TRACTOCILE VIALS 7.5mg /0.9 ml (Bolus Injection)

Product Monograph 

Ferring International Center, Kay Fiskers Plads 11, 2300 Copenhagen S, Denmark 

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The tocolytic with placebo-level 

cardiovascular risk 1 atosiban

Product Monograph 

Introduction 

Preterm birth is a continuing obstetric problem 

that contributes significantly to the incidence of 

perinatal death and long-term handicap. In this 

context, preterm births are believed to account 

for between 69% and 83% of neonatal deaths in 

various studies. 2-4 Despite this, the incidence of 

preterm birth has remained static for many years. 

One explanation for this is that the management 

of preterm labour has altered very little in the 

past 30 years. Strategies aimed at reducing the 

incidence of preterm birth include the 

identification of risk factors that increase the 

likelihood of preterm delivery. Treatment is then 

designed to target those risk factors and limit 

their effect. Although perinatal mortality has 

declined, mostly due to the improved management 

of very low birthweight babies rather than 

prevention of preterm labour, efforts to prevent 

preterm birth have been largely unsuccessful so far 

and preterm birth still represents a major 

healthcare problem to both developed and 

developing countries. 

Preterm labour is now known to exist as a 

heterogenous syndrome, with many different 

aetiologies, some more significant than others. 

This may help to explain why treatment strategies 

for preterm labour have been relatively 

unsuccessful to date. 

Pharmacological intervention, through the 

administration of tocolytic agents, is the current 

mainstay of therapy to suppress preterm labour. 

All of the currently available tocolytic agents 

share a similar level of efficacy, prolonging 

pregnancy for up to 48 hours. Their use is most 

effective at gestational ages below 30 weeks, and 

it has been shown that an extension of pregnancy, 

even of a few days, can have a major impact on 

survival and the prevention of morbidity at 24–28 

weeks gestation 5 . However, current tocolytic 

agents, such as beta-agonists, have significant side 

effects in the mother and fetus, which may cause 

clinically important complications. 

Tractocile ® is the first oxytocin antagonist to be 

specifically developed for the treatment of 

preterm labour. Tractocile ® has a specific mode 

of action, inhibiting oxytocin-induced uterine 

contractions by blocking oxytocin receptors in the 

uterus. Extensive clinical investigations have 

shown Tractocile ® to be at least as effective as 

current tocolytic agents. In addition, due to its 

novel and specific mode of action, Tractocile ® has 

a markedly improved maternal side effect profile 

compared with conventional therapies. 

This monograph provides an up to date review 

of all the data currently available on Tractocile ® . 

Information on the chemistry, pharmacology, 

clinical and preclinical development of Tractocile ® 

is provided. 

This monograph is provided as a reference 

source for obstetricians treating pregnant 

women in preterm labour. Current management 

strategies of treating preterm labour are 

reviewed and the benefits of using tocolytic 

agents are discussed. 

2 3

Contents 

Introduction ................................................................................3 

1 Preterm labour and birth......................................7 

Definition ............................................................................8 

Extent of the problem ........................................................8 

Risk factors ..........................................................................8 

Past obstetric history......................................................8 

Sociobiological variables ...............................................9 

Complications of the current pregnancy....................10 

Prediction/diagnosis..........................................................11 

Risk scoring systems .....................................................11 

Biochemical markers....................................................11 

Cervical status...............................................................11 

Early diagnosis..............................................................11 

2 Management of preterm labour.................13 

Diagnosis ...........................................................................14 

Objectives ..........................................................................15 

Guidelines for managing preterm labour ..................15 

Treatment ..........................................................................15 

Efficacy...............................................................................16 

Tocolytic therapy...............................................................16 

Beta-agonists................................................................16 

Prostaglandin synthetase inhibitors ...........................18 

Magnesium sulphate ...................................................19 

Calcium channel blockers ............................................20 

Oxytocin antagonists ...................................................21 

3 Tractocile ® ........................................................................23 

Rationale for development ..............................................24 

Mechanism of action ........................................................24 

Chemistry of Tractocile ® ....................................................24 

Preclinical studies ..............................................................25 

Receptor binding: affinity, specificity .........................25 

Pharmacological activity In vivo..................................25 

In vivo effect on uterine contractility .........................25 

Effect on labour duration............................................25 

Effect on prostaglandin release ..................................25 

Clinical pharmacodynamic studies ...................................26 

Clinical pharmacokinetic studies......................................26 

4 Clinical efficacy of Tractocile ® ....................29 

Phase II clinical experience ...............................................30 

Phase III studies .................................................................31 

Tractocile ® vs. ritodrine................................................31 

Tractocile ® vs. salbutamol ............................................32 

Tractocile ® vs. terbutaline............................................32 

Pooled analysis.............................................................32 

5 Clinical safety of Tractocile ® .........................35 

Phase II studies........................................................................36 

Phase III studies.......................................................................37 

Placebo controlled studies...............................................37 

Comparative studies ........................................................37 

Pooled analysis .................................................................37 

Infant follow up after beta-agonist tocolytic therapy..39 

6 Pharmaceutical application 

of Tractocile ® .................................................................41 

Therapeutic indication......................................................42 

Pharmaceutical form.........................................................42 

Dosage and administration ..............................................42 

Preparation of the initial i.v. solution for injection ...42 

Preparation of the diluted Concentrate for Solution 

for Infusion.................................................................. 43 

Contraindications............................................................. 43 

Precautions and warnings ................................................43 

Interaction with other medicinal products 

and other forms of interaction ........................................43 

Pregnancy and lactation...................................................43 

Undesirable effects ...........................................................43 

Overdose............................................................................43 

Storage and packaging information ...............................43 

7 Summary of the key benefits of Tractocile ® 

in the treatment of preterm labour .........45 

Proven efficacy and tolerability .......................................46 

Good safety profile ...........................................................46 

Absence of tachyphylaxis .................................................46 

Specific mode of action ....................................................46 

Rapid onset of action........................................................46 

Period of use .....................................................................46 

Conclusion ......................................................................47 

References..............................................................48-51 

4 5

6 

1 

Preterm labour and birth

Chapter 1 Preterm labour and birth 

1.1 Definition 

The last general consensus defined preterm birth as a 

gestational age less than 37 completed weeks or 259 days 

from the first day of the last menstrual period. 6 Low infant 

birth weight (

Chapter 1 Preterm labour and birth 

1.3.c Complications of the current pregnancy 

Infection 

In some populations, infection is believed to be 

responsible for up to 40% of preterm labour. 26 Vaginal 

microbial colonisation, vaginosis and even bacteriuria 

during the first and second trimester of pregnancy are 

known to increase the risk of preterm labour. There are 

three sources of evidence to suggest a role for infection 

in the onset of preterm labour: 27 

• administration of bacteria or bacterial products to 

animals results in either abortion or labour 

• systemic maternal infections such as pneumonia, 

malaria and typhoid fever are associated with the onset 

of labour 

• localised intrauterine infection is associated with 

preterm labour and delivery. 

Intrauterine infection is believed to originate in a number 

of ways: (1) ascending from the vagina and cervix; (2) 

through the placenta, (3) from the peritoneal cavity into 

the fallopian tubes; or (4) by iatrogenic means. 28 The most 

common pathway is believed to involve ascending 

infection from the vagina to the uterus. 29 Microbial 

invasion can take place in the absence of clinical or 

symptomatic signs of infection, therefore a positive 

amniotic fluid culture will be direct evidence of infection. 

Infection is thought to trigger preterm labour and 

membrane rupture via inflammation and the associated 

cytokine cascade (see figure 1). Once it has begun, the 

cytokine cascade persists. Antibiotics will therefore be 

unable to prevent the onset of birth, however, they can 

have an impact when used earlier in pregnancy. Trials 

have shown that antibiotic treatment of bacteriuria and 

vaginosis reduces the incidence of preterm birth. 30 

Figure 1. 

Plausible pathway for the initiation of preterm birth 

Fetal events: 

• Accelerated maturational changes 

• Stressors 

via CNS 

CRH 

Oxylacin 

Oxylacin 

Prostaglandins 

Cytokines 

Activation of 

receptor sites and 

calcium uptakes 

Myometrium 

Contraction 

Labour 

Cervix 

Effacement 

and dilation 

Maternal events: 

• Medical condition e.g. infection 

• Lifestyle 

• Strain 

• Psychological 

Oxylacin 

Prostaglandins 

Cytokines 

Maturational 

changes 

CRH 

Oxylacin 

Uteroplacental unit 

via CNS 

Plausible pathway for the initiation of preterm birth 

becomes detached from the uterine wall. This has been 

shown to be a strong predictive factor of preterm 

delivery. 33 

paramount importance to be able to predict accurately 

those women at risk. Before a decision to intervene in the 

pregnancy can be taken, it is essential that preterm 

labour has been diagnosed otherwise the mother or baby 

may experience unnecessary stress or harm. 

Several techniques have been developed in an 

attempt to identify women at risk of preterm birth, 

however, they are only predictions based on risk analysis. 

These techniques include risk-scoring systems, 

biochemical markers and cervical status. 

1.4.a Risk-scoring systems 

Since there are many risk factors associated with preterm 

birth, scoring systems have been developed. These 

systems have been designed to evaluate overall risk by 

assigning weighted scores to each factor’s relative 

importance. To be of any clinical use, the scoring systems 

should reproduce a high positive predictive value (a high 

proportion of true cases among all those with a positive 

test result) and be sensitive (able to detect true cases). 

Unfortunately, such risk scoring systems are neither 

predictive nor sensitive, typically having a positive 

predictive value of 17–34% and a sensitivity of

12 

2 

Management of preterm labour

Chapter 2 Management of preterm labour 

Once a clinical diagnosis of true preterm labour has 

been made, it is necessary to evaluate the management 

options available. A clinical diagnosis has traditionally 

been based on the presence of uterine contractions and 

cervical dilation. The accuracy of pregnant women to 

detect signals of preterm labour is poor with nulliparous 

women but improves in multiparous women. 42 

A thorough evaluation of a woman presenting with 

true preterm labour should include obstetric history, 

physical examination, infection screening, toxicology 

screening, immunopathology tests and ultrasound 

assessment (see table 2). 

2.1 Diagnosis 

The fundamental issue in the management of preterm 

labour is whether the risk of delivery outweighs the risk 

of prolonging the pregnancy. It would seem ideal to 

prolong pregnancy in all cases to maximise fetal 

development, but this is not always possible. The woman 

may be already in the later stages of active labour or 

serious adverse maternal/fetal factors may dictate the 

need for an immediate delivery. 43 Certain criteria have 

been proposed for the diagnosis of preterm labour in 

order to prevent unnecessary tocolytic therapy. These 

include a gestational age assessment, uterine 

contractions, membrane status, and cervical assessment. 

In some cases when gestational age is unknown it is 

important to determine whether a small fetus is preterm 

or growth restricted. Measurement of the fetal 

Medical history 

transcerebellar diameter by ultrasound may help 

distinguish them. 44 Regarding uterine contractions, it was 

found that at least five contractions per hour after 30 

weeks’ gestation is a strong indicator of preterm labour. 45 

Uterine contractions alone should not be relied upon, 

however, since experience shows that the rate of error 

when diagnosing preterm labour using this technique is 

more than 50%. 46 If the membranes are intact, a cervical 

dilation of at least 2 cm or effacement of 80% with 

regular uterine contractions are required for a diagnosis 

of preterm labour. Biochemical methods such as the fetal 

fibronectin test are also promising an earlier detection 

and diagnosis of preterm labour (see table 3). 

