SEE BOXED WARNING

Due to the rapid onset of its CNS depressant effects, sodium oxybate should only be ingested at bedtime, and while in bed. For at least 6 hours after ingesting sodium oxybate, patients must not engage in hazardous occupations or activities requiring complete mental alertness or motor coordination, such as operating machinery, driving a motor vehicle, or flying an airplane. When patients first start taking Xyrem or any other sleep medicine, until they know whether the medicine will still have some carryover effect on them the next day, they should use extreme care while performing any task that could be dangerous or requires full mental alertness.

Sodium oxybate is a CNS depressant with the potential to impair respiratory drive, especially in patients with already-compromised respiratory function. In overdoses, life-threatening respiratory depression has been reported (see OVERDOSAGE). In clinical trials two subjects had profound CNS depression. A 39 year-old woman, a healthy volunteer received a single 4.5 g dose of sodium oxybate after fasting for 10 hours. An hour later, while asleep, she developed decreased respiration and was treated with an oxygen mask. An hour later, this event recurred. She also vomited and had fecal incontinence. In another case, a 64 year-old narcoleptic man was found unresponsive on the floor on Day 170 of treatment with sodium oxybate at a total daily dose of 4.5 g/night. He was taken to an emergency room where he was intubated. He improved and was able to return home later the same day. Two other patients discontinued sodium oxybate because of severe difficulty breathing and an increase in obstructive sleep apnea.

The respiratory depressant effects of Xyrem, at recommended doses, were assessed in 21 patients with narcolepsy, and no dose-related changes in oxygen saturation were demonstrated in the group as a whole. One of these patients had significant concomitant pulmonary illness, and 4 of the 21 had moderate-to-severe sleep apnea. One of the 4 patients with sleep apnea had significant worsening of the apnea/hypopnea index during treatment, but worsening did not increase at higher doses. Another patient discontinued treatment because of a perceived increase in clinical apnea events. In the randomized controlled Trials 3 and 4, a total of 40 narcolepsy patients were included with a baseline apnea/hypopnea index of 16 to 67 events per hour indicative of mild to severe sleep disordered breathing. None of the 40 patients had a clinically significant worsening of their respiratory function as measured by apnea/hypopnea index and pulse oximetry while receiving sodium oxybate at dosages of 4.5 to 9 g/night in divided dosages. Nevertheless, caution should be observed if Xyrem is prescribed to patients with compromised respiratory function. Prescribers should be aware that sleep apnea has been reported with a high incidence (even 50%) in some cohorts of narcoleptic patients.

During clinical trials, 2.6% of patients treated with sodium oxybate experienced confusion. Fewer than 1% of patients discontinued the drug because of confusion. Confusion was reported at all recommended doses from 6 to 9 g/night. In a controlled trial where patients were randomized to fixed total daily doses of 3, 6, and 9 g/night or placebo, a dose-response relationship for confusion was demonstrated with 17% of patients at 9 g/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/night dose, there was a single event of confusion in one patient at the 9 g/night dose. In the majority of cases in all clinical trials, confusion resolved either soon after termination of dosing or with continued treatment. However, patients treated with Xyrem who become confused should be evaluated fully, and appropriate intervention considered on an individual basis.

Other neuropsychiatric events included psychosis, paranoia, hallucinations, and agitation. The emergence of thought disorders and/or behavior abnormalities when patients are treated with sodium oxybate requires careful and immediate evaluation.

In clinical trials, 3.2% of patients treated with sodium oxybate reported depressive symptoms. In the majority of cases, no change in sodium oxybate treatment was required. Four patients (<1%) discontinued because of depressive symptoms. In the controlled clinical trial where patients were randomized to fixed doses of 3, 6, 9 g/night or placebo, there was a single event of depression at the 3 g/night dose. In Trial 3, where patients were titrated from an initial 4.5 g/night starting dose, the incidence of depression was 1 (1.7%), 1 (1.5%), 2 (3.2%), and 2 (3.6%) for the placebo, 4.5g, 6 g, and 9 g/night doses respectively.

In the 717 patient dataset, there were two suicides and one attempted suicide recorded in patients with a previous history of depressive psychiatric disorder. Of the two suicides, one patient used sodium oxybate in conjunction with other drugs. Sodium oxybate was not involved in the second suicide. Sodium oxybate was the only drug involved in the attempted suicide. A fourth patient without a previous history of depression attempted suicide by taking an overdose of a drug other than sodium oxybate.

The emergence of depression when patients are treated with Xyrem requires careful and immediate evaluation. Patients with a previous history of a depressive illness and/or suicide attempt should be monitored especially carefully for the emergence of depressive symptoms while taking Xyrem.

There is very limited experience with sodium oxybate in the elderly. Therefore, elderly patients should be monitored closely for impaired motor and/or cognitive function when taking sodium oxybate.

Incontinence

During clinical trials, 7% of narcoleptic patients treated with sodium oxybate experienced either a single episode or sporadic nocturnal urinary incontinence and <1% experienced a single episode of nocturnal fecal incontinence. Less than 1% of patients discontinued as a result of incontinence. Incontinence has been reported at all doses tested.

In a controlled trial where patients were randomized to fixed total daily doses of 3, 6, and 9 g/night or placebo, a dose-response relationship for urinary incontinence was demonstrated with 14% of patients initiated at 9 g/night experiencing urinary incontinence. In the same trial, one patient experienced fecal incontinence when initiated at a dose of 9 g/night and discontinued treatment as a result.

