Source: European Medicines Agency (EU) Revision Year: 2025 Publisher: UCB Pharma SA, Allée de la Recherche 60, B-1070 Brussels, Belgium
Pharmacotherapeutic group: Other nervous system drugs
ATC code: N07XX04
Sodium oxybate is a central nervous system depressant which reduces excessive daytime sleepiness and cataplexy in patients with narcolepsy and modifies sleep architecture reducing fragmented nighttime sleep. The precise mechanism by which sodium oxybate produces an effect is unknown, however sodium oxybate is thought to act by promoting slow (delta) wave sleep and consolidating night-time sleep. Sodium oxybate administered before nocturnal sleep increases Stages 3 and 4 sleep and increases sleep latency, whilst reducing the frequency of sleep onset REM periods (SOREMPs). Other mechanisms, which have yet to be elucidated, may also be involved. In the clinical trial database, greater than 80% of patients maintained concomitant stimulant use.
The effectiveness of sodium oxybate for the treatment of narcolepsy symptoms was established in four multicentre, randomised, double-blind, placebo-controlled, parallel-group trials (Trial 1, 2, 3 and 4) in patients with narcolepsy with cataplexy except for trial 2 where cataplexy was not required for enrolment Concomitant stimulant use was permitted in all trials (except for the active-treatment phase of Trial 2); antidepressants were withdrawn prior to active treatment in all trials with the exception of Trial 2. In each trial, the daily dose was divided into two equal doses. The first dose each night was taken at bedtime and the second dose was taken 2.5 to 4 hours later.
Table 2. Summary of clinical trials performed using sodium oxybate for the treatment of narcolepsy:
| Trial | Primary Efficacy | N | Secondary Efficacy | Duration | Active treatment and Dose (g/d) |
|---|---|---|---|---|---|
| Trial 1 | EDS (ESS); CGIc | 246 | MWT/Sleep Architecture/ Cataplexy/Naps/FOSQ | 8 weeks | Sodium oxybate 4.5 – 9 |
| Trial 2 | EDS (MWT) | 231 | Sleep Architecture/ ESS/CGIc/Naps | 8 weeks | Sodium oxybate 6 – 9 Modafinil 200-600 mg |
| Trial 3 | Cataplexy | 136 | EDS (ESS)/CGIc/Naps | 4 weeks | Sodium oxybate 3 – 9 |
| Trial 4 | Cataplexy | 55 | None | 4 weeks | Sodium oxybate 3 – 9 |
EDS – Excessive daytime sleepiness; ESS – Epworth Sleepiness Scale; MWT – Maintenance of Wakefulness Test; Naps – Number of inadvertent daytime naps; CGIc – Clinical Global Impression of Change; FOSQ – Functional Outcomes of Sleep Questionnaire
Trial 1 enrolled 246 patients with narcolepsy and incorporated a 1 week up-titration period. The primary measures of efficacy were changes in excessive daytime sleepiness as measured by the Epworth Sleepiness Scale (ESS), and the change in the overall severity of the patient’s narcolepsy symptoms as assessed by the investigator using the Clinical Global Impressions of Change (CGI-c) measure.
Table 3. Summary of ESS in Trial 1:
| Epworth Sleepiness Scale (ESS; range 0-24) | ||||
|---|---|---|---|---|
| Dose Group [g/d (n)] | Baseline | Endpoint | Median Change from Baseline | Change from Baseline Compared to Placebo (p-value) |
| Placebo (60) | 17.3 | 16.7 | -0.5 | - |
| 4.5 (68) | 17.5 | 15.7 | -1.0 | 0.119 |
| 6 (63) | 17.9 | 15.3 | -2.0 | 0.001 |
| 9 (55) | 17.9 | 13.1 | -2.0 | <0.001 |
Table 4. Summary of CGI-c in Trial 1:
| Clinical Global Impressions of Change (CGI-c) | ||
|---|---|---|
| Dose Group [g/d (n)] | Responders* N (%) | Change from Baseline Compared to Placebo (p-value) |
| Placebo (60) | 13 (21.7) | - |
| 4.5 (68) | 32 (47.1) | 0.002 |
| 6 (63) | 30 (47.6) | <0.001 |
| 9 (55) | 30 (54.4) | <0.001 |
* The CGI-c data were analysed by defining responders as those patients who were very much improved or much improved.
