AHFS Class:

• Wakefulness-promoting Agents 28:20.80

Generic Name(s):

• Sodium Oxybate

• Calcium, Magnesium, Potassium, and Sodium Oxybates

Sodium oxybate is the sodium salt of γ-hydroxybutyrate (GHB), an endogenous compound and metabolite of the neurotransmitter GABA; the drug is a CNS depressant that exhibits anticataplectic and potent hypnotic activity.1,2,14,15

Calcium, magnesium, potassium, and sodium oxybates is a preparation of sodium oxybate with a composition of cations resulting in a lower sodium content.15,19 Unless otherwise specified in this monograph, the term “lower-sodium oxybate” refers to the formulation containing calcium, magnesium, potassium and sodium oxybates (Xywav^®).15

Narcolepsy

Sodium oxybate is used in the management of excessive daytime sleepiness or cataplexy in patients with narcolepsy.1,7,8,10,20,15,17,19,20 The drug is commercially available as an immediate-release oral solution (Xyrem^®) for such use in patients 7 years of age or older and also as an extended-release oral suspension (Lumryz^®) for use in adults.1,14 A lower-sodium oxybate formulation (Xywav^®) is also available for use in patients 7 years of age and older and contains the same active moiety as sodium oxybate, but with a composition of cations (calcium, magnesium, and potassium) resulting in 92% less sodium.15,19

Clinical Experience

Efficacy of sodium oxybate immediate-release oral solution (Xyrem^®) in adults with narcolepsy has been established in 2 randomized, placebo-controlled clinical trials; approximately 80% of patients enrolled in these trials were receiving a CNS stimulant concomitantly.1,8,10 In one study of 4 weeks' duration in patients with narcolepsy who had moderate to severe cataplexy (median of 21 cataplexy attacks per week) at baseline, the median number of attacks per week was reduced by 7, 10, or 16 in those receiving sodium oxybate 3, 6, or 9 g daily, respectively; the median number of attacks per week was reduced by 4 in those receiving placebo. 1,7,8 Dose-related improvement also was observed in secondary measures of efficacy (i.e., daytime sleepiness, inadvertent daytime naps/sleep attacks, nocturnal awakening).7,8 In a controlled, randomized, withdrawal trial in patients with narcolepsy who had received long-term (7-44 months) therapy with sodium oxybate in an open-label trial, the median increase from baseline in the number of cataplexy attacks over a 2-week period was 21 in those who discontinued sodium oxybate compared with no increase in those who continued receiving the drug.1,7,10

Efficacy of sodium oxybate immediate-release oral solution (Xyrem^®) in the management of excessive daytime sleepiness in adults with narcolepsy has been established in 2 double-blind, placebo-controlled studies.1 In the first study, patients with moderate to severe symptoms at study entry (median Epworth Sleepiness Scale [ESS; a measure of sleepiness in everyday situations] score of 18 and Maintenance of Wakefulness Test [MWT] score of 8.3 minutes) were randomized to receive 4.5, 6, or 9 g of sodium oxybate nightly or placebo.1 Approximately 78% of patients enrolled in this study were receiving a CNS stimulant concomitantly.1 Therapy with 6 or 9 g of sodium oxybate nightly was associated with improvement in daytime sleepiness (ESS score) and overall disease status (Clinical Global Impression of Change [CGI-C]) at 8 weeks (study end point) compared to the placebo group.1 The median decrease in ESS score from baseline in those receiving 6 or 9 g of sodium oxybate nightly was 2 or 5, respectively; the median decrease in ESS score was 0.5 in those receiving placebo.1 Overall disease status was rated as much improved or very much improved on the CGI-C in 52 or 64% of those receiving 6 or 9 g of sodium oxybate, respectively, and in 22% of those receiving placebo.1 In the second study, patients with moderate to severe symptoms (median ESS score of 15 and MWT score of 10.3 minutes) who had received stable dosages of modafinil (200-600 mg daily) prior to study entry were randomized to receive sodium oxybate (6 g nightly increased to 9 g nightly), modafinil (prior dosage), sodium oxybate (6 g nightly increased to 9 g nightly) in conjunction with modafinil (prior dosage), or placebo.1 Therapy with sodium oxybate alone or in conjunction with modafinil was associated with enhanced ability to stay awake compared to placebo; the mean improvement in MWT score from baseline was 0.6 minutes in those receiving sodium oxybate alone and 2.7 minutes in those receiving sodium oxybate in conjunction with modafinil.1 Patients receiving placebo had a mean deterioration in MWT score of 2.7 minutes.1 The study was not designed to compare the effects of sodium oxybate alone with the effects of modafinil alone, since the dosage of modafinil was not titrated to the maximum effective dosage.1

Efficacy of sodium oxybate immediate-release oral solution (Xyrem^®) in pediatric patients with narcolepsy has been established in a double-blind, placebo-controlled, randomized-withdrawal study in patients 7 to 17 years of age who were experiencing at least 14 cataplexy attacks in a typical 2-week period prior to any treatment.1,20 Eligible patients were either already taking sodium oxybate or were naïve to treatment; approximately 50% were receiving concomitant CNS stimulants.1,20 Treatment-naïve patients were titrated to a stable dose of sodium oxybate; a total of 63 patients were then randomized to receive placebo or remain on sodium oxybate for 2 weeks.1,20 Because the efficacy criterion was met at a pre-planned interim analysis, the placebo arm of the study was discontinued; 33 patients then received sodium oxybate on an open-label basis during the double-blind treatment period.1,20 Patients who were taking stable doses of sodium oxybate who were withdrawn from treatment and randomized to placebo during the double-blind treatment period had a statistically significant increase in cataplexy attacks (median increase of 12.7 attacks per week) compared to those who were randomized to continue treatment with sodium oxybate (median increase of 0.3 attacks per week).1,20

