Sodium Oxybate Formulations In the Management of Narcolepsy: A Focus on Patient Preference 

Sodium Oxybate in the Management of Narcolepsy:
One Molecule, Three Formulations – and the Critical Role of Shared Decision-Making in Its Use
Clete A. Kushida, MD, PhD and Michael J. Thorpy, M

Introduction

Three different oxybate formulations are available for the management of narcolepsy with/without cataplexy. While there are dosing differences between them, all are equally efficacious. Shared decision-making (SDM) between patient and clinician is important when selecting the best formulation for each patient. In this ECHO, Drs. Kushida and Thorpy 1) discuss the individual product attributes of the available oxybate formulations, 2) address patient and clinician preferences when selecting a formulation, and 3) provide strategies by which clinicians can elicit a patient’s goals and concerns related to their treatment for narcolepsy with/without cataplexy.

The Oxybate Formulations for Narcolepsy with/without Cataplexy

Oxybate formulations indicated to treat narcolepsy all contain the same active ingredient, oxybate, and as mentioned are all equally effective.¹ All oxybate formulations treat the three main symptoms of narcolepsy: excessive daytime sleepiness (EDS), abnormal rapid eye movement (REM) sleep phenomena of which cataplexy is the primary symptom, and disturbed nocturnal sleep.^1,2

In 2002, Xyrem became the first sodium oxybate-based medication approved for narcolepsy.^3,4 The 9-g maximum dosage contains 1.64 g of sodium. In 2020, Xywav was introduced as a formulation with 92% less sodium than Xyrem, achieved by incorporating mixed salts of oxybates including calcium, magnesium, potassium, and sodium.^5,6

Xyrem and Xywav are dosed twice nightly, with the first dose taken before bedtime and the second dose 2.5 to 4 hours after bedtime.^3,4,6 Both medications are typically offered in equal doses, although dosing may be asymmetrical. Twice-nightly dosing can be an impediment to treatment adherence as this requires patients to awaken for the second dose.³ Patients often relate that they have difficulty awakening for the second dose or take the second dose later than prescribed. As the second dose must be taken approximately 4 hours before awakening in the morning, late dosing can adversely impact alertness during the subsequent day.

A third oxybate-based formulation is Lumryz.⁷ Lumryz contains the same maximum dose sodium per night as Xyrem, but Lumryz is a novel extended-release formulation requiring only a single dose before bedtime.^4,6,7

Each oxybate formulation is available through its own Risk Evaluation and Mitigation Strategy (REMS) program to ensure safe use.^8,9 All the oxybate formulations have boxed warnings about central nervous system depression, abuse, and misuse.^4,6,7 In clinical trials, the most common adverse effects of the oxybates in adults (≥5%) were nausea, dizziness, enuresis, headache, vomiting, somnolence, anxiety, insomnia, decreased appetite, hyperhidrosis, diarrhea, dry mouth, parasomnia, fatigue, and tremor.^4,6

When prescribing an oxybate formulation for narcolepsy with/without cataplexy, clinicians need to consider adherence to the dosing regimen. Moreover, in a younger patient with a preexisting sleep debt, waking in the middle of the night may be a struggle for them and/or their caregiver. Conversely, patients who inadvertently take the second dose too soon (<2.5 hours after the first dose) may experience moderate to severe adverse effects, such as breathing difficulties, dizziness, seizures, falling, vomiting, or enuresis.⁹

“Because the second dose has to be taken at least 4 hours before awakening in the morning, sometimes people may be too late to take that second dose.”

—Michael J. Thorpy, MD

The sodium content in some oxybate formulations can be a prescribing issue for certain patients,  particularly those who have impaired renal function, congestive heart failure, or uncontrolled hypertension.^5,10 That said, given that all three oxybate formulations are equally effective for treating the three main symptoms of narcolepsy—EDS, abnormal REM sleep phenomena, and disturbed nocturnal sleep—the patient must be involved in determining the formulation with which they would be most compliant. This is why shared decision making (SDM) has become an essential dialogue when prescribing an oxybate formulation that best fits into a patient’s routine.¹⁰

“Shared decision-making, or SDM, is critical in optimizing patient outcomes and ensuring long-term adherence to therapy for narcolepsy with or without cataplexy.”

