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EFFICACY IN IDIOPATHIC HYPERSOMNIA

XYWAV is the only FDA‑approved treatment option for adult patients with Idiopathic Hypersomnia (IH)1,2

XYWAV was evaluated in a phase III, double‑blind, placebo‑controlled, randomized withdrawal, multicenter study of 154 patients with IH aged 19 to 75.1,3

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Full Study Design

XYWAV has been evaluated across these key measures:

  • Epworth Sleepiness Scale
    (ESS)    —Assesses excessive daytime sleepiness (EDS) or patient perceptions of likelihood they will fall asleep during usual daily activities.1,3 See ESS data
  • Patient Global Impression of Change (PGIc)—Assesses patient perceptions of symptom change from "very much improved" to "very much
    worse."1,3 See PGIc data
  • Idiopathic Hypersomnia Severity Scale (IHSS)—Assesses the severity of idiopathic hypersomnia symptoms, such as excessive sleepiness, prolonged sleep duration, cognitive impairment, and sleep inertia.1,3 See IHSS data
  • Exploratory endpoint: Visual Analog Scale for Sleep Inertia (VAS-SI)—Assesses the severity of sleep inertia in patients on a self-reported scale of 0 to 100.3,4 See VAS-SI data

primary efficacy endpoint: efficacy in EXCESSIVE daytime sleepiness (as measured by ess)

Significant worsening of daytime sleepiness in patients randomized to placebo during the 2-week, double-blind, randomized withdrawal period1,3

Mean ESS score remained stable from the end of the SDP through the end of the 2-week DB RWP with XYWAV—but worsened with placebo1,3

Bar graph showing ESS scores of patients titrated to an effective dose of XYWAV.

ESS scores higher than 10 are indicative of excessive daytime sleepiness.5

Limitations: Trial was not designed to demonstrate efficacy during the OTTP; all patients were taking active drug while dose was being titrated to individual optimized dose; no conclusions can be drawn about the effect of XYWAV during this period.

*LS mean difference between XYWAV and placebo in the change in ESS score from end of 2-week SDP to end of 2-week DB RWP3

DB RWP = Double-Blind, Randomized Withdrawal Period; ESS = Epworth Sleepiness Scale; LS = Least Squares; OTTP = Open-Label Treatment Titration and Optimization Period; SDP = Stable-Dose Period.

See more ESS data:

Swipe to view rest of chart

Bar graph showing ESS scores of patients over a 24-week period.

ESS scores higher than 10 are indicative of excessive daytime sleepiness.5

Limitations: Trial was only designed to evaluate efficacy during the DB RWP period. During the OTTP and OLE periods, all patients were taking active drug and no conclusions can be drawn about the effect of XYWAV. In addition, during the OLE, data are not available for all patients at all timepoints (number of patients declined over time).

94% of patients (106 out of 113) who completed the DB RWP (including those on placebo)
continued into the XYWAV 24‑week open-label extension.3

DB RWP = Double-Blind, Randomized Withdrawal Period; ESS = Epworth Sleepiness Scale; OLE = Open-Label Extension; OTTP = Open-Label Treatment Titration and Optimization Period; SDP = Stable-Dose Period.

A bar chart showing the changes in ESS score and the relation to once or twice nightly dosing regimen.

XYWAV dosing regimen was initiated at the discretion of the investigator according to clinical presentation. Patients were considered for XYWAV once nightly if they reported difficulty awakening as a result of sleep inertia or long sleep time, and twice-nightly dosing if they reported disrupted nighttime sleep or difficulty with sleep maintenance. For twice-nightly regimens, doses were divided equally or unequally, with the first dose administered at bedtime and the second dose administered 2.5 to 4 hours later. At the start of the DB RWP, the median nightly dose of XYWAV was 4.5 g in the once-nightly group and 7.5 g in the twice-nightly group. There were no meaningful differences in demographics, baseline characteristics, or disease severity between patients receiving XYWAV once nightly vs twice nightly.1

Limitations: This was an exploratory analysis and was outside of the statistical hierarchy; efficacy conclusions cannot be drawn. The LS mean differences were obtained from ANCOVA models, with the change in ESS total score from the end of SDP to the end of DB RWP as the responsive variable and ESS total score at end of SDP. A separate model was used for each regimen.

ANCOVA = Analysis of Covariance; DB RWP = Double-Blind, Randomized-Withdrawal Period; ESS = Epworth Sleepiness Scale; LS = Least Squares; SDP = Stable-Dose Period.

