Oxytocin

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

Composition:

Active substance: oxytocin;

1 ml contains 5 IU oxytocin;

Excipients: chlorobutanol hemihydrate, water for injections.

Pharmaceutical form. Solution for injection.

Main physicochemical properties: clear colorless liquid with a specific odor.

Pharmacotherapeutic group. Posterior pituitary hormones. Oxytocin and analogues. Oxytocin.

ATC code H01BB02.

Pharmacological properties.

Pharmacodynamics.

The clinical and pharmacological properties of oxytocin are similar to those of endogenous oxytocin from the posterior pituitary. The uterine musculature contains oxytocin-sensitive receptors belonging to the family of G-protein-coupled receptors. Oxytocin induces contractions of the uterine smooth muscle by increasing intracellular calcium concentration, thereby mimicking normal, spontaneous uterine contractile activity and temporarily impeding uterine blood flow.

With increasing amplitude and duration of muscle contractions, cervical dilation and effacement occur. As pregnancy progresses, the number of oxytocin receptors and the uterus's sensitivity to oxytocin increase, reaching their maximum by the end of pregnancy. In certain doses, oxytocin can enhance uterine contractility to a level characteristic of spontaneous labor activity, up to a tetanic state.

Oxytocin causes contraction of myoepithelial cells adjacent to the alveoli of the mammary gland, thus promoting milk ejection.

By acting on vascular smooth muscle, oxytocin induces vasodilation, increases blood flow in the kidneys, coronary vessels, and cerebral vessels. Arterial pressure usually remains unchanged; however, with intravenous administration of large doses or concentrated oxytocin solution, arterial pressure may transiently decrease, leading to reflex tachycardia and reflex increase in cardiac output. Following a brief initial drop in arterial pressure, a prolonged, albeit mild, elevation in blood pressure may occur.

Unlike vasopressin, oxytocin has weak antidiuretic activity. Hyperhydration is possible when oxytocin is used concomitantly with large volumes of electrolyte-free fluids and/or rapid administration.

Pharmacokinetics.

After intravenous administration, oxytocin's effect on the uterus appears almost immediately and lasts about one hour. After intramuscular administration, the myotonic effect begins within the first 3–7 minutes and persists for 2–3 hours.

Similar to vasopressin, oxytocin is distributed throughout the extracellular space. Small amounts of oxytocin likely enter the fetal circulation.

The elimination half-life of oxytocin is 1–6 minutes and is shorter in late pregnancy and during lactation. The majority of the drug undergoes rapid metabolism in the liver and kidneys. Enzymatic hydrolysis inactivates oxytocin, primarily by tissue oxytocinase (oxytocinase is also present in the placenta and blood plasma). Only a small amount of oxytocin is excreted unchanged in urine.

Renal insufficiency

Studies in patients with renal insufficiency 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 insufficiency

Studies in patients with hepatic insufficiency have not been conducted. A change in the pharmacokinetics of the drug in patients with impaired liver function is unlikely, since the enzyme metabolizing oxytocin (oxytocinase) is present not only in the liver, but its activity in the placenta increases significantly near term. Thus, biotransformation of oxytocin under conditions of impaired liver function would not result in a significant change in metabolic clearance.

Clinical characteristics.

Indications.

Oxytocin is used to initiate and stimulate uterine contractile activity.

Indications for use in the prepartum period.

Induction of labor.

Induction of labor with oxytocin is indicated at term or near term in cases of arterial hypertension (e.g., preeclampsia, eclampsia, or presence of cardiovascular or renal disease), erythroblastosis fetalis, maternal or gestational diabetes mellitus, antepartum hemorrhage, or when early delivery is required, as well as in cases of premature rupture of membranes without spontaneous onset of uterine contractions. Planned induction of uterine contractile activity with oxytocin may be indicated in post-term pregnancy (beyond 42 weeks). Induction of uterine contractility may also be indicated in cases of intrauterine fetal death or intrauterine growth restriction.

Augmentation of uterine contractility.

During the first or second stage of labor, oxytocin may be administered intravenously by infusion to augment contractions in prolonged labor or in cases of dysfunctional inertia of the uterus.

Indications for use in the postpartum period.

In cases of uterine atony, to control postpartum hemorrhage.

Other indications for use.

For adjunctive therapy in incomplete abortion or missed abortion.

Diagnostic use.

For assessment of fetal embryonic-placental respiratory capacity (oxytocin challenge test).

Contraindications.

Oxytocin, injection solution, is contraindicated in the following cases:

− clinically narrow pelvis;

− unfavorable fetal position preventing spontaneous vaginal delivery without prior intervention (e.g., transverse fetal position);

− obstetric emergencies where the benefit-to-risk ratio for the fetus or mother necessitates surgical intervention;

− fetal distress occurring well before term;

− use in the absence of uterine contractile activity or in the presence of severe toxemia;

− hypertonic uterine contractions;

− hypersensitivity to any component of the medicinal product;

− induction or augmentation of uterine contractility when vaginal delivery is contraindicated, e.g., in cases of cord presentation or prolapse, complete placenta previa, or vasa previa;

− dystocia;

− severe cardiovascular disorders.

