β –agonists use is decreasing worldwide due to safer alternative: Atosiban. Atosiban: as effective as nifedipine with fewer cardiovascular side effects.

1. Atosiban

2. Dr. Niranjan Chavan
MD, FCPS, DGO, DFP, MICOG, DICOG, FICOG
Professor and Unit Chief, L.T.M.M.C & L.T.M.G.H
Chairperson, FOGSI Oncology and TT Committee (2012-2014)
Treasurer, MOGS (2017- 2018)
Chair and Convener, FOGSI Cell- Violence against Doctors (2015-2016)
Chief Editor, AFG Times (2015-2017)
Editorial Board, European Journal of Gynecologic Oncology
Editor of FOGSI FOCUS, MOGS, AFG & IAGE Newsletters
Member, Managing Committee, IAGE (2013-2017)
Member , Oncology Committee, AOFOG (2013 -2015)
Recipient of 6 National & International Awards
Author of 15 Research Papers and 19 Scientific Chapters
Course Co-Ordinator, of 11 batches, of MUHS recognized Certificate Course of
Basic Infertility Management Including Endoscopy (BIMIE) at LTMGH

3. • On December 25, 1642 when a widow gave
birth prematurely to a male child, his mother
Hannah Ayscough reportedly described that
child as
“so small that he could have been put into a
quart mug” (≈ 1.3 liters)”
One of the earliest descriptions
of Preterm birth.
The infant survived and grew up to be “Sir Isaac Newton.”
Tan TC. Tocolytic treatment for the management of preterm labour: a systematic review. Singapore Med J. 2006 May;47(5):361-6.
“However, a significant proportion of preterm births do
not survive, let alone grow to become Newton.”

4. Indian Scenario

5. Tocolytic Therapy:
Historical perspective
• 1970s- β1-agonists (isoxuprine) were introduced.
FDA approval ritodrine
• 1980s- “decade of β 2-agonists” (salbutamol,
terbutaline, orciprenaline, fenoterol & Other-
MgSO4,indomethacin.
Expert Opin. Pharmacother. (2014) 15(5):585-588.
•1960s- the management - bed rest, hydration, opiate analgesia & iv alcohol.
•1990s- Reappraisal of the use of β2-agonists due to concerns about
serious adverse effects e.g. pulmonary edema.
Subsequently, a gradual drift away from -β2-agonists to atosiban, nifedipine.

6. Preterm labor: One syndrome, many causes

7. Complications of Preterm Delivery
• 75% of neonatal mortality occurs in Preterm Infants.
• The long-term sequelae of PTB include:
– CNS complications, such as cerebral palsy,seizures
– Neurodevelopmental delay
– Respiratory complications
– bronchopulmonary dysplasia,RDS
– Blindness & deafness
– GIT: Necrotising enterocolitis
– Cardiovascular: PDA, persistent fetal circulation
– Metabolic: hypoglycemia, hypocalcemia, jaundice
Highest incidence of complications in births occurring at <30 weeks gestation.

8. Spectrum of Tocolytic
Agents
 β-mimetics
 MgSO4
 Nitric Oxide donors
 Cyclo-oxygenase inhibitors
 Ca Channel Blockers
 Oxytocin antagonist
 Progesterone
Gr. tokos: childbirth, lytic: capable of dissolving

9. An Ideal Tocolytic
Agent
• Modes of Action: Uterospecific
• Efficacy: Short term as well as long term
• Safety: Maternal & neonatal
• Cost: Affordable
• Licensing for use: Approved /off label
• Evidence: Cochrane, RCOG, RCT

10. Rationale for Tocolysis
• To prolong pregnancy and to aim for term delivery. (This is still what women and the lay
public expect from us.)
• This idea -superseded by recent dogma : tocolytics are given to delay delivery for 48
hours,
– To allow Ante partum glucocorticoids to induce lung maturation
– In utero transfer to a tertiary care centre with NICU facilities
– Delay of delivery to permit growth, maturation & to reduce perinatal mortality &
morbidity
Ronald F Lamont. Expert Rev. Obstet. Gynecol. 3(2), 163–174 (2008).

