Tractocile® is indicated to delay imminent pre‑term birth in pregnant
adult women with:
− Regular uterine contractions of at least 30 seconds duration at a
rate of ≥ 4 per 30 minutes.
− A cervical dilation of 1 to 3 cm (0‑3 for nulliparas) and effacement
of ≥ 50%.
− A gestational age from 24 until 33 completed weeks.
− A normal foetal heart rate.

Posology
Treatment with Tractocile® should be initiated and maintained by a
physician experienced in the treatment of pre‑term labour.
Tractocile® is administered intravenously in three successive stages:
An initial bolus dose (6.75 mg), performed with Tractocile®
6.75 mg/ 0.9 ml solution for injection, immediately followed by a
continuous high dose infusion (loading infusion 300 micrograms/ min)
of Tractocile® 37.5 mg/ 5 ml concentrate for solution for infusion
during three hours, followed by a lower dose of Tractocile®
37.5 mg/ 5 ml concentrate for solution for infusion (subsequent infusion
100 micrograms/ min) up to 45 hours.
The duration of the treatment should not exceed 48 hours. The total
dose given during a full course of Tractocile® therapy should preferably
not exceed 330.75 mg of atosiban.
Intravenous therapy using the initial bolus injection should be started
as soon as possible after diagnosis of pre‑term labour. Once the bolus
has been injected, proceed with the infusion.
In the case of persistence of uterine contractions during treatment
with Tractocile®, alternative therapy should be considered.
The following table shows the full posology of the bolus injection
followed by the infusion:

Re-treatment:
In case a re-treatment with atosiban is needed, it should also
commence with a bolus injection of Tractocile® 6.75 mg/ 0.9 ml,
solution for injection followed by infusion with Tractocile® 37.5 mg/
5 ml, concentrate for solution for infusion.
Patients with renal or hepatic impairment
There is no experience with atosiban treatment in patients with
impaired function of the liver or kidneys.
Renal impairment is not likely to warrant a dose adjustment, since
only a small extent of atosiban is excreted in the urine. In patients
with impaired hepatic function, atosiban should be used with caution.
Paediatric population
The safety and efficacy of Tractocile® in pregnant women aged less
than 18 years have not been established.
No data are available.
Method of administration
For instructions on preparation of the medicinal product before
administration, please refer to “Special Precautions for Disposal and
Other Handling section”.

Tractocile® must not be used in the following conditions: − Gestational age below 24 or over 33 completed weeks. − Premature rupture of the membranes >30 weeks of gestation. − Abnormal foetal heart rate. − Antepartum uterine haemorrhage requiring immediate delivery. − Eclampsia and severe pre-eclampsia requiring delivery. − Intrauterine foetal death. − Suspected intrauterine infection. − Placenta praevia. − Abruptio placenta. − Any other conditions of the mother or foetus, in which continuation of pregnancy is hazardous. − Hypersensitivity to the active substance(s) or to any of the listed excipients.

When atosiban is used in patients in whom premature rupture of
membranes cannot be excluded, the benefits of delaying delivery
should be balanced against the potential risk of chorioamnionitis.
There is no experience with atosiban treatment in patients with
impaired function of the liver or kidneys.
Renal impairment is not likely to warrant a dose adjustment, since
only a small extent of atosiban is excreted in the urine. In patients
with impaired hepatic function, atosiban should be used with caution.
There is only limited clinical experience in the use of atosiban in
multiple pregnancies or the gestational age group between 24 and
27 weeks, because of the small number of patients treated. The benefit
of atosiban in these subgroups is therefore uncertain.
Re-treatment with Tractocile® is possible, but there is only limited
clinical experience available with multiple re-treatments, up to 3 retreatments.
In case of intrauterine growth retardation, the decision to continue or
reinitiate the administration of Tractocile® depends on the assessment
of foetal maturity.
Monitoring of uterine contractions and foetal heart rate during
administration of atosiban and in case of persistent uterine
contractions should be considered.
As an antagonist of oxytocin, atosiban may theoretically facilitate
uterine relaxation and postpartum bleeding therefore blood loss after
delivery should be monitored. However, inadequate uterus contraction
postpartum was not observed during the clinical trials.
Multiple pregnancy and medicinal products with tocolytic activity
like calcium channel blockers and betamimetics are known to be
associated with increased risk of pulmonary oedema. Therefore,
atosiban should be used with caution in case of multiple pregnancy
and/ or concomitant administration of other medicinal products with
tocolytic activity.

It is unlikely that atosiban is involved in cytochrome P450 mediated
drug‑drug interactions as in vitro investigations have shown that
atosiban is not a substrate for the cytochrome P450 system, and
does not inhibit the drug metabolising cytochrome P450 enzymes.
Interaction studies have been performed with labetalol and betamethasone
in healthy, female volunteers. No clinically relevant interaction was found
between atosiban and bethamethasone or labetalol.

