View source for Atosiban

{{Short description|Chemical compound}}
{{Use British English|date=April 2020}}
{{Use dmy dates|date=April 2020}}
{{Infobox drug
| Verifiedfields = changed
| Watchedfields = changed
| verifiedrevid = 457801156
| drug_name         = 
| INN               = 
| type              = <!-- empty -->
| image = Atosiban SW.svg
| width = 275
| alt               = 
| caption           =

<!-- Clinical data -->
| pronounce         = 
| tradename = Tractocile, Antocin, others<ref>{{cite web | title=Atosiban International Drug Names | website=Drugs.com | date=10 April 2020 | url=https://www.drugs.com/international/atosiban.html | access-date=29 April 2020 | archive-date=27 December 2019 | archive-url=https://web.archive.org/web/20191227225421/https://www.drugs.com/international/atosiban.html }}</ref>
| Drugs.com = {{drugs.com|UK|Tractocile}}
| MedlinePlus       = 
| licence_CA        = <!-- Health Canada may use generic or brand name (generic name preferred) -->
| licence_EU = yes
| DailyMedID        = <!-- DailyMed may use generic or brand name (generic name preferred) -->
| licence_US        = <!-- FDA may use generic or brand name (generic name preferred) -->
| pregnancy_AU      = <!-- A / B1 / B2 / B3 / C / D / X -->
| pregnancy_AU_comment = 
| pregnancy_US      = <!-- A / B / C / D / X / N -->
| pregnancy_US_comment = 
| pregnancy_category= 
| dependency_liability = 
| addiction_liability = 
| routes_of_administration = [[Intravenous therapy|Intravenous]]
| class             = 
| ATCvet            = 
| ATC_prefix = G02
| ATC_suffix = CX01
| ATC_supplemental  =

<!-- Legal status -->
| legal_AU = S4
| legal_AU_comment = 
| legal_BR =  <!-- OTC, A1, A2, A3, B1, B2, C1, C2, C3, C4, C5, D1, D2, E, F-->
| legal_BR_comment = 
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| legal_CA_comment = 
| legal_DE = <!-- Anlage I, II, III or Unscheduled-->
| legal_DE_comment = 
| legal_NZ = <!-- Class A, B, C -->
| legal_NZ_comment = 
| legal_UK = POM
| legal_UK_comment = <ref>{{cite web | title=Tractocile 7.5 mg/ml Solution for Injection - Summary of Product Characteristics (SmPC) | website=(emc) | url=https://www.medicines.org.uk/emc/product/1290/smpc | access-date=29 April 2020}}</ref><ref>{{cite web | title=Tractocile 7.5 mg/ml Concentrate for Solution for Infusion - Summary of Product Characteristics (SmPC) | website=(emc) | date=24 June 2013 | url=https://www.medicines.org.uk/emc/product/1292/smpc | access-date=29 April 2020}}</ref>
| legal_US = <!-- OTC / Rx-only / Schedule I, II, III, IV, V -->
| legal_US_comment = 
| legal_EU = Rx-only
| legal_EU_comment = <ref name="Tractocile EPAR" />
| legal_UN = <!-- N I, II, III, IV / P I, II, III, IV-->
| legal_UN_comment = 
| legal_status      = Rx-only

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<!-- Identifiers -->
| CAS_number_Ref = {{cascite|changed|??}}
| CAS_number = 90779-69-4
| CAS_supplemental  = 
| PubChem = 5311010
| IUPHAR_ligand = 2213
| DrugBank_Ref      = 
| DrugBank          = DB09059
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 4470550
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = 081D12SI0Z
| KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = D03008
| ChEBI_Ref         = 
| ChEBI             = 
| ChEMBL_Ref = {{ebicite|changed|EBI}}
| ChEMBL = 378642
| NIAID_ChemDB      = 
| PDB_ligand        = 
| synonyms          =

