Xywav Drug Information

Narcolepsy XYWAV is indicated for the treatment of cataplexy or excessive daytime sleepiness (EDS) in patients 7 years of age and older with narcolepsy.

Idiopathic Hypersomnia XYWAV is indicated for the treatment of idiopathic hypersomnia (IH) in adults.

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). 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)

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. Table 2: Recommended XYWAV Dosage for Patients 7 Years of Age and Older*

Dosing Information in Adult Patients with Idiopathic Hypersomnia (IH) The dosage and regimen of XYWAV should be individualized based on clinical presentation. 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 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.

Important Administration Instructions for All Patients Administer XYWAV at least 2 hours after eating. Prepare all doses of XYWAV prior to bedtime. Prior to ingestion, each dose of XYWAV should be diluted with approximately ¼ cup (approximately 60 mL) of water in the empty pharmacy-provided containers.

Solutions prepared following dilution should be consumed within 24 hours. Patients should take each dose of XYWAV while in bed and lie down immediately after dosing, and remain in bed following ingestion of each dose. XYWAV may cause patients to fall asleep abruptly without first feeling drowsy.

Patients will often fall asleep within 5 minutes of taking XYWAV, and will usually fall asleep within 15 minutes, though the time it takes any individual patient to fall asleep may vary from night to night. If dosing twice nightly, patients may need to set an alarm to awaken for the second dose. If the second dose is missed, that dose should be skipped and XYWAV should not be taken again until the next night.

Two XYWAV doses should never be taken at one time.

Patients Transitioning from Xyrem to XYWAV On the first night of dosing with XYWAV, initiate treatment at the same dose (gram for gram) and regimen as Xyrem. Titrate as needed based on efficacy and tolerability.

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.

Dosage Adjustment with Co-administration of Divalproex Sodium When initiating divalproex sodium in patients taking a stable dosage of XYWAV, a reduction of the XYWAV dosage by at least 20% is recommended with initial concomitant use. When initiating XYWAV in patients already taking divalproex sodium, a lower starting dosage of XYWAV is recommended. Subsequently, the dosage of XYWAV can be adjusted based on individual clinical response and tolerability.

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. 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).

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. 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). Additional information regarding safety in pediatric patients appears in the following sections: • Respiratory Depression and Sleep-Disordered Breathing • Depression and Suicidality • Other Behavioral or Psychiatric Adverse Reactions • Parasomnias 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). The study was conducted in 154 adult male and female patients ages 19 to 75 years of age with IH. 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%). 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 s 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.

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.

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.

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. 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 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 mg/kg/day or rabbits 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.

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 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. 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 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).

• XYWAV is contraindicated for use in:
• Combination with sedative hypnotics.
• Combination with alcohol.
• Patients with succinic semialdehyde dehydrogenase deficiency.
• In combination with sedative hypnotics or alcohol
• Succinic semialdehyde dehydrogenase deficiency

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.