—Clete A. Kushida, MD, PhD

Shared Decision-Making in Narcolepsy with/without Cataplexy: Quality of Life Issues

Narcolepsy is a burdensome illness for the patient.¹⁰ The main symptom, EDS, affects every aspect of a patient’s life, including their driving, which puts them at risk of a motor vehicle accident.¹¹ Narcolepsy with/without cataplexy can substantially impair an individual’s daily routine and personal and professional productivity, as well as their psychosocial interactions and intimacy. For these reasons, it is imperative that individuals adhere to their daily treatment.

“It’s important that we effectively treat the daytime sleepiness not only for the patient’s comfort and benefit of being without the sleepiness, but also from a safety point of view and other peoples’ safety.”

—Michael J. Thorpy, MD

Abnormal REM sleep phenomena, such as cataplexy, occurs in narcolepsy.¹¹ Cataplexy can be frightening and disabling, especially in an untreated patient. After laughing or hearing a joke, for example, an individual with cataplexy may fall to the ground, resulting in injuries.¹¹

Another symptom of abnormal REM sleep is sleep-related hallucination.¹¹ Patients with this presentation start to dream as they are waking up or as they are falling asleep, which also can be frightening.  Nightmares and weird or distressing dreams can persist into periods when the patient is awake. Sleep paralysis can be horrifying to the patient, and often occurs in patients with untreated or undertreated narcolepsy.¹¹ Such sleep disturbances result in daytime symptoms that interfere with an individual’s schoolwork or work activities, not to mention an individual’s daily routine.

The purpose of undertaking SDM is to find the best therapy for the patient, one that addresses their symptoms, eases their concerns, and leads to medication compliance. All these issues affect prescribing decisions. Some patients may be concerned about their lifelong need to take scheduled medications and whether these treatments will become habit-forming.¹⁰ Others may be concerned about the potential side effects of taking a chronic medication, including gastrointestinal disturbances, metabolic changes, and drug-drug interactions.^10,11 This is not an easy discussion, but patients are typically motivated as the impact of narcolepsy on their quality of life is substantial.

Shared Decision-Making in Narcolepsy with/without Cataplexy: Advantages for the Patient

A complex disorder such as narcolepsy warrants a frank discussion with patients, starting with the initial evaluation. SDM allows patients to consider the affected aspects of their lifestyle and their treatment goals, and to bring other important parts of their life into the therapy plan. Diet and exercise should also be taken into consideration for treatment planning.¹⁰ Clinicians should inquire about use of lifestyle substances such as caffeine, nicotine, alcohol, cannabis, and other drugs, ideally before devising a treatment plan.¹⁰ Incorporation of SDM into treatment discussions between clinicians and patients is proven to improve patients’ adherence to therapy and lessen their anxiety or fear about the proposed treatment.¹⁰

“Part of the reason why there’s such an emphasis on shared decision-making, instead of a more ‘paternalistic’ approach towards the patient, is shared decision-making really includes the ability to discuss with the patient their lifestyle and how important different facets of their life are to the prescribed treatment.”

—Clete A. Kushida, MD, PhD

Sleep habits are another critical consideration to address during the SDM discussion. Patients need to be candid about their sleep schedule – when they go to bed and when they wake up. If they tend to sleep deeply through the night and have difficulty waking up during the night, once-nightly dosing may be preferrable to a medication requiring twice-nightly dosing.³ At least 8 hours of nighttime sleep with stable bedtime and wake times are essential. Also, as patients are usually part of a family unit, family issues also need to be addressed. Thus, SDM need not take place only between the patient and the physician, but instead may involve the entire family as a means to optimize outcomes.

Concluding Comments

To optimize treatment outcomes, patients should seek clinicians who are familiar with the oxybate formulations indicated for narcolepsy with/without cataplexy. When discussing treatment approaches with their clinicians, patients should be urged to detail all their concerns about the debilitating nature of narcolepsy and be open about what aspects of their condition most affect their daily routine. By engaging in a fully informed SDM conversation, patients and their clinicians can arrive at mutual decisions about the best treatment course for narcolepsy. The result will be better adherence to the chosen regimens and improved quality of life for patients and their family.

References:

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7. Lumryz. Prescribing information. Avadel CNS Pharmaceuticals, LLC; 2023. Accessed January 24, 2024. https://www.avadel.com/lumryz-prescribing-information.pdf
8. US Food and Drug Administration. Approved Risk Evaluation and Mitigation Strategies (REMS). Accessed January 25, 2024. https://www.accessdata.fda.gov/scripts/cder/rems/index.cfm
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