TABLE 2. CLINICAL APPROACH TO THE EVALUATION OF TRUE PRETERM LABOUR 

Physical examination General examination Abdominal examination 

Fetal assessment 

Sterile speculum examination 

Digital vaginal examination 

Infection screening 

Fetal lung maturity studies 

Urine toxicology screen Medications Substance abuse 

Immunopathology studies Antinuclear antibody Lupus anticoagulant 

Anticardiolipin antibody 

Ultrasound assessment 

Doppler velocimetry 

TABLE 3. CRITERIA FOR THE DIAGNOSIS 

OF PRETERM LABOUR 

• Gestational age: 20–37 weeks 

• Regular uterine contractions: ≥ 5–8 minutes apart, 

lasting 30 seconds 

• Amniotic membranes: ruptured. If intact, then at least 

one of the following is also required: 

• Cervical changes (by one observer) 

• Cervical effacement > 75% 

• Cervical dilation > 2 cm 

Post-partum investigations Placental pathology Post-partum infection screening 

Urinary tract studies 

Hysterosalpingogram 

2.2 Objectives 

The objectives of managing preterm labour are to 

minimise perinatal morbidity and mortality while 

preserving maternal health. 47 Initial management 

options include: (1) immediate delivery, e.g. fetal death 

or risk of maternal complications; (2) allow delivery to 

proceed naturally, e.g. labour is too advanced to 

inhibit; (3) delay delivery; (4) observe with no specific 

action; (5) transfer to a specialised tertiary care centre 

(see figure 2). 48 Passive management of preterm labour 

such as bed rest and sedation has not demonstrated 

any significant benefit, however, the addition of 

intravenous hydration may be effective short term by 

improving uterine blood flow and reducing myometrial 

activity. 

2.2.a Guidelines for managing preterm labour 

The Australian Government has produced the first set of 

recommendations for the management of preterm 

birth, “Clinical Practice Guidelines for Care Around 

Preterm Birth”. 49 The main points taken from these 

guidelines are as follows: 

• Target audience: healthcare professionals, educational 

establishments & consumers 

• The guidelines were based on an evidence-rating 

system so that informed decisions could be made on 

available evidence-based medicine, with Level I 

(evidence obtained form a systematic review of all 

relevant randomised, controlled trials [Cochrane 

Database]) being the ‘gold standard’ 

• Key factors highlighted by these guidelines included: 

– Communication 

– Medical indicators of risk 

– Social and lifestyle factors 

– Risk assessment 

– Diagnosis 

– Clinical prevention 

– Tocolysis 

– Pharmacological treatments after PPROM 

– Pharmacological treatments to improve neonatal 

outcome 

– Place of birth and level of care 

– Care of the preterm infant 

– Support for families 

– Care and follow-up after leaving hospital 

– Prevention and treatment of specific conditions 

Figure 2. 

No cervical change 

Observe 

2.3 Treatment 

Threatened 

preterm 

labour 

Cervical 

change ie. 2 cm 

dilated or 80% effaced 

Tocolysis 

contraindicated 

or>34 completed weeks 

Allow 

delivery 

Diagnostic workup 

to determine cause 

Advanced labour or 

fetal distress 

Delivery 

(prior to 

next pregnancy) 

Tocolysis indicated 

and gestational age 

between 20-34 weeks 

Administer tocolytic 

and corticosteroids 

Clinical algorithm for the treatment of threatened 

preterm labour (McNamara and Vintziteos, 1997) 

Once the decision to delay delivery has been made, and 

providing there are no contraindications, the woman 

should receive active management involving tocolytic 

therapy. Acute episodes of preterm labour can be 

managed actively, e.g. tocolysis, although long-term 

monitoring and maintenance tocolytic therapy may be 

required in order to avoid a recurrence during the 

remainder of the pregnancy. However, there is no 

evidence to suggest that maintenance therapy is 

clinically effective at preventing a recurrence of 

preterm labour. 

Treatment for preterm labour consists of several 

therapeutic approaches. Tocolysis is regarded as firstline 

treatment together with corticosteroids (used to 

aid fetal lung maturation) and antibiotics (used as a 

prophylactic). Once uterine activity is inhibited or few 

contractions are recorded (ie. ≤4 per hour) after 

intravenous tocolysis, oral or intravenous maintenance 

tocolysis may be initiated, providing maternal and fetal 

monitoring is continued. If side effects are excessive, 

the infusion rate can be altered (titrated) accordingly. 

On the first day following successful tocolytic 

treatment, strict bed rest is usually advised and if after 

two days contractions are rare or absent, the woman’s 

condition is considered to be stable. Women with 

abnormal cervical change are usually observed for 

longer periods. Other factors leading to a longer 

duration of hospitalisation include a complicating 

diagnosis (e.g.. urinary tract infection) and low 

gestational age. In most uncomplicated cases, 

hospitalisation does not exceed 3–4 days. 

14 15


2.4 Efficacy 

Evaluating the effectiveness of a therapeutic intervention 

has been complicated by the outcome variables used to 

define whether treatment is successful. The real impact of 

a therapeutic intervention should improve perinatal 

outcomes. In the past, clinicians have regarded outcomes 

such as small increases in birth weight and length of 

gestational age as indicators of success. However, the 

widespread use of pharmacological agents has not 

significantly reduced the rate of low-birthweight infants. 

This may be explained by the fact that only 10–20% of 

women at risk for preterm delivery are actually suitable 

candidates for the use of tocolytic agents. 9 

2.5 Tocolytic therapy 

The treatment of preterm labour by reducing or stopping 

preterm uterine contractions has been a therapeutic 

approach for more than 40 years. Intervention with 

pharmacological agents is the preferred first-line 

treatment of preterm labour. A number of tocolytic 

agents have been used over the last 40 years with varying 

levels of success. 

2.5.a Beta-agonists 

Beta-agonists are the most widely used tocolytic agents, 

although their use is primarily associated with treating 

asthma. In 1961, the non-selective beta-agonist 

isoxsuprine was the first agent proposed for the 

treatment of preterm contractions. However, because of 

its significant side effects, including maternal hypotension 

and fetal bradycardia, its clinical use was limited. The 

introduction of ritodrine over 20 years ago heralded the 

arrival of the first of the selective beta-agonists, which 

also include salbutamol, terbutaline and fenoterol. 

Mode of action 

Beta 1 and beta 2 receptors are located in most organ 

systems in the body. The beta 1 receptors mediate 

stimulatory effects and predominate in the heart, small 

intestine and adipose tissue. The beta 2 receptors mediate 

relaxant/inhibitory effects and are located in the uterus, 

blood vessels, bronchioles and liver. 

Beta-agonists exert their tocolytic effect by acting 

on intramembranous beta 2 receptors in the uterus, 

thereby relaxing the smooth muscle of the myometrium. 

Stimulation of these receptors activates the enzyme 

adenylate cyclase, which leads to an increase in 

intracellular cAMP. The cAMP acts as a secondary 

messenger, initiating a series of cellular reactions which 

ultimately reduce intracellular calcium levels, which in 

turn decreases the sensitivity of the contractile unit 

within the uterus wall to the effects of calcium and 

prostaglandins. 

Some beta-agonists have a greater selectivity for 

inhibition of uterine contractility than others, but 

none of those developed so far are entirely specific to 

beta 2 receptors in the uterus. It is the non-selectivity of 

beta-agonists that explains their unfavourable safety 

profile. The potential to stimulate other organ 

systems gives rise to serious systemic side effects to 

both the mother and fetus. 

Clinical efficacy 

All of the randomised, controlled trials of betaagonists 

are summarised in table 4. A meta-analysis of 

16 methodologically-acceptable trials using a database 

of 890 women indicated that beta-agonists delayed 

delivery for up to 48 hours, reduced the frequency of 

preterm birth and low birthweight babies, but without 

a reduction in perinatal mortality or the incidence of 

severe neonatal respiratory problems. 50 The Canadian 

Preterm Labor Investigators Group reported similar 

findings in women treated with oral and intravenous 

ritodrine in a placebo-controlled study. 51 More recent 

and larger placebo-controlled trials have also raised 

uncertainties regarding the use of maintenance betaagonist 

therapy. 52,53 

Terbutaline is another selective beta 2 -agonist in 

which studies have also presented conflicting results 

regarding prolonging pregnancy. Comparative trials 

with ethanol, 54 ritodrine and magnesium sulphate 

demonstrated a similar short-term efficacy in the 

treatment of preterm labour. 55 Another commonly 

used beta-agonist is salbutamol, although it does not 

confer any apparent advantages over the other betaagonists 

regarding effectiveness and side effects. 

Clinical safety 

Since beta-receptors are ubiquitous in body systems, any 

pharmacological intervention will be expected to 

induce a wide range of side effects. Even though the 

rationale for beta-agonist administration is based on 

their activity at receptors in the myometrium, they elicit 

a number of systemic side effects that are unrelated to 

their action in the uterus. Consequently, there are a 

variety of serious complications associated with their 

use in both mother and fetus. 

Maternal adverse effects 

The most significant side effects elicited by beta-agonists 

affect the cardiovascular system. Beta-agonists produce a 

general vasodilation resulting in systolic hypotension, 

which induces a compensatory increase in maternal 

cardiac output of up to 40–60%. 56 Although a decrease in 

peripheral vascular resistance occurs, this is offset by the 

large increase in cardiac output, which is further 

exacerbated by the antidiuretic effect of beta-agonists 

after long-term therapy. The resulting hypertension may 

contribute towards an underlying cardiac disease or 

TABLE 4. KEY RANDOMISED, CONTROLLED CLINICAL TRIALS OF CURRENT TOCOLYTIC AGENTS 

Study drug Control drug Total no. women Outcome parameter Success rate Reference 

Ritodrine Placebo 30 Delivery delayed >48 hours 50 vs. 55% [84] 

76 Delivery delayed >48 hours 73 vs. 69% [85] 

708 Delivery delayed >48 hours 79 vs. 65%* 

Mean days gained 28 vs. 25 days [49] 

63 Delivery delayed > 7 days 80 vs. 48%* [86] 

29 Delivery delayed > 7 days 29 vs. 27% [87] 


99 Mean days gained 34 vs. 25 days [89] 


Terbutaline Placebo 38 Delivery delayed > 48 hours 54 vs. 38% [91] 

30 Delivery delayed > 7 days 87 vs. 27%* [92] 


Ritodrine 58 Delivery delayed > 48 hours 73 vs. 77% [94] 

85 Delivery delayed > 48 hours 45 vs. 69% [53] 

99 Delivery delayed > 72 hours 80 vs. 67% [95] 

Salbutamol Placebo 144 Delivery 24 hours 94 vs. 22%* [98] 

Ritodrine 100 Delivery delayed >48 hours 94 vs. 83% [68] 


Terbutaline 71 Mean days gained 43 vs. 41 days [100] 

MgSO4 Placebo 35 Delivery delayed > 48 hours 38 vs. 37% [91] 


Terbutaline 86 Delivery delayed > 48 hours 70 vs. 45% [53] 

Indomethacin 80 Delivery delayed > 48 hours 93 vs. 92% [102] 

Nifedipine Placebo 40 Delivery delayed > 48 hours 63 vs. 23%* [77] 



185 Delivery delayed > 7 days 62 vs. 50 %* [79] 

Terbutaline 53 Delivery delayed > 48 hours 68 vs. 67% [80] 

* Statistically significant (p

Chapter 2 Management of Preterm labour 

Fetal/neonatal adverse effects 

Beta-agonists readily cross the placental barrier and 

accumulate in the fetal circulation, increasing uteroplacental 

blood flow. This is supported by the fact that 

fetal tachycardia occurs upon administration of betaagonist 

therapy. Despite several reports of fetal 

cardiovascular changes, none of them are considered to 

be life threatening. Effects on fetal metabolic systems 

include hypoglycaemia, believed to be related to 

hyperinsulinaemia, and elevated growth hormone levels 

induced by beta-agonist stimulation of the fetal 

pancreas. Continuous beta-agonist therapy for greater 

than six weeks is associated with an increased risk of 

reactive hypoglycaemia after birth. 64 

Regarding the neonate, there have been no reports 

of adverse effects immediately following delivery, 

although there have been isolated cases of transient 

neonatal tachycardia and tachyarrhythmia reported in 

preterm neonates exposed to beta-agonist therapy. 65 

Fetal and neonatal adverse events are summarised in 

table 6. 

