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The following adverse reactions appear in other sections of the labeling:
- CNS depression [see WARNINGS AND PRECAUTIONS]
- Abuse and Misuse [see WARNINGS AND PRECAUTIONS]
- Respiratory Depression and Sleep-disordered Breathing [see WARNINGS AND PRECAUTIONS]
- Depression and Suicidality [see WARNINGS AND PRECAUTIONS]
- Other Behavioral or Psychiatric Adverse Reactions [see WARNINGS AND PRECAUTIONS]
- Parasomnias [see WARNINGS AND PRECAUTIONS]
- Use in Patients Sensitive to High Sodium Intake [see WARNINGS AND PRECAUTIONS]
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.
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 6.1 and Table 3 presents adverse reactions from three pooled, controlled trials (N1, N3, N4,) in patients with narcolepsy.
Adverse Reactions Leading to Treatment Discontinuation:
Of the 398 Xyrem-treated patients with narcolepsy, 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:
Adverse Reactions Occurring at an Incidence of 2% or greater:
Table 3 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 3 :Adverse Reactions Occurring in ≥ 2%
of 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 /MedDRA Preferred Term||Placebo
|ANY ADVERSE REACTION||62||45||55||70|
|Abdominal pain upper||2||3||1||2|
|GENERAL DISORDERS AND ADMINISTRATIVE SITE CONDITIONS|
|Feeling drunk||1||0||< 1||3|
|MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS|
|Pain in extremity||1||3||1||1|
|Muscle spasms||2||2||< 1||2|
|NERVOUS SYSTEM DISORDERS|
|Disturbance in attention||0||1||0||4|
|RENAL AND URINARY DISORDERS|
|SKIN AND SUBCUTANEOUS TISSUE DISORDERS|
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.
The following additional adverse reactions that have a likely causal relationship to Xyrem exposure have been identified during postmarketing use of Xyrem. These adverse reactions include: arthralgia, decreased appetite, fall, fluid retention, hangover, headache, hypersensitivity, hypertension, memory impairment, panic attack, vision blurred, and weight decreased. Because these reactions are reported voluntarily, it is not always possible to reliably estimate their frequency.
Read the Xyrem (sodium oxybate) Side Effects Center for a complete guide to possible side effects
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.
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 [see DOSAGE AND ADMINISTRATION and CLINICAL PHARMACOLOGY]. Prescribers are advised to monitor patient response closely and adjust dose accordingly if concomitant use of Xyrem and divalproex sodium is warranted.
Drug Abuse And Dependence
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.
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.
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 therapeutic dose range. Signs and symptoms of GHB withdrawal following abrupt discontinuation included insomnia, restlessness, anxiety, psychosis, lethargy, nausea, tremor, sweating, muscle cramps, tachycardia, headache, dizziness, rebound fatigue and sleepiness, confusion, and, particularly in the case of severe withdrawal, visual hallucinations, agitation, and delirium. 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 therapeutic 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 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.
Read the Xyrem Drug Interactions Center for a complete guide to possible interactions
Last reviewed on RxList: 4/28/2014
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