Sodium Oxybate (Xyrem)

Limitations of Use

Xyrem may only be dispensed to patients enrolled in the Xyrem Success Program

Cataplexy in Narcolepsy

Xyrem (sodium oxybate) oral solution is indicated for the treatment of cataplexy in narcolepsy.

Excessive Daytime Sleepiness in Narcolepsy

Xyrem (sodium oxybate) oral solution is indicated for the treatment of excessive daytime sleepiness (EDS) in narcolepsy.

WARNING

Xyrem (sodium oxybate) is a CNS depressant. In clinical trials at recommended doses obtundation and clinically significant respiratory depression occurred in Xyrem-treated patients. Almost all of the patients who received Xyrem during clinical trials in narcolepsy were receiving central nervous system stimulants.

Xyrem (sodium oxybate) is the sodium salt of gamma hydroxybutyrate (GHB). Abuse of GHB, either alone or in combination with other CNS depressants, is associated with CNS adverse reactions, including seizure, respiratory depression, decreases in the level of consciousness, coma, and death.

Because of the risks of CNS depression, abuse, and misuse, Xyrem is available only through a restricted distribution program called the Xyrem Success Program, using a centralized pharmacy. Prescribers and patients must enroll in the program.

For further information go to www.XYREM.com or call 1-866-XYREM88 (1-866-997-3688).

Xyrem can cause serious side effects, including:

• Breathing problems, including:
  • slower breathing
  • trouble breathing
  • short periods of not breathing while sleeping (sleep apnea).

People who already have breathing or lung problems have a higher chance of having breathing problems when they use Xyrem.

• Mental health problems, including:
  • confusion
  • seeing or hearing things that are not real (hallucinations)
  • unusual or disturbing thoughts (abnormal thinking)
  • feeling anxious or upset
  • depression
  • thoughts of killing yourself or trying to kill yourself

Call your doctor right away if you have symptoms of mental health problems.

• Sleepwalking. Sleepwalking can cause injuries. Call your doctor if you start sleepwalking. Your doctor should check you.

The most common side effects of Xyrem include:

• nausea
• dizziness
• vomiting
• bedwetting
• diarrhea

Your side effects may increase when you take higher doses of Xyrem. Xyrem can cause physical dependence and craving for the medicine when it is not taken as directed. These are not all the possible side effects of Xyrem.

For more information, ask your doctor or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

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.

The recommended starting dose is 4.5 grams (g) per night administered orally in two equal, divided doses: 2.25 g at bedtime and 2.25 g taken 2.5 to 4 hours later. Increase the dose by 1.5 g per night at weekly intervals (additional 0.75 g at bedtime and 0.75 g taken 2.5 to 4 hours later) to the effective dose range of 6 g to 9 g per night orally. Doses higher than 9 g per night have not been studied and should not ordinarily be administered.

Take the first dose of Xyrem at least 2 hours after eating because food significantly reduces the bioavailability of sodium oxybate. Prepare both doses of Xyrem prior to bedtime. Prior to ingestion, each dose of Xyrem should be diluted with approximately ¼ cup (approximately 60 mL) of water in the empty pharmacy vials provided.

Patients should take Xyrem while in bed and lie down immediately after dosing as Xyrem may cause them to fall asleep abruptly without first feeling drowsy. Patients will often fall asleep within 5 minutes of taking Xyrem, and will usually fall asleep within 15 minutes, though the time it takes any individual patient to fall asleep may vary from night to night.

Rarely, patients may take up to 2 hours to fall asleep. Therefore, patients should remain in bed following ingestion of the first dose, and should not take the second dose until 2.5 to 4 hours later. Patients may need to set an alarm to awaken for the second dose.

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.

Pregnancy category C

There are no adequate and well-controlled studies in pregnant women. Xyrem should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Oral administration of sodium oxybate to pregnant rats (150, 350, or 1,000 mg/kg/day) or rabbits (300, 600, or 1,200 mg/kg/day) throughout organogenesis produced no clear evidence of developmental toxicity.

The highest doses tested in rats and rabbits were approximately 1 and 3 times, respectively, the maximum recommended human dose (MRHD) of 9 g per night on a body surface area (mg/m2 ) basis. Oral administration of sodium oxybate (150, 350, or 1,000 mg/kg/day) to rats throughout pregnancy and lactation resulted in increased stillbirths and decreased offspring postnatal viability and body weight gain at the highest dose tested.

The no-effect dose for pre- and postnatal developmental toxicity in rats is less than the MRHD on a mg/m2 basis.

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 Xyrem is administered to a nursing woman.

How does sodium oxybate (Xyrem) work?

Xyrem is a CNS depressant. The mechanism of action of Xyrem in the treatment of narcolepsy is unknown. Sodium oxybate is the sodium salt of gamma hydroxybutyrate, an endogenous compound and metabolite of the neurotransmitter GABA.

It is hypothesized that the therapeutic effects of Xyrem on cataplexy and excessive daytime sleepiness are mediated through GABAB actions at noradrenergic and dopaminergic neurons, as well as at thalamocortical neurons.