11. The unstoppable positive feedback loop in labour: oxytocin neurons become
sensitized to incoming signals from the uterus which results in ever-increasing
oxytocin secretion and uterine contraction, terminating in birth.
Douglas AJ. Preterm labour: tsunami waves? J Neuroendocrinol. 2010Sep;22(9):1040-1.
Scientific Justification for : oxytocin
receptor antagonist

12. Scientific Justification for
Atosiban
• Oxytocin is fundamentally involved in the mechanism of preterm labour.
• Oxytocin receptors are crucial for the onset of human labor.1
• Plays two important roles in :
 the initiation of labour &
 the expulsive phase of labour
• Atosiban acts only on myometrium/myoepithelial tissue (most uterospecific).
– Best maternal and fetal safety profile
– Only tocolytic drug without serious ADR
• Atosiban was developed specifically to treat preterm labor
• Atosiban “an advance” in currently available tocolytics &
• Should be a first-line tocolytic for the management of spontaneous preterm
labour.2
2. Experimental Physiology (2001) 86.2, 297–302.
1. Science. 1982 Mar 12;215(4538):1396-8.

13. Atosiban: A novel Tocolytic
Agent

14. ATOSIBAN: Represent an advance in
currently available tocolytics .
 Atosiban is specifically developed as tocolytics/uterospecific
 Acts only on Myometrium/myoepithelial tissue.
 Best maternal and fetal safety profile
 Only tocolytic drug without serious ADR
 Safest choice In:
 Multiple pregnancies,
 Expanded blood volume &
 Anemia
Where use of other tocolytics
predispose to pulmonary
edema.
Di Renzo GC. J Perinat Med. 2006; 34(5):359-66.

15. Recommended
atosiban in the
management of
Preterm labor. [3,4]
Atosiban
1. Presented at Ninth World Conference in Perinatal Medicine. Symposium on Uterine
Contractility, [Berlin] 2009).
2. Lamont CD. Expert Opin Drug Saf. 2016 Sep;15(9):1163-73.
3. Rcog. Tocolytic drugs for women in preterm labour: Royal College of Obste-
tricians and Gynaecologists (RCOG). 2002.
4. Expert Opin Pharmacother. 2014 Apr;15(6):787-97.
Atosiban as a first-line tocolytic for the
management of Spontaneous Preterm Labor.[1,2]
International Preterm Labour Guidelines
and Tocolytic Treatment Recommendations
advocate

16. Atosiban: International Preterm Labour Guidelines &
Tocolytic Treatment Recommendations
Countries Guidelines &
Organizations
Recommendations
United
Kingdom
Royal College of Obstetricians
and Gynaecologists (R.C.O.G.)
If tocolytics are to be used, atosiban or
nifedipine are preferable.
Atosiban is licensed and nifedipine is not.
β2-agonists should not be used.
Spain PTL guideline No 10-S.E.G.O.
(Spanish Society of Gynecology and
Obstetrics)
Atosiban to be used as first choice
Austria O.E.G.G.G.
(Austrian Society GYN/OB)
Atosiban or β-agonists.
Atosiban first line for certain patient groups.
Belgium G.G.O.L.F.B. & V.V.O.G. Atosiban 1st line treatment (treatment of
choice)
Netherlands Dutch Gynecology Society
(N.V.O.G.)
Atosiban a ‘first choice’ for tocolysis.
1. Ref: Presented at Ninth World Conference in Perinatal Medicine. Symposium on Uterine Contractility, [Berlin] 2009.
2. Lamont CD. Expert Opin Drug Saf. 2016 Sep;15(9):1163-73.

