Xyrem (Sodium oxybate) - Uses, Dose, Side effects

Xyrem (Sodium oxybate) is an inhibitory neurotransmitter that is used to treat patients with excessive daytime sleepiness especially when associated with sudden muscle weakness. It is also used in some parts of the world as an intravenous anesthetic for alcohol withdrawal syndrome.

Xyrem (Sodium oxybate) Uses:

  • Narcolepsy:

    • It is recommended for treating cataplexy or excessive daytime drowsiness in narcolepsy individuals younger than 7 years old.
  • Limitations [Ref]:

    • Concomitant sedative and hypnotic medications including opioid analgesics, benzodiazepines, sedating antidepressants, antipsychotics, sedating anti-epileptic medications, general anaesthetics, muscle relaxants, alcohol, or illicit narcotics shouldn't be taken with it.
    • Moreover, due to the possibility of respiratory depression, it should not be used on individuals with chronic lung illness.
       

Xyrem (Sodium oxybate) dose in adults:

Xyrem (Sodium oxybate) dose in the treatment of Narcolepsy (excessive daytime sleepiness/ cataplexy):

 

  • Initial: 2.25 g per mouth before the patient goes to sleep, and 2.25 g 2.5 to 4 hours later (4.5 g per night).
  • Gradually increase the dose by 1.5 g per night (0.75 g before bed and 0.75 g 2.5 to 4 hours later).
  • The usual effective dosage range: 6 to 9 g per night (maximum dose: 9 g per night).

Dosage adjustment for concomitant therapy:

  • Dose reduction to 20% with concurrent divalproex sodium is necessary.

Missed dose:

  • If the second dose is missed, therapy should be resumed by omitting the missed dose.
  • It is not advisable to take both doses simultaneously.

Xyrem (Sodium oxybate) dose in children:

Xyrem (Sodium oxybate) dose in the treatment of Narcolepsy (excessive daytime sleepiness/ cataplexy):

Note: Dose is given according patient weight and titrated according to the  efficacy and tolerance.

  • Children ≥7 years and Adolescents:

    • Weight<20 kg:

      • The manufacturer's labelling doesn't specify any particular dose.
      • Lower initial dosage, lower maximum weekly dosage increases, and lower total maximum nightly dosage should be considered.
    • Weight 20 to <30 kg:

      • Initial: Up to 1 g per oral at bedtime after the patient is in bed, and up to 1 g 2.5 to 4 hours later (up to 2 g per night).
      • Titrate dose by 1 g per night (0.5 g at bedtime and 0.5 g 2.5 to 4 hours later) in weekly intervals
      • The maximum dose is 3 g/dose or 6 g per night.
    • Weight 30 to <45 kg:

      • Initial: Up to 1.5 g per oral at bedtime after the patient is in bed, and up to 1.5 g 2.5 to 4 hours later (up to 3 g per night).
      • Titrate dose by 1 g per night (0.5 g at bedtime and 0.5 g 2.5 to 4 hours later) in weekly intervals
      • The maximum dose is 3.75 g/dose or 7.5 g per night.
    • Weight ≥45 kg:

      • Initial: Up to 2.25 g at bedtime after the patient is in bed, and up to 2.25 g 2.5 to 4 hours later (up to 4.5 g per night).
      • Titrate dose by 1.5 g per night (0.75 g at bedtime and 0.75 g 2.5 to 4 hours later) in weekly intervals
      • The maximum dose is 4.5 g/dose or 9 g per night.
    • Dosage adjustment for concomitant therapy:

      • Same as for adults.
    • Missed dose:

      • Same as for adults.

Pregnancy Risk Factor: C

  • If the intravenous solution is administered during labor and delivery, it has been shown to cross over the placenta.
  • Neonates with sleepiness had a lower Apgar score.

Use of sodium oxybate during breastfeeding

  • Breast milk contains sodium oxybate, so breastfeeding should be avoided for at least 6-8 hours after the second dose.
  • The decision to continue nursing while receiving therapy is based on the risks and advantages of breastfeeding for the newborn as well as the advantages for the mother, according to the manufacturer's instructions.

Xyrem (Sodium oxybate) Dose adjustment in renal disease:

There are no dosage adjustments provided in the manufacturer's labeling.

Xyrem (Sodium oxybate) Dose adjustment in liver disease:

Reduce initial doses by 50%.

