Narcolepsy Consensus Guidelines

Cardiovascular Risks in People With Narcolepsy:

Expert Panel Consensus
Recommendations

Kwon Y, Gami AS, Javaheri S, et al.

J Am Heart Assoc. 2024;13(16):e035168.

Disclaimer:

This journal article is being provided as a professional courtesy by Jazz Pharmaceuticals. This scientific publication contains information not contained within the accompanying package inserts. XYWAV^® (calcium, magnesium, potassium, and sodium oxybates) oral solution and XYREM^® (sodium oxybate) oral solution have only been proven safe and effective for the treatment of cataplexy and/or excessive daytime sleepiness (EDS) in patients 7 years of age and older with narcolepsy. Providing this e-print should not be construed as a recommendation for use of any Jazz Pharmaceuticals product for nonapproved uses. Prior to prescribing, please refer to the accompanying Prescribing Information that includes approved indications and a complete discussion of the risks and benefits associated with our product(s).

The opinions expressed in this e-print do not necessarily reflect those of Jazz Pharmaceuticals. Readers are encouraged to contact the primary author with questions regarding the contents of the e-print. Jazz Pharmaceuticals does not assume responsibility for any injury and/or damage to any persons or property out of, or related to, any use of the information contained in this e-print.

Sources of Funding:

This study was sponsored by Jazz Pharmaceuticals. Jazz Pharmaceuticals provided funding to Peloton Advantage for medical writing and editorial support. Jazz Pharmaceuticals did not conduct a review of the manuscript.

Disclosures:

Dr Kwon has consulted for Jazz Pharmaceuticals and Caretaker Medical and has received funding from the National Institutes of Health, Department of Defense, and ResMed Foundation. Dr Gami has consulted for Jazz Pharmaceuticals. Dr Javaheri has received payment from Jazz Pharmaceuticals for presentation and for participation in the consensus panel that developed these recommendations, is on the speakers bureau of Avadel and Idorsia Pharmaceuticals, has received payment from Eli Lilly and Company for consultation, and is a consultant to Zoll-Respicardia. Dr Pressman has participated in the Cardiometabolic Health Congress, a division of Tarsus Medical. Dr Scammell has consulted for Avadel, Axsome, Consynance, Eisai, Harmony Biosciences, Idorsia, Jazz Pharmaceuticals, Merck, Paladin Labs, Orion Pharma, Takeda, Tris Pharmaceuticals, Vertex Pharmaceuticals, and Woolsey Pharmaceuticals; and has received research grants from the National Institutes of Health, Avadel, Merck, Harmony Biosciences, Jazz, and Takeda. Dr Surkin has participated in advisory boards for Jazz Pharmaceuticals, Takeda Pharmaceuticals, and Alkermes Inc. Dr Zee serves on scientific advisory boards for Jazz, Eisai, and Harmony Biosciences; serves as a consultant for CVS Caremark; and owns stock in Teva.

Please see the Important Safety Information below and accompanying full Prescribing Information, including BOXED Warning, for XYWAV and XYREM.

Click here to access the full article

INDICATIONS AND USAGE

XYWAV^® (calcium, magnesium, potassium, and sodium oxybates) oral solution, 0.5 g/mL total salts (equivalent to 0.413 g/mL of oxybate) is indicated for the treatment of cataplexy or excessive daytime sleepiness (EDS) in patients 7 years of age and older with narcolepsy.

Important Safety Information

WARNING: CENTRAL NERVOUS SYSTEM DEPRESSION and ABUSE AND MISUSE.

Central Nervous System Depression
XYWAV is a CNS depressant. Clinically significant respiratory depression and obtundation may occur in patients treated with XYWAV at recommended doses. Many patients who received XYWAV during clinical trials in narcolepsy were receiving CNS stimulants.
Abuse and Misuse
The active moiety of XYWAV is oxybate or gamma-hydroxybutyrate (GHB). Abuse or misuse of illicit GHB, either alone or in combination with other CNS depressants, is associated with CNS adverse reactions, including seizure, respiratory depression, decreases in the level of consciousness, coma, and death.

