Sodium Oxybate

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Continuing Education Activity

Sodium oxybate is a medication used to manage and treat narcolepsy with cataplexy or excessive daytime sleepiness. It is a Central Nervous System (CNS) depressant class of drugs. This activity will highlight the mechanism of action, adverse event profile, and other key factors (e.g., off-label uses, dosing, monitoring, relevant interactions) pertinent to the interprofessional healthcare team members in the treatment of patients with narcolepsy with cataplexy or excessive daytime sleepiness and related conditions.

Objectives:

  • Identify the indications for sodium oxybate use.
  • Summarize the most common adverse events associated with sodium oxybate therapy.
  • Explain the importance of monitoring for patients on sodium oxybate therapy, including signs of excessive CNS depression.
  • Outline some healthcare team strategies to improve the outcome of patients using sodium oxybate.

Indications

Sodium oxybate is the sodium salt of gamma-hydroxybutyrate(GHB), an endogenous metabolite of the inhibitory neurotransmitter GABA. 

FDA-approved Indication

  • Sodium oxybate was approved in 2002 by the U.S Food and Drug Administration (FDA) for cataplexy or excessive daytime sleepiness (EDS) treatment in patients with narcolepsy who are seven years of age and older. 
  • Narcolepsy is a clinical syndrome of excessive daytime sleepiness, cataplexy, and sleep paralysis, hypnagogic hallucinations.
  • Cataplexy is the most severe symptom of narcolepsy, which can result in the impairment of everyday living. If a patient has narcolepsy with cataplexy, the term for this condition is narcolepsy type I (NT1). In patients with narcolepsy, sodium oxybate has been shown to increase slow-wave sleep duration, delta power and improve sleep quality.[1][2]

REMS Program

  • Sodium oxybate is limited for distribution to patients enrolled in the drug manufacturer's Risk Evaluation and Mitigation (REMS) program. The program originated to mitigate the risk of abuse and misuse.
  • To prescribe sodium oxybate, all prescribers are required to enroll and comply with all requirements of the program. A central pharmacy will only dispense sodium oxybate to patients enrolled in the REMS program who have been counseled on the risks and proper use of sodium oxybate.[3]

Mechanism of Action

  • The precise mechanism by which sodium oxybate improves symptoms in patients with narcolepsy is not well understood. There is a hypothesis that improved sleep might be due to the increased time spent in Stages N2 and N3, and the decrease shift to stages N1/Wake/REM, resulting in a deeper sleep.[4]
  • Sodium oxybate is the sodium salt of gamma-hydroxybutyrate (GHB), an endogenous compound and metabolite of the neurotransmitter GABA. It is postulated that the therapeutic effects of sodium oxybate on cataplexy and excessive daytime sleepiness are attributed to GABA-B receptor agonist activity.
  • Several studies have shown that the drug has effects that mimic that of ethanol. It does this mainly by binding to GABA and extra-synaptic GABA. Compared to a placebo group, a controlled group of alcoholic dependent subjects will show up to a 34 percent increase in abstinence. The idea supports the already established use of sodium oxybate in countries like Australia and Italy, which have used the drug for over 25 years as an agent for alcohol withdrawal syndrome (AWS) and maintain abstinence.[5]
  • Narcolepsy is a complex sleep disorder that results in a disrupted sleep-wake cycle, with the loss of hypocretin (orexin). Even though it is the most common cause of EDS, it often goes undiagnosed due to a lack of experience of clinicians or because it is confused with other psychiatric disorders. Early diagnosis and treatment are crucial as it has been shown to improve the outcome of the patient.[6]

Pharmacokinetics

  • Pharmacokinetics of GHB is nonlinear and is similar following single or repeated dosing of sodium oxybate.

Absorption

  • Following oral ingestion of sodium oxybate, GHB is absorbed rapidly across the clinical dose range, with an absolute bioavailability of about 88%. A high-fat diet delays the absorption of sodium oxybate.

Distribution

  • GHB is a hydrophilic compound with plasma protein binding less than one percent.

Metabolism

  • Studies indicate that metabolism is the major elimination pathway for GHB, producing carbon dioxide and water via the tricarboxylic acid (Krebs) cycle. An alternate pathway of biotransformation involves β-oxidation via 3,4-dihydroxybutyrate to carbon dioxide and water. No active metabolites have been identified. 

