Dr. Ahmed Sodium Oxybate was approved by the FDA in 2002 as an oral solution under the brand name, Xyrem (Jazz Pharmaceuticals).
It has been approved for the treatment of Narcolepsy in adults and children 7 years of age or older.
What is Narcolepsy?
Narcolepsy is a sleep disorder. It is considered a neurodegenerative disorder characterized by the loss of neurons in your brain that may result in any one or all of the following symptoms:
- Excessive daytime sleepiness
- Sudden sleeping attacks during wake hours without prior anticipation
- Frequent awakening from sleep at night
These symptoms may also be present:
Cataplexy:
Sudden attacks of loss of muscle tone and power. Most people have cataplexy during a sudden change in emotions such as laughter or excitement.
Sleep paralysis:
Sleep paralysis is a condition when a person can not talk or move at the onset of sleep.
Although, the condition is harmless, however, sleep paralysis may be one of the horrible symptoms of Narcolepsy.
Sometimes, this is associated with severe anxiety and chest pain as well.
Hypnagogic hallucinations:
This is a state of seeing, hearing, or feeling things that are not actually present, especially while the person is falling asleep. These can be very frightening, real, and very intense.
Narcolepsy Subtypes:
Narcolepsy is classified into two subtypes, Type 1 and Type 2.
- Narcolepsy Type 1: Narcolepsy with Cataplexy
- Narcolepsy Type 2: Narcolepsy without Cataplexy
In Narcolepsy Type 1, it is thought to be caused by a complete loss of all the neurons that contain Orexin (hypocretin). It is probably an immune-mediated disorder [Ref].
In Narcolepsy Type 2, the exact mechanism is not known but it is probably due to the incomplete loss of neurons containing Orexin.
The most recent detailed classification of narcolepsy is as follows [Ref]:
- Narcolepsy with hypocretin deficiency but no cataplexy
- Narcolepsy without hypocretin deficiency but with cataplexy
- Autosomal dominant cerebellar ataxia, narcolepsy, and deafness
- Autosomal dominant narcolepsy, type 2 diabetes, and obesity
- Narcolepsy caused by another medical disorder
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Medications Approved for the Treatment of Narcolepsy:
The first-line treatment for excessive daytime somnolence is:
- Modafinil, or
- Armodafinil
The second line of treatment is amphetamines (Methylphendate)
The first line of treatment for Cataplexy is Sodium Oxybate (Xyrem). Clomipramine, Venlafaxine, and Fluoxetine may also be used to treat Cataplexy.
Newer drugs are being developed including one recently approved by the FDA, Pitolisant, an oral tablet under the brand name, Wakix.
Most stimulant drugs cause anxiety, racing heartbeats, and headaches. In addition, these drugs may need monitoring as physical dependence and abuse is not uncommon.
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Role of Sodium Oxybate in the Management of Narcolepsy:
Sodium Oxybate (Xyrem) has been evaluated in different clinical trials including children. It has been shown to significantly improve the symptoms of Cataplexy and Daytime sleepiness compared to a placebo medicine.
In addition, Xyrem is most effective when given with Modafinil.
The efficacy of Sodium Oxybate was evaluated in 136 patients who had attacks of Cataplexy every week.
The drug was found to have a significant effect on the symptoms of Cataplexy and Narcolepsy as given in the table below [Ref]:
| Aspect | Findings | P value at 9 gm/night dose |
| Weekly Cataplexy Attacks | ↓↓ at all doses but greater reduction at 9 gm per night dose | 0.0008 |
| Daytime Sleepiness (ESS) | ↓↓ (Significant reduction at 9 gm per night dose) | 0.0001 |
| Clinical Global Impression (CGI-c) | ↓↓ (Dose-dependent effect) | 0.0002 |
| Inadvertent Naps/Sleep Attacks | ↓ (Dose-dependent effect) | 0.0122 |
| Nighttime Awakenings | ↓ (Dose-dependent effect) | 0.0035 |
In another placebo-controlled multicentered clinical trial that evaluated 228 patients with Cataplexy, Sodium Oxybate was found to significantly improve the symptoms of Cataplexy even in low doses.
The table summarizes the results here:
| Sodium Oxybate Dosage (g) | Median Decrease in Weekly Cataplexy Attacks |
| Placebo | N/A |
| 4.5 g | 57.0% |
| 6 g | 65.0% |
| 9 g | 84.7% |
A significant improvement in the symptoms was noted, however, the improvement was dose-dependent with the higher dose being more effective [Ref].
| Observation / Result | Dosage (g) | Statistical Significance |
| ↑ > 10 minutes in the MWT | 9 | p < 0.001 |
| ESS ↓ (dose-related) | 6, 9 | p < 0.001 |
| ↓ Inadvertent Naps | 6, 9 | p < 0.001 |
| CGI-c Improvement | All | p < 0.001 |
Xyrem has also been shown to have superior effects, especially on symptoms of daytime sleepiness when combined with Modafinil.
