Steritocin 10

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT STERITOCIN 10

Composition:

Active substance: oxytocin;

1 ml of solution contains 10 IU of oxytocin;

Excipients: ethanol 96%, chlorobutanol hemihydrate, sodium acetate trihydrate, sodium chloride, glacial acetic acid, water for injections.

Pharmaceutical form. Injection solution.

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

Pharmacotherapeutic group. Hormones for systemic use, excluding sex hormones and insulin. Posterior pituitary hormones. Oxytocin and analogues.

ATC code H01BB02.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action

Oxytocin is a cyclic nonapeptide obtained by chemical synthesis. This synthetic form is identical to the natural hormone that accumulates in the posterior pituitary and is released into systemic circulation during labor and lactation.

Oxytocin most intensively stimulates uterine smooth muscle at the end of pregnancy, during labor, and immediately after childbirth. At this time, the number of oxytocin receptors in the myometrium increases.

Oxytocin receptors are G-protein-coupled receptors. Activation of oxytocin receptors by oxytocin leads to calcium release from intracellular pools and contractile activity of the myometrium.

Oxytocin induces rhythmic contractions in the upper segment of the uterus, similar in frequency, strength, and duration to physiological contractions during spontaneous labor.

Synthetic oxytocin does not contain vasopressin; however, even in its pure form, it may exert a weak antidiuretic effect similar to that of vasopressin.

In vitro studies have shown that prolonged administration of oxytocin leads to desensitization of oxytocin receptors, likely due to downregulation of oxytocin binding sites, destabilization of oxytocin receptor mRNA, and internalization of oxytocin receptors.

Plasma concentration levels and onset/duration of effect

Intravenous infusion. When oxytocin is administered via continuous intravenous infusion at doses used to induce or augment labor, the uterine response develops gradually and reaches a steady state within 20–40 minutes. The corresponding plasma oxytocin levels are comparable to concentrations observed during the first stage of spontaneous labor. For example, plasma oxytocin concentrations in 10 pregnant women with term pregnancy receiving 4 milliunits per minute via intravenous infusion ranged from 2 to 5 micro-units/mL. After discontinuation of the infusion or significant reduction in infusion rate (e.g., in cases of hyperstimulation), uterine activity rapidly decreases but may persist at a low level.

Pharmacokinetics.

Absorption

Following intravenous administration, oxytocin's effect on the uterus appears almost immediately and lasts for approximately 1 hour. After intramuscular administration, the myotonic effect begins within 3–7 minutes and lasts for 2–3 hours.

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

Distribution

The volume of distribution at steady state, determined in 6 healthy male volunteers after intravenous injection, is 12.2 L or 0.17 L/kg. Plasma protein binding is negligible. Oxytocin can cross the placental barrier in both directions and has been detected in small amounts in breast milk.

Biotransformation/metabolism

Oxytocinase is a glycoprotein aminopeptidase produced during pregnancy and present in plasma, capable of degrading oxytocin. Oxytocinase is produced in both the mother and the fetus. The liver and kidneys play the main role in the metabolism and elimination of oxytocin. Thus, oxytocin biotransformation involves the liver, kidneys, and systemic circulation.

Elimination

The elimination half-life of oxytocin ranges from 3 to 20 minutes. Metabolites and less than 1% of unchanged drug are excreted in urine. Metabolic clearance rate in pregnant women is 20 mL/kg/min.

Renal impairment

Studies in patients with renal impairment have not been conducted. However, considering the route of elimination and impaired renal excretion of oxytocin due to its antidiuretic effect, accumulation of oxytocin is possible, potentially prolonging its effect.

Hepatic impairment

Studies in patients with hepatic impairment have not been conducted. Changes in pharmacokinetics in patients with liver dysfunction are unlikely, as the enzyme responsible for oxytocin metabolism (oxytocinase) is not limited to the liver, and oxytocinase activity in the placenta increases significantly toward the time of delivery. Therefore, oxytocin biotransformation in the presence of impaired liver function will not lead to significant changes in metabolic clearance.

Preclinical safety data

Preclinical safety data for oxytocin, based on results from standard studies of acute single-dose toxicity, genotoxicity, and mutagenicity, do not indicate specific risks for humans.

Clinical characteristics.

Indications.

Oxytocin is used to stimulate and enhance uterine contractile activity.

Antepartum period

• Induction of labor for medical reasons, for example in cases of post-term pregnancy, premature rupture of membranes, pregnancy-induced hypertension (pre-eclampsia).
• Stimulation of labor in cases of uterine inertia with hypotonic contractions.
• At early stages of pregnancy, as an adjunctive therapy in cases of incomplete, inevitable abortion or missed abortion (missed miscarriage).

Postpartum period

• During cesarean section, immediately after delivery of the baby.
• Control of postpartum hemorrhage and uterine hypotonia.

