SODIUM OXYBATE oral solution

SODIUM OXYBATE oral solution

SODIUM OXYBATE oral solution

Sodium oxybate, a CNS depressant, is the active ingredient in Sodium Oxybate Oral Solution. 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 Sodium Oxybate Oral Solution contains 0.5 g of sodium oxybate in purified water, USP.

Mechanism of Action

Sodium oxybate is a CNS depressant. The mechanism of action of sodium oxybate 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 sodium oxybate on cataplexy and excessive daytime sleepiness are mediated through GABAB actions at noradrenergic and dopaminergic neurons, as well as at thalamocortical neurons.

INDICATIONS AND USAGE

Limitations of Use: Sodium Oxybate Oral Solution may only be dispensed to patients enrolled in the Sodium Oxybate REMS Program.

Cataplexy in Narcolepsy: Sodium Oxybate Oral Solution is indicated for the treatment of cataplexy in narcolepsy.

Excessive Daytime Sleepiness in Narcolepsy: Sodium Oxybate Oral Solution is indicated for the treatment of excessive daytime sleepiness (EDS) in narcolepsy.

DOSAGE AND ADMINISTRATION

Healthcare professionals who prescribe sodium oxybate must enroll in the Sodium Oxybate REMS Program and must comply with the requirements to ensure safe use of sodium oxybate.

Dosing Information: 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 (see Table 1). 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.

Table 1: Sodium Oxybate Dose Regimen (g = grams)

If A Patient’s Total Nightly Dose is:Take at Bedtime:Take 2.5 to 4 Hours Later:
4.5 g per night2.25 g2.25 g
6 g per night3 g3 g
7.5 g per night3.75 g3.75 g
9 g per night4.5 g4.5 g

Important Administration Instructions

Take the first dose of sodium oxybate at least 2 hours after eating because food significantly reduces the bioavailability of sodium oxybate.

Prepare both doses of sodium oxybate prior to bedtime. Prior to ingestion, each dose of sodium oxybate should be diluted with approximately ¼ cup (approximately 60 mL) of water in the empty dosing cups provided with your prescription. Patients should take both doses of sodium oxybate while in bed and lie down immediately after dosing as sodium oxybate may cause them to fall asleep abruptly without first feeling drowsy. Patients will often fall asleep within 5 minutes of taking sodium oxybate, 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. Patients should remain in bed following ingestion of the first and second doses, and should not take the second dose until 2.5 to 4 hours after the first dose. Patients may need to set an alarm to awaken for the second dose. Rarely, patients may take up to 2 hours to fall asleep.

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Dose Modification in Patients with Hepatic Impairment

The recommended starting dose in patients with hepatic impairment is 2.25 g per night administered orally in two equal, divided doses: approximately 1.13 g at bedtime and approximately 1.13 g taken 2.5 to 4 hours later

Dose Adjustment with Co-Administration of Divalproex Sodium

Pharmacokinetic and pharmacodynamic interactions have been observed when sodium oxybate is co-administered with divalproex sodium. For patients already stabilized on sodium oxybate, it is recommended that addition of divalproex sodium should be accompanied by an initial reduction in the nightly dose of sodium oxybate by at least 20%. For patients already taking divalproex sodium, it is recommended that prescribers use a lower starting sodium oxybate dose when introducing sodium oxybate oral solution. Prescribers should monitor patient response and adjust dose accordingly.

CONTRAINDICATIONS

Sodium Oxybate Oral Solution is contraindicated in patients being treated with sedative hypnotic agents.

Patients should not drink alcohol when using Sodium Oxybate Oral Solution.

Sodium Oxybate Oral Solution is contraindicated in patients with succinic semialdehyde dehydrogenase deficiency. This is a rare disorder of inborn error of metabolism variably characterized by mental retardation, hypotonia, and ataxia.

WARNINGS AND PRECAUTIONS

Central Nervous System Depression: Sodium oxybate is a central nervous system (CNS) depressant. Alcohol and sedative hypnotics are contraindicated in patients who are using sodium oxybate. The concurrent use of sodium oxybate with other CNS depressants, including but not limited to opioid analgesics, benzodiazepines, sedating antidepressants or antipsychotics, sedating anti-epileptic drugs, general anesthetics, muscle relaxants, and/or illicit CNS depressants, may increase the risk of respiratory depression, hypotension, profound sedation, syncope, and death. If use of these CNS depressants in combination with sodium oxybate is required, dose reduction or discontinuation of one or more CNS depressants (including sodium oxybate) should be considered. In addition, if short-term use of an opioid (e.g. post- or perioperative) is required, interruption of treatment with sodium oxybate should be considered.