If a patient experiences urinary or fecal incontinence during Xyrem therapy, the prescriber should consider pursuing investigations to rule out underlying etiologies, including worsening sleep apnea or nocturnal seizures, although there is no evidence to suggest that incontinence has been associated with seizures in patients being treated with Xyrem.

The term ²sleepwalking² in this section refers to confused behavior occurring at night and, at times, associated with wandering. It is unclear if some or all of these episodes correspond to true somnambulism, which is a parasomnia occurring during non-REM sleep, or to any other specific medical disorder. Sleepwalking was reported in 4% of 717 patients treated in clinical trials with sodium oxybate. In sodium oxybate-treated patients <1% discontinued due to sleepwalking. In controlled trials of up to 4 weeks duration, the incidence of sleepwalking was 1% in both placebo and sodium oxybate-treated patients. Sleepwalking was reported by 32% of patients treated with sodium oxybate for periods up to 16 years in one independent uncontrolled trial. Fewer than 1% of the patients in that trial discontinued due to sleepwalking. Five instances of significant injury or potential injury were associated with sleepwalking during a clinical trial of sodium oxybate including a fall, clothing set on fire while attempting to smoke, attempted ingestion of nail polish remover, and overdose of oxybate. Therefore, episodes of sleepwalking should be fully evaluated and appropriate interventions considered.

Daily sodium intake in patients taking sodium oxybate is provided below and should be considered in patients with heart failure, hypertension or compromised renal function.

Patients with compromised liver function will have an increased elimination half-life and systemic exposure to sodium oxybate (see Pharmacokinetics). The starting dose should thereforebe decreased by one-half in such patients, and response todose increments monitored closely(see DOSAGE AND ADMINISTRATION).

No studies have been conducted in patients with renal failure. Because less than 5% of sodium oxybate is excreted via the kidney, no dose adjustment should be necessary in patients with renal impairment. The sodium load associated with administration of sodium oxybate should be considered in patients with renal insufficiency.

Laboratory tests are not required to monitor patient response or adverse events resulting from sodium oxybate administration.

In an open-label trial of long term exposure to sodium oxybate, which extended as long as 16 years for some patients, 30% (26/87) of patients tested had at least one positive anti-nuclear antibody (ANA) test. Of the 26, 17 patients had multiple positive ANA tests over time. The clinical course of these patients was not always clearly recorded, but one patient was clearly diagnosed with rheumatoid arthritis at the time of the first recorded positive ANA test. No instances of systemic lupus erythematosus have been reported in patients taking sodium oxybate.

Carcinogenicity, Mutagenicity, Impairment of Fertility

Sodium oxybate was not carcinogenic in rats administered oral doses of up to 1000 mg/kg/day (2 times the exposure in humans receiving the maximum recommended dose (MRHD) of 9 g/day, on an AUC basis) for 83 weeks in the male rats and for 104 weeks in female rats. The results of 2-year carcinogenicity studies in mouse and rat with gamma-butyrolactone, a compound that is metabolized to sodium oxybate in vivo, showed no clear evidence of carcinogenic activity. The plasma AUCs of sodium oxybate achieved at the high doses in these studies were ½ (mice and female rats) and 1/10 (male rats) the plasma AUCs at the MRHD.

Sodium oxybate was negative in the Ames microbial mutagen test, an in vitro chromosomal aberration assay in CHO cells, and an in vivo rat micronucleus assay.

Sodium oxybate did not impair fertility in rats at doses up to 1000 mg/kg (approximately equal to the maximum recommended human daily dose on a mg/m² basis).

Pregnancy

Pregnancy Category B: Reproduction studies conducted in pregnant rats at doses up to 1000 mg/kg (approximately equal to the maximum recommended human daily dose on a mg/m² basis) and in pregnant rabbits at doses up to 1200 mg/kg (approximately 3 times the maximum recommended human daily dose on a mg/m² basis) revealed no evidence of teratogenicity. In a study in which rats were given sodium oxybate from Day 6 of gestation through Day 21 postpartum, slight decreases in pup and maternal weight gains were seen at 1000 mg/kg; there were no drug effects on other developmental parameters. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Labor and Delivery

Sodium oxybate has not been studied in labor or delivery. In obstetric anesthesia using an injectable formulation of sodium oxybate newborns had stable cardiovascular and respiratory measures but were very sleepy, causing a slight decrease in Apgar scores. There was a fall in the rate of uterine contractions 20 minutes after injection. Placental transfer is rapid, but umbilical vein levels of sodium oxybate were no more than 25% of the maternal concentration. No sodium oxybate was detected in the infants blood 30 minutes after delivery. Elimination curves of sodium oxybate between a 2-day old infant and a 15-year old patient were similar. Subsequent effects of sodium oxybate on later growth, development and maturation in humans are unknown.

Nursing Mothers

It is not known whether sodium oxybate is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when sodium oxybate is administered to a nursing woman.

Pediatric Use

Safety and effectiveness in patients under 16 years of age have not been established.

Race and Gender Effects

There were too few non-Caucasian patients to permit evaluation of racial effects on safety or efficacy. More than 90% of the subjects in clinical trials were Caucasian.

The database was 58% female. No important differences in safety or efficacy of Xyrem were noted between men and women. The overall percentage of patients with at least one adverse event was slightly higher in women (80%) than in men (69%). The incidence of serious adverse events and discontinuations due to adverse events were similar in both men and women.

Bookmark this page: