Xywav Drug Information

• 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.

• 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. Adverse reactions occurring in ≥2% of patients treated with XYWAV in the open-label titration and stable dose periods in Study 2 are shown in Table 5: Table 5: Adverse Reactions Occurring in ≥2% of Patients Treated with XYWAV in the Open-Label Titration and Stable Dose Periods in Study 2 * includes anxiety, nervousness, and panic attack † includes middle insomnia, initial insomnia, insomnia, and terminal insomnia ‡ includes hyperhidrosis and night sweats § includes fatigue and asthenia ¶ includes somnolence and sedation # includes confusional arousal, sleep paralysis, nightmare, sleep talking, somnambulism, and hypnopompic hallucination ♠ includes balance disorder and ataxia Adverse Reaction Open-Label Titration Period + Stable Dose Period (up to 16 weeks) (N=154) % Nausea 21 Headache 16 Anxiety * 12 Dizziness 12 Insomnia † 9 Hyperhidrosis ‡ 8 Decreased appetite 8 Vomiting 7 Dry mouth 6 Diarrhea 5 Fatigue § 5 Somnolence ¶ 5 Tremor 5 Parasomnia # 5 Balance disorder ♠ 3 Muscle spasms 3 Fall 3 Paresthesia 3 Snoring 3 Weight decreased 3 Bruxism 3 Confusional state 3 Depressed mood 3 Feeling drunk 3 Irritability 3 Additional Adverse Reactions Adverse reactions observed in clinical studies with Xyrem (≥2%), but not observed in Study 1 or Study 2 at a frequency of higher than 2%, and which may be relevant for XYWAV: Pain, pain in extremity, cataplexy, disturbance in attention, sleep paralysis, and disorientation. 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of sodium oxybate. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: Arthralgia, fall*, fluid retention, hangover, hypersensitivity, hypertension, memory impairment, nocturia, and vision blurred. * The sudden onset of sleep in patients taking sodium oxybate, including in a standing position or while rising from bed, has led to falls complicated by injuries, in some cases requiring hospitalization.

• 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 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 . 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 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.

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 . 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).

• 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 )

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.

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.

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.

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.