Xywav

Calcium, magnesium, potassium, and sodium oxybates · Solution · Oral

Prescription (Rx) Central Nervous System Depressant

Boxed warning. 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 [see Warnings and Precautions ( 5.1 , 5.4 )]. Many patients who received XYWAV during clinical trials in narcolepsy and idiopathic hypersomnia were receiving central nervous system stimulants [see Clinical Studies ( 14.1 , 14.2 , 14.3 )].
• 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 [see Warnings and Precautions ( 5.2 )]. Because of the risks of CNS depression and…

Uses

1 INDICATIONS AND USAGE XYWAV is a central nervous system depressant indicated for the treatment of:
• Cataplexy or excessive daytime sleepiness (EDS) in patients 7 years of age and older with narcolepsy ( 1.1 ).
• Idiopathic Hypersomnia (IH) in adults ( 1.2 ). 1.1 Narcolepsy XYWAV is indicated for the treatment of cataplexy or excessive daytime sleepiness (EDS) in patients 7 years of age and older with narcolepsy. 1.2 Idiopathic Hypersomnia XYWAV is indicated for the treatment of idiopathic hypersomnia (IH) in adults.

Dosage and administration

See Full Prescribing Information for complete dosing instructions ( 2.1 - 2.7 ). Dosage for Adult Patients with Narcolepsy
• Initiate dosage at 4.5 g per night orally, divided into two doses ( 2.1 ).
• Titrate to effect in increments of up to 1.5 g per night per week ( 2.1 ).
• Recommended dosage range: 6 g to 9 g per night orally, divided into two doses ( 2.1 ).
• Doses may be divided equally or unequally and the first dose taken at bedtime and the second dose taken 2.5 to 4 hours later ( 2.1 ). Dosage for Pediatric Patients with Narcolepsy (7 Years of Age and Older)
• The recommended starting dosage, titration regimen, and maximum total nightly dosage are based on body weight (2.2 ). Dosage for Adult Patients with Idiopathic Hypersomnia
• XYWAV can be administered as a twice or once nightly regimen in adults ( 2.3 ).
• Twice nightly: Initiate dosage at 4.5 g or less per night orally, divided into two doses. Titrate to effect in increments of up to 1.5 g per night per week, up to 9 g total nightly dose ( 2.3 ).
• Once nightly: Initiate dosage at 3 g or less per night orally, as one dose. Titrate to effect in increments of up to 1.5 g per night per week, up to 6 g total nightly dose ( 2.3 ). Important Administration Information
• Administer XYWAV at least 2 hours after eating ( 2.4 ).
• Prepare XYWAV prior to bedtime; dilute with approximately ¼ cup of water in pharmacy-provided containers ( 2.4 ).
• Take XYWAV while in bed and lie down after dosing ( 2.4 ). For Patients Transitioning from Xyrem to XYWAV: Initiate at the same dose and regimen as Xyrem (gram for gram). Titrate as needed based on efficacy and tolerability ( 2.5 ). Patients with Hepatic Impairment Recommended starting dosage is one-half of the original dosage per night administered orally, divided into two doses ( 2.6 ). 2.1 Dosing Information in Adult Patients with Narcolepsy The recommended starting dosage is 4.5 grams (g) per night administered orally, divided into two doses: 2.25 g at bedtime and 2.25 g taken 2.5 to 4 hours later (see Table 1). Increase the dosage by up to 1.5 g per night per week (e.g., 0.75 g at bedtime and 0.75 g taken 2.5 to 4 hours later), to the recommended dosage range of 6 g to 9 g per night. The dosage may be gradually titrated based on efficacy and tolerability. Some patients may achieve better responses with unequal doses at