Excretion

  • The clearance of GHB is almost entirely by biotransformation to carbon dioxide, which is then eliminated by exhalation. Thus, on average, less than 5% of unchanged drug appears in human urine within 6 to 8 hours after dosing.[7]

Administration

  • Sodium oxybate comes as an oral solution (0.5 g/ml), with two equal doses administered daily. Before ingestion, each dose of sodium oxybate should be diluted with approximately ¼ cup (about 60 mL) of water in the empty pharmacy containers provided. Patients should take both doses while in bed and lie down immediately after dosing as sodium oxybate may cause them to fall asleep abruptly without first feeling drowsy.
  • Initially, patients can begin taking 4.5 g/night, the patient should take the first dose of 2.25 g before bed, and the patient should take the second dose consisting of another 2.5 g 2.25 to 4 hours after the first dose. After that, the dosage can increase based on the tolerability and efficacy response of the patient; the maximum dose is 9 g/ night. If the second dose is missed, skip the dose and resume the usual dosing schedule the next day. Do not administer two doses at the same time.
  • A placebo-controlled study showed that improvements of symptoms with sodium oxybate occur in a dose-dependent manner at 4.5 g, 6 g, and 9 g per night; patients report a decrease in cataplexy attacks as well as diminished excessive daytime sleepiness.[4][8]

Pregnancy Considerations

  • There are no adequate data on the developmental risk associated with sodium oxybate in pregnant women. 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; however, oral administration to rats throughout pregnancy and lactation resulted in increased stillbirths and decreased offspring postnatal viability and growth, at a clinically relevant dose.
  • In obstetric anesthesia using an injectable sodium oxybate, newborns had stable cardiovascular and respiratory functions but demonstrated drowsiness, causing a slight decrease in Apgar scores. In addition, there was a fall in the rate of uterine contractions 20 minutes after injection. The placental transfer is rapid, and gamma-hydroxybutyrate (GHB) has been detected in newborns at delivery after intravenous administration of GHB to mothers.
  • Based on animal data, sodium oxybate may cause fetal harm. (Class B)

Breastfeeding Considerations

  • Infants have been successfully breastfed by mothers taking sodium oxybate therapeutically for narcolepsy. With the typical two doses per night treatment regimen, nursing should usually be withheld from the first dose to 4 to 6 hours after the second dose, and breastfeeding can be continued during the day.[9][10] 
  • For lactating mothers, it is essential to note that gamma-hydroxybutyrate(GHB) is excreted in breast milk. It is crucial to monitor the health of their infants. A 2016 case report study presented a 27-year-old primigravida patient who was taking sodium oxybate for symptom control. The patient was seeking lactation advice; health experts advised her to avoid breastfeeding 4 hours after taking a dose. Using follow-up phone interviews, the mother explained that she did not experience any difficulties with breastfeeding. There were no noted adverse effects on the infant. Based on the pediatrics chart record, the infant showed appropriate milestones.[11]

Renal Impairment

  • Sodium oxybate has a high salt content. Therefore, in patients sensitive to salt intake (e.g., those with heart failure, hypertension, or renal impairment), count the daily sodium intake in each dosage of sodium oxybate. Consider using lower-sodium oxybate(92% less sodium compared to conventional sodium oxybate).[12]

Hepatic Impairment

  • Product labeling suggests that the recommended starting dosage in patients with hepatic impairment is one-half of the original dosage per night, administered orally divided into two doses.
  • Sodium oxybate is unlikely to cause clinically apparent liver injury. Likelihood score: E.[13]

Adverse Effects

  • The most frequent side effect of sodium oxybate is nausea and vomiting. Other reported symptoms include dizziness, headache, urinary incontinence, and confusion. Overall, the incidence of side effects increases at higher doses and tends to subside with treatment discontinuation.[4]
  • More serious side effects are rare, but researchers have noted severe acute psychosis, anxiety, and suicidal ideation.[14]
  • Additionally, patients taking sodium oxybate often experience weight loss. The speculation is that the weight loss is due to increased physical activity and decreased caloric intake. In the study, weight loss was most significant in patients with a higher body mass index (BMI). In conclusion, weight loss might be a possible benefit of sodium oxybate treatment in patients with a high BMI who suffer from narcolepsy.[15] 
  • Most reported serious side effects of sodium oxybate are due to illicit drug consumption. Abuse or misuse of gamma-hydroxybutyrate (GHB) with other agents that cause changes in alertness (or consciousness) has implications pointing to severe side effects such as respiratory depression, seizures, altered mental status (AMS), and death.[16]
  • Parasomnias have been reported. The clinician should inquire about episodes of sleepwalking. Sodium oxybate has also been linked to sleep-driving and sleep-related eating disorders.[17]

Contraindications

  • Sodium oxybate is contraindicated in patients being treated with sedative-hypnotic agents such as benzodiazepines.

  • Sodium oxybate is contraindicated in the patients drinking alcohol. 

