Sodium Oxybate

• •
  Central Nervous System Depression
  Sodium Oxybate Oral Solution is a CNS depressant. In clinical trials at recommended doses, obtundation and clinically significant respiratory depression occurred in adult patients treated with Sodium Oxybate Oral Solution

  [see Warnings and Precautions (

  5.1 Central Nervous System Depression

  Sodium Oxybate Oral Solution is a central nervous system (CNS) depressant. In adult clinical trials at recommended doses, obtundation and clinically significant respiratory depression occurred in patients treated with Sodium Oxybate Oral Solution. Sodium Oxybate Oral Solution is contraindicated in combination with alcohol and sedative hypnotics. The concurrent use of Sodium Oxybate Oral Solution with other CNS depressants, including but not limited to opioid analgesics, benzodiazepines, sedating antidepressants or antipsychotics, sedating anti-epileptic drugs, general anesthetics, muscle relaxants, and/or illicit CNS depressants, may increase the risk of respiratory depression, hypotension, profound sedation, syncope, and death. If use of these CNS depressants in combination with Sodium Oxybate Oral Solution is required, dose reduction or discontinuation of one or more CNS depressants (including Sodium Oxybate Oral Solution) should be considered. In addition, if short-term use of an opioid (e.g., post- or perioperative) is required, interruption of treatment with Sodium Oxybate Oral Solution should be considered.

  Healthcare providers should caution patients about operating hazardous machinery, including automobiles or airplanes, until they are reasonably certain that Sodium Oxybate Oral Solution does not affect them adversely (e.g., impair judgment, thinking, or motor skills). Patients should not engage in hazardous occupations or activities requiring complete mental alertness or motor coordination, such as operating machinery or a motor vehicle or flying an airplane, for at least 6 hours after taking Sodium Oxybate Oral Solution. Patients should be queried about CNS depression‑related events upon initiation of Sodium Oxybate Oral Solution therapy and periodically thereafter.

  Sodium Oxybate Oral Solution is available only through a restricted program under a REMS

  [see Warnings and Precautions ]

  .

  )].

  Many patients who received Sodium Oxybate Oral Solution during clinical trials in narcolepsy were receiving central nervous system stimulants

  [see Clinical Trials (

  14 CLINICAL STUDIES

  The efficacy of Sodium Oxybate Oral Solution for the treatment of cataplexy or excessive daytime sleepiness (EDS) in patients 7 years of age and older with narcolepsy has been established in the following adequate and well-controlled trials:

  • •Cataplexy in adult narcolepsy in Trials N1 and N2
    [see Clinical Studies ]
  • •Excessive Daytime Sleepiness (EDS) in adult narcolepsy in Trials N3 and N4
    [see Clinical Studies ]
  • •Cataplexy and EDS in pediatric narcolepsy in Trial N5
    [see Clinical Studies (
    14.3
    )]

  14.1 Cataplexy in Adult Narcolepsy

  The effectiveness of Sodium Oxybate Oral Solution 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 5). 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 Sodium Oxybate Oral Solution independent of stimulant use. In each trial, the treatment period was 4 weeks and the total nightly Sodium Oxybate Oral Solution 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, Sodium Oxybate Oral Solution 3 g per night, Sodium Oxybate Oral Solution 6 g per night, or Sodium Oxybate Oral Solution 9 g per night.

  Trial N2 was a randomized-withdrawal trial with 55 narcoleptic patients who had been taking open-label Sodium Oxybate Oral Solution 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 Sodium Oxybate Oral Solution 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 5
  
  Median Number of Cataplexy Attacks in Trials N1 and N2

  Trial/Dosage Group	Baseline	Median Change from Baseline	Comparison to Placebo (p‑value)
  Trial N1 (Prospective, Randomized, Parallel Group Trial)
  		(median attacks/week)
  Placebo (n=33)	20.5	-4	–
  Sodium Oxybate Oral Solution 6 g per night (n=31)	23.0	-10	0.0451
  Sodium Oxybate Oral Solution 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	–
  Sodium Oxybate Oral Solution (n=26)	1.9	0	<0.001

  In Trial N1, both the 6 g and 9 g per night Sodium Oxybate Oral Solution 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 Sodium Oxybate Oral Solution therapy experienced a significant increase in cataplexy attacks (p<0.001), providing evidence of long-term efficacy of Sodium Oxybate Oral Solution. 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.