Contraindications.

Hypersensitivity to the active substance or to any of the excipients of the medicinal product.

Hyperactive uterine contractions, mechanical obstruction to labor, fetal distress.

Any conditions where, for safety reasons concerning the fetus or the mother, vaginal delivery is not recommended and/or contraindicated, including:

• clinically narrow pelvis;
• fetal presentation abnormalities;
• placenta previa or vasa previa;
• placental abruption;
• prolapse of the umbilical cord or its loops;
• excessive stretching or compromised uterine integrity predisposing to rupture, as in multiple pregnancies;
• polyhydramnios;
• multiple pregnancies.

Presence of a uterine scar resulting from major surgical procedures, including a scar from previous cesarean section.

STERITOCIN 10 must not be used for prolonged periods in patients with oxytocin-resistant uterine inertia, severe pre-eclamptic toxemia, or severe cardiovascular disorders.

STERITOCIN 10 must not be used within 6 hours after administration of vaginal prostaglandins.

Interaction with other medicinal products and other forms of interaction.

Medicinal products whose concomitant use with oxytocin is not recommended:

Prostaglandins and their analogs. Prostaglandins and their analogs enhance myometrial contractile activity; thus, oxytocin may potentiate prostaglandin-induced uterine contractions and vice versa (see section "Contraindications").

Medicinal products that prolong the QT interval. Oxytocin is considered potentially arrhythmogenic. It should be used with caution in patients with risk factors for developing torsades de pointes ventricular tachycardia, such as concomitant use of drugs capable of prolonging the QT interval, or in patients with a history of long QT syndrome (see section "Special precautions for use").

Interactions to be taken into account:

Inhalation anesthetics. Inhalation anesthetics (such as cyclopropane, halothane, isoflurane, sevoflurane, desflurane) exert a relaxing effect on the uterus and cause significant suppression of uterine tone, which may reduce the uterotonic effect of oxytocin. Cases of cardiac arrhythmias have also been reported with concomitant use of inhalation anesthetics and oxytocin.

Vasoconstrictors/sympathomimetics. Oxytocin may enhance the pressor effects of vasoconstrictors and sympathomimetics, even those contained in local anesthetics.

Agents for caudal anesthesia. Oxytocin, when administered during or after caudal anesthesia, may potentiate the pressor effect of sympathomimetic vasoconstrictor agents.

Special precautions for use

Intravenous infusion is the preferred route of administration for STERITOCIN 10. Rapid intravenous bolus injection of large volumes of oxytocin is not recommended, as it may cause acute, transient hypotension, leading to hyperemia and reflex tachycardia.

Induction of labor

Induction of labor with STERITOCIN 10 should be applied strictly according to medical indications. Administration of STERITOCIN 10 must be performed in a hospital setting under physician supervision.

Cardiovascular diseases

STERITOCIN 10 should be used with caution in patients with predisposition to myocardial ischemia due to prior cardiovascular diseases (such as hypertrophic cardiomyopathy, heart valve disease and/or ischemic heart disease, including coronary artery spasm) to avoid significant changes in blood pressure and heart rate in these patients.

QT interval prolongation syndrome

STERITOCIN 10 should be administered cautiously to patients with QT interval prolongation syndrome or related symptoms, as well as to patients receiving medications known to prolong the QT interval.

Oxytocin administration for labor stimulation

Fetal distress and fetal death. Excessive doses of oxytocin may lead to uterine hyperstimulation, which can result in fetal distress, asphyxia, and fetal death, or may cause hypertonus, tetanic contractions, or uterine rupture. Continuous monitoring of fetal heart rate and uterine contractility is essential for dose adjustment based on individual response.

Particular caution is required when administering oxytocin to patients with clinically narrow pelvis, secondary uterine inertia, mild or moderate pregnancy-induced arterial hypertension, or heart failure, as well as in women aged 35 years or older, or in those with a prior cesarean section scar in the lower uterine segment.

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

Intrauterine fetal death

Rapid 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.

Water intoxication

Since oxytocin has a weak antidiuretic effect, prolonged intravenous (IV) administration in high doses, especially when combined with large-volume fluid infusion (e.g., during treatment of threatened or failed abortion or postpartum hemorrhage), may lead to water intoxication associated with hyponatremia. Concurrent administration of oxytocin and IV fluids may result in a combined antidiuretic effect, leading to hypervolemia and subsequent development of hemodynamic pulmonary edema even in the absence of hyponatremia.

To avoid these rare complications during prolonged administration of high-dose oxytocin, the following safety measures should be observed:

• Use an electrolyte-containing solvent (not dextrose);
• Administer infusions in small volumes (during induction or stimulation of labor at late gestational stages, oxytocin concentrations exceeding the recommended levels may be used);
• Limit fluid intake and maintain accurate fluid balance records;
• Laboratory testing of electrolyte levels is indicated if electrolyte imbalance is suspected.