Atosiban should only be used when pre‑term labour has been
diagnosed between 24 and 33 completed weeks of gestation. If
during pregnancy the woman is already breast-feeding an earlier
child, then breast-feeding should be discontinued during treatment
with Tractocile®, since the release of oxytocin during breast-feeding
may augment uterine contractility, and may counteract the effect of
tocolytic therapy.
In atosiban clinical trials no effects were observed on breast-feeding.
Small amounts of atosiban have been shown to pass from plasma
into the breast milk of breast-feeding women.
Embryo‑foetal toxicity studies have not shown toxic effects of
atosiban. No studies were performed that covered fertility and early
embryonic development.

Not relevant.

Possible adverse reactions of atosiban were described for the mother
during the use of atosiban in clinical trials. In total 48% of the patients
treated with atosiban experienced adverse reactions during the
clinical trials. The observed adverse reactions were generally of a
mild severity. The most commonly reported adverse reaction in the
mother is nausea (14 %).
For the newborn, the clinical trials did not reveal any specific adverse
reactions of atosiban. The infant adverse reactions were in the range
of normal variation and were comparable with both placebo and
betamimetic group incidences.
The frequency of adverse reactions listed below is defined using
the following convention: Very common (≥1/10); Common (≥1/100 to
<1/10); Uncommon (≥1/1,000 to <1/100); Rare (≥1/10,000 to <1/1,000).
Within each frequency grouping, adverse reactions are presented in
order of decreasing seriousness.
Very Common: Nausea.
Common: Hyperglycaemia, Headache, Dizziness, Tachycardia,
Hypotension, Hot flush, Vomiting, Injection site reaction.
Uncommon: Insomnia, Pruritis, Rash, Pyrexia.
Rare: Allergic reaction, Uterine haemorrhage, uterine atony.
Post-marketing experience:
Respiratory events like dyspnoea and pulmonary oedema, particularly
in association with concomitant administration of other medicinal
products with tocolytic activity, like calcium antagonists and
betamimetics, and/or in women with multiple pregnancy, have been
reported post-marketing.

Few cases of atosiban overdosing were reported, they occurred
without any specific signs or symptoms.
There is no known specific treatment in case of an overdose.

Pharmacotherapeutic group: Other gynecologicals, ATC code:
G02CX01.
Tractocile® contains atosiban (INN), a synthetic peptide
([Mpa1,D‑Tyr(Et)2,Thr4,Orn8]-oxytocin) which is a competitive
antagonist of human oxytocin at receptor level. In rats and guinea
pigs, atosiban was shown to bind to oxytocin receptors, to decrease
the frequency of contractions and the tone of the uterine musculature,
resulting in a suppression of uterine contractions. Atosiban was also
shown to bind to the vasopressin receptor, thus inhibiting the effect of
vasopressin. In animals atosiban did not exhibit cardiovascular effects.
In human pre‑term labour, atosiban at the recommended dosage
antagonises uterine contractions and induces uterine quiescence.
The onset of uterus relaxation following atosiban is rapid, uterine
contractions being significantly reduced within 10 minutes to achieve
stable uterine quiescence (≤ 4 contractions/ hour) for 12 hours.
Phase III clinical trials (CAP‑001 studies) include data from 742 women
who were diagnosed with pre‑term labour at 23–33 weeks of gestation
and were randomised to receive either atosiban (according to this
labelling) or β-agonist (dose-titrated).
Primary endpoint: the primary efficacy outcome was the proportion
of women remaining undelivered and not requiring alternative
tocolysis within 7 days of treatment initiation. The data show that
59.6% (n=201) and 47.7% (n=163) of atosiban- and β-agonist-treated
women (p=0.0004), respectively, were undelivered and did not require
alternative tocolysis within 7 days of starting treatment. Most of the
treatment failures in CAP‑001 were caused by poor tolerability.
Treatment failures caused by insufficient efficacy were significantly
(p=0.0003) more frequent in atosiban (n=48, 14.2%) than in the
β-agonist-treated women (n=20, 5.8%).
In the CAP‑001 studies the probability of remaining undelivered
and not requiring alternative tocolytics within 7 days of treatment
initiation was similar for atosiban and beta-mimetics treated women
at gestational age of 24‑28 weeks. However, this finding is based on
a very small sample (n=129 patients).
Secondary endpoints: secondary efficacy parameters included the
proportion of women remaining undelivered within 48 h of treatment
initiation. There was no difference between the atosiban and
betamimetic groups with regard to this parameter.
Mean (SD) gestational age at delivery was the same in the two
groups: 35.6 (3.9) and 35.3 (4.2) weeks for the atosiban and β-agonist
groups, respectively (p=0.37). Admission to a neonatal intensive care
unit (NICU) was similar for both treatment groups (approximately 30%),
as was length of stay and ventilation therapy.
Mean (SD) birth weight was 2491 (813) grams in the atosiban group
and 2461 (831) grams in the β-agonist group (p=0.58).
Foetal and maternal outcome did apparently not differ between the
atosiban and the β-agonist group, but the clinical studies were not
powered enough to rule out a possible difference.
Of the 361 women who received atosiban treatment in the phase
III studies, 73 received at least one retreatment, 8 received at least
2 re-treatments and 2 received 3 re-treatments.
As the safety and efficacy of atosiban in women with a gestational
age of less than 24 completed weeks has not been established in
controlled randomised studies, the treatment of this patient group
with atosiban is not recommended.
In a placebo-controlled study, foetal/ infant deaths were 5/295 (1.7%)
in the placebo group and 15/288 (5.2%) in the atosiban group, of
which two occurred at five and eight months of age. Eleven out of
the 15 deaths in the atosiban group occurred in pregnancies with a
gestational age of 20 to 24 weeks, although in this subgroup patient
distribution was unequal (19 women on atosiban, 4 on placebo). For
women with a gestational age greater than 24 weeks there was no
difference in mortality rate (1.7% in the placebo group and 1.5% in
the atosiban group).

