Sodium oxybate

Clinical use of sodium oxybate was introduced in Europe in 1964 as an anesthetic given intravenously, but it was not widely used since it sometimes caused seizures. As of 2006, it was still authorized for this use in France and Italy but not widely used. and that its effectiveness "in treating major, clinically relevant narcolepsy symptoms and sleep architecture abnormalities" has been established. However, because of the risks of abuse associated with this medication, it is available in the US only through a REMS program mandated by the FDA. The program requires that providers who prescribe it are certified to do so, that it is dispensed only from a central pharmacy that is certified to do so, and that people to whom it is prescribed must be enrolled in a program for the drug and must document that they are using the drug safely. Over the years, several studies were conducted to further substantiate sodium oxybate efficacy in these indications. Results of small studies suggest it may be "better than naltrexone and disulfiram regarding abstinence maintenance and prevention of craving in the medium term, i.e. 3–12 months". In a 2014 review, Gillian Keating described sodium oxybate as a "useful option for the treatment of alcohol withdrawal syndrome and for the maintenance of abstinence in alcohol dependence". In this context, a study published in 2019 analyzed safety data from 40 clinical trials and from a pharmacovigilance database covering around 260,000 alcohol-dependent patients treated with sodium oxybate in Italy and Austria. Results showed that sodium oxybate was well-tolerated, risks were controlled, and no safety concerns were reported. A group of international researchers has also considered in 2018 that "sodium oxybate has an excellent risk benefit ratio for this indication" and that it is "a very promising therapeutic option for the most severe alcohol-dependent patients and may provide substantial clinical and public health benefit and costs". Multiple trials have shown sodium oxybate to be effective in treating important symptoms of fibromyalgia, such as pain and poor sleep structure. However, in 2010, the FDA voted unanimously against this indication, with commenters citing its potential for abuse as a street drug. Pregnant women should not take it, and women should not become pregnant while taking it. It is excreted in breast milk and should not be used by mothers who are breast feeding. ==Adverse effects==

The US label for sodium oxybate has a black box warning because it is a central nervous system depressant (CNS depressant) and for its potential for abuse. Other potential adverse side effects include respiratory depression, seizures, coma, and death, especially when it is taken in combination with other CNS depressants such as alcohol. Sodium oxybate causes dizziness, nausea, and headache in 10% to 20% of people who take it; nausea is more common in women than men. Between 1% and 10% of people experience nasal congestion, runny nose, or sore throat, loss of appetite, distorted sense of taste, cataplexy, weakness, nervousness or anxiety, depressed mood, nightmares or abnormal dreams, sleep paralysis, sleepwalking, or other sleep disturbances including insomnia, sleepiness or sedation, falls, vertigo, tremor, balance disorder, cognitive issues including disturbance in attention, confusion or disorientation, numbed sense of touch, tingling, blurred vision, heart palpitations, high blood pressure, shortness of breath, snoring, vomiting, diarrhea, stomach pain, excessive sweating, rashes, joint pain, muscle pain, back pain, muscle spasms, bedwetting, urinary incontinence, and swelling of the limbs. ==Overdose==

Reports of overdose in medical literature are generally from abuse, and often involve other drugs as well. Symptoms include vomiting, excessive sweating, periods of stopped breathing, seizures, agitation, loss of psychomotor skills, and coma. Overdose can lead to death due to respiratory depression. People who overdose may die from asphyxiation resulting from choking on vomit and/or aspiration. People that have overdosed or suspected of overdosing may need to be made to vomit, be intubated, or/and put on a ventilator. == Interactions ==

Sodium oxybate should not be used with other drugs that are CNS depressants like alcohol or sedatives. Use with divalproex results in about a 25% increase in the availability of sodium oxybate. ==Pharmacology==

Pharmacodynamics The full mechanism of action of sodium oxybate is poorly understood. Pharmacokinetics Sodium oxybate is rapidly absorbed with high bioavailability, however due to a very high rate of first-pass metabolism the effective bioavailability is only about 25%. Less than 1% is bound to plasma protein. The average time to peak plasma concentration ranges from 0.5 to 1.25 hours. It does not inhibit cytochrome P450 enzymes in the liver at therapeutic concentrations. ==Chemistry==

Sodium oxybate is the sodium salt of γ-hydroxybutyric acid (GHB). Its systematic chemical name is sodium 4-hydroxybutanoate, though synonyms like sodium γ-hydroxybutyrate are commonly used. Its condensed structural formula is (molecular formula: ) and its molar mass is 126.09 g mol−1. It is highly hydrophilic. Treating the salt with acid allows the carboxylic acid form of the compound, which is GHB, to be recovered. ==History==