17. Countries Guidelines & Organizations Recommendations
France PTL Guidelines C.N.G.O.F.
(College National des
Gynecologues et Obstetriciens
Francais)
Atosiban, first line of treatment.
In multiple pregnancies
recommended
first line: atosiban or nifedipine
Portugal No National Guidelines Atosiban or nifedipine are the
most prescribed tocolytic drug.
Atosiban recommended for diabetic
patients, multiple pregnancies and
women with cardiac pathology.
Italy S.L.O.G. Atosiban first line for “risk patient”
Atosiban: International Preterm Labour Guidelines &
Tocolytic Treatment Recommendations
Ref: Presented at Ninth World Conference in Perinatal Medicine. Symposium on Uterine Contractility, [Berlin] 2009

18. Countries Guidelines & Organizations Recommendations
Denmark Danish Society of Obstetrics
and Gynecology (D.S.O.G.)
Recommendation of Atosiban as first line
of treatment
Sweden No national guidelines. Work
in Progress
80% of the guidelines at level III
hospitals are recommending atosiban as
1st line.
Germany D.G.G.G.
(German Society of Gynecologists &
Obstetricians)
Atosiban, fenoterol, nifedipine are
recommended.
Atosiban has less side effects.
Norway Norwegian Society of
Obstetrics and Gynaecology
(N.G.F.)
1.Atosiban 2. Nifedipine
3. Indomethicin 4. Terbutaline
Atosiban: International Preterm Labour Guidelines &
Tocolytic Treatment Recommendations
1. Ref: Presented at Ninth World Conference in Perinatal Medicine. Symposium on Uterine Contractility, [Berlin] 2009.
2. Lamont CD. Expert Opin Drug Saf. 2016 Sep;15(9):1163-73.

19. Peptide structures of oxytocin
and atosiban.
Difference at
Positions- 1,2,4,8
Atosiban (INN) is a synthetic peptide ([Mpa1,D-Tyr(Et)2,Thr4,Orn8]-oxytocin)
Ronald F Lamont. Expert Rev. Obstet. Gynecol. 3(2), 163–174 (2008).
Atosiban = structure similar to oxytocin -> inhibit uterus contractions

20. Oxytocin: Mechanism of
action
Vrachnis N. Int J Endocrinol. 2011;2011:350546.

21. Mechanism of action of Atosiban
A competitive antagonist of human oxytocin receptor
Expert Rev. Obstet. Gynecol. 3(2), 163–174 (2008).
Atosiban

22. During the second half of pregnancy, uterus
shows an increase in the expression of oxytocin
receptors (100-200fold) & increasingly
sensitive to oxytocin.
Oxytocin also secreted by Decidua
(Placenta), Extra embryonic fetal
tissue.
The Role of Oxytocin/ Oxytocin
Receptor in Parturition
Terzidou V. Mechanical stretch up-regulates the human oxytocin receptor in primary human uterine myocytes. J
Clin Endocrinol Metab. 2005 Jan;90(1):237-46.

23. • Decreases the frequency & tone of uterine
contractions.
• Antagonizes uterine contractions & induces uterine
quiescence.
• The onset of uterine relaxation is rapid, contractions
significantly reduced within 10 min to achieve
stable uterine quiescence (≤ 4 contractions/hour)
for 12 hours.
Pharmacodynamics
Ronald F Lamont.. Expert Rev. Obstet. Gynecol. 3(2), 163–174 (2008).

24. Therapeutic Indications
• Indicated to delay imminent pre-term birth in pregnant adult women
with:
 Regular uterine contractions of at least 30 seconds duration at a rate of ≥ 4
per 30 minutes
 Cervical dilation of 1 to 3 cm (0-3 for nulliparas) and effacement of ≥ 50%.
 Gestational age from 24 until 33 completed weeks
 Normal foetal heart rate
Tractocile International prescribing information.

25. Standard Dosing
Regimen for Atosiban
Step Regimen Infusion rate Duration
1 0.9 ml I.V.
injection
Bolus (6.75 mg) Given over 1 minute
2 I.V. loading infusion 300µg/min 3 hr
3
I.V. infusion. 100 µg/min
Up to 45 hours
Administered Intravenously in Three Successive Stages
Tractocile International prescribing information.

27. Contraindications
− Gestational age : < 24 or > 33
completed wks.
− PROM >30 wks of gestation
− Abnormal foetal heart rate
− Antepartum uterine hemorrhage
− Eclampsia & severe pre-eclampsia
− Intrauterine foetal death
− Suspected intrauterine infection
(chorioamnionitis)
− Placenta praevia, Abruptio placenta
− Any other conditions of the mother or
foetus, in which continuation of pregnancy is
hazardous
− Hypersensitivity to the atosiban or excipients
Tractocile International prescribing information.

