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Xyrem

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Xyrem

CLINICAL PHARMACOLOGY

Mechanism Of Action

Xyrem is a CNS depressant. The mechanism of action of Xyrem in the treatment of narcolepsy is unknown. 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 of Xyrem on cataplexy and excessive daytime sleepiness are mediated through GABAB actions at noradrenergic and dopaminergic neurons, as well as at thalamocortical neurons.

Pharmacokinetics

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

Absorption

Following oral administration, sodium oxybate 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, the plasma levels of sodium oxybate 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. Administration of Xyrem 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 by a mean of 59% and of systemic exposure (AUC) by 37%.

Distribution

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

Metabolism

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 beta-oxidation. The 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. 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.

Elimination

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 drug appears in human urine within 6 to 8 hours after dosing. Fecal excretion is negligible. Sodium oxybate has an elimination half-life of 0.5 to 1 hour.

Specific Populations

Geriatric

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

Pediatric

The pharmacokinetics of sodium oxybate in patients younger than 18 years of age have not been studied.

Gender

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

Race

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

Renal Impairment

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

Hepatic Impairment

The pharmacokinetics of Xyrem 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 oral 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 t½ of 59 and 32 minutes, respectively, versus 22 minutes). The starting dose of Xyrem should be reduced by one-half in patients with liver impairment [see DOSAGE AND ADMINISTRATION; Use in Specific Populations].

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 therapeutic doses.

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

  • Divalproex sodium: Co-administration of Xyrem (6 g per day as two equal doses of 3 grams dosed four hours apart) with divalproex sodium (valproic acid, 1250 mg per day) increased mean systemic exposure to sodium oxybate as shown by AUC by approximately 25% , while Cmax was comparable. Co-administration did not appear to affect the pharmacokinetics of valproic acid. A greater impairment on some tests of attention and working memory was observed with co-administration of both drugs than with either drug alone [see DRUG INTERACTIONS and DOSAGE AND ADMINISTRATION].
  • Diclofenac: Co-administration of Xyrem (6 g per day as two equal doses of 3 grams dosed four hours apart) with diclofenac (50 mg/dose twice per day) showed no significant differences in systemic exposure to sodium oxybate . Co-administration did not appear to affect the pharmacokinetics of diclofenac.
  • Ibuprofen: Co-administration of Xyrem (6 g per day as two equal doses of 3 grams dosed four hours apart) with ibuprofen (800 mg/dose four times per day also dosed four hours apart) resulted in comparable systemic exposure to sodium oxybate as shown by plasma Cmax and AUC values. Co-administration did not affect the pharmacokinetics of 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 oxybate kinetics. In addition, drug interaction studies in healthy adults demonstrated no pharmacokinetic or clinically significant pharmacodynamic interactions between sodium oxybate and the SNRI duloxetine HCl.

Clinical Studies

Cataplexy In Narcolepsy

The effectiveness of Xyrem in the treatment of cataplexy was established in two randomized, double-blind, placebo-controlled, multicenter, parallel-group trials (Trials N1 and N2) in patients with narcolepsy (see Table 4). In Trials N1 and N2, 85% and 80% of patients, respectively, were also being treated with CNS stimulants. The high percentages of concomitant stimulant use make it impossible to assess the efficacy and safety of Xyrem independent of stimulant use. In each trial, the treatment period was 4 weeks and the total nightly Xyrem doses ranged from 3 g to 9 g, with the total nightly dose administered as two equal doses. The first dose each night was taken at bedtime and the second dose was taken 2.5 to 4 hours later. There were no restrictions on the time between food consumption and dosing.

Trial N1 enrolled 136 narcoleptic patients with moderate to severe cataplexy (median of 21 cataplexy attacks per week) at baseline. Prior to randomization, medications with possible effects on cataplexy were withdrawn, but stimulants were continued at stable doses. Patients were randomized to receive placebo, Xyrem 3 g per night, Xyrem 6 g per night, or Xyrem 9 g per night.

Trial N2 was a randomized withdrawal trial with 55 narcoleptic patients who had been taking open-label Xyrem for 7 to 44 months prior to study entry. To be included, patients were required to have a history of at least 5 cataplexy attacks per week prior to any treatment for cataplexy. Patients were randomized to continued treatment with Xyrem at their stable dose (ranging from 3 g to 9 g per night) or to placebo for 2 weeks. Trial N2 was designed specifically to evaluate the continued efficacy of sodium oxybate after long-term use.

The primary efficacy measure in Trials N1 and N2 was the frequency of cataplexy attacks.

Table 4 : Median Number of Cataplexy Attacks in Trials N1 and N2

Trial/Dosage Group  Baseline  Median Change from Baseline  Comparison to Placebo (p­value) 
Trial N1 (Prospective, Randomized, Parallel Group Trial)
    (median attacks/week)
Placebo (n=33) 20.5
-4 -
Xyrem 6 g per night (n=31) 23.0 -10 0.0451
Xyrem 9 g per night (n=33) 23.5 -16 0.0016
Trial N2 (Randomized Withdrawal Trial)
  (median attacks/2 weeks)
Placebo (n=29) 4.0 21 -
Xyrem (n=26) 1.9 0 < 0.001

In Trial N1, both the 6 g and 9 g per night Xyrem doses resulted in statistically significant reductions in the frequency of cataplexy attacks. The 3 g per night dose had little effect. In Trial N2, patients randomized to placebo after discontinuing long-term open-label Xyrem therapy experienced a significant increase in cataplexy attacks (p < 0.001), providing evidence of long-term efficacy of Xyrem. In Trial N2, the response was numerically similar for patients treated with doses of 6 g to 9 g per night, but there was no effect seen in patients treated with doses less than 6 g per night, suggesting little effect at these doses.

