Terus

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

Composition:

Active substance: oxytocin;

1 ml of injection solution contains oxytocin – 10 IU (16.667 mcg);

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

Pharmaceutical form. Injection solution.

Main physicochemical properties: a clear, colorless solution, free from visible mechanical particles, filled into a transparent glass ampoule USP type I.

Pharmacotherapeutic group. Hormones for systemic use (excluding sex hormones and insulin). Pituitary, hypothalamic hormones and their analogues. Posterior pituitary hormones. Oxytocin and its derivatives. Oxytocin. 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 breastfeeding.

Oxytocin most intensively stimulates the smooth muscle of the uterus 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 these receptors by oxytocin leads to the release of calcium from intracellular pools and induces contractile activity of the myometrium.

Oxytocin induces rhythmic contractions in the upper uterine segment, similar in frequency, strength, and duration to physiological contractions during 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.

According to in vitro studies, prolonged administration of oxytocin leads to desensitization of oxytocin receptors, likely due to suppression 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 for induction or augmentation of labor, the uterine response develops gradually and reaches a steady state within 20–40 minutes. Plasma oxytocin concentrations achieved are comparable to those observed during spontaneous labor. For example, plasma oxytocin concentrations in 10 pregnant women with term gestation receiving 4 milliunits per minute via intravenous infusion ranged from 2 to 5 micro-units/mL. Upon discontinuation of the infusion or significant reduction in infusion rate (e.g., in cases of hyperstimulation), uterine activity rapidly decreases and may persist at a lower level of intensity.

Pharmacokinetics

Absorption

Plasma oxytocin concentrations in pregnant women with term gestation receiving 4 milliunits per minute via intravenous infusion ranged from 2 to 5 micro-units/mL.

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 of oxytocin is negligible. Oxytocin is able to cross the placental barrier in both directions and has been detected in small amounts in breast milk.

Biotransformation/metabolism

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

Elimination

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

Renal impairment

Studies in patients with renal impairment have not been conducted. However, considering the route of elimination and reduced renal excretion of oxytocin due to its antidiuretic effect, there is a possibility of oxytocin accumulation, which may prolong its action.

Hepatic impairment

Studies in patients with hepatic impairment have not been conducted. Significant changes in the pharmacokinetics of oxytocin in patients with impaired liver function are unlikely, since the enzyme responsible for oxytocin metabolism (oxytocinase) is not only present in the liver, but its activity in the placenta increases significantly toward the time of delivery. Thus, oxytocin biotransformation in patients with impaired liver function is not expected to result in 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, indicate no specific risk for humans.

Clinical characteristics.

Indications.

Use in the antepartum period

• Induction of labor for medical reasons, for example, in cases of post-term pregnancy, premature rupture of fetal membranes, pregnancy-induced hypertension (pre-eclampsia).
• Induction of labor in the presence of uterine inertia.
• In early pregnancy as an additional therapy in cases of incomplete abortion, inevitable abortion, or missed abortion.

Use in the postpartum period

• During cesarean section, but after delivery of the infant.
• Prevention and treatment of postpartum uterine atony and hemorrhage.

Contraindications.

• Hypersensitivity to the active substance or to any of the excipients of the medicinal product (see section "Composition");
• hypertonic uterine contractions, mechanical obstruction to labor, fetal distress.

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

• clinically narrow pelvis;
• malpresentation of the fetus;
• placenta previa or vasa previa;
• placental abruption;
• prolapse or protrusion of the umbilical cord;
• excessive stretching or reduced resistance of the uterus to rupture, as in multiple pregnancy;
• polyhydramnios;
• multiple pregnancy;
• presence of a uterine surgical scar, including a scar from previous cesarean section.

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

Oxytocin must not be administered within 6 hours after the use of vaginal prostaglandins.

Interaction with other medicinal products and other forms of interaction.

Medicinal products whose concomitant use is not recommended

Prostaglandins and their analogs

Prostaglandins and their analogs enhance the contractile activity of the myometrium; therefore, oxytocin may potentiate prostaglandin-induced uterine contractions and vice versa.

Medicinal products capable of prolonging the QT interval

Oxytocin is considered a potentially arrhythmogenic agent and should be used with caution in patients with risk factors for developing torsades de pointes, such as concomitant use of medicinal products capable of prolonging the QT interval, or in patients with a history of long QT syndrome.

Interactions to be considered

Inhalational anesthetics

Inhalational anesthetics (such as cyclopropane, halothane, 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 inhalational anesthetics and oxytocin.

Vasoconstrictors/sympathomimetics

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

Medicinal products for caudal anesthesia

When administered during or after caudal anesthesia, oxytocin may potentiate the pressor effect of sympathomimetic vasoconstrictor medicinal products.

Special precautions for use

Oxytocin should only be administered as an intravenous infusion. Under no circumstances should it be given as an intravenous bolus injection, as this may cause acute transient hypotension leading to hyperemia and reflex tachycardia.

Induction of labour

Induction of labour with oxytocin should be performed only under strict medical indications. The drug must be administered only in hospital settings and under the supervision of a qualified physician.

Cardiovascular disorders

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

QT interval prolongation syndrome

Oxytocin should be administered cautiously to patients with QT interval prolongation syndrome or associated symptoms, as well as to patients receiving drugs known to prolong the QT interval.

