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EFFICACY & SAFETY

The efficacy and safety of XYWAV in adult patients with narcolepsy was evaluated in a clinical trial1,2

Study 1 was a phase 3, placebo-controlled, double-blind, randomized-withdrawal study that evaluated the efficacy and safety of XYWAV for the treatment of cataplexy and EDS in adults with narcolepsy.1,2

CLINICAL TRIAL OVERVIEW: Primary efficacy endpoint

No median change in average number of weekly cataplexy attacks in adult patients who continued taking XYWAV1

Patients who were randomized to discontinue stable doses of XYWAV and take placebo during the double-blind, randomized-withdrawal period experienced a significant worsening in average weekly number of cataplexy attacks compared with patients randomized to continue XYWAV treatment.

See Study Design

PRIMARY EFFICACY ENDPOINT: MEDIAN CHANGE IN FREQUENCY OF CATAPLEXY ATTACKS FROM BASELINE TO THE DOUBLE-BLIND, RANDOMIZED-WITHDRAWAL PERIOD1,2*

 *The change in average number of weekly cataplexy attacks was calculated from the 2 weeks of the stable-dose period (baseline) to the 2 weeks of the double-blind, randomized-withdrawal period.

 

The bottom and top edges of the box indicate the first and third quartiles, the line inside the box is the median, and the marker inside the box is the mean. The whiskers extending from the box indicate the minimum and maximum after removing outliers.2

 

Q1 = first quartile; Q3 = third quartile.

Post hoc analysis: Cataplexy-free days per week during the double-blind, randomized-withdrawal period3

A post hoc analysis that evaluated cataplexy-free days/week based on daily patient cataplexy frequency diaries completed from the beginning of the open-label titration period through the end of the double-blind randomized-withdrawal period of Study 1.3 This analysis was exploratory and not powered to determine statistical significance.

CATAPLEXY-FREE DAYS PER WEEK DURING THE DOUBLE-BLIND, RANDOMIZED-WITHDRAWAL PERIOD* (EFFICACY POPULATION)3

*Cataplexy-free days per week were calculated from daily diaries completed by participants for the primary efficacy analysis during each study period. Weekly cataplexy-free days were calculated using diary data as (# days with 0 cataplexy attacks)/(# days with diary data) x 7.

 

Defined as participants who took ≥1 dose of double-blind study drug and had ≥1 post-randomization efficacy assessment.

 

Limitations: Results based on post hoc analysis of average cataplexy-free days per week (0-7) from patient reports in daily cataplexy diaries throughout the main part of Study 1. Limitations include that this was an exploratory post hoc analysis, and as such, statistical comparisons were not performed. Any missing diary data are assumed to be missing completely at random, and the number of days without cataplexy attacks is treated as a continuous variable.

No median change in ESS scores in adult patients randomized to continue XYWAV1,2

Patients who were randomized to discontinue stable doses of XYWAV and take placebo during the double-blind, randomized-withdrawal period experienced significant worsening in ESS score compared with patients randomized to continue XYWAV treatment.1

KEY SECONDARY EFFICACY ENDPOINT: CHANGE IN EPWORTH SLEEPINESS SCALE SCORE,* AS A MEASURE OF CHANGE IN EDS, FROM THE END OF THE STABLE-DOSE PERIOD TO THE END OF THE DOUBLE-BLIND, RANDOMIZED-WITHDRAWAL PERIOD1,2

*The ESS is a tool to measure daytime sleepiness in adults. A score of 0-10 is considered normal; >10 suggests excessive daytime sleepiness (EDS); and ≥16 suggests high levels of EDS.4,5

 

The bottom and top edges of the box indicate the first and third quartiles, the line inside the box is the median, and the marker inside the box is the mean. The whiskers extending from the box indicate the minimum and maximum after removing outliers.2

 

Q1 = first quartile; Q3 = third quartile.