28.  ADRs were generally of a mild severity.
 The most commonly reported adverse reaction
in the mother is Nausea (11 %).
 No specific ADR in newborn.
Di Renzo GC, Roura LC; European Association of Perinatal Medicine-Study Group on Preterm Birth. Guidelines for the management of spontaneous
preterm labor. J Perinat Med. 2006; 34(5):359-66.
Adverse Reactions

29. Infant: Long term Safety
According to a current meta-analysis of 9
randomized no fetal side effects have been
reported.
A follow-up study of infants born after
tocolysis with atosiban revealed no ill
effect on their psychosocial and
motor development up to the age of
two years.
The Worldwide Atosiban versus Beta-agonists Study Group. BJOG. 2001 Feb;108(2):133-42.

30. Atosiban Safety - assessment of
placental & fetal circulation.
Grzesiak M, Wilczynski J. Preliminary report of 48-hours Atosiban administration in spontaneous preterm labor - Doppler blood flow assessment of
placental and fetal circulation. Neuro Endocrinol Lett. 2013;34(7):681-6.
Atosiban doesn't alter uterine nor fetal arterial blood
flow pattern.
Hemodynamic cardiac activity in fetuses remains
unaffected.

31.  Patients with renal or hepatic impairment
a) Renal impairment is not likely to warrant a dose adjustment.
b) Should be used with caution in impaired hepatic function
 Paediatric population
a) The safety and efficacy in pregnant women < 18 yrs have not been
established.
 Atosiban is not involved in CYP450 mediated drug-drug interactions.
 No clinically relevant interaction was found between atosiban and
bethamethasone or labetalol
Tractocile International prescribing information.

32. Regulatory affairs
 Jan. 2000 :Atosiban approved in the European Union.
 On 30 May 2013 The EMA granted a marketing authorisation for
atosiban SUN (Sun Pharmaceutical) a generic of Tractocile.
 Oct. 2014 : Approved In India.(Zuventus health care ltd)
 As of June 2007 atosiban is approved in 67 countries, excluding
the USA, Japan.
Ronald F Lamont. Expert Rev. Obstet. Gynecol. 3(2), 163–174 (2008).

33. Pharmacovigilance
 Following the launch of atosiban in 2000, the
calculated cumulative patient exposure to atosiban
(Jan 2000 to Dec 2005) is estimated at 156,468
treatment cycles.
 To date, routine monitoring of drug safety has
revealed no important safety issues.
Ronald F Lamont. Expert Rev. Obstet. Gynecol. 3(2), 163–174 (2008).

35. The Clinical Experience of Atosiban in Preterm
Labour
Aims: To evaluate the efficacy, safety and tolerability of atosiban in delaying
preterm labour.
Study design: A prospective, open label, non comparative study
Place of Study: Lokmanya Tilak Municipal Medical College Mumbai, India.
Methodology:
• Pregnant women (N=110) between the gestational age of 24 to 34 wks,
presenting with signs of preterm labour were enrolled in the study.
• Efficacy, safety & tolerability of atosiban were assessed for a period of 72
hrs.
Dewan B, Shah D. BJMMR.2016;13(7):1-9. Article no.BJMMR.23823.

36. Efficacy analysis based on duration of tocolysis
89.09% 89.09% 88.18%
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
48 hrs 72 hrs At discharge
Figure 1: Percentage of patients remaining undelivered at 48 hrs, 72 hrs and at
discharge (≤7 day)
1. No alternative tocolytics were required during the entire study
2. Atosiban retreatment not required by any patient (upto 7days)
3. 100% Successful in multiple birth pregnancy (7 out of 7 patients)
4. No Fetal or Maternal Side effects observed.
5. All patients tolerated Atosiban well
Dewan B, Shah D. BJMMR.2016;13(7):1-9. Article no.BJMMR.23823.

37. The strong evidence base for atosiban in SPTL
 >350 research articles, earliest 1985 compared to nifedipine (poor
quality evidence) & β-agonist (ritodrine, Isoxsuprine, Terbutaline, fenoterol).
From its clinical introduction in open-label pilot studies through Phase
II, Phase III, worldwide comparative studies and Phase IV studies a
robust evidence base for atosiban has established.
Lyndrup J, Lamont RF. The choice of a tocolytic for the treatment of preterm labor: a critical evaluation of nifedipine versus atosiban.
Expert Opin Investig Drugs. 2007 Jun;16(6):843-53.

