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Sodium Oxybate

Pronunciation

(SOW dee um ox i BATE)

Index Terms

  • 4-Hydroxybutyrate
  • Gamma Hydroxybutyric Acid
  • GHB
  • Oxybate
  • Sodium 4-Hydroxybutyrate

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution, Oral:

Xyrem: 500 mg/mL (180 mL)

Brand Names: U.S.

  • Xyrem

Pharmacologic Category

  • Central Nervous System Depressant

Pharmacology

Sodium oxybate is derived from gamma aminobutyric acid (GABA) and acts as an inhibitory chemical transmitter in the brain. May function through specific receptors for gamma hydroxybutyrate (GHB) and GABA (B).

Absorption

Rapid

Distribution

190 to 384 mL/kg

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

Excretion

Primarily pulmonary (as carbon dioxide); urine (<5% as unchanged drug); feces (negligible)

Time to Peak

30 to 75 minutes

Half-Life Elimination

30 to 60 minutes

Protein Binding

<1%

Special Populations: 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).

Use: Labeled Indications

Narcolepsy: Treatment of cataplexy and excessive daytime sleepiness in patients with narcolepsy

Contraindications

Concomitant use with ethanol or sedative-hypnotic agents; succinic semialdehyde dehydrogenase deficiency

Dosing: Adult

Narcolepsy (excessive daytime sleepiness/cataplexy): Oral:

U.S. labeling: Initial: 2.25 g at bedtime after the patient is in bed, and 2.25 g 2.5 to 4 hours later (4.5 g per night). Titrate dose by 1.5 g per night (0.75 g at bedtime and 0.75 g 2.5 to 4 hours later) in weekly intervals; usual effective dosage range: 6 to 9 g per night (maximum dose: 9 g per night).

Canadian labeling: Initial: 2.25 g at bedtime after the patient is in bed, and 2.25 g 2.5 to 4 hours later (4.5 g per night). Increase/decrease dose by 1.5 g per night (0.75 g at bedtime and 0.75 g 2.5 to 4 hours later) every 2 weeks; usual effective dosage range: 6 to 9 g per night (maximum dose: 9 g per night).

Dosage adjustment for concomitant therapy: Patients stabilized on sodium oxybate should have dose reduced by at least 20% with the addition of divalproex sodium. The sodium oxybate starting dose should be reduced for patients already taking divalproex sodium. Adjust dose as necessary.

Dosing: Geriatric

Refer to adult dosing. Use with caution; initiate at lower dosage range. Limited studies available in patients >65 years.

Dosing: Renal Impairment

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

Dosing: Hepatic Impairment

Initial: ~1.13 g at bedtime after the patient is in bed and ~1.13 g 2.5 to 4 hours later (2.25 g per night)

Reconstitution

Prepare both doses prior to bedtime and place safely near bed, out of reach of pets and children. Each dose should be diluted with 60 mL of water in the provided child-resistant dosing cups. Once diluted, solutions should be used within 24 hours.

Administration

Oral: Administer on an empty stomach; separate last meal (or food) and first dose by ≥2 hours; try to take at similar time each day. Doses should be administered while in bed; patient should lie down immediately after dose and should remain in bed. Both doses should be prepared prior to bedtime. The first dose is taken at bedtime and the second dose is taken 2.5 to 4 hours later; an alarm clock may need to be set for the second dose. Patients typically fall asleep within 5-15 minutes; patients may take up to 2 hours to fall asleep (rare).

Dietary Considerations

Contains a high sodium content; limit dietary intake of sodium.

Storage

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 and in a safe and secure place (may need to be locked up).

