Xyrem Side Effects

Generic Name: sodium oxybate

Please note - some side effects for Xyrem may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.

Xyrem Side Effects - for the Professional

Xyrem

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

System Organ Class	Placebo N = 34	Sodium Oxybate Dosage (g/night) at Onset
MedDRA Preferred Term		3 N = 34	6 N = 33	9 N = 35
Ear and labyrinth disorders
Tinnitus	0	2 (5.9%)	0	0
Eye disorders
Vision blurred	1 (2.9%)	2 (5.9%)	0	0
Gastrointestinal disorders
Abdominal Pain Upper	0	0	1 (3.0%)	4 (11.4%)
Diarrhea	0	0	2 (6.1%)	3 (8.6%)
Dyspepsia	2 (5.9%)	1 (2.9%)	3 (9.1%)	3 (8.6%)
Nausea	2 (5.9%)	3 (8.8%)	8 (24.2%)	14 (40.0%)
Vomiting	0	0	3 (9.1%)	8 (22.9%)
General disorders and administration site conditions
Feeling Drunk	0	0	0	3 (8.6%)
Lethargy	0	2 (5.9%)	0	0
Pain	1 (2.9%)	1 (2.9%)	1 (3.0%)	2 (5.7%)
Infections and infestations
Gastroenteritis viral	0	0	2 (6.1%)	0
Nasopharyngitis	1 (2.9%)	1 (2.9%)	2 (6.1%)	2 (5.7%)
Upper respiratory tract infection	1 (2.9%)	1 (2.9%)	2 (6.1%)	0
Injury, poisoning and procedural complications
Post procedural pain	0	0	0	2 (5.7%)
Investigations
Blood pressure increased	1 (2.9%)	0	2 (6.1%)	0
Musculoskeletal and connective tissue disorders
Back Pain	2 (5.9%)	0	2 (6.1%)	2 (5.7%)
Cataplexy	0	0	0	3 (8.6%)
Muscular weakness	0	2 (5.9%)	1 (3.0%)	0
Nervous system disorders
Disturbance in attention	0	1 (2.9%)	0	3 (8.6%)
Dizziness	2 (5.9%)	8 (23.5%)	10 (30.3%)	13 (37.1%)
Headache	8 (23.5%)	3 (8.8%)	7 (21.2%)	13 (37.1%)
Hypoaesthesia	0	2 (5.9%)	0	0
Sleep Paralysis	1 (2.9%)	1 (2.9%)	2 (6.1%)	5 (14.3%)
Somnolence	3 (8.8%)	4 (11.8%)	4 (12.1%)	5 (14.3%)
Psychiatric disorders
Confusional state	0	2 (5.9%)	1 (3.0%)	2 (5.7%)
Depression	0	2 (5.9%)	0	0
Disorientation	1 (2.9%)	1 (2.9%)	0	3 (8.6%)
Nightmare	0	1 (2.9%)	2 (6.1%)	0
Sleep disorder	0	0	2 (6.1%)	1 (2.9%)
Sleep walking	0	0	0	2 (5.7%)
Renal and urinary disorders
Enuresis	0	0	1 (3.0%)	6 (17.1%)
Respiratory, thoracic and mediastinal disorders
Pharyngolaryngeal pain	2 (5.9%)	0	3 (9.1%)	1 (2.9%)
Skin and subcutaneous tissue disorders
Hyperhidrosis	0	1 (2.9%)	1 (3.0%)	2 (5.7%)

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

System Organ Class	Placebo N = 60	Sodium Oxybate Dosage (g/night) at Onset
MedDRA Preferred Term		4.5 N = 185	6 N = 114	9 N = 46
Gastrointestinal disorders
Nausea	2 (3.3%)	14 (7.6%)	12 (10.5%)	9 (19.6%)
Vomiting	1 (1.7%)	3 (1.6%)	4 (3.5%)	4 (8.7%)
Nervous system disorders
Disturbance in attention	0	2 (1.1%)	0	3 (6.5%)
Dizziness	1 (1.7%)	17 (9.2%)	9 (7.9%)	4 (8.7%)
Somnolence	0	2 (1.1%)	0	5 (10.9%)
Renal and urinary disorders
Enuresis	1 (1.7%)	6 (3.2%)	4 (3.5%)	6 (13.0%)

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.