Efficacy of once-nightly administration of sodium oxybate extended-release suspension (Lumryz^®) in adults with narcolepsy was established in a double-blind, randomized, placebo-controlled study.14 A total of 212 patients were randomized to sodium oxybate extended-release suspension or placebo; 65% were receiving concomitant stimulant therapy.14 Patients randomized to sodium oxybate were titrated to a stable dose of 4.5, 6, 7.5, or 9 g administered once per night.14 Results showed statistically significant improvements in the 3 co-primary end points of Maintenance of Wakefulness Test (MWT), Clinical Global Impression-Improvement (CGI-I), and mean change in weekly cataplexy attacks for the 6, 7.5, and 9 g doses of sodium oxybate compared with placebo.14

Efficacy of lower-sodium oxybate (Xywav^®) for the management of cataplexy and excessive daytime sleepiness in adults with narcolepsy was established in a double-blind, placebo-controlled, randomized-withdrawal study.15,16 The study consisted of a 12-week, open-label, optimized treatment and titration period, followed by a 2-week stable-dose period, and then a 2-week, double-blind, randomized-withdrawal period.16 Patients entering the study were either taking a stable dosage of sodium oxybate only, sodium oxybate and another anticataplectic, a non-sodium oxybate anticataplectic, or were cataplexy-treatment naïve.15 Patients taking sodium oxybate at study entry were switched to lower-sodium oxybate and treatment-naïve patients were initiated on lower-sodium oxybate; additional anticataplectic medications were tapered and all patients received only lower sodium oxybate for the optimized treatment and titration period.15,16 CNS stimulants were allowed at study entry, and approximately 59% of patients continued taking a stable dose of stimulant throughout the stable-dose and double-blind, randomized-withdrawal period.15,16 The primary efficacy endpoint was the 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 period.15,16 Patients taking stable doses of lower-sodium oxybate who discontinued treatment and were randomized to placebo during the double-blind, withdrawal period experienced a significant worsening in the average weekly number of cataplexy attacks (median increase of 2.4 cataplexy attacks per week) compared with patients randomized to continue treatment with lower-sodium oxybate (median increase of 0 cataplexy attcks per week).15,16

Safety and efficacy of lower-sodium oxybate (Xywav^®) for the treatment of cataplexy or excessive daytime sleepiness in pediatric patients 7 years of age and older is supported by evidence from clinical studies of sodium oxybate in pediatric patients 7 to 17 years of age, a study in adults showing a treatment effect of lower-sodium oxybate similar to that observed with sodium oxybate, pharmacokinetic data of sodium oxybate from adult and pediatric patients, and pharmacokinetic data of lower-sodium oxybate from healthy adult volunteers.15

Clinical Perspective

Narcolepsy is a CNS disorder characterized by somnolence, often accompanied by sudden attacks of muscle weakness (cataplexy) while awake and disturbed nocturnal sleep, and occasionally accompanied by hypnagogic hallucinations and/or sleep paralysis before falling asleep or upon awakening.7,8,12 Cataplexy occurs in about 60-75% of patients with narcolepsy and may be precipitated by laughter or other emotions such as anger, surprise, or excitement.7 The excessive sleepiness of narcolepsy consists of both a background feeling of sleepiness that is present much of the time and a strong, sometimes irresistible, urge to sleep at recurring intervals throughout the day.12

The American Academy of Sleep Medicine (AASM) strongly recommends the use of sodium oxybate (versus no treatment) for adults with narcolepsy.22 Evidence from randomized controlled studies and observational studies demonstrate the effectiveness of the drug in improving excessive daytime sleepiness, cataplexy, and disease severity.22 The AASM task force states that the benefits of sodium oxybate outweigh the risks (e.g., abuse or misuse, CNS effects, respiratory depression) and that the balance between the desirable and undesirable effects of the drug strongly favor use of the drug.22 The balance of risks and harms is likely to be different, however, for pregnant and breastfeeding women because of the drug's risk for fetal harm.22 AASM suggests the use of sodium oxybate (versus no treatment) for pediatric patients with narcolepsy, but gives this a conditional recommendation.22

Idiopathic Hypersomnia

Calcium, magnesum, potassium and sodium oxybates (lower-sodium oxybate; Xywav^®) is used in the management of idiopathic hypersomnia in adults.15 22

Clinical Experience

Efficacy of lower-sodium oxybate in the management of idiopathic hypersomnia was established in a double-blind, placebo-controlled, randomized-withdrawal study in adult patients.15 The study consisted of a 10-week, open-label treatment titration and optimization period, with up to 4 additional weeks to allow for an optimally effective and tolerable dose, followed by a 2-week, stable dose period and then a 2-week, double-blind, randomized-withdrawal period.15 The primary efficacy endpoint was the change in ESS score from the end of the stable dose period to the end of the randomized-withdrawal period.15 Secondary efficacy endpoints included patient global impression of change and the Idiopathic Hypersomnia Severity Scale (IHSS), both assessed as a change from the end of the stable dose period to the end of the randomized-withdrawal period.15

Patients taking stable doses of lower-sodium oxybate who were withdrawn from treatment and randomized to placebo during the double-blind, randomized-withdrawal period experienced significant worsening in ESS score compared with patients randomized to continue treatment with lower-sodium oxybate across all dosing regimens.15 The median change in ESS was 0 for patients receiving lower-sodium oxybate and 8 for patients receiving placebo.15 Patients receiving placebo reported a significant worsening of symptoms of idiopathic hypersomnia overall compared to patients receiving lower-sodium oxybate as reported by the patient global impression of change and the IHSS assessments.15

Efficacy and safety of lower-sodium oxybate were maintained or improved during the 6-month, open-label extension study in patients with idiopathic hypersomnia, as demonstrated by the reported decrease in ESS scores from 6.7 in week 2 of the open label period to 5.3 at the end of the 24-week study and decrease in IHSS scores over the 24-week period.18