Infant follow up studies of up to 9 years have not 

indicated any significant difference in outcome between 

infants treated with beta-agonists and untreated 

preterm controls. 

Potential therapeutic benefit 

Ritodrine was licensed for use in the United States for 

nearly 20 years. However, its licence for preterm labour 

has since been rescinded by the US FDA. A review of the 

available data suggests perinatal improvements using i.v. 

ritodrine have only been documented in women prior to 

33 gestational weeks while the efficacy of current oral 

dosing remains questionable, with doubts concerning 

whether ritodrine can reach adequate serum levels to 

achieve tocolysis. 66 One of the problems associated with 

the clinical trials to date has been the poor selection 

criteria. It has been proposed that maternal and neonatal 

adverse effects could be minimised if women most likely 

to respond to treatment were included in the studies 

together with stricter adherence to the study protocols. 

These recommendations also apply to terbutaline 

and salbutamol. Newer, more selective beta 2 – agonists 

including fenoterol and hexoprenaline have displayed 

similar tocolytic effects as well as similar adverse 

effects, however they have not been properly 

evaluated in a controlled clinical setting. 

2.5.b Prostaglandin synthetase inhibitors 

Prostaglandin synthetase inhibitors are effective drugs 

for inhibiting preterm labour. The most commonly used 

prostaglandin synthetase inhibitor is indomethacin, 

which has an efficacy at least equivalent to betaagonists 

and generally causes fewer maternal side 

effects. However, it is less well tolerated by the fetus, 

therefore its use should be restricted below 30–32 

weeks gestation. Although indomethacin is used in 

Europe there are concerns over its safety profile in the 

fetus and neonate due to the incidence of significant 

cardiovascular side effects. 


Prostaglandins have an integral role in the modulation 

of uterine contractility during preterm labour. 

Prostaglandins activate calcium channels within the 

myometrium and function as a secondary messenger, 

increasing intracellular calcium levels via the sarcoplasmic 

reticulum. Current prostaglandin synthetase inhibitors 

target the cyclooxygenase (COX) enzyme, which prevents 

the synthesis of prostaglandins from their precursor, 

arachidonic acid. There are two forms of the COX 

enzyme, an inducible (COX-2) and constitutive 

(COX-1) form. The production of COX-1 is relatively 

constant throughout pregnancy, whereas COX-2 rises 

markedly during labour. COX-1 predominates in fetal 

cardiovascular tissue while COX-2 is located in the fetal 

membranes and myometrium. Indomethacin affects both 

forms of the enzyme hence potential fetal side effects. 


Initial observations of women taking high-dose 

salicylates showed a greater frequency delivering post- 

term, with increases in mean gestational age. Initial 

studies with prostaglandin synthetase inhibitors in 

women requiring further tocolytic treatment after 

initial agents had failed showed encouraging results. 67 

Indomethacin was the first prostaglandin synthetase 

inhibitor to be used as a tocolytic agent. Placebocontrolled 

and comparative studies of indomethacin 

demonstrated that indomethacin was more effective 

than placebo in delaying preterm delivery during a 24- 

hour course of therapy. Regarding the comparative 

studies, indomethacin was at least as effective as betaagonists 

and magnesium sulphate with respect to delay 

of delivery (see table 4). 



Maternal side effects associated with prostaglandin 

synthetase inhibitors are minimal. The most common 

include gastro-intestinal irritation and proctitis, but 

these are generally tolerated by women. Effects on 

platelet function are theoretically reversible, however 

there are conflicting reports of altered maternal 

bleeding times. 68 Prolonged therapy has been 

associated with altered T-cell suppressor activity in the 

mother, although the clinical significance of this 

remains to be seen. 69 

Fetal/neonatal effects 

One of the first complications of indomethacin therapy 

affects the renal system, resulting in a reduction in 

amniotic fluid (oligohydramnios). This is believed to occur 

in up to 10–30% of exposed fetuses. 70,71 Both short- and 

long-term exposure has been shown to significantly 

decrease urine production in the fetus. This was found to 

be dose dependent, 72 unrelated to the duration of 

therapy 71 and reversible upon cessation of therapy. High 

levels in the neonate are also associated with an 

increased risk of necrotizing enterocolitis which causes 

gastro-intestinal bleeding. 73 

There are also significant effects on the cardiovascular 

system, with 20–50% of exposed fetuses displaying 

vasoconstriction of the ductus arteriosus. This may last up 

to 2 hours following each dose, which resolves 

completely after 24 hours. 74 Furthermore, the effect is 

related to gestational age, with maximum constriction 

noted in gestational ages beyond 32 weeks. 75 This is 

thought to occur with both short- and long-term 

exposure. The exact mechanism by which this constriction 

can lead to in utero heart failure remains undetermined, 

however chronic constriction may result in hypertrophy 

of the fetal pulmonary vasculature leading to 

hypertension. Other potential risks associated with 

prostaglandin synthetase inhibitors are listed in table 7. 


Although the prostaglandin synthetase inhibitors are 

regarded as one of the most effective tocolytic agents, 

their clinical use should be restricted to short-term 

administration only due to their significant and severe 

fetal and neonatal side effects. Alternatives to 

indomethacin include sulindac, which has the benefit 

of being unable to cross the placenta. It is, however, an 

inhibitor of both forms of the COX enzyme with the 

potential to cause maternal side-effects. 

There are also specific inhibitors designed to target 

only the COX-2 inducible form. Such drugs are still at an 

early stage of development, although an improved 

fetal safety profile is anticipated. A recent report on the 

use of nimesulide (COX-2 inhibitor) has, however, cast 

doubt on the safety of these drugs. A recent case study 

reported neonatal irreversible end stage renal failure 

after maternal ingestion of nimesulide used as a 

tocolytic for 6 weeks. 76 

2.5.c Magnesium sulphate 

In the USA, the familiarity of administering magnesium 

sulphate for the management of preeclampsia and an 

apparent lack of side effects helped encourage its use 

as a tocolytic agent. 

TABLE 5. POTENTIAL MATERNAL COMPLICATIONS ASSOCIATED WITH 

BETA-AGONIST ADMINISTRATION [BESINGER & IANNUCCI, 1997] 

Cardiovascular Metabolic Neuromuscular Other Multifactorial 

maternal death 

• Cardiac arrhythmia • Diabetic ketoacidosis • CNS stimulation • Agranulocytosis • Hyperthyroid crisis 

• Cardiac stimulation • Euglycaemic acidosis • Cerebral vasospasm/ • Altered thyroid function • Pulmonary oedema 

• Hypotension • Glucose intolerance ischaemia • Bone marrow suppression • Underlying cardiac 

• Myocardial infarction • Hyperglycaemia • Neuromuscular • Cutaneous vasculitis arrythmia 

• Myocardial ischaemia • Hyperinsulinaemia alterations • Elevated transaminase levels • Unrecognised 

• Peripartum cardiomyopathy • Hyperlactacidaemia • Tremor • Erythema multiforme cardiac disease 

• Peripheral vasodilation • Hypocalcaemia • Haemolytic anaemia 

• Pulmonary oedema • Hypoglycaemia 

• Sodium/water retention • Hypokalaemia 

• Tachycardia 

• Hypomagnesaemia 

TABLE 6. POTENTIAL FETAL/NEONATAL COMPLICATIONS ASSOCIATED WITH 

BETA-AGONIST ADMINISTRATION [BESINGER & IANNUCCI, 1997] 

Cardiac Metabolic Other 

• Altered utero-placental blood flow 

• Bradycardia 

• Cardiac arrhythmia 

• Cardiac stimulation 

• Cardiovascular decompensation 

• Exacerbation of fetal hypoxia 

• Myocardial ischaemia 

• Myocardial necrosis 

• Peripheral vasodilation 

• Septal hypertrophy 


• Hyperbilirubinaemia 

• Hypercholesterolaemia 

• Hyperglycaemia 

• Hyperinsulinaemia 

• Hypocalcaemia 

• Hypoglycaemia 

• Intraventricular 

haemorrhage 

• Leukaemoid reaction 

• Renal insufficiency 

• Retinopathy 

18 19



Magnesium sulphate has been known to reduce uterine 

contractility for a long time. The basis of its tocolytic 

action is still unknown, although it is presumed to 

involve competition with calcium for entry into muscle 

cells through voltage-gated calcium channels. Another 

theory is that magnesium competitively binds to calcium 

storage sites in the myometrial endoplasmic reticulum. 

Both mechanisms of action will inhibit the cellular influx 

of calcium necessary for smooth muscle contraction. 


A large comparative study reported treatment 

discontinuation due to adverse drug effects in 38% 

of patients treated with beta-agonists and only 

2% treated with magnesium sulphate. 55 However, 

magnesium is a non-specific agent and will compete 

with calcium throughout the body. Consequently, there 

is the potential for a number of widespread side 

effects. An increase in the availability of magnesium 

sulphate and its use in clinical practice has led to a 

greater number of reports of side effects, which has 

cast doubt on its continued use. (see table 8 for 

summary of maternal/fetal and neonatal effects). 


There is a dramatic difference in the rate and type of 

maternal side-effects reported. While initial reports 

seemed to be reassuring there are now calls for a 

re-evaluation of its use as a tocolytic in clinical practice. 

The cardiovascular safety of magnesium sulphate has 

recently been challenged. There have been several 

cases of pulmonary oedema and myocardial 

ischaemia reported, which suggest further potentially 

unrecognised myocardial complications. Significant 

prolongations in QT intervals may also be indicative of 

potential life-threatening arrhythmias. 


Significant accumulation of magnesium sulphate in the 

fetal circulation may contribute to reports of suppressed 

fetal breathing and movement, and neonatal 

respiratory depression. Another recent study suggests 

an increase in total paediatric mortality due to exposure 

to magnesium sulphate. 77 A subsequent meta-analysis 

suggested that magnesium sulphate may account for 

40% of total paediatric mortality, which translates to an 

increase in the absolute number of infant deaths by 

about 4800 every year in the USA. 78 


The evidence gathered so far for magnesium sulphate is 

often inconsistent and unreliable. At low doses, the 

side effects are minimal although its efficacy is no better 

than beta-agonists. At higher doses, it may be able to 

delay delivery for longer but with a subsequent increase 

in the severity of side effects. The likeliest role proposed 

for magnesium sulphate therapy is for short-term 

control of uterine activity, which provides a good 

margin of safety. 

2.5.d Calcium channel blockers 

Calcium channel blockers have proven to be as effective 

as beta-agonists and magnesium sulphate in delaying 

preterm labour. 79,80 However, the safety of the calcium 

channel blockers is still under scrutiny. Since they are 

already established in the treatment of several 

cardiovascular diseases, such as hypertension and 

angina, it is likely that they will cause cardiovascular 

side effects. Calcium channel blockers used as tocolytics 

include nifedipine and nicardipine. 