Study design

Study 1 was a phase 3, placebo-controlled, double-blind, randomized-withdrawal study that evaluated the efficacy and safety of XYWAV for the treatment of cataplexy and EDS in adults with narcolepsy.1,2

  • Enrolled 201 patients (18 to 70 years of age) with narcolepsy with cataplexy, with a baseline history of at least 14 cataplexy attacks in a typical 2-week period prior to any treatment for narcolepsy symptoms1
  • Stimulants were allowed at study entry, and 39% of patients (78/201) continued taking a stable dose of stimulant throughout the stable-dose and double-blind randomized-withdrawal periods1
  • Participants were categorized into groups based on their cataplexy treatment (or no cataplexy treatment) at study entry1,2

STUDY DESIGN1,2

OPEN-LABEL TITRATION (12 WEEKS) AND STABLE-DOSE (2 WEEKS) PERIODS1,2

  • Patients taking XYREM® (sodium oxybate) oral solution at study entry were switched (at a gram-for-gram dose) from XYREM to XYWAV for a minimum of 2 weeks and titrated, if needed, to a stable, tolerable, and effective dosage over 8 weeks1
    • Most patients who switched from XYREM to XYWAV (41/59; 69%) had no change in dosage from study entry to the stable-dose period, 27% (16/59) had an increase in dosage, and 3% (2/59) had a decrease in dosage1
    • Among patients whose dosage was changed, most changes were within 1 titration step (≤1.5 g)1
  • Patients not taking XYREM at study entry were initiated at 4.5 g/night of XYWAV and titrated at a rate of 1 or 1.5 g/night/week to a tolerable dose of XYWAV1
  • Patients taking an anticataplectic other than XYREM were tapered off the non-XYREM anticataplectic over 2-8 weeks1
  • All patients continued to take XYWAV only for the treatment of cataplexy during the last 2 weeks of the open-label titration period1
  • The open-label titration period was followed by a 2-week stable-dose period1

 

DOUBLE-BLIND, RANDOMIZED-WITHDRAWAL PERIOD (2 WEEKS)1

  • 134 of the 201 patients were randomized 1:1 either to continue treatment with XYWAV or to placebo in the 2-week double-blind, randomized-withdrawal period1

 

EFFICACY ENDPOINTS

  • Primary efficacy endpoint: Change in frequency of cataplexy attacks from the 2 weeks of the stable-dose period to the 2 weeks of the double-blind, randomized-withdrawal period1
  • Key secondary endpoint: Change in Epworth Sleepiness Scale score, as a measure of change in EDS, from the end of the stable-dose period to the end of the double-blind, randomized-withdrawal period1

The effectiveness of XYWAV in pediatric patients is based on a clinical study in patients treated with XYREM and additional pharmacokinetic information1

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.1

References:

  1. XYWAVTM (calcium, magnesium, potassium, and sodium oxybates). Prescribing Information. Palo Alto, CA: Jazz Pharmaceuticals, Inc.
  2. Bogan RK, Thorpy MJ, Dauvilliers Y, et al. Efficacy and safety of calcium, magnesium, potassium, and sodium oxybates (lower-sodium oxybate [LXB]; JZP-258) in a placebo-controlled, double-blind, randomized withdrawal study in adults with narcolepsy with cataplexy. Sleep. Published online October 14, 2020. doi.org/10.1093/sleep/zsaa206.
  3. Dauvilliers Y, Foldvary-Schaefer N, Bogan RK, et al. Cataplexy-free days in a phase 3, placebo-controlled, double-blind, randomized-­withdrawal study of calcium, magnesium, potassium, and sodium oxybates in adults with narcolepsy with cataplexy. Poster presented at: APSS SLEEP 2020 Virtual Meeting; August 27-30, 2020.
  4. Johns MW. A new method for measuring daytime sleepiness: the Epworth sleepiness scale. Sleep. 1991;14(6):540-545.
  5. Johns M, Hocking B. Excessive daytime sleepiness: daytime sleepiness and sleep habits of Australian workers. Sleep. 1997;20(10):844-849.