Clinical Perspective

Idiopathic hypersomnia is a neurologic condition that is characterized by excessive daytime sleepiness, uncontrollable need to sleep with long unrefreshing naps, and difficulty waking up from sleep in most instances despite average or longer amounts of nocturnal sleep for at least 3 months.16 Cataplexy is not present.16 This condition usually presents as a chronic and disabling excessive daytime sleepiness in an adolescent or young adult, with the majority complaining of "sleep drunkenness" or difficulty waking up from sleep with transient confusion upon awakening.16 The American Academy of Sleep Medicine (AASM) suggests the use of sodium oxybate for the treatment of idiopathic hypersomnia in adults with narcolepsy, but gives this a conditional recommendation because the overall quality of evidence is low.22

General

Patient Monitoring

• Monitor patients for events related to CNS depression upon initiation of therapy and periodically thereafter.1,14,15
• Monitor patients with a history of a depressive illness and/or suicide attempt carefully for the emergence of depressive symptoms.1,14,15
• Monitor patients for an emergence or increase of behavioral or psychiatric events.1,14,15

REMS

• Because of the risks of CNS depression, abuse, and misuse, commercially available sodium oxybate and lower-sodium oxybate preparations are prescribed and distributed under a restricted distribution program (XYWAV and Xyrem REMS and the LUMRYZ REMS).1,14,15
• Prescribers and patients must enroll in the program.1,14,15 The goals of the program are to restrict access to sodium oxybate-containing preparations and to educate clinicians and patients about the risks and benefits of the drugs.1
• Information regarding the distribution programs may be obtained by contacting the central pharmacy for XYWAV and XYREM REMS at 866-997-3688 or by visiting [Web] or for LUMRYZ REMS at 877-453-1029 or by visiting [Web].1,14,15

Administration

Sodium oxybate is available as an immediate-release oral solution (Xyrem^®) and extended-release granules for oral suspension (Lumryz^®).1,14 Calcium, magnesum, potassium and sodium oxybates (lower-sodium oxybate) is available as an oral solution (Xywav^®).15

Sodium oxybate oral solution (Xyrem^®) should be stored at 25°C (excursions permitted between 15-30°C).1,15 Extended-release granules (Lumryz^®) and lower-sodium oxybate oral solution (Xywav^®) should be stored at 20-25°C (excursions permitted between 15-30°C).14,15

Oral Administration

Sodium Oxybate Immediate-release Oral Solution

The total nightly dosage of sodium oxybate oral solution (Xyrem^®) is administered orally in 2 equally divided doses.1 Because food reduces oral bioavailability of sodium oxybate, the drug should be administered at least 2 hours after eating.1 The first dose of sodium oxybate is taken at bedtime (while in bed), and the second dose is taken 2.5-4 hours later after the first dose (while in bed).1 Both doses should be prepared before bedtime and used within 24 hours.1 Each dose of sodium oxybate must be diluted with approximately 1/4 cup (approximately 60 mL of water) in the child-resistant vial provided by the pharmacy.1 The patient will probably need to set an alarm clock to awaken for the second dose; the second dose should be placed in close proximity to the patient's bed.1 The patient should lie down and remain in bed after each dose of sodium oxybate as the drug may cause them to fall asleep abruptly without first feeling drowsy.1

If a second dose is missed, that dose should be skipped and sodium oxybate oral solution should not be taken again until the next night.1 Both doses of sodium oxybate should never be taken at one time.1

Sodium Oxybate Extended-release Oral Suspension

Sodium oxybate extended-release oral suspension (Lumryz^®) is taken orally as a single dose at bedtime.14 The drug is commercially available as granules that should be prepared by suspending in water at bedtime prior to administration.14 The prescribed dose of sodium oxybate extended-release granules should be suspended in approximately 1/3 cup (approximately 80 mL) of water in the mixing cup provided by the pharmacy.14 Do not use hot water to prepare the mixture.14 Take the oral suspension within 30 minutes after mixing and at least 2 hours after eating as food reduces the oral bioavailability.14 Patients should take the oral suspension while in bed and lie down immediately and remain in bed after dosing as the drug may cause them to fall asleep abruptly without first feeling drowsy.14

Calcium, Magnesum, Potassium and Sodium Oxybates (Lower-Sodium Oxybate) Oral Solution

Lower-sodium oxybate oral solution (Xywav^®) is taken orally in 2 evenly divided doses nightly for patients with narcolepsy and in 2 evenly divided doses or as a single dose in patients with idiopathic hypersomnia.15 Because food reduces oral bioavailability of lower-sodium oxybate, the drug should be administered at least 2 hours after eating.15 Patients should take each dose while in bed and lie down immediately and remain in bed following ingestion of each dose as the drug may cause them to fall asleep abruptly without first feeling drowsy.15 All doses should be prepared before bedtime and used within 24 hours.15 Prior to ingestion, the dose of lower-sodium oxybate oral solution should be diluted with approximately 1/4 cup (approximately 60 mL) of water in the empty container provided by the pharmacy.15 If dosing twice nightly, the first dose is taken at bedtime and the second dose is taken 2.5-4 hours later after the first dose.15 The patient will probably need to set an alarm clock to awaken for the second dose; the second dose should be placed in close proximity to the patient's bed.15 The patient should lie down and remain in bed after each dose.15

If the second dose is missed, that dose should be skipped and another dose should not be taken again until the next night.15 Two doses of sodium oxybate should never be taken at one time.15

Dosage

Adult Dosage

Narcolepsy (Excessive Daytime Sleepiness and Cataplexy)

Sodium oxybate immediate-release oral solution (Xyrem®) : The recommended initial dosage of immediate-release sodium oxybate oral solution for adults with narcolepsy is 4.5 g daily administered nightly in 2 divided doses of 2.25 g each, with the first dose taken at bedtime and the second dose taken 2.5 to 4 hours after the first dose.1 Dosage can be increased in increments of 1.5 g daily (0.75 g per dose) at intervals of 1 week to the maximum recommended dosage range of 6 to 9 g daily (divided in 2 doses).1 The dosage may be gradually titrated based on efficacy and tolerability.1 Doses greater than 9 g daily have not been studied and should not ordinarily be administered.1