Because of the risks of CNS depression and abuse and misuse, XYWAV is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the XYWAV and XYREM REMS.

Contraindications

XYWAV is contraindicated in combination with sedative hypnotics or alcohol and in patients with succinic semialdehyde dehydrogenase deficiency.

Warnings and Precautions

CNS Depression: Use caution when considering the concurrent use with other CNS depressants. If concurrent use is required, consider dose reduction or discontinuation of one or more CNS depressants (including XYWAV). Consider interrupting XYWAV treatment if short-term opioid use is required. After first initiating treatment and until certain that XYWAV does not affect them adversely, caution patients against hazardous activities requiring complete mental alertness or motor coordination such as operating hazardous machinery, including automobiles or airplanes. Also caution patients against these hazardous activities for at least 6 hours after taking XYWAV. Patients should be queried about CNS depression-related events upon initiation of XYWAV therapy and periodically thereafter.
Abuse and Misuse: XYWAV is a Schedule III controlled substance. The rapid onset of sedation, coupled with the amnestic features of GHB, particularly when combined with alcohol, has proven to be dangerous for the voluntary and involuntary user (eg, assault victim).
Respiratory Depression and Sleep-Disordered Breathing: XYWAV may impair respiratory drive, especially in patients with compromised respiratory function. In overdoses of oxybate and with illicit use of GHB, life-threatening respiratory depression has been reported. Increased apnea and reduced oxygenation may occur with XYWAV administration in adult and pediatric patients. A significant increase in the number of central apneas and clinically significant oxygen desaturation may occur in patients with obstructive sleep apnea treated with XYWAV. Prescribers should be aware that sleep-related breathing disorders tend to be more prevalent in obese patients, in men, in postmenopausal women not on hormone replacement therapy, and among patients with narcolepsy.
Depression and Suicidality: In Study 1, the pivotal clinical trial in adult patients with narcolepsy (n=201), depression and depressed mood were reported in patients treated with XYWAV. In most cases, no change in XYWAV treatment was required. Two suicides and two attempted suicides occurred in adult clinical trials with oxybate (same active moiety as XYWAV). One patient experienced suicidal ideation and two patients reported depression in a pediatric clinical trial with oxybate. Monitor patients for the emergence of increased depressive symptoms and/or suicidality while taking XYWAV, which require careful and immediate evaluation.
Other Behavioral or Psychiatric Adverse Reactions: Monitor patients for impaired motor/cognitive function or the emergence of or increase in anxiety and/or confusion. The emergence or increase in the occurrence of behavioral or psychiatric events in patients taking XYWAV should be carefully monitored.
Parasomnias: In pivotal clinical trials, parasomnias including sleepwalking were reported in adult patients treated with XYWAV. Parasomnias, including sleepwalking, also have been reported in a pediatric clinical trial with sodium oxybate (same active moiety as XYWAV) and in postmarketing experience with sodium oxybate. Episodes of sleepwalking should be fully evaluated and appropriate interventions considered.

Most Common Adverse Reactions

In Study 1, the most common adverse reactions (incidence ≥5% of XYWAV-treated patients) were headache, nausea, dizziness, decreased appetite, parasomnia, diarrhea, hyperhidrosis, anxiety, and vomiting.

In the pediatric clinical trial with XYREM (same active moiety as XYWAV) in patients 7 years of age and older with narcolepsy, the most common adverse reactions (≥5%) were nausea (20%), enuresis (19%), vomiting (18%), headache (17%), weight decreased (13%), decreased appetite (9%), dizziness (8%), and sleepwalking (6%). The safety profile in pediatric patients with XYWAV is expected to be similar to that of adult patients treated with XYWAV and to that of pediatric patients treated with XYREM.

Please see full Prescribing Information, including Boxed Warning.

INDICATIONS AND USAGE

XYREM^® (sodium oxybate) oral solution, 0.5 g/mL is indicated for the treatment of cataplexy or excessive daytime sleepiness (EDS) in patients 7 years of age and older with narcolepsy.