In healthy non-pregnant subjects receiving atosiban infusions
(10 to 300 micrograms/ min over 12 hours), the steady state plasma
concentrations increased proportionally to the dose.
The clearance, volume of distribution and half‑life were found to be
independent of the dose.
In women in pre‑term labour receiving atosiban by infusion
(300 micrograms/ min for 6 to 12 hours), steady state plasma
concentrations were reached within one hour following the start of
the infusion (mean 442 ± 73 ng/ ml, range 298 to 533 ng/ ml).
Following completion of the infusion, plasma concentration rapidly
declined with an initial (tα) and terminal (tβ) half‑life of 0.21 ± 0.01 and
1.7 ± 0.3 hours, respectively. Mean value for clearance was 41.8 ±
8.2 litres/ h. Mean value of volume of distribution was 18.3 ± 6.8 litres.
Plasma protein binding of atosiban is 46 to 48% in pregnant women.
It is not known whether the free fraction in the maternal and foetal
compartments differs substantially. Atosiban does not partition into
red blood cells.
Atosiban passes the placenta. Following an infusion of 300 micrograms/
min in healthy pregnant women at term, the foetal/ maternal atosiban
concentration ratio was 0.12.
Two metabolites were identified in the plasma and urine from
human subjects. The ratios of the main metabolite M1 (des‑(Orn8,
Gly‑NH2 9)‑[Mpa1, D‑Tyr(Et)2, Thr4]-oxytocin) to atosiban
concentrations in plasma were 1.4 and 2.8 at the second hour
and at the end of the infusion respectively. It is not known whether
M1 accumulates in tissues. Atosiban is found in only small quantities
in urine, its urinary concentration is about 50 times lower than that
of M1. The proportion of atosiban eliminated in faeces is not known.
The main metabolite M1 is approximately 10 times less potent than
atosiban in inhibiting oxytocin-induced uterine contractions in vitro.
Metabolite M1 is excreted in milk.
There is no experience with atosiban treatment in patients with
impaired function of the liver or kidneys.
Renal impairment is not likely to warrant a dose adjustment, since
only a small extent of atosiban is excreted in the urine. In patients
with impaired hepatic function, atosiban should be used with caution.
It is unlikely that atosiban inhibits hepatic cytochrome P450 isoforms
in humans.

N/A

Mannitol
Hydrochloric acid 1M
Water for injections

In the absence of compatibility studies, this medicinal product must
not be mixed with other medicinal products.

See outer carton. Once the vial has been opened, the dilution must be performed immediately. Diluted solution for intravenous administration should be used within 24 hours after preparation.

Store in a refrigerator (2°C‑8°C). Store in the original package in order
to protect from light.

One vial of concentrate for solution for infusion contains 5 ml solution,
corresponding to 37.5 mg atosiban.
Colourless glass vials, clear borosilicated (type I) sealed with grey
siliconised bromo‑butyl rubber stopper, type I, and flip‑off cap of
polypropylene and aluminium.
The pack contains one Unit.

The vials should be inspected visually for particulate matter and
discoloration prior to administration.
Preparation of the intravenous infusion solution:
For intravenous infusion, following the bolus dose, Tractocile®
37.5 mg/ 5 ml, concentrate for solution for infusion should be diluted
in one of the following solutions:
− Sodium chloride 9 mg/ ml (0.9%) solution for injection.
− Ringer’s lactate solution.
− 5% w/v glucose solution.
Withdraw 10 ml solution from a 100 ml infusion bag and discard.
Replace it by 10 ml Tractocile® 37.5 mg/ 5 ml concentrate for solution
for infusion from two 5 ml vials to obtain a concentration of 75 mg
atosiban in 100 ml.
The reconstituted product is a clear, colourless solution without
particles.
The loading infusion is given by infusing 24 ml/ hour (i.e. 18 mg/ h) of
the above prepared solution over the 3 hour period under adequate
medical supervision in an obstetric unit. After three hours the infusion
rate is reduced to 8 ml/ hour.
Prepare new 100 ml bags in the same way as described to allow the
infusion to be continued.
If an infusion bag with a different volume is used, a proportional
calculation should be made for the preparation.
To achieve accurate dosing, a controlled infusion device is
recommended to adjust the rate of flow in drops/ min. An intravenous
microdrip chamber can provide a convenient range of infusion rates
within the recommended dose levels for Tractocile®.
If other medicinal products need to be given intravenously at the
same time, the intravenous cannula can be shared or another site of
intravenous administration can be used. This permits the continued
independent control of the rate of infusion.