Sodium oxybate extended-release oral suspension (Lumryz®) : The recommended initial dosage of sodium oxybate extended-release oral suspension in adults with narcolepsy is 4.5 g nightly administered in a single dose.14 Increase the dosage by 1.5 g per night at weekly intervals up to the maximum recommended dosage range of 6 to 9 g daily.14 The dosage may be gradually titrated based on efficacy and tolerability.14 Doses greater than 9 g daily have not been studied and should not ordinarily be administered.14

Transitioning from immediate-release to extended-release sodium oxybate: Adult patients who are currently being treated with immediate-release sodium oxybate oral solution (Xyrem^®) may be switched to the extended-release oral suspension (Lumryz^®) at the nearest equivalent dosage in grams per night (e.g., 7.5 g sodium oxybate oral solution [divided into two 3.75 g doses nightly] to 7.5 g extended-release suspension once each night).14

Lower-sodium oxybate oral solution (Xywav®) : The recommended initial dosage of lower-sodium oxybate in adults with narcolepsy is 4.5 g daily administered nightly in 2 divided doses of 2.25 g each, with the first dose taken at bedtime and the second dose taken 2.5 to 4 hours later.15 Some patients may achieve better responses with unequal nightly doses.15 Dosage can be increased in increments of up to 1.5 g daily (0.75 g per dose) at weekly intervals up to maximum recommended dosage of 6 to 9 g daily (given in 2 divided doses).15 The dosage may be gradually titrated based on efficacy and tolerability.15 Doses greater than 9 g daily have not been studied and should not ordinarily be administered.15

Transitioning from immediate-release sodium oxybate to lower-sodium oxybate: On the first night of dosing with lower-sodium oxybate, initiate treatment at the same dose (g for g) and regimen as immediate-release sodium oxybate oral solution; titrate as necessary based on efficacy and tolerability.15

Idiopathic Hypersomnia

Lower-sodium oxybate oral solution (Xywav®) : The recommended initial dosage of lower-sodium oxybate in adults with idiopathic hypersomnia is up to 4.5 g daily administered nightly in 2 divided doses (up to 2.25 g each dose), with the first dose taken at bedtime and the second dose taken 2.5 to 4 hours later.15 Some patients may achieve better responses with unequal nightly doses.15 Dosage may be increased in increments of up to 1.5 g per night (divided into 2 doses) at weekly intervals up to a recommended maximum dosage of 9 g daily (divided in 2 doses).15 Doses greater than 9 g daily have not been studied and should not ordinarily be administered.15

Alternatively, a single dose of up to 3 g may be given once nightly.15 Dosage may be increased in increments of up to 1.5 g per night at weekly intervals up to a maximum recommended dosage of 6 g daily.15 Single doses greater than 6 g have not been studied and should not be administered.

During titration, the dosing regimen may be changed between twice nightly and once nightly as needed based on efficacy and tolerability.15

Transitioning from immediate-release sodium oxybate to lower-sodium oxybate: On the first night of dosing with lower-sodium oxybate, initiate treatment at the same dose (g for g) and regimen as immediate-release sodium oxybate oral solution; titrate as necessary based on efficacy and tolerability.15

Pediatric Dosage

Narcolepsy (Excessive Daytime Sleepiness and Cataplexy)

Sodium oxybate immediate-release oral solution (Xyrem®) in pediatric patients ≥7 years of age: Sodium oxybate immediate-release oral solution is administered orally twice nightly, taken at bedtime and 2.5 to 4 hours later.1 The recommended starting dosage, titration regimen, and maximum total nightly dosage for pediatric patients with excessive daytime sleepiness or cataplexy are based on patient weight.1 (See Table 1) The dosage may be gradually titrated based on efficacy and tolerability.1 Some pediatric patients may achieve better responses with unequal doses at bedtime and 2.5 to 4 hours later.1

Lower-sodium oxybate oral solution (Xywav®) in pediatric patients ≥7 years of age: Lower-sodium oxybate oral solution is administered orally twice nightly, taken at bedtime and 2.5 to 4 hours later.15 The recommended starting dosage, titration regimen, and maximum total nightly dosage for pediatric patients with excessive daytime sleepiness or cataplexy are based on patient weight.15 (See Table 2) Some patients may achieve better responses with unequal nightly doses at bedtime and 2.5 to 4 hours later.15 The dosage may be gradually titrated based on efficacy and tolerability.15 Doses higher than 9 g per night have not been studied and should not ordinarily be administered.15

Transitioning from immediate-release sodium oxybate to lower-sodium oxybate: On the first night of dosing with lower-sodium oxybate, initiate treatment at the same dose (g for g) and regimen as immediate-release sodium oxybate oral solution; titrate as necessary based on efficacy and tolerability.15

Dosage Adjustment for Concomitant Administration with Divalproex Sodium

When initiating divalproex sodium in patients taking a stable dosage of immediate-release sodium oxybate or lower-sodium oxybate, a reduction of the sodium oxybate dosage by at least 20% is recommended.1,15 When initiating immediate-release sodium oxybate or lower-sodium oxybate in patients already taking divalproex sodium, a lower starting dosage of sodium oxybate is recommended.1,15 Subsequently, adjust the dosage of sodium oxybate based on individual clinical response and tolerability.1,15

The manufacturer of sodium oxybate extended-release suspension states that no dosage changes are recommended based on pharmacokinetic studies.14 However, a pharmacodynamic interaction between sodium oxybate and divalproex sodium, a sedative antiepileptic drug, cannot be ruled out.14

Special Populations

Hepatic Impairment

The recommended initial dosage of sodium oxybate immediate-release oral solution and lower-sodium oxybate oral solution in patients with hepatic impairment is one-half of the original daily dosage given nightly in 2 divided doses (one-half each usual dose).1,15

Sodium oxybate extended-release oral suspension should not be initiated in patients with hepatic impairment because appropriate dosage adjustments cannot be made with the available dosage strengths.14 Patients with hepatic impairment who have been titrated to a maintenance dosage of another sodium oxybate preparation can be switched to the extended-release oral suspension if the appropriate dosage strength is available.14

Renal Impairment

The manufacturers make no specific dosage recommendations for sodium oxybate preparations in patients with renal impairment.1,14,15