The calcium channel blockers have a powerful uterine 

relaxant effect, which is mediated by inhibiting the 

cellular influx of calcium by blocking the voltage-gated 

channels present in the myometrium. Animal and 

human in vitro models have demonstrated a 

suppression of prostaglandin and oxytocin-induced 

uterine contractions. Calcium channel blockers have yet 

to be approved for use as a tocolytic agent. 


Early studies with nifedipine were encouraging, with 

subsequent placebo-controlled and comparative 

studies revealing an efficacy similar to beta-agonists in 

the short and long term. 81,82 (Table 9 summarises 

TABLE 7. POTENTIAL MATERNAL AND FETAL/NEONATAL COMPLICATIONS ASSOCIATED WITH 

PROSTAGLANDIN SYNTHETASE INHIBITOR ADMINISTRATION [BESINGER & IANNUCCI, 1997] 

Maternal complications 

• Altered bleeding times 

• Altered immune response 

• Antipyresis 

• Gastro-intestinal irritation 

• Platelet dysfunction 

• Renal dysfunction 

Fetal/neonatal complications 

• Altered cerebral blood flow 

• Altered immune response 

• Constriction of ductus arteriosus 

• Cystic brain lesions 

• Exacerbation of congenital heart disease 

• Fetal hydrops 

• Hyperbilirubinaemia 

• Intraventricular haemorrhage 

• Isolated ileal perforation 

• Necrotising enterocolitis 

• Oligohydramnios 

• Oliguria 

• Patent ductus arteriosus 

• Persistent pulmonary 

hypertension 

• Renal dysfunction 

maternal/fetal and neonatal side effects). Until larger 

clinical trials have been undertaken, these preliminary 

findings remain unsupported. 

Clinical Safety 


Due to their clinical indication, the cardiovascular side 

effects of the calcium channel blockers are well known. 

In pregnant women they are used to control 

preeclampsia, however they are not recommended as a 

first-line therapy for pregnancy-induced hypertension. 

Reports of reflex tachycardia and reduced atrioventricular 

conduction as a consequence of 

hypotension are common. Despite these concerns their 

effect on the cardiovascular system appears to be less 

severe compared with beta-agonists. Theoretically, 

calcium channel blockers may predispose to pulmonary 

oedema, although overall clinical experience with 

nifedipine in pregnant women suggests a minimal 

number of cardiovascular and metabolic side effects. 


Fetal cardiovascular function appears to be essentially 

unchanged with short-term nifedipine therapy. Of the 

limited number of studies conducted so far, few have 

demonstrated any significant fetal or neonatal 

morbidity. However, there is still concern regarding 

safety due to the lack of adequate data. Furthermore, 

calcium channel blockers can cross the placenta and 

affect fetal oxygen availability and blood flow in animal 

studies. 83 This observation is supported by animal 

experiments in which nifedipine caused hypoxia and 

acidosis in the sheep fetus. The deterioration of blood 

gases was out of proportion with the transient decrease 

in uroplacental blood flow, demonstrating that another 

mechanism exists during nifedipine infusion. 84 Such 

observations have led to the suggestion that sublingual 

nifedipine should be removed from the market. 85 


There is clinical evidence to suggest calcium channel 

blockers may have the potential to become an acceptable 

tocolytic. However, the safety of this class of drug does 

require further scrutiny. It is also worth noting that none 

of the tocolytics mentioned so far have undergone 

specific evaluation/ development for preterm labour. 

(Table 4 summarises the key comparative trials that have 

been conducted on the current tocolytics). 86,87 

2.5.e Oxytocin antagonists 

Until recently, oxytocin was regarded as having a 

minor role in the initiation of human labour. However, 

increasing evidence suggests that oxytocin is one of 

the key components in the initiation of labour. It has 

been shown to have a direct role in uterine 

contractility – by stimulating the myometrium – and an 

indirect role – by increasing the production of prostaglandins 

in the decidua. This discovery led to the 

development of oxytocin antagonists designed to 

suppress the dual effect of oxytocin. 

The most promising of the oxytocin antagonists is 

atosiban. It is an analogue of oxytocin and has been 

rationally designed to compete with endogenous 

oxytocin at both the myometrial and decidual oxytocin 

receptors. Clinical studies have shown it to be an effective 

and safe tocolytic agent. 


MAGNESIUM SULPHATE ADMINISTRATION [BESINGER & IANNUCCI, 1997] 


• Altered cardiac conduction 

• Cardiac arrest 

• Chest tightness 

• Dysphagia/ aspiration 

• Generalised muscle weakness 


• Hypothermia 

• Hyperkalaemia 

• Neuromuscular blockade 

• Ophthalmological alterations 

• Osmotic diuresis 

• Pulmonary oedema 

• Respiratory arrest 

• Respiratory depression 

• Subendocardial ischaemia 

• Water retention 


• Altered biophysical activities 

• Altered heart rate variability 

• Amniotic accumulation 

• Hypermagnesaemia 

• Hypotonia 

• Meconium ileus 

• Neonatal rickets 

• Respiratory depression 


CALCIUM CHANNEL BLOCKER ADMINISTRATION [BESINGER & IANNUCCI, 1997] 


• Altered cardiac conduction 

• Cutaneous vasodilation 

• Drug-induced hepatitis 

• Fluid retention 


• Hypoglycaemia 

• Hypotension 



• Altered uteroplacental 

blood flow 


20 

21

3 

Tractocile ® 

22 

23

Chapter 3 Tractocile ® Figure 3. Peptide structures of oxytocin and atosiban 

3.1 Rationale for development 

Oxytocin is now recognised as a potent agent that has a 

central role in the initiation of myometrial contractions 

during late pregnancy. The development of an analogue 

of oxytocin would, in theory, either imitate or block its 

effect. The rationale for the development of Tractocile ® 

(atosiban), trademark of Ferring BV, The Netherlands 

was based on the production of a novel compound 

which was highly specific for the uterus, but with a 

limited number or an absence of systemic side effects. 

The ideal outcome would be to produce a compound 

that is effective, safe and well tolerated. 

In 1960, Law and du Vigneaud first demonstrated 

partial uterotonic antagonism by modifying the oxytocin 

molecule at position 2. 88 Further changes to the parent 

molecule produced a series of analogues displaying full 

oxytocin antagonism. Later studies investigated the 

effect of O-alkylation at position 2 of the oxytocin 

molecule and the effect such analogues had on pregnant 

and non-pregnant human myometrial tissue and in 

animal models in vivo. 89 One of these analogues 

(a deaminated, O-Ethyl substitution at position 2) 

proved to be a full antagonist in vitro, however, showed 

only a partial effect when tested in women. This led to 

further developments until finally modifications at 

positions 1, 2, 4 and 8 of the oxytocin molecule produced 

an analogue, atosiban [1-deamino-2-D-Tyr-(O-Et)-4-Thr- 

8-Orn]-OT, with a high receptor affinity for the oxytocin 

receptor in vitro, and rat uterus in vitro and in vivo 

(figure 3). Further studies demonstrated atosiban to be 

the most potent analogue developed for inhibiting 

uterine contractions initiated by oxytocin in human 

pregnant and non-pregnant tissue, and in oestrus rats in 

vivo. 90 Atosiban was shown to lack any agonist properties 

and was therefore selected for further clinical 

investigation into its role as an oxytocin antagonist. 

3.2 Mechanism of action 

Oxytocin is believed to initiate myometrial contractility by 

a direct effect on membrane-bound receptors leading to 

an increase in intracellular calcium (see figure 4). Oxytocin 

also acts indirectly by stimulating the release of 

prostaglandins in decidual and fetal membranes, thereby 

contributing further to myometrial contractions and 

initiating cervical ripening. Tractocile ® acts by competing 

with oxytocin for receptors in the myometrium, and 

potentially in the decidual and fetal membranes as well. 

This results in a dose-dependent inhibition of uterine 

contractility and, furthermore, studies have shown a 

reduction in oxytocin-mediated prostaglandin release. 

Studies have also shown that Tractocile ® has an equal if 

not a greater affinity for vasopressin receptors compared 

with oxytocin receptors due to their close chemical 

homology. 91,92 This does not represent a clinical problem 

regarding vasopressin-like side effects because there is a 

H 

6 

7 

8 

1 2 

Cys 

Cys 

Pro 

Leu 

Tyr 

substantial increase in the expression of oxytocin 

receptors and no change in vasopressin receptor 

numbers in the uterus during labour. 

Further studies have investigated Tractocile ® on 

receptor binding and its effect on intracellular 

secondary messengers. Lopez-Bernal et al 93 showed a 

dose-dependent inhibition of oxytocin-stimulated 

inositol phosphate production, and Thornton et al 94 

demonstrated the abolishment of oxytocin-induced 

increases in intracellular Ca 2+ and spontaneous 

fluctuations in calcium. This final effect suggests that 

an additional intracellular process may be attributed 

to Tractocile ® following receptor binding. 

The utero-specificity of Tractocile ® provides a better 

safety profile and an effective alternative to the 

current tocolytics responsible for multi-organ side 

effects. However, because of its inhibitory effect on 

vasopressin receptors, there is the potential to cause a 

number of hypothetical secondary effects such as 

water resorption by the kidney, vasoconstriction and 

stimulation of adrenocorticotrophin hormone. Clinical 

studies have failed to demonstrate any of these effects 

and, on the contrary, have shown Tractocile ® to be a 

well-tolerated tocolytic agent. The efficacy of 

Tractocile ® is expected to be at least comparable to 

other tocolytic agents due to the multifactorial 

aetiologies responsible for preterm labour. Tractocile ® 

will affect one, if not more, of the pathways associated 

with the initiation of preterm labour. 

3.3 Chemistry of Tractocile ® 

3 

Gin 

Asn 

4 

5 

Gly 

9 

Oxytocin 

Ile 

NH 2 

Tractocile ® contains atosiban, a synthetic cyclic 

nonapeptide. Its chemical name is 1-(3-mercaptopropanoic 

acid)-2-(O-ethyl-D-tyrosine)-4-L-threonine-8-L ornithineoxytocin, 

with a formula C43H67N11O12S2. It has a 

molecular mass of 993.5 Daltons and is available as an 

acetate salt in the form of a whitish lyophilised amorphous 

powder. Potential isomerism can occur since the molecule 

contains a total of nine chiral centres. All of the amino acids 

H 

6 

7 

8 

1 2 

Mpa 

Cys 

Pro 

Orn 

Tyr 

D 

3 

Thr 

Asn 

4 

5 

Gly 

9 

Atosiban 

Ile 

NH 2 

O 

Oxytocin 

receptor 

are in the L-form, except tyrosine which exists in the 

D-form. The molecule can exist as either the Cis or 

Trans isomer at the cysteine-proline link, but the 

Trans configuration is the most common. Eleven 

diastereoisomers with one chiral centre can potentially 

be formed during the manufacture of Tractocile ® but it 

is possible to produce molecules with multiple chirality. 

Tractocile ® is highly soluble in water and is presented 

as a solution for parenteral administration at a 

concentration of 7.5 mg/ml. 

3.4 Preclinical studies 

O 

Ca 2+ 

Oxytocin 

Oxytocin 

binding 

increases 

intracellular 

Ca 2+ calcium 

Ca 2+ 

Ca 2+ Increase in 

myometrial Ca 2+ 

contractility 

Uterine contractions 

Figure 4. Schematic diagram of how Tractocile ® 

competitively inhibits oxytocin at its receptor 

3.4.a Receptor binding: affinity, specificity 

A number of preclinical toxicological and receptor 

binding studies were conducted in vitro and in vivo 

in animals, and in vitro in human tissue preparations. 