INDICATIONS AND USAGE

XYWAVTM (calcium, magnesium, potassium, and sodium oxybates) oral solution, 0.5 g/mL total salts (equivalent to 0.413 g/mL of oxybate) is indicated for the treatment of cataplexy or excessive daytime sleepiness (EDS) in patients 7 years of age and older with narcolepsy.

Important Safety Information

WARNING: CENTRAL NERVOUS SYSTEM DEPRESSION and ABUSE AND MISUSE.

  • Central Nervous System Depression

XYWAV is a CNS depressant. Clinically significant respiratory depression and obtundation may occur in patients treated with XYWAV at recommended doses. Many patients who received XYWAV during clinical trials in narcolepsy were receiving CNS stimulants.

  • Abuse and Misuse

The active moiety of XYWAV is oxybate or gamma-hydroxybutyrate (GHB). Abuse or misuse 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.

Because of the risks of CNS depression and abuse and misuse, XYWAV is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the Xywav and Xyrem REMS.

 

Contraindications

XYWAV is contraindicated

  • in combination with sedative hypnotics or alcohol and
  • in patients with succinic semialdehyde dehydrogenase deficiency.

 

Warnings and Precautions

Central Nervous System Depression

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 (eg, post- or perioperative) is required, interruption of treatment with XYWAV should be considered.

 

After first initiating treatment and until certain that XYWAV does not affect them adversely (eg, impair judgment, thinking, or motor skills), caution patients against hazardous activities requiring complete mental alertness or motor coordination such as operating hazardous machinery, including automobiles or airplanes. Also caution patients against these hazardous activities 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.

 

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 (eg, assault victim). Physicians should carefully evaluate patients for a history of drug abuse and follow such patients closely.

 

XYWAV and XYREM REMS Program

Because of the risks of central nervous system depression and abuse and misuse, XYWAV is available only through a restricted distribution program called the Xywav and Xyrem REMS Program.

Notable requirements of the Xywav and Xyrem REMS Program 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 Program with documentation of safe use

Further information is available at www.XywavXyremREMS.com or 1-866-997-3688.

 

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. 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. 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.

 

Depression and Suicidality

In a randomized-withdrawal clinical trial in adult patients with narcolepsy (n=201), depression and depressed mood were reported in 3% and 4%, respectively, of patients treated with XYWAV. Two patients (1%) discontinued XYWAV because of depression. In most cases, no change in XYWAV treatment was required. In clinical trials of Xyrem (same active moiety as XYWAV) in adult patients with narcolepsy (n=781), adverse reactions of depression were reported by 7% of 781 patients treated with Xyrem, with four patients (<1%) discontinuing because of depression. In most cases, no change in Xyrem treatment was required. 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. Of the two suicides, one patient used Xyrem in conjunction with other drugs. Xyrem was not involved in the second suicide.

 

In the pediatric clinical trial with Xyrem (same active moiety as XYWAV) in patients with narcolepsy (n=104), one patient experienced suicidal ideation while taking Xyrem and two patients reported depression. The emergence of depression in patients treated with XYWAV requires careful and immediate evaluation. Monitor patients for the emergence of increased depressive symptoms and/or suicidality while taking XYWAV, which require careful and immediate evaluation.

 

Other Behavioral or Psychiatric Adverse Reactions

In a randomized-withdrawal clinical trial in adult patients, confusion occurred in 1% of patients treated with XYWAV and anxiety occurred in 5% of patients treated with XYWAV. One patient experienced visual hallucinations and confusion after ingesting approximately 9 grams of XYWAV. Other neuropsychiatric reactions reported in clinical trials of Xyrem (same active moiety as XYWAV) in adult patients with narcolepsy and in the postmarketing setting included hallucinations, paranoia, psychosis, aggression, and agitation.

 

In a pediatric clinical trial with Xyrem (same active moiety as XYWAV) in patients with narcolepsy, neuropsychiatric reactions, including acute psychosis, confusion, and anxiety, were reported while taking Xyrem.