Geriatric Patients

Select dosage in geriatric patients with caution, usually starting at lower end of dosage range, because of age-related decreases in hepatic, renal, and/or cardiac function and considering concomitant disease and other drug therapy.1,14,15

Contraindications

• Concomitant therapy with sedative-hypnotic agents or concomitant use with alcohol.1,14,15
• Succinic semialdehyde dehydrogenase (SSADH) deficiency.1,14,15

Warnings/Precautions

Warnings

CNS Depression

Sodium oxybate is a CNS depressant.1,2,4,5,6,14,15 Obtundation and respiratory depression have occurred in patients receiving the drug at recommended dosages in clinical trials.1,14,15 A boxed warning about this risk has been included in the prescribing information for the drug.1,14,15 Concomitant use of sodium oxybate with other CNS depressants may increase the risk of respiratory depression, hypotension, profound sedation, syncope, and death.1,14,15

Death has been reported in patients receiving sodium oxybate.13 Although the cause of death has been unclear in many of the reported cases because of incomplete information or the presence of potential confounding factors, a number of fatalities have involved patients with underlying conditions that may have been predisposed to CNS and respiratory depression (e.g., sleep apnea, chronic obstructive pulmonary disease [COPD]), individuals with psychiatric disorders (e.g., depression, substance abuse), use for off-label indications, use of excessive or rapidly titrated dosages, or concomitant use of alcohol or one or more CNS depressants.13

Because of the rapid onset of CNS depressant effects, sodium oxybate and lower-sodium oxybate should be administered at bedtime and while in bed.1,14,15 Patients must not engage in hazardous occupations or activities requiring complete mental alertness or physical coordination (e.g., operating machinery, driving a motor vehicle, flying an airplane) for at least 6 hours after a dose is administered.1 In addition, patients should be cautioned about operating a motor vehicle or other heavy machinery or performing tasks that could be hazardous or require complete mental alertness until they are reasonably certain that sodium oxybate does not adversely affect their ability to engage in such activities.1,14,15 Patients should be asked about events related to CNS depression upon initiation of therapy and periodically thereafter.1

Abuse and Misuse Potential

Abuse of illicit forms of sodium oxybate (γ-hydroxybutyrate [GHB]; sodium salt of GHB), either alone or in combination with other CNS depressants, has been associated with a number of serious adverse CNS effects including seizures, respiratory depression, profound decreases in the level of consciousness, coma, and death; circumstances surrounding these events (e.g., the dose of GHB [sodium oxybate] ingested, the amount of alcohol or other drugs ingested concomitantly) often are unclear.1,2,3,4,5,6,14,15 A boxed warning about this risk has been included in the prescribing information for the drug.1,14,15 The rapid onset of sedation and the amnestic effects of the drug, particularly when combined with alcohol, have proven dangerous for voluntary and involuntary users (e.g., assault victims).1 Because misuse and abuse of sodium oxybate (GHB) have been reported, patients with a history of drug abuse should be carefully evaluated and followed closely for signs of misuse or abuse (e.g., dosage escalation, drug-seeking behavior, feigned cataplexy).1,14,15 Commercially available sodium oxybate-containing preparations are subject to control as schedule III drugs and are only available through a restricted distribution program.1,14,15 Nonmedical use of sodium oxybate is subject to control as a schedule I drug.1,14,15

Tolerance to the effects of sodium oxybate has not been observed in clinical trials in patients with narcolepsy.7,15 However, severe dependence and craving have been reported with recreational use of the drug in the same dosages7 or those far in excess15 as those used in clinical trials.7,15

Other Warnings/Precautions

Respiratory Depression and Sleep-Disordered Breathing

Sodium oxybate is a CNS depressant that has the potential to impair respiratory drive, especially in patients with preexisting respiratory impairment.1 Life-threatening respiratory depression has occurred following overdosage of the drug.1 Respiratory depression and an increase in obstructive sleep apnea have occurred in adult and pediatric patients with narcolepsy receiving sodium oxybate in clinical trials.1 Most adult patients receiving sodium oxybate in clinical trials were receiving a CNS stimulant concomitantly; whether concomitant use of a CNS stimulant affected nocturnal respiration remains to be determined.1 In a study assessing the effects of sodium oxybate in adult patients with obstructive sleep apnea, use of the drug was associated with an increase in the number of central sleep apnea episodes, and clinically important oxygen desaturation occurred in several patients.1 During polysomnographic evaluation (PSG), central sleep apnea and oxygen desaturation were observed in pediatric patients with narcolepsy treated with sodium oxybate.1 Sodium oxybate should be used cautiously in patients with respiratory impairment (e.g., sleep apnea, COPD).1,13 Clinicians should be aware that sleep-related breathing disorders tend to be more prevalent in obese patients, in men, and in postmenopausal women not receiving hormone replacement therapy, as well as in patients with narcolepsy.1

Depression and Suicidality

Depression and suicidality have occurred in adult and pediatric patients receiving sodium oxybate and lower-sodium oxybate in clinical trials.1,14,15 Two suicides and two attempted suicides were reported in patients with narcolepsy receiving sodium oxybate in adult clinical trials; three of these cases involved patients with a history of depressive disorders.1 One patient experienced suicidal ideation and two patients reported depression while taking sodium oxybate in a pediatric clinical study.1 In controlled trials with immediate release sodium oxybate, extended-release sodium oxybate, and lower-sodium oxybate, depression was reported in patients at a range of nightly dosages.1,14,15

The emergence of symptoms of depression in patients treated with sodium oxybate preparations requires careful and immediate evaluation.1,14,15 Patients with a previous history of a depressive illness and/or suicide attempt should be monitored carefully for the emergence of depressive symptoms while taking sodium oxybate preparations.1,14,15