The receptor affinities of Tractocile ® , vasopressin 

and oxytocin were demonstrated to be similar in 

myometrial membrane preparations. 91 Tractocile ® was 

also able to displace vasopressin from its receptor site. 

In vitro, in human myometrium, Tractocile ® was shown 

to completely inhibit oxytocin-induced increases in 

intracellular calcium but did not prevent this increase 

when it was either potassium- or prostaglandin E 2 - 

induced. 94,95 This indicates that Tractocile ® is specific to 

the action of oxytocin. 

Another observation in rats after chronic treatment 

with oxytocin demonstrated a down-regulation in 

receptor numbers with continued exposure to 

oxytocin, whereas chronic exposure to Tractocile ® 

appeared to increase the number of receptors and the 

affinity for the receptors. 96 

3.4.b Pharmacological activity in vitro 

The effect of Tractocile ® has been evaluated in vitro in 

isolated preparations from normal or pregnant animal 

O 

Ca 2+ 

T 

T 

Ca 2+ 

Tractocile ® 

Ca 2+ 

O 

Tractocile ® blocks 

increase in 

intracellular 

calcium 

Ca 2+ 

Ca 2+ 

Inhibition of 

myometrial 

contractility 

Inhibition of contractions 

and human uterus. Tractocile ® inhibited oxytocin-induced 

contractions in a dose dependent, competitive fashion. 97 

The activity of Tractocile ® was also tested in non-pregnant 

and term pregnant human myometrial tissue. 90 No effect 

was seen on the non-pregnant strips, although the effect 

of vasopressin was antagonised. On myometrial strips 

obtained following elective Caesarean section from 

women at term, Tractocile ® displayed a greater efficacy, 

suppressing oxytocin-induced contractions before the 

beginning of labour, while during labour the 

spontaneous activity of the muscle was more sensitive to 

the antagonistic effect of Tractocile ® . 98 

3.4.c In vivo effect on uterine contractility 

The ability of Tractocile ® to inhibit uterine contractility 

has been investigated in the rat, guinea pig and monkey. 

In the pregnant monkey, premature contractions and 

anticipated deliveries can be induced by continuous 

infusion of androstenedione. Tractocile ® (6 µg/kg/min) 

inhibited the uterine muscle contractions induced by 

androstenedione in all pregnant animals. 99 

3.4.d Effect on labour duration 

In rats, Tractocile ® (s.c. every 5 mins) given 1 hour after 

delivery of the first pup delayed the birth of the second 

pup in a dose-dependent fashion. Continuous infusion 

(50 µg/min) delayed birth by approximately 1 hour 

beyond that observed in the control group. 100 

3.4.e Effect on prostaglandin release 

Tractocile ® was infused into pregnant ewes to investigate 

the effect on circulating maternal and fetal 

prostaglandins. The injection of oxytocin induced the 

production of maternal PGF 2a . This response was reduced 

in a dose-dependent manner when Tractocile ® was 

infused two hours earlier. 101 

Regarding the safety data from the preclinical studies, 

Tractocile ® did not have any significant effect on the CNS, 

cardiovascular, pulmonary, urinary or metabolic systems. 

Ca 2+ 

M Y O M E T R I U M 

24 25

Chapter 3 Tractocile ® 

3.5 Clinical pharmacodynamic studies 

There have been several open label, uncontrolled studies 

designed to investigate the effect of Tractocile ® on 

uterine contractions. Åkerlund et al 102 and Hauksson et 

al 103 administered Tractocile ® to healthy, non-pregnant 

women at a dose of 10 µg/kg, either as a repeat dose or a 

single bolus. Both studies showed an inhibition of uterine 

contractions during menstruation and vasopressininduced 

contractions. A similar study by Åkerlund 104 

showed Tractocile ® (10 µg/kg; single dose) to be capable 

of relieving the acute symptoms of dysmenorrhoea 

compared to placebo in a randomised, double-blind, 

placebo-controlled study. Further studies were aimed at 

evaluating the ability of Tractocile ® to inhibit uterine 

contractions in women with preterm labour. Åkerlund et 

al showed a total inhibition in 46% (6/13) of women 

receiving >25 µg/min for >2 hours. 105 This was supported 

by results from Andersen et al who showed a total 

inhibition of preterm contractions in 50% (6/12) of 

women on >25 µg/min for 8–13 hours. 106 Investigations 

into effects on lipid or carbohydrate metabolism, in 

which a single bolus dose of 10 µg/kg was administered 

to healthy, non-pregnant women, showed that 

Tractocile ® had no clinically significant effect. 107 

3.6 Clinical pharmacokinetic studies 

A total of 13 preclinical trials designed to investigate 

the pharmacokinetics of Tractocile ® are briefly described. 

The optimal dose, route of administration and important 

pharmacokinetic parameters were determined (Tables 

10–12). The bioavailability of Tractocile ® was compared 

between two parenteral routes of administration in early 

clinical studies by Åkerlund et al 105 and Lundin et al 108 . The 

clearance rate and half-life were evaluated for the i.v. 

route and bioavailability determined for i.n. (intranasal) 

Tractocile ® . Both studies showed the intravenous route to 

be more favourable. In the Åkerlund study, the 

bioavailability of i.n. Tractocile ® was estimated to be 

5.5%. A maximal plasma concentration was achieved 

within 2 minutes via i.v. administration, explaining the 

almost immediate inhibition observed in uterine 

contractions. The study by Lundin et al measured peak 

plasma concentrations in 2–8 minutes after i.v. compared 

with 10–45 minutes with i.n. routes. 108 Another study by 

Lundin et al evaluated the pharmacokinetic parameters 

for i.v Tractocile ® administered as a bolus dose. 109 These 

tended to be much higher than the previous studies, due 

to a more efficient method, with the half-life estimated 

at 39 minutes and the clearance rate approximately 

23 l/hr. The bioavailability of Tractocile ® after 

subcutaneous administration was also studied in healthy, 

non-pregnant female subjects receiving either 7.5 mg i.v. 

or s.c. 110 Absorption by the s.c. route was rapid, taking 

approximately 30 minutes to reach peak plasma 

concentration, and bioavailability was 97%. To observe 

any possible differences regarding how the body 

processed Tractocile ® in its suggested clinical role, 

pharmacokinetic parameters were evaluated in women 

with preterm labour. Tractocile ® infused at 300 µg/min 

TABLE 10. BASIC PHARMACOKINETIC PROPERTIES OF TRACTOCILE ® 

Study Aim of study Subjects (no./type) Dose (µg/kg) Effect of Tractocile ® 

Åkerlund 1986 

Lundin 1986 

Lundin 1993 

Zinny 1995 

Goodwin 1995 

Describe plasma 

concentratrion and 

body clearance with i.v. 

or i.n. administration 


concentration and 

body clearance with 

i.v. or i.n. 



body clearance 



bioavailability after 

s.c. injection 


concentration, body 

clearance and 

inhibitory activity 

11/Healthy, 

non-pregnant 

11/Healthy, 

non-pregnant 

8/Healthy, 

non-pregnant 

18/Healthy 

non-pregnant 

8/ Preterm 

labour 

10 i.v., 100 i.n 

repeat bolus 

10 i.v., 100 i.n. 

single bolus 

5 mg i.v. 

single bolus 

7.5 mg i.v., 7.5, 15, 

30 mg s.c. 

single bolus 

300 µg/min i.v. 

6–12 hours 

Inhibition of contractions 

Chapter 3 Tractocile ® 

The clinical dose of Tractocile ® for infusion was 

proposed as 300 µg/min. Doses higher than this level 

600 

have not been investigated in clinical trials. This current 

rate provides a concentration of 450 ng/ml which 

500 

theoretically should be sufficient to saturate every 

oxytocin receptor in the uterus. A bolus dose of 6.75 mg 

400 

achieves immediate uterine quiescence, which is then 

maintained at a steady state concentration during the 

infusion period ensuring optimal exposure of the uterus 

to the drug (see figure 5). 

Valenzuela et al determined the degree of placental 

300 

200 

100 

transfer of Tractocile ® to the fetus. 116 This was conducted 

in healthy, pregnant women receiving 300 µg/min over 

0 

3.5 to 8 hours. Fetal plasma concentrations were 12% of 

the mother’s levels, and the ratio between fetus and 

Time (hours) 

mother did not change during infusion. 

Bolus Infusion 

The extent of plasma protein and erythrocyte 

Group (mg) (µg/min) 

binding was investigated in plasma from fasted, 

1 

6.75 1300 

pregnant women. Labelled Tractocile ® was added to 

2 

placebo 300 

their plasma in vitro at clinically relevant concentrations 

and was subsequently measured for free and unbound 

levels. Results indicated a moderate degree of protein 

binding in the range of 45.7 to 47.5%. Regarding 

erythrocyte binding, there was no partitioning into red 

blood cells. 117 

Finally, regarding pharmacokinetics, two studies 

were conducted to investigate the metabolism of 

Tractocile ® . Unchanged Tractocile ® and two metabolites, 

one major and one minor, were identified in the plasma 

and urine of pregnant subjects. The major metabolite 

underwent further tests regarding its ratio in maternal 

and fetal plasma, with approximately a three-fold 

higher concentration in the mother. 118,119 3 

4 

Dose 

2.0 

0.6 

selection 

100 

process for Figure 5. Tractocile ® 

Atosiban plasma concentration (ng/ml) 

0 2 4 6 8 

Clinical efficacy of Tractocile ® 

30 

4 

28

Chapter 4 Clinical efficacy of Tractocile ® 

4.1 Phase II clinical experience 

Dose ranging and initial efficacy studies of atosiban were 

investigated in a clinical setting in three phase II trials. 

The first of this series of studies was aimed at evaluating 

the efficacy and safety of atosiban in decreasing or 

arresting uterine contractility in women with threatened 

preterm labour. 120 A double-blind, placebo-controlled, 

randomised trial investigated both primary and 

secondary efficacy variables in 118 women (atosiban 

n=59, placebo n= 59). The primary variable involved 

evaluating the percentage change in the number of 

uterine contractions occurring in a one-hour observation 

period compared with the subsequent two-hour 

treatment period. The secondary efficacy parameters 

assessed the proportion of women whose contractions 

stopped during treatments, and changes in cervical 

dilation and effacement. During treatment 77% of 

women receiving atosiban experienced a reduction of 

≥40% in the number ofuterine contractions compared 

with 32% of placebo-treated women. In women with a 

gestational age ≥28 weeks, the response rate in relation 

to a reduction of contractions was greater in the 

atosiban group and above 31 weeks this difference was 

statistically significant (p


(Table 14, Figure 6). Secondary outcomes, such as 

reduction in uterine contraction rate and mean 

gestational age, were similar in both groups. It was 

concluded that Tractocile ® and ritodrine were 

comparable with regard to delaying delivery. However, 

in terms of tocolytic efficacy and tolerability, Tractocile ® 

was superior to ritodrine. 

4.2.b Tractocile ® vs. salbutamol 

This randomised study enrolled 240 women with 

preterm labour who received either Tractocile ® or 

salbutamol (2.5–45 µg/min). As a measure of tocolytic 

effectiveness, Tractocile ® and salbutamol were 

comparable in terms of the number of women 

remaining undelivered after 48 hours and 7 days 

(Table 15). When the tocolytic efficacy and tolerability 

outcome was considered, Tractocile ® was found to be 

statistically significantly superior to salbutamol after 

7 days of starting treatment. The number of women 

remaining undelivered and not requiring an alternative 

tocolytic therapy within 7 days was 58.8% in the 

Tractocile ® group and 46.3% in the salbutamol group 

(p=0.02) (Table 15, Figure 6). Secondary outcomes were 

again comparable between treatment groups. 