  14.2 Excessive Daytime Sleepiness in Adult Narcolepsy

  The effectiveness of Sodium Oxybate Oral Solution 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 6 to 8). 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, Sodium Oxybate Oral Solution 4.5 g per night, Sodium Oxybate Oral Solution 6 g per night, or Sodium Oxybate Oral Solution 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 Sodium Oxybate Oral Solution compared to the placebo group.

  Table 6
  
  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	-0.5	-
  Sodium Oxybate Oral Solution 6 g per night (n=58)	19.0	16.0	-2.0	<0.001
  Sodium Oxybate Oral Solution 9 g per night (n=47)	19.0	12.0	-5.0	<0.001

  Table 7
  
  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 (n=59)	22%	-
  Sodium Oxybate Oral Solution 6 g per night (n=58)	52%	<0.001
  Sodium Oxybate Oral Solution 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, Sodium Oxybate Oral Solution, modafinil, or Sodium Oxybate Oral Solution plus modafinil. Sodium Oxybate Oral Solution 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 Sodium Oxybate Oral Solution plus modafinil treatment groups at the patient’s prior dose. Trial N4 was not designed to compare the effects of Sodium Oxybate Oral Solution to modafinil because patients receiving modafinil were not titrated to a maximal dose. Patients randomized to placebo or to Sodium Oxybate Oral Solution 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 Sodium Oxybate Oral Solution and Sodium Oxybate Oral Solution plus modafinil groups compared to the placebo group.

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

  Table 8
  
  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	-
  Sodium Oxybate Oral Solution (modafinil withdrawn) (n=50)	11.3	12.0	0.6	<0.001
  Sodium Oxybate Oral Solution plus modafinil (n=54)	10.4	13.2	2.7	<0.001

  14.3 Cataplexy and Excessive Daytime Sleepiness in Pediatric Narcolepsy

  The effectiveness of Sodium Oxybate Oral Solution in the treatment of cataplexy and excessive daytime sleepiness in pediatric patients 7 years of age and older with narcolepsy was established in a double-blind, placebo-controlled, randomized-withdrawal study (Trial N5) (NCT02221869). The study was conducted in 106 pediatric patients (median age: 12 years; range: 7 to 17 years) with a baseline history of at least 14 cataplexy attacks in a typical 2-week period prior to any treatment for narcolepsy symptoms. Of the 106 patients, 2 did not receive study drug and 63 patients were randomized 1:1 either to continued treatment with Sodium Oxybate Oral Solution or to placebo. Randomization to placebo was stopped early as the efficacy criterion was met at the pre-planned interim analysis.

  Patients entered the study either taking a stable dose of Sodium Oxybate Oral Solution or were Sodium Oxybate Oral Solution-naïve. CNS stimulants were allowed at entry, and approximately 50% of patients used a stable dose of stimulant throughout the stable-dose and double-blind periods. Sodium Oxybate Oral Solution-naïve patients were initiated and titrated based on body weight over a period of up to 10 weeks. The total nightly dose was administered in two divided doses, with the first dose given at nighttime and the second given 2.5 to 4 hours later

  [see Dosage and Administration ]

  . Once a stable dose of Sodium Oxybate Oral Solution had been achieved, these patients entered the 2-week stable-dose period; patients taking a stable dose of Sodium Oxybate Oral Solution at study entry remained taking this dose for 3 weeks, prior to randomization. Efficacy was established at doses ranging from 3 g to 9 g of Sodium Oxybate Oral Solution per night.

  The primary efficacy measure was the change in frequency of cataplexy attacks. In addition, change in cataplexy severity was evaluated with the Clinical Global Impression of Change for cataplexy severity

  [see Clinical Studies for description of scale]

  . The efficacy of Sodium Oxybate Oral Solution in the treatment of excessive daytime sleepiness in pediatric patients with narcolepsy was evaluated with the change in the Epworth Sleepiness Scale (Child and Adolescent) score. The Epworth Sleepiness Scale (Child and Adolescent) is a modified version of the scale used in adult clinical trials described above

  [see Clinical Studies for description and scoring]

  . The overall change in narcolepsy condition was assessed by the Clinical Global Impression of Change for narcolepsy overall. Efficacy was assessed during or at the end of the 2-week double-blind treatment period, relative to the last 2 weeks or end of the stable-dose period (see Tables 9 and 10).