bedtime and 2.5 to 4 hours later. Doses higher than 9 g per night have not been studied and ordinarily should not be administered. Table 1: Recommended Adult XYWAV Dosage Regimen (g = grams) Note: Some patients may achieve better responses with unequal nightly doses at bedtime and 2.5 to 4 hours later. If a Patient’s Total Nightly Dosage Is: Take at Bedtime: Take 2.5 to 4 Hours Later: 4.5 g per night 2.25 g 2.25 g 6 g per night 3 g 3 g 7.5 g per night 3.75 g 3.75 g 9 g per night 4.5 g 4.5 g 2.2 Dosing Information in Pediatric Patients with Narcolepsy For pediatric patients 7 years of age and older, XYWAV is administered orally twice per night. The recommended starting pediatric dosage, titration regimen, and maximum total nightly dosage are based on patient weight, as specified in Table 2. The dosage may be gradually titrated based on efficacy and tolerability. Doses higher than 9 g per night have not been studied and ordinarily should not be administered. Table 2: Recommended XYWAV Dosage for Patients 7 Years of Age and Older* * For patients who sleep more than 8 hours per night, the first nightly dose of XYWAV may be given at bedtime or after an initial period of sleep. ** If XYWAV is used in patients 7 years of age and older who weigh less than 20 kg, a lower starting dosage, lower maximum weekly dosage increases, and lower total maximum nightly dosage should be considered. Note: Some patients may achieve better responses with unequal nightly doses at bedtime and 2.5 to 4 hours later. Patient Weight Initial Dosage Maximum Weekly Dosage Increase Maximum Recommended Dosage Take at Bedtime: Take 2.5 to 4 Hours Later: Take at Bedtime: Take 2.5 to 4 Hours Later: Take at Bedtime: Take 2.5 to 4 Hours Later: <20 kg** There is insufficient information to provide specific dosing recommendations for patients who weigh less than 20 kg. 20 kg to <30 kg ≤1 g ≤1 g 0.5 g 0.5 g 3 g 3 g 30 kg to <45 kg ≤1.5 g ≤1.5 g 0.5 g 0.5 g 3.75 g 3.75 g ≥45 kg ≤2.25 g ≤2.25 g 0.75 g 0.75 g 4.5 g 4.5 g 2.3 Dosing Information in Adult Patients with Idiopathic Hypersomnia (IH) The dosage and regimen of XYWAV should be individualized based on clinical presentation [see Clinical Studies ( 14.3 )] . XYWAV can be administered as a twice nightly or once nightly regimen. The recommended starting dose, titration guidance, and maximum nightly doses appear in Table 3: Table 3: Recommended Nightly Dosage in Adult Patients with IH * Some patients may achieve better responses with unequal nightly doses at bedtime and 2.5 to 4 hours later. † The first dose should be taken at bedtime and the second dose taken 2.5 to 4 hours later. Dosing Regimen Starting Nightly Dose Titration Increments Maximum Total Nightly Dose Twice nightly *,† ≤4.5 g per night divided into two doses (e.g., 2.25 g each) ≤1.5 g per night per week (divided into two doses) 9 g (divided into two doses) Once nightly ≤3 g per night ≤1.5 g per night per week 6 g The increase in the total nightly dose should not exceed 1.5 g /week. During titration, the dosing regimen may be changed between twice nightly and once nightly, as needed based on efficacy and tolerability [see Clinical Studies ( 14.3 )] . Doses higher than 9 g per night or single dose administrations higher than 6 g have not been studied and should not be administered. 2.4 Important Administration Instructions for All Patients Administer XYWAV at least 2 hours after eating [see Clinical Pharmacology ( 12.3 )] . Prepare all doses of XYWAV prior to bedtime.