A bar chart showing the ESS score changes in patients with or without long sleep time.

This is an exploratory sub-group analysis of the mITT, which included 24 patients with long sleep time and 91 patients without long sleep time. Long sleep time was clinician reported at study entry based on ICSD-II or ICSD-III criteria. Demographic and baseline characteristics were generally well balanced between groups, with the exception of region. The low number of participants with long sleep overall, and the imbalance between those with long sleep recruited in Europe and North America, may limit generalizability.8

Limitations: This was an exploratory analysis and was outside of the statistical hierarchy; efficacy conclusions cannot be drawn. The LS mean differences were obtained from ANCOVA models, with the change in ESS total score from the end of SDP to the end of DB RWP as the responsive variable and covariates of treatment group, baseline medication group, and ESS total score at end of SDP. A separate model was used for each sleep category.

*Long sleep time was defined as ≥11 hours or more of sleep in 24 hours.8

ANCOVA = Analysis of Covariance; DB RWP = Double-Blind, Randomized-Withdrawal Period; ESS = Epworth Sleepiness Scale; ICSD = International Classification of Sleep Disorders; LS = Least Squares; mITT = Modified Intention-to-Treat; SDP = Stable-Dose Period.

Watch experts discuss ESS data

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key secondary endpoint: patient perception of change in symptoms (as measured by pgic)

Significantly more patients reported worsening* of IH overall when randomized to placebo during the 2-week, double-blind, randomized withdrawal period1

Percentage of patients reporting worsening* IH overall at the end of the 2-week DB RWP1,9

A chart showing the percentage of patients with worsening symptoms measured by PGIc.

of patients continuing treatment with XYWAV reported improvement† or no change in their overall idiopathic hypersomnia at the end of DB RWP (compared to how they felt during the stable-dose period)

*Worsening of idiopathic hypersomnia defined as "minimally, much worse, or very much worse" PGIc scores.1

†Improvement of idiopathic hypersomnia defined as "minimally, much, or very much improved" PGIc scores.9

DB RWP = Double-Blind, Randomized-Withdrawal Period; PGIc = Patient Global Impression of Change.

key secondary endpoint: efficacy in idiopathic hypersomnia symptom severity (as measured by ihss)

Significant worsening in IH symptom severity in patients randomized to placebo during the 2-week, double-blind, randomized withdrawal period1,3

Mean IHSS score remained stable from the end of the SDP through the end of the 2-week DB RWP with XYWAV—but worsened with placebo1,3,6

Bar graph showing IHSS scores of patients titrated to an effective dose of XYWAV.

Limitations: Trial was not designed to demonstrate efficacy during the OTTP; all patients were taking active drug while dose was being titrated to individual optimized dose; no conclusions can be drawn about the effect of XYWAV during this period.

IHSS Score Ranges10,11

Bar graph showing IHSS scores of patients titrated to an effective dose of XYWAV.

*Estimated median difference between XYWAV and placebo in change in IHSS from end of SDP to end of DB RWP8

DB RWP = double-blind, randomized withdrawal period; IHSS = Idiopathic Hypersomnia Severity Scale; OTTP = open-label treatment titration and optimization period; SDP = stable-dose period.

See more IHSS data:

Swipe to view rest of chart

Line chart showing IHSS scores over a 24-week period for patients titrated to an effective dose of XYWAV.

IHSS score of 22 is the best cutoff value for discriminating between untreated patients with IH and controls.10

Limitations: Trial was only designed to evaluate efficacy during the DB RWP period. During the OTTP and OLE periods, all patients were taking active drug and no conclusions can be drawn about the effect of XYWAV. In addition, during the OLE, data are not available for all patients at all timepoints (number of patients declined over time).

94% of patients (106 out of 113) who completed the DB RWP
(including those on placebo) continued into the XYWAV 24‑week open-label extension.3

DB RWP = Double-Blind, Randomized Withdrawal Period; IHSS = Idiopathic Hypersomnia Severity Scale; OLE = Open-Label Extension; OTTP = Open-Label Treatment Titration and Optimization Period; SDP = Stable-Dose Period.

A bar chart showing the changes in IHSS score and the relation to once or twice nightly dosing regimen.