<!-- Chemical and physical data -->
| IUPAC_name = 1-(3-Mercaptopropanoic acid)-<br />2-(''O''-ethyl-<small>D</small>-tyrosine)-4-<small>L</small>-threonine-<br />8-<small>L</small>-ornithine-oxytocin
| C=43 | H=67 | N=11 | O=12 | S=2
| SMILES = O=C(N)CNC(=O)[C@@H](NC(=O)[C@H]3N(C(=O)[C@H]1NC(=O)[C@@H](NC(=O)[C@@H](NC(=O)[C@@H](NC(=O)[C@H](NC(=O)CCSSC1)Cc2ccc(OCC)cc2)[C@@H](C)CC)[C@H](O)C)CC(=O)N)CCC3)CCCN
| Jmol              = 
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 1S/C43H67N11O12S2/c1-5-23(3)35-41(63)53-36(24(4)55)42(64)50-29(20-32(45)56)38(60)51-30(43(65)54-17-8-10-31(54)40(62)49-27(9-7-16-44)37(59)47-21-33(46)57)22-68-67-18-15-34(58)48-28(39(61)52-35)19-25-11-13-26(14-12-25)66-6-2/h11-14,23-24,27-31,35-36,55H,5-10,15-22,44H2,1-4H3,(H2,45,56)(H2,46,57)(H,47,59)(H,48,58)(H,49,62)(H,50,64)(H,51,60)(H,52,61)(H,53,63)/t23-,24+,27-,28+,29-,30-,31-,35-,36-/m0/s1
| StdInChI_comment  = 
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| StdInChIKey = VWXRQYYUEIYXCZ-OBIMUBPZSA-N
| density           = 
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}}

'''Atosiban''', sold under the brand name '''Tractocile''' among others, is an inhibitor of the hormones [[oxytocin]] and [[vasopressin]]. It is used as an [[intravenous]] [[medication]] as a [[labour repressant]] (tocolytic) to halt [[premature labor]]. It was developed by [[Ferring Pharmaceuticals]] in [[Sweden]] and first reported in the literature in 1985.<ref>{{cite journal | vauthors = Akerlund M, Carlsson AM, Melin P, Trojnar J | title = The effect on the human uterus of two newly developed competitive inhibitors of oxytocin and vasopressin | journal = Acta Obstetricia et Gynecologica Scandinavica | volume = 64 | issue = 6 | pages = 499–504 | year = 1985 | pmid = 4061066 | doi = 10.3109/00016348509156728 | s2cid = 25799128 }}</ref> Originally marketed by Ferring Pharmaceuticals, it is licensed in proprietary and generic forms for the delay of imminent preterm birth in pregnant adult women.

The most commonly reported [[side effect]] is [[nausea]].<ref name="Tractocile EPAR" />

== Medical uses ==
Atosiban is used to delay birth in adult women who are 24 to 33 weeks pregnant, when they show signs that they may give birth pre-term (prematurely).<ref name="Tractocile EPAR" /> These signs include regular contractions lasting at least 30 seconds at a rate of at least four every 30 minutes,<ref name="Tractocile EPAR" /> and dilation of the cervix (the neck of the womb) of 1 to 3&nbsp;cm and an effacement (a measure of the thinness of the cervix) of 50% or more.<ref name="Tractocile EPAR" /> In addition, the baby must have a normal heart rate.<ref name="Tractocile EPAR" />

== Pharmacology ==
=== Mechanism of action ===
Atosiban is a nonapeptide, desamino-oxytocin analogue, and a competitive vasopressin/oxytocin receptor antagonist (VOTra). Atosiban inhibits the oxytocin-mediated release of [[inositol trisphosphate]] from the myometrial cell membrane. As a result, reduced release of intracellular, stored calcium from the sarcoplasmic reticulum of myometrial cells and reduced influx of Ca<sup>2+</sup> from the extracellular space through voltage-gated channels occur. In addition, atosiban suppresses oxytocin-mediated release of PGE and PGF from the decidua.<ref>{{cite journal | vauthors = Sanu O, Lamont RF | title = Critical appraisal and clinical utility of atosiban in the management of preterm labor | journal = Therapeutics and Clinical Risk Management | volume = 6 | pages = 191–199 | date = April 2010 | pmid = 20463780 | pmc = 2861440 | doi = 10.2147/tcrm.s9378 | doi-access = free }}</ref>

In human preterm labour, atosiban, at the recommended dosage, antagonises uterine contractions and induces uterine quiescence. The onset of uterus relaxation following atosiban is rapid, uterine contractions being significantly reduced within 10 minutes to achieve stable uterine quiescence.