Dosage forms and strengths

3 DOSAGE FORMS AND STRENGTHS XYWAV is a clear to slightly opalescent oral solution at a total salt concentration of 0.5 g per mL. Each mL contains 0.5 g of total salts present as 0.234 g calcium oxybate, 0.096 g magnesium oxybate, 0.13 g potassium oxybate, and 0.04 g sodium oxybate (equivalent to 0.413 g total oxybate). Oral solution: 0.5 g/mL total salts (equivalent to 0.413 g/mL of oxybate) ( 3 )

Contraindications

4 CONTRAINDICATIONS XYWAV is contraindicated for use in:
• combination with sedative hypnotics [see Warnings and Precautions ( 5.1 )] .
• combination with alcohol [see Warnings and Precautions ( 5.1 , 5.2 )] .
• patients with succinic semialdehyde dehydrogenase deficiency [see Clinical Pharmacology ( 12.3 )] .
• In combination with sedative hypnotics or alcohol ( 4 )
• Succinic semialdehyde dehydrogenase deficiency ( 4 )

Warnings and precautions

• CNS depression: Use caution when considering the concurrent use of XYWAV with other CNS depressants ( 5.1 ).
• Caution patients against hazardous activities requiring complete mental alertness or motor coordination within the first 6 hours of dosing or after first initiating treatment until certain that XYWAV does not affect them adversely ( 5.1 ).
• Depression and suicidality: Monitor patients for emergent or increased depression and suicidality ( 5.5 ).
• Confusion/Anxiety: Monitor for impaired motor/cognitive function ( 5.6 ).
• Parasomnias: Evaluate episodes of sleepwalking ( 5.7 ). 5.1 Central Nervous System Depression XYWAV is a central nervous system (CNS) depressant. Clinically significant respiratory depression and obtundation has occurred in adult patients taking sodium oxybate (same active moiety as XYWAV) at recommended doses in clinical trials and may occur in patients treated with XYWAV at recommended doses. XYWAV is contraindicated in combination with alcohol and sedative hypnotics. 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 (e.g., post- or perioperative) is required, interruption of treatment with XYWAV should be considered. Healthcare providers should caution patients about operating hazardous machinery, including automobiles or airplanes, until they are reasonably certain that XYWAV does not affect them adversely (e.g., impair judgment, thinking, or motor skills). Patients should not engage in hazardous occupations or activities requiring complete mental alertness or motor coordination, such as operating machinery or a motor vehicle or flying an airplane, 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. XYWAV is available only through a restricted program under a REMS [see Warnings and Precautions ( 5.3 )] . 5.2 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 (e.g., assault victim). Because illicit use and abuse of GHB have been reported, healthcare providers should carefully evaluate patients for a history of drug abuse and follow them closely, particularly for signs of misuse or abuse of GHB (including but not limited to increase in size or frequency of dosing, drug-seeking behavior, feigned cataplexy) [see Drug Abuse and Dependence ( 9.2 )] . If abuse is suspected, treatment with XYWAV should be discontinued . XYWAV is available only through a restricted program under a REMS [see Warnings and Precautions ( 5.3 )] . 5.3 XYWAV and XYREM REMS XYWAV is available only through a restricted distribution program called the XYWAV and XYREM REMS because of the risks of central nervous system depression, and abuse and misuse [see Warnings and Precautions ( 5.1 , 5.2 )]. 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. 5.4 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 [see Overdosage ( 10 )]. 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. In a study assessing the respiratory-depressant effects of Xyrem (same active moiety as XYWAV) at doses up to 9 g per night in 21 adult patients with narcolepsy, no dose-related changes in oxygen saturation were demonstrated in the group as a whole. One of the four patients with preexisting moderate-to-severe sleep apnea had significant worsening of the apnea/hypopnea index during treatment. In a study assessing the effects of Xyrem 9 g per night in 50 adult patients with obstructive sleep apnea, Xyrem did not increase the severity of sleep‑disordered breathing and did not adversely affect the average duration and severity of oxygen desaturation overall. However, there was a significant increase in the number of central apneas in patients taking Xyrem, and clinically significant oxygen desaturation (≤55%) was measured in three patients (6%) after Xyrem administration, with one patient withdrawing from the study and two continuing after single brief instances of desaturation. During polysomnographic evaluation (PSG), central sleep apnea and oxygen desaturation were observed in pediatric patients with narcolepsy treated with Xyrem.