XYWAV dosing regimen was initiated at the discretion of the investigator according to clinical presentation. Patients were considered for XYWAV once-nightly if they reported difficulty awakening as a result of sleep inertia or long sleep time, and twice-nightly dosing if they reported disrupted nighttime sleep or difficulty with sleep maintenance. For twice-nightly regimens, doses were divided equally or unequally, with the first dose administered at bedtime and the second dose administered 2.5 to 4 hours later. At the start of the DB RWP, the median nightly dose of XYWAV was 4.5 g in the once nightly group and 7.5 g in the twice nightly group. There were no meaningful differences in demographics, baseline characteristics, or disease severity between patients receiving XYWAV once nightly vs twice nightly.1

Limitations: This was an exploratory analysis and was outside of the statistical hierarchy; efficacy conclusions cannot be drawn. The estimated median differences between treatment groups are from Hodges-Lehmann estimates. A separate model was used for each regimen.

DB RWP = Double-Blind, Randomized-Withdrawal Period; IHSS = Idiopathic Hypersomnia Severity Scale; SDP = Stable-Dose Period.

A bar chart showing the IHSS score changes in patients with or without long sleep time.

This is an exploratory sub-group analysis of the mITT, which included 24 patients with long sleep time and 91 patients without long sleep time. Long sleep time was clinician reported at study entry based on ICSD-II or ICSD-III criteria. Demographic and baseline characteristics were generally well balanced between groups, with the exception of region. The low number of participants with long sleep overall, and the imbalance between those with long sleep recruited in Europe and North America, may limit generalizability.8

Limitations: This was an exploratory analysis and was outside of the statistical hierarchy; efficacy conclusions cannot be drawn. The estimated median differences between treatment groups are from Hodges-Lehmann estimates. A separate model was used for each regimen.

*Long sleep time was defined as ≥11 hours or more of sleep in 24 hours.8

DB RWP = Double-Blind, Randomized-Withdrawal Period; ICSD = International Classification of Sleep Disorders; IHSS = Idiopathic Hypersomnia Severity Scale; mITT = Modified Intent-To-Treat; SDP = Stable-Dose Period.

exploratory endpoint

Visual Analog Scale-Sleep Inertia (VAS-SI)

From the end of the SDP to the end of the DB RWP, mean VAS-SI scores changed from 32.3 to 55.3 in participants randomized to placebo, and from 24.8 to 28.3 for those who continued on XYWAV4

Swipe to view rest of chart

Line chart showing VAS-SI scores.

Limitations: This was an exploratory analysis and was outside of the statistical hierarchy; efficacy conclusions cannot be drawn. The LS mean difference and 95% CI were obtained from ANCOVA models. Covariates in the model included: baseline medication group, treatment group, and mean VAS-SI daily score at the last week of SDP.

*Modified intent-to-treat population.

†Difference in change from end of SDP to end of DB RWP.

‡LXB, n=49; placebo, n=51.

CI = Confidence Interval; DB RWP = Double-Blind Randomized Withdrawal Period; LS = Least Squares; LXB = Lower-Sodium Oxybate;SD = Standard Deviation; SDP = Stable-Dose Period; VAS-SI = Visual Analog Scale for Sleep Inertia.

Using the VAS-SI, participants rated their difficulty awakening during baseline, SDP, and DB RWP on a 100-mm line with anchors at 0 (very easy) and 100 (very difficult).4

XYWAV was evaluated in a large phase III study of adult patients with IH1,3,4,12-14

The study population included patients with varying degrees of baseline severity.3

A chart showing how XYWAV was elevated in a phase three study for adult patients with IH.
  • Evaluated in adults: 154 patients, aged 19 to 75 (median age 39 years)
  • Treatment background (at baseline): Trial included patients (N=154) who were taking wake-promoting agents (WPAs) or stimulants only (53%), treatment-naive (43%), taking sodium oxybate plus a WPA or stimulant (4%), taking sodium oxybate only (1%)
  • Dosing regimens: Participants took either a twice-nightly or a once-nightly regimen at the discretion of the clinician according to the clinical presentation of each patient. Approximately 57% of patients continued taking a stable dose of stimulant along with XYWAV throughout the SDP and DB RWP
  • Baseline disease severity (based on CGI-S): Trial included patients (N=154) who were borderline to mildly ill (4%), moderately to markedly ill (77%), severely to extremely ill (20%)
  • Sleep time* (at baseline): Trial included patients (N=154) with long sleep time and without long sleep time; 20% and 80%, respectively
  • Over 6 months (204 days) mean exposure to XYWAV in safety population: Included titration, stable-dose period, randomized withdrawal period, and open-label extension

*Long sleep time based on ICSD-II or ICSD-III criteria.