 

The emergence or increase in the occurrence of behavioral or psychiatric events in patients taking XYWAV should be carefully monitored.

 

Parasomnias

Parasomnias can occur in patients taking XYWAV.

 

In a randomized-withdrawal clinical trial, parasomnias, including sleepwalking were reported in 6% of adult patients treated with XYWAV. In a clinical trial of Xyrem (same active moiety as XYWAV) in adult patients with narcolepsy, five instances of sleepwalking with potential injury or significant injury were reported. Parasomnias, including sleepwalking, have been reported in a pediatric clinical trial with sodium oxybate (same active moiety as XYWAV) and in postmarketing experience with sodium oxybate. Episodes of sleepwalking should be fully evaluated and appropriate interventions considered.

 

Most Common Adverse Reactions

In the adult clinical trial, in patients with narcolepsy, the most common adverse reactions (incidence ≥5% of XYWAV-treated patients) were headache, nausea, dizziness, decreased appetite, parasomnia, diarrhea, hyperhidrosis, anxiety, and vomiting.

 

In the pediatric clinical trial with Xyrem (same active moiety as XYWAV), that included pediatric patients 7 to 17 years of age with narcolepsy, 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%). 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.

 

Additional Adverse Reactions

Additional adverse reactions that occurred in ≥2% of adult patients treated with XYWAV in the Open-Label Titration and Stable Dose Periods of the randomized-withdrawal study in adult patients with narcolepsy with cataplexy (Study 1) were fatigue, dry mouth, depressed mood, enuresis, irritability, paresthesia, depression, tremor, somnolence, and muscle spasms.

 

Additional adverse reactions that occurred in ≥2% of patients in clinical studies with Xyrem (but not in Study 1) and which may be relevant for XYWAV, were pain, feeling drunk, pain in extremity, cataplexy, disturbance in attention, sleep paralysis, and disorientation.

 

Discontinuation: In a randomized-withdrawal clinical trial 9 of 201 adult 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.

 

In the pediatric clinical trial with Xyrem (same active moiety as XYWAV), 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).

 

Drug Interactions

XYWAV should not be used in combination with alcohol or sedative hypnotics. Use of other CNS depressants may potentiate the CNS-depressant effects of XYWAV.

 

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 and Lactation

There are no adequate data on the developmental risk associated with the use of XYWAV or sodium oxybate in pregnant women. XYWAV should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. 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

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.

 

Safety and effectiveness of XYWAV in pediatric patients below the age of 7 years have not been established.

 

Geriatric Use

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

The starting dose of XYWAV should be reduced in patients with liver impairment.

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.

 

Dependence and Tolerance

There have been case reports of withdrawal, ranging from mild to severe, following discontinuation of illicit use of GHB at frequent repeated doses (18 g to 250 g per day) in excess of the recommended dosage range. Signs and symptoms of GHB withdrawal following abrupt discontinuation included insomnia, restlessness, anxiety, psychosis, lethargy, nausea, tremor, sweating, muscle cramps, tachycardia, headache, dizziness, rebound fatigue and sleepiness, confusion, and, particularly in the case of severe withdrawal, visual hallucinations, agitation, and delirium. These symptoms generally abated in 3 to 14 days. In cases of severe withdrawal, hospitalization may be required. The discontinuation effects of XYWAV have not been systematically evaluated in controlled clinical trials.

 

In the clinical trial experience with XYREM in narcolepsy/cataplexy patients at recommended doses, two patients reported anxiety and one reported insomnia following abrupt discontinuation at the termination of the clinical trial; in the two patients with anxiety, the frequency of cataplexy had increased markedly at the same time. In the XYWAV clinical trial in adult narcolepsy/cataplexy patients at recommended doses, one patient reported insomnia following abrupt discontinuation of XYWAV.

 

Tolerance to XYWAV has not been systematically studied in controlled clinical trials. There have been some case reports of symptoms of tolerance developing after illicit use at dosages far in excess of the recommended XYWAV dosage regimen.

 

Please see full Prescribing Information, including BOXED Warning.

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