A Comprehensive Review of Solriamfetol to Treat Excessive Daytime Sleepiness

Abstract

Purpose of Review

This is a comprehensive review of the literature regarding the use of Solriamfetol for excessive daytime sleepiness. It covers the background and current therapeutic approaches to treating excessive daytime sleepiness, the management of common comorbidities, and the existing evidence investigating the use of Solriamfetol for this purpose.

Recent Findings

Excessive daytime sleepiness leads to worse quality of life, a medical sequela and significant economic cost. There are multiple phenotypes of excessive daytime sleepiness depending on the comorbidity making treatment challenging. Due to the complexity of etiology there is not a cure for this ailment. Solriamfetol is a norepinephrine/dopamine dual reuptake antagonist that can be used to manage daytime sleepiness. Solriamfetol was first approved by the FDA in 2018 for use in excessive daytime sleepiness associated with obstructive sleep apnea and narcolepsy. Ongoing literature has proved this drug to be a safe and effective alternative pharmacotherapy.

Summary

Recent epidemiological data estimate up to one-third of the general adult population suffers from excessive daytime sleepiness. There is no cure to daytime somnolence and current pharmacotherapeutic regimens have worrisome side effect profiles. Solriamfetol is a new class of drug that offers a safe and effective alternative option for clinical providers treating excessive daytime sleepiness.

Introduction

Between 20–30% of the general population is affected by excessive daytime sleepiness (EDS). Excessive daytime sleepiness imposes a tremendous burden on quality of life, safety to society as a whole and the economy.¹ A recent Sleep Health article called for a de-normalization of daytime sleepiness that results in living life in a constant daze and an awareness campaign for patients at risk of functional sleep impairment.² EDS is associated with many medical conditions but the most common are obstructive sleep apnea (OSA) and narcolepsy. Obstructive sleep apnea is defined as pauses in breathing while sleeping and occurs due to narrowed or blocked airways. Significant clinical consequences of OSA stem from decreased recurrent episodes of arousal and overall decreased sleep quality.³ Narcolepsy is a persistent neurological disease characterized by a diminished capacity to regulate sleep wake cycles secondary to a neurological circuit failure in hypocretin/orexin neurotransmission, brain regions and cell types.⁴ The current clinical arsenal for pharmacotherapy in EDS is first line use of modafinil/armodafinil and sodium oxybate wherein failure of these medications prompts a trial of stimulants such as methylphenidate and amphetamines.⁵ Most recently, the Food and Drug Administration approved Solriamfetol as a promising new wakefulness promoting agent for use in excessive daytime sleepiness. Solriamfetol belongs to a class of drugs called dopamine and norepinephrine reuptake inhibitors. Given the great need for new treatments in EDS, a myriad of literature over the last several years has evaluated the safety and efficacy of Solriamfetol. The purpose of this review is to investigate Solriamfetol as an emerging wakefulness promoting agent.

Obstructive Sleep Apnea and Narcolepsy Epidemiology, Pathophysiology, Risk Factors, and Presentation

Obstructive sleep apnea (OSA) is defined as 5 or more partial or complete obstructive breathing episodes per hour of sleep with symptoms of disrupted breathing, sleep interference, medical complications, or presence of at least 15 breathing events per hour.⁶ In the last several decades, the prevalence of OSA has increased 14–55% (depending on cohort) between 1988–1994 and 2007–2010.⁶ This increase was associated with a rise in obesity which contributes to larger neck girths and central body fat.⁶ Other risk factors for OSA include male sex, older age, oropharyngeal and airway variances, and nocturnal nasal congestion.⁶ The severity of sleep apnea is quantitatively measured by the apnea-hypopnea index (AHI). This measures the average number of breathing events, either oxygen desaturation or sleep fragmentation, per hour. Although the clinical importance of these two factors is controversial, the AHI provides a common language at to categorize sleep apnea.⁶

During normal sleep, blood pressure and heart rate decreases slightly as a result of increased parasympathetic and decreased sympathetic activity.⁷ When the airway becomes obstructed, negative pressure increases at the obstruction site and induces intermittent hypoxia. This activates a sympathetic response through renal, adrenal, and peripheral chemoreceptors leading to an increase in circulating catecholamines, renin, and angiotensin II and overall increase in blood pressure.⁸ The transient hypoxia and increase in blood pressure contributes to endothelial dysfunction and increases plasma levels of endothelin-1. Over time, the persistent sympathetic drive and endothelial injury leads to vascular remodeling and an elevation in baseline blood pressure.⁹ Unsurprisingly, hypertension is one of the most closely associated sequalae of OSA. A meta-analysis of prospective studies estimated that individuals with OSA had a 48% increase in risk of hypertension.¹⁰ There also appears to be a direct correlation with the severity of the disease, with an 1% increase in risk of hypertension for every unit (event/hour) increase in AHI.¹¹

OSA has also been linked to numerous other acute and chronic diseases. Sudden Cardiac Death (SCD) is one of most serious complications. Compared to the general population, people with OSA had a 2.57 times higher of rate of SCD.¹² This can be compounded with a higher rate of arrythmias, including atrial fibrillation and ventricular arrhythmias, which are an independent risk factor itself for SCD.¹³ In terms of non-cardiac implications of OSA, diabetes is a common comorbidity with OSA, which is possibly due to similar predispositions.¹⁴ One study found that in the primary care setting, roughly 18% of patients with diabetes also had OSA though the exact pathophysiologic link between these two diseases is not fully understood.¹⁴ The consequences of OSA also extends to socioeconomic burdens. It is also a known risk factor for motor vehicle accidents secondary due to excess fatigue and has been implicated in increased rates of work-related accidents and lowered job performance.¹⁵