Trial 2 compared the effects of orally administered sodium oxybate, modafinil and sodium oxybate + modafinil, with placebo in the treatment of daytime sleepiness in narcolepsy. During the 8 week double-blind period, patients took modafinil at their established dose or placebo equivalent. The sodium oxybate or placebo equivalent dose was 6 g/day for the first 4 weeks and was increased to 9 g/day for the remaining 4 weeks. The primary measure of efficacy was excessive daytime sleepiness as measured by objective response in MWT.
Table 5. Summary of MWT in Trial 2:
| TRIAL 2 | ||||
|---|---|---|---|---|
| Dose Group | Baseline | Endpoint | Mean Change from Baseline | Endpoint Compared to Placebo |
| Placebo (56) | 9.9 | 6.9 | -2.7 | - |
| Sodium Oxybate (55) | 11.5 | 11.3 | 0.16 | <0.001 |
| Modafinil (63) | 10.5 | 9.8 | -0.6 | 0.004 |
| Sodium Oxybate + Modafinil (57) | 10.4 | 12.7 | 2.3 | <0.001 |
Trial 3 enrolled 136 narcoleptic patients with moderate to severe cataplexy (median of 21 cataplexy attacks per week) at baseline. The primary efficacy measure in this trial was the frequency of cataplexy attacks.
Table 6. Summary of outcomes in Trial 3:
| Dosage | Number of Subjects | Cataplexy Attacks | ||
|---|---|---|---|---|
| Trial 3 | Baseline | Median Change from Baseline | Change from Baseline Compared to Placebo (p-value) | |
| Median attacks/week | ||||
| Placebo | 33 | 20.5 | -4 | - |
| 3.0 g/day | 33 | 20.0 | -7 | 0.5235 |
| 6.0 g/day | 31 | 23.0 | -10 | 0.0529 |
| 9.0 g/day | 33 | 23.5 | -16 | 0.0008 |
Trial 4 enrolled 55 narcoleptic patients who had been taking open-label sodium oxybate for 7 to 44 months. Patients were randomised to continued treatment with sodium oxybate at their stable dose or to placebo. Trial 4 was designed specifically to evaluate the continued efficacy of sodium oxybate after long-term use. The primary efficacy measure in this trial was the frequency of cataplexy attacks.
Table 7. Summary of outcome in Trial 4:
| Treatment Group | Number of Subjects | Cataplexy Attacks | ||
|---|---|---|---|---|
| Trial 4 | Baseline | Median Change from Baseline | Change from Baseline Compared to Placebo (p-value) | |
| Median attacks/two weeks | ||||
| Placebo | 29 | 4.0 | 21.0 | - |
| Sodium oxybate | 26 | 1.9 | 0 | p<0.001 |
In Trial 4, the response was numerically similar for patients treated with doses of 6 to 9 g/day, but there was no effect seen in patients treated with doses less than 6 g/day.
The effectiveness of sodium oxybate in paediatric patients with narcolepsy with cataplexy, was established in a double-blind, placebo-controlled, randomized-withdrawal, multicentre trial.
This study demonstrated the clinical efficacy of sodium oxybate in the treatment of cataplexy and Excess Daytime Sleepiness (EDS) in narcolepsy in pediatric subjects. 63 patients were randomized in the efficacy population where the primary efficacy endpoint in this trial was the change in number of weekly cataplexy attacks between the last two weeks of the stable dose period and the double-blind period.
During the double-blind period, the median (Q1, Q3) change from baseline (i.e. the last 2 weeks of the stable dose period) in the weekly number of cataplexy attacks was 12.71 (3.44, 19.77) for patients randomized to placebo and 0.27 (-1.00, 2.50) for patients randomized to sodium oxybate.
