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 re-treatments.
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
metabolizing 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-agonisttreated
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 product must be used immediately.

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

One vial of solution for injection contains 0.9 ml solution, corresponding to
6.75 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 initial intravenous injection:
Withdraw 0.9 ml of a 0.9 ml labelled vial of Tractocile® 6.75 mg/ 0.9 ml,
solution for injection and administer slowly as an intravenous bolus dose
over one minute, under adequate medical supervision in an obstetric unit. The
Tractocile® 6.75 mg/ 0.9 ml, solution for injection should be used immediately.