== Other uses ==
=== Atosiban use after assisted reproduction ===
Atosiban is useful in improving the pregnancy outcome of ''in vitro'' fertilization-embryo transfer (IVF-ET) in patients with [[repeated implantation failure]].<ref name="pmid21791296">{{cite journal | vauthors = Chou PY, Wu MH, Pan HA, Hung KH, Chang FM | title = Use of an oxytocin antagonist in in vitro fertilization-embryo transfer for women with repeated implantation failure: a retrospective study | journal = Taiwanese Journal of Obstetrics & Gynecology | volume = 50 | issue = 2 | pages = 136–140 | date = June 2011 | pmid = 21791296 | doi = 10.1016/j.tjog.2011.04.003 | doi-access = free }}</ref> The pregnancy rate improved from zero to 43.7%.<ref>{{cite journal | vauthors = Lan VT, Khang VN, Nhu GH, Tuong HM | title = Atosiban improves implantation and pregnancy rates in patients with repeated implantation failure | journal = Reproductive Biomedicine Online | volume = 25 | issue = 3 | pages = 254–260 | date = September 2012 | pmid = 22818095 | doi = 10.1016/j.rbmo.2012.05.014 }}</ref>

First- and second-trimester bleeding was more prevalent in ART than in spontaneous pregnancies. From 2004 to 2010,  33 first-trimester pregnancies with vaginal bleeding after ART with evident uterine contractions, when using atosiban and/or ritodrine, no preterm delivery occurred  before 30 weeks.<ref name=":2">{{cite journal | vauthors = Wu MY, Chen SU, Yang YS | title = Using atosiban in uterine contractions of early pregnancies after assisted reproduction | journal = Journal of the Formosan Medical Association = Taiwan Yi Zhi | volume = 110 | issue = 12 | page = 800 | date = December 2011 | pmid = 22248840 | doi = 10.1016/j.jfma.2011.11.016 | doi-access = free }}</ref>

In a 2010 meta-analysis,<ref>{{cite journal | vauthors = Conde-Agudelo A, Romero R, Kusanovic JP | title = Nifedipine in the management of preterm labor: a systematic review and metaanalysis | journal = American Journal of Obstetrics and Gynecology | volume = 204 | issue = 2 | pages = 134.e1–134.20 | date = February 2011 | pmid = 21284967 | pmc = 3437772 | doi = 10.1016/j.ajog.2010.11.038 | doi-access = free }}</ref> nifedipine is superior to [[Beta2-adrenergic agonist|β<sub>2</sub> adrenergic receptor agonists]] and [[magnesium sulfate]] for tocolysis in women with preterm labor (20–36 weeks), but it has been assigned to pregnancy category C by the U.S. Food and Drug Administration, so is not recommended before 20 weeks, or in the first trimester.<ref name=":2" /> A report from 2011 supports the use of atosiban, even at very early pregnancy, to decrease the frequency of uterine contractions to enhance success of pregnancy.<ref name="pmid21791296" />

== Pharmacovigilance ==
Following the launch of atosiban in 2000, the calculated cumulative patient exposure to atosiban (January 2000 to December 2005) is estimated as 156,468 treatment cycles. To date, routine monitoring of drug safety has revealed no major safety issues.<ref name = "Lamont_2008">{{Cite journal| vauthors = Lamont RF, Kam KY |date=March 2008|title=Atosiban as a tocolytic for the treatment of spontaneous preterm labor|journal=Expert Review of Obstetrics & Gynecology|volume=3|issue=2|pages=163–174|doi=10.1586/17474108.3.2.163|issn=1747-4108}}</ref>