4.2.c Tractocile ® vs. terbutaline 

In this comparative study, there were 244 women with 

preterm labour randomised to receive either Tractocile ® 

or terbutaline. Terbutaline was administered within its 

recommended dosage range of 5–20 µg/min. The 

primary outcome measuring the number of women 

remaining undelivered at 48 hours and 7 days showed 

Tractocile ® and terbutaline to be comparable (Table 16). 

In terms of tocolytic efficacy and tolerability, Tractocile ® 

was regarded as being at least as effective as 

terbutaline. The proportion of women remaining 

undelivered without requiring alternative tocolytic 

therapy after 7 days was 55.6% in the Tractocile ® group 

and 43.4% in the terbutaline group (p=0.08) (Table 16, 

Figure 6. 

Beta-agonist better 

Ritodrine 

Terbutaline 

Salbutamol 

Pooled 

TABLE 15. TOCOLYTIC EFFECTIVENESS AND TOCOLYTIC EFFICACY & TOLERABILITY 

OF TRACTOCILE ® AND SALBUTAMOL AT 48 HOURS AND 7 DAYS 

Number of women (%) 

Tractocile ® Salbutamol Odds 95% CI p value 

(n=119) (n=121) ratio 

Tocolytic effectiveness 

undelivered at 48 h 111 (93.3) 115 (95.0) 0.78 0.24–2.50 0.67 

undelivered at 7 days 107 (89.9) 109 (90.1) 1.04 0.39–2.77 0.94 

Tocolytic efficacy & 

tolerability* 

no failure at 48 h 95 (79.8) 91 (75.2) 1.58 0.85–2.95 0.15 

no failure at 7 days 70 (58.8) 56 (46.3) 1.89 1.10–3.24 0.02 

*Treatment failure = delivery within the time interval or need for alternative tocolysis 

0 1 2 3 4 5 

Odds ratio 

Homogeneity of centre effects test: 

χ 2 =36.29, df=42, p=0.72 

Tractocile ® better 

Tocolytic efficacy and tolerability outcome 

of the CAP-001 studies: odds ratio 

p-value 

0.029 

0.079 

0.021 

0.0003 

Figure 6). Secondary outcomes, as described in the 

previous studies, were all comparable between both 

treatment groups. 

4.2.d Pooled analysis 

This was a multinational, multicentre collaboration 

carried out in Australia, Canada, Czech Republic, 

Denmark, France, Israel, Sweden, and the UK. 124 As the 

three studies followed the same protocol (Table 17), 

which included strict inclusion/exclusion criteria, it was 

possible to provide an overall assessment of the clinical 

efficacy by pooling the data. The pooled analysis of the 

three CAP-001 studies contained 742 women diagnosed 

with preterm labour between 23 and 33 weeks of 

gestation. The main outcome of the study, although not 

predefined in the protocol, was the assessment of 

tocolytic effectiveness in the intention to treat analysis in 

terms of the total number of women undelivered at 48 

hours and 7 days of starting treatment. Tocolytic efficacy 

and tolerability was assessed in terms of the 

proportion of women who remained undelivered and 

who did not require alternative tocolysis after 7 days 

of starting therapy. 

For ethical reasons, a composite endpoint was used 

as a measure of efficacy (referred to as ‘tocolytic 

efficacy and tolerability’) since many of the investigators 

were opposed to a protocol that did not allow 

administration of alternative tocolysis in the event of the 

progression of labour (‘treatment failure’). However, 

treatment failure also included women who discontinued 

treatment due to adverse events and, consequently, the 

efficacy endpoint used in this study was a composite 

of both efficacy and tolerability. 

Summary of clinical efficacy 

Baseline characteristics of the Tractocile ® and betaagonist 

groups were comparable prior to the initiation of 

treatment. The undelivered rate at 48 hours for 

Tractocile ® and beta-agonists was comparable (88.1% 

and 88.9%, p=0.99). The proportion of women 

undelivered at 7 days, used as a measure of tocolytic 

effectiveness, was also comparable between the 

Tractocile ® and beta-agonist groups (79.7% vs.. 77.6%, 

p=0.28) (Table 18). The proportion of women remaining 

undelivered and not requiring alternative tocolysis after 7 

days of treatment was significantly higher in the 

Tractocile ® group (59.7%) compared with the betaagonist 

group (47.4%, p=0.0003) (Table 18, Figure 6), and 

TABLE 16. TOCOLYTIC EFFECTIVENESS AND TOCOLYTIC EFFICACY & TOLERABILITY OF TRACTOCILE ® 

AND TERBUTALINE AT 48 HOURS AND 7 DAYS 


Tractocile ® Terbutaline Odds 95% CI p value 

(n=115) (n=129) ratio 


undelivered at 48 h 99 (86.1) 110 (85.3) 1.11 0.52–2.38 0.78 

undelivered at 7 days 88 (76.5) 87 (67.4) 1.84 0.96–3.52 0.07 


tolerability* 

no failure at 48 h 83 (72.2) 88 (68.2) 1.22 0.67–2.22 0.52 

no failure at 7 days 64 (55.6) 56 (43.4) 1.62 0.94–2.77 0.08 


• Trial design 

TABLE 17. PRINCIPAL COMPONENTS OF THE COMMON STUDY PROTOCOL FOR THE 

CAP-001 CLINICAL STUDIES 

➞ Randomised, double-blind, double-dummy, beta-agonist-controlled trial 

• Population ➞ Women from 23 to 33 weeks gestation with regular uterine contractions (≥8 

contractions/h of ≥30 seconds duration), cervix 0–3 cm (nulliparous) or 1–3 cm 

(multiparous) dilated & ≥50% change in cervical length 

• Administration 

of study drugs 

• Primary outcomes/ 

endpoints 

➞ Tractocile ® administered as a 6.75 mg i.v. bolus then 300 µg/min i.v. for 3 h 

and 100 µg/min i.v. up to 45 h. Beta-agonists administered i.v. according to local 

practice guidelines 

➞ Proportion of women (%) remaining undelivered >7 days after starting treatment 

➞ Proportion of women (%) remaining undelivered and not requiring alternative 

tocolysis >7 days after starting treatment 

➞ Safety – all adverse events and vital signs reported from start of treatment until 

discharge from hospital 

32 33


there were also significantly fewer women in the 

Tractocile ® group requiring alternative tocolysis 

compared with the beta-agonist group (37.1% vs. 46.5%, 

p=0.01). Regarding secondary outcomes, Tractocile ® and 

beta-agonists were comparable in terms of their effects 

on uterine activity, reducing the number of contractions 

at a similar rate. Other comparable secondary outcomes 

included the number of women requiring retreatment, 

mean gestational age at delivery, and mean birth weight. 

Problems associated with the inclusion of women into 

clinical trials makes the evaluation of tocolytics difficult to 

demonstrate. Most women included in trials have already 

been transported to a hospital offering specialised care 

for preterm birth and may have already received tocolysis 

en route. Despite this the CAP-001 studies have 

demonstrated that regarding efficacy, Tractocile ® is 

comparable to the current standard tocolytics. 

TABLE 18. TOCOLYTIC EFFECTIVENESS AND TOCOLYTIC EFFICACY & TOLERABILITY OF TRACTOCILE ® 

AND BETA-AGONISTS AT 48 HOURS AND 7 DAYS [WORLDWIDE STUDY GROUP 2000]. 


Tractocile ® beta-agonists Odds 95% CI p value 

(n=360) (n=371) ratio 


undelivered at 48 h 317 (88.1) 330 (88.9) 1.00 0.62–1.62 0.99 

undelivered at 7 days 287 (79.7) 288 (77.6) 1.26 0.83–1.90 0.28 

5 

Clinical safety of Tractocile ® 


tolerability* 

no failure at 48 h 268 (74.4) 260 (70.1) 1.36 0.97–1.92 0.08 

no failure at 7 days 215 (59.7) 176 (47.4) 1.78 1.30–2.43 0.0003 


34

Chapter 5 Clinical safety of Tractocile ® 

There have been several phase II and III clinical trials 

designed to investigate the efficacy and safety of 

Tractocile ® (atosiban). The phase II studies evaluated 

atosiban either uncontrolled or by comparison with 

placebo, while the phase III studies compared Tractocile ® 

with placebo or beta-agonists, the only other class of 

drugs licensed for tocolytic therapy. 

5.1 Phase II studies 

There are three phase II clinical studies that have 

investigated the safety profile of atosiban. 115,120,121 The aim 

of these studies was to determine the efficacy and safety 

of atosiban regarding the reduction of uterine 

contractions in women with threatened preterm labour. 

Study PAT-U01 was a double-blind, placebocontrolled, 

randomised trial. Atosiban (i.v.) was 

administered at an infusion rate of 300 µg/min during a 

two-hour treatment period. 120 At the end of the study 

there were no drop outs reported due to adverse events. 

From a total of 56 patients in both study groups, adverse 

events were reported in three women from the atosiban 

group (nausea, vomiting and diarrhoea) compared with 

four from the placebo group (chest pain, headache, 

nausea), and a fetal death was reported in the placebo 

group. Therefore, it was considered unlikely that any of 

the maternal adverse events were associated with 

atosiban administration. In addition, maternal heart rate 

and blood pressure were not significantly different 

between the atosiban and placebo groups. 

Post-study follow up revealed that both groups were 

similar with respect to the proportion of women 

experiencing post-partum complications. Furthermore, 

infant assessment revealed no fetal toxicity. 

TABLE 19. SUMMARY OF SAFETY RESULTS IN STUDY L91-049 

6.5 mg + Placebo + 2 mg + 0.6 mg + Ritodrine 

300 µg/min 300 µg/min 100 µg/min 30 µg/min (n=56) 

(n=63) (n=59) (n=62) (n=57) 

Study drug discontinued 

due to adverse events 0 0 0 1 (1.7%) 15 (25.9%) 

Commonly reported 

maternal adverse events: 

Chest pain 1 (1.6%) 1 (1.7%) 1 (1.6%) 2 (3.4%) 9 (15.5%) 

Tachycardia 0 2 (3.4%) 0 0 21 (36.2%) 

Nausea 6 (9.5%) 3 (5.1%) 2 (3.1%) 3 (5.2%) 12 (20.7%) 

Vomiting 0 0 2 (3.1%) 2 (3.4%) 13 (22.4%) 

Headache 4 (6.3%) 1 (1.7%) 2 (3.1%) 5 (8.6%) 8 (13.8%) 

Neonatal outcome: 

RDS* 8 (13.1%) 7 (12.1%) 3 (4.9%) 2 (3.6%) 5 (8.9%) 

Death 0 1 1 1 1 

*Respiratory distress syndrome 

Study PAT-U02 investigated the same objectives as 

PAT-U01 except that the dosing period was extended. 121 

In this non-controlled study, women received 300 µg/min 

of atosiban for a 12-hour period. Atosiban was well 

tolerated and no women discontinued treatment. 

Maternal adverse events were predominantly mild 

and included headache, nausea and vomiting. However, 

one case of gallstone pancreatitis was reported. 

Regarding the fetus, one serious case of variable heart 

rate deceleration was reported, which resolved 

spontaneously in hospital. Neither of the serious 

maternal or fetal adverse events were considered to be 

related to drug treatment. Follow-up data did not 

reveal infant abnormalities or complications that could 

have been attributed to atosiban. 

