Oxytocin

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

Composition:

Active substance: oxytocin;

1 ml contains 5 IU oxytocin;

Excipients: glacial acetic acid, chlorobutanol hemihydrate, ethanol (96%), water for injections.

Pharmaceutical form. Solution for injection.

Main physicochemical properties: colorless clear solution.

Pharmacotherapeutic group. Hormones for systemic use, excluding sex hormones; posterior pituitary hormones, oxytocin and its derivatives. ATC code H01BB02.

Pharmacological properties.

Pharmacodynamics.

The clinical and pharmacological properties of oxytocin are similar to those of endogenous oxytocin produced by the posterior pituitary gland. The myometrium of the uterus contains oxytocin receptors belonging to the G-protein-coupled receptor family. Oxytocin induces contractions of the uterine smooth muscle by increasing intracellular calcium concentration, thereby producing contractions similar to those occurring during physiological spontaneous labor, and also transiently reduces uterine blood flow.

As the amplitude and duration of muscle contractions increase, cervical dilation and effacement occur. The number of oxytocin receptors and uterine sensitivity to oxytocin progressively increase during pregnancy, reaching their maximum at term. When administered in appropriate doses, oxytocin can enhance uterine contractility, ranging from moderate increases in the strength and frequency of spontaneous contractions (typical of physiological labor) to sustained tetanic contractions.

Oxytocin induces contraction of myoepithelial cells surrounding the alveoli of the mammary glands, thus promoting milk ejection.

By acting on vascular smooth muscle, oxytocin causes vasodilation and increases blood flow in the kidneys, coronary vessels, and cerebral vessels. Arterial pressure usually remains unchanged; however, intravenous (i.v.) administration of large doses of undiluted oxytocin solution may result in a transient decrease in arterial pressure, leading to reflex tachycardia and reflex increase in cardiac output. This is followed by a slight but sustained increase in arterial pressure.

Unlike vasopressin, oxytocin exerts minimal antidiuretic effects. However, administration of oxytocin together with large volumes of electrolyte-free fluids and/or too rapid infusion may lead to the development of hyperhydration.

Pharmacokinetics.

After intravenous administration, the uterine effect of oxytocin appears almost immediately and lasts for about 1 hour. After intramuscular administration, the myotonic effect begins within 3–7 minutes and persists for 2–3 hours.

Like vasopressin, oxytocin is distributed into the extracellular space. A small amount of oxytocin may cross into the fetal circulation.

The elimination half-life of oxytocin ranges from 1 to 6 minutes (shorter at late stages of pregnancy and during lactation). The majority of the drug undergoes rapid metabolism in the liver and kidneys. Oxytocin is inactivated via enzymatic hydrolysis, primarily by tissue oxytocinase. Oxytocinase is also present in placental tissue and blood plasma. Only a small fraction of oxytocin is excreted unchanged by the kidneys.

Renal impairment

Studies in patients with renal impairment have not been conducted. However, considering the elimination pathway and reduced renal excretion of oxytocin due to its antidiuretic effect, accumulation and prolonged action of oxytocin are possible.

Hepatic impairment

Studies in patients with hepatic impairment have not been conducted. Significant changes in the pharmacokinetics of the drug in patients with impaired liver function are unlikely, since the enzyme responsible for oxytocin metabolism (oxytocinase) is not only present in the liver, but also shows markedly increased activity in the placenta near the time of delivery. Thus, oxytocin biotransformation under conditions of impaired liver function is not expected to cause a significant change in metabolic clearance.

Clinical characteristics.

Indications.

Oxytocin is used to stimulate and enhance uterine contractile activity.

Use in the antepartum period

Induction of labor

For the purpose of labor induction, oxytocin is administered at term or near-term gestational age in the presence of arterial hypertension (e.g., preeclampsia, eclampsia, or in cases of cardiovascular or renal disease), fetal erythroblastosis, maternal or gestational diabetes mellitus, antepartum hemorrhage, or when early delivery is required, premature rupture of membranes, and inability to initiate spontaneous labor. Planned labor stimulation with oxytocin may be indicated in post-term pregnancy (more than 42 weeks of gestation), intrauterine fetal demise, or intrauterine fetal growth restriction.

Augmentation of uterine contractile activity

During the first or second stage of labor, oxytocin may be administered intravenously as an infusion to augment uterine contractile activity in cases of prolonged labor or dysfunctional uterine inertia.