Important Safety Information

WARNING: CENTRAL NERVOUS SYSTEM DEPRESSION and ABUSE AND MISUSE.

Central Nervous System Depression
XYREM is a Central Nervous System (CNS) depressant. In clinical trials at recommended doses, obtundation and clinically significant respiratory depression occurred in adult patients treated with XYREM. Many patients who received XYREM during clinical trials in narcolepsy were receiving CNS stimulants.
Abuse and Misuse
XYREM is the sodium salt of gamma hydroxybutyrate (GHB). Abuse or misuse of illicit GHB, either alone or in combination with other CNS depressants, is associated with CNS adverse reactions, including seizure, respiratory depression, decreases in the level of consciousness, coma, and death.

Contraindications

XYREM is contraindicated for use in combination with sedative hypnotics or alcohol and in patients with succinic semialdehyde dehydrogenase deficiency.

Warnings and Precautions

CNS Depression: Use caution when considering the concurrent use of XYREM with other CNS depressants. If concurrent use is required, consider dose reduction or discontinuation of one or more CNS depressants (including XYREM). Consider interrupting XYREM treatment if short-term opioid use is required. After first initiating treatment and until certain that XYREM does not affect them adversely, caution patients against hazardous activities requiring complete mental alertness or motor coordination such as operating hazardous machinery, including automobiles or airplanes. Also caution patients against these hazardous activities for at least 6 hours after taking XYREM. Patients should be queried about CNS depression-related events upon initiation of XYREM therapy and periodically thereafter.
Abuse and Misuse: XYREM is a Schedule III controlled substance. The rapid onset of sedation, coupled with the amnestic features of XYREM, particularly when combined with alcohol, has proven to be dangerous for the voluntary and involuntary user (eg, assault victim).
Respiratory Depression and Sleep-Disordered Breathing: XYREM may impair respiratory drive, especially in patients with compromised respiratory function. In overdoses, life-threatening respiratory depression has been reported. Prescribers should be aware that increased central apneas and clinically relevant desaturation events have been observed with XYREM administration in adult and pediatric patients. Sleep-related breathing disorders tend to be more prevalent in obese patients, in men, in postmenopausal women not on hormone replacement therapy and among patients with narcolepsy.
Depression and Suicidality: In adult clinical trials in patients with narcolepsy (n=781), depression was reported by 7% of XYREM-treated patients, with four patients (<1%) discontinuing because of depression. In the pediatric clinical trial in patients with narcolepsy (n=104), one patient experienced suicidal ideation and two patients reported depression while taking XYREM. Monitor patients for emergent or increased depression and/or suicidality, which require careful and immediate evaluation.
Other Behavioral or Psychiatric Adverse Reactions: Monitor patients for impaired motor/cognitive function or the emergence of or increase in anxiety and/or confusion. The emergence or increase in the occurrence of behavioral or psychiatric events in adult and pediatric patients taking XYREM should be carefully monitored.
Parasomnias: Episodes of sleepwalking should be fully evaluated and appropriate interventions considered. Five instances of significant injury or potential injury were associated with sleepwalking during a clinical trial of XYREM in adult patients with narcolepsy. Parasomnias, including sleepwalking, also have been reported in the pediatric clinical trial and in postmarketing experience with XYREM.
Patients Sensitive to High Sodium Intake: XYREM has a high salt content. In patients sensitive to salt intake (eg, those with heart failure, hypertension, or renal impairment), consider the amount of daily sodium intake in each dose of XYREM.

Most Common Adverse Reactions

In three controlled adult clinical trials in patients with narcolepsy, the most common adverse reactions (incidence ≥5% and twice the rate of placebo) in XYREM-treated patients were nausea, dizziness, vomiting, somnolence, enuresis, and tremor. In the pediatric clinical trial in patients 7 years of age and older with narcolepsy, the most common adverse reactions (≥5%) were nausea (20%), enuresis (19%), vomiting (18%), headache (17%), weight decreased (13%), decreased appetite (9%), dizziness (8%) and sleepwalking (6%).

Please see accompanying full Prescribing Information, including BOXED WARNING.