Sodium oxybate is a CNS depressant. In clinical trials at recommended doses, obtundation and clinically significant respiratory depression occurred in adult patients treated with sodium oxybate. Many patients who received sodium oxybate during clinical trials in narcolepsy were receiving CNS stimulants.
Sodium oxybate is the sodium salt of 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, abuse, and misuse, sodium oxybate is only available through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the Xywav and Xyrem REMS.
Narcolepsy (excessive daytime sleepiness/cataplexy): Note: Nightly, 2 doses are administered; some patients may require unequal doses to achieve optimal response. Dosing is present in mg/kg and grams; use precaution.
Children ≥7 years and Adolescents:
<20 kg: Oral: Limited data available: Initial: 60 to 90 mg/kg/night (total dose) in 2 divided doses; the first dose administered at bedtime after the patient is in bed, then 2.5 to 4 hours later, administer the second dose; titrate every 1 to 2 weeks until efficacy or development of intolerable side effects. Reported maximum daily dose: 180 mg/kg/night (Aran 2010; Moresco 2018).
20 to <30 kg: Oral: Initial: ≤1 g at bedtime after the patient is in bed, then 2.5 to 4 hours later, administer second dose of ≤1 g. After 1 week, titrate dose based on efficacy and tolerability at weekly intervals; increase dose in ≤0.5 g/dose (≤1 g/night) increments per week; maximum single dose: 3 g/dose; maximum daily dose: 6 g/night.
30 to <45 kg: Oral: Initial: ≤1.5 g at bedtime after the patient is in bed, then 2.5 to 4 hours later, administer second dose of ≤1.5 g. After 1 week, titrate dose based on efficacy and tolerability at weekly intervals; increase dose in ≤0.5 g/dose (≤1 g/night) increments per week; maximum single dose: 3.75 g/dose; maximum daily dose: 7.5 g/ night.
≥45 kg: Oral: Initial: ≤2.25 g at bedtime after the patient is in bed, then 2.5 to 4 hours later, administer second dose of ≤2.25 g . After 1 week, titrate dose based on efficacy and tolerability at weekly intervals; increase dose in ≤0.75 g/dose (1.5 g/night) increments per week; maximum single dose: 4.5 g/dose; maximum daily dose: 9 g/night.
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).
Children ≥7 years and Adolescents: Reduce initial total nightly dose by 50% and administer in 2 divided doses.
(For additional information see "Sodium oxybate (gamma hydroxybutyrate): Drug information")
Narcolepsy: Oral: Initial: 2.25 g at bedtime after the patient is in bed, and 2.25 g administered 2.5 to 4 hours later (4.5 g/night). May increase nightly dose by 1.5 g (0.75 g at bedtime and 0.75 g administered 2.5 to 4 hours later) at weekly intervals based on efficacy and tolerability; usual effective dosage range: 6 to 9 g per night. Maximum dose: 9 g/night.
Missed second dose: Skip dose and resume usual dosing schedule the next day. Do not administer 2 doses at the same time.
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).
Reduce initial dose(s) by 50%.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Solution, Oral:
Xyrem: 500 mg/mL (180 mL)
Generic: 500 mg/mL (180 mL)
Yes
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Solution, Oral:
Xyrem: 500 mg/mL (180 mL)
Sodium content for various doses:
|
Total nightly sodium oxybate dose |
Sodium content |
|---|---|
|
3 g |
550 mg |
|
4.5 g |
820 mg |
|
6 g |
1,100 mg |
|
7.5 g |
1,400 mg |
|
9 g |
1,640 mg |
C-I (illicit use); C-III (medical use)
In Canada, access to sodium oxybate is restricted under the Xyrem Success Program. The program is intended to educate prescribers, pharmacists, and patients on the safe use, storage, and handling of the drug, to maintain a registry of trained physicians, pharmacies, and patients, and to limit distribution through a single wholesaler to pharmacies on an as-needed basis after a prescription is received by the pharmacy. Initial dispensing of prescriptions should occur only after the prescriber, pharmacist, and patient have received and read the educational materials. Further information regarding the program may be obtained at 1-866-599-7365.