The final phase II study (L91-049) was a dose-ranging 

study designed to find the minimum effective dose of 

atosiban. 115 There were four randomised, double-blind 

atosiban groups and one open-label ritodrine group. 

Adverse events reported with an incidence ≥ 5% in the 

atosiban groups were headache and nausea. Almost 

26% of women receiving ritodrine discontinued 

treatment due to adverse events compared with only 

0.4% of women receiving atosiban (Table 19). 

Ritodrine was associated with an increase in maternal 

pulse rate and fetal heart rate, unlike atosiban where 

adverse cardiovascular effects were not reported. There 

were also differences between atosiban and ritodrine 

regarding metabolic effects, particularly hypokalaemia 

and hyperglycaemia, which were reported more 

frequently in the ritodrine group. 

Six maternal/fetal serious adverse events were 

reported in the atosiban groups (including one fetal 

death), while there were two cases of serious 

maternal/fetal adverse events in the ritodrine group. 

One infant death was reported in three of the atosiban 

groups and the ritodrine group (Table 19). None of the 

deaths or serious adverse events were judged to be 

related to treatment. 

5.2 Phase III studies 

5.2.a Placebo-controlled studies 

Two phase III, randomised, double-blind, placebocontrolled 

studies (PTL-096 and PTL-098) were carried 

out in the USA and South America. The significance of 

the safety results obtained from the PTL-096 study has 

been scrutinised due to the criteria used to recruit 

women into the studies. At randomisation, a 

significantly greater number of women below 26 weeks’ 

gestation and with more severe preterm labour were 

randomised to the atosiban group. This contributed 

substantially to the greater number of infant deaths 

reported in the atosiban group compared with the 

placebo group. However, the mortality rate in the 

atosiban group was similar to what would be expected 

for infants of similar gestational age in the normal 

population and consequently infant deaths were 

attributed to complications of extreme prematurity. 

Despite these methodological limitations, this study was 

able to support the safety profile of atosiban, since 

maternal and fetal adverse events were similar in the 

atosiban and placebo groups. 

The second study, PTL-098, investigated the potential 

use of atosiban in maintenance therapy in order to 

inhibit a second episode of preterm labour. Similar to the 

safety results reported in PTL-096, maternal adverse 

events and infant outcomes were comparable to placebo 

in this study. 125 The only maternal adverse event noted in 

the atosiban group were injection site reactions related 

to prolonged subcutaneous maintenance therapy. 

Infant outcomes after follow-up 

Table 20 presents the data from the two placebocontrolled 

studies, PTL-096 and PTL-098, after follow-up 

at 6, 12 and 24 months after birth. A total of 583 infants 

(288 atosiban, 295 placebo) were followed from PTL-096: 

73% returned for the 6-month follow-up, 65% for the 

12-month follow-up and 55% for the 24-month followup. 

From PTL-098, 563 infants (291 atosiban, 272 

placebo) were followed: 81% returned for the 6-month 

follow-up, 74% for the 12-month follow-up and 55% for 

the 24-month follow-up. No unexpected developmental 

or neurological outcomes were found at 6-, 12- or 24- 

month follow up in the atosiban-treated group. 126,127 

5.2.b Comparative studies 

Three multinational, multicentre, double-blind, 

randomised, controlled trials (CAP-001) were 

designed to compare Tractocile ® (atosiban) with the 

beta-agonists, ritodrine, salbutamol and terbutaline. 

In addition, a pooled analysis incorporated all data 

from the three comparative trials. 141 This provided an 

overall assessment of the safety and tolerability of the 

three beta-agonists in comparison with Tractocile ® . In 

each study, the tocolytic agents were administered i.v. 

at their clinically recommended doses. In order to 

avoid repeating results from each of the three CAP- 

001 studies, only the pooled data will be discussed 

in detail below. 

5.2.c Pooled analysis 

A pooled analysis of the three comparative trials was 

performed to provide an overall statistical assessment 

of the safety data obtained. Overall, there was a total 

of 742 women included in the pooled analysis. 

TABLE 20. INFANT OUTCOMES OF ATOSIBAN COMPARED WITH PLACEBO 

Bayley II assessment of mental and motor development and neurological examination 

PTL-096 

PTL-098 

6 months Atosiban Placebo Atosiban Placebo 

Mental Development Index 95 95 100 100 

Physical Development Index 93 92 97 96 

Neurologically normal 89% 84% 88% 90% 









36 37

Tractocile ® (n=361) 


Chapter 5 Clinical safety of Tractocile ® Figure 9b. Reported neonatal adverse events in the Tractocile ® 

Maternal adverse events 

The most frequently reported maternal adverse event 

following beta-agonist treatment was tachycardia, 

which occurred at a similar rate across all three study arms 

(approx. 75%). Maternal tachycardia was defined as a 

maternal heart rate >120 bpm. Clinically important 

adverse events included a case of myocardial ischaemia 

and two cases of pulmonary oedema in the beta-agonist 

group. A third case of pulmonary oedema was reported 

in the Tractocile ® group after the woman had 

subsequently been given a beta-agonist as rescue 

therapy for 7 days following atosiban administration. 

The incidence of at least one maternal cardiovascular 

side effect was 8.3% in the atosiban group and 81.2% in 

the beta-agonist group. Maternal cardiovascular side 

effects included pulmonary oedema, chest pain, 

myocardial ischaemia, dyspnœa, palpitation, tachycardia, 

hypotension and syncope (Figure 7a). Constitutional 

adverse events such as vomiting, nausea and headache 

were also more frequently reported after beta-agonist 

administration (Figure 7b). 

Regarding those women who discontinued treatment 

due to adverse events, there were four (1.1%) from the 

Tractocile ® group and 56 (15.4%) from the beta-agonist 

group (p=0.0001) (Figure 8). The mean ± SD heart rate 

(bpm) in women when the study was discontinued was 

86.2±13.9 in the atosiban group and 124.7±19.6 in the 

beta-agonist group (p=0.0001). 

% Incidence 

75 

70 

65 

60 

55 

50 

45 

40 

35 

30 

25 

20 

15 

10 

5 

0 

* 

Pulmonary oedema 

Myocardial ischaemia 


Beta-agonists (n=372) 

Chest pain 

Dyspnœa 

Palpitation 

Tachycardia 

Hyperglycæmia 

Hypokalæmia 

* this single patient case occurred 

after switch to beta-agonist therapy 

% Incidence 

% Incidence 

100 

90 

80 

70 

60 

50 

40 

30 

20 

10 

0 

Figure 8. 

25 

20 

15 

10 

5 

0 

Frequency of treatment discontinuation due to 

maternal side effects according to the allocated 

study medication 

Nausea 


Maternal 

cardiovascular 

side effects 



Vomiting 

Headache 

Discontinuations 

due to side effects 

Tremor 

Hypertension 

Hypotension 

% Incidence 

Fetal adverse events 

The most frequently reported fetal adverse event was 

fetal tachycardia in the beta-agonist group (28%) 

compared with only 3% in the Tractocile ® group (Figure 

9a). Fetal tachycardia was defined as a fetal heart rate 

>170 bpm. Other events, such as fetal distress and 

bradycardia, were reported to a similar extent in both 

the Tractocile ® and beta-agonist groups. 

Neonatal adverse events 

Both treatment groups were considered to be 

comparable regarding neonatal morbidity (Figure 9b). 

Admissions to specialised intensive care units and the 

period of time spent in the unit were similar in both 

treatment groups (31% Tractocile ® vs. 30% betaagonists). 

Major congenital anomalies were reported 

in seven (1.7%) infants in the atosiban group and four 

infants (0.9%) in the beta-agonist groups. 

There were 18 fetal/infant deaths over the course of 

the studies. Six were reported in the Tractocile ® group 

(4 singleton and 2 twins) compared with 12 from the 

beta-agonist groups (5 singletons and 7 twins). 

Consequently, the perinatal mortality rate was 14.7 per 

1000 in the atosiban group and 27.7 per 1000 in the 

beta-agonist group. The indicated causes of death 

were complications associated with prematurity, such 

as infection, respiratory distress syndrome, necrotising 

enterocolitis and intraventricular haemorrhage. Of 

these deaths, three were intrauterine deaths, two in 

the beta-agonist group and one in the atosiban group. 

None of the deaths were regarded by the investigators 

to be related to the tocolytic agent. 

25 

20 

15 

10 

5 

0 

Tachycardia 



Bradycardia 

Fetal distress 

Fetal death 

Asphyxia 

Hypoxia 

% Incidence 

25 

20 

15 

10 

5 

0 

RDS 

Cerebral haemorrhage 


Apnoea 

and beta-agonist groups 

Bradycardia 

Arrhythmia 

Hypotension 

Summary 

The principal difference between Tractocile ® and 

beta-agonists in terms of safety outcomes was the 

incidence of maternal cardiovascular side effects 

(8.3% vs. 81.2%, p

Chapter 5 Clinical safety of Tractocile ® 

TABLE 21. INFANT OUTCOMES FOLLOWING TOCOLYTIC TREATMENT WITH BETA-AGONISTS 

Study Design Outcome 

Freysz et al 1977 

Polowczy et al 1984 

Hadders-Algra et al 1986 

Laros et al 1991 

Forty two infants from preterm women 

treated with ritodrine (60-80 mg/day) 

during a period from 3–93 days were 

matched with control infants. 

Twenty infants exposed to ritodrine 

during management of preterm labour 

were examined at 7–9 years of life and 

compared with matched controls. 

A group of 78 six-year-old infants 

exposed to ritodrine during pregnancy 

for an average of 28 days were matched 

with control groups. 

201 infants exposed to either isoxsuprine, 

ritodrine, terbutaline or a combination, 

compared with 130 controls. Follow up 

was analysed at 1, 3 and 4 years. 

There were no statistically significant differences 

between the two groups for any of the variables 

of development studied. 

No significant differences were detected 

regarding growth, neurological findings 

and psychometric testing. 

No significant differences were found regarding 

urinalysis, body length, weight, head 

circumference, neurological findings. However, 

school performances of ritodrine-treated infants 

were considered to be poorer. 

No significant differences were found in growth 

or development. Observations of time-related 

events did however suggest some evidence of 

greater mortality and trauma in 

the terbutaline group. 

6 

Pharmaceutical application 

of Tractocile ® 

40

Chapter 6 Pharmaceutical application of Tractocile ® 

6.1 Therapeutic indication 

Tractocile ® (atosiban) is indicated to delay imminent 

preterm birth in pregnant women with: 

• a gestational age between 24 and 33 completed weeks 

• regular uterine contractions of at least 30 seconds, 

duration at a rate of ≥4 per 30 minutes 

• age ≥18 years 

• a cervical dilation of 1–3 cm (0–3 cm for nulliparous 

women) and effacement of ≥50% 

• normal fetal heart rate. 

6.2 Pharmaceutical form 

Tractocile ® is available at a concentration of 7.5 mg/ml of 

atosiban in: 

• 0.9 ml vial for i.v. bolus injection (‘Solution for Injection’) 

• 5 ml vial for i.v. infusion (‘Concentrate for Solution 

for Infusion’) 

6.3 Dosage and administration 

The duration of treatment should not exceed 48 hours 

and the total dose administered should preferably not 

exceed 330 mg atosiban during a full course of Tractocile ® 

therapy. In the Phase III clinical trials, the majority of 

women were administered Tractocile ® for a total of 18 

hours (one vial of 0.9 ml plus four vials of 5 ml). 

