TRACTOCILE 7.5mg / ml concentrate for injection medication leaflet

Tractocile 37.5 mg/5 ml concentrate for solution for infusion

Each vial of 5 ml solution contains 37.5 mg atosiban (as acetate).

Each ml of solution contains 7.5 mg atosiban.

After dilution, the concentration of atosiban is 0.75 mg/ml.

For a full list of excipients, see section 6.1.

Concentrate for solution for infusion (sterile concentrate).

Clear, colourless solution without particles.

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

Treatment with Tractocile should be initiated and maintained by a physician experienced in the treatment ofpre-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 highdose infusion (loading infusion 300 micrograms/min) of Tractocile 37.5 mg/5 ml concentrate for solution forinfusion during three hours, followed by a lower dose of Tractocile 37.5 mg/5 ml concentrate for solution forinfusion (subsequent infusion 100 micrograms/min) up to 45 hours. The duration of the treatment should notexceed 48 hours. The total dose given during a full course of Tractocile therapy should preferably not exceed330.75 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 ofpre-term labour. Once the bolus has been injected, proceed with the infusion. In the case of persistence ofuterine 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 dose1 0.9 ml intravenous bolus Not applicable 6.75 mginjection given over 1 minute2 3 hours intravenous loading 24 ml/hour (300 µg/min) 54 mginfusion3 Up to 45 hours subsequent 8 ml/hour (100 µg/min) Up to 270 mgintravenous infusion

In case a re-treatment with atosiban is needed, it should also commence with a bolus injection of Tractocile6.75 mg/0.9 ml, solution for injection followed by infusion with Tractocile 37.5 mg/5 ml, concentrate forsolution for infusion.

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 excretedin the urine. In patients with impaired hepatic function, atosiban should be used with caution.

The safety and efficacy of Tractocile in pregnant women aged less than 18 years have not been established.

No data are available.

For instructions on preparation of the medicinal product before administration, see section 6.6.

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.

When atosiban is used in patients in whom premature rupture of membranes cannot be excluded, the benefitsof 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 excretedin the urine. In patients with impaired hepatic function, atosiban should be used with caution (see sections4.2 and 5.2).

There is only limited clinical experience in the use of atosiban in multiple pregnancies or the gestational agegroup between 24 and 27 weeks, because of the small number of patients treated. The benefit of atosiban inthese subgroups is therefore uncertain.

Re-treatment with Tractocile is possible, but there is only limited clinical experience available with multiplere-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 ofpersistent uterine contractions should be considered.

As an antagonist of oxytocin, atosiban may theoretically facilitate uterine relaxation and postpartum bleedingtherefore blood loss after delivery should be monitored. However, inadequate uterus contraction postpartumwas 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 shouldbe used with caution in case of multiple pregnancy and/or concomitant administration of other medicinalproducts with tocolytic activity (see section 4.8).

It is unlikely that atosiban is involved in cytochrome P450 mediated drug-drug interactions as in vitroinvestigations have shown that atosiban is not a substrate for the cytochrome P450 system, and does notinhibit the drug metabolising cytochrome P450 enzymes.

Interaction studies have been performed with labetalol and betamethasone in healthy, femalevolunteers. 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 weeksof gestation. If during pregnancy the woman is already breast-feeding an earlier child, then breast-feedingshould be discontinued during treatment with Tractocile, since the release of oxytocin during breast-feedingmay 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 beenshown 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 thatcovered fertility and early embryonic development (see section 5.3).

Not relevant.

Possible adverse reactions of atosiban were described for the mother during the use of atosiban in clinicaltrials. In total 48% of the patients treated with atosiban experienced adverse reactions during the clinicaltrials. The observed adverse reactions were generally of a mild severity. The most commonly reportedadverse reaction in the mother is nausea (14 %).

For the newborn, the clinical trials did not reveal any specific adverse reactions of atosiban. The infantadverse 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 Very Common Uncommon Rare

Class (SOC) common

Immune system disorders Allergic reaction

Metabolism and nutrition Hyperglycaemiadisorders

Psychiatric disorder Insomnia

Nervous system disorders Headache,

Dizziness

Cardiac disorders Tachycardia

Vascular disorders Hypotension,

Hot flush

Gastrointestinal disorders Nausea Vomiting

Skin and subcutaneous tissue Pruritis,disorders Rash

Reproductive system and Uterine haemorrhage,breast disorder uterine atony

General disorders and Injection site Pyrexiaadministration site reactionconditions

Respiratory events like dyspnoea and pulmonary oedema, particularly in association with concomitantadministration 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 suspected adverse reactions after authorisation of the medicinal product is important. It allowscontinued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are askedto report any suspected adverse reactions via the national reporting system listed in Appendix V.