Other Behavioral and Psychiatric Effects

Confusion, and other neuropsychiatric events (e.g., psychosis, paranoia, hallucinations, aggression, agitation, anxiety) have occurred in adult patients receiving immediate-release sodium oxybate at recommended dosages in clinical trials.1,15 In a controlled trial of immediate-release sodium oxybate, the incidence of confusion appears to increase with increasing dosage.1 Other psychiatric reactions occuring in adult clinical studies of extended-release sodium oxybate included irritability, emotional disorder, panic attack, agitation, delirium, and obsessive thoughts.14 In a clinical study in pediatric patients with narcolepsy receiving immediate-release sodium oxybate, psychosis, confusion, and anxiety were reported.1 Patients receiving sodium oxybate preparations who become confused or who experience thought disorders and/or behavioral abnormalities require careful, immediate evaluation and monitoring.1,14,15

Parasomnia

Confused behavior at night, sometimes associated with wandering (sleepwalking), has occurred in adult and pediatric patients receiving sodium oxybate preparations.1,14,15 Since instances of substantial or potential injury associated with sleepwalking occurred rarely during clinical trials of sodium oxybate in patients with narcolepsy, episodes of such activity in patients receiving the drug should be fully evaluated and appropriate interventions considered.1,14,15

Sodium Content

Sodium oxybate immediate-release oral solution and sodium oxybate extended-release suspension have high salt content.1,14 Sodium content should be considered in patients at risk such as those with heart failure, hypertension, or renal impairment.1 See Table 3 for the approximate sodium content in each dose of the immediate-release oral solution1 and Table 4 for the approximate sodium content in each nightly dose of the extended-release oral suspension.14

Lower-sodium oxybate contains 92% less sodium per g (87-131 mg in the dose range of 6-9 g/night) than sodium oxybate.17,19,21

Specific Populations

Pregnancy

There are no available data on the developmental risk associated with the use of sodium oxybate in pregnant women.1,14,15 Mixed evidence is available from animal studies; in pregnant rats and rabbits, administration 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.1

Sodium oxybate and lower-sodium oxybate have not been studied in labor or delivery; but use of an injectable formulation of sodium oxybate resulted in very sleepy newborns with a decrease in Apgar scores.1

Lactation

Insufficient information is available on the risk of sodium oxybate to a breastfed infant, and on milk production in nursing mothers.1,1,14,15 The metabolite, GHB, is excreted in human milk after oral administration of sodium oxybate.1 Caution is advised if the drug is administered in nursing women.1,14,15

Pediatric Use

Safety and efficacy of sodium oxybate immediate-release oral solution (Xyrem^®) have been established in pediatric patients 7 years of age and older for the management of narcolepsy in a double-blind, placebo-controlled, randomized-withdrawal study.1

In a study of pediatric patients with narcolepsy, serious adverse reactions included 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.1,20

Safety and efficacy of lower-sodium oxybate (Xywav^®) for the treatment of cataplexy or excessive daytime sleepiness in pediatric patients 7 years of age and older are supported by evidence from clinical studies of sodium oxybate in pediatric patients 7 to 17 years of age, a study in adults showing a treatment effect of lower-sodium oxybate similar to that observed with sodium oxybate, pharmacokinetic data of sodium oxybate from adult and pediatric patients, and pharmacokinetic data of lower-sodium oxybate from healthy adult volunteers.15

Safety and efficacy of sodium oxybate extended-release suspension (Lumryz^®) have not been established in pediatric patients.14

Safety and effectiveness of sodium oxybate and lower-sodium oxybate in pediatric patients younger than 7 years of age have not been established.1,15

Geriatric Use

Clinical studies of sodium oxybate and lower-sodium oxybate in patients with narcolepsy or idiopathic hypersomnia did not include sufficient numbers of patients 65 years of age or older to determine whether geriatric patients respond differently than younger adults.1,14,15 In clinical trials of sodium oxybate in another patient population (i.e., patients with disorders other than narcolepsy), the incidence of headaches was higher in geriatric patients compared with younger adults.1 In general, dosage selection in geriatric patients should be cautious, usually starting at the lower end of the dosage range, because of the greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease and drug therapy in these patients.1 Geriatric patients receiving sodium oxybate should be monitored for impaired motor or cognitive function.1

Hepatic Impairment

Elimination half-life and systemic exposure to sodium oxybate are increased in patients with hepatic impairment.1 Dosage of sodium oxybate immediate-release solution and lower-sodium oxybate solution should be reduced by half in such patients.1,15 Sodium oxybate extended-release suspension should not be initiated in patients with hepatic impairment because appropriate dosage adjustments for initiation of treatment cannot be made with the available dosage strengths, but patients who have been titrated to a maintenance dosage of another sodium oxybatepreparation can be switched to the extended-release suspension if the appropriate dosage strength is available.14

Renal Impairment

The sodium content of sodium oxybate preparations should be considered in patients with renal impairment.1,14

Common Adverse Effects

Adverse effects occurring in 5% or more of adult patients receiving sodium oxybate (Xyrem^®) in controlled clinical trials and at least twice as frequently as with placebo include nausea, dizziness, vomiting, somnolence, enuresis, and tremor.1

Adverse effects occurring in 5% or more of adult patients receiving extended-release sodium oxybate (Lumryz^®) in controlled clinical trials and at least twice as frequently as with placebo include nausea, dizziness, enuresis, headache, and vomiting.14

Adverse effects occurring in 5% or more of adult patients receiving lower-sodium oxybate (Xywav^®) in controlled clinical trials for narcolepsy or idiopathic hypersomnia include nausea, headache, dizziness, anxiety, insomnia, decreased appetite, hyperhidrosis, vomiting, diarrhea, dry mouth, parasomnia, somnolence, fatigue, and tremor.15

Adverse reactions occurring 5% or more of pediatric patients receiving immediate-release sodium oxybate (Xyrem^®) include nausea, enuresis, vomiting, headache, decreased weight, decreased appetite, dizziness, and sleepwalking.1

CNS Depressants

Concomitant use of sodium oxybate with alcohol, sedative hypnotics, or other CNS depressants may markedly impair consciousness and cause respiratory depression.1,13,14,15 Sodium oxybate and lower-sodium oxybate are contraindicated in patients receiving sedative-hypnotic agents.1,13,14,15 Ingestion of alcohol also is contraindicated in patients receiving sodium oxybate or lower-sodium oxybate.1,13,14,15

