Wikipedia

Atosiban

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.[5] Originally marketed by Ferring Pharmaceuticals, it is licensed in proprietary and generic forms for the delay of imminent preterm birth in pregnant adult women.

Atosiban
Clinical data
Trade namesTractocile, Antocin, others[1]
AHFS/Drugs.comUK Drug Information
License data
Routes of
administration		Intravenous
ATC code
Legal status
Legal status
  • AU: S4 (Prescription only)
  • UK: POM (Prescription only)[2][3]
  • EU: Rx-only[4]
  • In general: ℞ (Prescription only)
Identifiers
  • 1-(3-Mercaptopropanoic acid)-
    2-(O-ethyl-D-tyrosine)-4-L-threonine-
    8-L-ornithine-oxytocin
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.234.128 Edit this at Wikidata
Chemical and physical data
FormulaC43H67N11O12S2
Molar mass994.19 g·mol−1
3D model (JSmol)
  • 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
  • InChI=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 checkY
  • Key:VWXRQYYUEIYXCZ-OBIMUBPZSA-N checkY
 ☒NcheckY (what is this?)  (verify)

The most commonly reported side effect is nausea.[4]

Medical uses

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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).[4] These signs include regular contractions lasting at least 30 seconds at a rate of at least four every 30 minutes,[4] and dilation of the cervix (the neck of the womb) of 1 to 3 cm and an effacement (a measure of the thinness of the cervix) of 50% or more.[4] In addition, the baby must have a normal heart rate.[4]

Pharmacology

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Mechanism of action

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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 Ca2+ from the extracellular space through voltage-gated channels occur. In addition, atosiban suppresses oxytocin-mediated release of PGE and PGF from the decidua.[6]

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

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Atosiban use after assisted reproduction

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Atosiban is useful in improving the pregnancy outcome of in vitro fertilization-embryo transfer (IVF-ET) in patients with repeated implantation failure.[7] The pregnancy rate improved from zero to 43.7%.[8]

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.[9]

In a 2010 meta-analysis,[10] nifedipine is superior to β2 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.[9] 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.[7]

Pharmacovigilance

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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.[11]

Regulatory affairs

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Atosiban was approved in the European Union in January 2000 and launched in the European Union in April 2000.[11][4] As of June 2007, atosiban was approved in 67 countries, excluding the United States and Japan.[11] 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).[11] 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.[12]

Systematic reviews

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In a systematic review of atosiban for tocolysis in preterm labour, six clinical studies — two compared atosiban to placebo and four atosiban to a 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.[13]

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.[14]

Clinical trials

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Atosiban vs. nifedipine

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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.[15] 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.[15] They have the same efficacy and associated minor side effects.[15] However, flushing, palpitation, and hypotension were significantly higher in the nifedipine group.[15]

A 2012 clinical trial compared tocolytic efficacy and tolerability of atosiban with that of nifedipine.[16] 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).[16] Atosiban has fewer failures within 48 hours.[16] Nifedipine may be associated with a longer postponement of delivery.[16]

A 2009 randomised controlled study demonstrated for the first time the direct effects of atosiban on fetal movement, heart rate, and blood flow.[17] Tocolysis with either atosiban or nifedipine combined with betamethasone administration had no direct fetal adverse effects.[17]

Atosiban vs. ritodrine

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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.[18]

