Oxybate salts (calcium, magnesium, potassium, and sodium) are CNS depressants. Clinically significant respiratory depression and obtundation may occur in patients treated with oxybate salts (calcium, magnesium, potassium, and sodium) at recommended doses. Many patients who received oxybate salts (calcium, magnesium, potassium, and sodium) during clinical trials in narcolepsy and idiopathic hypersomnia were receiving CNS stimulants.
The active moiety of oxybate salts (calcium, magnesium, potassium, and sodium) 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, oxybate salts (calcium, magnesium, potassium, and sodium) is available only 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 presented as grams of oxybate.
Children ≥7 years and Adolescents:
<20 kg: Oral: There are no specific dosage recommendations in the manufacturer's labeling due to insufficient data; however, a lower initial starting dose and lower maximum dosages are recommended.
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.
Converting from sodium oxybate (Xyrem) to oxybate salts (calcium, magnesium, potassium, and sodium oxybate) (Xywav): Discontinue sodium oxybate (Xyrem) and initiate oxybate salts (calcium, magnesium, potassium, and sodium) (Xywav) at the same dose (gram per gram); titrate as needed based on efficacy and tolerability.
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 "Oxybate (gamma hydroxybutyrate) salts: Drug information")
Hypersomnia (idiopathic):
Once-nightly dosing: Initial: Oral: ≤3 g at bedtime after the patient is in bed. May increase nightly dose by ≤1.5 g at weekly intervals based on efficacy and tolerability; maximum dose: 6 g/night.
Twice-nightly dosing: Initial: Oral: ≤2.25 g at bedtime after the patient is in bed and ≤2.25 g taken 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 2.5 to 4 hours later) at weekly intervals based on efficacy and tolerability; maximum dose: 9 g/night. Note: Some patients may achieve better responses with unequal nightly doses at bedtime and 2.5 to 4 hours later.
Narcolepsy: Oral: Initial: 2.25 g at bedtime after the patient is in bed, and 2.25 g taken 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 2.5 to 4 hours later) at weekly intervals based on efficacy and tolerability; usual effective dosage range: 6 to 9 g/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.
Conversion from sodium oxybate to oxybate salts (calcium, magnesium, potassium, and sodium): On the first night of dosing with oxybate salts (calcium, magnesium, potassium, and sodium), initiate treatment at the same dose (gram for gram) and regimen as sodium oxybate.
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); however, not renally eliminated.
Reduce initial dose by 50%.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Solution, Oral:
Xywav: 500 mg/mL (180 mL) [barley free, gluten free, rye free, wheat free]
No
Each mL contains 0.5 g of oxybate salts present as 0.234 g calcium oxybate, 0.096 g magnesium oxybate, 0.13 g potassium oxybate, and 0.04 g sodium oxybate.
C-I (illicit use); C-III (medical use)
An FDA-approved patient medication guide, which is available with the product information and at https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/212690s010lbl.pdf#page=29, 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 immediately 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 is administered 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 dose at bedtime. For patients taking a second nightly dose, administer second 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 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 between 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C (59°F and 86°F). Dispense in tight containers. Diluted solution should be consumed within 24 hours.
Treatment of cataplexy or excessive daytime sleepiness (EDS) in patients with narcolepsy (FDA approved in ages ≥7 years and adults); treatment of idiopathic hypersomnia (FDA approved in adults).
Oxybate salts (calcium, magnesium, potassium, and sodium) may be confused with sodium oxybate.
Xywav may be confused with Xyrem.
Use of oxybate salts was associated with neuropsychiatric effects in adult and pediatric patients during clinical trials, including agitation, anxiety, confusion, irritability, panic attack, tension, and visual hallucinations; aggression, paranoia, and psychosis have also been reported with sodium oxybate (which has the same active moiety as oxybate salts).
Treatment discontinuation has been reported in patients who experienced neuropsychiatric effects.
Clinically significant central nervous system (CNS) depression, respiratory depression, and obtundation may occur in adult and pediatric patients, even at recommended doses. Increased apnea (including sleep-related apnea) and clinically relevant reduced oxygenation may also occur. CNS and respiratory depression are reversible following dosage modification, interruption of therapy, and/or discontinuation.
Mechanism: Dose-related (Teter 2001); related to the pharmacologic action (ie, GABAB receptor activity)
Onset: Rapid
Risk factors:
• Concomitant use with other CNS depressants (eg, opioids, benzodiazepines, sedating antidepressants/antipsychotics/antiseizure medications, general anesthetics, muscle relaxants, illicit CNS depressants); associated with an increased risk of respiratory depression, hypotension, profound sedation, syncope, and death. Note: Use of oxybate salts is contraindicated with alcohol and sedative hypnotics.
• Impaired respiratory drive:
- Preexisting compromised respiratory function
• Sleep-related breathing disorders:
- Obesity
- Male patients
- Female patients who are postmenopausal and not on hormone-replacement therapy
- Patients with narcolepsy
Parasomnias, including abnormal dreams, night terrors, sleep paralysis, sleep talking, and somnambulism, have been reported in both adult and pediatric patients during clinical trials. Parasomnias have led to treatment discontinuation.
Treatment with oxybate salts was associated with an increased incidence of depression (including depressed mood), suicidal ideation, and suicidal tendencies in both adult and pediatric patients during clinical trials. Treatment discontinuation secondary to depression was also reported.
Risk factors:
• Prior history of depression and/or suicide attempt
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.
>10%:
Gastrointestinal: Nausea (13%)
Nervous system: Headache (20%)
1% to 10%:
Dermatologic: Diaphoresis (including night sweats: 6%)
Gastrointestinal: Decreased appetite (8%), diarrhea (6%), vomiting (5%), xerostomia (4%)
Genitourinary: Urinary incontinence (4%)
Nervous system: Anxiety (including agitation, panic attack, and tension: 5%), confusion (1%), depressed mood (4%), depression (3%), dizziness (10%), drowsiness (2%), fatigue (including asthenia: 4%), irritability (3%), parasomnias (including abnormal dreams, night terrors, sleep paralysis, sleep talking, and somnambulism with a potential for injury: 6%), paresthesia (3%)
Neuromuscular & skeletal: Muscle spasm (2%), tremor (3%)
<1%: Nervous system: Visual hallucination
Frequency not defined:
Nervous system: Central nervous system depression, obtundation, suicidal ideation, suicidal tendencies
Respiratory: Respiratory depression
Concomitant use with sedative hypnotics or alcohol; succinic semialdehyde dehydrogenase deficiency.
Disease-related concerns:
• Hepatic insufficiency: Use with caution in patients with preexisting liver impairment.
Other warnings/precautions:
• Tolerance/withdrawal: Tolerance to oxybate salts (calcium, magnesium, potassium, and sodium), 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
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 of oxybate salts (calcium, magnesium, potassium, and sodium) immediately following a high-fat meal decreases gamma-hydroxybutyrate Cmax by 33% and AUC by 16%. Management: Administer first nightly dose at least 2 hours after eating.
The active moiety of oxybate salts, gamma-hydroxybutyrate, crosses the placenta. The injection formulation of sodium oxybate, when used as an anesthetic during labor and delivery, was shown to cause a slight decrease in Apgar scores due to sleepiness in the neonate.
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 oxybate salts (calcium, magnesium, potassium, and sodium) is oxybate or gamma-hydroxybutyrate (GHB). The therapeutic effects of GHB, a metabolite of GABA, are hypothesized to be mediated by GABAB receptor activity at noradrenergic, dopaminergic, and thalamocortical neurons.
Onset: Rapid (≤5 to 15 minutes).
Distribution: Vd: 190 to 384 mL/kg.
Protein binding: <1%.
Metabolism: Primarily via the Krebs cycle to form water and carbon dioxide; secondarily via beta oxidation; no active metabolites.
Half-life elimination: ~0.66 hours.
Time to peak: ~1.3 hours.
Excretion: Primarily via biotransformation to carbon dioxide and expiration; Urine: <5% as unchanged drug.
Hepatic function: AUC is doubled, elimination half-life is longer, and oral clearance is reduced in cirrhotic patients (Child-Pugh class A and C).
Oxybate salts (eg, sodium oxybate) have been known as a 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 Programs" and "Prescribing and Access Restrictions"). Detailed instructions for the use of oxybate salts (calcium, magnesium, potassium, and sodium) should be provided to the patient and health care provider prior to dispensing the first dose.
Solution (Xywav Oral)
500 mg/mL (per mL): $36.93
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