Drug Interactions

Alcohol (Ethyl): May enhance the CNS depressant effect of Sodium Oxybate. Avoid combination

Azelastine (Nasal): CNS Depressants may enhance the CNS depressant effect of Azelastine (Nasal). Avoid combination

Benzodiazepines: May enhance the CNS depressant effect of Sodium Oxybate. Avoid combination

Blonanserin: CNS Depressants may enhance the CNS depressant effect of Blonanserin. Consider therapy modification

Brimonidine (Topical): May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

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 patches (Butrans brand) at 5 mcg/hr in adults when used with other CNS depressants. Consider therapy modification

Cannabis: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

CNS Depressants: Sodium Oxybate may enhance the CNS depressant effect of CNS Depressants. Management: Consider alternatives to combined use. When combined use is needed, consider minimizing doses of one or more drugs. Use of sodium oxybate with alcohol or sedative hypnotics is contraindicated. Consider therapy modification

Dimethindene: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Dronabinol: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Droperidol: May enhance the CNS depressant effect of CNS Depressants. Management: Consider dose reductions of droperidol or of other CNS agents (e.g., opioids, barbiturates) with concomitant use. Consider therapy modification

HYDROcodone: CNS Depressants may enhance the CNS depressant effect of HYDROcodone. Management: Consider starting with a 20% to 30% lower hydrocodone dose when using together with any other CNS depressant. Dose reductions in the other CNS depressant may also be warranted. Consider therapy modification

Hypnotics (Nonbenzodiazepine): May enhance the CNS depressant effect of Sodium Oxybate. Avoid combination

Kava Kava: May enhance the adverse/toxic effect of CNS Depressants. Monitor therapy

Magnesium Sulfate: May enhance the CNS depressant effect of CNS Depressants. 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 adult dose of CNS depressant agents by 50% with initiation of concomitant methotrimeprazine therapy. Further CNS depressant dosage adjustments should be initiated only after clinically effective methotrimeprazine dose is established. Consider therapy modification

MetyroSINE: CNS Depressants may enhance the sedative effect of MetyroSINE. Monitor therapy

Minocycline: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Nabilone: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Orphenadrine: CNS Depressants may enhance the CNS depressant effect of Orphenadrine. Avoid combination

OxyCODONE: CNS Depressants may enhance the CNS depressant effect of OxyCODONE. Management: When oxycodone is combined with another CNS depressant, a dose reduction of one or both agents should be considered. The extended release oxycodone starting dose should be reduced 50% to 67% when initiated in patients already receiving CNS depressants. Consider therapy modification

Paraldehyde: CNS Depressants may enhance the CNS depressant effect of Paraldehyde. Avoid combination

Perampanel: May enhance the CNS depressant effect of CNS Depressants. Management: Patients taking perampanel with any other drug that has CNS depressant activities should avoid complex and high-risk activities, particularly those such as driving that require alertness and coordination, until they have experience using the combination. Consider therapy modification

Pramipexole: CNS Depressants may enhance the sedative effect of Pramipexole. Monitor therapy

ROPINIRole: CNS Depressants may enhance the sedative effect of ROPINIRole. Monitor therapy

Rotigotine: CNS Depressants may enhance the sedative effect of Rotigotine. Monitor therapy

Rufinamide: May enhance the adverse/toxic effect of CNS Depressants. Specifically, sleepiness and dizziness may be enhanced. Monitor therapy

Selective Serotonin Reuptake Inhibitors: CNS Depressants may enhance the adverse/toxic effect of Selective Serotonin Reuptake Inhibitors. Specifically, the risk of psychomotor impairment may be enhanced. Monitor therapy

Tapentadol: May enhance the CNS depressant effect of CNS Depressants. Management: Start tapentadol at a dose of one-third to one-half of the normal dose if being initiated in a patient who is taking another drug with CNS depressant effects. Monitor closely for evidence of excessive CNS depression. Consider therapy modification

Tetrahydrocannabinol: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Thalidomide: CNS Depressants may enhance the CNS depressant effect of Thalidomide. Avoid combination

Valproate Products: May increase the serum concentration of Sodium Oxybate. Management: Consider a sodium oxybate dose reduction of at least 20% if combined with valproic acid. Consider therapy modification

Adverse Reactions

>10%:

Central nervous system: Dizziness (9% to 15%)

Gastrointestinal: Nausea (8% to 20% dose related), vomiting (2% to 11%; dose related)