An FDA-approved patient medication guide, which is available with the product information and at https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/021196s040lbl.pdf#page=25, must be dispensed with this medication.
Oral: Administer on an empty stomach (at least 2 hours after eating); administration at similar times each night is preferred. Each nightly dose should be administered while patient is sitting up in bed; then patient should lie down and remain in bed; sleep generally occurs within 5 to 15 minutes (generally abruptly without patient feeling drowsy). Both doses should be prepared prior to bedtime. The first dose is administered at bedtime and the second dose 2.5 to 4 hours later; an alarm clock may need to be set for the second dose. For patients who sleep >8 hours per night the first dose may be administered at bedtime or after an initial period of sleep. After use, rinse containers with water.
Missed dose: If the second dose is missed, skip that dose and resume therapy the next night; do not administer both doses at the same time. Diluted doses that are not used should be properly and promptly disposed.
Oral: Administer on an empty stomach, ≥2 hours after eating. Administer first dose at bedtime. Administer second nightly dose 2.5 to 4 hours after the first dose; an alarm clock may need to be set for the second dose. Prepare both doses prior to bedtime. Prior to ingestion, dilute each dose with approximately ¼ cup (60 mL) water in provided empty pharmacy containers. Administer both doses while patient is in bed; patient should lie down immediately after dose and remain in bed.
Store at 25°C (77°F); excursions are permitted between 15°C and 30°C (59°F and 86 °F). Store in the original bottle. Dispense in tight containers. Diluted solution should be consumed within 24 hours.
Treatment of cataplexy and excessive daytime sleepiness in patients with narcolepsy (FDA approved in ages ≥7 years and adults).
Sodium oxybate may be confused with oxybate salts (calcium, magnesium, potassium, and sodium).
Xyrem may be confused with Xywav.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Adverse reactions reported in adults unless otherwise indicated.
>10%:
Endocrine & metabolic: Weight loss (children and adolescents: 13%)
Gastrointestinal: Nausea (children, adolescents, and adults: 8% to 20%), vomiting (children, adolescents, and adults: 2% to 18%)
Genitourinary: Urinary incontinence (children and adolescents: 19%; adults: 3% to 7%)
Nervous system: Confusion (3% to 17%), dizziness (children, adolescents, and adults: 8% to 15%), headache (children and adolescents: 17%)
1% to 10%:
Cardiovascular: Peripheral edema (3%)
Dermatologic: Hyperhidrosis (1% to 3%)
Gastrointestinal: Decreased appetite (children and adolescents: 9%), diarrhea (3% to 4%), upper abdominal pain (3%)
Nervous system: Anxiety (2% to 6%), cataplexy (2%), depression (children, adolescents, adults: 2% to 7%), disorientation (2% to 3%), disturbance in attention (1% to 4%), drowsiness (8%), intoxicated feeling (3%), irritability (3%), pain (3%), paresthesia (2% to 3%), severe central nervous system depression (2%), sleep paralysis (3%), somnambulism (children, adolescents, and adults: 3% to 6%), tremor (2% to 5%)
Neuromuscular & skeletal: Limb pain (3%)
<1%: Nervous system: Suicidal ideation (children, adolescents, adults), suicidal tendencies
Frequency not defined (all populations):
Hematologic & oncologic: Oxygen desaturation
Nervous system: Obtundation
Respiratory: Respiratory depression
Postmarketing (any populations):
Cardiovascular: Hypertension
Endocrine & metabolic: Fluid retention
Genitourinary: Nocturia
Hypersensitivity: Hypersensitivity reaction
Nervous system: Aggressive behavior, agitation, drug abuse, falling, hallucination, hangover effect, memory impairment, panic attack, paranoid ideation, parasomnias (sleep driving, sleep eating) (Wallace 2011), psychosis (including acute psychosis) (Langford 2011)
Neuromuscular & skeletal: Arthralgia
Ophthalmic: Blurred vision
Respiratory: Sleep apnea (Hartley 2011)
Concomitant use with alcohol or sedative-hypnotic agents; succinic semialdehyde dehydrogenase deficiency
Canadian labeling: Additional contraindications (not in US labeling): Hypersensitivity to sodium oxybate or any component of the formulation
Concerns related to adverse effects:
• Behavioral and psychiatric effects: Use has been associated with aggression, agitation, anxiety, confusion, depression, paranoia, psychosis, suicidality, and hallucinations; use caution in patients with history of depression and/or suicide attempt.