Common Side Effects of Xyrem (Sodium oxybate):

  • Central Nervous System:

    • Confusion
    • Headache
    • Dizziness
  • Endocrine & Metabolic:

    • Weight Loss
  • Gastrointestinal:

    • Nausea
    • Vomiting
  • Genitourinary:

    • Urinary Incontinence

Uncommon Side Effects of Sodium Oxybate:

  • Cardiovascular:

    • Peripheral Edema
  • Central Nervous System:

    • Drowsiness
    • Depression
    • Somnambulism
    • Anxiety
    • Disturbance In Attention
    • Intoxicated Feeling
    • Irritability
    • Pain
    • Sleep Paralysis
    • Disorientation
    • Paresthesia
    • Severe Central Nervous System Depression
  • Dermatologic:

    • Hyperhidrosis
  • Gastrointestinal:

    • Decreased Appetite
    • Diarrhea
    • Upper Abdominal Pain
  • Neuromuscular & Skeletal:

    • Tremor
    • Limb Pain
    • Cataplexy

Rare side effects of Xyrem (Sodium Oxybate):

  • Central Nervous System:

    • Central Nervous System Depression
    • Obtundation
    • Sleep Apnea
  • Hematologic & Oncologic:

    • Oxygen Desaturation
  • Respiratory:

    • Respiratory Depression

Contraindication to Xyrem (Sodium oxybate):

These include:

  • Concurrent treatment with ethanol, sedatives and hypnotics
  • Succinic semialdehyde-dehydrogenase insufficient
  • Hypersensitivity to sodium oxygenate or any component of this formulation

Warnings and precautions

  • Depression in the central nervous system:

    • Anxiety, confusion, and psychosis are possible outcomes.
    • Individuals who have attempted suicide or have a history of depression should exercise caution.
    • Patients should wait no more than six hours after taking the second dose of this drug before engaging in activities that call for mental alertness.
    • Respiratory depression, hypotension, and excessive sedation are all risks exacerbated by concurrent CNS depressions. It's critical to change dosages or cease utilising one or more CNS depressants (including sodium oxygenate).
  • Respiratory depression [US Boxed Warning]

    • Respiratory depression can be severe with sodium oxybate. Careful monitoring is recommended.
  • Cardiovascular disease

    • Patients with hypertension or heart failure should be cautious.
  • Hepatic impairment

    • Patients with hepatic impairment will need to adjust their dose.
  • Renal impairment

    • Patients with impaired renal function should be cautious about the high sodium content of this product.
  • Sleep-related breathing disorders

    • Obesity, being postmenopausal, and being narcoleptic are additional risk factors for sleep disturbed breathing during therapy.

Sodium oxybate (gamma hydroxybutyrate): Drug Interaction

Risk Factor C (Monitor therapy)

Alizapride

May enhance the CNS depressant effect of CNS Depressants.

Brimonidine (Topical)

May enhance the CNS depressant effect of CNS Depressants.

Bromopride

May enhance the CNS depressant effect of CNS Depressants.

Cannabidiol

May enhance the CNS depressant effect of CNS Depressants.

Cannabis

May enhance the CNS depressant effect of CNS Depressants.

Chlorphenesin Carbamate

May enhance the adverse/toxic effect of CNS Depressants.

Dimethindene (Topical)

May enhance the CNS depressant effect of CNS Depressants.

Dronabinol

May enhance the CNS depressant effect of CNS Depressants.

Kava Kava

May enhance the adverse/toxic effect of CNS Depressants.

Lofexidine

May enhance the CNS depressant effect of CNS Depressants. Management: Drugs listed as exceptions to this monograph are discussed in further detail in separate drug interaction monographs.

Magnesium Sulfate

May enhance the CNS depressant effect of CNS Depressants.

MetyroSINE

CNS Depressants may enhance the sedative effect of MetyroSINE.

Minocycline

May enhance the CNS depressant effect of CNS Depressants.

Nabilone

May enhance the CNS depressant effect of CNS Depressants.

Piribedil

CNS Depressants may enhance the CNS depressant effect of Piribedil.

Pramipexole

CNS Depressants may enhance the sedative effect of Pramipexole.

ROPINIRole

CNS Depressants may enhance the sedative effect of ROPINIRole.

Rotigotine

CNS Depressants may enhance the sedative effect of Rotigotine.

Rufinamide

May enhance the adverse/toxic effect of CNS Depressants. Specifically, sleepiness and dizziness may be enhanced.

Selective Serotonin Reuptake Inhibitors

CNS Depressants may enhance the adverse/toxic effect of Selective Serotonin Reuptake Inhibitors. Specifically, the risk of psychomotor impairment may be enhanced.

Tetrahydrocannabinol

May enhance the CNS depressant effect of CNS Depressants.

Tetrahydrocannabinol and Cannabidiol

May enhance the CNS depressant effect of CNS Depressants.

Risk Factor D (Consider therapy modification)

Blonanserin

CNS Depressants may enhance the CNS depressant effect of Blonanserin.

Buprenorphine

CNS Depressants may enhance the CNS depressant effect of Buprenorphine. Management: Consider reduced doses of other CNS depressants, and avoiding such drugs in patients at high risk of buprenorphine overuse/self-injection. Initiate buprenorphine at lower doses in patients already receiving CNS depressants.

