Xywav

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). 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.

Note: Some patients may achieve better responses with unequal nightly doses at bedtime and 2.5 to 4 hours later.

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.

* 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.

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 ].

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:

* 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.

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 ]. Doses higher than 9 g per night or single dose administrations higher than 6 g have not been studied and should not be administered.

Important Administration Instructions for All Patients

Administer XYWAV at least 2 hours after eating [see Clinical Pharmacology ]. 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 [see Adverse Reactions ].

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 [see Dosage and Administration ].

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 [see Use in Specific Populations and Clinical Pharmacology ].

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 [see Drug Interactions and Clinical Pharmacology ]. 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.

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/m2) 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/m2 basis.

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.

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 and Clinical Studies ].

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 and Adverse Reactions ].

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

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.

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 and Clinical Pharmacology ].