CGI-S = Clinical Global Impression of Severity; DB RWP = Double-Blind, Randomized Withdrawal Period; ICSD = International Classification of Sleep Disorders; OLE = Open-Label Extension; OTTP = Open-Label Treatment Titration and Optimization Period; SDP = Stable-Dose Period.

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Watch the video about the key efficacy endpoints in a study on XYWAV.

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Key efficacy endpoints in Study 2

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SUBGROUP ANALYSES

References:

  1. XYWAV® (calcium, magnesium, potassium, and sodium oxybates). Prescribing Information. Palo Alto, CA: Jazz Pharmaceuticals, Inc.
  2. FDA grants first of its kind indication for chronic sleep disorder treatment. News release. U.S. Food and Drug Administration; August 12, 2021. Accessed June 17, 2024. https://www.fda.gov/news‑events/press-announcements/fda-grants-first-its-kind-indication-chronic-sleep-disorder-treatment
  3. Dauvilliers Y, Arnulf I, Foldvary-Schaefer N, et al. Safety and efficacy of lower‑sodium oxybate in adults with idiopathic hypersomnia: a phase 3, placebo‑controlled, double‑blind, randomised withdrawal study. Lancet Neurol. 2022;21(1):53‑65.
  4. Bogan K, Dauvilliers Y, Thorpy MJ, et al. Effect of lower-sodium oxybate on sleep inertia in idiopathic hypersomnia in a double-blind randomized withdrawal study. Poster presented at: Sleep 2021, the 35th Annual Meeting of the Associated Professional Sleep Societies (APSS); June 10-13, 2021; Virtual Meeting.
  5. Johns MW. A new method for measuring daytime sleepiness: the Epworth Sleepiness Scale. Sleep. 1991;14(6):540-545.
  6. Data on File (XYW-2021-040). Palo Alto, CA: Jazz Pharmaceuticals, Inc.
  7. Arnulf I, Morse AM, Chandler P, Parvataneni R, Chen D, Dauvilliers Y. Efficacy and safety of once- and twice-nightly dosing of lower-sodium oxybate in adults with idiopathic hypersomnia. Poster presented at: Sleep 2021, the 35th Annual Meeting of the Associated Professional Sleep Societies (APSS); June 10-13, 2021; Virtual Meeting.
  8. Bogan RK, Arnulf I, Thorpy MJ, et al. Efficacy and safety of lower-sodium oxybate in adults with idiopathic hypersomnia, with and without long sleep time. Poster presented at: Sleep 2021, the 35th Annual Meeting of the Associated Professional Sleep Societies (APSS); June 10-13, 2021; Virtual Meeting.
  9. Dauvilliers Y, Arnulf I, Foldvary-Schaefer N, et al. Placebo-controlled, double-blind, randomized withdrawal study of lower-sodium oxybate in adults with idiopathic hypersomnia. Poster presented at: Sleep 2021, the 35th Annual Meeting of the Associated Professional Sleep Societies (APSS); June 10-13, 2021; Virtual Meeting.
  10. Dauvilliers Y, Evangelista E, Barateau L, et al. Measurement of symptoms in idiopathic hypersomnia: the Idiopathic Hypersomnia Severity Scale. Neurology. 2019;92(15):e1754-e1762.
  11. Rassu AL, Evangelista E, Barateau L, et al. Idiopathic Hypersomnia Severity Scale to better quantify symptoms severity and their consequences in idiopathic hypersomnia. J Clin Sleep Med. 2022;18(2):617-629.
  12. A multicenter study of the efficacy and safety of JZP-258 in the treatment of idiopathic hypersomnia (IH) with an open-label safety extension. ClinicalTrials.gov identifier: NCT03533114. Updated June 11, 2021. Accessed June 17, 2024. https://clinicaltrials.gov/ct2/show/NCT03533114
  13. U.S. National Library of Medicine. Clinicaltrials.gov search results for Idiopathic Hypersomnia. Updated June 11, 2021. Accessed June 17, 2024. https://clinicaltrials.gov/ct2/results?cond=Idiopathic+Hypersomnia
  14. Sodium oxybate in idiopathic hypersomnia (SODHI). ClinicalTrials.gov identifier: NCT03597555. Updated February 12, 2021. Accessed June 17, 2024. https://www.clinicaltrials.gov/ct2/show/NCT03597555

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, and for the treatment of idiopathic hypersomnia (IH) in adults.