Alexander Zaytsev worked on this chemical family and published work on it in 1874. The first extended research into sodium oxybate and its use in humans was conducted in the early 1960s by Henri Laborit to study the neurotransmitter GABA. It was studied for a range of uses, including obstetric surgery, during childbirth, and as an anxiolytic; there were anecdotal reports of it having antidepressant and aphrodisiac effects as well. The FDA issued a warning in November 1990 that the sale of GHB was illegal. At the same time, research on the use of sodium oxybate had formalized, as a company called Orphan Medical Inc. had filed an Investigational New Drug application and was running clinical trials with the intention of gaining regulatory approval for use to treat narcolepsy. In 1996, Orphan contracted with Lonza Group, a contract manufacturer for supply of the drug. In 2000, the Hillory J. Farias and Samantha Reid Date-Rape Prevention Act of 2000 was signed into law in the US, which put GHB on Schedule I of the Controlled Substances Act, but sodium oxybate, when used under an IND or NDA from the US FDA, was considered a Schedule III substance, but with Schedule I trafficking penalties. Sodium oxybate was approved by the FDA in 2002 under the brand name Xyrem with a strict risk control strategy to prevent drug diversion and control the risk of abuse by people to whom it was prescribed. Orphan Medical licensed the right to market the drug in Europe to Celltech in 2003. In 2004, Celltech was acquired by UCB and in 2005 Jazz Pharmaceuticals acquired Orphan Medical. In January 2007, Valeant announced that Jazz Pharmaceuticals had licensed the rights to market Xyrem in Canada to Valeant. Jazz Pharmaceuticals and Valeant terminated the agreement in 2017. In July 2007, Jazz Pharmaceuticals and their subsidiary, Orphan Medical, pleaded guilty to a criminal charge of felony misbranding in their marketing of sodium oxybate; they also settled a civil suit at the same time. Jazz Pharmaceuticals paid $20 million in total and agreed to a corporate integrity agreement and to implement internal reforms. The FDA sent Jazz Pharmaceuticals an FDA warning letter about safety violations in September 2007. In October 2011, the FDA sent Jazz Pharmaceuticals another FDA warning letter for failing to collect, evaluate, and promptly report adverse effects to the FDA after it started marketing the drug. It sent another letter in 2013 saying that the problems described in the 2011 letter appeared to be resolved. In January 2017, the FDA approved the first generic sodium oxybate product for narcolepsy symptoms, which is also subject to the same REMS program conditions as the original. By April 2017, seven companies had filed Abbreviated New Drug Applications (ANDAs) with the FDA to market generic versions of Xyrem, which resulted in Jazz Pharmaceuticals filing patent infringement cases against them. Hikma Pharmaceuticals had been the first company to file an ANDA and Jazz Pharmaceuticals settled with them in April 2017; under the agreement Hikma could begin selling an authorized generic in 2023 under Jazz Pharmaceuticals' REMS, and would have five years of exclusivity, however, those conditions could change if Jazz Pharmaceuticals' patents were invalidated. In 2023, Jazz Pharmaceuticals licensed the right to produce an authorized generic of Xyrem to Hikma Pharmaceuticals, marketed as "Sodium Oxybate Oral Solution". In May 2023, the FDA approved Lumryz, an extended-release oral suspension of sodium oxybate allowing for once-nightly dosing. ==Society and culture==

Cases of severe dependence and cravings have been reported with excessive and illicit use of this medication. GHB, the protonated (acidic) form of this salt, has been used to commit drug-facilitated sexual assault and date rape, though the illicit form of GHB typically has different characteristics from pharmaceutical-grade sodium oxybate. Regulation In the United States, GHB is a Schedule I controlled substance, while sodium oxybate, when used under an FDA NDA or IND application, is classified as a Schedule III controlled substance for medicinal use under the Controlled Substances Act, with illicit use subject to Schedule I penalties. which at typical doses is £6,500 to £13,100 per year. Jazz Pharmaceuticals raised the price of Xyrem 841% earning a total of $569 million in 2013 and representing more than 50% of Jazz Pharmaceutical's revenues. The first authorized generic sodium oxybate, produced by Hikma Pharmaceuticals, was made available in January 2023. The cost of pharmaceuticals, including sodium oxybate, tends to be lower in these countries. In May 2016 they were ordered by the High Court to provide funding to treat a teenager with severe narcolepsy. The judge criticised their "thoroughly bad decision" and "absurd" policy discriminating against the girl when hundreds of other NHS patients already receive the drug. ==Names==

Sodium oxybate is the common name for the chemical; it has no international nonproprietary name (INN). As of April 2018, sodium oxybate is sold under the following brands: Alcover (Italy), Gamma-OH (France), Natrii oxybutyras Kalceks (Latvia), Somsanit (Germany), Xyrem (many countries by Jazz Pharmaceuticals and UCB). In 2023, the first authorized generic of Xyrem was made available in the US. ==Research==

Jazz Pharmaceuticals has been developing JZP-386, a deuterated analog of sodium oxybate. The company presented Phase I results in 2015, stating that deuterium-related effects made it necessary to do further formulation work as part of the drug's development. ==See also==