Ondansetron

Ondansetron

Systematic (IUPAC) name
(RS)-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-2,3-dihydro-1H-carbazol-4(9H)-one
Clinical data
Trade names	Zofran Ondisolv
AHFS/Drugs.com	monograph
MedlinePlus	a601209
Pregnancy cat.	B1 (AU) B (US)
Legal status	Prescription Only (S4) (AU) ℞-only (US)
Routes	Oral, rectal, IV, IM
Pharmacokinetic data
Bioavailability	~60%
Protein binding	70%-76%
Metabolism	Hepatic (CYP3A4, CYP1A2, CYP2D6)
Half-life	5.7 hours
Excretion	Renal
Identifiers
CAS number	99614-02-5 Y
ATC code	A04AA01
PubChem	CID 4595
IUPHAR ligand	2290
DrugBank	DB00904
ChemSpider	4434 Y
UNII	4AF302ESOS Y
KEGG	D00456 Y
ChEMBL	CHEMBL46 Y
Chemical data
Formula	C18H19N3O
Mol. mass	293.4 g/mol
SMILES O=C3c2c1ccccc1n(c2CCC3Cn4ccnc4C)C
InChI InChI=1S/C18H19N3O/c1-12-19-9-10-21(12)11-13-7-8-16-17(18(13)22)14-5-3-4-6-15(14)20(16)2/h3-6,9-10,13H,7-8,11H2,1-2H3 Y Key:FELGMEQIXOGIFQ-UHFFFAOYSA-N Y
Y (what is this?)  (verify)

Ondansetron (INN) (/ɒnˈdænsɛtrɒn/; developed and first marketed by GlaxoSmithKline as Zofran) is a serotonin 5-HT₃ receptor antagonist used mainly as an antiemetic (to treat nausea and vomiting), often following chemotherapy. It affects both peripheral and central nerves. Ondansetron reduces the activity of the vagus nerve, which deactivates the vomiting center in the medulla oblongata, and also blocks serotonin receptors in the chemoreceptor trigger zone. It has little effect on vomiting caused by motion sickness, and does not have any effect on dopamine receptors or muscarinic receptors.

Medical uses

Chemotherapy

The 5-HT₃ receptor antagonists are the primary drugs used to treat and prevent chemotherapy-induced nausea and vomiting (CINV). A common use case is to give them intravenously about 30 minutes before commencement of a chemotherapy treatment.

Post operative

A number of medications including ondansetron appear to be effective in controlling post-operative nausea and vomiting (PONV). It is unclear if it is better than or worse than other agents like droperidol, metoclopramide, or cyclizine.

Other

Although it is effective, the high cost of the brand-name version had limited its use to controlling PONV and CINV. It is also used off-label to treat hyperemesis gravidarum, but there is no conclusive data available on its safety in pregnancy, especially during the first trimester. It is also used to treat cyclic vomiting syndrome; although there have been no formal trials to confirm efficacy, case reports suggests it can be helpful in some cases.

Adverse effects

Ondansetron is a well-tolerated drug with few side effects. Constipation, dizziness and headache are the most commonly reported side effects associated with its use. There have been no significant drug interactions reported with this drug's use. It is broken down by the hepatic cytochrome P450 system and it has little effect on the metabolism of other drugs broken down by this system.

On September 15, 2011, the U.S. FDA issued a Medwatch Safety Alert for ondansetron in patients with congenital Long QT syndrome, a heart arrhythmia. The FDA further required GlaxoSmithKline to conduct a thorough QT study to determine the degree to which ondansetron may cause QT interval prolongation. On June 29, 2012, the FDA issued a Drug Safety Communication Update entitled New information regarding QT prolongation with ondansetron (Zofran). Ondansetron was included in the List of Potential Signals of Serious Risks/New Safety Information Identified by the FDA Adverse Event Reporting System (FAERS) between January– March 2013. As a result of these concerns, the rarely prescribed 32-mg dose of ondansetron was voluntarily removed from the market in December, 2012.

History

A vial of ondansetron for intravenous injection

Ondansetron was developed around 1984 by scientists working at Glaxo's laboratories in London. It is in both the imidazole and carbazole families of heterocyclic compounds. After several attempts the company successfully filed for U.S. patent protection for the drug in 1986. U.S. Patent 4,695,578 was granted in September 1987 while U.S. Patent 4,753,789 was granted in June 1988. U.S. Patent 5,578,628, a divisional patent of U.S. Patent 4,753,789, was granted on November 26, 1996. Ondansetron was granted FDA approval as Zofran in January 1991. Glaxo did pediatric research on Zofran's uses, and gained a patent extension as a result, extending U.S. exclusivity until December 24, 2006. The FDA subsequently approved the first generic versions in December 2006, with marketing approval granted to Teva Pharmaceuticals USA and SICOR Pharmaceuticals.

Brand names

Ondansetron is marketed by GlaxoSmithKline (GSK) under the trade name Zofran. Other manufacturers include Pfizer Injectables (Ondanzetron), Opsonin Pharma Bangladesh (Anset), Strativa Pharmaceuticals (Zuplenz), Indswift Ltd. (Ondisolv), Cipla Ltd. (Emeset), Gedeon Richter Ltd. (Emetron), Korea United Pharmaceuticals (Emodan), Zentiva a.s. (Ondemet), Strides Arcolab (Setronax), Emistat (Unimed and Unihealth Bangladesh Ltd.) Glenmark Generics Ltd. (India) (Ondansetron) and Novell Pharmaceutical Laboratories (Ondavell). On May 29, 2006, Baxter Healthcare received tentative approval to market its own label of Ondansetron Injection, USP, 8 mg/50 mL and 32 mg/50 mL iso-osmotic sodium chloride solution, beginning upon expiration of GSK's patent later that year.

