Tractocil

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT TRACTOCYREL® (TRACTOCILE®)

Composition:

Active substance: atosiban;

1 ml of solution contains 7.5 mg of atosiban acetate calculated as atosiban;

Excipients: mannitol (E 421), diluted hydrochloric acid, water for injections.

Pharmaceutical form. Injection solution.

Pharmacotherapeutic group. Gynecological medicines. ATC code G02C X01.

Clinical characteristics.

Indications.

Tractocile is indicated for the prevention of preterm labor in pregnant women who meet all of the following conditions:

• regular uterine contractions lasting at least 30 seconds and occurring more than 4 times within 30 minutes;
• cervical dilatation from 1 to 3 cm (0–3 cm in women giving birth for the first time) and cervical effacement greater than 50%;
• women over 18 years of age;
• gestational age between 24 and 33 completed weeks;
• normal fetal heart rate.

Contraindications.

Tractocile should not be used in the following cases:

• gestational age less than 24 or more than 33 completed weeks;
• preterm premature rupture of membranes at a gestational age above 30 weeks;
• abnormal fetal heart rate;
• intrauterine growth restriction and abnormal fetal heart rate (FHR);
• antepartum uterine bleeding requiring immediate delivery;
• eclampsia and severe pre-eclampsia requiring immediate delivery;
• intrauterine fetal death;
• suspicion of intra-amniotic infection;
• placenta praevia;
• placental abruption;
• any other conditions affecting either the mother or the fetus where continuation of pregnancy poses a risk;
• hypersensitivity to the active substance or to any of the excipients in the patient's medical history.

Method of administration and dosage

Treatment with Tractocile must be prescribed and administered by a qualified physician experienced in the management of preterm labor.

Tractocile is administered intravenously in 3 consecutive steps:

1. initially, Tractocile, injection solution, is administered as a bolus dose of 6.75 mg;
2. immediately after this, a continuous infusion of Tractocile, concentrate for infusion solution, at a high dose of 300 \µg/min (loading infusion) is administered for 3 hours;
3. thereafter, a prolonged infusion of the concentrate at a lower dose of 100 \µg/min is administered for up to 45 hours. The total duration of treatment should not exceed 48 hours.

The total dose of the drug throughout the entire treatment course must not exceed 330.75 mg of atosiban.

The intravenous bolus dose should be administered immediately after diagnosis of preterm labor. After administration of the bolus injection, the infusion should be started without delay. If uterine contractility persists during treatment with Tractocile, alternative therapy should be considered.

Data on the use of the drug in patients with hepatic or renal impairment are lacking. Dosage adjustment is not required in renal impairment, as only a very small amount of atosiban is excreted in urine. Atosiban should be used with caution in patients with hepatic impairment.

The table below presents the complete dosing regimen for bolus administration and subsequent infusion:

Re-administration

If re-administration of atosiban is required, treatment should also be initiated with a bolus injection of the injection solution, followed by infusion of the concentrate solution for infusion.

Re-treatment can be initiated at any time after the first treatment and can be repeated up to 3 times (see section "Special Instructions").

Instructions for administration

Before administration, the vials should be inspected visually for presence of particles and discoloration of the solution.

Withdraw 0.9 mL of Tractocile from the vial and administer intravenously slowly over 1 minute under close medical supervision in an obstetric unit.

The injection solution must be used immediately.

Adverse Reactions

During clinical studies, possible adverse reactions in the mother were described, and no specific adverse effects of atosiban in newborns were observed. Adverse effects observed in infants were within normal limits.

The following adverse effects were reported in women:

Very common (≥1/10)

Gastrointestinal disorders: nausea.

Common (≥1/100, <1/10)

Metabolism and nutrition disorders: hyperglycaemia.

Nervous system disorders: headache, dizziness.

Cardiovascular disorders: tachycardia, arterial hypotension, hot flushes.

Gastrointestinal disorders: vomiting.

General disorders at the site of administration: reaction at the site of administration.

Uncommon (≥1/1000, <1/100)

Psychiatric disorders: insomnia.

Skin and subcutaneous tissue disorders: pruritus, rash.

General disorders at the site of administration: hyperthermia.

Rare (≥1/10000, <1/1000)

Reproductive system and breast disorders: uterine haemorrhage, uterine atony.

One case of allergic reaction has been reported.

Respiratory events such as dyspnoea and pulmonary oedema, particularly when associated with concomitant administration of other tocolytic agents such as calcium antagonists and beta-mimetics, and/or multiple gestation, have been reported in the post-marketing period.

Overdose

Several cases of overdose have been reported, none of which were associated with specific symptoms or signs. There is no known specific antidote in the event of overdose.

Use during pregnancy or breastfeeding

Atosiban should only be administered in cases of diagnosed preterm labour between 24 and 33 completed weeks of gestation.

If a woman is breastfeeding a previously born infant during pregnancy, breastfeeding should be discontinued during treatment with Tractocile due to the release of oxytocin in breast milk, which may promote uterine contractions and counteract the effect of tocolytic therapy.

During clinical trials, no effect of atosiban on lactation was observed. It has been demonstrated that small amounts of atosiban are excreted into breast milk.

Embryo-fetotoxicity studies have not revealed any toxic effects of atosiban.

Fertility and early embryogenesis studies have not been conducted.

Children

Not applicable to children.

