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A total of 717 narcoleptic patients were exposed to sodium oxybate in clinical trials. The most commonly observed adverse events associated with the use of sodium oxybate were:

Headache (22%), nausea (21%), dizziness (17%), nasopharyngitis (8%), somnolence (8%), vomiting (8%), and urinary incontinence (7%).

Two deaths occurred in these clinical trials, both from drug overdoses. Both of these deaths resulted from ingestion of multiple drugs, including sodium oxybate in one patient.

In these clinical trials, 10% of patients discontinued because of adverse events. The most frequent reasons for discontinuation ( > 1%) were nausea (2%), dizziness (2%) and vomiting (1%).

Approximately 9% of patients receiving sodium oxybate in 5 placebo-controlled clinical trials (n=443) withdrew due to an adverse event, compared to 1% receiving placebo (n=79). The reasons for discontinuation that occurred more frequently in sodium oxybate-treated patients than placebo-treated patients were: nausea (2%), dizziness (2%), vomiting (1%); as well as urinary incontinence, confusional state, dyspnea, hypesthesia, paresthesia, somnolence, tremor, vertigo, and blurred vision, all occurring in < 1% of patients.

Incidence in Controlled Clinical Trials

Most Commonly Reported Adverse Events in Controlled Clinical Trials

The most commonly reported adverse events ( ≥ 5%) in placebo controlled clinical trials associated with the use of sodium oxybate and occurring more frequently than seen in placebo-treated patients were: nausea (19%), dizziness (18%), headache (18%), vomiting (8%), somnolence (6%), urinary incontinence (6%), and nasopharyngitis (6%). These incidences are based on combined data from Trial 1, Trial 2, Trial 3, and two smaller randomized, double-blind, placebo-controlled, cross-over trials (n=655).

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 practice. The adverse reaction information from clinical trials does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating incidence rates.

The data presented below come from two placebo-controlled clinical trials, Trial 1 and Trial 3.

Tables 6 and 7 list the incidence of treatment-emergent adverse events in Trials 1 and 3, respectively, for which there was an incidence of ≥ 5% and the incidence in at least one dosage group on sodium oxybate was greater than placebo. The number of patients in each dosage group represents the total number of patients treated at each dose. Treatment was initiated at assigned doses of 3, 6, and 9 g in Trial 1.

Table 6: Incidence (%) of Treatment-Emergent Adverse Events in Trial 1

Table 7: Incidence (%) of Treatment-Emergent Adverse Events in Trial 3 where dose titration from 4.5 to 9 grams occurred in weekly intervals

Dose Response Information

Discontinuations of treatment due to adverse events were most common at the highest dose of sodium oxybate. 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 events was notably higher at 9 g/d. Dizziness was most common at 3 and 9 g/night.

Less Common Adverse Events

During clinical trials sodium oxybate was administered to 717 patients with narcolepsy, and 182 healthy volunteers. A total of 283 patients and 25 healthy volunteers received 9 g/night, the maximum recommended dose. A total of 334 patients received sodium oxybate for at least one year. To establish the rate of adverse events, data from all subjects receiving any dose of sodium oxybate were pooled. All adverse events reported by at least two people are included except for those already listed elsewhere in the labeling, terms too general to be informative, or events unlikely to be drug induced. Events are classified by body system and listed under the following definitions: frequent adverse events (those occurring in at least 1/100 people); infrequent events (those occurring in 1/100 to 1/1000 people). These events are not necessarily related to sodium oxybate treatment.

Blood and lymphatic system disorders

Frequent: none; Infrequent: leukopenia, lymphadenopathy.

Cardiac disorders

Frequent: none; Infrequent: tachycardia.

Ear and labyrinth disorders

Frequent: ear pain, vertigo; Infrequent: ear discomfort, tinnitus.

Eye disorders

Frequent: vision blurred; Infrequent: conjunctivitis, eye irritation, eye pain, eye redness, eye swelling, keratoconjunctivitis sicca, miosis.