  Pediatric patients taking stable doses of Sodium Oxybate Oral Solution who were withdrawn from Sodium Oxybate Oral Solution treatment and randomized to placebo during the double-blind treatment period experienced a statistically significant increase in weekly cataplexy attacks compared with patients who were randomized to continue treatment with Sodium Oxybate Oral Solution. Patients randomized to receive placebo during the double-blind treatment period experienced a statistically significant worsening of EDS compared with patients randomized to continue receiving Sodium Oxybate Oral Solution (see Table 9).

  Table 9
  
  Number of Weekly Cataplexy Attacks and Epworth Sleepiness Scale (Child and Adolescent) Score (Trial N5)

  Treatment Group	Baseline*,†	Double-blind Treatment Period‡,§	Median Change from Baseline	Comparison to Placebo (p-value¶)
  Median Number of Cataplexy Attacks (attacks/week)
  Placebo (n=32)	4.7	21.3	12.7	-
  Sodium Oxybate Oral Solution (n=31)	3.5	3.8	0.3	<0.0001
  Median Epworth Sleepiness Scale (Child and Adolescent) Score
  Placebo (n=31**)	11	12	3	-
  Sodium Oxybate Oral Solution (n=30**)	8	9	0	0.0004

  ^*For weekly number of cataplexy attacks, baseline value is calculated from the last 14 days of the stable-dose period.
  
  ^†For Epworth Sleepiness Scale score, baseline value is collected at the end of stable-dose period.
  
  ^‡Weekly number of cataplexy attacks is calculated from all days within the double-blind treatment period.
  
  ^§For Epworth Sleepiness Scale, value is collected at the end of the double-blind treatment period.
  
  ^¶P-value from rank-based analysis of covariance (ANCOVA) with treatment as a factor and rank baseline value as a covariate.
  
  ** One patient in each of the treatment groups did not have baseline ESS score available and were not included in this analysis.
  
  

  Patients randomized to receive placebo during the double-blind treatment period experienced a statistically significant worsening of cataplexy severity and narcolepsy overall according to the clinician’s assessment compared with patients randomized to continue receiving Sodium Oxybate Oral Solution (see Table 10).

  Table 10
  
  Clinical Global Impression of Change (CGIc) for Cataplexy Severity and Narcolepsy Overall (Trial N5)

  Worsened, %†	CGIc Cataplexy Severity*		CGIc Narcolepsy Overall*
  	Placebo (n=32)	Sodium Oxybate Oral Solution (n=29)‡	Placebo (n=32)	Sodium Oxybate Oral Solution (n=29)‡
  Much worse or very much worse	66%	17%	59%	10%
  p-value§	0.0001		<0.0001

  ^*Responses indicate change of severity or symptoms relative to receiving Sodium Oxybate Oral Solution treatment at baseline.
  
  ^†Percentages based on total number of observed values.
  
  ^‡Two patients randomized to Sodium Oxybate Oral Solution did not have the CGIc assessments completed and were excluded from the analysis.
  
  ^§P-value from Pearson’s chi-square test.

  )].
  
  
  
  

• •
  Abuse and Misuse
  Sodium Oxybate is the sodium salt of gamma-hydroxybutyrate (GHB). Abuse or misuse of illicit GHB, either alone or in combination with other CNS depressants, is associated with CNS adverse reactions, including seizure, respiratory depression, decreases in the level of consciousness, coma, and death

  [see Warnings and Precautions (

  5.2 Abuse and Misuse

  Sodium Oxybate Oral Solution is a Schedule III controlled substance. The active ingredient of Sodium Oxybate Oral Solution, sodium oxybate or gamma-hydroxybutyrate (GHB), is a Schedule I controlled substance. Abuse of illicit GHB, either alone or in combination with other CNS depressants, is associated with CNS adverse reactions, including seizure, respiratory depression, decreases in the level of consciousness, coma, and death. The rapid onset of sedation, coupled with the amnestic features of Sodium Oxybate Oral Solution, particularly when combined with alcohol, has proven to be dangerous for the voluntary and involuntary user (e.g., assault victim). Because illicit use and abuse of GHB have been reported, physicians should carefully evaluate patients for a history of drug abuse and follow such patients closely, observing them for signs of misuse or abuse of GHB (e.g., increase in size or frequency of dosing, drug-seeking behavior, feigned cataplexy)

  [see Drug Abuse and Dependence ]

  .