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 acompetitive antagonist of human oxytocin at receptor level. In rats and guinea pigs, atosiban was shown tobind 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 vasopressinreceptor, 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 inducesuterine quiescence. The onset of uterus relaxation following atosiban is rapid, uterine contractions beingsignificantly reduced within 10 minutes to achieve stable uterine quiescence (≤ 4 contractions/hour) for12 hours.

Phase III clinical trials (CAP-001 studies) include data from 742 women who were diagnosed with pre-termlabour at 23-33 weeks of gestation and were randomised to receive either atosiban (according to thislabelling) or β-agonist (dose-titrated).

Primary endpoint: the primary efficacy outcome was the proportion of women remaining undelivered andnot 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 undeliveredand 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 weresignificantly (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 tocolyticswithin 7 days of treatment initiation was similar for atosiban and beta-mimetics treated women at gestationalage 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 remainingundelivered within 48 h of treatment initiation. There was no difference between the atosiban and beta-mimetic 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 forthe 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-agonistgroup (p=0.58).

Fetal and maternal outcome did apparently not differ between the atosiban and the β-agonist group, but theclinical 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 re-treatment, 8 received at least 2 re-treatments and 2 received 3 re-treatments (see section 4.4).

As the safety and efficacy of atosiban in women with a gestational age of less than 24 completed weeks hasnot been established in controlled randomised studies, the treatment of this patient group with atosiban is notrecommended (see section 4.3).

In a placebo-controlled study, fetal/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 inthe atosiban group occurred in pregnancies with a gestational age of 20 to 24 weeks, although in thissubgroup patient distribution was unequal (19 women on atosiban, 4 on placebo). For women with agestational age greater than 24 weeks there was no difference in mortality rate (1.7% in the placebo groupand 1.5% in the atosiban group).

In healthy non-pregnant subjects receiving atosiban infusions (10 to 300 micrograms/min over 12 hours), thesteady 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), steadystate 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 freefraction in the maternal and fetal compartments differs substantially. Atosiban does not partition into redblood cells.

Atosiban passes the placenta. Following an infusion of 300 micrograms/min in healthy pregnant women atterm, the fetal/maternal atosiban concentration ratio was 0.12.

Two metabolites were identified in the plasma and urine from human subjects. The ratios of the mainmetabolite M1 (des-(Orn8, Gly-NH 9)-[Mpa12 , D-Tyr(Et)2, Thr4]-oxytocin) to atosiban concentrations inplasma were 1.4 and 2.8 at the second hour and at the end of the infusion respectively. It is not knownwhether M1 accumulates in tissues. Atosiban is found in only small quantities in urine, its urinaryconcentration is about 50 times lower than that of M1. The proportion of atosiban eliminated in faeces is notknown. 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 (see section 4.6).

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 excretedin the urine. In patients with impaired hepatic function, atosiban should be used with caution (see sections4.2 and 4.4).

It is unlikely that atosiban inhibits hepatic cytochrome P450 isoforms in humans (see section 4.5).

No systemic toxic effects were observed during the two-week intravenous toxicity studies (in rats and dogs)at doses which are approximately 10 times higher than the human therapeutic dose, and during the three-months toxicity studies in rats and dogs (up to 20 mg/kg/day s.c.). The highest atosiban subcutaneous dosenot producing any adverse effects was approximately two times the therapeutic human dose.

No studies were performed that covered fertility and early embryonic development. Reproduction toxicitystudies, with dosing from implantation up to late stage pregnancy, showed no effects on mothers and fetuses.

The exposure of the rat fetus was approximately four times that received by the human fetus duringintravenous infusions in women. Animal studies have shown inhibition of lactation as expected from theinhibition of action of oxytocin.

Atosiban was neither oncogenic nor mutagenic in in vitro and in vivo tests.

Mannitol

Hydrochloric acid 1M

Water for injections

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinalproducts except those mentioned in section 6.6.

4 years.

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.

For storage conditions after first opening and dilution of the medicinal product, see section 6.3.

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 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 forinfusion 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 Tractocile37.5 mg/5 ml concentrate for solution for infusion from two 5 ml vials to obtain a concentration of 75 mgatosiban 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 the3 hour period under adequate medical supervision in an obstetric unit. After three hours the infusion rate isreduced 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 thepreparation.

To achieve accurate dosing, a controlled infusion device is recommended to adjust the rate of flow indrops/min. An intravenous microdrip chamber can provide a convenient range of infusion rates within therecommended dose levels for Tractocile.

If other medicinal products need to be given intravenously at the same time, the intravenous cannula can beshared or another site of intravenous administration can be used. This permits the continued independentcontrol of the rate of infusion.

Ferring Pharmaceuticals A/S

Amager Strandvej 4052770 Kastrup

Denmark

Tel: +45 88 33 88 34

EU/1/99/124/002

Date of first authorisation: 20 January 2000

Date of latest renewal: 20 January 2010

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.