Gastrointestinal disorders

Frequent: constipation, dyspepsia, toothache; Infrequent:abdominal distension, dysphagia, eructation, fecal incontinence, flatulence, gastroesophageal reflux disease, oral pain, retching, salivary hypersecretion, stomach discomfort.

General disorders and administration site conditions

Frequent: asthenia, chest pain, fatigue, influenza like illness, malaise, pyrexia; Infrequent:chest discomfort, discomfort, edema, feeling abnormal, feeling cold, feeling hot, feeling hot and cold, feeling jittery, gait abnormal, hangover, lethargy, sensation of foreign body, sluggishness.

Immune system disorders

Frequent: none; Infrequent: hypersensitivity, multiple allergies.

Infections and infestations

Frequent: bronchitis, gastroenteritis viral, influenza, nasopharyngitis, sinusitis, upper respiratory tract infection, urinary tract infection; Infrequent: bladder infection, bronchial infection, cellulitis, dental caries, ear infection, fungal infection, gastroenteritis, herpes simplex, herpes zoster, laryngitis, localized infection, otitis externa, pharyngitis, pneumonia, tinea pedis, tooth abscess, tooth infection, vaginal infection, vaginal mycosis.

Injury, poisoning and procedural complications

Frequent: contusion, fall, pain trauma activated; Infrequent: ankle fracture, back injury, concussion, head injury, joint sprain, limb injury, muscle strain, post procedural pain, road traffic accident, skin laceration, tooth injury.

Investigations

Frequent: weight decreased; Infrequent: alanine aminotransferase increased, blood alkaline phosphatase increased, blood calcium decreased, blood cholesterol increased, blood glucose increased, blood uric acid increased, blood urine, electrocardiogram abnormal, heart rate increased, liver function test abnormal, protein urine, respiratory rate increased, urine analysis abnormal.

Metabolism and nutrition disorders

Frequent: anorexia; Infrequent: decreased appetite, hypernatremia, hypocalcemia, increased appetite.

Musculoskeletal and connective tissue disorders

Frequent: arthralgia, back pain, myalgia, neck pain; Infrequent: arthritis, chest wall pain, joint stiffness, joint swelling, muscle tightness, muscle twitching, muscular weakness, musculoskeletal discomfort, musculoskeletal stiffness, polyarthritis, sensation of heaviness, tendonitis.

Neoplasms benign, malignant and unspecified

Frequent: none; Infrequent: cyst.

Nervous system disorders

Frequent: balance disorder, headache, hypoesthesia, memory impairment; Infrequent: coordination abnormal, depressed level of consciousness, dizziness postural, dysarthria, dysgeusia, dyskinesia, dysstasia, head discomfort, hyperaesthesia, mental impairment, migraine, myoclonus, paralysis, psychomotor hyperactivity, restless leg syndrome, sedation, sinus headache, sleep talking, sudden onset of sleep, syncope, tension headache.

Psychiatric disorders

Frequent: abnormal dreams, confusional state, depression, insomnia, nervousness, nightmare, sleep disorder; Infrequent: affect lability, crying, emotional disorder, euphoric mood, fear, hallucination-auditory, hypnagogic hallucination, initial insomnia, libido increased, middle insomnia, mood altered, panic disorder, paranoia, restlessness, sleep attacks, stress symptoms.

Renal and urinary disorders

Frequent: none; Infrequent: chromaturia, hematuria, incontinence, micturition urgency, nocturia, pollakiuria, proteinuria, urinary incontinence.

Reproductive system and breast disorders

Frequent: none; Infrequent: ovarian cyst, vaginal hemorrhage.

Respiratory, thoracic and mediastinal disorders

Frequent: cough, dyspnea, nasal congestion, pharyngolaryngeal pain, sinus congestion; Infrequent: allergic sinusitis, apnea, asthma, dry throat, hiccups, hyperventilation, nocturnal dyspnea, oropharyngeal swelling, respiratory disorder, rhinitis, rhinitis allergic, sinus disorder, snoring, throat secretion increased, upper respiratory tract congestion.

Skin and subcutaneous tissue disorders

Frequent: pruritis; Infrequent: acne, alopecia, cold sweat, dermatitis contact, night sweats, rosacea, skin irritation, urticaria.

