Atoziban 7.5mg/ml 5 ml

Pharmacotherapeutic group:

Rod activity suppressant – oxytocin receptor blocker

ATC:

G.02.C.X Other drugs for use in gynecology

G.02.C.X.01 Atoziban

Pharmacodynamics:

Atoziban is a synthetic peptide that is a competitive antagonist of human oxytocin at the receptor level. Atoziban binds to oxytocin receptors, reducing the frequency of uterine contractions and myometrial tone, leading to suppression of uterine contractility. Atoziban also binds to vasopressin receptors, inhibiting the effect of vasopressin, but has no effect on the cardiovascular system.

In the case of premature labor in a woman atoziban in the recommended doses suppresses uterine contractions and provides the uterus with functional peace.

The uterus relaxation begins immediately after injection of atoziban. Within 10 minutes myometrium contractile activity is significantly reduced, maintaining stable uterine functional rest (≤4 contractions per hour) for 12 h.

Pharmacokinetics:
Pharmacokinetic parameters of atoziban (volume of distribution, clearance and half-life) are independent of dose.

Distribution

After intravenous (IV) infusion (300 mcg/min for 6-12 h), the maximum plasma concentration of atoziban is reached within 1 h after infusion initiation (average 442±73 ng/mL, range 298 to 533 ng/mL). Atoziban penetrates through the placental barrier. The ratio of atoziban concentration in the fetus and in the maternal body is 0.12.

Atoziban binding to blood plasma proteins in pregnant women is 46-48%. Mean volume of distribution is 18.3±6.8 liters.

Metabolism

Two metabolites have been identified in human plasma and urine. The ratio of the concentration of the main metabolite M1 to the concentration of atoziban in blood plasma was 1.4 and 2.8 at the 2nd hour of infusion and after discontinuation, respectively. Metabolite Ml has pharmacological activity on a par with atoziban and penetrates into breast milk. Inhibition of cytochrome P450 isoforms by atoziban is unlikely.

Excretion

After discontinuation of infusion, plasma atoziban concentrations rapidly decrease with initial (tα) and final (tβ) elimination half times of 0.21±0.01 and 1.7±0.3 h, respectively. The average clearance of atoziban is 41.8±8.2 L/h.

Atoziban is detected in the urine in very small amounts, its concentration in the urine is 50 times lower than the concentration of the metabolite Ml. The amount of atoziban excreted through the intestine was not determined.

Indications

Atoziban is used for the threat of preterm labor in pregnant women over 18 years of age at 24 to 33 full weeks of gestation with a normal fetal heart rate in the following cases:

– regular uterine contractions of at least 30 s and a frequency of more than 4 for 30 minutes;

– cervical opening of 1 to 3 cm (0-3 cm for non-pregnant women).

Active ingredient

Atoziban

Composition

For 1 ml:

active substance: atoziban acetate converted into atoziban 7.5 mg;

excipients: mannitol 50.0 mg, 1M hydrochloric acid solution to pH 4.5, water for injections up to 1 ml.

How to take, the dosage

Atoziban is administered by IV immediately after the diagnosis of preterm labor in 3 steps:

1) first, a 0.9 mL vial of the drug is administered within 1 min without dilution (initial dose is 6.75 mg);

2) immediately thereafter, an infusion of atoziban at a dose of 300 mcg/min for 3 h (infusion rate is 24 mL/h, atoziban dose is 18 mg/h);

3) followed by a prolonged (up to 45 h) infusion of atoziban at a dose of 100 mcg/min (infusion rate 8 ml/h, atoziban dose 6 mg/h).

The total duration of treatment should not exceed 48 hours. The maximum dose of atoziban for the entire course should not exceed 330.75 mg.

If there is a need for repeated administration of atoziban, it should also be started with Stage 1 followed by infusion of atoziban (Stages 2 and 3).

Retreatment can be started at any time after the first use of the drug and can be repeated up to 3 cycles.

