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Drug Details

Xyrem 500 mg/ml oral solution

• Drug Class Description
  Other nervous system medicinal products - ATC code: N07XX04
• Generic Name
  Sodium Oxybate
• Presentation
  Oral solution. The oral solution is clear to slightly opalescent.
• Description
  Each ml of solution contains 500 mg of sodium oxybate.
• Indications
  

  Treatment of narcolepsy with cataplexy in adult patients.

• Adult Dosage
  

  Treatment should be initiated by and remain under the guidance of a physician experienced in the treatment of sleep disorders.

  Due to the well known potential of abuse of sodium oxybate, physicians should evaluate patients for a history of or susceptibility to drug abuse prior to commencing treatment. During treatment, patients should be monitored for the risk of diversion, misuse and abuse of sodium oxybate.

  Posology The recommended starting dose is 4.5 g/day sodium oxybate divided into two equal doses of 2.25 g/dose. The dose should be titrated to effect based on efficacy and tolerability up to a maximum of 9 g/day divided into two equal doses of 4.5 g/dose by adjusting up or down in dose increments of 1.5 g/day (i.e. 0.75 g/dose). A minimum of one to two weeks is recommended between dose increments. The dose of 9 g/day should not be exceeded due to the possible occurrence of severe symptoms at doses of 18 g/day or above.

  Single doses of 4.5 g should not be given unless the patient has been titrated previously to that dose level.

  Discontinuation of Xyrem

  The discontinuation effects of sodium oxybate have not been systematically evaluated in controlled clinical trials.

  If the patient stops taking the medicinal product for more than 14 consecutive days, titration should be restarted from the lowest dose.

  Special populations

  Patients with hepatic impairment

  The starting dose should be halved in all patients with hepatic impairment, and response to dose increments monitored closely.

  Patients with renal impairment

  All patients with impaired renal function should consider a dietary recommendation to reduce sodium intake.

  Method of administration

  Xyrem should be taken orally upon getting into bed and again between 2.5 to 4 hours later. It is recommended that both doses of Xyrem should be made up at the same time upon retiring to bed.

  Xyrem is provided for use with a graduated measuring syringe and two 90 ml dosing cups with child resistant caps. Each measured dose of Xyrem must be dispensed into the dosing cup and diluted with 60 ml of water prior to ingestion. Because food significantly reduces the bioavailability of sodium oxybate, patients should eat at least several (2-3) hours before taking the first dose of Xyrem at bedtime. Patients should always observe the same timing of dosing in relation to meals.

• Child Dosage
  

  The safety and efficacy of sodium oxybate in children and adolescents aged 0-18 years has not been established. No data is available. Therefore the use of sodium oxybate in children and adolescents in not recommended.

• Elderly Dosage
  

  Elderly patients should be monitored closely for impaired motor and/or cognitive function when taking sodium oxybate.

   

• Contra Indications
  

  Hypersensitivity to the active substance or to any of the excipients.

  Patients with major depression

  Patients with succinic semialdehyde dehydrogenase deficiency.

  Patients being treated with opioids or barbiturates.

• Special Precautions
  

  Xyrem has the potential to induce respiratory depression

  Respiratory depression

  Sodium oxybate also has the potential to induce respiratory depression. Apnoea and respiratory depression have been observed in a fasting healthy subject after a single intake of 4.5 g (twice the recommended starting dose). Patients should be questioned regarding signs of Central Nervous System (CNS) or respiratory depression. Special caution should be observed in patients with an underlying respiratory disorder. Because of the higher risk of sleep apnoea, patients with a BMI 40 kg/m2 should be monitored closely when taking sodium oxybate.

  Approximately 80% of patients who received sodium oxybate during clinical trials maintained CNS stimulant use. Whether this affected respiration during the night is unknown. Before increasing the sodium oxybate dose, prescribers should be aware that sleep apnoea occurs in up to 50% of patients with narcolepsy.

  Abuse potential and dependence

  Sodium oxybate, which is as the sodium salt of GHB, is a CNS depressant active substance with well known abuse potential. Prior to treatment physicians should evaluate patients for a history of or susceptibility to drug abuse. Patients should be routinely monitored and in the case of suspected abuse, treatment with sodium oxybate should be discontinued.

  There have been case reports of dependence after illicit use of GHB at frequent repeated doses (18 to 250 g/day) in excess of the therapeutic dose range. Whilst there is no clear evidence of emergence of dependence in patients taking sodium oxybate at therapeutic doses, this possibility cannot be excluded.

  CNS depression

  The combined use of alcohol or any CNS depressant medicinal product with sodium oxybate may result in potentiation of the CNS-depressant effects of sodium oxybate. Therefore, patients should be warned against the use of alcohol in conjunction with sodium oxybate.