Surgical and medical procedures

Frequent: none; Infrequent: endodontic procedure.

Vascular disorders

Frequent: hypertension; Infrequent: hypotension, peripheral coldness.

Drug Abuse And Dependence

Controlled Substance Class

Xyrem (sodium oxybate) is classified as a Schedule III controlled substance by Federal law. The active ingredient, sodium oxybate or gamma-hydroxybutyrate (GHB), is listed in the most restrictive schedule of the Controlled Substances Act (Schedule I). Thus, non-medical uses of sodium oxybate (Xyrem (sodium oxybate) or GHB) are classified under Schedule I.

Abuse, Dependence, and Tolerance

Abuse

See applicable directions for use under Handling And Disposal below. Although sodium oxybate (also known as GHB) has not been systematically studied in clinical trials for its potential for abuse, illicit use and abuse have been reported. Sodium oxybate is a psychoactive drug that produces a wide range of pharmacological effects. It is a sedative-hypnotic that produces dose and concentration dependent central nervous system effects in humans. The onset of effect is rapid, enhancing its desirability as a drug of abuse or misuse.

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 (assault victim) user.

GHB is abused in social settings primarily by young adults. GHB has some commonalties 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. Dependence is indicated by the use of increasingly large doses, increased frequency of use, and continued use despite adverse consequences. Some of the doses reported abused in the "rave" setting have been similar to the dose range studied for therapeutic treatment of cataplexy.

Hospital emergency department reports increased 100-fold from 1992 to 1999 (source: Substance Abuse Mental Health Services Administration, Drug Abuse Warning Network [DAWN]). Sixty percent of the ED reports involved individuals 25 years and younger. Numerous deaths had been reported over that period of time, typically involving GHB in combination with alcohol and other drugs, including five in the DAWN system in which GHB was the only drug that could be identified. However, the incidence of hospital emergency department reports of events involving GHB and GHB-related analogs has decreased by about 33% since 2000, and reports to the American Association of Poison Control Centers of GHB exposures has decreased from 1916 (involving 6 deaths) in 2001 to 800 (without any deaths) in 2003.

Dependence

There have been case reports of dependence after illicit use of GHB at frequent repeated doses (18 to 250 g/day), in excess of the therapeutic dose range. In these cases, the signs and symptoms of abrupt discontinuation included an abstinence syndrome consisting of insomnia, restlessness, anxiety, psychosis, lethargy, nausea, tremor, sweating, muscle cramps, and tachycardia. These symptoms generally abated in 3 to 14 days. The discontinuation effects of sodium oxybate have not been systematically evaluated in controlled clinical trials. An abstinence syndrome has not been reported in clinical investigations. Although the clinical trial experience with sodium oxybate in narcolepsy/cataplexy patients at therapeutic doses does not show clear evidence of a withdrawal syndrome, 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 sodium oxybate has not been systematically studied in controlled clinical trials. Open-label, long-term ( ≥ 6 months) clinical trials did not demonstrate development of tolerance. There have been some case reports of symptoms of tolerance developing after illicit use at dosages far in excess of the recommended Xyrem (sodium oxybate) dosage regimen. Clinical studies of sodium oxybate in the treatment of alcohol withdrawal suggest a potential cross-tolerance with alcohol. 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). Physicians should document the diagnosis and indication for Xyrem (sodium oxybate) , being alert to drug-seeking behavior and/or feigned cataplexy.

Interactions between sodium oxybate and three drugs commonly used in patients with narcolepsy (zolpidem tartrate, protriptyline HCl, and modafinil) have been evaluated in formal studies. Sodium oxybate, in combination with these drugs, produced no significant pharmacokinetic changes for either drug (see Pharmacokinetics). However, pharmacodynamic interactions cannot be ruled out. Nonetheless, sodium oxybate should not be used in combination with sedative hypnotics or other CNS depressants. Alteration of gastric pH with omeprazole produced no significant change in the oxybate kinetics.

Last reviewed on RxList: 4/2/2009
This monograph has been modified to include the generic and brand name in many instances.