== Regulatory affairs ==
Atosiban was approved in the European Union in January 2000 and launched in the European Union in April 2000.<ref name="Lamont_2008" /><ref name="Tractocile EPAR">{{cite web | title=Tractocile EPAR | website=[[European Medicines Agency]] (EMA) | date=17 September 2018 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/tractocile | access-date=29 April 2020}} {{PD-notice}}</ref> As of June 2007, atosiban was approved in 67 countries, excluding the United States and Japan.<ref name="Lamont_2008" /> It was understood that Ferring did not expect to seek approval for atosiban in the US or Japan, focusing instead on development of new compounds for use in Spontaneous Preterm Labor (SPTL).<ref name = "Lamont_2008" />  The fact that atosiban only had a short duration before it was out of patent that the parent drug company decided not to pursue licensing in the US.<ref>{{cite journal | vauthors = Lamont CD, Jørgensen JS, Lamont RF | title = The safety of tocolytics used for the inhibition of preterm labour | journal = Expert Opinion on Drug Safety | volume = 15 | issue = 9 | pages = 1163–1173 | date = September 2016 | pmid = 27159501 | doi = 10.1080/14740338.2016.1187128 | quote = It was for this reason and the fact that Tractocile (atosiban) only had a short duration before it was out of patent that the parent drug company decided not to pursue licensing in the USA. | s2cid = 4937942 }}</ref>

== Systematic reviews ==
In a [[systematic review]] of atosiban for tocolysis in preterm labour, six clinical studies — two compared atosiban to [[placebo]] and four atosiban to a [[Beta-adrenergic agonist|β agonist]] — showed a significant increase in the proportion of women undelivered by 48 hours in women receiving atosiban compared to placebo. When compared with β agonists, atosiban increased the proportion of women undelivered by 48 hours and was safer compared to β agonists. Therefore, oxytocin antagonists appear to be effective and safe for tocolysis in preterm labour.<ref>{{cite journal | vauthors = Coomarasamy A, Knox EM, Gee H, Khan KS | title = Oxytocin antagonists for tocolysis in preterm labour -- a systematic review | journal = Medical Science Monitor | volume = 8 | issue = 11 | pages = RA268–RA273 | date = November 2002 | pmid = 12444392 }}</ref>

A 2014 systematic review by the [[Cochrane Collaboration]] showed that while atosiban had fewer side effects than alternative drugs (such as [[ritodrine]]), other beta blockers, and calcium channel antagonists, it was no better than [[placebo]] in the major outcomes i.e. pregnancy prolongation or neonatal outcomes. The finding of an increase in infant deaths in one placebo-controlled trial warrants caution. Further research is recommended.<ref>{{cite journal | vauthors = Flenady V, Reinebrant HE, Liley HG, Tambimuttu EG, Papatsonis DN | title = Oxytocin receptor antagonists for inhibiting preterm labour | journal = The Cochrane Database of Systematic Reviews | issue = 6 | article-number = CD004452 | date = June 2014 | pmid = 24903678 | doi = 10.1002/14651858.CD004452.pub3 | pmc = 11086629 }}</ref>

=== Clinical trials ===

==== Atosiban vs. nifedipine ====
A 2013 retrospective study comparing the efficacy and safety of atosiban and [[nifedipine]] in the suppression of preterm labour concluded that atosiban and nifedipine are effective in delaying delivery for seven days or more in women presenting with preterm labour.<ref name="pmid23259877" /> A total of 68.3% of women in the atosiban group remained undelivered at seven days or more, compared with 64.7% in the nifedipine group.<ref name="pmid23259877" /> They have the same efficacy and associated minor side effects.<ref name="pmid23259877" /> However, flushing, palpitation, and hypotension were significantly higher in the nifedipine group.<ref name="pmid23259877">{{cite journal | vauthors = Saleh SS, Al-Ramahi MQ, Al Kazaleh FA | title = Atosiban and nifedipine in the suppression of pre-term labour: a comparative study | journal = Journal of Obstetrics and Gynaecology | volume = 33 | issue = 1 | pages = 43–45 | date = January 2013 | pmid = 23259877 | doi = 10.3109/01443615.2012.721822 | s2cid = 20753923 }}</ref>