38. Atosiban:
Open label
studies

40. Tocolytic effectiveness after 48 hours treatment with
atosiban: tocolytic success 79%.
BJOG: An International Journal of Obstetrics & Gynaecology
pages 113-115, 22 DEC 2003 DOI: 10.1046/j.1471-0528.2003.00056.x
http://onlinelibrary.wiley.com/doi/10.1046/j.1471-0528.2003.00056.x/full#f1

41. Tocolytic effectiveness after 7 days treatment with
atosiban: tocolytic success 64%.
BJOG: An International Journal of Obstetrics & Gynaecology
pages 113-115, 22 DEC 2003 DOI: 10.1046/j.1471-0528.2003.00056.x
http://onlinelibrary.wiley.com/doi/10.1046/j.1471-0528.2003.00056.x/full#f2

42. Tocolytic effect on labour (preterm labour
=≥4 contractions per 30 min).
BJOG: An International Journal of Obstetrics & Gynaecology
pages 113-115, 22 DEC 2003 DOI: 10.1046/j.1471-0528.2003.00056.x
http://onlinelibrary.wiley.com/doi/10.1046/j.1471-0528.2003.00056.x/full#f3

43. Days gained after tocolysis with atosiban.
BJOG: An International Journal of Obstetrics & Gynaecology
pages 113-115, 22 DEC 2003 DOI: 10.1046/j.1471-0528.2003.00056.x
http://onlinelibrary.wiley.com/doi/10.1046/j.1471-0528.2003.00056.x/full#f4
The overall mean number of days gained after the start of tocolysis was 31
days, whereas in the subgroup of women with PPROM the interval until
delivery was 9.3 days and in women with preterm labour 41.0 days

44. Percentage of patients who remained undelivered
0
10
20
30
40
50
60
70
80
Percentage of
undelivered patients
at 24 hours.
Percentage of
undelivered patients
at 48 hours.
Percentage of
undelivered patients
at 7 days.
58 55
48
74
69
65
Placebo
Atosiban
Am J Obstet Gynecol..2000 May;182(5):1173-83.
Percentageofpatients

45. Mean Percent Changes in the Number of Uterine contractions before & after treatment (2 hr)
Am J Obstet Gynecol. 1994 Feb;170(2):474-8.
-26.4
-55.3-60
-50
-40
-30
-20
-10
0
%DecreaseinUterine
contractions
Placebo
Atosiban

46. SN Title Test
&compara
tor drug
Study design n Remark
1. Hadar E.
Am J Obstet Gynecol. 2013
Jun 15. pii: S0002-
9378(13)00542-5.
Atosiban Open label
Comparative
21 atosiban (Tractocile) reduces uterine electrical activity in women
with preterm labor.
2.
Wu MY.Taiwan J Obstet
Gynecol. 2010 Dec;49(4):495-
9.
Atosiban Case report 1
Atosiban has few side effects and assisted in prolonging a
pregnancy involving twins that experienced extremely preterm
premature rupture of membranes.
3.
Moraloglu O. Reprod Biomed
Online. 2010 Sep;21(3):338-
43.
atosiban RCT 180 Results have indicated that atosiban increases the implantation
rate and pregnancy rate after IVF-embryo transfer.
4. Maagaard M. Ugeskr Laeger.
2009 Mar 9;171(11):907.
Case report Long-term treatment with a combination of tocolytics, Atosiban and
diclofenac inhibited labour until week 26 + 3 where both babies
were born.
5. Pierzynski P. Fertil Steril. 2007
Jul;88(1):213.e19-22.
Atosiban Case report. The treatment decreased the uterine contractile activity and
resulted in successful embryo implantation and a normal twin
diamniotic pregnancy.
6 Husslein P. BJOG. 2006 Dec;
113 Suppl 3:105-10.
Atosiban open-label,
RCT
105 The use of atosiban was effective for the delay of preterm labour
and presented no safety concerns irrespective of the time it was
administered.