  Sodium Oxybate Oral Solution is available only through a restricted program under a REMS

  [see Warnings and Precautions ].

  )].

  
  
  

Sodium Oxybate Oral Solution is indicated for the treatment of cataplexy or excessive daytime sleepiness (EDS) in patients 7 years of age and older with narcolepsy.

• •Initiate dosage at 4.5 g per night orally, divided into two doses (
  2.1 Adult Dosing Information

  The recommended starting dosage is 4.5 grams (g) per night administered orally, divided into two doses: 2.25 g at bedtime and 2.25 g taken 2.5 to 4 hours later (see Table 1). Increase the dosage by 1.5 g per night at weekly intervals (additional 0.75 g at bedtime and 0.75 g taken 2.5 to 4 hours later) to the effective dosage range of 6 g to 9 g per night orally. The dosage may be gradually titrated based on efficacy and tolerability. Doses higher than 9 g per night have not been studied and should not ordinarily be administered.

  Table 1: Recommended Adult Sodium Oxybate Oral Solution Dose Regimen (g = grams)

  If a Patient’s Total Nightly Dose is:	Take at Bedtime:	Take 2.5 to 4 Hours Later:
  4.5 g per night	2.25 g	2.25 g
  6 g per night	3 g	3 g
  7.5 g per night	3.75 g	3.75 g
  9 g per night	4.5 g	4.5 g
  ).
• •Titrate to effect in increments of 1.5 g per night at weekly intervals (0.75 g at bedtime and 0.75 g taken 2.5 to 4 hours later) (
  2.1 Adult Dosing Information

  The recommended starting dosage is 4.5 grams (g) per night administered orally, divided into two doses: 2.25 g at bedtime and 2.25 g taken 2.5 to 4 hours later (see Table 1). Increase the dosage by 1.5 g per night at weekly intervals (additional 0.75 g at bedtime and 0.75 g taken 2.5 to 4 hours later) to the effective dosage range of 6 g to 9 g per night orally. The dosage may be gradually titrated based on efficacy and tolerability. Doses higher than 9 g per night have not been studied and should not ordinarily be administered.

  Table 1: Recommended Adult Sodium Oxybate Oral Solution Dose Regimen (g = grams)

  If a Patient’s Total Nightly Dose is:	Take at Bedtime:	Take 2.5 to 4 Hours Later:
  4.5 g per night	2.25 g	2.25 g
  6 g per night	3 g	3 g
  7.5 g per night	3.75 g	3.75 g
  9 g per night	4.5 g	4.5 g
  ).
• •Recommended dosage range: 6 g to 9 g per night orally (
  2.1 Adult Dosing Information

  The recommended starting dosage is 4.5 grams (g) per night administered orally, divided into two doses: 2.25 g at bedtime and 2.25 g taken 2.5 to 4 hours later (see Table 1). Increase the dosage by 1.5 g per night at weekly intervals (additional 0.75 g at bedtime and 0.75 g taken 2.5 to 4 hours later) to the effective dosage range of 6 g to 9 g per night orally. The dosage may be gradually titrated based on efficacy and tolerability. Doses higher than 9 g per night have not been studied and should not ordinarily be administered.

  Table 1: Recommended Adult Sodium Oxybate Oral Solution Dose Regimen (g = grams)

  If a Patient’s Total Nightly Dose is:	Take at Bedtime:	Take 2.5 to 4 Hours Later:
  4.5 g per night	2.25 g	2.25 g
  6 g per night	3 g	3 g
  7.5 g per night	3.75 g	3.75 g
  9 g per night	4.5 g	4.5 g
  ).

• •The recommended starting dosage, titration regimen, and maximum total nightly dosage are based on body weight (
  2.2 Pediatric Dosing Information

  Sodium Oxybate Oral Solution is administered orally twice nightly. The recommended starting pediatric dosage, titration regimen, and maximum total nightly dosage are based on patient weight, as specified in Table 2. The dosage may be gradually titrated based on efficacy and tolerability.