Narcolepsy is a disease characterized by immune-related attack of orexin-producing neurons in the central nervous system (CNS).¹⁶ Normal wakefulness is promoted by the Reticular Activating System (RAS) which induces the release of stimulating neurotransmitters like dopamine, norepinephrine, serotonin, and histamine that inhibit REM.¹⁶ It also suppresses the ventrolateral preoptic area (sleep-promoting area of the hypothalamus) and inhibits GABA, thereby decreasing muscle function and tone.¹⁶ In the lateral hypothalamus, orexin-containing neurons promote activation of the RAS nuclei leading to the cascade associated with wakefulness. When sleeping, orexin is decreased which suppresses RAS activity.¹⁶ In narcolepsy, the decreased number of orexin-producing neurons means there is an absence of constant, wake-promoting neurotransmitters in the brain and thus, sleepiness is readily inducible.¹⁶

The prevalence of narcolepsy is estimated to be roughly 0.04% of the population with the onset typically in adolescence.¹⁷ Patients with this disease can be ‘triggered’ by stressful, emotional, or otherwise arousing events that triggers irresistible sleepiness.¹⁷ In type 1 narcolepsy, patients present with both daytime sleepiness (EDS) and cataplexy, whereas type 2 narcolepsy has EDS without cataplexy.¹⁸ The diagnosis of narcolepsy is based on presence of REM sleep after sudden onset of sleep, little-to-no orexin in cerebrospinal fluid, and HLA-DQB1*06:02 positivity.¹⁹ The evaluation of narcolepsy typically involves polysomnograms to rule out other sleep disorders, followed by the Multiple Sleep Latency Test (MSLT) which helps report rapid onset of REM sleep.¹⁶ There are also several scales used in practice, such as the Epworth Sleepiness Scale, which is based on patient responses and can help classify and grade severity of narcolepsy.¹⁷

Narcolepsy has been implicated as a risk factor for several psychiatric disorders. One nationwide study reported a 4-fold increase in risk of people with narcolepsy developing a psychosis disorder.²⁰ Another study found patients with narcolepsy were at a greater risk for having any depressive disorder, dysthymic disorder, and major depressive disorder when compared to control subjects.²¹ Notably, over 50% of patients with narcolepsy had been diagnosed with depression prior to receiving the diagnosis of narcolepsy which reaffirms the difficulty of diagnosis due to overlapping symptoms.²¹

There are also physical manifestations associated with narcolepsy. Fatigue is one of the most frequently reported symptoms that may lead to impairments and negative effects in daily life.²² Obesity is another potential consequence, with about 30% of patients with narcolepsy having a BMI over 30 kg/m². This may seem paradoxical as patients with narcolepsy have less of the appetite-increasing effects from orexin. However, it is hypothesized that despite decreased intake of food, orexin also has a role in metabolism and in its absence, there leading to a discrepancy between energy intake and expenditure.²³ Patients with narcolepsy also have an increased risk of cardiovascular and endocrine comorbidities, as well as injuries such as bone fractures.^22,24 Finally, narcolepsy is linked with a range of autoimmune diseases due to its own autoimmune pathogenesis. Studies have found a significant association between comorbidities with narcolepsy and other autoimmune diseases such as systemic lupus erythematosus and multiple sclerosis suggests some people may be more genetically predisposed to narcolepsy.²⁵

Current Treatment of OSA and Narcolepsy

The first-line treatment for OSA is continuous positive airway pressure (CPAP) which lowers the AHI by providing pneumatic pressure to maintain airway patency.⁹ CPAP has been consistently shown to significantly improve sleepiness, neurocognitive impairment, and hypertension.²⁶ While effective at relieving symptoms, patients struggle with compliance resulting in low usage.²⁷ Other mechanical therapies include oral appliances and surgery but have not been shown to have significant efficacy.²⁷

There has also been an effort to treat OSA using pharmacotherapy measures targeting serotonergic, noradrenergic, and GABAergic targets. Desipramine is a tricyclic antidepressant with strong noradrenergic and mild serotonergic and antimuscarinic shown to reduce OSA severity by improving airway collapsibility.²⁸ Zolpidem is a hypnotic that targets GABAergic receptors that also has the potential to address OSA by increasing the responsiveness of pharyngeal muscles during airway narrowing.²⁹ Interesting, there is also evidence that mechanical training modalities like playing the didgeridoo regularly and oropharyngeal exercises can decrease OSA severity.²⁷

