Sodium Oxybate

Class: Central Nervous System Agents, Miscellaneous
VA Class: CN900
Chemical Name: 4-hydroxy-butanoic acid sodium salt
Molecular Formula: C4H7NaO3
CAS Number: 502-85-2
Brands: Xyrem

Warning(s)

  • Abuse Potential
  • A known drug of abuse.1 2 3 4 5 6 (See Misuse and Abuse Potential under Cautions.)

  • Abuse of illicit forms of sodium oxybate (γ-hydroxybutyrate [GHB]), alone or in combination with other CNS depressants, associated with serious adverse CNS effects, including seizures, respiratory depression, decreases in level of consciousness, coma, and death.1 2 3 4 5 6

  • Adverse CNS and Respiratory Effects
  • CNS depressant.1 Obtundation and respiratory depression reported in clinical trials at recommended dosages.1 Most patients with narcolepsy were receiving a CNS stimulant concomitantly.1 (See CNS Depression and also see Respiratory Effects under Cautions.)

  • Restricted Distribution Program
  • Because of risks of CNS depression, abuse, and misuse, available only through the Xyrem Success Program from a centralized pharmacy.1

  • Prescribers and patients must enroll in the program (866-997-3688 or ).1

REMS:

FDA has deemed that sodium oxybate has in effect an approved REMS. (See .) The REMS may apply to one or more preparations of sodium oxybate and consists of the following: elements to assure safe use. (See General under Dosage and Administration.)

Introduction

CNS depressant that exhibits anticataplectic1 and potent hypnotic2 activity.1

Uses for Sodium Oxybate

Narcolepsy

Management of excessive daytime sleepiness and/or cataplexy in patients with narcolepsy.1 7 8 10

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Sodium Oxybate Dosage and Administration

General

  • Restricted distribution program (Xyrem Success Program) in effect due to abuse potential and risk of adverse CNS and respiratory effects.1 (See Boxed Warning.)

Administration

Oral Administration

Administer orally in 2 equally divided doses daily.1 Administer at least 2 hours after eating.1

Dilute each dose with approximately 60 mL of water in the child-resistant vial provided by pharmacy.1 Prepare both doses before bedtime.1

Take first dose at bedtime and second dose 2.5–4 hours later (while sitting in bed).1

May need to set alarm clock to awaken for second dose; place second dose in close proximity to bed.1

Lie down and remain in bed after each dose.1

Dosage

Adults

Narcolepsy
Oral

Initially, 4.5 g nightly in 2 doses of 2.25 g each.1 Increase dosage in increments of 1.5 g daily (0.75 g per dose) at 1-week intervals to a maximum dosage of 9 g daily.1

Prescribing Limits

Adults

Narcolepsy
Oral

Maximum 9 g daily.1

Special Populations

Hepatic Impairment

Initially, 2.25 g nightly in 2 doses of approximately 1.13 g each.1

Renal Impairment

Specific dosage recommendation not available.1

Geriatric Patients

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

Cautions for Sodium Oxybate

Contraindications

  • Concomitant therapy with sedative-hypnotic agents or concomitant use of alcohol.1

  • Succinate-semialdehyde dehydrogenase deficiency.1

Warnings/Precautions

Warnings

CNS Depression

Obtundation and respiratory depression reported at recommended dosages in clinical trials.1 (See Respiratory Effects under Cautions and see Advice to Patients.)

Concomitant use with other CNS depressants may increase risk of respiratory depression, hypotension, profound sedation, syncope, and death.1 (See Specific Drugs under Interactions.)

Deaths reported, although cause of death sometimes indeterminable.13 Confounding factors have included underlying conditions that may predispose to CNS and respiratory depression (e.g., sleep apnea, COPD), preexisting psychiatric disorders (e.g., depression, substance abuse), use for off-label indications, use of excessive or rapidly titrated dosages, and concomitant use of alcohol or other CNS depressant(s).13

Monitor patients for events related to CNS depression upon initiation of therapy and periodically thereafter.1

Respiratory Effects

Respiratory drive may be impaired, especially in patients with preexisting respiratory impairment.1 Life-threatening respiratory depression reported with overdosage.1 Respiratory depression and an increase in obstructive sleep apnea reported in clinical trials.1 Increased central sleep apnea and oxygen desaturation reported in patients with obstructive sleep apnea.1