Renal impairment

STERITOCIN 10 should be used with caution in patients with severe renal dysfunction due to possible fluid retention and oxytocin accumulation.

Anaphylaxis in women with latex allergy

Anaphylactic reactions have been reported after oxytocin administration in women with known latex allergy. Due to structural similarity between oxytocin and latex proteins, latex allergy or sensitivity may be an important risk factor for anaphylaxis following administration of STERITOCIN 10.

Excipients

STERITOCIN 10 contains a negligible amount of ethanol (0.0061 ml / 0.005 mg per ampoule).

STERITOCIN 10 contains less than 1 mmol of sodium (23 mg) per ampoule, i.e., it is practically sodium-free (0.176 mg / 0.0073 mmol per ampoule).

Use during pregnancy or breastfeeding

Pregnancy

The drug is used for labor stimulation under strictly defined indications.

Studies on the effects of oxytocin on animal reproductive function have not been conducted.

Based on extensive clinical experience, chemical structure, and pharmacological properties of oxytocin, no risk of fetal malformations is expected when the drug is used appropriately.

One study showed that administration of oxytocin to rats during early pregnancy at doses considered to substantially exceed the maximum recommended human dose resulted in embryonic death. Standard reproductive toxicity studies with oxytocin are lacking.

Breastfeeding period

Oxytocin may pass into breast milk in small amounts.

However, adverse effects on the newborn are not expected, as oxytocin undergoes rapid inactivation upon entering the gastrointestinal tract.

Ability to affect reaction speed when driving or operating machinery

Oxytocin may induce labor; therefore, caution should be exercised when driving vehicles or operating machinery. Women experiencing contractions should not drive.

Administration and Dosage

STERITOCIN 10 should be administered as an intravenous (i.v.) infusion, preferably using an infusion pump with variable rate. It may also be given via intramuscular (i.m.) injections (however, i.v. administration provides a faster onset of action, allowing better control over dosing).

Induction of labor or stimulation of uterine contractions. STERITOCIN 10 should not be administered within 6 hours after vaginal prostaglandins. STERITOCIN 10 should be given as an i.v. drip infusion, preferably using an infusion pump with variable rate. For drip infusion, 5 IU (8.3 mcg) of STERITOCIN 10 is recommended to be added to 500 mL of physiological electrolyte solution (such as 0.9% sodium chloride solution). For patients in whom sodium chloride cannot be used, 5% glucose solution should be used as the diluent. To ensure uniform mixing, the bottle or bag containing the solution should be inverted several times before administration.

The initial infusion rate should be set between 2 and 8 drops per minute (1–4 milliunits/min). The rate may be gradually increased at intervals of not less than 20 minutes, by increments of no more than 1–2 milliunits/min, until achieving a contraction pattern resembling normal labor. In near-term pregnancies, this is often achieved with an infusion rate of less than 20 drops/min (10 milliunits/min). The recommended maximum infusion rate is 40 drops/min (20 milliunits/min). In unusual cases requiring higher doses, such as intrauterine fetal death or labor induction at early gestational stages when the uterus is less sensitive to oxytocin, higher concentrations of oxytocin are recommended, for example, 10 IU in 500 mL.

When using an infusion pump that delivers smaller volumes than drip infusion, the appropriate concentration within the recommended dosage range should be calculated according to the pump’s specifications.

Throughout the infusion, the frequency, strength, and duration of uterine contractions, as well as fetal heart rate, must be carefully monitored. After achieving an adequate uterine activity level—defined as 3–4 contractions every 10 minutes—the infusion rate can usually be reduced. In case of uterine hyperactivity and/or fetal distress, the infusion should be stopped immediately.

If regular contractions are not achieved in women with term or near-term pregnancy after administration of 5 IU, labor induction should be discontinued. The attempt may be repeated the next day, starting again with an infusion rate of 2 to 8 drops per minute (1–4 milliunits/min).

In women receiving STERITOCIN 10 for labor induction or augmentation, the infusion should continue at a higher rate during the third stage of labor and for several hours thereafter.

Incomplete, inevitable abortion or missed abortion: 5 IU via i.v. infusion (5 IU diluted in physiological saline and administered as i.v. drip infusion, preferably using an infusion pump with variable rate over 5 minutes), with further i.v. infusion at a rate of 20 to 40 milliunits/min if necessary.

Caesarean section: 5 IU via i.v. infusion (5 IU diluted in physiological saline and administered as i.v. drip infusion, preferably using an infusion pump with variable rate over 5 minutes) immediately after delivery of the fetus.