Compared to OSA, there are generally more pharmaceutical options for treating narcolepsy. First-line treatment for narcolepsy includes the stimulant modafinil, which increases dopaminergic activity at the synapse to promote wakefulness.³⁰ The drug acts quickly, within a few hours, and reaches steady state within 2–4 days.³¹ Armodafinil is an enantiomer of modafinil that can reach higher plasma levels than modafinil, resulting in longer-lasting effect and increased sleep latency.³¹ Additional stimulants that can be used to treat narcolepsy are methylphenidates and amphetamines, both which work by increasing dopamine and norepinephrine in the synapse.³¹ However, compared to modafinil and armodafinil, carry a higher abuse potential and tolerance frequently occurs.³¹ Antidepressants have also shown some efficacy in the treatment of narcolepsy. Tricyclic antidepressants (TCAs), particularly clomipramine, are no longer first-line but are still widely used to treat cataplexy. They act by directly inhibiting serotonin reuptake and indirectly inhibiting adrenergic reuptake.³¹ Unfortunately, TCAs are associated with adverse effects including QRS prolongation, seizures, and withdrawal “rebound cataplexy” which limits their use.³¹ Selective serotonin reuptake inhibitors (SSRIs) and serotonin and norepinephrine reuptake inhibitors (SNRIs) have also been studied in the treatment cataplexy in narcolepsy. The most notable of these is venlafaxine, which is widely used for its similarly potent effects as clomipramine.³¹

Separate from the stimulants and antidepressants is sodium oxybate, a drug that binds to GABAb receptors and has been shown to treat cataplexy in a significant, dose-dependent manner by several studies.^32,33 Although effective, the time of response was about 25 days to reach maximum dose, substantially more than the modafinil.³⁴ Baclofen is another medication with potential to treat excessive sleepiness through its inhibitory actions in the CNS. A small study of 5 narcolepsy patients taking baclofen found that these patients had less sleep fragmentation and thus, had better sleep maintenance and less daytime sleepiness.³⁵ Finally, Solriamfetol is selective dopamine and norepinephrine reuptake inhibitor that is not yet FDA approved for excessive sleepiness but has shown significant improvements in wakefulness in the phase 2b study. This study also demonstrated the drug was well-tolerated though carried higher risks of insomnia and headache.³⁶

Solriamfetol Drug Information

In 2019, Solriamfetol, sold under the brand name SUNOSI licensed by Jazz Pharmaceuticals was approved by the FDA to improve wakefulness in adult patients with excessive daytime sleepiness associated with narcolepsy or obstructive sleep apnea.³⁷

General Administration

SUNOSI is tablet form, taken orally, and classified as a schedule IV drug. SUNOSI is administered 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.³⁷ There are different dosing recommendations for SUNOSI depending on indications of treatment.

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.³⁷

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.³⁷

Clinical Assessment

The US Office of Clinical Pharmacology (OCP) recommends the addition of language to the label to communicate the increased risk of insomnia, increased systolic blood pressure, increased diastolic blood pressure, and increased heart rate in patients with moderate or severe renal impairment. Jazz Pharmaceuticals notes that Solriamfetol is not recommended for patients with end-stage renal disease.^37,38

Quality Assessment

The US Office of Pharmaceutical Quality (OPQ) note key findings regarding SUNOSI in application and are as follows: [1] the score line for the 75 mg tablet was approved, allowing the tablet to be split in half to achieve a 37.5 mg dose for patients. Tablet breakability and split tablet stability were demonstrated per FDA’s guidance on scored tablets, and [2] based on the stability data provided, OPQ granted a 30-month shelf life for the drug product when stored at USP Controlled Room Temperature.^37,38

Solriamfetol Mechanism of Action

Multiple monoaminergic pathways, including dopamine, norepinephrine, and serotonin, play a role in maintaining wakefulness in an individual.³⁹ Irregularities in these pathways can lead to excessive daytime sleepiness known as hypersomnia. Both Solriamfetol and amphetamines help prevent hypersomnia induced by narcolepsy and obstructive sleep apnea by binding to norepinephrine and dopamine transporters, selectively inhibiting their reuptake into neurons and increasing their concentrations within the synapse.³⁹ The decreased reuptake of dopamine and norepinephrine caused by Solriamfetol and amphetamines results in an increased extracellular concentration of these monoamines and therefore causes an increased activity of their respective pathways in the hindbrain.⁴⁰ This increase in concentration allots for a dose-dependent increase in wakefulness. Additionally, amphetamines also cause sympathomimetic effects by inducing the release of norepinephrine and dopamine from the same areas of the hindbrain; however, this monoamine releasing effect does not occur with Solriamfetol.³⁹

Solriamfetol, (R)-2-amino-3-phenylpropylcarbamate hydrochloride, is a phenylalanine-derived compound that binds to monoamine transporters.⁴¹ Specifically, it binds to and inhibits human dopamine transporter (hDAT) and human norepinephrine transporters (hNET), blocking their reuptake into the neuron and increasing the extracellular concentrations of these monoamines.⁴⁰ It should be noted that Solriamfetol has no significant impact on the reuptake of the monoamine serotonin (5-HT). Serotonin can still be transported back into the synapse by the human 5-HT transporter (hSERT) in the presence of Solriamfetol.⁴⁰ Solriamfetol does not significantly bind to or impact other pathways included in wakefulness, including histamine receptors, hypocretin receptors, nicotinic acetylcholine receptors, GABA receptors, and it does not inhibit MAO-A or MAO-B enzymes.⁴⁰