Special precautions for use

When atosiban is used in patients in whom premature rupture of membranes is possible, the benefits of delaying delivery should outweigh the potential risk of developing chorioamnionitis.

Experience with the use of atosiban in patients with impaired hepatic or renal function is lacking.

Atosiban is not administered in cases of abnormal placental attachment.

Experience with the use of atosiban in multiple pregnancies, as well as at gestational ages from 24 to 27 weeks, is limited.

Repeat administration of Tractocile is possible, but not more than 3 times (due to lack of clinical experience).

In cases of intrauterine growth restriction, the decision regarding continuation or repeat administration of Tractocile depends on the assessment of fetal maturity.

With persistent uterine muscle activity during atosiban administration, monitoring of uterine contractions and fetal heart rate should be performed.

As an oxytocin antagonist, atosiban may theoretically enhance uterine relaxation and provoke postpartum uterine bleeding; therefore, blood loss during delivery should be continuously assessed.

Multiple pregnancy and the use of tocolytic agents such as calcium channel blockers and beta-mimetics are known to be associated with an increased risk of pulmonary edema. Therefore, atosiban should be used with caution in cases of multiple pregnancy and/or concomitant use of other tocolytics.

Ability to influence reaction rate while driving or operating machinery

The effect on the ability to drive vehicles or operate machinery has not been evaluated due to the clinical context being inappropriate.

Interaction with other medicinal products and other forms of interaction

In vitro studies have shown that atosiban is not a substrate of the cytochrome P450 system and does not inhibit the metabolism of drugs by enzymes of this system; therefore, it is unlikely that atosiban will be involved in drug interactions mediated by cytochrome P450.

No clinically significant interactions were observed when atosiban was used concomitantly with betamethasone and labetalol. Other studies on drug interactions with antibiotics, ergot alkaloids, and antihypertensive agents have not been conducted.

Pharmacological properties.

Pharmacodynamics.

Atosiban is a synthetic peptide and a competitive antagonist of human oxytocin at the receptor level. By binding to oxytocin receptors, it reduces the frequency of uterine contractions and the tone of the myometrium, resulting in suppression of uterine contractions. Atosiban also binds to vasopressin receptors, thereby inhibiting the effects of vasopressin.

In cases of preterm labor, atosiban at recommended doses suppresses uterine contractions and provides functional uterine quiescence. Uterine relaxation begins almost immediately after administration of atosiban. Within 10 minutes, myometrial contractile activity significantly decreases, and stable functional uterine quiescence (fewer than 4 contractions per hour) is maintained for up to 12 hours.

Pharmacokinetics.

In healthy non-pregnant women who received atosiban as an infusion (10 to 300 mcg/min for 12 hours), steady-state plasma concentrations increased proportionally with dose. Drug clearance, volume of distribution, and elimination half-life were independent of dose.

In pregnant women receiving atosiban as an intravenous infusion (300 mcg/min for 6–12 hours) due to preterm labor, steady-state plasma concentrations were achieved within 1 hour after the start of infusion (mean 442 ± 73 ng/mL, range 298–533 ng/mL).

After infusion discontinuation, plasma concentration of the drug rapidly declines, with initial (tα) and terminal (tβ) half-life values of 0.21 ± 0.01 and 1.7 ± 0.3 hours, respectively. Mean drug clearance is 41.8 ± 8.2 L/h. Mean volume of distribution is 18.3 ± 6.8 L.

Plasma protein binding of atosiban in pregnant women ranges from 46% to 48%.

Atosiban crosses the placenta. Two metabolites have been identified in human plasma and urine. The ratio of the main metabolite M1 (des-(ornithine, glycine-NH2)-[Mpa, D-tyrosine(Et)2, threonine]-oxytocin) concentration to atosiban concentration in plasma was 1.4 and 2.8 at 2 hours during infusion and after its discontinuation, respectively. It is unknown whether M1 accumulates in tissues. Atosiban is detected in urine in very small amounts, with its concentration in urine being 50 times lower than that of M1. The percentage of atosiban excreted in feces is unknown. The main metabolite M1 is approximately 10 times weaker than atosiban in inhibiting oxytocin-induced uterine contractions in vitro. Metabolite M1 passes into breast milk.

Pharmaceutical characteristics.

Main physicochemical properties: clear, colorless solution, free from visible particles.

Incompatibilities.

Due to lack of compatibility studies, this medicinal product should not be mixed with any other medicinal products. If another medicinal product needs to be administered simultaneously, the same cannula or a different intravenous injection site may be used. This allows continuous independent control of infusion rates.

Shelf life. 4 years.

Storage conditions.

Store in a refrigerator (at 2–8 °C) in the original packaging. Keep out of the reach of children.

Packaging. 0.9 mL of injectable solution in a vial; 1 vial in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

Responsible for manufacturing, primary packaging, quality control, and batch release:

Ferring GmbH, Germany / Ferring GmbH, Germany.

Responsible for secondary packaging:

Ferring-Léčiva, a.s. / Ferring-Léčiva, a.s.

Address.

Wittland 11, 24109 Kiel, Germany / Wittland 11, 24109 Kiel, Germany.

Ke Skále 455, 252 42 Vestec u Prahy (areál spol. ECP, a.s.), Czech Republic / Ke Skále 455, 252 42 Vestec u Prahy (areál spol. ECP, a.s.), Czech Republic.