Concomitant use of sodium oxybate with other CNS depressants (e.g., opiate analgesics, benzodiazepines, sedating antidepressants or antipsychotics, sedating anti-epileptics, general anesthetics, muscle relaxants, illicit CNS depressants) also may increase the risk of respiratory depression, hypotension, profound sedation, syncope, and death; such concomitant use generally should be avoided.1,13,14,15 If concomitant use is required, dosage reduction or discontinuance of one or more CNS depressants (including sodium oxybate) should be considered.1,13,14,15 If short-term use of an opiate (e.g., postoperative or perioperative use) is required, interruption of sodium oxybate therapy should be considered.1,13,14,15

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.1 An initial dose reduction of at least 20% for sodium oxybate immediate-release (Xyrem^®) and lower-sodium oxybate (Xywav^®) is recommended when used concomitantly with divalproex sodium.1,15 Prescribers should monitor patient response closely and adjust dose accordingly if concomitant use of sodium oxybate or lower-sodium oxybate and divalproex sodium is necessary.1,15

Concomitant use of a single dose of extended-release sodium oxybate (Lumryz^®) with divalproex sodium extended-release at steady state resulted in an approximate 18% increase in drug exposure (AUC), which is not expected to be clinically meaningful.14 A single dose of extended-release sodium oxybate did not appear to affect the pharmacokinetics of divalproex sodium.14 However, a pharmacodynamic interaction between extended-release sodium oxybate and divalproex sodium, a sedative antiepileptic drug, cannot be ruled out.14

Fomepizole

No pharmacokinetic interaction.1 Pharmacodynamic interaction cannot be ruled out.1

Modafinil

No pharmacokinetic interaction.1 Pharmacodynamic interaction cannot be ruled out.1

Omeprazole

No change in sodium oxybate pharmacokinetics secondary to omeprazole-related alterations of gastric pH. 1

Protriptyline

No pharmacokinetic interaction.1 Pharmacodynamic interaction cannot be ruled out.1

Zolpidem

No pharmacokinetic interaction.1 Pharmacodynamic interaction cannot be ruled out.1

Description

Sodium oxybate is a potent, rapidly acting CNS depressant that exhibits anticataplectic activity and potent hypnotic activity.1 The drug also exhibits hypnotic, amnesic, and hypotonic (i.e., causes hypotonia) activity.2,3,4,5,6 Sodium oxybate, which occurs endogenously as γ-hydroxybutyrate (GHB) (a metabolite of γ-aminobutyric acid [GABA]),2,4,5,6 is structurally and pharmacologically distinct from other currently available exogenous CNS depressants; the mechanism of anticataplectic action is unknown.1 It is hypothesized that the effects of sodium oxybate on cataplexy and excessive daytime sleepiness are mediated through GABA_B actions at noradrenergic and dopaminergic neurons, as well as thalamocortical neurons.1

Lower-sodium oxybate is a mixture of calcium oxybate, magnesium oxybate, potassium oxybate, and sodium oxybate and contains the same active moiety as sodium oxybate (γ-hydroxybutyrate; GHB); the combination of cations results in 92% less sodium in the preparation compared to sodium oxybate.15,19

Sodium oxybate is the sodium salt of γ-hydroxybutyrate (GHB), a known drug of abuse.1,2,3,4,5,6

Sodium oxybate is rapidly absorbed; the peak plasma concentrations for the oral solution are attained within 0.5-1.25 hours.1 The time to peak plasma concentrations is 1.5 hours for the extended-release suspension and 1.3 hours for the lower-sodium oral solution.14,15 The absolute bioavailability of the oral solution is approximately 88%.1 Nonlinear pharmacokinetics for the oral solution exist; plasma concentrations increase 3.7-fold as dose is doubled from 4.5 to 9 g.1 A high-fat meal delays the time to peak plasma concentrations (to 2 hours) and reduces peak plasma concentrations by 59% and AUC by 37% for the oral solution.1 A high-fat meal delays the time to peak plasma concentrations (to 1.5 hours) and reduces peak plasma concentrations by 33% and AUC by 14% for the extended-release suspension.14 A high-fat meal reduces the peak plasma concentrations by 33% and AUC by 16% for the lower-sodium oral solution.15

Protein binding is <1%.1 Sodium oxybate is metabolized principally by 4-hydroxybutyrate dehydrogenase to succinate semialdehyde; succinate semialdehyde is then biotransformed to succinate by the enzyme succinate-semialdehyde dehydrogenase.1 Succinate enters the Krebs cycle where it is metabolized to carbon dioxide and water.1 Fecal excretion is negligible; <5% is excreted in urine as unchanged drug.1 The half-life of sodium oxybate oral solution is 0.5-1 hour.1 In vitro data indicate that sodium oxybate does not inhibit the cytochrome P-450 (CYP) isoenzymes 1A2, 2C9, 2C19, 2D6, 2E1, or 3A.1