Table 8. Summary of outcome in study 13-005 in children/adolescents:
| Treatment Group | Number of Patients | Weekly Number of Cataplexy Attacks (median) | ||
|---|---|---|---|---|
| Baseline (i.e. Last 2 weeks of stable dose period) | Double-blind period | Change from Baseline | ||
| Placebo | 32 | 4.67 | 21.25 | 12.71 |
| Sodium oxybate | 31 | 3.50 | 3.77 | 0.27 |
| p-value | <0.0001 | |||
When subgroup analyses by age group (7-11 years and 12-17 years) were conducted for the primary endpoint, similar results were observed. During the Double-blind Treatment Period, among subjects aged 7 to 11 years, the median (Q1, Q3) change from baseline in the weekly number of cataplexy attacks was 18.32 (7.58, 35.75) for subjects randomized to Placebo and 0.13 (-1.15, 2.05) for subjects randomized to sodium oxybate (p<0.0001). During the Double-blind Treatment Period, among subjects aged 12 to 17 years, the median (Q1, Q3) change from baseline in the weekly number of cataplexy attacks was 9.39 (1.08, 16.12) for subjects randomized to Placebo and 0.58 (-0.88, 2.58) for subjects randomized to sodium oxybate (p=0.0044)
During the Double-blind Treatment Period, the median (Q1, Q3) change of the secondary endpoint (change in ESS scores) from baseline (which occurred at Visit 3 – the end of the Stable Dose Period) in Epworth Sleepiness Scale for Children and Adolescent (ESS-CHAD) score was 3.0 (1.0, 5.0) for subjects randomized to Placebo and 0.0 (-1.0, 2.0) for subjects randomized to sodium oxybate. The comparison of the rank change from baseline between treatments was statistically significant (p=0.0004) when analyzed by ANCOVA modeling containing treatment as a factor and rank baseline value as a covariate. Subjects randomized to Placebo had, on average, higher ESS (CHAD) scores at baseline compared to those on sodium oxybate.
Table 9. Summary of ESS (CHAD) Score during the Double-blind Treatment Period (Efficacy Population):
| Treatment Group | Number of Patients | Change in ESS (CHAD) Score (median) | ||
|---|---|---|---|---|
| Baseline (Visit 3-End of Stable Dose Period) | End of Double- blind Treatment Period (Visit 4) | Change from Baseline | ||
| Placebo | 32 | 11.0 | 12.0 | 3.0 |
| Sodium oxybate | 31 | 8.0 | 9.0 | 0.0 |
| p-value | 0.0004 | |||
Abbreviations: ESS (CHAD) = Epworth Sleepiness Scale for Children and Adolescents
Sodium oxybate is rapidly and almost completely absorbed after oral administration; absorption is delayed and decreased by a high fat meal. It is eliminated mainly by metabolism with a half-life of 0.5 to 1 hour. Pharmacokinetics is nonlinear with the area under the plasma concentration curve (AUC) versus time curve increasing 3.8-fold as dose is doubled from 4.5 g to 9 g. The pharmacokinetics is not altered with repeat dosing.
Sodium oxybate is absorbed rapidly following oral administration with an absolute bioavailability of about 88%. The average peak plasma concentrations (1st and 2nd peak) following administration of a 9 g daily dose divided into two equivalent doses given four hours apart were 78 and 142 μg/mL, respectively. The average time to peak plasma concentration (Tmax) ranged from 0.5 to 2 hours in eight pharmacokinetic studies. Following oral administration, the plasma levels of sodium oxybate increase more than proportionally with increasing dose. Single doses greater than 4.5 g have not been studied. Administration of sodium oxybate immediately after a high fat meal resulted in delayed absorption (average Tmax increased from 0.75 hr to 2.0 hr) and a reduction in peak plasma level (Cmax) by a mean of 58% and of systemic exposure (AUC) by 37%.
Sodium oxybate is a hydrophilic compound with an apparent volume of distribution averaging 190-384 mL/kg. At sodium oxybate concentrations ranging from 3 to 300 μg/mL, less than 1% is bound to plasma proteins.
Animal studies indicate that metabolism is the major elimination pathway for sodium oxybate, producing carbon dioxide and water via the tricarboxylic acid (Krebs) cycle and secondarily by β-oxidation. The primary pathway involves a cytosolic NADP+-linked enzyme, GHB dehydrogenase, that catalyses 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 metabolised to carbon dioxide and water. A second mitochondrial oxidoreductase enzyme, a transhydrogenase, also catalyses the conversion to succinic semialdehyde in the presence of α-ketoglutarate. An alternate pathway of biotransformation involves β-oxidation via 3,4-dihydroxybutyrate to Acetyl CoA, which also enters the citric acid cycle to result in the formation of carbon dioxide and water. No active metabolites have been identified.
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 μg/mL). These levels are considerably higher than levels achieved with therapeutic doses.