Use in the postpartum period

Control of postpartum hemorrhage and uterine atony.

Other indications for use

As an adjunctive therapy in incomplete abortion or threatened abortion.

Diagnostic use

Assessment of fetal embryonic-placental respiratory reserve in high-risk pregnancies (oxytocin challenge test).

Contraindications.

Oxytocin for injection is contraindicated in the following cases:

• Clinically narrow pelvis;
• Unfavorable fetal position or presentation that prevents vaginal delivery without prior intervention (e.g., transverse fetal lie);
• Emergent obstetric conditions where the benefit-risk ratio for the fetus or mother necessitates immediate surgical intervention;
• Development of fetal distress prior to the onset of labor;
• Prolonged use in the absence of uterine contractions or in the presence of severe toxemia;
• Hypertonic uterine contractions;
• Hypersensitivity to the active substance or to any of the excipients of the medicinal product (see section "Excipients");
• Induction of labor or augmentation of uterine contractile activity when vaginal delivery is contraindicated (e.g., placental previa, prolapsed umbilical cord, vasa previa);
• Severe cardiovascular disease.

Interaction with other medicinal products and other forms of interaction.

There have been reports of severe arterial hypertension when oxytocin was administered 3–4 hours after prophylactic administration of vasoconstrictors in combination with caudal anesthesia.

Anesthesia with cyclopropane, enflurane, halothane, or isoflurane may alter the effects of oxytocin on the cardiovascular system, leading to unexpected outcomes such as arterial hypotension. Concurrent use of oxytocin and cyclopropane anesthesia may also cause sinus bradycardia and atrioventricular rhythm.

Oxytocin should be administered with caution to patients receiving medicinal products that may prolong the QTc interval.

Prostaglandins have been shown to potentiate the effects of oxytocin; therefore, their concomitant use is not recommended. Due to enhanced uterine contractility, caution should be exercised when prostaglandins and oxytocin are used sequentially.

Concomitant use of oxytocin with other labor inducers or abortifacients may lead to uterine hypertonia (increased tone), uterine rupture, or cervical trauma; for example, prostaglandin use may increase stimulation of labor and uterine musculature.

Therefore, during administration of the drug, strict monitoring of the following parameters in patients is required:

• Acid-base balance;
• Frequency, duration, and strength of uterine contractions;
• Fetal heart rate;
• Maternal blood pressure and heart rate;
• Uterine tone;
• Fluid intake and output balance.

Special precautions for use.

Except for special cases, oxytocin should not be used in the following situations:

• premature labor;
• borderline degree of clinically narrow pelvis (disproportion between fetal head size and maternal pelvis);
• previous major surgical interventions on the cervix or body of the uterus, including cesarean section;
• excessive uterine distension;
• multiple pregnancies;
• invasive cervical cancer;

Oxytocin must not be administered before engagement of the fetal head or breech into the pelvic inlet.

Identification of special cases caused by combinations of various factors is the responsibility of the physician. The potential beneficial effects of oxytocin therapy should be carefully weighed against the risk of rare but serious events such as uterine hypertonus or tetany.

For the purpose of labor induction and augmentation of uterine contractility, oxytocin must be administered intravenously only, in a hospital setting, and under appropriate medical supervision. Each patient receiving oxytocin infusion must be under continuous supervision by a physician experienced in the use of this drug.

To avoid complications during oxytocin administration, continuous monitoring of the following parameters is required:

• uterine contractile activity;
• maternal and fetal heart rate;
• maternal arterial blood pressure.

If uterine hyperactivity occurs, oxytocin administration must be stopped immediately; oxytocin-induced uterine contractions usually subside shortly after discontinuation of the drug.

When used correctly, oxytocin produces uterine contractions similar to those in normal labor. Excessive stimulation due to incorrect use of the drug is dangerous for both the mother and the fetus.

Uterine hypercontractility may develop despite correct dosing and adequate medical supervision in patients with hypersensitivity to oxytocin.

When administering the drug, one should consider the potential risk of increased bleeding and development of afibrinogenemia.

Stimulation of labor should be avoided in cases of intrauterine fetal death and/or presence of meconium in amniotic fluid, as this may lead to amniotic fluid embolism.

Oxytocin should not be used for prolonged periods in cases of oxytocin-resistant uterine inertia, severe preeclamptic toxemia, or severe cardiovascular disorders.

