Xywav (calcium, magnesium, potassium, and sodium oxybates) - 2 indications

Scroll down for information on each indication:

• for the treatment of cataplexy or excessive daytime sleepiness in patients 7 years of age and older with narcolepsy; approved July of 2020
• for Idiopathic Hypersomnia (IH) in adults; approved August of 2021

General Information

Xywav (calcium, magnesium, potassium, and sodium oxybates) is a central nervous system depressant.

Xywav is specifically indicated for the following conditions:

• for the treatment of cataplexy or excessive daytime sleepiness in patients 7 years of age and older with narcolepsy
• for the treatment of idiopathic hypersomnia (IH) in adults

Xywav is supplied as a solution for oral administration. Scroll down for the recommended dosing/administration for each indication.

Mechanism of Action

Xywav is a CNS depressant. The exact mechanism of action of Xywav in the treatment of narcolepsy 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 on cataplexy and excessive daytime sleepiness are mediated through GABAB actions during sleep at noradrenergic and dopaminergic neurons, as well as at thalamocortical neurons.

Side Effects

Adverse effects associated with the use of Xywav in adults may include, but are not limited to, the following:

• headache
• nausea
• dizziness
• decreased appetite
• parasomnia
• diarrhea
• hyperhidrosis
• anxiety
• vomiting

Adverse effects associated with the use of Xywav in pediatrics may include, but are not limited to, the following:

• enuresis
• nausea
• headache
• vomiting
• weight decreased
• decreased appetite
• dizziness

The Xywav drug label comes with the following Black Box Warning: Central Nervous System Depression: Xywav is a CNS depressant, and respiratory depression can occur with Xywav use. Abuse and Misuse: The active moiety of Xywav is oxybate or gamma-hydroxybutyrate (GHB). Abuse or misuse of illicit GHB is associated with CNS adverse reactions, including seizure, respiratory depression, decreased consciousness, coma, and death. Xywav is available only through a restricted program called the Xywav REMS.

Indication 1 - for the treatment of cataplexy or excessive daytime sleepiness in patients 7 years of age and older with narcolepsy

approved July of 2020

Dosing/Administration

Adult Dosing Information:

• 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.
• 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.

Pediatric Dosing Information: 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. Please see drug label for weight specifications. 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.

Clinical Trial Results

The FDA approval of Xywav was based on two phase 3 clinical trials: one in adults and one in pediatrics. 

Adults: A global, double-blind, placebo-controlled, randomized-withdrawal, multicenter study evaluated the efficacy and safety of JZP-258 in the treatment of cataplexy and EDS in adults with narcolepsy. The primary endpoint was the change in the weekly number of cataplexy attacks, and the key secondary endpoint was the change in the Epworth Sleepiness Scale (ESS) score with JZP-258 compared to placebo. The study enrolled 201 participants and randomized 134 participants, comprising a heterogeneous population, which included those previously treated with sodium oxybate and naïve to sodium oxybate, with or without other anticataplectic treatments. During the double-blind withdrawal period, there was a significant increase in median weekly number of cataplexy attacks in participants randomized to placebo compared with participants randomized to JZP-258 (median [Q1, Q3]: 2.35 versus 0.00 [−0.49, 1.75], respectively. At the end of the double-blind withdrawal period, there was a significant increase in median ESS scores in participants randomized to placebo compared with participants randomized to JZP- 258 (median [Q1, Q3]: 2.0 versus 0.0, respectively.

Pediatrics: The effectiveness of Xyrem in the treatment of cataplexy and excessive daytime sleepiness in pediatric patients 7 years of age and older with narcolepsy was established in a double-blind, placebo-controlled, randomized-withdrawal study. The study was conducted in 106 pediatric patients (median age: 12 years; range: 7 to 17 years) with a baseline history of at least 14 cataplexy attacks in a typical 2-week period prior to any treatment for narcolepsy symptoms. Of the 106 patients, 2 did not receive study drug and 63 patients were randomized 1:1 either to continued treatment with Xyrem or to placebo. Randomization to placebo was stopped early as the efficacy criterion was met at the pre-planned interim analysis. The primary efficacy measure was the change in frequency of cataplexy attacks. Pediatric patients taking stable dosages of Xyrem who discontinued Xyrem treatment and were randomized to placebo during the double-blind treatment period experienced a statistically significant increase in weekly cataplexy attacks compared with patients who were randomized to continue treatment with Xyrem. Patients randomized to receive placebo during the double-blind treatment period experienced a statistically significant worsening of EDS compared with patients randomized to continue receiving Xyrem. 

Indication 2 - Idiopathic Hypersomnia (IH) in adults

approved August of 2021

Dosing/Administration

Xywav can be administered as a twice or once nightly regimen in adults.

• 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.
• 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

Clinical Trial Results

This FDA approval is based on the global Phase 3 double-blind, multicenter, placebo-controlled, randomized withdrawal study that demonstrated the efficacy and safety of Xywav for the treatment of idiopathic hypersomnia in adults (n=154, 115 of whom were evaluable for efficacy data). In the study, Xywav demonstrated statistically significant and clinically meaningful differences compared to placebo in change in the primary endpoint of Epworth Sleepiness Scale score and secondary endpoints of Patient Global Impression of Change and the Idiopathic Hypersomnia Severity Scale.