Dosing and uses of Xyrem (sodium oxybate)
Adult dosage forms and strengths
oral solution
- 500mg/mL
Narcolepsy
Indicated for treatment of cataplexy in narcolepsy; also indicated for excessive daytime sleepiness in narcolepsy
Initial: 4.5 g/day, divided HS and 2.5-4 hr later
Increase dose by 1.5 g per night at weekly intervals (additional 0.75 g at bedtime and 0.75 g taken 2.5 to 4 hr later) to the effective dose range of 6-9 g/night PO; not to exceed 9 g/night
Dosage modifications
Hepatic impairment: Decrease initial dose by 50% and titrate slowly to response; elimination half-life is significantly increased
Renal impairment: No dose adjustment necessary
Coadministration with divalproex sodium
- Patients already stabilized on sodium oxybate: Decrease night dose of sodium oxybate by at least 20% when starting divalproex sodium
- Patients already taking divalproex sodium: Use a lower starting sodium oxybate dose; monitor dose and adjust dose accordingly
Dosing Considerations
Contains high sodium content
3 g/night: 550 mg sodium
4.5 g/night: 820 mg sodium
6 g/night: 1100 mg sodium
7.5 g/night: 1400 mg sodium
9 g/night: 1640 mg sodium
Administration
Dilute each dose in 2 oz (60 mL) water
Avoid food for at least 2 hr before dose
Take both doses of sodium oxybate while in bed and lie down immediately after dosing
Sodium oxybate may cause patients to fall asleep abruptly without first feeling drowsy
Patients will often fall asleep within 5 minutes of dose, and will usually fall asleep within 15 minutes
Patients should remain in bed following ingestion of the first and second doses, and should not take the second dose until 2.5-4 hr after the first dose
Patients may need to set an alarm to awaken for the second dose
Pediatric dosage forms and strengths
oral solution
- 500mg/mL
Narcolepsy
Indicated for treatment of cataplexy in narcolepsy; also indicated for excessive daytime sleepiness in narcolepsy
<16 years: Safety and efficacy not established
≥16 years
- Initial: 4.5 g/day, divided HS and 2.5-4 hr later
- Increase dose by 1.5 g per night at weekly intervals (additional 0.75 g at bedtime and 0.75 g taken 2.5 to 4 hr later) to the effective dose range of 6-9 g/night PO; not to exceed 9 g/night
Dosage modifications
Hepatic impairment: Decrease initial dose by 50% and titrate slowly to response; elimination half-life is significantly increased
Renal impairment: No dose adjustment necessary
Coadministration with divalproex sodium
- Patients already stabilized on sodium oxybate: Decrease night dose of sodium oxybate by at least 20% when starting divalproex sodium
- Patients already taking divalproex sodium: Use a lower starting sodium oxybate dose; monitor dose and adjust dose accordingly
Dosing Considerations
Contains high sodium content
3 g/night: 550 mg sodium
4.5 g/night: 820 mg sodium
6 g/night: 1100 mg sodium
7.5 g/night: 1400 mg sodium
9 g/night: 1640 mg sodium
Administration
Dilute each dose in 2 oz (60 mL) water
Avoid food for at least 2 hr before dose
Take both doses of sodium oxybate while in bed and lie down immediately after dosing
Sodium oxybate may cause patients to fall asleep abruptly without first feeling drowsy
Patients will often fall asleep within 5 minutes of dose, and will usually fall asleep within 15 minutes
Patients should remain in bed following ingestion of the first and second doses, and should not take the second dose until 2.5-4 hr after the first dose
Patients may need to set an alarm to awaken for the second dose
Xyrem (sodium oxybate) adverse (side) effects
>10%
Headache (20-25%)
Nausea (20-25%)
Dizziness (10-19%)
Pain (10-19%)
Somnolence (10-19%)
Pharyngitis (10-19%)
Infection (10-19%)
1-10%
Flu syndrome (5-9%)
Accidental injury (5-9%)
Diarrhea (5-9%)
Sporadic urinary incontinence (5-9%)
Vomiting (5-9%)
Rhinitis (5-9%)
Asthenia (5-9%)
Sinusitis (5-9%)
Nervousness (5-9%)
Back pain (5-9%)
Confusion (5-9%)
Sleepwalking (5-9%)
Depression (5-9%)
Dyspepsia (5-9%)
Abd pain (5-9%)
Abnormal dreams (5-9%)
Insomnia (5-9%)
<1%
Psychosis
Paranoia
Hallucinations
Agitation
Warnings
Black box warnings
Sodium oxybate (GHB) is a known drug of abuse; abuse has been associated with CNS adverse events, including seizures, respiratory depression, profound decreases in level of consciousness, coma, and death
Even at recommended doses, use has been associated with confusion, depression, and other neuropsychiatric events
Reports of respiratory depression occurred in clinical trials' almost all of the patients who received sodium oxybate during clinical trials were receiving CNS stimulants
Only available through the Xyrem Success Program, which uses a centralized pharmacy at the phone number 1- 866-XYREM88 (1-866-997-3688); the Success Program provides educational materials to the prescriber and the patient explaining the risks and proper use of sodium oxybate, and the required prescription form
Once documented that the patient has read and/or understood the materials, the drug will be shipped to the patient; the program also recommends patient follow-up every 3 months
Physicians are expected to report all serious adverse events to the manufacturer
Contraindications
Hypersensitivity
Concomitant sedative-hypnotic drugs or other drugs used for insomnia
Coadministration with alcohoL
Succinic semialdehyde dehydrogenase deficiency
Cautions
Schedule III agent; available only through the Xyrem Success Program, 1-866-997-3688
Abuse can be fataL
Risks of: depression, respiratory depression, confusion, neuropsychiatric events
Only take at bedtime; do not operate machinery for at least 6 hr after dose
Use with caution in patients with sleep apnea
Do not drink alcoholic beverages (see Contraindications)
Product has high salt content; caution in patients who are sensitive to salt intake (eg, heart failure, hypertension, renal impairment)
Pregnancy and lactation
Pregnancy category: C
Lactation: Unknown if distributed in human breast milk; caution advised
Pregnancy categories
A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.
B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.
C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.
D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.
X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.
NA: Information not available.
Pharmacology of Xyrem (sodium oxybate)
Mechanism of action
CNS depressant; sodium oxybate is the sodium salt of gamma hydroxybutyrate, an endogenous compound and metabolite of the neurotransmitter GABA
It is hypothesized that the therapeutic effects on cataplexy and excessive daytime sleepiness are mediated through GABAB actions at noradrenergic and dopaminergic neurons, as well as at thalamocortical neurons
Absorption
Bioavailability: 88% (fasting)
Peak plasma time: 0.5-1.25 hr (fasting); 0.75-2 hr (high fat meal)
Food delays absorption and a reduction in peak plasma concentration by a mean of 59% and of systemic exposure (AUC) by 37%
Distribution
Protein bound: <1%
Vd: 190-384 mL/kg
Metabolism
The major elimination pathway is by producing carbon dioxide and water via the tricarboxylic acid (Krebs) cycle and secondarily by beta-oxidation
Primary pathway involves a cytosolic NADP+-linked enzyme, GHB dehydrogenase that catalyzes the conversion of sodium oxybate to succinic semialdehyde, which is then biotransformed to succinic acid by the enzyme succinic semialdehyde dehydrogenase
Succinic acid enters the Krebs cycle where it is metabolized to carbon dioxide and water
Elimination
Half-life: 0.5-1 hr
Clearance is almost entirely by biotransformation to CO2, which is then eliminated by expiration
Excretion: Mostly lung (expiration of CO2); <5% urine
