²) 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 m²), moderate (eGFR 30–59 mL/min/1.73 m²), or severe (eGFR <30 mL/min/1.73 m²) renal impairment, respectively. Exposure (AUC) and half-life of solriamfetol was significantly increased in patients with ESRD (eGFR <15 mL/min/1.73 m²)

  [see Use in Specific Populations ]

  . An average of 21% of solriamfetol was removed by hemodialysis. In general, median T_maxvalues 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 (IC₅₀of 146 μM) and MATE1 (IC₅₀of 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.

  

  ):
  • 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.

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.

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

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/m² body surface area. Oral administration of solriamfetol to pregnant rats during pregnancy and lactation at doses ≥ 7 times the MRHD based on mg/m² body surface area resulted in maternal toxicity and adverse effects on fertility, growth, and development in offspring

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.

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/m² 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/m² 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/m² 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/m² 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/m² 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/m² body surface area.

• 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 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 ]

  .

  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 ]

  .

  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 , Clinical Pharmacology ]

  .
  )
• 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 Psychiatric Symptoms

  Psychiatric adverse reactions have been observed in clinical trials with SUNOSI, including anxiety, insomnia, and irritability

  [see Adverse Reactions ]

  .

  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 , Clinical Pharmacology ]

  .

  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.
  )