Atosiban

Last updated

Atosiban
Atosiban SW.svg
Clinical data
Trade names Tractocile, Antocin, others [1]
AHFS/Drugs.com UK 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 InfoCard 100.234.128 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C43H67N11O12S2
Molar mass 994.19 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 Yes check.svgY
  • Key:VWXRQYYUEIYXCZ-OBIMUBPZSA-N Yes check.svgY
 X mark.svgNYes check.svgY  (what is this?)    (verify)

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.

Contents

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

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). [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

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 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

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. [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

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

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

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

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. [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

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]

Related Research Articles

<span class="mw-page-title-main">Terbutaline</span> Chemical compound

Terbutaline, sold under the brand names Bricanyl and Marex among others, is a β2 adrenergic receptor agonist, used as a "reliever" inhaler in the management of asthma symptoms and as a tocolytic to delay preterm labor for up to 48 hours. This time can then be used to administer steroid injections to the mother which help fetal lung maturity and reduce complications of prematurity. It should not be used to prevent preterm labor or delay labor more than 48–72 hours. In February 2011, the Food and Drug Administration began requiring a black box warning on the drug's label. Pregnant women should not be given injections of the drug terbutaline for the prevention of preterm labor or for long-term management of preterm labor, and should not be given oral terbutaline for any type of prevention or treatment of preterm labor "due to the potential for serious maternal heart problems and death."

<span class="mw-page-title-main">Misoprostol</span> Medication to induce abortion and treat ulcers

Misoprostol is a synthetic prostaglandin medication used to prevent and treat stomach and duodenal ulcers, induce labor, cause an abortion, and treat postpartum bleeding due to poor contraction of the uterus. It is taken by mouth when used to prevent gastric ulcers in people taking nonsteroidal anti-inflammatory drugs (NSAID). For abortions it is used by itself or in conjunction with mifepristone or methotrexate. By itself, effectiveness for abortion is between 66% and 90%. For labor induction or abortion, it is taken by mouth, dissolved in the mouth, or placed in the vagina. For postpartum bleeding it may also be used rectally.

Uterine contractions are muscle contractions of the uterine smooth muscle that can occur at various intensities in both the non-pregnant and pregnant uterine state. The non-pregnant uterus undergoes small, spontaneous contractions in addition to stronger, coordinated contractions during the menstrual cycle and orgasm. Throughout gestation, the uterus enters a state of uterine quiescence due to various neural and hormonal changes. During this state, the uterus undergoes little to no contractions, though spontaneous contractions still occur for the uterine myocyte cells to experience hypertrophy. The pregnant uterus only contracts strongly during orgasms, labour, and in the postpartum stage to return to its natural size.

Labor induction is the process or treatment that stimulates childbirth and delivery. Inducing (starting) labor can be accomplished with pharmaceutical or non-pharmaceutical methods. In Western countries, it is estimated that one-quarter of pregnant women have their labor medically induced with drug treatment. Inductions are most often performed either with prostaglandin drug treatment alone, or with a combination of prostaglandin and intravenous oxytocin treatment.

Tocolytics are medications used to suppress premature labor. Preterm birth accounts for 70% of neonatal deaths. Therefore, tocolytic therapy is provided when delivery would result in premature birth, postponing delivery long enough for the administration of glucocorticoids, which accelerate fetal lung maturity but may require one to two days to take effect.

Bloody show or show is the passage of a small amount of blood or blood-tinged mucus through the vagina near the end of pregnancy. It is caused by thinning and dilation of the cervix, leading to detachment of the cervical mucus plug that seals the cervix during pregnancy and tearing of small cervical blood vessels, and is one of the signs that labor may be imminent. The bloody show may be expelled from the vagina in pieces or altogether and often appears as a jelly-like piece of mucus stained with blood. Although the bloody show may be alarming at first, it is not a concern of patient health after 37 weeks gestation.

<span class="mw-page-title-main">Uterine rupture</span> Medical condition

Uterine rupture is when the muscular wall of the uterus tears during pregnancy or childbirth. Symptoms, while classically including increased pain, vaginal bleeding, or a change in contractions, are not always present. Disability or death of the mother or baby may result.

<span class="mw-page-title-main">Prelabor rupture of membranes</span> Breakage of the amniotic sac before the onset of labour

Prelabor rupture of membranes (PROM), previously known as premature rupture of membranes, is breakage of the amniotic sac before the onset of labour. Women usually experience a painless gush or a steady leakage of fluid from the vagina. Complications in the baby may include premature birth, cord compression, and infection. Complications in the mother may include placental abruption and postpartum endometritis.

A contraction stress test (CST) is performed near the end of pregnancy to determine how well the fetus will cope with the contractions of childbirth. The aim is to induce contractions and monitor the fetus to check for heart rate abnormalities using a cardiotocograph. A CST is one type of antenatal fetal surveillance technique.

<span class="mw-page-title-main">Cervical effacement</span> Thinning and shortening of the cervix

Cervical effacement or cervical ripening refers to the thinning and shortening of the cervix. This process occurs during labor to prepare the cervix for dilation to allow the fetus to pass through the vagina. While this a normal, physiological process that occurs at the later end of pregnancy, it can also be induced through medications and procedures.

