XYREM® (sodium oxybate) oral solution

XYREM® (sodium oxybate) oral solution, CIII

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XYREM® (sodium oxybate) oral solution

Sodium oxybate, a CNS depressant, is the active ingredient in Xyrem. The chemical name for sodium oxybate is sodium 4-hydroxybutyrate. The molecular formula is C4H7NaO3, and the molecular weight is 126.09 g/mole.

Sodium oxybate is a white to off-white, crystalline powder that is very soluble in aqueous solutions. Each mL of Xyrem contains 0.5 g of sodium oxybate (equivalent to 0.413 g/mL of oxybate) in USP Purified Water, neutralized to pH 7.5 with malic acid.

Indications and usage

Xyrem is a central nervous system depressant indicated for the treatment of cataplexy or excessive daytime sleepiness (EDS) in patients 7 years of age and older with narcolepsy.

Mechanism of Action

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 (GHB), 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.

Dosage and administration

Adult Dosing Information

The recommended starting dosage is 4.5 grams (g) per night administered orally divided into two, doses: 2.25 g at bedtime and 2.25 g taken 2.5 to 4 hours later. Increase the dosage 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 dosage range of 6 g to 9 g per night orally. The dosage may be gradually titrated based on efficacy and tolerability. Doses higher than 9 g per night have not been studied and should not ordinarily be administered.

Dosage for Pediatric Patients (7 years of Age and Older)

The recommended starting dosage, titration regimen, and maximum total nightly dosage are based on body weight

Contraindications

  • In combination with sedative hypnotics or alcohol
  • Succinic semialdehyde dehydrogenase deficiency

Warnings and precautions

  • CNS depression: Use caution when considering the concurrent use of Xyrem with other CNS depressants
  • Caution patients against hazardous activities requiring complete mental alertness or motor coordination within the first 6 hours of dosing or after first initiating treatment until certain that Xyrem does not affect them adversely
  • Depression and suicidality: Monitor patients for emergent or increased depression and suicidality
  • Confusion/Anxiety: Monitor for impaired motor/cognitive function
  • Parasomnias: Evaluate episodes of sleepwalking
  • High sodium content in Xyrem: Monitor patients with heart failure, hypertension, or impaired renal function

Adverse reactions

Most common adverse reactions in adults (≥5% and at least twice the incidence with placebo) were nausea, dizziness, vomiting, somnolence, enuresis, and tremor.

Most common adverse reactions in pediatric patients (≥5%) were enuresis, nausea, headache, vomiting, weight decreased, decreased appetite, and dizziness.

Drug interactions

Alcohol, Sedative Hypnotics, and CNS Depressants: Xyrem is contraindicated for use in combination with alcohol or sedative hypnotics. Use of other CNS depressants may potentiate the CNS-depressant effects of Xyrem

Divalproex Sodium: Concomitant use of Xyrem with divalproex sodium results in an increase in systemic exposure to GHB, which was shown to cause a greater impairment on some tests of attention and working memory in a clinical study. An initial dose reduction of Xyrem is recommended when used concomitantly with divalproex sodium. Prescribers are advised to monitor patient response closely and adjust dose accordingly if concomitant use of Xyrem and divalproex sodium is warranted.

Use in specific populations

Pregnancy: There are no adequate data on the developmental risk associated with the use of sodium oxybate in pregnant women.

Lactation: GHB is excreted in human milk after oral administration of sodium oxybate. There is insufficient information on the risk to a breastfed infant, and there is insufficient information on milk production in nursing mothers. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Xyrem and any potential adverse effects on the breastfed infant from Xyrem or from the underlying maternal condition.

Pediatric Use: The safety and effectiveness of Xyrem in the treatment of cataplexy or excessive daytime sleepiness in pediatric patients (7 years of age and older) with narcolepsy have been established in a double-blind, placebo-controlled, randomized-withdrawal study

Drug abuse and dependence

Controlled Substance: Xyrem is a Schedule III controlled substance under the Federal Controlled Substances Act. Non-medical use of Xyrem could lead to penalties assessed under the higher Schedule I controls.

Abuse: 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.

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Drug abuse is the intentional non-therapeutic use of a drug product or substance, even once, for its desirable psychological or physiological effects. Misuse is the intentional use, for therapeutic purposes of a drug by an individual in a way other than prescribed by a health care provider or for whom it was not prescribed. Drug misuse and abuse may occur with or without progression to addiction.

Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that may include a strong desire to take the drug, difficulties in controlling drug use (e.g., continuing drug use despite harmful consequences, giving a higher priority to drug use than other activities and obligations), and possible tolerance or physical dependence.

Dependence: Physical dependence is a state that develops as a result of physiological adaptation in response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or a significant dose reduction of a drug. 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 recommended dosage 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.

Tolerance: Tolerance is a physiological state characterized by a reduced response to a drug after repeated administration (i.e., a higher dose of a drug is required to produce the same effect that was once obtained at a lower dose). Tolerance to Xyrem has not been systematically studied in controlled clinical trials. There have been some case reports of symptoms of tolerance developing after illicit use at dosages far in excess of the recommended Xyrem dosage regimen.

Overdosage

Information regarding overdose with Xyrem is derived largely from reports in the medical literature that describe symptoms and signs in individuals who have ingested GHB illicitly. In these circumstances the co-ingestion of other drugs and alcohol was common, and may have influenced the presentation and severity of clinical manifestations of overdose.

Information about signs and symptoms associated with overdosage with Xyrem derives from reports of illicit use of GHB. Patient presentation following overdose is influenced by the dose ingested, the time since ingestion, the co-ingestion of other drugs and alcohol, and the fed or fasted state. Patients have exhibited varying degrees of depressed consciousness that may fluctuate rapidly between a confusional, agitated combative state with ataxia and coma.

Emesis (even when obtunded), diaphoresis, headache, and impaired psychomotor skills have been observed. No typical pupillary changes have been described to assist in diagnosis; pupillary reactivity to light is maintained. Blurred vision has been reported.

An increasing depth of coma has been observed at higher doses. Myoclonus and tonic-clonic seizures have been reported. Respiration may be unaffected or compromised in rate and depth. Cheyne-Stokes respiration and apnea have been observed. Bradycardia and hypothermia may accompany unconsciousness, as well as muscular hypotonia, but tendon reflexes remain intact.

Recommended Treatment of Overdose

General symptomatic and supportive care should be instituted immediately, and gastric decontamination may be considered if co-ingestants are suspected. Because emesis may occur in the presence of obtundation, appropriate posture (left lateral recumbent position) and protection of the airway by intubation may be warranted. Although the gag reflex may be absent in deeply comatose patients, even unconscious patients may become combative to intubation, and rapidsequence induction (without the use of sedative) should be considered. Vital signs and consciousness should be closely monitored.

The bradycardia reported with GHB overdose has been responsive to atropine intravenous administration. No reversal of the central depressant effects of Xyrem can be expected from naloxone or flumazenil administration. The use of hemodialysis and other forms of extracorporeal drug removal have not been studied in GHB overdose. However, due to the rapid metabolism of sodium oxybate, these measures are not warranted.

Storage

Keep out of reach of children. Xyrem should be stored at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) (see USP Controlled Room Temperature).

Dispense in tight containers. Solutions prepared following dilution should be consumed within 24 hours.

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