Side effects

The following clinically significant adverse reactions appear in other sections of the labeling:
• CNS depression [see Warnings and Precautions ( 5.1 )]
• Abuse and Misuse [see Warnings and Precautions ( 5.2 )]
• Respiratory Depression and Sleep-Disordered Breathing [see Warnings and Precautions ( 5.4 )]
• Depression and Suicidality [see Warnings and Precautions ( 5.5 )]
• Other Behavioral or Psychiatric Adverse Reactions [see Warnings and Precautions ( 5.6 )]
• Parasomnias [see Warnings and Precautions ( 5.7 )] Most common adverse reactions in adults with narcolepsy or IH (≥5%) were nausea, headache, dizziness, anxiety, insomnia, decreased appetite, hyperhidrosis, vomiting, diarrhea, dry mouth, parasomnia, somnolence, fatigue, and tremor ( 6.1 ). In a pediatric study with sodium oxybate (same active moiety as XYWAV), the most common adverse reactions (≥5%) were nausea, enuresis, vomiting, headache, weight decreased, decreased appetite, dizziness, and sleepwalking ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Jazz Pharmaceuticals, Inc. at 1-800-520-5568, or FDA at 1-800-FDA-1088 or www.fda.gov/Medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Adult Patients with Narcolepsy The safety of XYWAV was evaluated in a 16‑week double-blind placebo-controlled randomized-withdrawal study in patients with narcolepsy with cataplexy (Study 1), which was followed by an open-label extension phase lasting 24 weeks [see Clinical Studies ( 14.1 )] . Study 1 included an open‑label titration period (OL OTTP), a stable-dose period (SDP), and a double‑blind, placebo‑controlled, randomized-withdrawal period (DB RWP). A total of 201 patients, ages 18 to 70 years, received XYWAV at individually titrated doses for 14 weeks, followed by randomization to XYWAV or matching placebo for 2 weeks of treatment. The mean exposure to XYWAV during this study, including titration, the randomized withdrawal period, and the open-label extension, was 151 days. In patients who remained on treatment, adverse reactions tended to occur early and diminish over time. Adverse Reactions Leading to Treatment Discontinuation in Study 1 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%). The majority of adverse reactions leading to discontinuation began during the first few weeks of treatment. Commonly Observed Adverse Reactions The most common adverse reactions in Study 1 (incidence ≥5% of XYWAV-treated patients) were headache, nausea, dizziness, decreased appetite, parasomnia, diarrhea, hyperhidrosis, anxiety, and vomiting. Adverse Reactions Occurring at an Incidence of 2% or Greater: Table 4 lists adverse reactions observed in the open-label titration and stable dose periods of Study 1 that occurred at a frequency of 2% or greater in adult patients treated with XYWAV. Table 4: Adverse Reactions Occurring in ≥2% of Adult Patients Treated with XYWAV in the Open-Label Titration and Stable Dose Periods in Study 1 * * Adverse reactions related to XYWAV were reported less frequently, as an overall incidence, in patients on Xyrem at study entry than in Xyrem-naïve patients. † Includes abnormal dreams, abnormal sleep-related event, rapid eye movements sleep abnormal, sleep paralysis, sleep talking, sleep terror, sleep-related eating disorder, somnambulism ‡ Includes hyperhidrosis and night sweats § Includes anxiety, agitation, panic attack, tension ¶ Includes fatigue and asthenia Adverse Reaction Open-Label Titration Period + Stable Dose Period (14 weeks) (N=201) % Headache 20 Nausea 13 Dizziness 10 Decreased appetite 8 Parasomnia † 6 Diarrhea 6 Hyperhidrosis ‡ 6 Anxiety § 5 Vomiting 5 Fatigue ¶ 4 Dry mouth 4 Depressed mood 4 Enuresis 4 Irritability 3 Paresthesia 3 Depression 3 Tremor 3 Somnolence 2 Muscle spasms 2 Pediatric Patients (7 Years of Age and Older) with Narcolepsy In the pediatric clinical trial with Xyrem (same active moiety as XYWAV), 104 patients aged 7 to 17 years (37 patients aged 7 to 11 years; 67 patients aged 12 to 17 years) with narcolepsy received Xyrem for up to one year [see Clinical Studies ( 14.2 )] . This study included an open-label safety continuation period in which eligible patients received Xyrem for up to an additional 2 years. The median and maximum exposure across the entire study were 371 and 987 days, respectively. Adverse Reactions Leading to Treatment Discontinuation In the pediatric clinical trial with Xyrem, 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 in the Xyrem Pediatric Clinical Trial 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%). Additional information regarding safety in pediatric patients appears in the following sections:
• Respiratory Depression and Sleep-Disordered Breathing [see Warnings and Precautions ( 5.4 )]
• Depression and Suicidality [see Warnings and Precautions ( 5.5 )]
• Other Behavioral or Psychiatric Adverse Reactions [see Warnings and Precautions ( 5.6 )]
• Parasomnias [see Warnings and Precautions ( 5.7 )] The overall adverse reaction profile of Xyrem in the pediatric clinical trial was similar to that seen in the adult clinical trial program.

Drug interactions

• Concomitant use with divalproex sodium: An initial reduction in XYWAV dose of at least 20% is recommended ( 2.7 , 7.2 ). 7.1 Alcohol, Sedative Hypnotics, and CNS Depressants XYWAV is contraindicated for use in combination with alcohol or sedative hypnotics. Use of other CNS depressants may potentiate the CNS-depressant effects of XYWAV [see Warnings and Precautions ( 5.1 )] . 7.2 Divalproex Sodium 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 [see Clinical Pharmacology ( 12.3 )] . 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 [see Dosage and Administration ( 2.7 )]. Prescribers are advised to monitor patient response closely and adjust dose accordingly if concomitant use of XYWAV and divalproex sodium is warranted.

