Date Printed: March 17, 2018: 10:21 AM

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Original Effective Date: 06/15/09

Reviewed: 04/12/17

Revised: 05/15/17

Subject: Sodium Oxybate (Xyrem®) Oral


Dosage/ Administration Position Statement Billing/Coding Reimbursement Program Exceptions Definitions
Related Guidelines Other References Updates  


Sodium oxybate is the sodium salt of gamma hydroxybutyric acid (GHB), a naturally-occurring central nervous system transmitter with sedative and anesthetic properties. It was first approved by the FDA in July 2002 for the treatment of cataplexy attacks in patients with narcolepsy. In November 2005 the indication was expanded to include the treatment of excessive daytime sleepiness in patients with narcolepsy. Sodium oxybate differs from modafinil and other stimulant treatments for narcolepsy in that it significantly decreases cataplexy episodes in addition to excessive daytime sleepiness (EDS); the drug is frequently prescribed along with stimulant therapies for narcolepsy. A mean decrease in the total number of weekly cataplexy episodes of nearly 70% has been reported in clinical trials. Cataplexy is a debilitating symptom characterized by loss of muscle control in response to strong emotions such as laughter, anger, or surprise and if severe can cause a person to collapse during waking hours.

Jazz Pharmaceuticals markets sodium oxybate under the trade name Xyrem. The drug is only available from a single centralized pharmacy to approved practitioners as part of the Xyrem REMS Program. New prescribers of Xyrem and patients must register as part of the REMS program.

Historically, GHB was originally used in Europe as an anesthetic in the 1960s, and was found beneficial for narcolepsy in 1976. The drug was first used in the US for the treatment of sleep disorders in the 1970s under FDA-approved investigational new drug protocols (INDs). The FDA has repeatedly notified the public that the drug is illegally marketed outside of approved INDs or NDAs. GHB can produce euphoria, making it a popular, but dangerous, drug of abuse; the compound has gained notoriety as a 'date rape' drug due to its sedative and amnestic properties. Illicit use of the drug has caused CNS depression, seizures, coma, and fatalities. In the early 1990's, GHB was commonly used as a dietary supplement for enhancing athletic performance and sexual activity, and as a sleep aid. As a result of serious adverse events associated with GHB use as a dietary supplement, the FDA intervened to prohibit marketing of GHB. In January 1999, the FDA warned that dietary supplements containing gamma butyrolactone (GBL) would also be considered unapproved new drugs due to the metabolism of GBL to GHB in vivo. These products are now considered illicit drugs (DEA schedule C-I).


Comparative Effectiveness

The Food and Drug Administration has deemed the drug(s) or biological product(s) in this coverage policy to be appropriate for self-administration or administration by a caregiver (i.e., not a healthcare professional). Therefore, coverage (i.e., administration) in a provider-administered setting such as an outpatient hospital, ambulatory surgical suite, physician office, or emergency facility is not considered medically necessary.

Initiation of sodium oxybate oral (Xyrem) meets the definition of medical necessity when ALL of the following criteria are met:

1. The dose of sodium oxybate does not exceed 9 gm/day (18 mL/day or 540 mL per 30 days)

2. Sodium oxybate is prescribed by a board-certified neurologist, psychiatrist, or sleep medicine specialist

3. Member is not being treated with any sedative hypnotic agents (e.g., benzodiazepines, barbiturates, zolpidem) as evidenced by paid claims history within the past 90 days, OR the provider attests that all hypnotic agents will be discontinued before initiating treatment with sodium oxybate

4. Member does not and will not consume any alcohol concomitantly with sodium oxybate

5. Member is experiencing daily periods of irrepressible need to sleep or daytime lapses into sleep occurring for at least 3 months