The dopamine effects of Solriamfetol are predominantly occurring in nuclear groups within the ventral periaqueductal gray, the ventral tegmental area, and the substantia nigra pars compacta.^39,42 The substantia nigra pars compacta has reciprocal connections to other sleep regulating areas in the brain and has the greatest impact on wakefulness. By blocking the reuptake of dopamine, Solriamfetol increases the concentration of each monoamine within the synapse. Increased dopamine allows it to interact with D1 and D2 receptors and promote wakefulness.⁴² Norepinephrine interactions that have an impact on wakefulness are primarily occurring in the locus coeruleus of the pons. Additional effects of norepinephrine occur within the hypothalamus, thalamus, basal forebrain, and cortex.^39,42 A larger norepinephrine concentration within the synapse increases the interactions between norepinephrine and noradrenergic receptors α 1-, α 2-, and β-adrenergic subtypes, resulting in a sympathomimetic effect.⁴²

Solriamfetol Pharmacokinetics and Pharmacodynamics

Pharmacodynamics

Solriamfetol expresses low affinity for the dopamine (Ki = 14.2 μM) and norepinephrine (Ki = 3.7 μM) receptors while inhibiting their uptake with a modest potency (IC50 = 2.9 μM and IC50 = 4.4 μM, respectively). Solriamfetol lacks any considerable binding affinity for the serotonin transporter and the receptors for; Dopamine, serotonin, norepinephrine, GABA, adenosine, histamine, orexin, benzodiazepine, muscarinic acetylcholine, or nicotinic acetylcholine.³⁷

Pharmacokinetics

Within the dose ranges of 42 to 1008 mg (0.28 to 6.7 times the maximum recommended dosage), Solriamfetol displays a constant half-life, or in other words, linear kinetics. The steady state is reached in three days with a once-per-day frequency of administration that should produce minimum accumulation.³⁷

Absorption & effect of food

Solriamfetol has a bioavailability of 95% that is rapidly absorbed. In a post-dose fasted state, the peak plasma concentration occurs within a medium T_max of 2 hours.³⁷ Coadministration with food results in a delayed absorption by ~1 hour, however, Solriamfetol can be taken in absence of consideration of meals. C_max and AUC_inf changes are minimally influenced with a food and drug combination.⁴³

Distribution

Less than 25% of Solriamfetol is bounded to plasma proteins (13.3 – 19.4%) within the ranges of 0.059 to 10.1 mcg/ml human plasma drug concentration. The volume of distribution is approximately 199 liters with the blood-to-plasma concentration ratios ranging from 1.16 to 1.29.³⁷

Elimination

Solriamfetol tablets demonstrates first order elimination with a T_½ of 7.1 hours. Unmetabolized renal excretion is extensive, accounting for 18.2 L/h of the total clearance of 19.5 L/h. A crossover, randomized, open-label study collected ~90% of the unmetabolized Solriamfetol in the urine post-48 hours of administration.⁴⁴ Approximately 1% of Solriamfetol collected metabolized to its’ inactive metabolite, N-acetyl Solriamfetol.³⁷

Specific Populations

Gender, age, and race have been shown to have no pharmacokinetically relevant effects on the clinically applicable aspects of Solriamfetol. However, it is important to note that clinical studies did not utilize dose adjustments for participants 65 or older and the safety and effectiveness in pediatric populations has not been established.³⁷ Renal dysfunction is associated with progressive decreases in clearance measured by elevations in AUC_inf (53%, 129%, 339%) and T_½ (1.2-, 1.9-, 3.9-fold) in mild, moderate, and severe renal impairment, respectively, in a phase one clinical study.⁴⁴ Overall exposure (AUC_t) in patients with ESRD was 4–5 fold higher in comparison to normal renal function (eGFR ≥ 90 mL/min/1.73m²) as well as a T_½ over 100 h. Solriamfetol is not recommended for individuals with ERD and dose adjustments are advised for moderate (initially 37.5 mg/day; maximum dose of 75 mg/day) to severe renal impairment (initial and maximum dose of 37.5 mg/day).¹ In vitro studies, Solriamfetol is not a potent inhibitor or inducer of CYPs (e.g. CYP 3A4, 2E1, 2D6, 1A2, 2C19) while also having pharmacokinetically irrelevant avidity and antagonistic disposition to transporter systems (e.g. OCT2, MATE1, OATP1B1). Clinically significant diverse drug interactions with highly active CYP450s and transporters is not presumed with patients taking Solriamfetol.³⁷ In contrast, Solriamfetol used concomitantly with drugs that elevate heart rate and/or blood pressure or with dopamine concentration elevating drugs or dopamine receptor agonists should be exercised with caution. Co-administration of Solriamfetol and MAOI or within 14 days of discontinuation of MAOIs should be avoided. MAOIs and noradrenergic drugs amalgamated with Solriamfetol may cause a subsequent hypertensive reaction and increase the risk with its associated complications.³⁷ Solriamfetol induced male rats had no effect on fertility and sperm concentrations given doses 2 and 7 times higher than the MRHD (maximum recommended human dose). However, they did have decrease sperm parameters when given a dosage approximately 22 times (350 mg/kg/day based on mg/m² body surface area) the MRHD without an impact on fertility. Female rats experienced similar results with no effect on fertility (based on mg/m² body surface area) during a time period of two weeks premating, during mating, and day 7 of gestation at 1, 4, and 19 times the MRHD.³⁷ Through extensive clinical research and pharmaceutical drug approval processes, Solriamfetol provided enough relevant evidence and efficacy to be approved by the FDA in March 2019.⁴⁵