• CNS depression: Sodium oxybate may impair physical or mental abilities. Patients must be instructed not to engage in hazardous activities requiring mental alertness or motor coordination for at least 6 hours after taking sodium oxybate.
• Parasomnias: Parasomnias, including sleepwalking, may occur with use. Evaluate episodes of sleepwalking and implement appropriate interventions.
• Respiratory depression: [US Boxed Warning]: In clinical trials at recommended doses, obtundation and clinically significant respiratory depression occurred in sodium oxybate-treated adult patients. Many of the patients who received sodium oxybate during clinical trials in narcolepsy were receiving CNS stimulants. Use with caution in patients with compromised respiratory function.
Disease-related concerns:
• Cardiovascular disease: Use with caution in patients with heart failure or hypertension; contains significant amounts of sodium.
• Hepatic impairment: Use with caution in patients with hepatic impairment; dosage adjustment is recommended.
• Renal impairment: Use with caution in patients with renal impairment due to significant amounts of sodium in the product.
• Sleep-related breathing disorders: Sleep-related breathing disorders (eg, sleep apnea) may occur during therapy; may be more common in patients that are obese, male, postmenopausal (not on hormone-replacement therapy), or narcoleptic. In pediatric patients, central sleep apnea and oxygen desaturation has been reported.
Special populations:
• Older adult: Although limited data exists, headache was observed at a higher incidence in older adults ≥65 years of age compared to younger adults. Older adults may also be at increased risk for other CNS effects; use with caution and monitor cognitive/motor function closely.
Other warnings/precautions:
• Abuse/misuse/diversion: [US Boxed Warning]: Sodium oxybate (the sodium salt of gamma hydroxybutyrate [GHB]) is a CNS depressant controlled substance with abuse potential. Seizures, respiratory depression, decreases in level of consciousness, coma, and death have been reported when GHB, either alone or in combination with other CNS depressants, has been abused. Health care providers should be alert to problems of abuse, misuse, and diversion. Patients should be evaluated for a history of drug abuse and should be monitored for signs of misuse, abuse, and addiction.
• Restricted access: [US Boxed Warning]: Sodium oxybate is available only through a restricted distribution program to prescribers and patients enrolled in the Xywav and Xyrem REMS and dispensed to the patient only by the central pharmacy that is specially certified (1-866-997-3688 or www.xywavxyremrems.com).
• Sodium: Contains high sodium content: Use with caution in patients sensitive to high sodium intake (eg, renal impairment, heart failure, hypertension).
• Tolerance/withdrawal: Tolerance to sodium oxybate, or withdrawal following its discontinuation, has not been clearly defined in controlled clinical trials, but has been reported at larger doses used for illicit purposes.
None known.