6. Member has a diagnosis of EITHER Type 1 or Type 2 narcolepsy, and ALL condition specific criteria are met:

a. Type 1 narcolepsy (narcolepsy with cataplexy)

i. Member has clear historic evidence of cataplexy

b. Type 2 narcolepsy (narcolepsy without cataplexy)

i. Alternative causes of EDS (e.g., insufficient sleep, obstructive sleep apnea, delayed sleep phase disorder, or the effect of medication or substances or their withdrawal) have been ruled out or adequately addressed

ii. Member has had an inadequate therapeutic response with a trial of at least 8 weeks, had persistent intolerable adverse effects, or has a contraindication to treatment of at least ONE medication from BOTH of the following groups (the specific adverse effect and/or contraindication must be specified for each drug):

• Group 1: modafinil (Provigil) or armodafinil (Nuvigil)

• Group 2: an amphetamine-based stimulant or a methylphenidate-based stimulant

7. Member’s diagnosis of narcolepsy has been confirmed by appropriately conducted overnight polysomnography (PSG) followed by multiple sleep latency test (MSLT) the next day - documentation and results of both tests must be provided and show both a mean sleep latency of ≤ 8 minutes AND two or more sleep onset REM periods (SOREMPs) on the MSL. A SOREMP, within 15 minutes of sleep onset, on the overnight PSG may replace one of the SOREMPs on the MSLT.

Duration of approval: 3 months

Continuation of sodium oxybate oral (Xyrem) meets the definition of medical necessity when ALL of the following criteria are met:

1. An authorization/reauthorization for sodium oxybate has been previously approved by Florida Blue in the past 2 years for the treatment of Type 1 or 2 narcolepsy, OR the member previously met ALL indication-specific initiation criteria

2. Sodium oxybate is prescribed by a board-certified neurologist, psychiatrist, or sleep medicine specialist

3. Member is not being treated with any sedative hypnotic agents (e.g., benzodiazepines, barbiturates, zolpidem) as evidenced by paid claims history within the past 90 days

4. Member is not consuming any alcohol concomitantly with sodium oxybate

5. The dose of sodium oxybate does not exceed 9 gm/day (18 mL/day or 540 mL per 30 days)

6. The member has a beneficial response to therapy as indicated by either of the following (corresponding to the type of narcolepsy being treated):

a. Type 1 narcolepsy (narcolepsy with cataplexy) - member has had a reduction in frequency of cataplexy attacks or symptoms of excessive daytime sleepiness as compared to before treatment with sodium oxybate – medical record documentation must be provided

b. Type 2 narcolepsy (narcolepsy without cataplexy) - member has had a reduction in symptoms of excessive daytime sleepiness as compared to before treatment with sodium oxybate – medical record documentation must be provided

Duration of approval: 1 year




Sodium oxybate is indicated for the treatment of cataplexy in narcolepsy and for the treatment of excessive daytime sleepiness (EDS) in narcolepsy. It is required to be taken at bedtime while in bed and again 2.5 to 4 hours later. The dose of sodium oxybate should be titrated to effect. The recommended starting dose is 4.5 g/night divided into 2 equal doses of 2.25 g. The starting dose then can be increased to a maximum of 9 g/night in increments of 1.5 g/night (0.75 g/dose). One to 2 weeks are recommended between dosage increases to evaluate clinical response and minimize adverse reactions. The effective dose range of sodium oxybate is 6 to 9 g/night. The efficacy and safety of sodium oxybate at doses higher than 9 g/night have not been investigated, and doses more than 9 g/night ordinarily should not be administered. Prepare both doses of sodium oxybate prior to bedtime. Each dose of sodium oxybate must be diluted with 2 ounces (i.e., 60 mL, one-fourth cup, 4 tablespoons) of water in the child-resistant dosing cups provided prior to ingestion. The first dose is to be taken at bedtime while in bed and the second taken 2.5 to 4 hours later; both doses should be taken while seated in bed. Members probably will need to set an alarm to awaken for the second dose. The second dose must be prepared prior to ingesting the first dose and should be placed in close proximity to the member’s bed. After ingesting each dose, members should lie down and remain in bed.Because food significantly reduces the bioavailability of sodium oxybate, the member should allow at least 2 hours after eating before taking the first dose of sodium oxybate. Members should try to minimize variability in time of dosing in relation to meals.