In a clinical trial, Sleep Latency increased from 10 minutes to 13 minutes when patients were given modafinil and Sodium Oxybate, whereas no change was noted when Sodium oxybate was given alone versus sleep latency reduced from 9 minutes to 6 minutes in the placebo group.
| Observation / Result | Treatment Group | Daytime Sleep Latency (SL) at Baseline | Daytime Sleep Latency (SL) after treatment |
| ↓ Daytime SL on the MWT | Placebo | 9.74 min | 6.87 min |
| No decrease in SL | SO (Sodium Oxybate) | No Change | |
| ↑ Daytime SL | SO/Modafinil Combination | 10.43 min | 13.15 min |
The above data show that Sodium Oxybate is an effective treatment with a novel mechanism of action for treating Narcolepsy and Cataplexy.
It has additive effects when combined with Modafinil or Armodafinil.
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Sodium Oxybate (Xyrem) Mechanism of Action:
The Mechanism of action of Sodium Oxybate Xyrem is not very clear. It is said to have a similar effect as ethanol.
Sodium Oxybate acts on the GABA receptors just like ethanol. It is in fact the sodium compound of gamma-hydroxybutyrate which is a neurotransmitter and acts on the sleep pathways via the GABA receptors [Ref]
It is similar to ethanol as ethanol is metabolized to Beta-hydroxybutyrate while Xyrem is the sodium salt of Gamma Hydroxybutyrate.
The effects of Sodium Oxybate are so similar to ethanol that in Australia and Italy, it is used for alcohol dependence and withdrawal syndrome [Ref].
The effect of Sodium Oxybate is primarily mediated by GABA-B receptors in the brain (nor-adrenergic, dopaminergic, and thalamocortical neurons in particular) [Ref].
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Sodium Oxybate (Xyrem) Indications and Dosing:
Xyrem is indicated for the treatment of Narcolepsy in children of 7 years and older and adults. It is used to treat daytime sleepiness as well as Cataplexy (sudden loss of muscle tone).
It is available as an oral solution that contains 0.5 g/ml of Oxybate Sodium, equivalent to 0.413 g/ml of Oxybate.
Sodium Oxybate (Xyrem) Dose [Ref]:
In adults, it is given in a dose of 4.5 gm at night divided as 2.25 gm at bedtime and then 2.25 gm after 2.5 to 4 hours.
The dose may be increased to 6 gms (3 gm at bedtime and 3 gm later), 7.5 gm (3.75 gm at bedtime and 3.75 gm later), up to a maximum dose of 9 gm (4.5 gm at bedtime and 4.5 gm 2.5 to 4 hours later).
Recommended Pediatric Xyrem Dosage
| Patient Weight | Initial Dosage | Maximum Increase in Weekly Dosage | Maximum Recommended Dosage |
|---|---|---|---|
| 20 kg to <30 kg | ≤1 g at bedtime and the same dose 2.5 to 4 hours later | 1 gm (in two divided doses: 0.5 g at bedtime and 2.5 to 4 hours later) | 3 g at bedtime and the same dose 2.5 to 4 hours later |
| 30 kg to <45 kg | ≤1.5 g at bedtime and the same dose 2.5 to 4 hours later | 1 gm (in two divided doses: 0.5 at bedtime and 2.5 to 4 hours later) | 3.75 g at bedtime and the same dose 2.5 to 4 hours later |
| ≥45 kg | ≤2.25 g at bedtime and the same dose 2.5 to 4 hours later | 1.5 gm (in two divided doses: 0.75 at bedtime and 2.5 to 4 hours later) | 4.5 g at bedtime and the same dose 2.5 to 4 hours later |
Note: <20 kgs: Insufficient information available.
After the first dose, the patient usually falls asleep within 5 to 15 minutes. The second dose is cumbersome but the patient should set an alarm after 2.5 to 4 hours and take the second dose.
The second dose should not be taken within 2.5 hours of taking the first dose as sometimes it takes up to 2 hours for the patient to fall asleep and may not wake up after that.
Similarly, after 4 hours, if the dose is missed, the second dose should be skipped.
Xyrem dose in patients with hepatic impairment should be reduced to half. Similarly, in patients who are prescribed Valproic acid, the dose of Xyrem should be reduced by 20%.
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Sodium Oxybate (Xyrem) Contraindications and Precautions:
Sodium Oxybate (Xyrem) is not for use in patients who are already taking a sedative or a hypnotic drug.
Concurrent use of Xyrem with alcohol, sedatives, and other CNS depressants increases the risk of respiratory depression, hypotension, and even death.
In addition to avoiding the concomitant use of a hypnotic and a sedative drug, all patients are advised not to drive or perform tasks that require mental alertness at least within 6 hours of taking the drug.
Avoid Alcohol:
Xyrem should not be used with alcohol because of the risk of respiratory depression.
Avoid in patients with succinic semialdehyde dehydrogenase deficiency:
This is a rare childhood inborn error of metabolism manifesting as hypotonia, mental retardation, and ataxia. Xyrem is contraindicated in these patients.