Use with caution, if at all, in patients with respiratory impairment (e.g., sleep apnea, COPD).1 13 Be aware that sleep-related breathing disorders tend to be more prevalent in obese patients and in postmenopausal women not receiving hormone replacement therapy as well as in patients with narcolepsy.1

Misuse and Abuse Potential

Severe dependence and craving reported following illicit use at dosages similar to those used in clinical trials.1 7 Potential for misuse and abuse.1 (See Boxed Warning and see Preparations.)

Carefully evaluate patients with history of drug abuse and closely monitor for signs of misuse or abuse (e.g., dosage escalation, drug-seeking behavior, feigned cataplexy).1

Other Warnings/Precautions

Behavioral and Psychiatric Effects

Confusion (dose related), depression, and other neuropsychiatric events (e.g., psychosis, paranoia, hallucinations, agitation, anxiety) reported at recommended dosages.1 Suicide or attempted suicide reported in narcolepsy clinical trials in 4 patients; 3 had history of depressive disorder.1

Immediately and carefully evaluate patients who become confused or depressed or who experience thought disorders and/or behavioral abnormalities.1 Carefully monitor patients with history of mental depression or suicide attempt for emergence of depressive symptoms.1 Carefully monitor patients with new or worsening anxiety.1

Parasomnia

Confused behavior at night, sometimes associated with wandering (sleepwalking), has occurred.1 Substantial injury or potential injury associated with sleepwalking reported rarely.1 Evaluate these episodes and consider appropriate interventions.1

Sodium Content

Each gram of sodium oxybate contains approximately 7.9 mEq (182 mg) of sodium.1 Consider sodium content in patients with heart failure, hypertension, or renal impairment.1

Specific Populations

Pregnancy

Category C.1

Lactation

Not known whether distributed into milk; caution advised.1

Pediatric Use

Safety and efficacy not established in pediatric patients.1

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether geriatric patients respond differently than younger adults; select dosage with caution.1 Higher incidence of headaches reported in geriatric patients compared with younger adults in clinical studies in patients with disorders other than narcolepsy.1

Monitor geriatric patients for impaired motor and cognitive function.1

Hepatic Impairment

Elimination half-life and systemic exposure increased; dosage adjustment recommended.1 (See Hepatic Impairment under Dosage and Administration.)

Renal Impairment

Not studied in patients with renal impairment.1

Consider sodium content.1 (See Sodium Content under Cautions.)

Common Adverse Effects

Nausea, dizziness, vomiting, somnolence, enuresis, tremor.1

Interactions for Sodium Oxybate

Does not inhibit CYP1A2, 2C9, 2C19, 2D6, 2E1, or 3A.1

Specific Drugs

Drug

Interaction

Comments

CNS depressants

Possible respiratory depression and marked impairment of consciousness13

Concomitant use with sedative-hypnotic agents or alcohol contraindicated1 13

Concomitant use with other CNS depressants not recommended; if required, consider dosage reduction or discontinuance of one or more CNS depressants (including sodium oxybate)1 13

Consider interrupting sodium oxybate therapy during short-term (e.g., perioperative, postoperative) opiate use1 13

Duloxetine

Pharmacokinetic or pharmacodynamic interaction unlikely1

Fomepizole

Pharmacokinetic interaction unlikely1

Pharmacodynamic interaction cannot be ruled out1

Modafinil

Pharmacokinetic interaction unlikely1

Pharmacodynamic interaction cannot be ruled out1

Omeprazole

Change in sodium oxybate pharmacokinetics due to alterations in gastric pH unlikely1

Protriptyline

Pharmacokinetic interaction unlikely1

Pharmacodynamic interaction cannot be ruled out1

Zolpidem

Pharmacokinetic interaction unlikely1

Pharmacodynamic interaction cannot be ruled out1

Sodium Oxybate Pharmacokinetics

Absorption

Bioavailability

Rapidly absorbed; peak plasma concentrations attained within 0.5–1.25 hours.1

Absolute bioavailability is approximately 88%.1

Nonlinear pharmacokinetics; plasma concentrations increase 3.7-fold as dose is doubled from 4.5 to 9 g.1

