What is Xyrem (sodium oxybate)?

Xyrem (sodium oxybate) oral solution is a central nervous system (CNS) depressant used to treat cataplexy and excessive daytime sleepiness in narcolepsy. Xyrem 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:

Because of the risks of CNS depression, abuse, and misuse, Xyrem is available only through a restricted distribution program called the Xyrem Success Program, using a centralized pharmacy. Prescribers and patients must enroll in the program.

Common side effects of Xyrem include:

Serious side effects of Xyrem include:

Call your doctor right away if you have symptoms of mental health problems.

Drug interactions of Xyrem include alcohol or sedative hypnotics, which may potentiate the CNS-depressant effects of Xyrem. 

There are no adequate and well-controlled studies of Xyrem in pregnant women. Xyrem should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. 

It is unknown if Xyrem is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Xyrem is administered to a breastfeeding woman.

What are the important side effects of sodium oxybate (Xyrem)?

WARNING

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 Success Program, using a centralized pharmacy. Prescribers and patients must enroll in the program.

For further information go to www.XYREM.com or call 1-866-XYREM88 (1-866-997-3688).

Xyrem can cause serious side effects, including:

  • Breathing problems, including:
    • slower breathing
    • trouble breathing
    • short periods of not breathing while sleeping (sleep apnea).
      • People who already have breathing or lung problems have a higher chance of having breathing problems when they use Xyrem.
  • Mental health problems, including:
    • confusion
    • seeing or hearing things that are not real (hallucinations)
    • unusual or disturbing thoughts (abnormal thinking)
    • feeling anxious or upset
    • depression
    • thoughts of killing yourself or trying to kill yourself
      • Call your doctor right away if you have symptoms of mental health problems.
  • Sleepwalking. Sleepwalking can cause injuries. Call your doctor if you start sleepwalking. Your doctor should check you.

The most common side effects of Xyrem include:

Your side effects may increase when you take higher doses of Xyrem. Xyrem can cause physical dependence and craving for the medicine when it is not taken as directed. These are not all the possible side effects of Xyrem.

For more information, ask your doctor or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Xyrem (sodium oxybate) side effects list for healthcare professionals

The following clinically significant adverse reactions appear in other sections of the labeling:

  • CNS depression
  • Abuse and Misuse
  • Respiratory Depression and Sleep-Disordered Breathing
  • Depression and Suicidality
  • Other Behavioral or Psychiatric Adverse Reactions
  • Parasomnias
  • Use in Patients Sensitive to High Sodium Intake

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

Adult Patients

Xyrem was studied in three placebo-controlled clinical trials (Trials N1, N3, and N4, described in Sections 14.1 and 14.2) in 611 patients with narcolepsy (398 subjects treated with Xyrem, and 213 with placebo). A total of 781 patients with narcolepsy were treated with Xyrem in controlled and uncontrolled clinical trials.

Section below and Table 4 present adverse reactions from three pooled, controlled trials (N1, N3, N4) in patients with narcolepsy.

Adverse Reactions Leading To Treatment Discontinuation

Of the 398 patients with narcolepsy treated with Xyrem, 10.3% of patients discontinued because of adverse reactions compared with 2.8% of patients receiving placebo. The most common adverse reaction leading to discontinuation was nausea (2.8%). The majority of adverse reactions leading to discontinuation began during the first few weeks of treatment.

Commonly Observed Adverse Reactions In Controlled Clinical Trials

The most common adverse reactions (incidence ≥5% and twice the rate seen with placebo) in patients treated with Xyrem were nausea, dizziness, vomiting, somnolence, enuresis, and tremor.

Adverse Reactions Occurring At An Incidence Of 2% Or Greater

Table 4 lists adverse reactions that occurred at a frequency of 2% or more in any treatment group for three controlled trials and were more frequent in any Xyrem treatment group than with placebo. Adverse reactions are summarized by dose at onset. Nearly all patients in these studies initiated treatment at 4.5 g per night. In patients who remained on treatment, adverse reactions tended to occur early and to diminish over time.

Table 4 : Adverse Reactions Occurring in ≥2% of Adult Patients and More Frequently with Xyrem than Placebo in Three Controlled Trials (N1, N3, N4) by Body System and Dose at Onset

System Organ Class/Adverse ReactionPlacebo
(n=213) %
Xyrem 4.5 g
(n=185) %
Xyrem 6 g
(n=258) %
Xyrem 9 g
(n=178) %
ANY ADVERSE REACTION62455570
GASTROINTESTINAL DISORDERS
Nausea381320
Vomiting12411
Diarrhea2434
Abdominal pain upper2312
Dry mouth2121
GENERAL DISORDERS AND ADMINISTRATIVE SITE CONDITIONS
Pain11<13
Feeling drunk10<13
Edema peripheral1300
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS
Pain in extremity1311
Cataplexy1112
Muscle spasms22<12
NERVOUS SYSTEM DISORDERS
Dizziness491115
Somnolence4138
Tremor0025
Paresthesia1213
Disturbance in attention0104
Sleep paralysis1013
PSYCHIATRIC DISORDERS
Disorientation1123
Anxiety1112
Irritability10<13
Sleep walking0003
RENAL AND URINARY DISORDERS
Enuresis1337
SKIN AND SUBCUTANEOUS TISSUE DISORDERS
Hyperhidrosis0113

Dose-Response Information

In clinical trials in narcolepsy, a dose-response relationship was observed for nausea, vomiting, paresthesia, disorientation, irritability, disturbance in attention, feeling drunk, sleepwalking, and enuresis. The incidence of all these reactions was notably higher at 9 g per night.

