Myrosiban

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT MIROSIBAN (MIROSIBAN)

Composition:

Active substance: atosiban acetate;

1 vial (0.9 mL of injection solution) contains 6.75 mg of atosiban (as acetate);

Excipients: mannitol (E 421), 1 M hydrochloric acid solution, water for injections.

Pharmaceutical form. Injection solution.

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

Pharmacotherapeutic group. Other agents used in gynecology.

ATC code: G02C X01.

Pharmacological properties.

Pharmacodynamics.

The medicinal product Miosiban contains atosiban, a synthetic peptide ([Mpa1,D-tyrosine(Et)2,threonine4,ornithine8]-oxytocin), which is a competitive antagonist of human oxytocin at the receptor level. It is known that atosiban, by binding to oxytocin receptors, reduces the frequency of uterine contractions and the tone of the myometrium, resulting in inhibition of uterine contractions. Atosiban also binds to vasopressin receptors, thereby inhibiting its effects. In animals, atosiban had no effect on the cardiovascular system.

In cases of preterm labour in humans, atosiban at the recommended doses inhibits uterine contractions and provides functional quiescence of the uterus. Uterine relaxation begins almost immediately after administration of atosiban. Within 10 minutes, contractile activity of the uterus is significantly reduced, and stable functional quiescence of the uterus (≤ 4 contractions/hour) is maintained for 12 hours.

Pharmacokinetics.

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

In women receiving atosiban as an infusion (300 mcg/min for 6–12 hours) due to preterm labour, steady-state plasma concentration was achieved within 1 hour after the start of infusion (on average 442 ± 73 ng/mL, ranging from 298 to 533 ng/mL).

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

Plasma protein binding of atosiban in pregnant women ranges from 46% to 48%. It is unknown whether the free fraction differs significantly between maternal and fetal compartments. Atosiban does not penetrate into erythrocytes.

Atosiban crosses the placenta. After infusion of 300 mcg/min in a healthy pregnant woman, the ratio of atosiban concentration in the fetus to that in the mother was 0.12.

Two metabolites have been identified in human plasma and urine. The ratio of the concentration of the main metabolite M1 (des-(ornithine8, glycine-NH29)-[Mpa1, D-tyrosine(Et)2, threonine4]-oxytocin) to atosiban concentration in plasma was 1.4 and 2.8 at the second hour of infusion and after its discontinuation, respectively. It is unknown whether M1 accumulates in tissues. Atosiban is detected in urine only in small amounts, with its concentration in urine approximately 50 times lower than that of M1. The fraction of atosiban excreted in feces is unknown. The main metabolite M1 inhibits oxytocin-induced uterine contractions in vitro approximately 10 times less potently than atosiban. Metabolite M1 is excreted into breast milk.

There is no experience with atosiban treatment in patients with hepatic or renal impairment. Renal impairment does not require dose adjustment, as only a negligible amount of atosiban is excreted in urine. Atosiban should be used with caution in patients with hepatic impairment.

It is unlikely that atosiban inhibits human hepatic cytochrome P450 isoenzymes.

Clinical characteristics.

Indications.

The medicinal product Myosiban is indicated for the prevention of preterm labour in pregnant women when all of the following conditions are present:

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

Contraindications.

Myosiban 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 over 30 weeks;
• abnormal fetal heart rate;
• antepartum uterine bleeding requiring immediate delivery;
• eclampsia and severe pre-eclampsia requiring immediate delivery;
• intrauterine fetal death;
• intrauterine growth restriction with abnormal fetal heart rate (FHR);
• suspicion of intrauterine 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 excipients in medical history.

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, the involvement of atosiban in drug interactions mediated by cytochrome P450 is unlikely.

A study on interaction with labetalol and betamethasone was conducted in healthy female volunteers. No clinically significant interaction between atosiban and betamethasone or labetalol was observed.

Other drug interaction studies with antibiotics, ergot alkaloids, and antihypertensive agents have not been performed.

Special precautions for use

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

Atosiban is not used in cases of abnormal placental attachment.

There is no experience with atosiban treatment in patients with hepatic or renal impairment. Renal impairment does not require dose adjustment, as only a negligible amount of atosiban is excreted in urine. Atosiban should be used with caution in patients with hepatic impairment.

Experience with atosiban use in multiple pregnancies or at gestational ages from 24 to 27 weeks is limited due to the small number of patients treated with the drug. Therefore, the benefit of atosiban in these groups has not been established.

Repeated administration of the medicinal product Mirosiban is possible, but not more than 3 times (due to limited clinical experience).

In cases of intrauterine growth restriction, the decision on continuing or repeating administration of Mirosiban depends on the assessment of fetal maturity.

In case of prolonged uterine muscle activity during atosiban infusion, monitoring of uterine contractions and fetal heart rate should be performed.

As an oxytocin antagonist, atosiban may theoretically enhance uterine relaxation and lead to postpartum uterine bleeding; therefore, blood loss should be monitored after delivery. However, inadequate postpartum uterine contractions were not observed during clinical trials.

Multiple pregnancies and the use of tocolytic agents such as calcium channel blockers and beta-mimetics are associated with an increased risk of pulmonary edema. Therefore, atosiban should be used with caution in multiple pregnancies and/or when other tocolytic drugs are used concomitantly.