Food

High-fat meal delays time to peak plasma concentrations (to 2 hours) and reduces peak plasma concentrations by 59% and AUC by 37%.1

Special Populations

AUC values increased 100% in patients with cirrhosis.1

Distribution

Plasma Protein Binding

<1%.1

Elimination

Metabolism

Metabolized to carbon dioxide and water.1

Elimination Route

Carbon dioxide eliminated by expiration.1 Fecal excretion negligible; <5% excreted in urine as unchanged drug.1

Half-life

0.5–1 hour.1

Special Populations

Half-life increased in patients with cirrhosis; dosage adjustment recommended in patients with hepatic impairment.1 (See Hepatic Impairment under Dosage and Administration.)

Not studied in patients with renal impairment.1

Pharmacokinetic profile in individuals 65–75 years of age similar to that in younger adults (48–64 years of age).1

Stability

Storage

Oral

Oral Solution

25°C (may be exposed to 15–30°C).1

Actions

  • Potent, rapidly acting CNS depressant.1 Structurally and pharmacologically distinct from other currently available CNS depressants.1

  • Occurs endogenously as GHB (a metabolite of GABA); also called GHB.2 4 5 6

  • Improves excessive daytime sleepiness in patients with narcolepsy.1

  • Exhibits anticataplectic activity in patients with narcolepsy.1 Mechanism of anticataplectic action is unknown.1

  • Effects on cataplexy and excessive daytime sleepiness thought to be mediated through GABAB actions at noradrenergic and dopaminergic neurons, as well as thalamocortical neurons.1

  • Also exhibits hypnotic, amnesic, and hypotonic (i.e., causes hypotonia) activity.2 3 4 5 6

Advice to Patients

  • Importance of following the Xyrem Patient Success Program.1

  • Importance of providing patient a copy of manufacturer's patient information (medication guide).1 (See REMS.)

  • Importance of taking the first dose immediately before bedtime and the second dose 2.5–4 hours later.1 Take the first dose at least 2 hours after a meal.1 Importance of lying down and sleeping after each dose.1 Onset of sleep may occur abruptly and rapidly (e.g., within 5–15 minutes).1 Do not administer at any time other than at night.1

  • Avoid 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.1 Avoid performing these tasks until effects of sodium oxybate on the individual are known.1

  • Necessity of frequent clinician visits (e.g., every 3 months) for review of dosage titration and monitoring of response and adverse effects.1

  • Importance of not using alcohol or sedative-hypnotics.1

  • Risk of respiratory depression.1

  • Importance of patients and their families being alert to and immediately reporting emergence of depression or suicidality and any unusual changes in thoughts or behavior.1

  • Risk of sleepwalking.1 Importance of contacting clinician if sleepwalking occurs.1

  • Importance of informing patients who are sensitive to salt intake (e.g., those with heart failure, hypertension, renal impairment) of the high sodium content of sodium oxybate and the need to limit sodium intake.1

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs.1

  • Importance of informing patient of other important precautionary information.1 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Commercially available sodium oxybate oral solution is subject to control under the Federal Controlled Substances Act of 1970 as a schedule III (C-III) drug.1 The active ingredient, sodium oxybate (also called GHB) is subject to control as a schedule I (C-I) drug.1 Nonmedical uses of the commercially available preparation also are subject to control as a schedule I (C-I) drug.1

Distribution is restricted.1 (See Boxed Warning.)

Sodium Oxybate

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

For solution, concentrate

500 mg/mL

Xyrem ( C-III; available with press-in bottle adapter, 10-mL measuring syringe, and two 90-mL pharmacy vials)

Jazz Pharmaceuticals

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions November 14, 2013. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. Jazz Pharmaceuticals. Xyrem (sodium oxybate) oral solution prescribing information. Palo Alto, CA; 2012 Dec.

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. June 2002.

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]

9. Orphan Medical, Minnetonka, MN: Personal communication.

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]

11. Jazz Pharmaceuticals. Xyrem Success Program for Physicians. From Xyrem web site. Accessed 16 May 2006.

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.

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