Advice to Patients

• Advise the patient and/or caregiver to read the manufacturer's patient information (medication guide).1,14,15
• Inform patients and/or caregivers that sodium oxybate can cause CNS depression, including respiratory depression, hypotension, profound sedation, syncope, and death.1,14 Instruct patients to not engage in activities requiring mental alertness or motor coordination, including operating hazardous machinery, for at least 6 hours after taking sodium oxybate.1,14,15
• Inform patients and/or caregivers that the active ingredient of sodium oxybate is gamma-hydroxybutyrate (GHB), which is associated with serious adverse reactions with illicit use and abuse.1,14,15
• Sodium oxybate and lower-sodium oxybate are available only through restricted programs called the XYWAV and XYREM REMS^® or the LUMRYX REMS^®.1,14,15 Inform the patient and/or caregiver that the drug is available only from the central pharmacy participating in the program and will be dispensed and shipped only to patients enrolled in the program.1,14,15 Also provide patients and/or caregivers with the telephone number and website for information on how to obtain the product.1,14,15
• Advise patients and/or caregivers that alcohol and other sedative hypnotics should not be taken with sodium oxybate.1,14,15
• Inform patients that they are likely to fall asleep quickly after taking sodium oxybate (often within 5 and usually within 15 minutes), but the time it takes to fall asleep can vary from night to night.1,14,15 The sudden onset of sleep, including in a standing position or while rising from bed, has led to falls complicated by injuries, in some cases requiring hospitalization.1,14,15 Instruct patients to remain in bed following ingestion of the first and second nightly doses.1,15 Instruct patients to not take their second nightly dose until 2.5 to 4 hours after the first dose.1,15
• Inform patients and/or caregivers that the first nightly dose should be taken at least 2 hours after eating.1,14,15
• Inform patients that sodium oxybate may impair respiratory drive, especially in patients with compromised respiratory function, and may cause apnea.1,14,15
• Instruct patients and/or caregivers to contact a healthcare provider immediately if the patient develops depressed mood, markedly diminished interest or pleasure in usual activities, significant change in weight and/or appetite, psychomotor agitation or retardation, increased fatigue, feelings of guilt or worthlessness, slowed thinking or impaired concentration, or suicidal ideation.1,14,15
• Inform patients and/or caregivers that sodium oxybate can cause behavioral or psychiatric adverse reactions, including confusion, anxiety, and psychosis.1,14 Instruct them to notify their healthcare provider if any of these types of symptoms occur.1,14,15
• Instruct patients and/or caregivers that sodium oxybate has been associated with sleepwalking and other behaviors during sleep, and to contact their healthcare provider if this occurs.1,14,15
• Instruct patients and/or caregivers that sodium oxybate (Xyrem^®, Lumryz^®) contains a significant amount of sodium and patients who are sensitive to sodium (e.g., those with heart failure, hypertension, or renal impairment) should limit their sodium intake.1,14
• Advise women to inform their clinician if they are or plan to become pregnant or plan to breast-feed.1,14,15
• Advise patients to inform their clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary and herbal supplements, as well as any concomitant illnesses.1,14,15
• Advise patients of other important precautionary information.1,14,15

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

1. Jazz Pharmaceuticals. Xyrem^® (sodium oxybate) oral solution prescribing information. Palo Alto, CA; 2023 Apr.

2. Sweetman SC, ed. Martindale: the complete drug reference. 33rd ed. London: The Pharmaceutical Press; 2002:1268.

3. Nightingale SL. Warning about GHB. JAMA . 1991; 265:1802. [PubMed 1848642]

4. Anon. Multistate outbreak of poisonings associated with illicit use of gammy hydroxy butyrate. JAMA . 1991; 265:447-8. [PubMed 1985226]

5. Galloway GP, Frederick SL, Staggers F Jr. Physical dependence on sodium oxybate. Lancet. 1994; 343:57.

6. European Monitoring Centre for Drugs and Drug Addiction (EMCDDA). Report on the risk assessment of GHB in the framework of the joint action on new synthetic drugs. From the EMCDDA website ([Web]).

7. Anon. Gamma hydroxybutyrate (Xyrem) for narcolepsy. Med Lett Drugs Ther . 2002; 44:103-5. [PubMed 12473959]

8. The U.S. Xyrem^® Multicenter Study Group. A randomized, double-blind, placebo-controlled multicenter trial comparing the effects of three doses of orally administered sodium oxybate with placebo for the treatment of narcolepsy. Sleep . 2002; 25:42-9. [PubMed 11833860]

10. The U.S. Xyrem^® Multicenter Study Group. Sodium oxybate demonstrates long-term efficacy for the treatment of cataplexy in patients with narcolepsy. Sleep Med . 2004; 5:119-23. [PubMed 15033130]

12. Zeman A, Britton T, Douglas N et al. Narcolepsy and excessive daytime sleepiness. BMJ . 2004; 329:724-8. [PubMed 15388615]

13. US Food and Drug Administration. FDA drug safety communication: Warning against use of Xyrem (sodium oxybate) with alcohol or drugs causing respiratory depression. Rockville, MD; 2012 Dec 17. From FDA website. [Web]

14. Avadel CNS Pharmaceuticals. Lumryz^®(sodium oxybate) for extended-release oral suspension prescribing information. Chesterfield, MO; 2023 May.

15. Jazz Pharmaceuticals. Xywav^® (calcium, magnesium, potassiu, and sodium oxybates) oral solution prescribing information. Palo Alto, CA; 2023 Apr.

16. Idiopathic Hypersomnia. National Library of Medicine, National Institues of Health. Stat Pearls. Updated 2023 July 31. Accessed February 15, 2024.

17. Schneider LD, Morse AM, Strunc MJ et al. Long-term treatment of narcolepsy and idiopathic hypersomnia with low-sodium oxybate. Nature and Science of Sleep. 2023; 15:663-675.

18. Morse AM, Davusvilliers Y, Arnulf I et al. Long-term efficacy and safety of low-sodium oxybate in an open-label extension period of a placebo-controlled, double-blind, randomized withdrawal study in adults with idiopathic hypersomnia. J Clin Sleep Med. 2023; 19:1811-22.

19. 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 J 2021:44:1-13.

20. Plazzi G, Ruoff C, Lecendreux M et al. Treatment of paediatric narcolepsy with sodiumoxybate: a double-blind, placebo-controlled,randomised-withdrawal multicentre study andopen-label investigation. Lancet Child Adolesc Health. 2018; 2:483-494.

21. Husain AM, Zee PC, Leary EB, et al. Dosing and transition characteristics in people with narcolepsytransitioning from sodium oxybate to low-sodium oxybate: Data from thereal-world TENOR study. Sleep Medicine. 2024; 113:328-337.

22. Maski K, Trotti LM, Kotagal S et wl. Treatment of central disorders of hypersomnolence: an American Academy of Sleep Medicine clinical practice guideline. J Clin Sleep Med. 2021 Sep 1;17(9):1881-1893. doi: 10.5664/jcsm.9328. PMID: 34743789.