Use in specific populations

• Pregnancy: Based on animal data, may cause fetal harm ( 8.1 ).
• Geriatric patients: Monitor for impaired motor and/or cognitive function when taking XYWAV ( 8.5 ). 8.1 Pregnancy Risk Summary There are no adequate data on the developmental risk associated with the use of XYWAV or sodium oxybate in pregnant women. Oral administration of sodium oxybate to pregnant rats (0, 150, 350, or 1,000 mg/kg/day) or rabbits (0, 300, 600, or 1,200 mg/kg/day) throughout organogenesis produced no clear evidence of developmental toxicity; however, oral administration to rats throughout pregnancy and lactation resulted in increased stillbirths and decreased offspring postnatal viability and growth, at a clinically relevant dose [see Data] . In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. The background risk of major birth defects and miscarriage for the indicated population is unknown. Clinical Considerations Labor or Delivery XYWAV has not been studied in labor or delivery. In obstetric anesthesia using an injectable formulation of sodium oxybate, newborns had stable cardiovascular and respiratory measures but were very sleepy, causing a slight decrease in Apgar scores. There was a fall in the rate of uterine contractions 20 minutes after injection. Placental transfer is rapid, and gamma-hydroxybutyrate (GHB) has been detected in newborns at delivery after intravenous administration of GHB to mothers. Subsequent effects of sodium oxybate on later growth, development, and maturation in humans are unknown. Data Animal Data Oral administration of sodium oxybate to pregnant rats (0, 150, 350, or 1,000 mg/kg/day) or rabbits (0, 300, 600, or 1,200 mg/kg/day) throughout organogenesis produced no clear evidence of developmental toxicity. The highest doses of sodium oxybate tested in rats and rabbits were approximately 1 and 3 times, respectively, the maximum recommended human dose (MRHD) of 9 g per night on a body surface area (mg/m 2 ) basis. Additionally, oral administration of sodium oxybate (0, 150, 350, or 1,000 mg/kg/day) to rats throughout pregnancy and lactation resulted in increased stillbirths and decreased offspring postnatal viability and body weight gain at the highest dose tested. The no-effect dose for pre- and post-natal developmental toxicity in rats is less than the MRHD on a mg/m 2 basis. 8.2 Lactation Risk Summary 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. 8.4 Pediatric Use Narcolepsy 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. 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 [see Adverse Reactions ( 6.1 ) and Clinical Studies ( 14.1 , 14.2 )]. In the pediatric clinical trial with sodium oxybate administration in patients with narcolepsy, serious adverse reactions of central sleep apnea and oxygen desaturation documented by polysomnography evaluation; depression; suicidal ideation; neuropsychiatric reactions including acute psychosis, confusion, and anxiety; and parasomnias, including sleepwalking, have been reported [see Warnings and Precautions ( 5.4 , 5.5 , 5.6 , 5.7 ) and Adverse Reactions ( 6.1 )] . Safety and effectiveness of XYWAV for the treatment of cataplexy or excessive daytime sleepiness in pediatric patients below the age of 7 years have not been established. Idiopathic Hypersomnia Safety and effectiveness of XYWAV for the treatment of idiopathic hypersomnia in pediatric patients have not been established. Juvenile Animal Toxicity Data In a study in which sodium oxybate (0, 100, 300, or 900 mg/kg/day) was orally administered to rats during the juvenile period of development (postnatal days 21 through 90), mortality was observed at the two highest doses tested. Deaths occurred during the first week of dosing and were associated with clinical signs (including decreased activity and respiratory rate) consistent with the pharmacological effects of the drug. Reduced body weight gain in males and females and delayed sexual maturation in males were observed at the highest dose tested. The no-effect dose for adverse effects in juvenile rats is associated with plasma exposures (AUC) less than that at the maximum recommended human dose (9 g/night). 8.5 Geriatric Use Clinical studies of XYWAV or Xyrem in patients with narcolepsy or IH did not include sufficient numbers of subjects age 65 years and older to determine whether they respond differently from younger subjects. In clinical studies of sodium oxybate in another population, 39 (5%) of 874 patients were 65 years or older. Discontinuations of treatment due to adverse reactions were increased in the elderly compared to younger adults (21% vs. 19%). Frequency of headaches was markedly increased in the elderly (39% vs. 19%). The most common adverse reactions were similar in both age categories.

Pregnancy

8.1 Pregnancy Risk Summary There are no adequate data on the developmental risk associated with the use of XYWAV or sodium oxybate in pregnant women. Oral administration of sodium oxybate to pregnant rats (0, 150, 350, or 1,000 mg/kg/day) or rabbits (0, 300, 600, or 1,200 mg/kg/day) throughout organogenesis produced no clear evidence of developmental toxicity; however, oral administration to rats throughout pregnancy and lactation resulted in increased stillbirths and decreased offspring postnatal viability and growth, at a clinically relevant dose [see Data] . In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. The background risk of major birth defects and miscarriage for the indicated population is unknown. Clinical Considerations Labor or Delivery XYWAV has not been studied in labor or delivery. In obstetric anesthesia using an injectable formulation of sodium oxybate, newborns had stable cardiovascular and respiratory measures but were very sleepy, causing a slight decrease in Apgar scores. There was a fall in the rate of uterine contractions 20 minutes after injection. Placental transfer is rapid, and gamma-hydroxybutyrate (GHB) has been detected in newborns at delivery after intravenous administration of GHB to mothers. Subsequent effects of sodium oxybate on later growth, development, and maturation in humans are unknown. Data Animal Data Oral administration of sodium oxybate to pregnant rats (0, 150, 350, or 1,000 mg/kg/day) or rabbits (0, 300, 600, or 1,200 mg/kg/day) throughout organogenesis produced no clear evidence of developmental toxicity. The highest doses of sodium oxybate tested in rats and rabbits were approximately 1 and 3 times, respectively, the maximum recommended human dose (MRHD) of 9 g per night on a body surface area (mg/m 2 ) basis. Additionally, oral administration of sodium oxybate (0, 150, 350, or 1,000 mg/kg/day) to rats throughout pregnancy and lactation resulted in increased stillbirths and decreased offspring postnatal viability and body weight gain at the highest dose tested. The no-effect dose for pre- and post-natal developmental toxicity in rats is less than the MRHD on a mg/m 2 basis.