Abuse and Misuse: Sodium Oxybate Oral Solution is a Schedule III controlled substance. The active ingredient of Sodium Oxybate Oral Solution, sodium oxybate or gamma-hydroxybutyrate (GHB), is a Schedule I controlled substance. Abuse of illicit 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. The rapid onset of sedation, coupled with the amnestic features of sodium oxybate, particularly when combined with alcohol, has proven to be dangerous for the voluntary and involuntary user (e.g., assault victim). 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).

Respiratory Depression and Sleep-Disordered Breathing: Sodium oxybate may impair respiratory drive, especially in patients with compromised respiratory function. In overdoses, life-threatening respiratory depression has been reported.

Prescribers should be aware that sleep-related breathing disorders tend to be more prevalent in obese patients and in postmenopausal women not on hormone replacement therapy as well as among patients with narcolepsy.

Parasomnias: Sleepwalking, defined as confused behavior occurring at night and at times associated with wandering, was reported in 6% of 781 patients with narcolepsy treated with sodium oxybate in controlled and long-term open-label studies, with <1% of patients discontinuing due to sleepwalking.

Use in Patients Sensitive to High Sodium Intake

Sodium oxybate has a high salt content. In patients sensitive to salt intake (e.g., those with heart failure, hypertension, or renal impairment) consider the amount of daily sodium intake in each dose of sodium oxybate. Table 2 provides the approximate sodium content per sodium oxybate oral solution dose.

Table 2: Approximate Sodium Content per Total Nightly Dose of Sodium Oxybate (g = grams)

Sodium Oxybate DoseSodium Content/Total Nightly Exposure
3 g per night550 mg
4.5 g per night820 mg
6 g per night1100 mg
7.5 g per night1400 mg
9 g per night1640 mg

The following additional adverse reactions that have a likely causal relationship to sodium oxybate exposure have been identified during postmarketing use of sodium oxybate. These adverse reactions include: arthralgia, decreased appetite, fall, fluid retention, hangover, headache, hypersensitivity, hypertension, memory impairment, panic attack, vision blurred, and weight decreased. Because these reactions are reported voluntarily, it is not always possible to reliably estimate their frequency.

DRUG INTERACTIONS

Alcohol, Sedative Hypnotics, and CNS Depressants: Sodium oxybate should not be used in combination with alcohol or sedative hypnotics. Use of other CNS depressants may potentiate the CNS-depressant effects of sodium oxybate.

Divalproex Sodium : Concomitant use of sodium oxybate with divalproex sodium resulted in a 25% mean increase in systemic exposure to sodium oxybate (AUC ratio range of 0.8 to 1.7) and in a greater impairment on some tests of attention and working memory. An initial sodium oxybate dose reduction of at least 20% is recommended if divalproex sodium is prescribed to patients already taking sodium oxybate. Prescribers are advised to monitor patient response closely and adjust dose accordingly if concomitant use of sodium oxybate and divalproex sodium is warranted.

USE IN SPECIFIC POPULATIONS

Pregnancy Category C: There are no adequate and well-controlled studies in pregnant women. Sodium oxybate should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

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 infant’s blood 30 minutes after delivery. Elimination curves of sodium oxybate between a 2day-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 pediatric patients have not been established.

Hepatic Impairment: The starting dose of sodium oxybate should be reduced by one-half in patients with liver impairment.

DRUG ABUSE AND DEPENDENCE

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

Abuse: 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 sodium oxybate, particularly when combined with alcohol, has proven to be dangerous for the voluntary and involuntary user (e.g., assault victim).

Dependence: 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 sodium oxybate have not been systematically evaluated in controlled clinical trials. In the clinical trial experience with sodium oxybate 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.

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Tolerance: Tolerance to sodium oxybate 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 sodium oxybate dosage regimen. Clinical studies of sodium oxybate in the treatment of alcohol withdrawal suggest a potential cross-tolerance with alcohol. The safety and effectiveness of sodium oxybate in the treatment of alcohol withdrawal have not been established.

OVERDOSAGE

Information about signs and symptoms associated with overdosage with sodium oxybate derives from reports of its illicit use. 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 rapid-sequence 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 sodium oxybate 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.

Poison Control Center

As with the management of all cases of drug overdosage, the possibility of multiple drug ingestion should be considered. The healthcare provider is encouraged to collect urine and blood samples for routine toxicologic screening, and to consult with a regional poison control center (1–800–222–1222) for current treatment recommendations.

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