Important Safety Information

WARNING: CENTRAL NERVOUS SYSTEM DEPRESSION and ABUSE AND MISUSE.

  • Central Nervous System DepressionXYWAV 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 and idiopathic hypersomnia were receiving CNS stimulants.
  • Abuse and MisuseThe 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

Central Nervous System Depression

The concurrent use of XYWAV with other CNS depressants, including but not limited to opioid analgesics, benzodiazepines, sedating antidepressants or antipsychotics, sedating anti-epileptic drugs, general anesthetics, muscle relaxants, and/or illicit CNS depressants, may increase the risk of respiratory depression, hypotension, profound sedation, syncope, and death. If use of these CNS depressants in combination with XYWAV is required, dose reduction or discontinuation of one or more CNS depressants (including XYWAV) should be considered. In addition, if short-term use of an opioid (eg, post- or perioperative) is required, interruption of treatment with XYWAV should be considered.

After first initiating treatment and until certain that XYWAV does not affect them adversely (eg, impair judgment, thinking, or motor skills), 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 active moiety of XYWAV is oxybate, also known as gamma-hydroxybutyrate (GHB), a Schedule I controlled substance. Abuse 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. 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). Physicians should carefully evaluate patients for a history of drug abuse and follow such patients closely.

XYWAV and XYREM REMS

  • Because of the risks of central nervous system depression and abuse and misuse, XYWAV is available only through a restricted distribution program called the XYWAV and XYREM REMS.

Notable requirements of the XYWAV and XYREM REMS include the following:

  • Healthcare Providers who prescribe XYWAV are specially certified
  • XYWAV will be dispensed only by the central pharmacy that is specially certified
  • XYWAV will be dispensed and shipped only to patients who are enrolled in the XYWAV and XYREM REMS with documentation of safe use

Further information is available at www.XYWAVXYREMREMS.com or 1-866-997-3688.

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 randomized-withdrawal clinical trial in adult patients with narcolepsy (n=201), depression and depressed mood were reported in 3% and 4%, respectively, of patients treated with XYWAV. Two patients (1%) discontinued XYWAV because of depression. In most cases, no change in XYWAV treatment was required.

In Study 2, the randomized-withdrawal clinical trial in adult patients with idiopathic hypersomnia (n=154), depression and depressed mood were reported in 1% and 3%, respectively, of patients treated with XYWAV. All patients continued XYWAV treatment.

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. These events occurred in patients with and without previous histories of depressive disorders. The emergence of depression in patients treated with XYWAV requires careful and immediate evaluation. Monitor patients for the emergence of increased depressive symptoms and/or suicidality while taking XYWAV.

Other Behavioral or Psychiatric Adverse Reactions

In Study 1, confusion and anxiety occurred in 1% and 5% of patients with narcolepsy treated with XYWAV, respectively. One patient experienced visual hallucinations and confusion after ingesting approximately 9 grams of XYWAV.

In Study 2, confusion and anxiety occurred in 3% and 16% of patients with idiopathic hypersomnia, respectively. One patient experienced visual hallucinations, which led to discontinuation of XYWAV.

Other neuropsychiatric reactions reported with oxybate (same active moiety as XYWAV) in adult or pediatric clinical trials and in the postmarketing setting include hallucinations, paranoia, psychosis, aggression, agitation, confusion and anxiety. The emergence or increase in the occurrence of behavioral or psychiatric events in patients taking XYWAV should be carefully monitored.

Parasomnias

Parasomnias can occur in patients taking XYWAV.

In Study 1 and Study 2, parasomnias, including sleepwalking, were reported in 6% and 5% of adult patients treated with XYWAV, respectively.

In a clinical trial of XYREM (same active moiety as XYWAV) in adult patients with narcolepsy, five instances of sleepwalking with potential injury or significant injury were reported. Parasomnias, including sleepwalking, 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

The most common adverse reactions (occurring in ≥5% of XYWAV-treated patients in adult clinical trials in either narcolepsy or IH) were nausea, headache, dizziness, anxiety, insomnia, decreased appetite, hyperhidrosis, vomiting, diarrhea, dry mouth, parasomnia, somnolence, fatigue, and tremor.