Publication bias

In 1997, ondansetron was the subject of a meta-analysis case-study published in the British Medical Journal. Researchers examined 84 trials, with 11,980 patients receiving ondansetron, published between 1991 and September 1996. Intravenous ondansetron 4 mg versus placebo was investigated in 16 reports and three further reports which had been duplicated six times. The number needed to treat (NNT) to prevent vomiting within 24 hours was 9.5, with 95% confidence interval 6.9 to 15, in the 16 non-duplicated reports. In the three duplicated reports, the NNT was significantly lower at 3.9 (3.3 to 4.8) with P<0.00001. When all 25 reports were combined the apparent number needed to treat improved to 4.9 (4.4 to 5.6). Inclusion of duplicate reports led to a 23% overestimation of ondansetron's antiemetic efficacy.

In addition, the authors found that the covert duplication of reports on ondansetron was not easy to detect, because of lack of cross-referencing between papers, and that reports containing duplicate findings were cited in eight reviews of the drug. Their analysis was a subject of an editorial in the Journal of the American Medical Association in 1999.

Research

During the past decade ondansetron has been increasingly used in the United States for Nausea and Vomiting of Pregnancy (NVP), owing to the lack of a drug approved by the U.S. Food and Drug Administration (FDA) for this condition (see also Hyperemesis gravidarum). While fetal safety data for doxylamine-pyridoxine are based on more than a quarter of a million pregnancies, the fetal safety data for ondansetron are based on fewer than 200 births. Moreover, a recent case-control study suggested there was an increased risk of cleft palate associated with ondansetron. Recently, the FDA issued a warning about potentially serious QT prolongation and torsade de pointes associated with ondansetron use; the warning included a list of precautions and tests that must be followed. The drug is not labeled for use in NVP in either the United States or Canada. Based on the data available today, ondansetron use cannot be assumed to be safe during pregnancy.

A small study raised concern about Zofran increasing the risk of cleft palate. Since then a much larger study has eased concerns in this area. The new study of more than 600,000 pregnancies in Denmark found no evidence of major birth-related problems. References to this study: http://www.parents.com/blogs/parents-news-now/2013/03/01/pregnancy/anti-nausea-drug-safe-for-pregnancy-study-finds/ http://www.usatoday.com/story/news/nation/2013/02/27/pregnancy-nausea-drug-fetus/1952181/ http://www.huffingtonpost.com/2013/02/27/zofran-pregnancy_n_2776753.html http://www.aboutlawsuits.com/zofran-pregnancy-study-no-risk-defects-41919/

Neuropsychiatric disorders

A 2006 double-blind, randomized controlled trial indicated that ondansetron may have value in the treatment of schizophrenia, as an adjunct to haloperidol. The study found the combination to significantly improve negative schizophrenia symptoms, and people taking both drugs experienced fewer of the adverse effects commonly associated with haloperidol. An earlier, smaller, open-label trial had found ondansetron to be useful in treating antipsychotic-induced tardive dyskinesia in people with schizophrenia, and the study patients also showed significant improvement in the disease's symptoms.

Early studies have also examined ondansetron as a possible treatment for psychosis resulting from advanced Parkinson's disease. Its apparent benefits despite a lack of any significant antagonistic properties at dopamine receptors or the 5-HT2A receptor raises interesting questions about the etiology of psychosis.

Hewlett and others found that the treatment of obsessive compulsive disorder with Ondansetron 1 mg three times daily was associated with a significant decrease in the Yale Brown Obsessive Compulsive scores in a small (n=8), 8-week, open-label study.

Substance use

Ondansetron lowers the cravings for alcohol, especially in early-onset alcoholics. In one cognitive-behavioral therapy study, ondansetron patients with early-onset alcoholism had fewer drinks per day and reported more days without drinking at all, as compared to the other groups in the study. Also of note, individuals with the LL genotype show significant improvements in alcohol misuse when treated with ondansetron, compared with individuals with the other genotypes of the 5HTTLPR polymorphism, who showed no improvement over placebo.

Researchers at the Stanford University School of Medicine have demonstrated that ondansetron might be useful and effective for treating withdrawal symptoms of opioid addictions. Unlike the existing treatments methadone and buprenorphine, it is not itself an opioid. Additionally, it does not require continued supervision like treatment with clonidine.

The original experiment used mice who were injected with increasing doses of morphine, assayed with naloxone and then underwent haplotypic analysis to isolate a gene candidate. HTR3A which codes for the 5-HT₃ receptor emerged as the primary candidate, which suggested 5-HT₃ antagonist ondansetron as a possible treatment. The researchers were then able to show using an acute morphine administration model the efficacy in withdrawal symptom control in humans.

Postanesthetic shivering

Two small, placebo-controlled trials have been conducted to assess the efficacy of ondansetron for postanesthetic shivering, a common occurrence after surgery. Ondansetron was found to be as effective as pethidine (meperidine, Demerol) when given as a single IV dose before anesthesia.

External links

• U.S. National Library of Medicine: Drug Information Portal - Ondansetron