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Side Effects by Body System - for Healthcare Professionals

Nervous system

Nervous system side effects associated with the administration of sodium oxybate have included headache (25%), dizziness (17%), sleepwalking (7%), and insomnia (5%). These data represent cumulative occurrences in all 448 clinical trial patients. Additionally, treatment emergent nervous system side effects from one clinical trial included amnesia (6%), hypesthesia (6%), and thinking abnormal (6%). These events occurred in a small study (n=35 for each dosing arm), therefore the percentage of occurrence may not represent the true incidence of the effect. Nervous system side effects that have occurred at a rate of less than 1% have included syncope, agitation, ataxia, convulsion, stupor, tremor, akathisia, apathy, coma, hypertonia, myoclonus, neuralgia, and paralysis.

Psychiatric

Psychiatric side effects associated with the administration of sodium oxybate have included somnolence (13%), nervousness (7%), confusion (7%), depression (6%), and abnormal dreams (6%). These data represent cumulative occurrences in all 448 clinical trial patients. Additionally, treatment emergent psychiatric side effects from one clinical trial included anxiety (6%) and sleep disorder (5%). These events occurred in a small study (n=35 for each dosing arm), therefore the percentage of occurrence may not represent the true incidence of the effect. Psychiatric side effects that have occurred at a rate of less than 1% have included depersonalization, suicide, euphoria, hallucinations, paranoid reaction, vertigo, decreased libido, and hangover effect.

Two patients included in the clinical trials of sodium oxybate committed suicide by overdosing on multiple drugs. Only one of the patients had taken sodium oxybate as part of the overdose medications.

Other

Other side effects including dependence and a withdrawal syndrome have been reported.

Patients have been reported showing up in emergency rooms after discontinuing frequent GHB abuse.

Gastrointestinal

Gastrointestinal system side effects associated with the administration of sodium oxybate have included nausea (21%), flu syndrome (9%), diarrhea (8%), vomiting (8%), dyspepsia (6%), and abdominal pain (6%). These data represent cumulative occurrences in all 448 clinical trial patients. Gastrointestinal system side effects that have occurred at a rate of less than 1% have included anorexia, fecal incontinence, and constipation.

Genitourinary

Genitourinary system side effects associated with the administration of sodium oxybate have included urinary incontinence (8%). These data represent cumulative occurrences in all 448 clinical trial patients. Additionally, treatment emergent genitourinary system side effects from one clinical trial included dysmenorrhea (6%). These events occurred in a small study (n=35 for each dosing arm), therefore the percentage of occurrence may not represent the true incidence of the effect. Genitourinary system side effects that have occurred at a rate of less than 1% have included albuminuria, cystitis, hematuria, urinary frequency and urinary urgency.

Musculoskeletal

Musculoskeletal system side effects associated with the administration of sodium oxybate have included asthenia (8%). These data represent cumulative occurrences in all 448 clinical trial patients. Additionally, treatment emergent musculoskeletal system side effects from one clinical trial included myasthenia (6%). These events occurred in a small study (n=35 for each dosing arm), therefore the percentage of occurrence may not represent the true incidence of the effect. Musculoskeletal system side effects that have occurred at a rate of less than 1% have included arthritis, leg cramps, and myalgia.

Dermatologic

Dermatologic side effects associated with the administration of sodium oxybate have included increased sweating (11%) which was observed as a treatment emergent side effect from one small study (n=35 for each dosing arm), therefore the percentage of occurrence may not represent the true incidence of the effect. Dermatologic side effects that have occurred at a rate of less than 1% have included mouth ulceration, stomatitis, acne, alopecia, rash, contact dermatitis, and urticaria.

Respiratory

Respiratory side effects have included respiratory depression, breathing difficulty during sleep, and worsening of sleep apnea.

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