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 use 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 has also been reported to cause sinus bradycardia and atrioventricular rhythm.

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

Prostaglandins enhance the effect of oxytocin; therefore, their concomitant use is not recommended. Due to increased uterine contractility, caution should be exercised when prostaglandins and oxytocin are used sequentially.

Concurrent use of oxytocin with other inducers of labor or abortion may lead to uterine hypertonia (increased tone), uterine rupture, or cervical trauma. For example, the use of prostaglandins may increase stimulation of labor and uterine musculature.

Therefore, strict monitoring is required during administration of the drug, including:

− acid-base balance;

− frequency, duration, and strength of uterine contractions;

− fetal heart rate;

− maternal heart rate and arterial pressure;

− uterine tone;

− fluid balance.

Special precautions for use

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

• Preterm labor;
• History of cervical or uterine surgery, including cesarean section;
• Excessive uterine distension;
• Multiple pregnancy;
• Invasive cervical carcinoma.

Oxytocin must not be used for labor induction before the fetal head or buttocks have engaged in the maternal pelvic inlet. Determination of such "special circumstances," resulting from a combination of various factors, is the responsibility of the physician. Before initiating oxytocin therapy, the expected benefits should be carefully weighed against the potential risks (such as possible uterine hypertonus and tetany).

For the purpose of labor induction and augmentation of uterine contractility, oxytocin must be administered exclusively intravenously, 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, the following parameters must be continuously monitored:

• Uterine contractions;
• Fetal and maternal heart rate;
• Maternal arterial blood pressure (BP).

At the first sign of uterine hyperactivity, oxytocin administration must be stopped immediately; as a result, drug-induced uterine contractions usually cease.

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

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

It should be noted that in cases of increased sensitivity to the drug, hypertonic contractions may occur even with standard doses. The possibility of increased bleeding and development of afibrinogenemia should be considered.

Oxytocin should not be administered for prolonged periods to patients with oxytocin-resistant uterine inertia, severe toxemia or preeclampsia, or severe cardiovascular disorders.

Oxytocin should not be administered as an intravenous bolus injection, as this may cause acute, transient hypotension accompanied by flushing and reflex tachycardia.

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

Oxytocin should be prescribed with caution to patients with "long QT interval syndrome" or related symptoms, as well as to patients receiving drugs that prolong the QT interval.

Fatal outcomes in mothers have been reported due to hypersensitivity reactions, hypertensive episodes, subarachnoid hemorrhage, uterine rupture, and fetal death from various causes during parenteral administration of oxytocin for labor induction and stimulation of uterine contractions.

Disseminated intravascular coagulation (DIC)

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 drug. The risk is particularly increased in women with additional risk factors for DIC: age over 35 years, complicated pregnancy (e.g., gestational diabetes, arterial hypertension, hypothyroidism), gestational age over 40 weeks. In such women, oxytocin and alternative drugs should be used with caution, and the physician must consider the possibility of DIC development.

Water intoxication

Since oxytocin has a weak antidiuretic effect, prolonged intravenous infusion of high doses of the drug combined with administration of large volumes of fluid (e.g., during treatment of threatened or failed 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 acute pulmonary edema without hyponatremia. To avoid these rare complications, the following safety measures should be followed when administering high doses of oxytocin for prolonged periods: use an electrolyte-containing solvent (not dextrose); intravenous infusions should be given 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.

Anaphylaxis in women with latex allergy

Cases of anaphylaxis after oxytocin administration in women with latex allergy have been reported. Due to the existing structural homology between oxytocin and latex, latex allergy/intolerance may be an important risk factor for anaphylaxis following oxytocin administration.

The drug is contraindicated in patients with a history of hypersensitivity to oxytocin.

Oxytocin must not be administered simultaneously via different routes. Oxytocin can be administered by only one route (either intravenously or intramuscularly).

Use during pregnancy or breastfeeding.

There are no known indications for use during the first trimester of pregnancy except in connection with spontaneous or induced termination of pregnancy. Extensive clinical experience, as well as the chemical structure and pharmacological properties of oxytocin, indicate that when used according to indications, the drug does not affect fetal malformation development.

Oxytocin passes into breast milk in small amounts.

In cases where the drug is used to control uterine bleeding, breastfeeding is possible only after completion of oxytocin therapy.

Ability to affect reaction speed when driving or operating machinery.

Oxytocin does not affect the ability to drive or operate machinery. The drug is administered in a hospital setting.

Administration and Dosage

The dosage should be determined according to the individual sensitivity of the pregnant woman and the fetus.