Clinical Studies: Safety and Efficacy

Excessive daytime sleepiness (EDS) is a common comorbidity in patients with obstructive sleep apnea (OSA), narcolepsy with and without cataplexy, and Parkinson’s disease (PD). As narcolepsy has no cure, treatment aims at alleviating morbidities, including EDS. Additionally, EDS often persists despite patient adherence to OSA treatment and thus bears significant cost to the healthcare industry. Stimulants, such as dextroamphetamine and methylphenidate are used to treat energy levels in general, modafinil and armodafinil are used to improve excess daytime sleepiness, and sodium oxybate is used for management of excess daytime sleepiness with cataplexy features. While these may be considered effective therapies, there remain concerns regarding the adverse effect (AE) profile and difficulties adequately selecting therapies for individual patients.⁴⁶ Currently, amphetamines lack well controlled studies demonstrating safety and efficacy, and have significant abuse potential. Modafinil and armodafinil do have short- and long-term randomized controlled studies detailing efficacy, however there is concern for waning effects throughout the day, leading to lack of benefit or need for second dosing. Additionally, their hepatic elimination can lead to significant drug-drug interactions, including decreased effectiveness of oral contraceptives.⁴⁷ Other medications, such as tricyclic antidepressants, selective serotonin reuptake inhibitors, and venlafaxine have been used off label but have lower levels of evidence.

As such, new medications with improved efficacy and a more well tolerated side effect profile are desired for the management of EDS and “sleep attacks” in patients with OSA, narcolepsy, and PD. Solriamfetol (formerly JZP-110 and ADX-N05) is a wake-promoting agent with both dopaminergic and noradrenergic reuptake inhibition activity, with no increased release of norepinephrine. Previous, non-clinical trials demonstrated a wake-promoting profile with no side effects frequently observed with stimulant usage. Additionally, compared to amphetamines, preclinical trials of Solriamfetol demonstrated a lack of rebound hypersomnia and recovery of rapid eye movement (REM) and non-REM sleep.³⁶

Bogan et al. demonstrated the safety and efficacy of Solriamfetol for treatment of EDS in narcolepsy using a randomized, double-blind, crossover study compared to placebo. They utilized Epworth sleepiness scale (ESS) and the maintenance of wakefulness test (MWT). Patients were randomized to either a two-week treatment with Solriamfetol or placebo, followed by 2-weeks of the converse. Patients received 150 mg/day for the first week of medication and titrated to 300 mg/day for their second week on therapy. After two weeks, change in MWT sleep latency had increased 11.8 minutes on Solriamfetol compared to placebo. This is beneficial as a longer MWT indicates a longer period of time required to fall asleep for a midday nap, which is an improvement in EDS. Final ESS scores decreased 6.7 in Solriamfetol compared to 2.4 in placebo group. Effects were statistically significant one-week after starting therapy and greater improvement was noted throughout the second week of therapy when dose increased from 150 mg/day to 300 mg/day. Additionally, they found Solriamfetol to be well tolerated, as no serious AE or discontinuations due to medication were noted during the study. The number of AE and patients reporting AEs remained similar between the first and second week of therapy, and the most common AEs were nausea (12%), noncardiac chest pain (9.1%), and headache (9.1%).⁴⁶

In order to measure the efficacy of Solriamfetol over a longer time period, Ruoff et al. conducted a randomized, placebo-control, double-blinded, parallel-group study of adults with narcolepsy. Patients received either placebo or Solriamfetol for 12 weeks. Those in the Solriamfetol group started at 150 mg/day for weeks one through four and titrated to 300 mg/day for weeks five through 12. Chances in baseline MWT sleep latency and clinical global impression-change (CGI-C) were primary endpoints, while a change in ESS score and patient global impression-change (PGI-C) were secondary endpoints. At four weeks, Solriamfetol showed improvement in MWT sleep latency of 9.5 minutes vs 1.4 minutes on placebo, additionally the 80% of patients experienced CGI-C improvements compared to 51% on placebo. Similarly, ESS scores decreased 5.6 compared to 2.4 on placebo. Results at 12 weeks were comparative, with the Solriamfetol group experiencing an even greater improvement in all end point values. A total of three patients treated with Solriamfetol discontinued the trial due to AEs but neither was determined to be secondary to the therapy. The most common AEs included insomnia (23%), headache (16%), nausea (14%), decreased appetite (14%), diarrhea (11%) and anxiety (11%).³⁶

In further studies, Schweitzer et al. compared Solriamfetol 37.5, 75, 150, and 300 mg to placebo for efficacy and safety in patients with EDS who had current or prior OSA. All doses except 37.5 mg lead to improvements in PGI-C, and improvements in MWT and ESS were seen in all doses. Positive effects were dose dependent and maintained throughout the 12-week study, however effects on MWT from 37.5 mg dose did wear off prior to end of day. Thus, Solriamfetol clinically increased wakefulness and decreased sleepiness in patients with EDS. Overall, AE profile was minimal, and most events were mild-to-moderate severity, although a higher percentage of patients on Solriamfetol withdrew compared to placebo (7.3% vs. 3.4%).⁴⁸