  Patients with porphyria

  Sodium oxybate is considered to be unsafe in patients with porphyria because it has been shown to be porphyrogenic in animals or in vitro systems.

  Benzodiazepines

  Given the possibility of increasing the risk of respiratory depression, the concomitant use of benzodiazepines and sodium oxybate should be avoided

  Neuropsychiatric events

  Patients may become confused while being treated with sodium oxybate. If this occurs, they should be evaluated fully, and appropriate intervention considered on an individual basis. Other neuropsychiatric events include anxiety, psychosis, paranoia, hallucinations, and agitation. The emergence of thought disorders and/or behavioural abnormalities when patients are treated with sodium oxybate requires careful and immediate evaluation.

  The emergence of depression when patients are treated with sodium oxybate requires careful and immediate evaluation. Patients with a previous history of a depressive illness and/or suicide attempt should be monitored especially carefully for the emergence of depressive symptoms while taking sodium oxybate. Major depression is contraindicated for use with Xyrem.

  If a patient experiences urinary or faecal incontinence during sodium oxybate therapy, the prescriber should consider pursuing investigations to rule out underlying aetiologies.

  Sleepwalking has been reported in patients treated in clinical trials with sodium oxybate. It is unclear if some or all of these episodes correspond to true somnambulism (a parasomnia occurring during non-REM sleep) or to any other specific medical disorder. The risk of injury or self-harm should be borne in mind in any patient with sleepwalking. Therefore, episodes of sleepwalking should be fully evaluated and appropriate interventions considered.

  Sodium intake

  Patients taking sodium oxybate will have an additional daily intake of sodium that ranges from 0.82 g (for a 4.5 g/day Xyrem dose) to 1.6 g (for a 9 g/day Xyrem dose). A dietary recommendation to reduce sodium intake should be carefully considered in the management of patients with heart failure, hypertension or compromised renal function.

  Patients with compromised liver function

  Patients with compromised liver function will have an increased elimination half-life and systemic exposure to sodium oxybate. The starting dose should therefore be halved in such patients, and response to dose increments monitored closely.

  Elderly

  There is very limited experience with sodium oxybate in the elderly. Therefore, elderly patients should be monitored closely for impaired motor and/or cognitive function when taking sodium oxybate.

  Childhood and adolescence

  Safety and effectiveness in children and adolescents has not been established, therefore use in patients under 18 years of age is not recommended.

  Epileptic patients

  Seizures have been observed in patients treated with sodium oxybate. In patients with epilepsy, the safety and efficacy of sodium oxybate has not been established, therefore use is not recommended.

  Rebound effects and withdrawal syndrome

  The discontinuation effects of sodium oxybate have not been systematically evaluated in controlled clinical trials. In some patients, cataplexy may return at a higher frequency on cessation of sodium oxybate therapy, however this may be due to the normal variability of the disease. Although the clinical trial experience with sodium oxybate in narcolepsy/cataplexy patients at therapeutic doses does not show clear evidence of a withdrawal syndrome, in rare cases, events such as insomnia, headache, anxiety, dizziness, sleep disorder, somnolence, hallucination, and psychotic disorders were observed after GHB discontinuation

• Interactions
  

  The combined use of alcohol with sodium oxybate may result in potentiation of the central nervous system-depressant effects of sodium oxybate. Patients should be warned against the use of any alcoholic beverages in conjunction with sodium oxybate.

  Sodium oxybate should not be used in combination with sedative hypnotics or other CNS depressants.

  Sedative hypnotics

  Drug interaction studies in healthy adults with sodium oxybate (single dose of 2.25 g) and lorazepam (an anxiolytic [benzodiazepine]; single dose of 2 mg) and zolpidem tartrate (a hypnotic [non-benzodiazepine]; single dose of 5 mg) demonstrated no pharmacokinetic interactions. Increased sleepiness was observed after concomitant administration of sodium oxybate (2.25 g) and lorazepam (2 mg). The pharmacodynamic interaction with zolpidem has not been assessed. When higher doses up to 9 g/d of sodium oxybate are combined with higher doses of hypnotics (within the recommended dose range) pharmacodynamic interactions associated with symptoms of CNS depression and/or respiratory depression cannot be excluded.

  Tramadol

  A drug interaction study in healthy adults with sodium oxybate (single dose of 2.25 g) and tramadol (a central acting opioid; single dose of 100 mg) demonstrated no pharmacokinetic/pharmacodynamic interaction. When higher doses up to 9 g/d of sodium oxybate are combined with higher doses of opioids (within the recommended dose range) pharmacodynamic interactions associated with symptoms of CNS depression and/or respiratory depression cannot be excluded.