  • Sodium oxybate is contraindicated in patients with succinic semialdehyde dehydrogenase(SSADH) deficiency. SSADH deficiency is a rare disorder of inborn error of metabolism variably characterized by mental retardation, hypotonia, and ataxia. In response to the enzyme deficiency, physiologic fluids from patients accumulate gamma-hydroxybutyrate (GHB).[16][18] 

  • The active ingredient of sodium oxybate is gamma-hydroxybutyrate (GHB), which is associated with severe adverse reactions and substance use disorder.
  • Boxed Warning(CNS Depression): Obtundation and clinically significant respiratory depression occurred in clinical trials at recommended doses in sodium oxybate-treated adult patients. Many of the patients who received sodium oxybate during clinical trials in narcolepsy were receiving CNS stimulants.

Monitoring

  • Diagnosis of narcolepsy is typically by polysomnography (PSG) followed by multiple sleep latency tests(MSLT).[19]
  • Monitor for Epworth Sleepiness Scale (ESS) to assess therapeutic response.[20]
  • Monitor for excessive daytime sleepiness, cataplexy episodes, sleep paralysis, and hypnagogic hallucinations.
  • While taking sodium oxybate, patients require monitoring for symptoms of excessive CNS depression, such as bradycardia or respiratory depression. Recommendations are for prescribers to start at a low dosage and adjust it according to the patient’s response. Patients should also engage in alcohol abstinence and strict adhesion to the drug regimen. The former can result in excessive CNS depression, and the latter can result in symptoms of increases CNS activation such as tachycardia and hypertension.
  • Monitor for respiratory and CNS depression.
  • Monitor for other sleep disorders, e.g., sleep apnea, periodic leg movements.
  • Monitor for the signs of excessive use, misuse.
  • Monitor for signs of anxiety or psychosis.
  • Monitor for suicidal ideations.

Toxicity

Sodium oxybate appears to be a safe drug, with the most common side effects being minor gastrointestinal upsets such as nausea and vomiting. More dangerous side effects have been attributed to illicit use, often taking a more significant dose than therapeutic.[21]

Clinical Features

  • Depressed consciousness may fluctuate rapidly between a confusional, agitated, combative state with ataxia and coma.
  • Emesis
  • Blurred vision
  • Myoclonus
  • Seizures
  • Respiratory depression-Cheyne-stokes respiration and apnea.
  • Bradycardia
  • Hypothermia
  • An increasing depth of coma has at higher doses.

Management

  • There is no antidote to sodium oxybate. Naloxone or flumazenil doesn't reverse the CNS depression induced by sodium oxybate.
  • General symptomatic and supportive care should be instituted immediately, and gastric decontamination may be considered if co-ingestants are suspected.
  • Emesis may occur in the presence of obtundation, place the patient inappropriate posture (left lateral recumbent position). 
  • Although the gag reflex may be absent in deeply comatose patients, even unconscious patients may become combative to intubation, and rapid-sequence induction is sometimes required.
  • Administer atropine to reverse the bradycardia associated with overdose.
  • Patients detoxifying from an overdose might experience withdrawal syndrome. Symptoms include insomnia, confusion, tachycardia, and hypertension. Benzodiazepine administration seems to be the first-line treatment, while baclofen or propofol is an option as a second-line treatment.[22]

Enhancing Healthcare Team Outcomes

Prescribers need to be cautious when prescribing a Schedule III controlled substance such as sodium oxybate due to the high potential for abuse. Sodium oxybate is usually prescribed for narcolepsy by a board-certified sleep medicine physician or neurologist. Pharmacists should ensure proper dosing and step-by-step instruction on taking sodium oxybate to minimize adverse events. Pharmacists should also counsel in detail regarding the potential adverse drug reactions. Specially trained nurses can monitor for the signs of improvement and should inform the prescriber of any discrepancies. Furthermore, nurses can reinforce the importance of strict adherence to the treatment regimen.

A 2009 forensic multi-drug intoxication fatality involving sodium oxybate presented a sleep apnea patient who had mistakenly received prescriptions for various CNS depressants, including sodium oxybate. Concomitant use of CNS depressant and the patient’s health history resulted in an unintentional overdose.[23] An extensive risk management program from the drug manufacturer can help to prevent the misuse of sodium oxybate. The program focuses on limiting drug distribution and educating patients on the proper use of the drug.[16]

In overdose, emergency department physicians and triage nurses should stabilize the vitals. Critical care physicians ensure proper care of intubated patients. The medical toxicologist can assist if multiple drug ingestions are suspected. If the poisoning was deliberate, referral to a psychiatrist is required. As depicted above, it is the responsibility of the entire healthcare team, such as clinicians (MDs, DOs, NPs, PAs), nurses, specialists, and pharmacists, to work in close collaboration. This kind of interprofessional team approach would maximize efficacy and minimize adverse drug reactions of sodium oxybate, translating to enhanced patient outcomes.[Level 5]


Article Details

Article Author

Alvio Dominguez

Article Author

Lucia Soca Gallego

Article Editor:

Mayur Parmar

Updated:

9/5/2021 7:28:33 PM

PubMed Link:

Sodium Oxybate

References

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