Prevention of postpartum uterine hemorrhage: the usual dose is 5 IU via i.v. infusion (5 IU diluted in physiological saline and administered as i.v. drip infusion, preferably using an infusion pump with variable rate over 5 minutes) immediately after delivery of the placenta.

Treatment of postpartum uterine hemorrhage: 5 IU via i.v. infusion (5 IU diluted in physiological saline and administered as i.v. drip infusion, preferably using an infusion pump with variable rate over 5 minutes); in severe cases, followed by i.v. infusion of a solution containing 5 to 20 IU of oxytocin in 500 mL of electrolyte solution, at a rate sufficient to control uterine atony.

Patients with renal impairment: studies in patients with renal impairment have not been conducted.

Patients with hepatic impairment: studies in patients with hepatic impairment have not been conducted.

Geriatric patients: studies in elderly patients (aged 65 years and older) have not been conducted.

Children.

Not applicable to children.

Overdose.

The lethal dose of oxytocin has not been established. Oxytocin is inactivated by proteolytic enzymes in the gastrointestinal tract. Therefore, following oral administration, oxytocin is not absorbed from the intestine, and toxic effects are unlikely.

Symptoms and consequences of overdose are described in the sections "Special precautions" and "Adverse reactions." In addition, cases of placental abruption and/or amniotic fluid embolism have been reported due to uterine hyperstimulation.

Treatment. At the first signs or symptoms of overdose during prolonged intravenous administration of STERITOCIN 10, the infusion should be stopped immediately and oxygen should be administered to the patient. In cases of water intoxication, fluid intake should be restricted, diuretics administered, electrolyte balance restored, and seizures monitored and managed if they occur. In the event of coma, appropriate professional care should be provided, including proper respiratory support.

Adverse reactions

Since uterine sensitivity varies, in some cases even doses considered low may cause uterine spasm. When oxytocin is administered intravenously by infusion for induction or stimulation of labor, excessively high doses may lead to overstimulation of the uterus, potentially resulting in fetal distress, asphyxia, or fetal death, and in the mother – uterine hypertonus, tonic seizures, soft tissue injury, or uterine rupture.

Rapid intravenous bolus injection of oxytocin in doses of several IU may cause acute, transient hypotension associated with flushing and reflex tachycardia. These rapid hemodynamic changes may lead to myocardial ischemia, particularly in patients with pre-existing cardiovascular disease.

Rapid intravenous bolus injection of oxytocin in doses of several IU may also lead to QTc interval prolongation.

In rare cases, pharmacological induction of labor using uterotonic agents, including oxytocin, has been associated with an increased risk of developing disseminated intravascular coagulation (DIC) in the postpartum period.

Since oxytocin exerts a weak antidiuretic effect, prolonged intravenous administration in high doses combined with administration of large volumes of fluid (e.g., during treatment of threatened or incomplete abortion or postpartum hemorrhage) may result in water intoxication.

Cases of water intoxication associated with maternal and neonatal hyponatremia have been reported when high doses of oxytocin were administered together with large volumes of electrolyte-free fluid over a prolonged period. The combined antidiuretic effect of oxytocin and intravenous fluids may lead to water overload, resulting in hypervolemia and subsequent development of hemodynamic form of acute pulmonary edema without hyponatremia. Symptoms of water intoxication include headache, anorexia, nausea, vomiting, and abdominal pain; lethargy, drowsiness, unconsciousness, and grand mal seizures; low serum electrolyte concentrations.

Adverse reactions are traditionally classified according to frequency of occurrence: very common (≥1/10); common (≥1/100, <1/10); uncommon (≥1/1000, <1/100); rare (≥1/10,000, <1/1000); very rare (≥1/100,000, <1/10,000), including isolated cases; frequency not known (cannot be estimated from available data).

Below is a list of adverse reactions reported from clinical trials of oxytocin, as well as adverse reactions reported after marketing of oxytocin-containing medicinal products.

The frequency of adverse reactions identified from spontaneous reports in the post-marketing period cannot be reliably estimated; therefore, such reactions are classified as those with unknown frequency.

Adverse reactions in the mother

Adverse reactions in the fetus/newborn

Shelf life. 2 years.

Storage conditions. Store in the original packaging at 2–8 °C, in a place inaccessible to children. Do not freeze.

The diluted preparation should be used immediately.

Incompatibility.

The drug is compatible with 0.9 % sodium chloride solution, 5 % glucose solution, Ringer's solution, and Ringer's acetate solution.

Oxytocin is incompatible with solutions containing sodium metabisulfite as a stabilizer.

Packaging. 1 ml in an ampoule, 5 or 10 ampoules in a contour pack, 1 contour pack in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

Steril-Jen Life Sciences (P) Ltd.

Manufacturer's address and location of its business activity.

No. 45, Mangalam Main Road, Villianur Commune, Puducherry, 605110, India