Cervical weakness, also called cervical incompetence or cervical insufficiency, is a medical condition of pregnancy in which the cervix begins to dilate (widen) and efface (thin) before the pregnancy has reached term. Definitions of cervical weakness vary, but one that is frequently used is the inability of the uterine cervix to retain a pregnancy in the absence of the signs and symptoms of clinical contractions, or labor, or both in the second trimester. Cervical weakness may cause miscarriage or preterm birth during the second and third trimesters. It has been estimated that cervical insufficiency complicates about 1% of pregnancies, and that it is a cause in about 8% of women with second trimester recurrent miscarriages.

<span class="mw-page-title-main">Uterine atony</span> Loss of tone in the uterine musculature

Uterine atony is the failure of the uterus to contract adequately following delivery. Contraction of the uterine muscles during labor compresses the blood vessels and slows flow, which helps prevent hemorrhage and facilitates coagulation. Therefore, a lack of uterine muscle contraction can lead to an acute hemorrhage, as the vasculature is not being sufficiently compressed. Uterine atony is the most common cause of postpartum hemorrhage, which is an emergency and potential cause of fatality. Across the globe, postpartum hemorrhage is among the top five causes of maternal death. Recognition of the warning signs of uterine atony in the setting of extensive postpartum bleeding should initiate interventions aimed at regaining stable uterine contraction.

<span class="mw-page-title-main">Postpartum bleeding</span> Loss of blood following childbirth

Postpartum bleeding or postpartum hemorrhage (PPH) is often defined as the loss of more than 500 ml or 1,000 ml of blood following childbirth. Some have added the requirement that there also be signs or symptoms of low blood volume for the condition to exist. Signs and symptoms may initially include: an increased heart rate, feeling faint upon standing, and an increased breathing rate. As more blood is lost, the patient may feel cold, blood pressure may drop, and they may become restless or unconscious. In severe cases circulatory collapse, disseminated intravascular coagulation and death can occur. The condition can occur up to twelve weeks following delivery in the secondary form. The most common cause is poor contraction of the uterus following childbirth. Not all of the placenta being delivered, a tear of the uterus, or poor blood clotting are other possible causes. It occurs more commonly in those who already have a low amount of red blood, are Asian, have a larger fetus or more than one fetus, are obese or are older than 40 years of age. It also occurs more commonly following caesarean sections, those in whom medications are used to start labor, those requiring the use of a vacuum or forceps, and those who have an episiotomy.

<span class="mw-page-title-main">Carbetocin</span> Medication used for preventing postpartum bleeding

Carbetocin, sold under the brand names Pabal among others, is a medication used to prevent excessive bleeding after childbirth, particularly following Cesarean section. It appears to work as well as oxytocin. Due to it being less economical than other options, use is not recommended by NHS Scotland. It is given by injection into a vein or muscle.

<span class="mw-page-title-main">Sulprostone</span> Chemical compound

Sulprostone is an analogue of prostaglandin E2 (PGE2) that has oxytocic activity in assays of rat kidney cells and tissues. There are four known receptors which mediate various but often different cellular and tissue responses to PGE2: prostaglandin EP1 receptor, prostaglandin EP2 receptor, prostaglandin EP3 receptor, and prostaglandin EP4 receptor. Sulprosotone binds to and activates the prostaglandin EP3 receptor with far greater efficacy than the other PGE2 receptors and also has the advantage of being relatively resistant, compared with PGE2, to becoming metabolically degraded. It is listed as a comparatively weak receptor agonist of the prostaglandin EP1 receptor. In all events, this as well as other potent synthetic EP3 receptor antagonists have the realized or potential ability to promote the beneficial effects of prostaglandin EP3 receptor activation.

A uterotonic, also known as an oxytocic or ecbolic, is a type of medication used to induce contraction or greater tonicity of the uterus. Uterotonics are used both to induce labor and to reduce postpartum hemorrhage.

Amnioinfusion is a method in which isotonic fluid is instilled into the uterine cavity.

Uterine Tachysystole is a condition of excessively frequent uterine contractions during pregnancy. It is most often seen in induced or augmented labor, though it can also occur during spontaneous labor, and this may result in fetal hypoxia and acidosis. This may have serious effects on both the mother and the fetus including hemorrhaging and death. There are still major gaps in understanding treatment as well as clinical outcomes of this condition. Uterine tachysystole is defined as more than 5 contractions in 10 minutes, averaged over a 30-minute period.

<span class="mw-page-title-main">Retosiban</span> Chemical compound

Retosiban also known as GSK-221,149-A is an oral drug which acts as an oxytocin receptor antagonist. It is being developed by GlaxoSmithKline for the treatment of preterm labour. Retosiban has high affinity for the oxytocin receptor and has greater than 1400-fold selectivity over the related vasopressin receptors

<span class="mw-page-title-main">Oxytocin (medication)</span> Medication made from the peptide oxytocin

Synthetic oxytocin, sold under the brand name Pitocin among others, is a medication made from the peptide oxytocin. As a medication, it is used to cause contraction of the uterus to start labor, increase the speed of labor, and to stop bleeding following delivery. For this purpose, it is given by injection either into a muscle or into a vein.

References

  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. 1 2 3 4 5 6 7 "Tractocile EPAR". European Medicines Agency (EMA). 17 September 2018. Retrieved 29 April 2020.PD-icon.svg 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. 1 2 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. 1 2 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. 1 2 3 4 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. 1 2 3 4 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. 1 2 3 4 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. 1 2 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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