Myrosiban

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

Composition:

Active substance: atosiban acetate;

1 vial (5 ml concentrate for infusion solution) contains 37.5 mg of atosiban (as acetate);

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

Pharmaceutical form. Concentrate for solution for infusion.

Main physicochemical characteristics: 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 Merosiban 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 the suppression of uterine contractions. Atosiban also binds to vasopressin receptors, thereby inhibiting vasopressin effects. In animals, atosiban had no effect on the cardiovascular system.

In cases of preterm labour in humans, atosiban at recommended doses suppresses uterine contractions and provides functional uterine quiescence. 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 over 12 hours), the steady-state plasma concentration increased proportionally with dose. Drug clearance, volume of distribution, and elimination half-life 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 reached within 1 hour after the start of infusion (mean 442 ± 73 ng/mL, range 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 2 hours during infusion and after its cessation, respectively. It is unknown whether M1 accumulates in tissues. Atosiban is detectable 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 hepatic cytochrome P450 isoenzymes in humans.

Clinical characteristics.

Indications.

The medicinal product Atosiban should be used to prevent preterm labour in pregnant women meeting all of the following criteria:

• 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.

Atosiban 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);
• suspected intrauterine infection;
• placenta praevia;
• placental abruption;
• any other maternal or fetal conditions where continuation of pregnancy poses a risk;
• hypersensitivity to the active substance or excipients in the patient's 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, involvement of atosiban in drug interactions mediated by cytochrome P450 is unlikely.

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

Other studies on drug interactions with antibiotics, ergot alkaloids, and antihypertensive agents have not been conducted.

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 in treating patients with hepatic or renal impairment using atosiban.

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 during pregnancy weeks 24 to 27 is limited due to the small number of patients treated with the drug. Therefore, the benefit of atosiban in these patient groups has not been established.

Repeated administration of the medicinal product Mirospan is possible, but no more than 3 times (due to limited clinical experience).

In cases of intrauterine growth restriction, the decision regarding continuation or repeated administration of the medicinal product Mirospan depends on the assessment of fetal maturity.

In the presence 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 agents 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 a woman is breastfeeding a previously born infant during pregnancy, breastfeeding should be discontinued during treatment with Mirospan, as oxytocin is secreted during lactation, which may increase uterine contractility and counteract the effect of tocolytic therapy.

During clinical trials with 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 or operate machinery has not been evaluated due to the clinical setting being inappropriate.

Method of administration and dosage.

Treatment with the medicinal product Merosiban must be prescribed and conducted by a physician experienced in the management of preterm labour.

Merosiban is administered intravenously in three consecutive steps:

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

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

After diagnosis of preterm labour, intravenous therapy should be initiated as soon as possible using an initial bolus injection of the medicinal product Merosiban, solution for injection (see the package leaflet for Merosiban, solution for injection, 6.75 mg / 0.9 mL). Following the bolus injection, the infusion should be started. If uterine contractility does not cease during treatment with Merosiban, alternative therapy should be considered.

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

Repeated Administration

If re-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 infusion of the medicinal product Myrosiban, concentrate for solution for infusion, 37.5 mg / 5 mL. Repeated treatment may be initiated at any time after the first treatment and may be repeated up to 3 times (see section "Special Instructions").

Patients with Renal or Hepatic Impairment

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.

Preparation of Solution for Intravenous Administration

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

After opening the concentrate vial, dilution should be performed immediately. The diluted solution for intravenous administration must be used within 24 hours after preparation.

For intravenous infusion, which should be initiated immediately after the bolus dose, the Myrosiban concentrate for solution for infusion 37.5 mg / 5 mL should be diluted in one of the following solutions:

• 0.9% sodium chloride solution,
• Ringer's lactate solution,
• 5% glucose solution.

From a 100 mL infusion bag, remove 10 mL of the respective solution and discard it. Add 10 mL of Myrosiban concentrate for solution for infusion 37.5 mg / 5 mL (2 vials of 5 mL each) to achieve a concentration of 75 mg of atosiban in 100 mL.

The resulting solution should be clear, colorless, and free of particles.

The loading infusion should be administered by delivering the prepared solution at a rate of 24 mL/h (i.e., 18 mg/h) over 3 hours under appropriate medical supervision in an obstetric unit. After 3 hours, the infusion rate should be reduced to 8 mL/h.

To continue the infusion, the next 100 mL should be prepared using the method described above.

The amount of drug must be recalculated to maintain the specified proportion if an infusion container of different volume is used.

To ensure accurate dosing, the infusion rate should be calibrated on the intravenous infusion device in drops/minute. An intravenous micro-drip infusion chamber may provide a convenient range of infusion rates within the recommended doses of the medicinal product Myrosiban.

Children

The safety and efficacy of Myrosiban in pregnant women under 18 years of age have not been established. Data are lacking; therefore, the drug should not be administered to children.

Overdose

Several cases of overdose have been reported, which occurred without specific symptoms or signs. A specific antidote for overdose is not known.

Adverse Reactions

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

Clinical trials did not reveal any specific adverse reactions to atosiban in newborns. Adverse reactions in infants were within normal expectations and were 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 (≥ 1/10000 to < 1/1000). Within each frequency group, adverse reactions are listed in decreasing order of severity.

Post-marketing surveillance data

During the post-marketing period of atosiban use, respiratory events such as dyspnoea and pulmonary oedema 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 medicinal product registration is highly important. It enables ongoing monitoring of the benefit-risk balance of the medicinal product. Healthcare and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy via 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 the reach of children.

Chemical and physical stability after opening the packaging has been demonstrated for 24 hours at 25 °C.

From a microbiological standpoint, the medicinal product should be used immediately. If not used immediately, the responsibility for storage conditions and duration lies with the user, and the storage period should generally not exceed 24 hours at 2 to 8 °C, unless reconstitution was performed under controlled and validated aseptic conditions.

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.

Packaging

5 ml concentrate for infusion solution in a vial; 1 vial in a cardboard box.

Prescription status

By prescription only.

Manufacturer

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

Manufacturer's address and location of its business operations

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