  Table 2: Recommended Pediatric Sodium Oxybate Oral Solution Dosage for Patients 7 Years of Age and Older*

  Patient Weight	Initial Dosage		Maximum Weekly Dosage Increase		Maximum Recommended Dosage
  	Take at Bedtime:	Take 2.5 to 4 Hours Later:	Take at Bedtime:	Take 2.5 to 4 Hours Later:	Take at Bedtime:	Take 2.5 to 4 Hours Later:
  <20 kg**	There is insufficient information to provide specific dosing recommendations for patients who weigh less than 20 kg.
  20 kg to <30 kg	≤1 g	≤1 g	0.5 g	0.5 g	3 g	3 g
  30 kg to <45 kg	≤1.5 g	≤1.5 g	0.5 g	0.5 g	3.75 g	3.75 g
  ≥45 kg	≤2.25 g	≤2.25 g	0.75 g	0.75 g	4.5 g	4.5 g

  *For patients who sleep more than 8 hours per night, the first dose of Sodium Oxybate Oral Solution may be given at bedtime or after an initial period of sleep.
  
  **If Sodium Oxybate Oral Solution is used in patients 7 years of age and older who weigh less than 20 kg, a lower starting dosage, lower maximum weekly dosage increases, and lower total maximum nightly dosage should be considered.
  
  Note: Some patients may achieve better responses with unequal doses at bedtime and 2.5 to 4 hours later.
  ).

• •Prepare both doses prior to bedtime; dilute each dose with approximately ¼ cup of water in pharmacy-provided containers (
  2.3 Important Administration Instructions for All Patients

  The total nightly dosage of Sodium Oxybate Oral Solution is divided into two doses. Prepare both doses of Sodium Oxybate Oral Solution prior to bedtime. Prior to ingestion, each dose of Sodium Oxybate Oral Solution should be diluted with approximately ¼ cup (approximately 60 mL) of water in the empty pharmacy containers provided.

  Take the first nightly dose of Sodium Oxybate Oral Solution at least 2 hours after eating

  [see Clinical Pharmacology ].

  Take the second nightly dose 2.5 to 4 hours after the first dose.

  Patients should take both doses of Sodium Oxybate Oral Solution while in bed and lie down immediately after dosing, and remain in bed following ingestion of each dose. Sodium Oxybate Oral Solution may cause patients to fall asleep abruptly without first feeling drowsy

  [see Adverse Reactions ]

  . Patients will often fall asleep within 5 minutes of taking Sodium Oxybate Oral Solution, and will usually fall asleep within 15 minutes, though the time it takes any individual patient to fall asleep may vary from night to night. Patients may need to set an alarm to awaken for the second dose. Rarely, patients may take up to 2 hours to fall asleep.

  If the second dose is missed, that dose should be skipped and Sodium Oxybate Oral Solution should not be taken again until the next night. Both Sodium Oxybate Oral Solution doses should never be taken at one time.
  ).
• •Allow 2 hours after eating before dosing (
  2.3 Important Administration Instructions for All Patients

  The total nightly dosage of Sodium Oxybate Oral Solution is divided into two doses. Prepare both doses of Sodium Oxybate Oral Solution prior to bedtime. Prior to ingestion, each dose of Sodium Oxybate Oral Solution should be diluted with approximately ¼ cup (approximately 60 mL) of water in the empty pharmacy containers provided.

  Take the first nightly dose of Sodium Oxybate Oral Solution at least 2 hours after eating

  [see Clinical Pharmacology ].

  Take the second nightly dose 2.5 to 4 hours after the first dose.

  Patients should take both doses of Sodium Oxybate Oral Solution while in bed and lie down immediately after dosing, and remain in bed following ingestion of each dose. Sodium Oxybate Oral Solution may cause patients to fall asleep abruptly without first feeling drowsy

  [see Adverse Reactions ]

  . Patients will often fall asleep within 5 minutes of taking Sodium Oxybate Oral Solution, and will usually fall asleep within 15 minutes, though the time it takes any individual patient to fall asleep may vary from night to night. Patients may need to set an alarm to awaken for the second dose. Rarely, patients may take up to 2 hours to fall asleep.