How supplied:

Each prescription includes a carton containing one bottle of Xyrem, a press-in-bottle-adaptor, an oral measuring device (plastic syringe), and a Medication Guide. The bottle contains 180 mL of Xyrem oral solution at a concentration of 0.5 g per mL (90 g per bottle). Each bottle of sodium oxybate is provided with a child-resistant cap. The pharmacy provides 2 dosing cups with child-resistant caps with each sodium oxybate shipment. Care should be taken to prevent access to this medication by children and pets.



Xyrem (sodium oxybate) is a CNS depressant. In clinical trials at recommended doses obtundation and clinically significant respiratory depression occurred in Xyrem-treated patients. Almost all of the patients who received Xyrem during clinical trials in narcolepsy were receiving central nervous system stimulants.

Xyrem (sodium oxybate) is the sodium salt of gamma hydroxybutyrate (GHB). Abuse of 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.

Because of the risks of CNS depression, abuse, and misuse, Xyrem is available only through a restricted distribution program called the Xyrem REMS Program, using the central pharmacy that is specially certified. Prescribers and patients must enroll in the program. For further information go to or call 1-866-XYREM88® (1-866-997-3688).


• Members being treated with sedative hypnotic agents

• Members should not drink alcohol when using sodium oxybate

• Members with succinic semialdehyde dehydrogenase deficiency. This is a rare disorder of inborn error of metabolism variably characterized by mental retardation, hypotonia, and ataxia.


• Central Nervous System Depression

Sodium oxybate is a central nervous system (CNS) depressant. Alcohol and sedative hypnotics are contraindicated in members who are using sodium oxybate. The concurrent use of sodium oxybate with other CNS depressants, including but not limited to opioid analgesics, benzodiazepines, sedating antidepressants or antipsychotics, 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 is required, dose reduction or discontinuation of one or more CNS depressants (including sodium oxybate) 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 should be considered.

Healthcare providers should caution members about operating hazardous machinery, including automobiles or airplanes, until they are reasonably certain that sodium oxybate does not affect them adversely (e.g., impair judgment, thinking, or motor skills). Members 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 the second nightly dose of sodium oxybate. Members should be queried about CNS depression-related events upon initiation of Sodium oxybate therapy and periodically thereafter.

Abuse and Misuse

Sodium oxybate is a Schedule III controlled substance. The active ingredient of 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, 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 members for a history of drug abuse and follow such members 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).

Xyrem REMS Program

The goal of the REMS program is to mitigate the risk of serious adverse outcomes resulting from inappropriate prescribing, misuse, abuse, and diversion of sodium oxybate by:

1. Informing prescribers, pharmacists, and patients of:

a. The risk of significant CNS and respiratory depression associated with sodium oxybate

b. The contraindication of use of sodium oxybate with sedative hypnotics and alcohol

c. The potential for abuse, misuse, and overdose associated with sodium oxybate

d. The safe use, handling, and storage of sodium oxybate

2. Ensuring that pharmacy controls exist prior to filling prescriptions for sodium oxybate that:

a. Screen for concomitant use of sedative hypnotics, and other potentially interacting agents

b. Monitor for inappropriate prescribing, misuse, abuse, and diversion of sodium oxybate

c. Notify prescribers when patients are receiving concomitant contraindicated medications or there are signs of potential abuse, misuse, or diversion

Program Elements:

o All prescribers must enroll in the Xyrem REMS Program and comply with requirements for prescribing sodium oxybate

o All patients must be enrolled in the Xyrem REMS Program to receive sodium oxybate.

o All patients are required to be counseled on the serious risks and safe use of sodium oxybate

o Sodium oxybate will be dispensed only by the central pharmacy that is specially certified

Respiratory Depression and Sleep-Disordered Breathing

Sodium oxybate may impair respiratory drive, especially in members with compromised respiratory function. In overdoses, life-threatening respiratory depression has been reported.