Use during pregnancy or breastfeeding

Pregnancy

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

Breastfeeding

If during pregnancy a woman is breastfeeding a previously born infant, breastfeeding should be discontinued during treatment with Mirosiban, because oxytocin is secreted during lactation, which may increase uterine contractility and counteract the effect of tocolytic therapy.

During clinical trials of atosiban, no effect on lactation was observed. It has been noted that small amounts of atosiban pass from plasma into human breast milk.

Reproductive function

Embryo-fetal toxicity studies did not reveal any toxic effects of atosiban. Fertility and early embryogenesis studies have not been conducted.

Ability to affect reaction rate when driving or operating machinery

The effect on the ability to drive and operate machinery has not been evaluated due to the clinical setting being inappropriate.

Administration and dosage.

Treatment with the medicinal product Atosiban should be prescribed and conducted by a physician experienced in managing preterm labor.

Atosiban is administered intravenously in three consecutive steps:

• administer an initial bolus dose (6.75 mg) of the medicinal product Atosiban, injection solution, 6.75 mg / 0.9 mL;
• immediately after this, perform a prolonged infusion of the medicinal product Atosiban, concentrate for infusion solution, 37.5 mg / 5 mL, at a high dose (loading infusion, 300 µg/min) for 3 hours;
• thereafter, continue with a lower-dose infusion of the medicinal product Atosiban, concentrate for infusion solution, 37.5 mg / 5 mL (maintenance infusion, 100 µg/min) for up to 45 hours.

The total duration of treatment should not exceed 48 hours. The cumulative dose throughout the entire course of therapy with the medicinal product Atosiban should not exceed 330.75 mg of atosiban.

Following diagnosis of preterm labor, intravenous therapy should be initiated as soon as possible with the initial bolus injection. After the bolus injection, the infusion should be started (see the instructions for medical use of the medicinal product Atosiban, concentrate for infusion solution, 37.5 mg / 5 mL). If uterine contractile activity does not cease during treatment with Atosiban, alternative therapy should be considered.

The table below provides complete dosing information for the bolus administration and subsequent infusion:

Repeat Administration

If repeat administration of atosiban is required, it should also be initiated with a bolus injection of the medicinal product Myrosiban, solution for injection, 6.75 mg / 0.9 mL, followed by an infusion of the medicinal product Myrosiban, concentrate for solution for infusion, 37.5 mg / 5 mL.

Patients with Renal or Hepatic Impairment

There is no experience in treating patients with atosiban who have hepatic or renal impairment. Renal impairment does not require dosage adjustment, as only a negligible amount of atosiban is excreted in urine. Atosiban should be used with caution in patients with hepatic impairment.

Instructions for Administration

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

Preparation of the solution for initial intravenous injection: withdraw 0.9 mL of solution from the 0.9 mL vial labeled "Myrosiban, solution for injection, 6.75 mg / 0.9 mL" and administer it slowly as an intravenous bolus over 1 minute under close medical supervision in an obstetric unit. The medicinal product Myrosiban, solution for injection, 6.75 mg / 0.9 mL should be used immediately.

Children

Not to be used in children, as the safety and efficacy of Myrosiban in pregnant women under 18 years of age have not been established. Data are lacking.

Overdose

Several cases of overdose have been reported, which occurred without specific symptoms or signs. There is no known specific antidote in case of overdose.

Adverse Reactions

During clinical trials, possible adverse reactions in the mother were described. Overall, adverse reactions occurred in 48% of patients treated with atosiban in clinical trials. The observed adverse events were generally mild in severity. Nausea was the most frequently reported event (14%).

Clinical studies revealed no specific adverse reactions to atosiban in newborns. Adverse reactions in infants were within normal ranges and comparable to those observed in placebo and beta-mimetic treatment groups.

The adverse reactions listed below are categorized by frequency as follows: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1000 to < 1/100); rare (≥ 1/10,000 to < 1/1000). Within each frequency group, adverse reactions are listed in order of decreasing frequency.

Post-marketing surveillance data

During the post-marketing period of atosiban use, respiratory events such as dyspnea and pulmonary edema have been reported, particularly when used concomitantly with other tocolytic agents such as calcium antagonists and beta-mimetics, and in women with multiple pregnancies.

Reporting suspected adverse reactions

Reporting of adverse reactions after drug registration is of great importance. It enables continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare and pharmaceutical professionals, as well as patients or their legal representatives, are encouraged to report all suspected adverse reactions and lack of efficacy through the automated pharmacovigilance information system at: https://aisf.dec.gov.ua/.

Shelf life.

3 years.

Storage conditions.

Store at 2 to 8 °C in the original packaging to protect from light. Keep out of reach and sight of children.

After first opening of the vial, the solution for injection must be used immediately.

Incompatibilities.

Due to the lack of compatibility studies, this medicinal product must not be mixed with any other medicinal products.

Packaging.

0.9 mL of solution for injection in a vial; 1 vial in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

LLC «PHARMIDEA» / Limited Liability Company «PHARMIDEA».

Manufacturer's address and place of business.

4 Rupnicu Str., Olaine, Olaine distrikt, LV-2114, Latvia /
4 Rupnicu Str., Olaine, Olaine distrikt, LV-2114, Latvia.