Similarly, Thorpy et al. showed that beneficial effects of Solriamfetol for EDS and MWT were observed at 1 week of use and continued for 12 weeks when on 150 mg or 300 mg dose. However, effects were more minimal on 75 mg, with improvement to EDS seen at week one but eventual tapering to no effect by the end of the study. Additionally, on 150 mg and 300 mg doses, effects were maintained throughout a 9-hour duration at the 12-week mark and is an improvement over agents such as armodafinil and modafinil where effects begin to taper after 4-to-5 hours. While a small increase in mean blood pressure and heart rate were observed, it was similar to previously reported studies and wake-promoting agents. Overall Solriamfetol was well tolerated throughout the duration of the study, with the most common adverse effects including headache, nausea, decreased appetite, nasopharyngitis, dry mouth, and anxiety.⁴⁹

Although prior studies have begun to show the efficacy and safety of Solriamfetol for use in narcolepsy, there was a need to stratify effect based on narcolepsy diagnoses with and without cataplexy traits. In a placebo-controlled, double-blind, randomized trial lasting 12 weeks, Dauvilliers et al. stratified patients with narcolepsy by cataplexy status, and treated with either placebo, or Solriamfetol (75, 150, or 300 mg/day). They also used MWT, ESS, and PGI-C as primary and secondary endpoints. Additionally, the frequency of cataplexy attacks was recorded and compared to reported baseline. At week 12, change from baseline of MWT, and ESS, in both cataplexy and non-cataplexy groups improved in a dose dependent manner over placebo. For PGI-C, the cataplexy group also showed a dose-dependent improvement compared to placebo, however the non-cataplexy group did not have a dose dependent response, instead showing similar efficacy for all doses. There were no changes in number of cataplexy attacks when compared to placebo. Finally, AEs were similar between both cataplexy subgroups, with the most common being headache, nausea, decreased appetite, and nasopharyngitis.⁵⁰

While Solriamfetol has had numerous prior studies validating the efficacy and safety in short term (< 12 weeks) usage, few have studied longer term effects. In a study by Malhotra et al., patients with OSA or narcolepsy were given Solriamfetol maintenance phase for 6 months after which, they were randomized into a two-week placebo-controlled randomized withdrawal (RW), where the control group was taken off Solriamfetol and switched to placebo. Using ESS, PGI-C, and CGI-C as endpoints, long term efficacy and safety were identified at this point and continuing for up to 48 weeks after RW period. At completion of the trial, ESS was 5.3 in placebo group and only 1.6 in Solriamfetol groups. Additionally, patients in placebo group reported worse scoring on PGI-C and CGI-C. The similar scorings between PGI-C and CGI-C is important as it highlights that the clinician and patient’s perception of drug benefit to be similar. The RW period is critical, as it shows the effects observed after the maintenance phase of treatment to be attributable to the medication, as these benefits disappeared in the RW placebo group. These results indicate the continued effectiveness of Solriamfetol, past the 12-week mark, which extends the known efficacy based on prior studies. Additionally, the AEs were mild and consistent with prior safety studies. Overall, the most common AEs were headache, nausea, nasopharyngitis, insomnia, dry mouth, anxiety, decreased appetite, and upper respiratory tract infections being most common.⁴⁷

A concern associated with stimulants and wake-promoting agents is their potential for abuse. Especially those which act to increase monoamine release. While Solriamfetol is a wake-promoting agent which modulates the reuptake of dopamine and norepinephrine, it does not have monoamine releasing activity, or at least less than that of traditional stimulants. While prior studies suggest a low potential for abuse, further assessments are important for understanding the abuse liability and potential prior to FDA approval. Carter et al. studied Solriamfetol for abuse potential in recreational polydrug users, based on ratings for Next Day Take Again, Drug Liking at the Moment, and Strength of Drug Effect over first 12 hours. Overall, Solriamfetol has an abuse potential similar to or lower than other schedule IV stimulants, with significant differences in the abuse potential profile. Supratherapeutic doses of 600 and 1200 mg were given to recreational polydrug users and effects evaluated using study parameters validated with phentermine as a positive control compared to placebo. Solriamfetol did have a dose-dependent Drug Liking at the Moment rating, which was significantly higher than placebo, however they were also significantly lower than phentermine 90 mg doses. Additionally, the differences became even more pronounced at 24-hour retrospective evaluation. Secondary measures, including negative drug effects, may explain the lower retrospective ratings, as Solriamfetol also was associated with higher ratings of Bad Effects and a dose-dependent increase in anxiety. There were no serious AEs despite using supratherapeutic doses which are four times the greatest therapeutic dose. Solriamfetol has pharmacodynamic properties similar to other stimulants, but is generally well tolerated and may have a lower abuse potential than other wake promoting or stimulant agents.⁵¹

While other studies have demonstrated the safety and efficacy of Solriamfetol for treatment of EDS, quality of life (QoL) is a critical end point for adequate therapy due to the psychological nature of EDS. Attempts to incorporate QoL using PGI-C, no studies have directly analyzed QoL effects and improvement. Weaver et al. report the effect of Solriamfetol on health-related quality of life (HRQoL), daily function, and work productivity in adults with OSA and EDS. Using Solriamfetol 37.5 mg, 75 mg, 150 mg, or 300 mg compared to placebo, patients completed validated questionnaires regarding perceived effects. At week 12, Solriamfetol increased functioning while decreasing perceived impairment on 150 mg and 300 mg doses across all various questionnaires⁵² similarly, Emsellem et al. investigated QoL improvements on Solriamfetol over a 12 week period. Patients randomized to 75, 150, or 300 mg compared to placebo completed validated surveys at the 12 week mark, with Solriamfetol 150 mg and 300 mg significantly improving functional status, HRQoL, and overall work productivity values.⁵³