Prescribers should be aware that sleep-related breathing disorders tend to be more prevalent in obese members and in postmenopausal women not on hormone replacement therapy as well as among members with narcolepsy.

Depression and Suicidality

In clinical trials in members with narcolepsy (n=781), there were two suicides and two attempted suicides in Sodium oxybate-treated members, including three members with a previous history of depressive psychiatric disorder. Of the two suicides, one member used Sodium oxybate in conjunction with other drugs. Sodium oxybate was not involved in the second suicide. Adverse reactions of depression were reported by 7% of 781 Sodium oxybate-treated members, with four members (< 1%) discontinuing because of depression. In most cases, no change in Sodium oxybate treatment was required.

In a controlled trial, with members randomized to fixed doses of 3 g, 6 g, or 9 g per night

Sodium oxybate or placebo, there was a single event of depression at the 3 g per night dose. In another controlled trial, with members titrated from an initial 4.5 g per night starting dose, the incidences of depression were 1 (1.7%), 1 (1.5%), 2 (3.2%), and 2 (3.6%) for the placebo, 4.5 g, 6 g, and 9 g per night doses, respectively.

The emergence of depression in members treated with Sodium oxybate requires careful and immediate evaluation. Members with a previous history of a depressive illness and/or suicide attempt should be monitored carefully for the emergence of depressive symptoms while taking Sodium oxybate.

Other Behavioral or Psychiatric Adverse Reactions

During clinical trials in narcolepsy, 3% of 781 members treated with Sodium oxybate experienced confusion, with incidence generally increasing with dose.

Less than 1% of members discontinued the drug because of confusion. Confusion was reported at all recommended doses from 6 g to 9 g per night. In a controlled trial where members were randomized to fixed total daily doses of 3 g, 6 g, or 9 g per night or placebo, a dose-response relationship for confusion was demonstrated, with 17% of members at 9 g per night experiencing confusion. In all cases in that controlled trial, the confusion resolved soon after termination of treatment. In Trial 3 where sodium oxybate was titrated from an initial 4.5 g per night dose, there was a single event of confusion in one member at the 9 g per night dose. In the majority of cases in all clinical trials in narcolepsy, confusion resolved either soon after termination of dosing or with continued treatment. However, members treated with Sodium oxybate who become confused should be evaluated fully, and appropriate intervention considered on an individual basis.

Anxiety occurred in 5.8% of the 874 members receiving Sodium oxybate in clinical trials in another population. The emergence of or increase in anxiety in members taking Sodium oxybate should be carefully monitored.

Other neuropsychiatric reactions reported in Sodium oxybate clinical trials included hallucinations, paranoia, psychosis, and agitation. The emergence of thought disorders and/or behavior abnormalities requires careful and immediate evaluation.


Sleepwalking, defined as confused behavior occurring at night and at times associated with wandering, was reported in 6% of 781 members with narcolepsy treated with Sodium oxybate in controlled and long-term open-label studies, with < 1% of members discontinuing due to sleepwalking. Rates of sleepwalking were similar for members taking placebo and members taking Sodium oxybate in controlled trials It is unclear if some or all of the reported sleepwalking episodes correspond to true somnambulism, which is a parasomnia occurring during non-REM sleep, or to any other specific medical disorder. Five instances of significant injury or potential injury were associated with sleepwalking during a clinical trial of Sodium oxybate in members with narcolepsy.

Parasomnias including sleepwalking have been reported in postmarketing experience with Sodium oxybate. Therefore, episodes of sleepwalking should be fully evaluated and appropriate interventions considered.

Use in Members Sensitive to High Sodium Intake

Sodium oxybate has a high salt content. In members sensitive to salt intake (e.g., those with heart failure, hypertension, or renal impairment) consider the amount of daily sodium intake in each dose of sodium oxybate. The table below provides the approximate sodium content per sodium oxybate dose.

