Sodium Oxybate

Dosage Forms

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

Solution, Oral:

Xyrem: 500 mg/mL (180 mL)

Pharmacology

Mechanism of Action

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).

Pharmacokinetics/Pharmacodynamics

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%

Use in Specific Populations

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 or excessive daytime sleepiness in patients ≥7 years of age with narcolepsy

Contraindications

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

Canadian labeling: Additional contraindications (not in US labeling): Hypersensitivity to sodium oxybate or any component of the formulation

Dosage and Administration

Dosing: Adult

Narcolepsy (excessive daytime sleepiness/cataplexy): Oral: 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).

Dosage adjustment for concomitant therapy: Patients stabilized on sodium oxybate should have the sodium oxybate 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.

Missed dose: If the second dose is missed, skip that dose and resume therapy the next night; do not take both doses at the same time.

Dosing: Geriatric

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

Dosing: Pediatric

Narcolepsy (excessive daytime sleepiness/cataplexy): Note: Dose based on patient weight; dose may be titrated based on efficacy and tolerability. Some patients may require unequal doses to achieve optimal response.

Children ≥7 years and Adolescents: Oral:

<20 kg: There is no specific dosing provided in the manufacturer's labeling (insufficient information). Consider lower initial dosage, lower maximum weekly dosage increases, and lower total maximum nightly dosage.

20 to <30 kg: Oral: Initial: Up to 1 g at bedtime after the patient is in bed, and up to 1 g 2.5 to 4 hours later (up to 2 g per night). Titrate dose by 1 g per night (0.5 g at bedtime and 0.5 g 2.5 to 4 hours later) in weekly intervals; maximum dose: 3 g/dose; 6 g per night.

30 to <45 kg: Oral: Initial: Up to 1.5 g at bedtime after the patient is in bed, and up to 1.5 g 2.5 to 4 hours later (up to 3 g per night). Titrate dose by 1 g per night (0.5 g at bedtime and 0.5 g 2.5 to 4 hours later) in weekly intervals; maximum dose: 3.75 g/dose; 7.5 g per night.

≥45 kg: Oral: Initial: Up to 2.25 g at bedtime after the patient is in bed, and up to 2.25 g 2.5 to 4 hours later (up to 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; maximum dose: 4.5 g/dose; 9 g per night.

Dosage adjustment for concomitant therapy: Patients stabilized on sodium oxybate should have the sodium oxybate 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.

Missed dose: If the second dose is missed, skip that dose and resume therapy the next night; do not take both doses at the same time.

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 to 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

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

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

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

Bromperidol: May enhance the CNS depressant effect of CNS Depressants. 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. Consider therapy modification

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

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

Chlorphenesin Carbamate: May enhance the adverse/toxic 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 (Topical): 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 (eg, opioids, barbiturates) with concomitant use. Exceptions to this monograph are discussed in further detail in separate drug interaction monographs. Consider therapy modification

HYDROcodone: CNS Depressants may enhance the CNS depressant effect of HYDROcodone. Management: Avoid concomitant use of hydrocodone 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. 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

Lofexidine: May enhance the CNS depressant effect of CNS Depressants. Management: Drugs listed as exceptions to this monograph are discussed in further detail in separate drug interaction monographs. 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 (Systemic): 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

Oxomemazine: May enhance the CNS depressant effect of CNS Depressants. 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. 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

Piribedil: CNS Depressants may enhance the CNS depressant effect of Piribedil. Monitor therapy

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

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

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: Avoid concomitant use of tapentadol 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. Consider therapy modification

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

Tetrahydrocannabinol and Cannabidiol: 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: Confusion (adults: 3% to 17%), headache (≤16%), dizziness (6% to 15%)

Endocrine & metabolic: Weight loss (≤12%)

Gastrointestinal: Nausea (8% to 20%), vomiting (2% to 16%)

Genitourinary: Urinary incontinence (children and adolescents: 18%; adults: 3% to 7%)

1% to 10%:

Cardiovascular: Peripheral edema (adults: 3%)

Central nervous system: Drowsiness (adults: 8%), depression (adults: 3% to 7%), somnambulism (adults: 3% to 6%), anxiety (adults: 2% to 6%), disturbance in attention (adults: 1% to 4%), intoxicated feeling (adults: 3%), irritability (adults: 3%), pain (adults: 3%), sleep paralysis (adults: 3%), disorientation (adults: 2% to 3%), paresthesia (adults: 2% to 3%), severe central nervous system depression (adults: 2%)

Dermatologic: Hyperhidrosis (adults: 1% to 3%)

Gastrointestinal: Decreased appetite (≤8%), diarrhea (adults: 3% to 4%), upper abdominal pain (adults: 3%)

Neuromuscular & skeletal: Tremor (adults: 2% to 5%), limb pain (adults: 3%), cataplexy (adults: 2%)

Frequency not defined:

Central nervous system: Central nervous system depression, obtundation, sleep apnea

Hematologic & oncologic: Oxygen desaturation

Respiratory: Respiratory depression

<1%, postmarketing, and/or case reports: Acute psychosis, aggressive behavior, agitation, arthralgia, blurred vision, falling, fluid retention, hallucination, hangover effect, hypersensitivity reaction, hypertension, increased libido, memory impairment, nocturia, panic attack, paranoia, psychosis, suicidal ideation

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 adult patients. Many 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

Pregnancy Considerations

The injection formulation, when used as an anesthetic during labor and delivery, was shown to cross the placenta; a slight decrease in Apgar scores due to sleepiness in the neonate was observed.

Patient Education

What is this drug used for?

• It is used to treat sudden loss of muscle tone (cataplexy) in patients with narcolepsy.
• It is used to treat a lot of sleepiness during the day in patients with narcolepsy.

Frequently reported side effects of this drug

• Fatigue
• Nausea
• Vomiting
• Bedwetting
• Tremors
• Headache (children)
• Weight loss (children)
• Lack of appetite (children)

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• Depression like thoughts of suicide, anxiety, emotional instability, or confusion.
• Sensing things that seem real but are not
• Confusion
• Behavioral changes
• Sleepwalking
• Sleep apnea
• Severe dizziness
• Passing out
• Trouble breathing
• Slow breathing
• Shallow breathing
• Signs of a significant reaction like 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. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.