Xyrem is a Controlled Substance:
Xyrem is a Schedule III controlled substance. Misusing it and combining it with alcohol or other CNS depressant drugs may result in seizures, respiratory depression, and even death.
The rapid onset of sedation and Xyrem’s amnestic effects, particularly when combined with alcohol, increase the potential for serious criminal misuse, as reported in the literature.
Doctors should assess patients’ history of substance abuse, carefully watch for indicators of GHB misuse like escalated dosing and drug-seeking actions, and be vigilant for individuals who might feign cataplexy.
Respiratory Depression:
Xyrem can impair breathing, especially in those with respiratory issues like COPD, uncontrolled asthma, and interstitial lung disease. Overdoses have led to life-threatening respiratory depression.
Studies show mixed effects on breathing in adults with narcolepsy and sleep apnea, including worsened apnea in some cases.
Xyrem didn’t worsen sleep-disordered breathing severity but increased central apneas and oxygen drops in sleep apnea patients.
Similar issues were seen in pediatric patients. A few adults faced CNS depression and breathing problems with Xyrem, but most didn’t show significant breathing worsening.
Prescribers should consider respiratory risks, especially in those with existing breathing disorders, obesity, postmenopausal women not on hormone therapy, and narcolepsy.
Depression and Suicidal Risks:
An increased risk of suicide and depression was observed with Xyrem in adult patients with narcolepsy. The risk was high in patients with a history of depression.
Depression resulted in 7% of the participants, leading to <1% discontinuation. Controlled trials showed low occurrences of depression.
In a pediatric trial (n=104), one patient had suicidal thoughts with Xyrem.
Monitoring and prompt evaluation are vital for detecting emerging depression, especially in those with prior depression or suicide attempts, while using Xyrem.
Other psychiatric problems:
Confusion was reported in 17% while anxiety developed in 5.8% of the participants in the clinical trial.
Other adverse events reported in post-marketing surveillance were hallucinations, paranoia, psychosis, aggression, and agitation.
Children also developed acute psychosis, confusion, and anxiety. The manufacturer recommends watching for neuropsychiatric symptoms while Xyrem is used.
Parasomnias:
Sleepwalking was observed in patients taking Xyrem. Sleepwalking can lead to injury and harm and hence needs to be monitored while using Xyrem.
Fluid and Sodium Overload:
Sodium Oxybate, as the name suggests, contains a lot of sodium. Patients with conditions that necessitate the use of low sodium should be advised the drug with extreme caution.
These include hypertension, heart failure, kidney disease, and liver disease.
The sodium content in per night dose of Xyrem (Sodium Oxybate) are:
| Xyrem Dose | Sodium Content |
| 3 g per night | 550 mg |
| 4.5 g per night | 820 mg |
| 6 g per night | 1100 mg |
| 7.5 g per night | 1400 mg |
| 9 g per night | 1640 mg |
Low-dose formulations have been successfully tried and may replace the original Xyrem especially in individuals with heart disease and hypertension.
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Sodium Oxybate (Xyrem) Side effects:
| System/Side effect | Placebo (n=213) | Xyrem 4.5g (n=185) | Xyrem 6g (n=258) | Xyrem 9g (n=178) |
| Any Side Effect | 62% | 45% | 55% | 70% |
| Gastrointestinal Disorders | ||||
| Nausea | 3% | 8% | 13% | 20% |
| Vomiting | 1% | 2% | 4% | 11% |
| Diarrhea | 2% | 4% | 3% | 4% |
| Abdominal pain | 2% | 3% | 1% | 2% |
| Dry mouth | 2% | 1% | 2% | 1% |
| General Disorders And Administrative Site Reaction | ||||
| Pain | 1% | 1% | <1% | 3% |
| Feeling drunk | 1% | 0% | <1% | 3% |
| Edema | 1% | 3% | 0% | 0% |
| Musculoskeletal And Connective Tissue Disease | ||||
| Pain in extremity | 1% | 3% | 1% | 1% |
| Cataplexy | 1% | 1% | 1% | 2% |
| Muscle spasms | 2% | 2% | <1% | 2% |
| Nervous System Disorders | ||||
| Dizziness | 4% | 9% | 11% | 15% |
| Somnolence | 4% | 1% | 3% | 8% |
| Tremor | 0% | 0% | 2% | 5% |
| Paresthesia | 1% | 2% | 1% | 3% |
| Disturbance in attention | 0% | 1% | 0% | 4% |
| Sleep paralysis | 1% | 0% | 1% | 3% |
| Psychiatric Disorders | ||||
| Disorientation | 1% | 1% | 2% | 3% |
| Anxiety | 1% | 1% | 1% | 2% |
| Irritability | 1% | 0% | <1% | 3% |
| Sleepwalking | 0% | 0% | 0% | 3% |
| Renal And Urinary Disorders | ||||
| Enuresis | 1% | 3% | 3% | 7% |
| Skin And Subcutaneous Tissue Disorders | ||||
| Hyperhidrosis | 0% | 1% | 1% | 3% |
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