Summary

Excessive daytime sleepiness impacts nearly 1/3 of all adults in the US and imposes a tremendous burden on society. Solriamfetol is a promising novel compound that works by increasing neurosynaptic dopamine and norepinephrine. A litany of literature has shown superior efficacy with a mild to moderate safety profile when compared to placebo treatment in multiple phenotypes of excessive daytime sleepiness (e.g.: OSA, narcolepsy with and without cataplexy, Parkinson’s disease). Unlike stimulants such as dextroamphetamine and methylphenidate, Solriamfetol does not have cardiac effects, hypersomnia and withdrawal effects.⁵⁴ Solriamfetol requires further evaluation but it is emerging a safe alternative drug to Modafinil or Armodafinil.

Table 1. Studies Reviewing the Clinical Efficacy and Safety of Solriamfetol for Excessive Daytime Sleepiness.

Author (Year)		Groups Studied and Intervention		Results and Findings		Conclusions
Ruoff et al. (2016) Ruoff C, Swick TJ, Doekel R, Emsellem HA, Feldman NT, Rosenberg R, et al. Effect of Oral JZP-110 (ADX-N05) on Wakefulness and Sleepiness in Adults with Narcolepsy: A Phase 2b Study. Sleep. 2016;39(7):1379–1387.		N = 93, adults with Epworth sleepiness scale (ESS) > 10 and maintenance of wakefulness test (MWT) < 10 min JZP-110 150 mg/day weeks 1–4 and 300 mg/day weeks 5–12 vs. placebo		JZP-110 improved sleep latency, percentage of patients with clinical global impression-change (CGI-C) and mean change in ESS compared to placebo. JZP-110 increases rate of insomnia (15% increased risk), headache (6% increased risk), nausea (8% increased risk), diarrhea (5% increased risk), decreased appetite (14% increased risk) and anxiety (11% increase risk).		JZP-110 (Solriamfetol) doses 150–300 mg/day is well tolerated and improves ability to stay awake and subjective symptoms in adults with narcolepsy. JZP-110 is generally well tolerated.
Bogan et al. (2015) Bogan RK, Feldman N, Emsellem HA, Rosenberg R, Lu Y, Bream G, et al. Effect of oral JZP-110 (ADX-N05) treatment on wakefulness and sleepiness in adults with narcolepsy. Sleep Med. 2015;16(9):1102–1108.		N = 33, 37.1 yo mean age, 57.6% male, adults with Epworth sleepiness scale (ESS) > 10 and maintenance of wakefulness test (MWT) < 10 min JZP-110 150 mg/day weeks 1 and 3 increased to 300 mg/day weeks 2 and 4 vs. placebo		JZP-110 improved MWT sleep latency and ESS on each trial for weeks 1,2,3, and 4. Most common side effects of JZP-110 were nausea (12%), noncardiac discomfort (9.1%) and headache (9.1%).		JZP-110 (Solriamfetol) 150–300 mg/day improves excessive sleepiness after one week and efficacy continues through one month. JZP-110 is generally well tolerated.
Schweitzer et al. (2019) Schweitzer PK, Rosenberg R, Zammit GK, Gotfried M, Chen D, Carter LP, et al. Solriamfetol for excessive sleepiness in obstructive sleep apnea (TONES 3): A randomized controlled trial. Am J Respir Crit Care Med. 2019;199(11):1421–1431.		N = 476, adults with Epworth sleepiness scale (ESS) > 10 and maintenance of wakefulness test (MWT) < 10 min Solriamfetol (37.5, 75, 150, 300 mg) vs. placebo for 12 weeks		Solriamfetol doses > 37.5 improved patient global impression of change, MWT sleep latency and ESS scores at one week. Improvement continued for all 12 weeks. Most common side effects of Solriamfetol were headache (10.1%), nausea (7.9%), decreased appetite (7.6%), anxiety (7%), nasopharyngitis (5.1%).		Solriamfetol has clinically significant improvement in daytime sleepiness in patients with OSA and excessive daytime sleepiness. Solriamfetol adverse events were mild or moderate in severity.
Malhotra et al. (2019) Malhotra A, Shapiro C, Pepin J-L, Hedner J, Ahmed M, Foldvary-Schaefer N, et al. Long-term study of the safety and maintenance of efficacy of solriamfetol (JZP-110) in the treatment of excessive sleepiness in participants with narcolepsy or obstructive sleep apnea. 2019.		N = 643, 226 narcolepsy patient, 417 OSA patients. Solriamfetol vs. placebo given for 50 weeks with 2 week withdrawal after 6 months		Solriamfetol demonstrated sustained improvement in ESS, PGI-C and CGI-C scores over 1 year. A greater number of placebo patients reported subjectively worse outcomes after the randomized withdrawal trial compared to Solriamfetol patients. Most common side effects of Solriamfetol included headache, nausea, nasopharyngitis, insomnia, dry mouth, anxiety, decreased appetite, upper respiratory tract infection. 4.2% had > 1 AE.		Long term (50 weeks) maintenance therapy with Solriamfetol has superior efficacy and comparable safety profile compared to placebo in patients with OSA and narcolepsy.