Pediatric use

8.4 Pediatric Use Narcolepsy 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. 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 [see Adverse Reactions ( 6.1 ) and Clinical Studies ( 14.1 , 14.2 )]. In the pediatric clinical trial with sodium oxybate administration in patients with narcolepsy, serious adverse reactions of central sleep apnea and oxygen desaturation documented by polysomnography evaluation; depression; suicidal ideation; neuropsychiatric reactions including acute psychosis, confusion, and anxiety; and parasomnias, including sleepwalking, have been reported [see Warnings and Precautions ( 5.4 , 5.5 , 5.6 , 5.7 ) and Adverse Reactions ( 6.1 )] . Safety and effectiveness of XYWAV for the treatment of cataplexy or excessive daytime sleepiness in pediatric patients below the age of 7 years have not been established. Idiopathic Hypersomnia Safety and effectiveness of XYWAV for the treatment of idiopathic hypersomnia in pediatric patients have not been established. Juvenile Animal Toxicity Data In a study in which sodium oxybate (0, 100, 300, or 900 mg/kg/day) was orally administered to rats during the juvenile period of development (postnatal days 21 through 90), mortality was observed at the two highest doses tested. Deaths occurred during the first week of dosing and were associated with clinical signs (including decreased activity and respiratory rate) consistent with the pharmacological effects of the drug. Reduced body weight gain in males and females and delayed sexual maturation in males were observed at the highest dose tested. The no-effect dose for adverse effects in juvenile rats is associated with plasma exposures (AUC) less than that at the maximum recommended human dose (9 g/night).

Geriatric use

8.5 Geriatric Use Clinical studies of XYWAV or Xyrem in patients with narcolepsy or IH did not include sufficient numbers of subjects age 65 years and older to determine whether they respond differently from younger subjects. In clinical studies of sodium oxybate in another population, 39 (5%) of 874 patients were 65 years or older. Discontinuations of treatment due to adverse reactions were increased in the elderly compared to younger adults (21% vs. 19%). Frequency of headaches was markedly increased in the elderly (39% vs. 19%). The most common adverse reactions were similar in both age categories. 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.

Overdosage

10.1 Human Experience Information regarding overdose with XYWAV is derived largely from reports in the medical literature that describe symptoms and signs in individuals who have ingested GHB illicitly. In these circumstances the co-ingestion of other drugs and alcohol was common, and may have influenced the presentation and severity of clinical manifestations of overdose. In adult clinical trials with Xyrem (same active moiety as XYWAV), two cases of overdose were reported. In the first case, an estimated dose of 150 g, more than 15 times the maximum recommended dose, caused a patient to be unresponsive with brief periods of apnea and to be incontinent of urine and feces. This individual recovered without sequelae. In the second case, death was reported following a multiple drug overdose consisting of Xyrem and numerous other drugs. No cases of overdose (greater than 9 g) with XYWAV were reported in the XYWAV clinical trials. 10.2 Signs and Symptoms Information about signs and symptoms associated with overdosage with XYWAV derives from reports of illicit use of GHB. Patient presentation following overdose is influenced by the dose ingested, the time since ingestion, the co-ingestion of other drugs and alcohol, and the fed or fasted state. Patients have exhibited varying degrees of depressed consciousness that may fluctuate rapidly between a confusional, agitated combative state with ataxia and coma. Emesis (even when obtunded), diaphoresis, headache, and impaired psychomotor skills have been observed. No typical pupillary changes have been described to assist in diagnosis; pupillary reactivity to light is maintained. Blurred vision has been reported. An increasing depth of coma and acidosis have been observed at higher doses. Myoclonus and tonic-clonic seizures have been reported. Respiration may be unaffected or compromised in rate and depth. Cheyne-Stokes respiration and apnea have been observed. Bradycardia and hypothermia may accompany unconsciousness, as well as muscular hypotonia, but tendon reflexes remain intact. 10.3 Recommended Treatment of Overdose General symptomatic and supportive care should be instituted immediately, and gastric decontamination may be considered if co-ingestants are suspected. Because emesis may occur in the presence of obtundation, appropriate posture (left lateral recumbent position) and protection of the airway by intubation may be warranted. Although the gag reflex may be absent in deeply comatose patients, even unconscious patients may become combative to intubation, and rapid-sequence induction (without the use of sedative) should be considered. Vital signs and consciousness should be closely monitored. The bradycardia reported with GHB overdose has been responsive to atropine intravenous administration. No reversal of the central depressant effects of XYWAV can be expected from naloxone or flumazenil administration. The use of hemodialysis and other forms of extracorporeal drug removal have not been studied in GHB overdose, but have been reported in cases of acidosis associated with GHB ingestions of 125 g or greater; however, due to the rapid metabolism of oxybate, these measures may not be warranted. 10.4 Poison Control Center As with the management of all cases of drug overdosage, the possibility of multiple drug ingestion should be considered. The healthcare provider is encouraged to collect urine and blood samples for routine toxicologic screening, and to consult with a regional poison control center (1-800-222-1222) for current treatment recommendations.

