Xyrem Warnings, Precautions, Pregnancy, Nursing, Abuse - Sodium oxybate

Xyrem Warnings, Precautions, Pregnancy, Nursing, Abuse - Sodium oxybate

WARNINGS

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 oxy-bate, 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 driving a car, operating heavy machinery, or performing any other 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/day. 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. 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, 7% 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/day. In a controlled trial where patients were randomized to fixed total daily doses of 3, 6, and 9 g/day or placebo, a dose-response relationship for confusion was demonstrated with 17% of patients at 9 g/day experiencing confusion. In all cases, the confusion resolved soon after termination of treatment. In the majority of cases, confusion resolved 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, 6% of patients treated with sodium oxy-bate reported depressive symptoms. In the majority of cases, no change in sodium oxybate treatment was required. Three patients (<1%) discontinued because of depressive symptoms. In the controlled clinical trial where patients were randomized to fixed doses of 3, 6, 9 g/day or placebo, there was a single event of depression at the 3 g/day dose.

Among patients with a previous history of depressive psychiatric disorder, there were two suicides and one attempted suicide recorded in the 448 patient dataset. 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.

During clinical trials, 9% 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/day or placebo, a dose-response relationship for urinary incontinence was demonstrated with 14% of patients at 9 g/day experiencing urinary incontinence. In the same trial, one patient experienced fecal incontinence at a dose of 9 g/day 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 "sleepwalking" 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 7% of 448 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 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 ranges from 0.5 g (for a 3 g sodium oxybate dose) to 1.6 g (for a 9 g sodium oxybate dose). This 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 therefore be decreased by one-half in such patients, and response to dose 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.

INFORMATION FOR PATIENTS

The Xyrem Patient Success Program^SM includes detailed information about the safe and proper use of sodium oxy-bate, as well as information to help the patient prevent accidental use or abuse of sodium oxybate by others. Patients must confirm that they have read the materials before the first prescription will be filled. Prescribers will discuss the details of the program and the treatment (including the procedure for preparing the dose to be administered) prior to the initiation of treatment. Patients should also be informed that they must be seen by the prescriber frequently during the course of their treatment, and that a detailed account of the adverse reactions they may have experienced will be taken. Food significantly decreases the bioavailability of sodium oxybate (see Pharmacokinetics). Whether sodium oxybate is taken in the fed or fasted state may affect both the efficacy and safety of sodium oxybate for a given patient. Patients should be made aware of this and try to take the first dose several hours after a meal. Patients should be informed that sodium oxybate is associated with urinary and, less frequently, fecal incontinence. Patients should be instructed to lie down and sleep after each dose of sodium oxy-bate, and not to take sodium oxybate at any time other than at night, immediately before bedtime and again 2.5 to 4 hours later. Patients should be instructed that they should not take alcohol or other sedative hypnotics with sodium oxybate.

For additional information, patients should see the Medication Guide for Xyrem^®.

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 oxy-bate, 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.