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Oxybate (gamma hydroxybutyrate) salts: Drug information

Oxybate (gamma hydroxybutyrate) salts: Drug information
(For additional information see "Oxybate (gamma hydroxybutyrate) salts: Pediatric drug information" and see "Oxybate (gamma hydroxybutyrate) salts: Patient drug information")

For abbreviations, symbols, and age group definitions used in Lexicomp (show table)
ALERT: US Boxed Warning
Central nervous system depression

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.

Abuse and misuse

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.

Restricted access

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.

Brand Names: US
  • Xywav
Pharmacologic Category
  • Central Nervous System Depressant
Dosing: Adult

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.

Dosing: Kidney Impairment: Adult

There are no dosage adjustments provided in the manufacturer's labeling (has not been studied); however, not renally eliminated.

Dosing: Hepatic Impairment: Adult

Reduce initial dose by 50%.

Dosing: Pediatric

(For additional information see "Oxybate (gamma hydroxybutyrate) salts: Pediatric drug information")

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.

Dosing: Kidney Impairment: Pediatric

There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).

Dosing: Hepatic Impairment: Pediatric

Children ≥7 years and Adolescents: Reduce initial total nightly dose by 50% and administer in 2 divided doses.

Dosing: Older Adult

Refer to adult dosing; use with caution.

Dosage Forms: US

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]

Generic Equivalent Available: US

No

Dosage Forms Considerations

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.

Controlled Substance

C-I (illicit use); C-III (medical use)

Medication Guide and/or Vaccine Information Statement (VIS)

An FDA-approved patient medication guide, which is available with the product information and at https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/021196s035,212690s001s002lbl.pdf#page=29, must be dispensed with this medication.

Administration: Adult

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.

Administration: Pediatric

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.

Use: Labeled Indications

Hypersomnia (idiopathic): Treatment of idiopathic hypersomnia in adults.

Narcolepsy: Treatment of cataplexy or excessive daytime sleepiness in patients ≥7 years of age with narcolepsy.

Medication Safety Issues
Sound-alike/look-alike issues:

Oxybate salts (calcium, magnesium, potassium, and sodium) may be confused with sodium oxybate.

Xywav may be confused with Xyrem.

Adverse Reactions (Significant): Considerations
Behavioral and psychiatric effects

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.

CNS and respiratory depression

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

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.

Suicidal thinking and behavior

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

Adverse Reactions

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

Contraindications

Concomitant use with sedative hypnotics or alcohol; succinic semialdehyde dehydrogenase deficiency.

Warnings/Precautions

Concerns related to adverse effects:

• Behavioral and psychiatric effects: Use of oxybate salts (calcium, magnesium, potassium, and sodium) and sodium oxybate, which has the same active moiety, has been associated with aggression, agitation, amnesia, anxiety, confusion, depression, psychosis, suicidality, and visual hallucinations.

• CNS depression: Oxybate salts (calcium, magnesium, potassium, and sodium) 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 oxybate salts (calcium, magnesium, potassium, and sodium).

• Parasomnias: Parasomnias, including sleepwalking, may occur with use. Evaluate episodes of sleep walking and implement appropriate interventions.

• Respiratory depression: [US Boxed Warning]: At recommended doses, obtundation and clinically significant respiratory depression may occur. Many patients who received oxybate salts (calcium, magnesium, potassium, and sodium) during clinical trials in narcolepsy and idiopathic hypersomnia were receiving CNS stimulants. Use with caution in patients with compromised respiratory function. Concurrent use with other CNS depressants may increase the risk of respiratory depression, hypotension, profound sedation, syncope, and death. Use is contraindicated with alcohol and sedative hypnotics; concomitant CNS depressant use should generally be avoided; however, if concomitant use is required, dosage adjustments or discontinuation of 1 or more CNS depressant agent (including oxybate salts [calcium, magnesium, potassium, and sodium]) should be considered. If short-term opioid use is required, consider temporarily discontinuing oxybate salts (calcium, magnesium, potassium, and sodium).

Disease-related concerns:

• Hepatic insufficiency: Use with caution in patients with preexisting liver impairment.

• Sleep-related breathing disorders: Sleep-related breathing disorders (eg, sleep apnea, reduced oxygenation) may occur; may be more common in patients with narcolepsy, or that are obese, male, or postmenopausal (not on hormone-replacement therapy).

Other warnings/precautions:

• Abuse/misuse/diversion: [US Boxed Warning]: Oxybate salts (calcium, magnesium, potassium, and sodium; the salts of gamma hydroxybutyrate [GHB]) are CNS depressant controlled substances 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]: Oxybate salts (calcium, magnesium, potassium, and sodium) are available only through a restricted distribution program to prescribers and patients enrolled in the Xywav and Xyrem REMS Program and dispensed to the patient only by the central pharmacy that is specially certified (1-866-997-3688 or www.xywavxyremrems.com).

• 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.

Metabolism/Transport Effects

None known.

Drug Interactions

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

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

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

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

Food Interactions

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.

Pregnancy Considerations

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.

Breastfeeding Considerations

The active moiety of oxybate salts, gamma-hydroxybutyrate, is present in breast milk following oral administration of sodium oxybate.

According to the manufacturer, the decision to breastfeed during therapy should consider the risk of infant exposure, the benefits of breastfeeding to the infant, and the benefits of treatment to the mother.

Monitoring Parameters

Emergent or worsening depression, suicidal ideation, emergence or increase in the occurrence of behavioral or psychiatric events; impaired motor/cognitive function; drug abuse/misuse.

Mechanism of Action

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.

Pharmacokinetics

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.

Pharmacokinetics: Additional Considerations

Hepatic function: AUC is doubled, elimination half-life is longer, and oral clearance is reduced in cirrhotic patients (Child-Pugh class A and C).

Pricing: US

Solution (Xywav Oral)

500 mg/mL (per mL): $36.93

Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.

REFERENCES

  1. Xywav (calcium, magnesium, potassium, and sodium oxybate) [prescribing information]. Palo Alto, CA: Jazz Pharmaceuticals Inc; August 2021.
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