A 2012 clinical trial compared tocolytic efficacy and tolerability of atosiban with that of nifedipine.<ref name="pmid23168756" /> Forty-eight (68.6%) women allocated to atosiban and 39 (52%) to nifedipine did not deliver and did not require an alternate agent at 48 hours, respectively (p=.03).<ref name="pmid23168756" /> Atosiban has fewer failures within 48 hours.<ref name="pmid23168756" /> Nifedipine may be associated with a longer postponement of delivery.<ref name="pmid23168756">{{cite journal | vauthors = Salim R, Garmi G, Nachum Z, Zafran N, Baram S, Shalev E | title = Nifedipine compared with atosiban for treating preterm labor: a randomized controlled trial | journal = Obstetrics and Gynecology | volume = 120 | issue = 6 | pages = 1323–1331 | date = December 2012 | pmid = 23168756 | doi = 10.1097/aog.0b013e3182755dff | s2cid = 22487349 | doi-access = free }}</ref>

A 2009 randomised controlled study demonstrated for the first time the direct effects of atosiban on fetal movement, heart rate, and blood flow.<ref name="pmid19479644" /> Tocolysis with either atosiban or nifedipine combined with betamethasone administration had no direct fetal adverse effects.<ref name="pmid19479644">{{cite journal | vauthors = de Heus R, Mulder EJ, Derks JB, Visser GH | title = The effects of the tocolytics atosiban and nifedipine on fetal movements, heart rate and blood flow | journal = The Journal of Maternal-Fetal & Neonatal Medicine | volume = 22 | issue = 6 | pages = 485–490 | date = June 2009 | pmid = 19479644 | doi = 10.1080/14767050802702349 | s2cid = 35810758 }}</ref>

==== Atosiban vs. ritodrine ====
Multicentre, controlled trial of atosiban vs. ritodrine in 128 women shows a significantly better tocolytic efficacy after 7 days in the atosiban group than in the ritodrine group (60.3 versus 34.9%), but not at 48 hours (68.3 versus 58.7%). Maternal adverse events were reported less frequently in the atosiban group (7.9 vs 70.8%), resulting in fewer early drug terminations due to adverse events (0 versus 20%). Therefore, atosiban is superior to ritodrine  in the treatment of preterm labour.<ref>{{cite journal | vauthors = Shim JY, Park YW, Yoon BH, Cho YK, Yang JH, Lee Y, Kim A | title = Multicentre, parallel group, randomised, single-blind study of the safety and efficacy of atosiban versus ritodrine in the treatment of acute preterm labour in Korean women | journal = BJOG | volume = 113 | issue = 11 | pages = 1228–1234 | date = November 2006 | pmid = 16978233 | doi = 10.1111/j.1471-0528.2006.01053.x | s2cid = 27031083 }}</ref>

== References ==
{{Reflist}}

== External links ==
* {{cite web | url = https://druginfo.nlm.nih.gov/drugportal/name/atosiban | archive-url = https://web.archive.org/web/20210514092706/https://druginfo.nlm.nih.gov/drugportal/name/Atosiban | archive-date = 14 May 2021 | publisher = U.S. National Library of Medicine | work = Drug Information Portal | title = Atosiban }}

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[[Category:Oxytocin receptor antagonists]]
[[Category:Peptides]]
[[Category:Tocolytics]]
[[Category:Vasopressin receptor antagonists]]
[[Category:Ethoxy compounds]]
[[Category:Nonapeptides]]
[[Category:Sec-Butyl compounds]]