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program
Alcohol (Ethyl): May enhance the CNS depressant effect of Oxybate Salt Products. Risk X: Avoid combination
Alizapride: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Azelastine (Nasal): May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination
Benzodiazepines: May enhance the CNS depressant effect of Oxybate Salt Products. Risk X: Avoid combination
Blonanserin: CNS Depressants may enhance the CNS depressant effect of Blonanserin. Management: Use caution if coadministering blonanserin and CNS depressants; dose reduction of the other CNS depressant may be required. Strong CNS depressants should not be coadministered with blonanserin. Risk D: Consider therapy modification
Brimonidine (Topical): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Bromopride: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Bromperidol: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination
Buprenorphine: CNS Depressants may enhance the CNS depressant effect of Buprenorphine. Management: Consider reduced doses of other CNS depressants, and avoiding such drugs in patients at high risk of buprenorphine overuse/self-injection. Initiate buprenorphine at lower doses in patients already receiving CNS depressants. Risk D: Consider therapy modification
Cannabinoid-Containing Products: CNS Depressants may enhance the CNS depressant effect of Cannabinoid-Containing Products. Risk C: Monitor therapy
Chlormethiazole: May enhance the CNS depressant effect of CNS Depressants. Management: Monitor closely for evidence of excessive CNS depression. The chlormethiazole labeling states that an appropriately reduced dose should be used if such a combination must be used. Risk D: Consider therapy modification
Chlorphenesin Carbamate: May enhance the adverse/toxic effect of CNS Depressants. Risk C: Monitor therapy
CNS Depressants: May enhance the CNS depressant effect of Oxybate Salt Products. Management: Consider alternatives to this combination when possible. If combined, dose reduction or discontinuation of one or more CNS depressants (including the oxybate salt product) should be considered. Interrupt oxybate salt treatment during short-term opioid use Risk D: Consider therapy modification
DexmedeTOMIDine: CNS Depressants may enhance the CNS depressant effect of DexmedeTOMIDine. Management: Monitor for increased CNS depression during coadministration of dexmedetomidine and CNS depressants, and consider dose reductions of either agent to avoid excessive CNS depression. Risk D: Consider therapy modification
Difelikefalin: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Dimethindene (Topical): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Droperidol: May enhance the CNS depressant effect of CNS Depressants. Management: Consider dose reductions of droperidol or of other CNS agents (eg, opioids, barbiturates) with concomitant use. Risk D: Consider therapy modification
Flunarizine: CNS Depressants may enhance the CNS depressant effect of Flunarizine. Risk X: Avoid combination
HydrOXYzine: May enhance the CNS depressant effect of CNS Depressants. Management: Consider a decrease in the CNS depressant dose, as appropriate, when used together with hydroxyzine. Increase monitoring of signs/symptoms of CNS depression in any patient receiving hydroxyzine together with another CNS depressant. Risk D: Consider therapy modification
Hypnotics (Nonbenzodiazepine): May enhance the CNS depressant effect of Oxybate Salt Products. Risk X: Avoid combination
Kava Kava: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Kratom: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination
Lisuride: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Lofexidine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Magnesium Sulfate: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Methotrimeprazine: CNS Depressants may enhance the CNS depressant effect of Methotrimeprazine. Methotrimeprazine may enhance the CNS depressant effect of CNS Depressants. Management: Reduce the usual dose of CNS depressants by 50% if starting methotrimeprazine until the dose of methotrimeprazine is stable. Monitor patient closely for evidence of CNS depression. Risk D: Consider therapy modification
Metoclopramide: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
MetyroSINE: CNS Depressants may enhance the sedative effect of MetyroSINE. Risk C: Monitor therapy
Minocycline (Systemic): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Olopatadine (Nasal): May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination
Opioid Agonists: CNS Depressants may enhance the CNS depressant effect of Opioid Agonists. Management: Avoid concomitant use of opioid agonists and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Risk D: Consider therapy modification
Orphenadrine: CNS Depressants may enhance the CNS depressant effect of Orphenadrine. Risk X: Avoid combination
