4.1. Therapeutic indications

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

4.2. Posology and method of administration

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 of Tractocile 6.75 mg/0.9 ml, solution for injection (see Summary of Product Characteristics of this product) 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:

Step

Regimen

Infusion rate

Atosiban dose

1

0.9 ml intravenous bolus injection given over 1 minute

Not applicable

6.75 mg

2

3 hours intravenous loading infusion

24 ml/hour (300 µg/min)

54 mg

3

Up to 45 hours subsequent intravenous infusion

8 ml/hour (100 µg/min)

Up to 270 mg

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, see section 6.6.

4.3. Contraindications

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 excipients listed in section 6.1.

4.4. Special warnings and precautions for use

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 (see sections 4.2 and 5.2).

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 (see section 4.2).

In case of intrauterine growth retardation, the decision to continue or reinitiate the administration of Tractocile depends on the assessment of fetal maturity.

Monitoring of uterine contractions and fetal 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 beta-mimetics 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 (see section 4.8).

4.5. Interaction with other medicinal products and other forms of interaction

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.

4.6. Fertility, pregnancy and lactation

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-fetal toxicity studies have not shown toxic effects of atosiban. No studies were performed that covered fertility and early embryonic development (see section 5.3).

4.7. Effects on ability to drive and use machines

Not relevant.

4.8. Undesirable effects

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 beta-mimetic 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.

MedDRA System Organ Class (SOC)

Very common

Common

Uncommon

Rare

Immune system disorders

Allergic reaction

Metabolism and nutrition disorders

Hyperglycaemia

Psychiatric disorder

Insomnia

Nervous system disorders

Headache, Dizziness

Cardiac disorders

Tachycardia

Vascular disorders

Hypotension, Hot flush

Gastrointestinal disorders

Nausea

Vomiting

Skin and subcutaneous tissue disorders

Pruritis, Rash

Reproductive system and breast disorder

Uterine haemorrhage, uterine atony

General disorders and administration site conditions

Injection site reaction

Pyrexia

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 beta-mimetics, and/or in women with multiple pregnancy, have been reported post-marketing.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme, website: www.mhra.gov.uk/yellowcard.

4.9. Overdose

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.