  If the second dose is missed, that dose should be skipped and Sodium Oxybate Oral Solution should not be taken again until the next night. Both Sodium Oxybate Oral Solution doses should never be taken at one time.
  ).
• •Take each dose while in bed and lie down after dosing (
  2.3 Important Administration Instructions for All Patients

  The total nightly dosage of Sodium Oxybate Oral Solution is divided into two doses. Prepare both doses of Sodium Oxybate Oral Solution prior to bedtime. Prior to ingestion, each dose of Sodium Oxybate Oral Solution should be diluted with approximately ¼ cup (approximately 60 mL) of water in the empty pharmacy containers provided.

  Take the first nightly dose of Sodium Oxybate Oral Solution at least 2 hours after eating

  [see Clinical Pharmacology ].

  Take the second nightly dose 2.5 to 4 hours after the first dose.

  Patients should take both doses of Sodium Oxybate Oral Solution while in bed and lie down immediately after dosing, and remain in bed following ingestion of each dose. Sodium Oxybate Oral Solution may cause patients to fall asleep abruptly without first feeling drowsy

  [see Adverse Reactions ]

  . Patients will often fall asleep within 5 minutes of taking Sodium Oxybate Oral Solution, and will usually fall asleep within 15 minutes, though the time it takes any individual patient to fall asleep may vary from night to night. Patients may need to set an alarm to awaken for the second dose. Rarely, patients may take up to 2 hours to fall asleep.

  If the second dose is missed, that dose should be skipped and Sodium Oxybate Oral Solution should not be taken again until the next night. Both Sodium Oxybate Oral Solution doses should never be taken at one time.
  ).

Sodium Oxybate Oral Solution is a clear to slightly opalescent oral solution, in a concentration of 0.5 g per mL (0.5 g/mL of sodium oxybate equivalent to 0.413 g/mL of oxybate).

• •Pregnancy: Based on animal data, may cause fetal harm (
  8.1 Pregnancy

  Risk Summary

  There are no adequate data on the developmental risk associated with the use of sodium oxybate in pregnant women. Oral administration of sodium oxybate to pregnant rats (150, 350, or 1,000 mg/kg/day) or rabbits (300, 600, or 1,200 mg/kg/day) throughout organogenesis produced no clear evidence of developmental toxicity; however, oral administration to rats throughout pregnancy and lactation resulted in increased stillbirths and decreased offspring postnatal viability and growth, at a clinically relevant dose

  [see Data]

  .

  In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. The background risk of major birth defects and miscarriage for the indicated population is unknown.

  Clinical Considerations

  Labor or Delivery

  Sodium Oxybate Oral Solution has not been studied in labor or delivery. In obstetric anesthesia using an injectable formulation of sodium oxybate, newborns had stable cardiovascular and respiratory measures but were very sleepy, causing a slight decrease in Apgar scores. There was a fall in the rate of uterine contractions 20 minutes after injection. Placental transfer is rapid and gamma-hydroxybutyrate (GHB) has been detected in newborns at delivery after intravenous administration of GHB to mothers. Subsequent effects of sodium oxybate on later growth, development, and maturation in humans are unknown.

  Data

  Animal Data

  Oral administration of sodium oxybate to pregnant rats (150, 350, or 1,000 mg/kg/day) or rabbits (300, 600, or 1,200 mg/kg/day) throughout organogenesis produced no clear evidence of developmental toxicity. The highest doses tested in rats and rabbits were approximately 1 and 3 times, respectively, the maximum recommended human dose (MRHD) of 9 g per night on a body surface area (mg/m²) basis.

  Oral administration of sodium oxybate (150, 350, or 1,000 mg/kg/day) to rats throughout pregnancy and lactation resulted in increased stillbirths and decreased offspring postnatal viability and body weight gain at the highest dose tested. The no-effect dose for pre- and post-natal developmental toxicity in rats is less than the MRHD on a mg/m²basis.
  ).
• •Geriatric patients: Monitor for impaired motor and/or cognitive function when taking Sodium Oxybate Oral Solution (
  8.5 Geriatric Use

  Clinical studies of Sodium Oxybate Oral Solution in patients with narcolepsy did not include sufficient numbers of subjects age 65 years and older to determine whether they respond differently from younger subjects. In controlled trials in another population, 39 (5%) of 874 patients were 65 years or older. Discontinuations of treatment due to adverse reactions were increased in the elderly compared to younger adults (21% vs. 19%). Frequency of headaches was markedly increased in the elderly (39% vs. 19%). The most common adverse reactions were similar in both age categories. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
  ).