Oxomemazine: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination
Oxybate Salt Products: CNS Depressants may enhance the CNS depressant effect of Oxybate Salt Products. Management: Consider alternatives to this combination when possible. If combined, dose reduction or discontinuation of one or more CNS depressants (including the oxybate salt product) should be considered. Interrupt oxybate salt treatment during short-term opioid use Risk D: Consider therapy modification
OxyCODONE: CNS Depressants may enhance the CNS depressant effect of OxyCODONE. Management: Avoid concomitant use of oxycodone and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Risk D: Consider therapy modification
Paraldehyde: CNS Depressants may enhance the CNS depressant effect of Paraldehyde. Risk X: Avoid combination
Piribedil: CNS Depressants may enhance the CNS depressant effect of Piribedil. Risk C: Monitor therapy
Pramipexole: CNS Depressants may enhance the sedative effect of Pramipexole. Risk C: Monitor therapy
Procarbazine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Rilmenidine: Oxybate Salt Products may enhance the CNS depressant effect of Rilmenidine. Risk X: Avoid combination
Ropeginterferon Alfa-2b: CNS Depressants may enhance the adverse/toxic effect of Ropeginterferon Alfa-2b. Specifically, the risk of neuropsychiatric adverse effects may be increased. Management: Avoid coadministration of ropeginterferon alfa-2b and other CNS depressants. If this combination cannot be avoided, monitor patients for neuropsychiatric adverse effects (eg, depression, suicidal ideation, aggression, mania). Risk D: Consider therapy modification
ROPINIRole: CNS Depressants may enhance the sedative effect of ROPINIRole. Risk C: Monitor therapy
Rotigotine: CNS Depressants may enhance the sedative effect of Rotigotine. Risk C: Monitor therapy
Rufinamide: May enhance the adverse/toxic effect of CNS Depressants. Specifically, sleepiness and dizziness may be enhanced. Risk C: Monitor therapy
Thalidomide: CNS Depressants may enhance the CNS depressant effect of Thalidomide. Risk X: Avoid combination
Valerian: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Valproate Products: May increase the serum concentration of Oxybate Salt Products. Management: Decrease the dose of the oxybate salt product by at least 20% when initiating therapy with valproate products. When initiating oxybate salt products in patients taking valproate products, use a lower starting dose of the oxybate salt. Risk D: Consider therapy modification
Administration immediately after a high-fat meal delays absorption and decreases peak serum gamma-hydroxybutyrate level. Management: Administer on an empty stomach ≥2 hours after eating.
Contains a high sodium content; limit dietary intake of sodium.
The injection formulation, when used as an anesthetic during labor and delivery, was shown to cross the placenta; a slight decrease in Apgar scores due to sleepiness in the neonate was observed.
Signs and symptoms of depression or suicidality; emergence of anxiety, confusion, thought disorders, or behavior abnormalities; drug abuse, misuse, and addiction.
The active moiety of sodium oxybate is gamma-hydroxybutyrate (GHB). The therapeutic effects of GHB, a metabolite of gamma aminobutyric acid (GABA), are hypothesized to be mediated by GABAB receptor activity at noradrenergic, dopaminergic, and thalamocortical neurons.
Note: Pharmacokinetic parameters in pediatric patients 7 to 17 years were reported as being similar to adult patients.
Onset: Rapid (≤5 to 15 minutes).
Absorption: Rapid; high-fat meals delay absorption (average Tmax increased 1.25 hours) and reduce the Cmax by a mean 59% and AUC by 37%.
Distribution: 190 to 384 mL/kg.
Protein binding: <1%.
Metabolism: Primarily via the Krebs cycle to form water and carbon dioxide; secondarily via beta oxidation; significant first-pass effect; no active metabolites; metabolic pathways are saturable.
Bioavailability: ~88%.
Half-life elimination: 30 to 60 minutes.
Time to peak: 30 to 75 minutes.
Excretion: Primarily pulmonary (as carbon dioxide); urine (<5% as unchanged drug); feces (negligible).
Hepatic function impairment: AUC is doubled, elimination half-life is longer, and oral clearance is reduced in cirrhotic patients (Child-Pugh class A and C).
Sodium oxybate is a known substance of abuse. When used illegally, it has been referred to as a "date-rape drug." As part of the FDA approval for prescription use, all patients and prescribers must be enrolled in a program designed to restrict its distribution and to provide postmarketing evaluations (see "REMS Program" and "Prescribing Access and Restrictions"). Detailed instructions for the use of sodium oxybate should be provided to the patient and health care provider prior to dispensing the first dose.
Solution (Xyrem Oral)
500 mg/mL (per mL): $40.07
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