Introduction

Sodium oxybate has emerged as a crucial therapeutic option for managing narcolepsy symptoms, particularly cataplexy and excessive daytime sleepiness.^1,2 However, the sodium content of nightly dosing has come under scrutiny as the underlying pathology of narcolepsy increases patient’s general risk for cardiovascular disease (CVD).^3,4 Notwithstanding, recent long-term studies on the use of sodium oxybate provide reassuring data regarding its cardiovascular safety and show no significant increase in adverse cardiovascular events or blood pressure changes in patients without preexisting CVD.^5-10 This summary explores the cardiovascular safety profile of sodium oxybate; the development of a more convenient once-nightly formulation with similar efficacy to twice-nightly sodium oxybate dosing; and the means to reduce the significant risk of dosing errors associated with twice-nightly formulations.

Cardiovascular Safety of Sodium Oxybate Formulations in Narcolepsy

Patients with narcolepsy tend to exhibit a greater risk for hypertension, hyperlipidemia, and increased cardiovascular risks related to the underlying pathology of narcolepsy: lack of hypocretin and chronic disruption of normal sleep patterns.³ As such, sodium intake is always a consideration in such patients, leading to concerns about the high sodium content in standard sodium oxybate products (Xyrem® @ twice-nightly dosing, Jazz Pharmaceuticals; and Lumryz™ @ once-nightly dosing, Avadel Pharmaceuticals).^11,12 Standard sodium oxybate products contain between 550 and 1640 mg of sodium in divided daily doses (depending on the 3- to 9-g dosage range) and a formulation with 92% less sodium content is available (Xywav®@ twice-nightly dosing, Jazz Pharmaceuticals).¹³ Although government guidelines recommend that adults limit sodium intake to 2300 mg daily, typical American consumption ranges from 3000 to 6000 mg daily.^14-16

A 2020 Sleep Medicine article reviewing the literature on sodium oxybate's cardiovascular risks in patients with narcolepsy found that both high sodium intake and narcolepsy-related comorbidities may contribute to increased cardiovascular risk.¹² However, data from studies regarding a high-sodium oxybate formulation (Xyrem®) in patients with narcolepsy have shown a very low frequency of cardiovascular side effects, such as hypertension, and no overall association with cardiovascular risk.^5-10 Without data that specifically address the cardiovascular risk of sodium oxybate based on its sodium content, clinical evidence to date suggests that sodium oxide treatment does not confer additional cardiovascular risk in patients with narcolepsy.

Multiple clinical trials of sodium oxybate, some of which have followed patients for nearly 2 years of treatment, have reported almost no cardiovascular events.^5-10 No cardiovascular events were reported in a multicenter, double-blind, randomized, placebo-controlled trial published in 2002 that compared the effects of 3 doses of sodium oxybate with placebo in 136 participants with narcolepsy.⁵ A year later, the same group published the results of a 12-month, multicenter, open-label extension trial, which evaluated the long-term safety and efficacy of sodium oxybate in 118 patients with narcolepsy. Only one cardiovascular event was reported, but it was not considered to be related to sodium oxybate therapy.⁶ No cardiovascular events were reported in a 2004 multicenter, randomized withdrawal trial of sodium oxybate's long-term efficacy for cataplexy in 55 patients with narcolepsy who had been taking the medication for between 7 and 44 months.⁷ The same was true of a multicenter, double-blind, randomized, placebo-controlled trial examining sodium oxybate's effects on cataplexy in 220 patients with narcolepsy that was reported a year later.⁸

In 2015, Mamelak and colleagues published the results of a 12-week, multicenter, open-label trial in 202 participants that evaluated the safety and efficacy of sodium oxybate titrated to effect; no cardiovascular events were reported during the trial.⁹ In 2018, Plazzi and colleagues published the results of a multicenter, double-blind, placebo-controlled, randomized withdrawal trial of sodium oxybate with an open-label extension in 106 children and adolescents and also reported no cardiovascular events.¹⁰

Rates of cardiovascular events are also very low in post-marketing studies of sodium oxybate.^17-19 For product introduction in the United States through March 2008, increased blood pressure was reported in 0.4% of 26,000 patients.¹⁷ An international post-marketing surveillance study from 2002 to 2011 identified 17 cardiac events and 6 cerebrovascular accidents.¹⁸ In a post-authorization surveillance study of 730 patients requested by the European Medicines Agency for sodium oxybate's risk management plan, treatment-emergent adverse events (AEs) in patients with narcolepsy (n = 670) included hypertension (0.4%), angina pectoris (0.3%), and cerebrovascular disorder and circulatory collapse (0.1% each).¹⁹

In summary, collective cardiovascular findings for sodium oxybate use in patients with narcolepsy demonstrate an exceptionally low frequency of cardiovascular side effects such as hypertension and no overall association with cardiovascular risk.