Chlormethiazole

May enhance the CNS depressant effect of CNS Depressants. Management: Monitor closely for evidence of excessive CNS depression. The chlormethiazole labeling states that an appropriately reduced dose should be used if such a combination must be used.

CNS Depressants

Sodium Oxybate may enhance the CNS depressant effect of CNS Depressants. Management: Consider alternatives to combined use. When combined use is needed, consider minimizing doses of one or more drugs. Use of sodium oxybate with alcohol or sedative hypnotics is contraindicated.

Droperidol

May enhance the CNS depressant effect of CNS Depressants. Management: Consider dose reductions of droperidol or of other CNS agents (eg, opioids, barbiturates) with concomitant use. Exceptions to this monograph are discussed in further detail in separate drug interaction monographs.

HYDROcodone

CNS Depressants may enhance the CNS depressant effect of HYDROcodone. Management: Avoid concomitant use of hydrocodone and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug.

Methotrimeprazine

CNS Depressants may enhance the CNS depressant effect of Methotrimeprazine. Methotrimeprazine may enhance the CNS depressant effect of CNS Depressants. Management: Reduce adult dose of CNS depressant agents by 50% with initiation of concomitant methotrimeprazine therapy. Further CNS depressant dosage adjustments should be initiated only after clinically effective methotrimeprazine dose is established.

OxyCODONE

CNS Depressants may enhance the CNS depressant effect of OxyCODONE. Management: Avoid concomitant use of oxycodone and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug.

Perampanel

May enhance the CNS depressant effect of CNS Depressants. Management: Patients taking perampanel with any other drug that has CNS depressant activities should avoid complex and high-risk activities, particularly those such as driving that require alertness and coordination, until they have experience using the combination.

Tapentadol

May enhance the CNS depressant effect of CNS Depressants. Management: Avoid concomitant use of tapentadol and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug.

Valproate Products

May increase the serum concentration of Sodium Oxybate. Management: Consider a sodium oxybate dose reduction of at least 20% if combined with valproic acid.

Risk Factor X (Avoid combination)

Alcohol (Ethyl)

May enhance the CNS depressant effect of Sodium Oxybate.

Azelastine (Nasal)

CNS Depressants may enhance the CNS depressant effect of Azelastine (Nasal).

Benzodiazepines

May enhance the CNS depressant effect of Sodium Oxybate.

Bromperidol

May enhance the CNS depressant effect of CNS Depressants.

Hypnotics (Nonbenzodiazepine)

May enhance the CNS depressant effect of Sodium Oxybate.

Orphenadrine

CNS Depressants may enhance the CNS depressant effect of Orphenadrine.

Oxomemazine

May enhance the CNS depressant effect of CNS Depressants.

Paraldehyde

CNS Depressants may enhance the CNS depressant effect of Paraldehyde.

Rilmenidine

May enhance the CNS depressant effect of Sodium Oxybate.

Thalidomide

CNS Depressants may enhance the CNS depressant effect of Thalidomide.

Monitoring parameters:

  • Signs and symptoms of depression and suicidal ideation
  • anxiety, confusion, thought disorders, or behavior abnormalities
  • drug abuse and addiction

How to administer Xyrem (Sodium oxybate)?

  • Doses should not be taken before bed. They should be administered orally, either in bed, on an empty stomach, and with a gap of 2 hours between each meal.
  • After receiving the dose, the patient should immediately lie down and remain in bed. 
  • It should take patients between 5 and 15 minutes to fall asleep. It is not uncommon for patients to sleep for more than 2 hours.
  • Before going to bed, take the first dose, and then 2.5 to 4 hours later, take the second dose. A programmed alarm may be necessary for a second dose.

Mechanism of action of Xyrem (Sodium oxybate):

  • Gamma aminobutyric acid (GABA) derivative sodium oxybate functions as an inhibitory chemical transmitter in the brain.
  • Specific receptors may be activated by gamma-hydroxybutyrate(GHB) or GABA (B).

AbsorptionRapid

Protein binding: 1%

Metabolism: It is formed primarily via the Krebs cycle to make water and carbon dioxide. Secondarily, it occurs via beta-oxidation which has significant first-pass effects.

Bioavailability: 88%

Half-life elimination: 30 to 60 minutes

Time to peak: 30 to 75 minutes

Excretion:

  • Primarily in lungs as carbon dioxide
  • In urine (<5% as unchanged drug)
  • In feces (negligible)

Sodium oxybate brand Names (International):

  • Xyrem
  • Alcover
  • Anetamin

Sodium Oxybate brand Names in Pakistan:

No Brands Available in Pakistan.