Description

11 DESCRIPTION XYWAV oral solution contains oxybate, a CNS depressant. The chemical name of oxybate is gamma-hydroxybutyrate (GHB). XYWAV contains a mixture of calcium oxybate, magnesium oxybate, potassium oxybate, and sodium oxybate equivalent to 0.5 g/mL, which corresponds to 0.413 g/mL oxybate. Each mL of XYWAV contains: 0.234 g calcium oxybate, Ca(C 4 H 7 O 3 ) 2 ; 0.096 g magnesium oxybate, Mg(C 4 H 7 O 3 ) 2 ; 0.13 g potassium oxybate, K(C 4 H 7 O 3 ); and 0.04 g sodium oxybate, Na(C 4 H 7 O 3 ) in dissociated form in the solution. The molecular weights of each are as follows: calcium oxybate is 246.3, magnesium oxybate is 230.5, potassium oxybate is 142.2, and sodium oxybate is 126.1. The chemical structure is: y =1 for Na + and K + ; y =2 for Mg 2+ and Ca 2+ The inactive ingredients are purified water and sucralose. XYWAV contains no ingredient made from a gluten‑containing grain (wheat, barley, or rye). chemical structure

Mechanism of action

12.1 Mechanism of Action XYWAV is a CNS depressant. The exact mechanism of action of XYWAV in the treatment of narcolepsy and idiopathic hypersomnia is unknown. XYWAV is a mixture of calcium oxybate, magnesium oxybate, potassium oxybate, and sodium oxybate (gamma-hydroxybutyrate). Gamma-hydroxybutyrate (GHB) is an endogenous compound and metabolite of the neurotransmitter GABA. It is hypothesized that the therapeutic effects of XYWAV are mediated through GABA B actions during sleep at noradrenergic and dopaminergic neurons, as well as at thalamocortical neurons.

How supplied

16.1 How Supplied XYWAV is a clear to slightly opalescent oral solution. Each prescription includes at least one bottle of XYWAV with attached press in bottle adaptor, an oral measuring device (plastic syringe), and a Medication Guide. The pharmacy provides two empty containers with child-resistant caps with each XYWAV shipment. Each amber bottle contains XYWAV oral solution at a concentration of 0.5 g/mL and has a child-resistant cap. One 180 mL bottle: NDC 68727-150-01 16.2 Storage Keep out of reach of children. XYWAV should be stored between 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C (59°F and 86°F) (see USP Controlled Room Temperature). Dispense in tight containers. Solutions prepared following dilution should be consumed within 24 hours. 16.3 Handling and Disposal XYWAV is a Schedule III drug under the Controlled Substances Act. XYWAV should be handled according to state and federal regulations. It is safe to dispose of XYWAV down the sanitary sewer.