47. SN Title Test
&compara
tor drug
Study design n Remark
7 Richter ON. Arch Gynecol
Obstet. 2005 Jun;272(1):26-30.
Epub 2004 Jul 23.
Atosiban prospective,
randomized
pilot study
20 In summary, atosiban showed itself to be effective for tocolytic
treatment for premature labor, even during 18 and 24 weeks of
pregnancy, while exhibiting its known, favorable profile of side
effects.
8 Lurie S. J Perinat Med.
2004;32(2):137-9.
Atosiban prospective
observational
study
15 Atosiban may be an effective treatment of uterine hyperactivity
during active labor.
9 Helmer H. BJOG. 2003 Apr;110
Suppl 20:113-5.
atosiban retrospective
study
208 Atosiban is an effective tocolytic drug in the treatment of preterm
labour and preterm rupture of the membranes. It has significantly
less side effects due to its lack of cardiovascular activity.
10 Herbst A. Eur J Obstet Gynecol
Reprod Biol. 2003 May
1;108(1):109-10.
atosiban Case report 1 Tocolytic therapy with a continuous infusion of the oxytocin
antagonist, atosiban, during 154 h. The delivery was postponed
for 12 days. The prolonged treatment was not associated with
maternal or fetal side effects.
11 Coomarasamy A. Med Sci
Monit. 2002 Nov;8(11):RA268-
73.
atosiban Meta-analysis
Cochrane
Oxytocin antagonists appear to be effective and safe for tocolysis
in preterm labour.

48. S
N
Title Test
&compara
tor drug
Study design n Remark
12 Goodwin TM. Am J Obstet
Gynecol. 1994 Feb;170(2):474-8.
atosiban RCT 120 A 2-hour infusion of the oxytocin antagonist atosiban resulted in a
significantly greater decline in contraction frequency compared
with controls.
13 Valenzuela GJ. Am J Obstet
Gynecol. 1995 Apr;172(4 Pt
1):1304-6.
atosiban Open label 8 Our results show minimal placental transfer of atosiban.
Administration of atosiban even at high doses up to the time of
delivery did not increase maternal blood loss at cesarean section.
14 Am J Perinatol. 1996
Apr;13(3):143-6.
Goodwin TM.
atosiban. An open-
labeled
62 Successful tocolysis was noted in 43 of 61 (70.5%). A decrease
in uterine contraction frequency of 50% or more was noted in 50
of 61 patients (82.0%).

49. Atosiban In Twin Pregnancy
• 60 twin pregnancy pts. who experienced late abortion & preterm labour,
randomly divided into 2 groups:
– The first group-30 cases of a short course - Atosiban for 18 hours, &
– The second group - 30 cases of a long course of Atosiban for 45 hours
Group n
(case)
48 h Efficacy
n
7 d efficacy
n
Short course of treatment 30 22 ( 73.3%) 14 (46.7%)
Long course of treatment 30 29 (96.7%) 24 (80%)
P-value 0.030 0.007
Comparison of the treatment efficacy between the two groups
Atosiban can effectively extend the pregnancy time for twin pregnancy with late abortion
and preterm labour.
Ya-Juan Xu. Int J Clin Exp Med 2016;9(2):3946-3952.

50. Summary
 Most of the tocolytics are not uterospecific & hence have multi-organ side
effects.
Atosiban:
 A new advance in the management of preterm labor.
 Uterospecific: placebo-level side effects & developed solely for the treatment of
spontaneous preterm labor.
 More efficacious than β-agonists & much safer, with a 10-fold decrease in CVS side
effects and a 15-fold decreased need to discontinue treatment owing to unacceptable
side effects.

51.  β –agonists use is decreasing worldwide due to safer alternative: Atosiban.
 Atosiban: as effective as nifedipine with fewer cardiovascular side effects.
 Nifedipine (oral) : rapid onset preparations compromise safety and slow-
release preparations compromise efficacy. [fetomaternal adverse effects]
 The high quality evidence base & serious concerns about the safety of other
agents : Guidelines recommend atosiban as first-line therapy for the
treatment of spontaneous preterm labor.
Summary