Once-Nightly Sodium Oxybate in Narcolepsy: Cardiovascular Safety Data

The once-nightly formulation of sodium oxybate (Lumryz™) combines immediate-release (IR) and controlled-release sodium oxybate microparticles, delivering the equivalent of two 3-g doses of the twice-nightly version.^13,20 Its pharmacokinetic (PK) profile allows for a more regular sleep pattern in the first half of the night compared with twice-nightly dosing formulations.²¹

To evaluate the clinical benefits of the optimized PK profile, researchers conducted the phase 3 REST-ON trial, a double-blind, placebo-controlled study examining the efficacy and safety of once-nightly sodium oxybate in patients with narcolepsy.²² Sodium oxybate demonstrated significant improvements versus placebo across all primary endpoints, including reduced sleepiness (measured by the Epworth Sleepiness Scale and sleep latency), decreased cataplexy attacks, and better overall clinical improvement ratings. There were no clinically meaningful changes from baseline in clinical laboratory values, blood pressure, or heart rate for once-nightly sodium oxybate compared with placebo.²²

A nocturnal questionnaire at baseline, patient preference questionnaire after 3 months on sodium oxybate, and an end-of-study questionnaire were used to assess outcomes in the phase 3 RESTORE extension study of participants with narcolepsy who switched from twice-nightly to once-nightly sodium oxybate.²³ Patients taking twice-nightly sodium oxybate at baseline reported inconvenience or adherence issues with chronically waking in the middle of the night to re-dose.²³

The 3 standard formulations of sodium oxybate (Xyrem®, Xywav®, and Lumryz™) are all listed as approved drug products with therapeutic equivalent evaluations, meaning they all work equivalently.^13,20,24,25 Clinicians should have confidence using any of these formulations to treat narcolepsy, including the once-nightly regimen.

Accidental Dosing Errors With Immediate-Release Sodium Oxybate in Narcolepsy

Sodium oxybate has been approved by the US Food and Drug Administration (FDA) to treat narcolepsy for more than 20 years. However, before 2023, the only available products were IR formulations given twice nightly—once at bedtime and a second dose 2.5 to 4 hours later. This dosing schedule had inherent risks which led to dosing administration errors, some of which were associated with severe injuries and several with deaths.²⁶

Given the concerns about dosing errors with IR formulations, researchers sought to quantify the scope and severity of the problem through analysis of data from the FDA Adverse Event Reporting System (FAERS). FAERS is an electronic database that supports post-marketing safety surveillance of approved drugs and biologics by enabling epidemiologists and scientists to store, analyze, and evaluate safety reports to detect potential safety signals. In a 2023 study, Gudeman and colleagues used FAERS data to assess the safety risks of accidental dosing errors surrounding IR twice-nightly sodium oxybate formulations.²⁶ Through March 31, 2022, there were 541 reports that included the term “inappropriate schedule of product administration” as a reaction to the IR twice-nightly oxybates.²⁶ In 178 of those reports, IR twice-nightly sodium oxybate was the suspect product and the patient had a serious outcome. Of these 178 reports, 41 were classified as serious and described patients accidentally taking their second dose less than 2.5 hours after the first dose and experiencing one or more AEs as a result.²⁶ The authors also examined the timing of dosing errors, which varied as follows: 20% of patients took their 2 doses at the same time or at almost the same time, and 39% and 61% of patients took their second dose less than 1 hour and between 1 and 2.5 hours after the first dose, respectively.²⁶

Factors that contributed to patient consumption of a second dose less than 2.5 hours after the first dose were also examined and included being distracted, forgetting or restarting routines, and sleepwalking, which is a known potential side effect of oxybates in general.²⁶ The authors found that some patients did not check or readjust their alarm clocks to ensure that enough time had passed before the first and second doses. Others misunderstood the prescribed dosing frequency or misread the directions.

Of the 129 patients who completed the baseline questionnaire, 69% reported missing their second dose, 80% of whom felt that their symptoms were worse the next day.²³ 94% of the participants who completed the patient preference questionnaire preferred once-nightly oxybate to twice-nightly oxybate dosing.²³ 79% of the switch participants who completed the end-of-study questionnaire were more satisfied with once-nightly sodium oxybate than with other narcolepsy treatments. At study completion, 91% said they were better able to sleep through the night since starting treatment with once-nightly sodium oxybate (Lumryz™) and more easily followed the recommended medication schedule for the once-nightly formulation compared with twice-nightly sodium oxybate dosing.

To help improve patient understanding of their sodium oxybate treatment regimen and its risks, sodium oxybate formulations are only available through a Risk Evaluation and Mitigation Strategy (REMS) program, which requires certification of prescribers and pharmacies, patient enrollment, and comprehensive screening and counseling. Patient education materials are also key for counseling about how to correctly use sodium oxybate products.

Conclusion

Although multiple clinical trials and post-marketing surveillance have established the cardiovascular safety profile of sodium oxybate, the risk of dosing errors with twice-nightly formulations remains an ongoing challenge. Development of a once-nightly formulation simplifies the regimen, addresses patient adherence issues, and reduces the risk of administration errors while maintaining therapeutic efficacy. This advance in treatment for narcolepsy, combined with continued REMS program oversight, provides clinicians and patients with an additional choice for therapy while prioritizing both safety and effectiveness.

References

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