Calcium, Magnesium, Potassium, and Sodium Oxybates

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.

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 )

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 )

• 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. Prescribers should be aware that increased central apneas and clinically relevant oxygen desaturation events have been observed with sodium oxybate administration in adult and pediatric patients. In clinical trials of Xyrem in 128 adult patients with narcolepsy, two patients had profound CNS depression, which resolved after supportive respiratory intervention. Two other patients discontinued sodium oxybate because of severe difficulty breathing and an increase in obstructive sleep apnea. In two controlled trials assessing PSG measures in adult patients with narcolepsy, 40 of 477 patients were included with a baseline apnea/hypopnea index of 16 to 67 events per hour, indicative of mild to severe sleep-disordered breathing. None of the 40 patients had a clinically significant worsening of respiratory function, as measured by apnea/hypopnea index and pulse oximetry at doses of 4.5 g to 9 g per night. 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.

5.5 Depression and Suicidality Depression, and suicidal ideation and behavior can occur in patients treated with XYWAV. In Study 1 [see Clinical Studies ( 14.1 )] , depression and depressed mood were reported in 3% and 4%, respectively, of patients treated with XYWAV. Two patients (1%) discontinued XYWAV because of depression, but in most cases, no change in XYWAV treatment was required. In Study 2 [see Clinical Studies ( 14.3 )] , depression and depressed mood were reported in 1 patient (1%) and in 5 patients (3%), respectively, of patients treated with XYWAV, all of whom continued XYWAV treatment. In clinical trials of Xyrem (same active moiety as XYWAV) in adult patients with narcolepsy (n=781), there were two suicides and two attempted suicides in patients treated with Xyrem, including three patients with a previous history of depressive psychiatric disorder. […]

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. 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. Adult Patients with Idiopathic Hypersomnia The safety of XYWAV was evaluated in a double-blind placebo-controlled randomized‑withdrawal study in patients with IH (Study 2). This study consisted of an open‑label titration period (OL OTTP) up to 14 weeks, a stable-dose period (SDP) for 2 weeks, a double‑blind, placebo‑controlled, randomized-withdrawal period (DB RWP) for 2 weeks, and an open-label extension period for 24 weeks (all study periods up to 42 weeks) [see Clinical Studies ( 14.3 )] . The study was conducted in 154 adult male and female patients ages 19 to 75 years of age with IH. The mean exposure to XYWAV during this study, including titration, the randomized withdrawal period, and the open-label extension, was 204 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 2 In Study 2, across all study periods (excluding placebo during the DB RWP) (up to 42 weeks), 17 of 154 patients (11%) 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%). 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 2 (incidence ≥5% of XYWAV‑treated patients) in addition to those observed in Study 1 as most common were insomnia, dry mouth, fatigue, somnolence, and tremor. The safety profile observed in Study 2 was similar to that of Study 1. […]

• 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.

• 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. 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.

8.6 Hepatic Impairment Because of an increase in exposure to XYWAV, the starting dose should be reduced by half in patients with hepatic impairment [see Dosage and Administration ( 2.6 ) and Clinical Pharmacology ( 12.3 )].

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.