Thorpy et al. (2019) Thorpy MJ, Shapiro C, Mayer G, Corser BC, Emsellem H, Plazzi G, et al. A randomized study of solriamfetol for excessive sleepiness in narcolepsy. Ann Neurol. 2019;85(3):359–370.		N = 236, adults with MCW sleep latency < 25 min and Epworth Sleepiness Scale (ESS) > 10 Solriamfetol (75, 150, 300 mg/day) vs. placebo for 12 weeks		Solriamfetol 150 mg and 300 mg improved MWT sleep latency and ESS scores at 12 weeks. 78.2% of 150 mg and 84.7% of 300 mg Solriamfetol patients had improved PGI-C compared to placebo. Most common side effects of Solriamfetol included headache (21.5%), nausea (10.7%), decreased appetite (10.7%), nasopharyngitis (9.0%), dry mouth (7.3%), and anxiety (5.1%).		Solriamfetol 150–300 mg/day is an efficacious therapy in excessive daytime sleepiness with a mild safety profile.
Dauvilliers et al. (2020) Dauvilliers Y, Shapiro C, Mayer G, Lammers GJ, Emsellem H, Plazzi G, et al. Solriamfetol for the Treatment of Excessive Daytime Sleepiness in Participants with Narcolepsy with and without Cataplexy: Subgroup Analysis of Efficacy and Safety Data by Cataplexy Status in a Randomized Controlled Trial. CNS Drugs. 2020;34(7):773–784.		N = 231, 117 narcolepsy w/cataplexy subgroup, 114 narcolepsy w/o cataplexy subgroup Solriamfetol (75, 150, 300 mg/day) vs. placebo over 12 weeks		Solriamfetol 150–300 mg/day showed improvements in MWT sleep latency in both cataplexy and non-cataplexy subgroups at week 12. Solriamfetol 150–300 mg/day showed improvement in ESS and PGI-C for cataplexy subgroup. Solriamfetol all doses showed improvement in ESS and PGI-C for non-cataplexy subgroup. Most common side effects of Solriamfetol included headache, nausea, decreased appetite, and nasopharyngitis without deviation between 75,150,300 mg doses.		Solriamfetol is effective in treating EDS in participants with narcolepsy with or without cataplexy at the 150 mg and 300 mg doses.
Carter et al. (2018) Carter LP, Henningfield JE, Wang YG, Lu Y, Kelsh D, Vince B, et al. A randomized, double-blind, placebo-controlled, crossover study to evaluate the human abuse liability of solriamfetol, a selective dopamine and norepinephrine reuptake inhibitor. J Psychopharmacol. 2018;32(12):1351–1361.		N = 43, 74.4% male, 29.3 yo mean age, adults with recent recreational substance abuse hx Crossover study with 6 sequences with 2 day washout periods between. Solriamfetol (300, 600, 1200 mg/day), vs. Phentermine (45, 90 mg/day) vs. placebo		Willingness to take drug again was significantly greater in Solriamfetol 300 mg/day compared to placebo and significantly less compared to Phentermine 45 mg/day and 90 mg/day. Ratings of negative subjective effects were higher with Solriamfetol 600 mg and 1200 mg compared to Phentermine.		High dose Solriamfetol (600–1200 mg) has abuse potential similar to or lower than Phentermine.
Weaver et al. (2020) Weaver TE, Drake CL, Benes H, Stern T, Maynard J, Thein SG, et al. Effects of Solriamfetol on Quality-of-Life Measures from a 12-Week Phase 3 Randomized Controlled Trial. Ann Am Thorac Soc. 2020;17(8):998–1007.		N = 476, adults with OSA and excessive daytime sleepiness Solriamfetol (37.5, 75, 150, 300 mg) vs. placebo over 12 weeks		Solriamfetol 150–300 mg/day improved functional outcomes of sleep questionnaire score, work productivity and activity impairment questionnaire, physical components summary, and mental components summary. AE included headache, nausea, decreased appetite, and anxiety.		Solriamfetol 150, 300 mg improves functioning, quality of life, work productivity in adults with OSA and excessive daytime sleepiness.
Emsellem et al. (2020) Emsellem HA, Thorpy MJ, Lammers GJ, Shapiro CM, Mayer G, Plazzi G, et al. Measures of functional outcomes, work productivity, and quality of life from a randomized, phase 3 study of solriamfetol in participants with narcolepsy. Sleep Med. 2020;67:128–136.		N = 239, adults with narcolepsy Solriamfetol (75, 150, 300 mg/day) vs. placebo over 12 weeks		Solriamfetol 300 mg/day improved functional outcomes of sleep questionnaire (FOSQ-10) and the physical component summary score of SF-36v2 compared to placebo. Solriamfetol 150 mg/day improved work productivity and activity impairment questionnaire (WPAI:SHP) compared to placebo.		Solriamfetol 150 and 300 mg doses improved functional status, health quality of life, and work productivity compared to placebo with mild to moderate side effects.