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
- Abuse Potential
A known drug of abuse.1 2 3 4 5 6 (See Misuse and Abuse Potential under Cautions.)
Recreational use associated with serious adverse CNS effects, including seizures, respiratory depression, profound decreases in level of consciousness, coma, and death;1 2 3 4 5 6 circumstances surrounding these events (e.g., dose ingested, amount of alcohol or other drugs ingested concomitantly) often unclear.1
- Adverse CNS and Respiratory Effects
Risk of confusion, depression, and other neuropsychiatric events, even at recommended dosages.1 (See CNS Effects under Cautions.)
Respiratory depression reported in clinical trials.1 Most patients were receiving a CNS stimulant concomitantly; effect of such concomitant use on nocturnal respiration not known.1 (See Respiratory Effects under Cautions.)
Do not use concomitantly with alcohol or other CNS depressants.1
- Restricted Distribution Program
Available only through the Xyrem Success Program.1
To order sodium oxybate, prescriber must first contact centralized pharmacy (866-997-3688), which will provide prescriber and patient with educational materials explaining the risks and appropriate use of the drug along with details of the program.1 Once it is documented that the patient has read and/or understood the materials, pharmacy will ship the drug to the patient.1
Prescriber sees patient at least every 3 months and reports serious adverse effects to the manufacturer.1
Information to help minimize risk of inadvertent use by others also available through this program.1
REMS:
FDA approved a REMS for sodium oxybate to ensure that the benefits of a drug outweigh the risks. The REMS may apply to one or more preparations of sodium oxybate and consists of the following: medication guide, elements to assure safe use, and implementation system. See the FDA REMS page () or the ASHP REMS Resource Center ().
Introduction
CNS depressant that exhibits anticataplectic1 and potent hypnotic2 activity.1
Uses for Sodium Oxybate
Narcolepsy
Management of excessive daytime sleepiness and cataplexy in patients with narcolepsy.1 7 8 10
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 several hours after eating; minimize variability in the timing of drug administration in relation to meals.1
Dilute each dose with 60 mL of water in the child-resistant dosing cup provided by manufacturer.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
Pediatric Patients
Narcolepsy
Oral
Adolescents ≥16 years of age: 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- to 2-week intervals to a maximum dosage of 9 g daily.1
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- to 2-week intervals to a maximum dosage of 9 g daily.1
Prescribing Limits
Pediatric Patients
Narcolepsy
Oral
Adolescents ≥16 years of age: Maximum 9 g daily.1
Adults
Narcolepsy
Oral
Maximum 9 g daily.1
Special Populations
Hepatic Impairment
Initially, 2.25 g nightly in 2 doses of 1.125 g each; adjust subsequent dosages to achieve desired effect.1 Closely monitor for potential adverse effects.1
Renal Impairment
Dosage adjustment not expected to be necessary.1
Cautions for Sodium Oxybate
Contraindications
Concomitant therapy with sedative-hypnotic agents.1
Succinate-semialdehyde dehydrogenase deficiency.1
Warnings/Precautions
Warnings
CNS Effects
Confusion, depression, and other neuropsychiatric events (e.g., psychosis, paranoia, hallucinations, agitation) reported at recommended dosages.1 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
Confused behavior at night, sometimes associated with wandering (sleepwalking), has occurred.1 Substantial injury or potential injury (e.g., a fall, clothing set on fire while attempting to smoke, attempted ingestion of nail polish remover, sodium oxybate overdose) associated with sleepwalking reported rarely.1 Evaluate these episodes and consider appropriate interventions.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 Caution in patients with respiratory impairment.1 Be aware that a high incidence (50%) of sleep apnea has been reported in some cohorts of narcoleptic patients.1
General Precautions
GU Effects
Single or sporadic episodes of nocturnal urinary incontinence reported.1 Consider investigations to rule out underlying etiologies (e.g., worsening sleep apnea, nocturnal seizures) if a patient experiences urinary incontinence; however, no evidence that incontinence is associated with seizures in these patients.1
GI Effects
Single episodes of nocturnal fecal incontinence reported in a few patients.1 Consider investigations to rule out underlying etiologies (e.g., worsening sleep apnea, nocturnal seizures) if a patient experiences fecal incontinence; however, no evidence that incontinence is associated with seizures in these patients.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).1 Clinicians should document diagnosis and indication for sodium oxybate therapy and be alert to drug-seeking behavior and/or feigned cataplexy.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 B.1
Lactation
Not known whether distributed into milk; caution advised.1
Pediatric Use
Safety and efficacy not established in children <16 years of age.1
Geriatric Use
Closely monitor for impaired motor and/or cognitive function; experience in this age group limited.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, headache, vomiting, somnolence, urinary incontinence, nasopharyngitis.1
Interactions for Sodium Oxybate
Does not inhibit CYP1A2, 2C9, 2C19, 2D6, 2E1, or 3A.1
Specific Drugs
Drug | Interaction | Comments |
|---|---|---|
CNS depressants | Possible additive sedative effects1 | Concomitant use with sedative-hypnotic agents contraindicated1 Concomitant use with alcohol or other CNS depressants not recommended1 |
Ethosuximide | Possible decreased sodium oxybate concentrations (based on animal data)1 | |
Levodopa | Possible decreased sodium oxybate concentrations (based on animal data)1 | |
Modafinil | Pharmacokinetic interaction unlikely1 Pharmacodynamic interaction cannot be ruled out1 | |
Omeprazole | Change in sodium oxybate pharmacokinetics due to alterations in gastric pH unlikely1 | |
Phenytoin | Possible increased sodium oxybate concentrations (based on animal data)1 | |
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 25%.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 58% 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; renal function not expected to affect pharmacokinetics of sodium oxybate.1
Stability
Storage
Oral
Oral Solution
25°C (may be exposed to 15–30°C).1
Diluted solution: Use within 24 hours (to minimize bacterial growth and contamination).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
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 taking the first dose immediately before bedtime and the second dose 2.5–4 hours later.1 Minimize variability in the timing of administration in relation to meals; take the first dose several hours after a meal.1 Importance of lying down and sleeping after each dose.1 Do not administer at any time other than at night.1
Risk of rapid onset of CNS depression.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 Use caution when performing these tasks until effects of sodium oxybate on the individual are known.1
Risk of other adverse effects, including nocturnal urinary or fecal incontinence.1
Necessity of frequent clinician visits for review of dosage titration and monitoring of response and adverse effects.1
Importance of not using alcohol or other CNS depressants (e.g., sedative-hypnotics).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.)
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 dosing cups) | Jazz Pharmaceuticals |
Disclaimer
This report on medications is for your information only, and is not considered individual patient advice. Because of the changing nature of drug information, please consult your physician or pharmacist about specific clinical use.
The American Society of Health-System Pharmacists, Inc. and Drugs.com represent that the information provided hereunder was formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. and Drugs.com make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to such information and specifically disclaims all such warranties. Users are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and the information is provided for informational purposes only. The entire monograph for a drug should be reviewed for a thorough understanding of the drug's actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. and Drugs.com do not endorse or recommend the use of any drug. The information is not a substitute for medical care.
AHFS Drug Information. © Copyright, 1959-2011, Selected Revisions October 27, 2011. 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; 2005 Nov.
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]
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