The clearance of sodium oxybate is almost entirely by biotransformation to carbon dioxide, which is then eliminated by expiration. On average, less than 5% of unchanged medicinal product appears in human urine within 6 to 8 hours after dosing. Faecal excretion is negligible.
In a limited number of patients greater than the age of 65 years the pharmacokinetics of sodium oxybate was not different compared to patients younger than 65 years of age.
The major pharmacokinetic characteristics of sodium oxybate in paediatric subjects are the same as those reported in pharmacokinetic studies of sodium oxybate in adults.
Paediatric and adult subjects receiving the same mg/kg dose have similar plasma concentration-time profiles (see section 4.2).
Because the kidney does not have a significant role in the excretion of sodium oxybate, no pharmacokinetic study in patients with renal dysfunction has been conducted; no effect of renal function on sodium oxybate pharmacokinetics would be expected.
Sodium oxybate undergoes significant presystemic (hepatic first-pass) metabolism. After a single oral dose of 25 mg/kg, AUC values were double in cirrhotic patients, with apparent oral clearance reduced from 9.1 in healthy adults to 4.5 and 4.1 mL/min/kg in Class A (without ascites) and Class C (with ascites) patients, respectively. Elimination half-life was significantly longer in Class C and Class A patients than in control subjects (mean t1/2 of 59 and 32 versus 22 minutes). The starting dose should be halved in all patients with hepatic impairment, and response to dose increments monitored closely (see section 4.2).
The effect of race on metabolism of sodium oxybate has not been evaluated.
Repeat administration of sodium oxybate to rats (90 days and 26 weeks) and dogs (52 weeks) did not result in any significant findings in clinical chemistry and micro- and macro pathology. Treatment- related clinical signs were mainly related to sedation, reduced food consumption and secondary changes in body weight, body weight gain and organ weights. The rat and dog exposures at the NOEL were lower (~50%) than that in humans. Sodium oxybate was non-mutagenic and non-clastogenic in in vitro and in vivo assays.
Gamma Butyrolactone (GBL), a pro-drug of GHB tested at exposures similar to the expected in man (1.21-1.64 times) has been classified by NTP as non-carcinogenic in rats and equivocal carcinogen in mice, due to slight increase of pheochromocytomas which was difficult to interpret due to high mortality in the high dose group. In a rat carcinogenicity study with oxybate no compound-related tumours were identified.
GHB had no effect on mating, general fertility or sperm parameters and did not produce embryo-foetal toxicity in rats exposed to up 1000 mg/kg/day GHB (1.64 times the human exposure calculated in nonpregnant animals). Perinatal mortality was increased and mean pup weight was decreased during the lactation period in high-dose F1 animals. The association of these developmental effects with maternal toxicity could not be established. In rabbits, slight foetotoxicity was observed.
In a 10-week repeat dose toxicity study conducted in juvenile rats treated from postnatal day 21 to 90, sodium oxybate produced adverse effects including mortalities during the first week of treatment, when animals were 21 to 27 days old, corresponding to an approximate age of 3-4 years in children. Acute toxicity appeared at exposures below those expected in paediatric patients and mortality was preceded by sodium oxybate-related clinical signs (bradypnea, deep breathing, decreased activity, uncoordinated gait, impaired righting reflex), in line with its expected pharmacology. The reason for this relatively stronger toxicity during the first week of treatment is not fully clear. It could be related to the fact that young animals appear to exhibit higher systemic exposure than older juvenile rats. It could also be due to higher sensitivity of pups to sodium oxybate compared to older juvenile and adult rats and/or to a tolerance development phenomenon. Reduced body weight and food consumption similarly as in adults were also observed, with additional respiratory signs (deep and slow breathing). Sodium oxybate did not produce adverse effects on growth and development up to exposure levels 2-to 4-fold higher than the exposure expected at the maximum recommended dose in paediatric subjects (200mg/kg/day in paediatric patients with body weight less than 45kg or 9g/day for paediatric patients with body weight ≥45kg).
Drug discrimination studies show that GHB produces a unique discriminative stimulus that in some respects is similar to that of alcohol, morphine and certain GABA-mimetic medicinal products. Self-administration studies in rats, mice and monkeys have produced conflicting results, whereas tolerance to GHB as well as cross-tolerance to alcohol and baclofen has been clearly demonstrated in rodents.
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