Intravenous bolus injection of oxytocin is contraindicated, as it may cause acute transient hypotension, leading to hyperemia and reflex tachycardia.

Oxytocin should be used with particular caution in patients with cardiovascular diseases (e.g., hypertrophic cardiomyopathy, valvular heart disease, and/or ischemic heart disease, including coronary artery spasm) and those predisposed to myocardial ischemia, to avoid significant changes in arterial blood pressure and heart rate.

Oxytocin should be administered cautiously in patients with long QT interval syndrome or related symptoms, as well as in patients taking drugs that prolong the QT interval.

Fatal maternal outcomes have been reported during parenteral administration of oxytocin for labor induction or augmentation of uterine contractility in the first and second stages of labor, due to anaphylactic reactions, subarachnoid hemorrhage, uterine rupture, and fetal death from various causes.

Disseminated intravascular coagulation

Rarely, pharmacological labor induction using uterotonic agents, including oxytocin, is associated with an increased risk of developing disseminated intravascular coagulation (DIC) in the postpartum period. This risk is directly related to pharmacological induction rather than to the use of a specific agent. The risk is primarily increased in women with additional risk factors for DIC: age over 35 years, complicated pregnancy course (e.g., gestational diabetes, arterial hypertension, hypothyroidism), gestational age exceeding 40 weeks. In such women, oxytocin and alternative drugs should be used cautiously, and the physician must consider the possibility of DIC development.

Water intoxication

Since oxytocin has a weak antidiuretic effect, prolonged intravenous administration of high doses of the drug in combination with large volumes of fluid (e.g., in the treatment of threatened or incomplete abortion or postpartum hemorrhage) may lead to water intoxication associated with hyponatremia. When oxytocin is administered together with intravenous fluids, a combined antidiuretic effect may occur, resulting in hypervolemia and subsequent development of hemodynamic pulmonary edema without hyponatremia. To avoid these rare complications during prolonged administration of high-dose oxytocin, the following safety measures should be observed: use an electrolyte-containing diluent (not dextrose); intravenous fluid infusions should be administered in small volumes (during induction or stimulation of labor at late gestational stages, oxytocin concentrations exceeding the recommended levels may be used); oral fluid intake should be restricted; fluid balance must be recorded; laboratory testing of electrolyte levels is indicated if electrolyte imbalance is suspected.

Oxytocin is contraindicated in patients with a history of hypersensitivity to the drug.

Different routes of oxytocin administration must not be used simultaneously.

Oxytocin may be administered by only one route at a time (either intravenously or intramuscularly).

Use during pregnancy or breastfeeding.

Pregnancy

During the first trimester of pregnancy, the drug is used only in cases of spontaneous or induced abortion; no other established indications exist. Based on extensive clinical experience, chemical structure, and pharmacological properties of the drug, administration of oxytocin for approved indications is not expected to increase the risk of fetal malformations.

Breastfeeding period

Oxytocin is present in small amounts in breast milk.

When oxytocin is administered to control postpartum uterine bleeding, breastfeeding should not be initiated until completion of the treatment course.

Ability to affect reaction rate when driving vehicles or operating machinery.

Oxytocin does not affect the ability to drive vehicles or operate machinery.

Administration and Dosage

Dosage

The dose must be individually adjusted according to the indication and taking into account the mother's and fetus's response to the drug.

Induction or stimulation of labor

Oxytocin must be administered exclusively as an intravenous infusion. Strict control of the infusion rate is mandatory. For safe induction or stimulation of labor, oxytocin should be administered using an infusion pump or similar device. Additionally, uterine contractions and fetal heart rate must be continuously monitored. In case of excessive uterine stimulation, oxytocin infusion should be discontinued immediately; a rapid reduction in excessive uterine activity will then occur.

Oxytocin infusion must not be administered within 6 hours after vaginal prostaglandin administration.

