Jane S. Ricciuti, RPh, MS

Disclosures

September 20, 2002

In This Article

CNS Agents

Xyrem
(sodium oxybate; gamma hydroxybutyrate [GHB]) Oral Solution

Manufacturer: Orphan Medical

Drug Approval Classification: Original New Drug Application (Approval Date: 7/17/02)

Indication: Xyrem oral solution is indicated for the treatment of cataplexy in patients with narcolepsy. In Xyrem clinical trials, approximately 80% of patients maintained concomitant stimulant use (see Black Box Warnings).

Dosing: Xyrem is to be taken at bedtime and again 2.5 to 4 hours later. The recommended starting dosage is 4.5 g/day divided into 2 equal doses of 2.25 g. The starting dosage can then be increased to a maximum of 9 g/day in increments of 1.5 g/day (0.75 g per dose). Two weeks are recommended between dosage increases to evaluate clinical response and minimize adverse effects. Xyrem is effective at dosages of 6-9 g/day.

Clinical Summary: Xyrem (sodium oxybate) is a CNS depressant with anticataplectic activity in patients with narcolepsy. Its precise mechanism of action is unknown.

Two 4-week, randomized, double-blind, placebo-controlled trials in patients with narcolepsy who were also being treated with CNS stimulants were the basis for FDA approval. Doses studied ranged from 3 to 9 g, with the daily dose divided into 2 equal doses. The main outcome measure was frequency of cataplexy attacks. Dosages of 6 g/day and 9 g/day demonstrated a mean change in baseline cataplexy attacks per week of 14 and 16, respectively.

Xyrem is contraindicated in patients with succinic semialdehyde dehydrogenase deficiency. This rare disorder is an inborn error of metabolism variably characterized by mental retardation, hypotonia, and ataxia.

Black Box Warning: Due to the known drug abuse of sodium oxybate (GHB), the FDA approval of Xyrem is contingent on a risk management plan that restricts distribution. The package insert for Xyrem includes a Black Box warning detailing the abuse potential and important CNS adverse events associated with its use, such as seizures and respiratory depression.

Xyrem is classified as a Schedule III controlled substance by federal law.

Adverse Effects: Xyrem is associated with the following more common adverse effects: headache (25%), nausea (21%), dizziness (17%), pain (16%), somnolence (13%), pharyngitis (11%), and infection (10%). Nausea and headache were the most frequent reasons for discontinuation of therapy, accounting for 2% and 1.3%, respectively, of cases discontinuing therapy.

Pharmacokinetics: Xyrem's half-life is 0.5-1.0 hour and it follows nonlinear pharmacokinetics. The clearance of sodium oxybate is almost entirely by biotransformation to carbon dioxide, which is then eliminated by expiration. On average, < 5% of unchanged drug appears in human urine within 6-8 hours after dosing.

Renal dysfunction does not affect Xyrem. Sodium oxybate undergoes significant presystemic (hepatic first-pass) metabolism. In patients with hepatic dysfunction, it is recommended to reduce the starting dose by half.

No pharmacokinetic drug interactions have been identified with protriptyline hydrochloride, zolpidem tartrate, and modafinil.

Xyrem (sodium oxybate) Labeling

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