If uterine contractility does not decrease after 3 cycles of therapy with atoziban, another tocolytic drug should be considered. Instructions for preparing a solution for infusion (step 2 and 3)

The concentrate is diluted in one of the following solutions:

– 0.9% sodium chloride solution;

– Ringer’s acetate solution;

– 5% glucose solution.

From a vial containing 100 ml of one of the above dilution solutions, 10 ml is drained. Then 10 ml (2 vials) of the drug is injected into the vial to obtain a concentration of 75 mg/100 ml.

The shelf life of the prepared solution for infusion is 24 hours. Do not use if insoluble particles are visible in the solution or the solution has changed color.

Particular categories of patients

Atoziban should not be used in pregnant women younger than 18 years of age because of lack of data on the effectiveness and safety in patients in this age group.

Renal dysfunction

There are no data on the use of Atoziban in patients with renal dysfunction.

There are no data on the use of Atoziban in patients with hepatic impairment.

Interaction

Atoziban has no effect on the pharmacokinetics of drugs metabolized with cytochrome P450.

No clinically significant interactions have been observed with atoziban and betamethasone.

Labetalol has no effect on the pharmacokinetics of atoziban.

A interaction of atoziban with antibiotics is unlikely.

The co-administration of atoziban with ergot alkaloids is not advisable due to the opposite pharmacological actions and indications of use.

Special Instructions

If there is no decrease in uterine contractility during atosiban infusion, uterine contractions should be monitored and the fetal heart rate should be monitored. Other drugs should also be considered.

The decision to continue or resume atoziban infusion for intrauterine fetal retention depends on the assessment of fetal maturity.

There is no experience of atoziban administration in pregnant women with hepatic or renal impairment. Caution should be exercised when prescribing atoziban to this category of patients.

Atoziban is not used in cases of abnormal placental attachment.

As an oxytocin antagonist, atoziban can theoretically promote uterine relaxation and induce postpartum uterine bleeding, so the degree of blood loss after delivery should be continuously assessed.

Effect on the ability to drive a vehicle and mech:
Not applicable, given the indications for use.

Contraindications

– History of hypersensitivity to atoziban or any of the excipients of the drug;

– gestational age less than 24 or more than 33 full weeks;

– premature rupture of membranes in pregnancy of more than 30 weeks;

– fetal intrauterine retardation;

– abnormal fetal heart rate (HR);

– uterine bleeding requiring immediate delivery;

– eclampsia and severe preeclampsia requiring immediate delivery;

– fetal intrauterine death;

– suspected chorioamnionitis;

– placenta previa;

– premature placental detachment;

– any conditions of the mother and fetus in which the preservation of pregnancy is dangerous;

– period of breastfeeding.

With caution:

If premature rupture of fetal membranes is suspected, the use of atoziban to prolong pregnancy should be compared with the potential risk of chorioamnionitis.

Atoziban should be used with caution in hepatic and renal dysfunction, in multiple gestation, at 24-27 weeks’ gestation (due to lack of sufficient clinical experience) and also when used together with other drugs with tocolytic effect.

Side effects

Adverse reactions are listed below by organ and system with the frequency of occurrence. Frequency criteria: very common (≥1/10), common (≥1/100, <1/10), not common (≥1/1000, <1/100), rare (≥1/10000, <1/1,000), very rare (<1 /10000), including individual reports.

Immune system disorders: rare – allergic reactions.

Gastrointestinal tract disorders: very often – nausea, often – vomiting.

Metabolism and nutrition disorders: often – hyperglycemia.

Nervous system disorders: often – headache, dizziness, not often – insomnia.

Heart disorders: often – tachycardia.

Vascular disorders: often – hypotension, hot flashes.

Skin and subcutaneous tissue disorders: not often – itching, skin rash.

Genital and mammary gland disorders: very rare – uterine bleeding / uterine atony.

General disorders and disorders at the injection site: often – hyperthermia at the injection site, not often – fever.

Overdose

Some cases of overdose are known. There are no specific symptoms and signs.

The treatment consists of symptomatic and supportive therapy. A specific antidote is not known.

Pregnancy use

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

Atoziban is contraindicated in breastfeeding.