For induction or stimulation of labor, oxytocin must be administered exclusively as an intravenous infusion. Adherence to the recommended infusion rate is mandatory. For safe administration of oxytocin, an infusion pump or similar device must be used, along with continuous monitoring of uterine contractions and fetal heart activity. In case of excessive intensification of uterine contractions, the infusion should be stopped immediately; as a result, excessive uterine muscle activity rapidly decreases.

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

1. Before initiating drug administration, begin infusion of physiological saline solution not containing oxytocin.
2. To prepare the standard infusion solution: dissolve the contents of 1 ampoule – 1 mL (5 IU) of oxytocin under sterile conditions in 1000 mL of diluent (0.9% sodium chloride solution, 5% glucose solution) and mix thoroughly by rotating the container. Each mL of the prepared solution contains 5 mIU of oxytocin. For accurate dosing of the infusion solution, an infusion pump or similar device should be used.
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 degree of uterine contractility is achieved. After achieving the desired frequency of uterine contractions corresponding to normal labor activity, in the absence of signs of fetal distress and with cervical dilation of 4–6 cm, the infusion rate may be gradually reduced at a pace similar to its prior escalation. During late pregnancy, infusion at higher rates requires caution; only in rare cases may rates up to 8–9 mIU/min be required. In preterm labor, accelerated oxytocin administration may be necessary; in individual cases, rates may exceed 20 mIU/min.

If adequate uterine contractile activity has not been achieved in a woman at term or near term after a total infusion of 5 IU of oxytocin, stimulation attempts should be discontinued. Labor stimulation may be resumed the following day, starting with a dose of 0.5–4 mIU/min.

1. Fetal heart rate, resting uterine tone, and frequency, duration, and strength of contractions should be monitored.
2. In case of uterine hyperactivity or fetal distress, oxytocin administration should be stopped immediately. The patient should receive oxygen therapy. The condition of both mother and fetus must remain under the supervision of a qualified physician.

Control of postpartum uterine bleeding:

a) Intravenous infusion (drip method): dissolve 10–40 IU of oxytocin in 1000 mL of diluent (0.9% sodium chloride solution, 5% glucose solution); for prevention of uterine atony, a dose of 20–40 mIU/min of oxytocin is usually required;

b) Intramuscular injection: 1 mL (5 IU) of oxytocin after placental delivery.

Adjuvant therapy in incomplete abortion or missed abortion.

Intravenous infusion of 10 IU oxytocin in 500 mL of 0.9% sodium chloride solution or a mixture of 5% dextrose with physiological saline at a rate of 20–40 drops/min.

Diagnosis of uteroplacental insufficiency (oxytocin challenge test).

Begin intravenous infusion at a rate of 0.5 mIU/min and double the rate every 20 minutes until the effective dose is reached, usually 5–6 mIU/min (maximum 20 mIU/min). After observing three moderate contractions lasting 40–60 seconds each within a 10-minute period, discontinue oxytocin administration and monitor for changes, particularly deceleration of fetal heart rate.

Administration method

Intravenous drip infusions or intramuscular injections.

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

Special patient categories

Elderly patients

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

Renal and hepatic impairment

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

Children. Not to be used in children.

Overdose.

Symptoms primarily depend on the degree of uterine hyperactivity, regardless of increased sensitivity to the drug. Hyperstimulation may lead to strong (hypertonic) and prolonged (tetanic) contractions or precipitate labor with a characteristic baseline uterine tone of 15–20 mm Hg or higher, measured between contractions. This may result in rupture of the uterine body or cervix, vaginal lacerations, postpartum hemorrhage, uteroplacental hypoperfusion, fetal heart rate deceleration, fetal hypoxia, hypercapnia, and fetal death.

Prolonged administration of high doses (40–50 mL/min) may be accompanied by a serious complication—water intoxication (hyponatremia) due to the antidiuretic effect of oxytocin. Treatment consists of discontinuing oxytocin infusion, restricting fluid intake, administering diuretics, intravenous hypertonic saline solution, correction of electrolyte imbalances, seizure control with barbiturates, and symptomatic treatment in a specialized intensive care unit for comatose patients.

Adverse reactions.

Adverse reactions in nursing mothers

Adverse reactions in the perinatal period

There are data indicating that during cesarean section under spinal anesthesia, intravenous bolus administration of oxytocin at a dose of 10 IU may lead to ST-T segment depression on ECG. Data sufficient for accurate assessment of the risk level are lacking, and the reasons for the increased risk are unknown.

Shelf life. 2 years.

Storage conditions. Store in the original packaging to protect from light at a temperature between 2°C and 8°C. Keep out of reach of children.

Incompatibility.

The medicinal product may be diluted in 0.9% sodium chloride solution for infusion, 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.
The drug should not be mixed in the same container with other medicinal products.

Packaging. 1 ml in an ampoule. 5 ampoules per blister, 1 or 2 blisters per cardboard pack.

Prescription status. Prescription only.

Manufacturer. LLC "FZ "STADA", Ukraine.

Manufacturer's name and address of the place of business.

37, Kyivska Street, Bila Tserkva, Kyiv region, 09100, Ukraine.