References

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  1. ^ "Atosiban International Drug Names". Drugs.com. 10 April 2020. Archived from the original on 27 December 2019. Retrieved 29 April 2020.
  2. ^ "Tractocile 7.5 mg/ml Solution for Injection - Summary of Product Characteristics (SmPC)". (emc). Retrieved 29 April 2020.
  3. ^ "Tractocile 7.5 mg/ml Concentrate for Solution for Infusion - Summary of Product Characteristics (SmPC)". (emc). 24 June 2013. Retrieved 29 April 2020.
  4. ^ a b c d e f g "Tractocile EPAR". European Medicines Agency (EMA). 17 September 2018. Retrieved 29 April 2020.   This article incorporates text from this source, which is in the public domain.
  5. ^ Akerlund M, Carlsson AM, Melin P, Trojnar J (1985). "The effect on the human uterus of two newly developed competitive inhibitors of oxytocin and vasopressin". Acta Obstetricia et Gynecologica Scandinavica. 64 (6): 499–504. doi:10.3109/00016348509156728. PMID 4061066. S2CID 25799128.
  6. ^ Sanu O, Lamont RF (April 2010). "Critical appraisal and clinical utility of atosiban in the management of preterm labor". Therapeutics and Clinical Risk Management. 6: 191–199. doi:10.2147/tcrm.s9378. PMC 2861440. PMID 20463780.
  7. ^ a b Chou PY, Wu MH, Pan HA, Hung KH, Chang FM (June 2011). "Use of an oxytocin antagonist in in vitro fertilization-embryo transfer for women with repeated implantation failure: a retrospective study". Taiwanese Journal of Obstetrics & Gynecology. 50 (2): 136–140. doi:10.1016/j.tjog.2011.04.003. PMID 21791296.
  8. ^ Lan VT, Khang VN, Nhu GH, Tuong HM (September 2012). "Atosiban improves implantation and pregnancy rates in patients with repeated implantation failure". Reproductive Biomedicine Online. 25 (3): 254–260. doi:10.1016/j.rbmo.2012.05.014. PMID 22818095.
  9. ^ a b Wu MY, Chen SU, Yang YS (December 2011). "Using atosiban in uterine contractions of early pregnancies after assisted reproduction". Journal of the Formosan Medical Association = Taiwan Yi Zhi. 110 (12): 800. doi:10.1016/j.jfma.2011.11.016. PMID 22248840.
  10. ^ Conde-Agudelo A, Romero R, Kusanovic JP (February 2011). "Nifedipine in the management of preterm labor: a systematic review and metaanalysis". American Journal of Obstetrics and Gynecology. 204 (2): 134.e1–134.20. doi:10.1016/j.ajog.2010.11.038. PMC 3437772. PMID 21284967.
  11. ^ a b c d Lamont RF, Kam KY (March 2008). "Atosiban as a tocolytic for the treatment of spontaneous preterm labor". Expert Review of Obstetrics & Gynecology. 3 (2): 163–174. doi:10.1586/17474108.3.2.163. ISSN 1747-4108.
  12. ^ Lamont CD, Jørgensen JS, Lamont RF (September 2016). "The safety of tocolytics used for the inhibition of preterm labour". Expert Opinion on Drug Safety. 15 (9): 1163–1173. doi:10.1080/14740338.2016.1187128. PMID 27159501. S2CID 4937942. 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.
  13. ^ Coomarasamy A, Knox EM, Gee H, Khan KS (November 2002). "Oxytocin antagonists for tocolysis in preterm labour -- a systematic review". Medical Science Monitor. 8 (11): RA268–RA273. PMID 12444392.
  14. ^ Flenady V, Reinebrant HE, Liley HG, Tambimuttu EG, Papatsonis DN (June 2014). "Oxytocin receptor antagonists for inhibiting preterm labour". The Cochrane Database of Systematic Reviews (6): CD004452. doi:10.1002/14651858.CD004452.pub3. PMC 11086629. PMID 24903678.
  15. ^ a b c d Saleh SS, Al-Ramahi MQ, Al Kazaleh FA (January 2013). "Atosiban and nifedipine in the suppression of pre-term labour: a comparative study". Journal of Obstetrics and Gynaecology. 33 (1): 43–45. doi:10.3109/01443615.2012.721822. PMID 23259877. S2CID 20753923.
  16. ^ a b c d Salim R, Garmi G, Nachum Z, Zafran N, Baram S, Shalev E (December 2012). "Nifedipine compared with atosiban for treating preterm labor: a randomized controlled trial". Obstetrics and Gynecology. 120 (6): 1323–1331. doi:10.1097/aog.0b013e3182755dff. PMID 23168756. S2CID 22487349.
  17. ^ a b de Heus R, Mulder EJ, Derks JB, Visser GH (June 2009). "The effects of the tocolytics atosiban and nifedipine on fetal movements, heart rate and blood flow". The Journal of Maternal-Fetal & Neonatal Medicine. 22 (6): 485–490. doi:10.1080/14767050802702349. PMID 19479644. S2CID 35810758.
  18. ^ Shim JY, Park YW, Yoon BH, Cho YK, Yang JH, Lee Y, Kim A (November 2006). "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". BJOG. 113 (11): 1228–1234. doi:10.1111/j.1471-0528.2006.01053.x. PMID 16978233. S2CID 27031083.
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  • "Atosiban". Drug Information Portal. U.S. National Library of Medicine.
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