Excessive Daytime Sleepiness In Narcolepsy

The effectiveness of Xyrem in the treatment of excessive daytime sleepiness in patients with narcolepsy was established in two randomized, double-blind, placebo-controlled trials (Trials N3 and N4) (see Tables 7 to 9). Seventy-eight percent of patients in Trial N3 were also being treated with CNS stimulants.

Trial N3 was a multicenter randomized, double-blind, placebo-controlled, parallel-group trial that evaluated 228 patients with moderate to severe symptoms at entry into the study including a median Epworth Sleepiness Scale (see below) score of 18, and a Maintenance of Wakefulness Test (see below) score of 8.3 minutes. Patients were randomized to one of 4 treatment groups: placebo, Xyrem 4.5 g per night, Xyrem 6 g per night, or Xyrem 9 g per night. The period of double-blind treatment in this trial was 8 weeks. Antidepressants were withdrawn prior to randomization; stimulants were continued at stable doses.

The primary efficacy measures in Trial N3 were the Epworth Sleepiness Scale and the Clinical Global Impression of Change. The Epworth Sleepiness Scale is intended to evaluate the extent of sleepiness in everyday situations by asking the patient a series of questions. In these questions, patients were asked to rate their chances of dozing during each of 8 activities on a scale from 0-3 (0=never; 1=slight; 2=moderate; 3=high). Higher total scores indicate a greater tendency to sleepiness. The Clinical Global Impression of Change is evaluated on a 7-point scale, centered at No Change, and ranging from Very Much Worse to Very Much Improved. In Trial N3, patients were rated by evaluators who based their assessments on the severity of narcolepsy at baseline.

In Trial N3, statistically significant improvements were seen on the Epworth Sleepiness Scale score at Week 8 and on the Clinical Global Impression of Change score at Week 8 with the 6 g and 9 g per night doses of Xyrem compared to the placebo group.

Table 5 : Change from Baseline in Daytime Sleepiness Score (Epworth Sleepiness Scale) at Week 8 in Trial N3 (Range 0-24)

Treatment Group  Baseline  Week 8  Median Change from Baseline at Week 8  p-value 
Placebo (n=59)  17.5 17 -0.5 -
Xyrem 6 g per night (n=58)  19 16 -2 < 0.001 
Xyrem 9 g per night (n=47)  19 12 -5 < 0.001 

Table 6 : Proportion of patients with a very much or much improved Clinical Global Impression of Change in Daytime and Nighttime Symptoms in Trial N3

Treatment Group  Percentages of Responders (Very Much Improved or Much Improved)  Change from Baseline Significance Compared to Placebo (p-value) 
Placebo (59)  22% -
Xyrem 6 g per night (n=58)  52% < 0.001 
Xyrem 9 g per night (n=47)  64% < 0.001 

Trial N4 was a multicenter randomized, double-blind, placebo-controlled, parallel-group trial that evaluated 222 patients with moderate to severe symptoms at entry into the study including a median Epworth Sleepiness Scale score of 15, and a Maintenance of Wakefulness Test (see below) score of 10.3 minutes. At entry, patients had to be taking modafinil at stable doses of 200 mg, 400 mg, or 600 mg daily for at least 1 month prior to randomization. The patients enrolled in the study were randomized to one of 4 treatment groups: placebo, Xyrem, modafinil, or Xyrem plus modafinil. Xyrem was administered in a dose of 6 g per night for 4 weeks, followed by 9 g per night for 4 weeks. Modafinil was continued in the modafinil alone and the Xyrem plus modafinil treatment groups at the patient's prior dose. Trial N4 was not designed to compare the effects of Xyrem to modafinil because patients receiving modafinil were not titrated to a maximal dose. Patients randomized to placebo or to Xyrem treatment were withdrawn from their stable dose of modafinil. Patients taking antidepressants could continue these medications at stable doses.

The primary efficacy measure in Trial N4 was the Maintenance of Wakefulness Test. The Maintenance of Wakefulness Test measures latency to sleep onset (in minutes) averaged over 4 sessions at 2-hour intervals following nocturnal polysomnography. For each test session, the subject was asked to remain awake without using extraordinary measures. Each test session is terminated after 20 minutes if no sleep occurs, or after 10 minutes, if sleep occurs. The overall score is the mean sleep latency for the 4 sessions.

In Trial N4, a statistically significant improvement in the change in the Maintenance of Wakefulness Test score from baseline at Week 8 was seen in the Xyrem and Xyrem plus modafinil groups compared to the placebo group.

This trial was not designed to compare the effects of Xyrem to modafinil, because patients receiving modafinil were not titrated to a maximally effective dose.

Table 7 : Change in Baseline in the Maintenance of Wakefulness Test Score (in minutes) at Week 8 in Trial N4

Treatment Group  Baseline  Week 8  Mean Change from Baseline at Week 8  p-value 
Placebo (modafinil withdrawn) (n=55)  9.7 6.9 -2.7 -
Xyrem (modafinil withdrawn) (n=50)  11.3 12 0.6 < 0.001 
Xyrem plus modafinil (n=54)  10.4 13.2 2.7 < 0.001 

Last reviewed on RxList: 4/28/2014
This monograph has been modified to include the generic and brand name in many instances.

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