Treatment with Tractocile ® should be initiated and 

maintained by a physician experienced in the treatment 

of preterm labour. Tractocile ® is administered i.v. in three 

stages (figure 10 and table 22): 

1. An initial bolus injection of 6.75 mg corresponding to 

7.5 mg/ml is recommended as soon as possible after 

preterm labour has been diagnosed 

2. Immediately followed by a continuous high-dose 

infusion of 300 µg/min for 3 hours, known as the 

‘loading infusion’ 

3. Followed by a lower dose infusion of 100 µg/min for 

a maximum of 45 hours, known as the ‘subsequent 

infusion’. 

If episodes of preterm labour recur after uterine 

quiescence has been achieved, the three-stage regimen 

above can be repeated. However, it is worth noting that 

a maximum of three re-treatments were administered to 

women during clinical trials. Alternative therapy should 

be considered in case of persistent uterine contractions. 

Step II - 'Loading infusion' 

Step I - 'Initial bolus i.v. injection' 

0.9 ml of Tractocile ® Solution 

for injection (7.5 mg/ml) 

Continuous infusion Tractocile ® Concentrate 

for Solution for infusion. Infusion rate of 

24 ml/hour=300 µg/min for 3 hours 

Step III - 'Subsequent infusion' 

Follow by a lower dose 

of Tractocile ® Concentrate for 

Solution for infusion 

Reduce infusion rate 

0f 8 ml/hour=100 µg/min 

for up to 45 hours 

TABLE 22. STANDARD DOSING REGIMEN FOR TRACTOCILE ® 

Withdraw 10 ml solution from 

a 100 ml infusion bag and 

discard. Replace it with 

(2 x 5 ml vials) Tractocile ® 

iv to pregnant woman 

Prepare a new 100 ml bag by 

withdrawing 10 ml solution 

from a 100 ml infusion bag 

and discard. Replace it with 

(2 x 5 ml vials) Tractocile ® 

i.v. to pregnant woman 

Figure 10. Visual representation of the administration 

of Tractocile ® 

6.3.a Preparation of the initial i.v. Solution for Injection 

The initial bolus should be administered as a 0.9 ml 

injection, equating to a dose of 6.75 mg Tractocile ® . 

Withdraw 0.9 ml of a 0.9 ml labelled vial of Tractocile ® 

7.5 mg/ml Solution for Injection and administer slowly 

as an i.v bolus over one minute. The Tractocile ® 7.5 

mg/ml Solution for Injection must be used immediately 

after opening. 

6.3.b Preparation of the diluted Concentrate for Solution 

for Infusion 

For the i.v. infusion, following the bolus dose, Tractocile ® 

7.5 mg/ml Concentrate for Solution for Infusion should 

be diluted in one of the following solutions: 

Stage Regimen Dose Rate Duration 

1 0.9ml i.v. injection 6.75 mg Bolus 1 min 

2 i.v. infusion 18 mg/h 24 ml/h 3 h 

3 i.v. infusion 6 mg/h 8 ml/h Up to 45 h 

• 0.9% (w/v) isotonic normal saline solution 

• Ringer’s lactate solution 

• 5% (w/v) isotonic glucose solution. 

Dilution must be performed immediately after opening. 

To prepare the infusion solution in a 100 ml infusion 

bag, withdraw 10 ml from the infusion bag and discard. 

This should be replaced by 10 ml Tractocile ® 7.5 mg/ml 

Concentrate for Solution for Infusion from two 5 ml vials, 

resulting in a concentration of 75 mg Tractocile ® in 

100 ml (figure 10). The loading infusion is delivered at a 

rate of 24 ml/hour, equivalent to a dose of 18 mg/hour 

(300 µg/min), for 3 hours. After 3 hours, this is reduced to 

a rate of 8 ml/hour, equivalent to a dose of 6 mg/hour 

(100 µg/min), for the remainder of the infusion. 

Prepare new 100 ml infusion bags in the same way as 

described above to allow the infusion to be continued 

uninterrupted. If an infusion bag with a different 

volume is used, a proportional calculation should be 

made for the preparation. The diluted Tractocile ® 

7.5 mg/ml Concentrate for Solution for Infusion must be 

used within 24 hours of preparation. 

To ensure accurate dosing, a controlled infusion 

device is recommended to adjust the rate of flow in 

drops/minute when required. An i.v. microdrip chamber 

can provide a convenient range of infusion rates within 

the recommended dose levels for Tractocile ® . 

6.4 Contraindications 

Tractocile ® should not be used in the following 

conditions: 

• gestational age below 24 or over 33 completed weeks 

• antepartum uterine haemorrhage requiring 

immediate delivery 

• eclampsia and severe preeclampsia requiring delivery 

• intrauterine fetal death 

• suspected intrauterine infection 

• placenta praevia 

• abruptio placenta 

• any other conditions of the mother or fetus, in which 

continuation of pregnancy is hazardous 

• known hypersensitivity to the active substance or any 

of the excipients 

• premature rupture of the membranes >30 weeks’ 

gestation 

• intrauterine growth retardation and abnormal fetal 

heart rate. 

6.5 Precautions and warnings 

During administration of Tractocile ® it is advisable to 

monitor maternal uterine contractions and fetal heart 

rate at regular intervals. It is also necessary to evaluate 

the benefit of delaying delivery against the potential 

risk of chorioamnionitis in women with suspected 

PROM. In women with intrauterine growth retardation, 

the decision whether to continue or restart treatment 

with Tractocile ® will be dependent upon the assessment 

of fetal maturity. There is no experience with 

Tractocile ® treatment in women with impaired kidney or 

liver function. 

As an antagonist of oxytocin, Tractocile ® may 

theoretically facilitate uterine relaxation and 

postpartum bleeding. Therefore, blood loss after 

delivery should be monitored. However, inadequate 

uterine contraction postpartum was not observed 

during the Phase III clinical trials. 

6.6 Interaction with other medicinal products 

and other forms of interaction 

Drug interaction studies have been performed 

investigating betamethasone and Labelatol. The 

studies conclude that co-administration of atosibanbetamethasone 

and atosiban–labelatol had no clinically 

relevant influence on drug bioavailability. A manuscript 

has been submitted and is pending publication. Data 

on file and available on request. 

6.7 Pregnancy and lactation 

No toxic effects of Tractocile ® have been reported in 

embryotoxicity studies. Small amounts of a metabolite 

of atosiban have been shown to pass from plasma 

into the breast milk of lactating women. 

6.8 Undesirable effects 

The undesirable maternal adverse reactions reported in 

clinical studies were generally of a mild severity and 

included nausea (14%), headache, vomiting, flushing, 

dizziness, tachycardia, hypotension, injection site reaction 

and hyperglycaemia (1–10%). 

For the newborn, the Phase III clinical trials did not 

reveal any specific undesirable effects of Tractocile ® . 

Infant outcomes were in the range of normal variation 

and were comparable to both placebo and beta-agonists. 

6.9 Overdose 

Few cases of Tractocile ® overdosing were reported 

during Phase III clinical trials and these cases occurred 

without any specific signs or symptoms. There is no 

known specific treatment in case of an overdose. 

6.10Storage and packaging information 

Tractocile ® will be available in single packs of 0.9 ml and 

5 ml vials. The shelf life of Tractocile ® is 2 years when 

stored in the original container at a temperature of 

2–8°C. Once opened, Tractocile ® must be used 

immediately (0.9 ml) or diluted immediately (5 ml). 

Dilutions should be used within 24 hours of preparation. 

42 43

7 

Summary of the key benefits of 

Tractocile ® in the treatment 

of preterm labour

Chapter 7 Summary of the key benefits of Tractocile ® in the treatment of preterm labour 

7.1 Proven efficacy and tolerability 

The efficacy of Tractocile ® is demonstrated most clearly 

in the comparative studies with beta-agonists. As a 

tocolytic, this group of drugs are currently the most 

popular in clinical practice, therefore, the results from 

the CAP-001 studies are very encouraging for 

Tractocile ® . As demonstrated in the pooled analysis, 

Tractocile ® was statistically superior to beta-agonist 

treatment in terms of its efficacy and tolerability. 

There was a higher proportion of women remaining 

undelivered and not requiring alternative tocolytic 

treatment within 7 days in the Tractocile ® group 

compared with the beta-agonists. In addition, 

Tractocile ® demonstrated statistical superiority in terms 

of an increased delay in delivery from the start of 

treatment or the requirement of alternative tocolytic 

therapy. Regarding tocolytic effectiveness, defined as 

the proportion of women undelivered at 7 days, 

Tractocile ® was comparable to the beta-agonists. There 

was also no difference between the two treatments 

regarding secondary outcomes such as mean 

gestational age at delivery and mean birth weight. 

7.2 Superior safety profile 

Tractocile ® has proven to be superior to current 

standard tocolytic therapy and shown to be well 

tolerated by women with preterm labour and by the 

fetus. Tractocile ® is associated with a placebo-level 

incidence of cardiovascular adverse events. The few 

adverse events that have been reported were mild 

or moderate in severity and were more likely to result 

from iatrogenic causes such as the delivery process and 

the consequences of prematurity rather than 

the drug itself. Tractocile ® is the only tocolytic with 

proven short-term and long-term safety for mother 

and baby. 

7.3 Absence of tachyphylaxis 

There have been no reports of tachyphylaxis with 

maintenance Tractocile ® therapy, however, this 

phenonomen is commonly associated with the use 

of beta-agonists. 

7.4 Specific mode of action 

Tractocile ® contains the oxytocin analogue atosiban, 

which is designed to compete with oxytocin at receptor 

sites in the myometrium and decidua of the uterus. 

Atosiban itself does not elicit a response once it 

occupies a receptor, therefore it acts as an antagonist 

blocking the activation of oxytocin receptors in the 

uterus. This blockade causes an inhibition of uterine 

contractility. Oxytocin receptors are predominantly 

found in the uterus, therefore, atosiban is organ 

specific, which explains the paucity of side effects. 

7.5 Rapid onset of action 

Tractocile ® has a rapid onset of action, inhibiting 

preterm uterine contractions at a comparable rate to 

beta-agonists. 

7.6 Period of use 

Studies have indicated an acceptable therapeutic 

window of between 24 and 33 gestational weeks. 

This is comparable to other tocolytic agents such as 

beta-agonists. 

Conclusion 

Although there have been improvements 

in neonatal survival after preterm birth this is 

associated with significant costs. The 

prevention of preterm birth is the ideal 

outcome in particular before 30 weeks’ 

gestation, below which time the mortality and 

morbidity are disproportionately high. Due to 

its heterogenous nature, preventative 

strategies for preterm birth are unlikely to be 

effective on a global scale since there will be 

more than one definitive treatment. Delaying 

preterm delivery will however help gain time 

to administer steroids, transfer the mother in 

utero to a tertiary centre and provide other 

measures to improve pregnancy outcome. 

Tocolytic success should be measured in 

terms of each day gained rather than a direct 

measure of gestational age at delivery. It is 

clear that some clinical benefit in the shortterm 

prolongation of pregnancy can be 

achieved using tocolytic therapy, however, 

the safety of these pharmacological agents 

remains a concern. It is the issue of safety 

that restricts tocolysis to gestational ages 

below 34 weeks. 

The introduction of oxytocin antagonists as 

a safe alternative to beta-agonists potentially 

allows for tocolysis at later gestational ages. 

Improved diagnostic techniques will 

inevitably result in the earlier identification of 

preterm labour and the more accurate 

selection of women in whom tocolysis will be 

beneficial. Together with improved 

approaches in treatment, the ultimate goal of 

prolonging pregnancy to an extent that 

provides substantial benefit for the infant 

and mother may soon be achievable. 

46 47

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TRACTOCILE VIALS 7.5mg /0.9 ml (Bolus Injection)

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