Cardiovascular Safety, Due to Reduced Sodium, Is the Basis for XYWAV Clinical Superiority Over XYREM, a High-Sodium Oxybate
The FDA determined that XYWAV is clinically superior to high-sodium oxybate XYREM® due to greater cardiovascular safety because the reduction in sodium at recommended doses will help a substantial portion of indicated patients reduce the risk of developing cardiovascular disease.*
“XYWAV is clinically superior to XYREM by means of greater safety because XYWAV provides a greatly reduced chronic sodium burden”
“The differences in sodium content between XYWAV and XYREM at recommended doses will be clinically meaningful in reducing cardiovascular morbidity in a substantial proportion of patients for whom the drug is indicated”
*Based on a determination of Orphan Drug Exclusivity (ODE) by the FDA Office of Orphan Products Development (OOPD) between XYWAV and XYREM. There are no head-to-head data for XYWAV and XYREM.
Reference: US Food & Drug Administration. https://www.fda.gov/industry/designating-orphan-product-drugs-and-biological-products/clinical-superiority-findings. Accessed March 4, 2024.
Clinical Superiority Designations
The FDA may award orphan drug exclusivity on the basis of demonstrated clinical superiority when the drug is shown to provide a significant therapeutic advantage over and above the same approved drug in one or more of the following ways.
Cardiovascular safety, due to reduced sodium, is the basis for XYWAV clinical superiority over XYREM.1,*
Summary of Clinical Superiority Criteria
Greater safety in a substantial portion of the target populations, eg, by the elimination of an ingredient or contaminant that is associated with frequent adverse effects. In some cases, direct comparative clinical trials will be necessary
*Based on a determination of Orphan Drug Exclusivity (ODE) by the FDA Office of Orphan Products Development (OOPD) between XYWAV and XYREM. There are no head-to-head data for XYWAV and XYREM.
Important Safety Information
Additional Adverse Reactions
Additional adverse reactions that occurred in ≥2% of adult patients with narcolepsy treated with XYWAV in the Open-Label Titration and Stable Dose Periods of Study 1 were fatigue, dry mouth, depressed mood, enuresis, irritability, paresthesia, depression, tremor, somnolence, and muscle spasms.
Adverse reactions that occurred in ≥2% of patients in clinical studies with XYREM (but not in Study 1) and which may be relevant for XYWAV, were pain, pain in extremity, cataplexy, disturbance in attention, sleep paralysis, and disorientation.
Discontinuation: In Study 1, 9 of 201 patients with narcolepsy (4%) reported adverse reactions that led to withdrawal from the study (anxiety, decreased appetite, depressed mood, depression, fatigue, headache, irritability, nausea, pain in extremity, parasomnia, somnolence, and vomiting). The most common adverse reaction leading to discontinuation was nausea (1.5%). The majority of adverse reactions leading to discontinuation began during the first few weeks of treatment.
In the pediatric clinical trial with XYREM (same active moiety as XYWAV), 7 of 104 patients reported adverse reactions that led to withdrawal from the study (hallucination, tactile; suicidal ideation; weight decreased; sleep apnea syndrome; affect lability; anger, anxiety, depression; and headache).
Adverse reactions that occurred in ≥2% of patients in clinical studies with XYREM (but not in Study 1) and which may be relevant for XYWAV, were pain, pain in extremity, cataplexy, disturbance in attention, sleep paralysis, and disorientation.
Discontinuation: In Study 1, 9 of 201 patients with narcolepsy (4%) reported adverse reactions that led to withdrawal from the study (anxiety, decreased appetite, depressed mood, depression, fatigue, headache, irritability, nausea, pain in extremity, parasomnia, somnolence, and vomiting). The most common adverse reaction leading to discontinuation was nausea (1.5%). The majority of adverse reactions leading to discontinuation began during the first few weeks of treatment.
In the pediatric clinical trial with XYREM (same active moiety as XYWAV), 7 of 104 patients reported adverse reactions that led to withdrawal from the study (hallucination, tactile; suicidal ideation; weight decreased; sleep apnea syndrome; affect lability; anger, anxiety, depression; and headache).
Drug Interactions
XYWAV is contraindicated in combination with alcohol or sedative hypnotics. Use of other CNS depressants may potentiate the CNS-depressant effects of XYWAV.
Concomitant use of sodium oxybate with divalproex sodium results in an increase in systemic exposure to GHB, which was shown to cause a greater impairment on some tests of attention and working memory in a clinical study. A similar increase in exposure is expected with concomitant use of XYWAV and divalproex sodium; therefore, an initial dose reduction of XYWAV is recommended when used concomitantly with divalproex sodium. Prescribers are advised to monitor patient response closely and adjust dose accordingly if concomitant use of XYWAV and divalproex sodium is warranted.
Concomitant use of sodium oxybate with divalproex sodium results in an increase in systemic exposure to GHB, which was shown to cause a greater impairment on some tests of attention and working memory in a clinical study. A similar increase in exposure is expected with concomitant use of XYWAV and divalproex sodium; therefore, an initial dose reduction of XYWAV is recommended when used concomitantly with divalproex sodium. Prescribers are advised to monitor patient response closely and adjust dose accordingly if concomitant use of XYWAV and divalproex sodium is warranted.
Pregnancy and Lactation
There are no adequate data on the developmental risk associated with the use of XYWAV or sodium oxybate in pregnant women. XYWAV should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. GHB is excreted in human milk after oral administration of sodium oxybate. There is insufficient information on the risk to a breastfed infant, and there is insufficient information on milk production in nursing mothers. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for XYWAV and any potential adverse effects on the breastfed infant from XYWAV or from the underlying maternal condition.
Reference: Orphan Drugs, Definitions. 21 CFR §316.3 (2024). Accessed May 31, 2024. https://www.ecfr.gov/current/title-21/chapter-I/subchapter-D/part-316#316.3
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.