1% to 10%:

Cardiovascular: Peripheral edema (≤3%)

Central nervous system: Somnolence (1% to 8%), attention disturbance (≤4%; dose related), drunk feeling (≤3%; dose related), irritability (≤3%; dose related), pain (≤3%), sleep paralysis (≤3%), sleepwalking (≤3%; dose related), disorientation (1% to 3%; dose related), anxiety (1% to 2%)

Dermatologic: Hyperhidrosis (1% to 3%)

Gastrointestinal: Diarrhea (3% to 4%), abdominal pain (1% to 3%)

Genitourinary: Enuresis (3% to 7%; dose related)

Neuromuscular & skeletal: Tremor (≤5%), pain in extremity (1% to 3%), paresthesia (1% to 3%; dose related)

Postmarketing and/or case reports: Arthralgia, appetite decreased, blurred vision, falling, fluid retention, hangover effect, headache, hypersensitivity, hypertension, memory impairment, panic attack, weight loss

ALERT: U.S. Boxed Warning

Central nervous system depression:

Sodium oxybate is a CNS depressant. In clinical trials at recommended doses, obtundation and clinically significant respiratory depression occurred in sodium oxybate–treated patients. Almost all of the patients who received sodium oxybate during clinical trials in narcolepsy were receiving CNS stimulants.

Misuse and abuse:

Sodium oxybate is the sodium salt of gamma hydroxybutyrate (GHB). Abuse of 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, abuse, and misuse, sodium oxybate is only available through a restricted distribution program called the Xyrem REMS Program, using the central pharmacy that is specially certified. Prescribers and patients must enroll in the program. For further information go to http://www.xyremrems.com or call 1-866-997-3688.

Warnings/Precautions

Concerns related to adverse effects:

• CNS depression: May cause anxiety, confusion, psychosis, paranoia, hallucinations, agitation, depression, suicidality and sleepwalking; use caution with in patients with history of depression and/or suicide attempt. Patients should be instructed not to engage in hazardous activities requiring mental alertness for at least 6 hours after taking the second nightly dose of this medication. Concurrent use with other CNS depressants may increase the risk of respiratory depression, hypotension, excessive 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 one or more CNS depressant agent (including sodium oxybate) should be considered. If short-term opioid use is required, consider temporarily discontinuing sodium oxybate.

• Respiratory depression: [US Boxed Warning]: In clinical trials at recommended doses, obtundation and clinically significant respiratory depression occurred in sodium oxybate-treated patients. Almost all 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. Concomitant use with CNS depressants may increase risk of syncope and hypotension; dosage adjustments should be considered.

• 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, postmenopausal (not on hormone replacement therapy), or narcoleptic.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

• Elderly: Although limited data exists, headache was observed at a higher incidence in older adults ≥65 years of age compared to younger adults. Elderly 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 Xyrem REMS Program and dispensed to the patient only by the central pharmacy that is speciality certified (1-866-997-3688 or www.xyremrems.com).

• Sodium: Contains high sodium content: Use with caution in patients sensitive to high sodium intake (eg, renal impairment, HF, 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.

Monitoring Parameters

Signs and symptoms of depression or suicidality; emergence of anxiety, confusion, thought disorders, or behavior abnormalities; drug abuse, misuse, and addiction

Pregnancy Risk Factor

C

Pregnancy Considerations

Adverse effects have been reported with maternal use. The injection formulation, when used as an anesthetic during labor and delivery, was shown to cross the placenta in concentrations ≤25% of maternal levels; a slight decrease in Apgar scores due to sleepiness in the neonate was observed. Sodium oxybate was not detected in infant blood 30 minutes after delivery.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience dizziness, fatigue, nausea, vomiting, bedwetting, tremors, or diarrhea. Have patient report immediately to prescriber signs of depression (suicidal ideation, anxiety, emotional instability, or illogical thinking), hallucinations, confusion, behavioral changes, sleepwalking, difficulty breathing, slow breathing, or shallow breathing (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

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