In controlled trials in narcolepsy, discontinuations of treatment due to adverse reactions were greater at higher doses of Xyrem.

Pediatric Patients (7 Years Of Age And Older)

In the pediatric clinical trial (Trial N5), 104 patients aged 7 to 17 years (37 patients aged 7 to 11 years; 67 patients aged 12 to 17 years) with narcolepsy received Xyrem up to 377 days (median exposure 332 days).

Adverse Reactions Leading To Treatment Discontinuation

In the pediatric clinical trial, 5 of 104 patients reported adverse reactions that led to withdrawal from the study (hallucination, tactile; suicidal ideation; weight decreased; sleep apnea syndrome; and affect lability).

Adverse Reactions In The Pediatric Clinical Trial

The most common adverse reactions (>5%) were enuresis (18%), nausea (17%), headache (16%), vomiting (16%), weight decreased (12%), decreased appetite (8%), and dizziness (6%).

Additional information regarding safety in pediatric patients appears in the following sections:

  • Respiratory Depression and Sleep-Disordered Breathing
  • Depression and Suicidality
  • Other Behavioral or Psychiatric Adverse Reactions
  • Parasomnias

The overall adverse reaction profile of Xyrem in the pediatric clinical trial was similar to that seen in the adult clinical trial program.

Postmarketing Experience

The following adverse reactions have been identified during postapproval use of Xyrem. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure:

What drugs interact with Xyrem (sodium oxybate)?

Alcohol, Sedative Hypnotics, And CNS Depressants

Xyrem should not be used in combination with alcohol or sedative hypnotics. Use of other CNS depressants may potentiate the CNS-depressant effects of Xyrem.

Divalproex Sodium

Concomitant use of Xyrem with divalproex sodium resulted in a 25% mean increase in systemic exposure to Xyrem (AUC ratio range of 0.8 to 1.7) and in a greater impairment on some tests of attention and working memory. An initial Xyrem dose reduction of at least 20% is recommended if divalproex sodium is prescribed to patients already taking Xyrem. Prescribers are advised to monitor patient response closely and adjust dose accordingly if concomitant use of Xyremand divalproex sodium is warranted.

Drug Abuse And Dependence

Controlled Substance

Xyrem is a Schedule III controlled substance under the Federal Controlled Substances Act. Non-medical use of Xyrem could lead to penalties assessed under the higher Schedule I controls.

Abuse

Xyrem (sodium oxybate), the sodium salt of GHB, produces dose-dependent central nervous system effects, including hypnotic and positive subjective reinforcing effects. The onset of effect is rapid, enhancing its potential for abuse or misuse.

The rapid onset of sedation, coupled with the amnestic features of Xyrem, particularly when combined with alcohol, has proven to be dangerous for the voluntary and involuntary user (e.g., assault victim).

Illicit GHB is abused in social settings primarily by young adults. Some of the doses estimated to be abused are in a similar dosage range to that used for treatment of patients with cataplexy. GHB has some commonalities with ethanol over a limited dose range, and some cross tolerance with ethanol has been reported as well. Cases of severe dependence and craving for GHB have been reported when the drug is taken around the clock. Patterns of abuse indicative of dependence include: 1) the use of increasingly large doses, 2) increased frequency of use, and 3) continued use despite adverse consequences.

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). Dispose of Xyrem according to state and federal regulations. It is safe to dispose of Xyrem down the sanitary sewer.

Dependence

There have been case reports of withdrawal, ranging from mild to severe, following discontinuation of illicit use of GHB at frequent repeated doses (18 g to 250 g per day) in excess of the recommended dosage range. Signs and symptoms of GHB withdrawal following abrupt discontinuation included:

These symptoms generally abated in 3 to 14 days. In cases of severe withdrawal, hospitalization may be required. The discontinuation effects of Xyrem have not been systematically evaluated in controlled clinical trials.

In the clinical trial experience with Xyrem in narcolepsy/cataplexy patients at recommended doses, two patients reported anxiety and one reported insomnia following abrupt discontinuation at the termination of the clinical trial; in the two patients with anxiety, the frequency of cataplexy had increased markedly at the same time.

Tolerance

Tolerance to Xyrem has not been systematically studied in controlled clinical trials. There have been some case reports of symptoms of tolerance developing after illicit use at dosages far in excess of the recommended Xyrem dosage regimen. Clinical studies of sodium oxybate in the treatment of alcohol withdrawal suggest a potential cross-tolerance with alcohol. The safety and effectiveness of Xyrem in the treatment of alcohol withdrawal have not been established.

Summary

Xyrem (sodium oxybate) oral solution is a central nervous system (CNS) depressant used to treat cataplexy and excessive daytime sleepiness in narcolepsy. Xyrem is the sodium salt of gamma hydroxybutyrate (GHB). Common side effects of Xyrem include nausea, dizziness, vomiting, bedwetting, and diarrhea. There are no adequate and well-controlled studies of Xyrem in pregnant women. Xyrem should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. It is unknown if Xyrem is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Xyrem is administered to a breastfeeding woman.

Treatment & Diagnosis

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Medically Reviewed on 5/13/2020
References
FDA Prescribing Information

Professional side effects and drug interactions sections courtesy of the U.S. Food and Drug Administration.
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