1. Prior to initiating oxytocin infusion, start infusion of physiological saline solution without oxytocin.
2. To prepare the standard infusion solution, mix 1 mL (5 IU) of oxytocin with 1000 mL of a non-hydrophilic diluent under sterile conditions. The solution should be thoroughly mixed by gently rotating the bottle. The resulting solution contains 5 mIU/mL of oxytocin. For accurate dosing, an infusion pump or similar device is recommended.
3. The initial infusion rate should not exceed 0.5–4 mIU/min. This rate may be increased every 20–40 minutes by 1–2 mIU/min until the desired intensity of uterine contractions is achieved. After achieving the desired frequency of uterine contractions (corresponding to normal labor activity), in the absence of signs of fetal distress and when cervical dilation reaches 4–6 cm, the infusion rate may be gradually reduced at a pace similar to the rate of increase. High infusion rates during late pregnancy require caution; rates up to 8–9 mIU/min may be required only in rare cases. In preterm labor, higher infusion rates may be needed, occasionally exceeding 20 mIU/min.
4. Fetal heart rate, resting uterine tone, and frequency, duration, and strength of uterine contractions must be monitored.
5. In case of uterine hyperactivity or fetal distress, oxytocin infusion must be stopped immediately and oxygen therapy provided to the mother. The physician must continuously monitor the condition of both mother and fetus.

Management of postpartum uterine bleeding

‒ Intravenous infusion (drip method): to control postpartum bleeding, mix 10–40 units of oxytocin in 1000 mL of a non-hydrophilic diluent. For prevention of uterine atony, an infusion rate of 20–40 mIU/min of oxytocin is usually required.

‒ Intramuscular administration: after placental delivery, 5 units of oxytocin may be administered intramuscularly.

Management of incomplete or missed abortion

Ten units of oxytocin should be added to 500 mL of physiological saline or a mixture of 5% dextrose and physiological saline; the infusion rate should be 20–40 drops/min.

Diagnosis of uteroplacental insufficiency (oxytocin challenge test)

The initial infusion rate should be 0.5 mIU/min. The infusion rate should be doubled every 20 minutes until the effective dose is reached (usually 5–6 mIU/min, maximum 20 mIU/min). After three moderate uterine contractions (each lasting 40–60 seconds) occur within a 10-minute period, the infusion should be discontinued and monitoring for late or variable decelerations in fetal heart rate should be performed.

Administration method

Intravenous infusion or intramuscular injection.

Oxytocin may only be administered parenterally (either intravenously or intramuscularly).

Special patient populations

Elderly patients

Studies in elderly patients (over 65 years of age) have not been conducted.

Renal and hepatic impairment

Studies in patients with renal or hepatic impairment have not been conducted.

Children. Not applicable to children.

Overdose.

Symptoms of overdose are primarily related to the degree of uterine sensitivity to oxytocin and are not necessarily associated with drug hypersensitivity. Hyperstimulation may result in strong (hypertonic) or prolonged (tetanic) contractions, or increased resting uterine tone (between contractions) to 15–20 mmHg or more, leading to disordered labor activity, rupture of the uterine body or cervix, vaginal lacerations, postpartum hemorrhage, uteroplacental insufficiency, fetal bradycardia, hypoxia, hypercapnia, and fetal death.

As a severe adverse reaction, seizures may occur due to water intoxication caused by the inherent antidiuretic effect of oxytocin, particularly when large doses (40–50 mL/min) are administered over a prolonged period. Treatment of water intoxication includes: discontinuation of oxytocin, restriction of fluid intake, administration of diuretics, intravenous hypertonic sodium chloride solution, correction of electrolyte imbalances, control of seizures with appropriate doses of barbiturates, and provision of professional care for comatose patients.

Side effects.

Side effects in nursing mothers

Adverse reactions in the perinatal period

In a randomized, double-blind, controlled study, ST-T segment depression on ECG was observed during cesarean section under spinal anesthesia following intravenous bolus administration of oxytocin at a dose of 10 IU. Data for accurate assessment of the risk level are insufficient, and the reasons for the increased risk are unknown.

Incompatibility.

The drug may be diluted in 0.9% sodium chloride injection solution, 5% glucose solution, or sodium lactate solutions. The prepared solution is physically and chemically stable for 8 hours after preparation. From a microbiological standpoint, the product should be used immediately. Do not mix with other medicinal products in the same container.

Excipients with known effects

Each 1 ml of solution contains 40 mg of ethanol.

Shelf life. 3 years.

Storage conditions. Store in the original packaging at 2–8 °C.

Keep the medication out of reach of children!

Packaging.

1 ml in a vial, 5 vials in a cardboard pack.

Prescription status.

Prescription only.

Manufacturer.

JSC "Gedeon Richter".

Manufacturer's address and location of business activity.

19–21 Demre utca, H-1103 Budapest, Hungary.