  Antidepressants

  Drug interaction studies in healthy adults demonstrated no pharmacokinetic interactions between sodium oxybate (single dose of 2.25 g) and the antidepressants protriptyline hydrochloride (single dose of 10 mg) and duloxetine (60 mg at steady state). No additional effect on sleepiness was observed when comparing single doses of sodium oxybate alone (2.25 g) and sodium oxybate (2.25 g) in combination with duloxetine (60 mg at steady state). Antidepressants have been used in the treatment of cataplexy. A possible additive effect of antidepressants and sodium oxybate cannot be excluded. The rate of adverse events has increased when sodium oxybate is co-administered with tricyclic antidepressants.

  Modafinil

  A drug interaction study in healthy adults demonstrated no pharmacokinetic interactions between sodium oxybate (single dose of 4.5 g) and modafinil (a stimulant; single dose of 200 mg). Sodium oxybate has been administered concomitantly with CNS stimulant agents in approximately 80% of patients in clinical studies in narcolepsy. Whether this affected respiration during the night is unknown.

  The co-administration of omeprazole (a medicinal product that alters gastric pH) has no clinically significant effect on the pharmacokinetics of sodium oxybate. The dose of sodium oxybate therefore does not require adjustment when given concomitantly with proton pump inhibitors.

  Studies in vitro with pooled human liver microsomes indicate that sodium oxybate does not significantly inhibit the activities of the human isoenzymes.

  Since sodium oxybate is metabolised by GHB dehydrogenase there is a potential risk of an interaction with medicinal products that stimulate or inhibit this enzyme (e.g. valproate, phenytoin or ethosuximide). No interaction studies have been conducted in human subjects.

• Adverse Drug Reactions
  

  The most commonly reported adverse reactions are dizziness, nausea, and headache, all occurring in 10% to 20% of patients.

  Frequency estimate: very common ( 1/10); common ( 1/100 to < 1/10); uncommon ( 1/1000 to < 1/100); rare ( 1/10,000 to < 1/1000); very rare (< 1/10,000); not known (cannot be estimated from the available data).

  Within each frequency grouping, adverse events are presented in order of decreasing seriousness.

  Immune system disorders:

  Uncommon : hypersensitivity

  Metabolism and nutrition disorders:

  Common: anorexia, decreased appetite

  Psychiatric disorders:

  Common: depression, cataplexy, anxiety, abnormal dreams, confusional state, disorientation, nightmares, sleepwalking, sleep disorder, insomnia, middle insomnia, nervousness

  Uncommon: suicide attempt, psychosis, paranoia, hallucination, abnormal thinking, agitation, initial insomnia

  Not known (cannot be estimated from the available data): suicidal ideation

  Nervous system disorders:

  Very common: dizziness, headache

  Common: sleep paralysis, somnolence, tremor, balance disorder, disturbance in attention, hypoaesthesia, paraesthesia, sedation, dysgeusia

  Uncommon: myoclonus, amnesia, restless legs syndrome

  Not known (cannot be estimated from the available data): convulsion

  Ear and labyrinth disorders:

  Common: vertigo

  Eye disorders:

  Common: blurred vision

  Cardiac disorders:

  Common: palpitations

  Vascular disorders:

  Common: hypertension

  Respiratory, thoracic and mediastinal disorders:

  Common: dyspnoea, snoring, nasal congestion

  Not known (cannot be estimated from the available data): respiratory depression, sleep apnoea

  Gastrointestinal disorders:

  Very common: nausea (the frequency of nausea is higher in women than men)

  Common: vomiting, diarrhoea, abdominal pain upper,

  Uncommon: faecal incontinence

  Skin and subcutaneous tissue disorders:

  Common: hyperhidrosis, rash

  Not known (cannot be estimated from the available data): urticaria

  Musculoskeletal, connective tissue and bone disorders:

  Common: arthralgia, muscle, spasms, back pain

  Renal and urinary disorders:

  Common: enuresis nocturna, urinary incontinence

  General disorders and administration site conditions:

  Common: asthenia, fatigue, feeling drunk, oedema peripheral

  Infections and infestations:

  Common: nasopharyngitis, sinusitis

  Investigations:

  Common: blood pressure increased, weight decreased

  Injury, poisoning and procedural complications

  Common: fall

  Description of selected adverse reactions

  In some patients, cataplexy may return at a higher frequency on cessation of sodium oxybate therapy, however this may be due to the normal variability of the disease. Although the clinical trial experience with sodium oxybate in narcolepsy/cataplexy patients at therapeutic doses does not show clear evidence of a withdrawal syndrome, in rare cases, adverse reactions such as insomnia, headache, anxiety, dizziness, sleep disorder, somnolence, hallucination, and psychotic disorders were observed after GHB discontinuation.