Patient information

Advise the patient and/or caregiver to read the FDA-approved patient labeling (Medication Guide and Instructions for Use). Central Nervous System Depression Inform patients and/or caregivers that XYWAV can cause central nervous system depression, including respiratory depression, hypotension, profound sedation, syncope, and death. Instruct patients not to engage in activities requiring mental alertness or motor coordination, including operating hazardous machinery, for at least 6 hours after taking XYWAV. Instruct patients and/or their caregivers to inform their healthcare providers of all the medications they take [see Warnings and Precautions ( 5.1 )]. Abuse and Misuse Inform patients and/or caregivers that the active ingredient of XYWAV is gamma-hydroxybutyrate (GHB), which is associated with serious adverse reactions with illicit use and abuse [see Warnings and Precautions ( 5.2 )]. XYWAV and XYREM REMS XYWAV is available only through a restricted program called the XYWAV and XYREM REMS [see Warnings and Precautions ( 5.3 )]. Inform the patient and/or caregiver of the following notable requirements:
• XYWAV is dispensed only by the central pharmacy
• XYWAV will be dispensed and shipped only to patients enrolled in the XYWAV and XYREM REMS XYWAV is available only from the central pharmacy participating in the program. Therefore, provide patients and/or caregivers with the telephone number and website for information on how to obtain the product. Alcohol or Sedative Hypnotics Advise patients and/or caregivers that alcohol and other sedative hypnotics should not be taken with XYWAV [see Contraindications ( 4 )] . Sedation Inform patients and/or caregivers that the patient is likely to fall asleep quickly after taking XYWAV (often within 5 and usually within 15 minutes), but the time it takes to fall asleep can vary from night to night. The sudden onset of sleep, including in a standing position or while rising from bed, has led to falls complicated by injuries, in some cases requiring hospitalization [see Adverse Reactions ( 6.2 )] . Instruct patients and/or caregivers that the patient should remain in bed following ingestion of each dose. Instruct patients and/or caregivers that the patient should not take a subsequent nightly dose until at least 2.5 to 4 hours after the previous dose [see Dosage and Administration ( 2.4 )] . Administration Instructions Inform patients to administer XYWAV at least 2 hours after eating. Inform patients and/or caregivers of patients taking XYWAV twice nightly, that the total nightly dosage of XYWAV is divided into two doses [see Dosage and Administration ( 2.4 )] . Inform patients if their nightly dose requires multiple draws. Instruct patients on how to perform the draws from the bottle. Respiratory Depression and Sleep-Disordered Breathing Inform patients that XYWAV may impair respiratory drive, especially in patients with compromised respiratory function, and may cause apnea [see Warnings and Precautions ( 5.4 )] . Depression and Suicidality Instruct patients and/or caregivers to contact a healthcare provider immediately if the patient develops depressed mood, markedly diminished interest or pleasure in usual activities, significant change in weight and/or appetite, psychomotor agitation or retardation, increased fatigue, feelings of guilt or worthlessness, slowed thinking or impaired concentration, or suicidal ideation [see Warnings and Precautions ( 5.5 )] . Other Behavioral or Psychiatric Adverse Reactions Inform patients and/or caregivers that XYWAV can cause behavioral or psychiatric adverse reactions, including confusion, anxiety, and psychosis. Instruct them to notify their healthcare provider if any of these types of symptoms occur [see Warnings and Precautions ( 5.6 )]. Sleepwalking Instruct patients and/or caregivers that XYWAV has been associated with sleepwalking and other behaviors during sleep, and to contact their healthcare provider if this occurs [see Warnings and Precautions ( 5.7 )] . Distributed By: Jazz Pharmaceuticals, Inc. Palo Alto, CA 94306 Protected by U.S. Patent Nos. 8,591,922; 8,772,306; 8,901,173; 9,050,302; 9,132,107; 9,486,426; 9,555,017; 10,195,168; 10,213,400; 10,675,258; 10,864,181; 11,253,494; 11,554,102; and 11,426,373.

Label text from the FDA structured product label by Jazz Pharmaceuticals, Inc. (revised Jul 1, 2025). Long sections are shortened; the complete label is on DailyMed.

Active ingredients

Xywav NDC products (1)

NDCStrength & formLabelerType
68727-150Sodium Oxybate .5 g/mL; Calcium Oxybate .5 g/mL; Potassium Oxybate .5 g/mL; Magnesium Oxybate .5 g/mL
Solution		Jazz Pharmaceuticals, Inc.NDA · DEA CIII

Frequently asked questions

What is Xywav used for?

1 INDICATIONS AND USAGE XYWAV is a central nervous system depressant indicated for the treatment of: • Cataplexy or excessive daytime sleepiness (EDS) in patients 7 years of age and older with narcolepsy ( 1.1 ). • Idiopathic Hypersomnia (IH) in adults ( 1.2 ). 1.1 Narcolepsy XYWAV is indicated for the treatment of cataplexy or excessive daytime sleepiness (EDS) in patients 7 years of age and…

What are the side effects of Xywav?

The following clinically significant adverse reactions appear in other sections of the labeling: • CNS depression [see Warnings and Precautions ( 5.1 )] • Abuse and Misuse [see Warnings and Precautions ( 5.2 )] • Respiratory Depression and Sleep-Disordered Breathing [see Warnings and Precautions ( 5.4 )] • Depression and Suicidality [see Warnings and Precautions ( 5.5 )] • Other Behavioral or… See the full label for the complete list.

Who makes Xywav?

Xywav is listed by 1 labeler in the FDA NDC directory, including Jazz Pharmaceuticals, Inc..