Approximate Sodium Content per Total Nightly Dose of Sodium oxybate (g = grams)

Sodium oxybate Dose

Sodium Content/Total Nightly Exposure

3 g per night

550 mg

4.5 g per night

820 mg

6 g per night

1100 mg

7.5 g per night

1400 mg

9 g per night

1640 mg


The following codes may be used to describe:

HCPCS Coding


Prescription drug, oral, non-chemotherapeutic, not otherwise specified

ICD-10 Diagnoses Codes That Support Medical Necessity


Narcolepsy, with cataplexy


Narcolepsy, without cataplexy


Refer to section entitled POSITION STATEMENT.


Federal Employee Program (FEP): Follow FEP guidelines.

State Account Organization (SAO): Follow SAO guidelines.

Medicare Advantage Products: No National Coverage Determination (NCD) and/or Local Coverage Determination (LCD) were found at the time of the last guideline review date.

Medicare Part D: Florida Blue has delegated to Prime Therapeutics authority to make coverage determinations for the Medicare Part D services referenced in this guideline.


Cataplexy: a condition, often associated with narcolepsy; marked by abrupt attacks of muscular weakness and hypotonia triggered by an emotional stimulus, such as mirth, anger, or fear.

Excessive Daytime Sleepiness: This refers to a condition where a person feels very drowsy during the day, even after getting adequate night time rest, and has a tendency to fall asleep or requires extra effort to avoid sleeping in inappropriate situations, such as at work or driving.  This condition is also defined as a score greater than or equal to 10 on the Epworth Sleepiness Scale.

Multiple Sleep Latency Test (MSLT): This is a test used in conjunction with polysomnography (PSG) to determine the presence and severity of sleepiness.  During this test, the subject is given the opportunity to take naps at specified time intervals.  The test consists of four or five nap opportunities at two hour intervals.  Each nap opportunity is 20 minutes in duration.  Individuals with excessive daytime sleepiness may fall asleep almost immediately, while those without excessive sleepiness may not fall asleep at all.  Severe sleepiness is usually associated with an MSLT mean sleep latency of less than 5 minutes.  The presence of sleep onset rapid eye movement (REM) and the number of naps in which sleep REM occurs are also determined.

Narcolepsy: recurrent, uncontrollable, brief episodes of sleep often associated with hallucinations just beforehand or just afterward.

Parasomnias: a category of sleep disorders that involve abnormal and unnatural movements, behaviors, emotions, perceptions, and dreams that occur while falling asleep, sleeping, between sleep stages, or during arousal from sleep.

Type 1 Narcolepsy: narcolepsy with cataplexy in which patients have very low CSF hypocretin/orexin levels resulting from extensive loss of hypothalamic neurons

Type 2 Narcolepsy: narcolepsy without cataplexy in which patients have normal or mildly decrease CSF hypocretin/orexin levels


Sleep Testing, 01-95828-01


None applicable.


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  15. Xyrem (sodium oxybate solution) [prescribing information]. Jazz Pharmaceuticals, Inc. Palo Alto, CA. January 2017.


This Medical Coverage Guideline (MCG) was approved by the BCBSF Pharmacy Policy Committee on 04/12/17.



New Medical Coverage Guideline.


Review and revision to guideline; consisting of updating precautions and references.


Revision to guideline; consisting of modifying coverage criteria.


Review and revision to guideline; consisting of updating references.


Review and revision to guideline; consisting of adding maximum dose to position statement and updating references.


Review and revision to guideline; consisting of updating description, position statement, precautions, definitions and references.


Revision: Program Exceptions section updated.


Review and revision to guideline; consisting of position statement.


Revision to guidelines; consisting of updating the position statement, addition of definitions, addition of coding information, and updating and addition of references.


Revision to guidelines; consisting of updating the position statement and references.


Revision: ICD-9 Codes deleted.


Review and revision to guideline consisting of updating the description section, position statement, definitions, related guidelines, and references.


Review and revision to guideline consisting of updating the description section, position statement, dosage/administration, precautions, and references.

Date Printed: March 17, 2018: 10:21 AM