Sodium oxybate is a CNS depressant. The mechanism of action of sodium oxybate oral solution in the treatment of narcolepsy is unknown. Sodium oxybate is the sodium salt of gamma-hydroxybutyrate (GHB), an endogenous compound and metabolite of the neurotransmitter GABA. It is hypothesized that the therapeutic effects of sodium oxybate on cataplexy and excessive daytime sleepiness are mediated through GABAB actions at noradrenergic and dopaminergic neurons, as well as at thalamocortical neurons.

Pharmacokinetics of GHB are nonlinear and are similar following single or repeat dosing of sodium oxybate oral solution.

Absorption

Following oral administration of sodium oxybate oral solution, GHB is absorbed rapidly across the clinical dose range, with an absolute bioavailability of about 88%. The average peak plasma concentrations (Cmax) following administration of each of the two 2.25 g doses given under fasting conditions 4 hours apart were similar. The average time to peak plasma concentration (Tmax) ranged from 0.5 to 1.25 hours. Following oral administration of sodium oxybate oral solution, the plasma levels of GHB increased more than dose-proportionally, with blood levels increasing 3.7-fold as total daily dose is doubled from 4.5 g to 9 g. Single doses greater than 4.5 g have not been studied.

Effect of Food

Administration of sodium oxybate immediately after a high-fat meal resulted in delayed absorption (average Tmax increased from 0.75 hr to 2 hr) and a reduction in Cmax of GHB by a mean of 59% and of systemic exposure (AUC) by 37%.

Distribution

GHB is a hydrophilic compound with an apparent volume of distribution averaging 190 mL/kg to 384 mL/kg. At GHB concentrations ranging from 3 mcg/mL to 300 mcg/mL, less than 1% is bound to plasma proteins.

Animal studies indicate that metabolism is the major elimination pathway for GHB, producing carbon dioxide and water via the tricarboxylic acid (Krebs) cycle and secondarily by beta-oxidation. The primary pathway involves a cytosolic NADP+-linked enzyme, GHB dehydrogenase, that catalyzes the conversion of GHB 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. A second mitochondrial oxidoreductase enzyme, a transhydrogenase, also catalyzes the conversion to succinic semialdehyde in the presence of α-ketoglutarate. An alternate pathway of biotransformation involves β-oxidation via 3,4-dihydroxybutyrate to carbon dioxide and water. No active metabolites have been identified.

Excretion

The clearance of GHB is almost entirely by biotransformation to carbon dioxide, which is then eliminated by expiration. On average, less than 5% of unchanged drug appears in human urine within 6 to 8 hours after dosing. Fecal excretion is negligible. GHB has an elimination half-life of 0.5 to 1 hour.

There is limited experience with sodium oxybate in the elderly. Results from a pharmacokinetic study (n=20) in another studied population indicate that the pharmacokinetic characteristics of GHB are consistent among younger (age 48 to 64 years) and older (age 65 to 75 years) adults.

Pediatric Patients

Pediatric use information is approved for Jazz Pharmaceuticals Inc.'s XYREM (sodium oxybate) Oral Solution. However, due to Jazz Pharmaceuticals Inc.'s marketing exclusivity rights, this drug product is not labeled with that pediatric information.

Male and Female Patients

In a study of 18 female and 18 male healthy adult volunteers, no gender differences were detected in the pharmacokinetics of GHB following a single sodium oxybate oral solution dose of 4.5 g.

Racial or Ethnic Groups

There are insufficient data to evaluate any pharmacokinetic differences among races.

Patients with Renal Impairment

No pharmacokinetic study in patients with renal impairment has been conducted.

Patients with Hepatic Impairment

The pharmacokinetics of GHB in 16 cirrhotic patients, half without ascites (Child's Class A) and half with ascites (Child's Class C), were compared to the kinetics in 8 subjects with normal hepatic function after a single sodium oxybate oral solution dose of 25 mg/kg. AUC values were double in the cirrhotic patients, with apparent oral clearance reduced from 9.1 mL/min/kg in healthy adults to 4.5 and 4.1 mL/min/kg in Class A and Class C patients, respectively. Elimination half-life was significantly longer in Class C and Class A patients than in control patients (mean t1/2 of 59 and 32 minutes, respectively, versus 22 minutes). The starting dose of sodium oxybate oral solution should be reduced in patients with liver impairment [see Dosage and Administration (2.4) and Use in Specific Populations (8.6)].

Drug Interactions Studies

Studies in vitro with pooled human liver microsomes indicate that sodium oxybate does not significantly inhibit the activities of the human isoenzymes CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, or CYP3A up to the concentration of 3 mM (378 mcg/mL), a level considerably higher than levels achieved with recommended doses.

Drug interaction studies in healthy adults (age 18 to 50 years) were conducted with sodium oxybate and divalproex sodium, diclofenac, and ibuprofen:

Drug interaction studies in healthy adults demonstrated no pharmacokinetic interactions between sodium oxybate and protriptyline hydrochloride, zolpidem tartrate, and modafinil. Also, there were no pharmacokinetic interactions with the alcohol dehydrogenase inhibitor fomepizole. However, pharmacodynamic interactions with these drugs cannot be ruled out. Alteration of gastric pH with omeprazole produced no significant change in the pharmacokinetics of GHB. In addition, drug interaction studies in healthy adults demonstrated no pharmacokinetic or clinically significant pharmacodynamic interactions between sodium oxybate and duloxetine HCl.