In the pediatric clinical trial with XYREM (same active moiety as XYWAV) that included pediatric patients 7 to 17 years of age 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 overall adverse reaction profile of XYREM in the pediatric clinical trial was similar to that seen in the adult clinical trial program. 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.

Additional Adverse Reactions

Adverse reactions that occurred in 2-<5% of adult patients treated with XYWAV in the Open-Label Titration and Stable Dose Periods of the randomized-withdrawal study in adult patients with narcolepsy with cataplexy (Study 1) were fatigue, dry mouth, depressed mood, enuresis, irritability, paresthesia, depression, tremor, somnolence, and muscle spasms. Adverse reactions occurring in 2-<5% of patients treated with XYWAV in the IH study include balance disorder, muscle spasms, fall, paresthesia, snoring, weight decreased, bruxism, confusional state, depressed mood, feeling drunk, and irritability.

Adverse reactions that occurred in ≥2% of patients in clinical studies with oxybate (but not in Study 1) and which may be relevant for XYWAV, were pain, feeling drunk, pain in extremity, cataplexy, disturbance in attention, sleep paralysis, and disorientation.

Discontinuation: In Study 1, 9 of 201 patients (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%). In Study 2, 17 of 154 (11%) patients across all study periods (excluding placebo during the DB RWP) (up to 42 weeks) reported adverse reactions that led to withdrawal from the study (anxiety, nausea, insomnia, vomiting, fatigue, feeling abnormal, fall, decreased appetite, dizziness, paresthesia, tremor, parasomnia, confusional state, hallucination visual, and irritability). The most common adverse reaction leading to discontinuation was anxiety (3.2%). In Study 1 and Study 2, 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.

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.

Pediatric Use

The safety and effectiveness of XYWAV for the treatment of cataplexy or excessive daytime sleepiness in pediatric patients 7 years of age and older with narcolepsy have been established. XYWAV has not been studied in a pediatric clinical trial for narcolepsy or IH. Use of XYWAV in pediatric patients 7 years of age and older with narcolepsy is supported by evidence from an adequate and well-controlled study of sodium oxybate in pediatric patients 7 to 17 years of age, a study in adults showing a treatment effect of XYWAV similar to that observed with sodium oxybate, pharmacokinetic data of sodium oxybate from adult and pediatric patients, and pharmacokinetic data of XYWAV from healthy adult volunteers.

Safety and effectiveness of XYWAV in pediatric patients below the age of 7 years with narcolepsy have not been established.

Safety and effectiveness of XYWAV for the treatment of idiopathic hypersomnia in pediatric patients have not been established.

Geriatric Use

In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Hepatic Impairment

The starting dose of XYWAV should be reduced in patients with liver impairment.
Dosage Modification in Patients with Hepatic Impairment:  The recommended starting dosage in patients with hepatic impairment is one-half of the original dosage per night, administered orally, divided into two doses.

Dependence and Tolerance

There have been case reports of withdrawal, ranging from mild to severe, following discontinuation of illicit use of GHB at frequent repeated doses (18 g to 250 g per day) in excess of the recommended dosage range. Signs and symptoms of GHB withdrawal following abrupt discontinuation included insomnia, restlessness, anxiety, psychosis, lethargy, nausea, tremor, sweating, muscle cramps, tachycardia, headache, dizziness, rebound fatigue and sleepiness, confusion, and, particularly in the case of severe withdrawal, visual hallucinations, agitation, and delirium. These symptoms generally abated in 3 to 14 days. In cases of severe withdrawal, hospitalization may be required.

In the clinical trial experience with XYREM in narcolepsy/cataplexy patients at recommended doses, two patients reported anxiety and one reported insomnia following abrupt discontinuation at the termination of the clinical trial; in the two patients with anxiety, the frequency of cataplexy had increased markedly at the same time. In the XYWAV clinical trial in adult narcolepsy/cataplexy patients at recommended doses, one patient reported insomnia following abrupt discontinuation of XYWAV. In the XYWAV clinical trial in adult idiopathic hypersomnia patients at recommended doses, six patients reported insomnia, two patients reported early insomnia, and one patient reported visual and auditory hallucinations following abrupt discontinuation of XYWAV.

Tolerance to XYWAV has not been systematically studied in controlled clinical trials. There have been some case reports of symptoms of tolerance developing after illicit use at dosages far in excess of the recommended XYWAV dosage regimen.

Please see full Prescribing Information, including BOXED Warning.

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