During administration of the drug for induction or stimulation of uterine contractions, the following may occur:

• Fetal distress and fetal death

Excessive doses of oxytocin may lead to uterine hyperstimulation, which can result in fetal distress, asphyxia, and death, or may cause hypertonus, tetanic contractions, or uterine rupture. Careful monitoring of fetal heart rate and uterine activity (frequency, strength, and duration of contractions) is essential to allow dose adjustment according to individual response.

Particular attention should be paid to patients with clinically narrow pelvis, secondary weakness of labour, mild or moderate arterial hypertension, cardiac disease, as well as to women aged 35 years or older or with a history of cesarean section scar in the lower uterine segment.

• Disseminated intravascular coagulation

Rarely, pharmacological induction of labour using uterotonic agents, including oxytocin, has been associated with an increased risk of developing disseminated intravascular coagulation 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 elevated in women with additional risk factors for disseminated intravascular coagulation: age ≥35 years, complicated pregnancy, and gestational age beyond 40 weeks. In such women, oxytocin and alternative medicinal products should be used with caution, and the physician must consider the possibility of developing disseminated intravascular coagulation.

Intrauterine fetal death

Intense uterine activity 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.

Water intoxication

Since oxytocin has a weak antidiuretic effect, prolonged intravenous (i.v.) administration of high doses of the drug, especially when combined with large volumes of fluid (e.g., in treatment of threatened or incomplete abortion or postpartum hemorrhage), may lead to water intoxication associated with hyponatremia. Combined administration of oxytocin and i.v. fluids may result in fluid overload leading to hemodynamic pulmonary edema without hyponatremia. To prevent these rare complications, the following safety measures should be observed when administering high doses of oxytocin over prolonged periods: use an electrolyte-containing diluent (not dextrose); infusions should be administered in small volumes (during induction or stimulation of labour at term, oxytocin concentrations exceeding the recommended levels may be used); oral fluid intake should be restricted; fluid balance should be monitored; laboratory testing of electrolyte levels is indicated if electrolyte imbalance is suspected.

Renal impairment

Oxytocin should be used with caution in patients with severe renal dysfunction due to the potential for fluid retention and oxytocin accumulation.

Anaphylaxis in women with latex allergy

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

Oxytocin is compatible with the following infusion solutions (appropriate consideration of electrolyte use should be given for individual patients): sodium/potassium chloride (103 mmol Na+ and 51 mmol K+), sodium bicarbonate 1.39%, sodium chloride 0.9%, sodium lactate 1.72%, dextrose 5%, levulose 20%, macrodex 6%, reomacrodex 10%, Ringer's solution when stored for 48 hours at 25°C.

Unused portions of the product should be disposed of according to local requirements.

This medicinal product contains less than 1 mmol (23 mg) of sodium per dose, i.e., it is practically sodium-free.

Use during pregnancy or breastfeeding

Pregnancy

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 the drug, administration of oxytocin for approved indications is not expected to increase the risk of fetal malformations.

Use during breastfeeding

Oxytocin passes into breast milk in small amounts. However, it is expected that oxytocin will not have harmful effects on the newborn, as it undergoes rapid inactivation in the gastrointestinal tract after oral ingestion.

Ability to affect reaction speed when driving or operating machinery

Oxytocin may trigger the onset of labour, which should be taken into account when driving or operating machinery. Women experiencing contractions should not drive or operate machinery.

Method of Administration and Dosage

Induction of labor or stimulation of uterine contractions. Oxytocin should not be administered within 6 hours after the use of vaginal prostaglandins. Oxytocin must be administered as an intravenous (i.v.) infusion, preferably using an infusion pump with variable flow rate. For intravenous infusion, 5 IU of oxytocin should be added to 500 mL of physiological electrolyte solution (e.g., 0.9% sodium chloride solution). In patients for whom sodium chloride is contraindicated, 5% dextrose solution should be used as the diluent. To ensure uniform mixing, the bottle or bag should be inverted several times before administration.

Initially, the infusion rate should be set between 2 and 8 drops/minute (1–4 milliunits/minute). This rate may be gradually increased at intervals of at least 20 minutes by no more than 1–2 milliunits/minute until the contraction pattern resembles that of normal labor. In near-term pregnancies, this is often achieved with an infusion rate of less than 20 drops/minute (10 milliunits/minute). The recommended maximum infusion rate is 40 drops/minute (20 milliunits/minute). In unusual cases requiring higher doses, such as intrauterine fetal death or early induction when the uterus is less sensitive to oxytocin, higher concentrations of oxytocin (e.g., 10 IU in 500 mL) may be used.

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. During infusion, the frequency, strength, and duration of uterine contractions, as well as fetal heart rate, must be closely monitored. Once adequate uterine activity (3–4 contractions every 10 minutes) is achieved, the infusion rate can usually be reduced. In case of uterine hyperactivity and/or fetal distress, the infusion must 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 following day, starting again with an infusion rate of 2 to 8 drops/minute (1–4 milliunits/minute).

In women who have received oxytocin for induction or augmentation of labor, the infusion should be continued with increased rate throughout the third stage of labor and for several hours thereafter.

Incomplete or inevitable abortion or missed miscarriage. 5 IU via i.v. infusion (5 IU diluted in physiological electrolyte solution and administered as i.v. drip infusion, preferably using an infusion pump with variable flow rate over more than 5 minutes), if necessary followed by continuous i.v. infusion at a rate of 20 to 40 milliunits/minute.

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

Prevention of postpartum uterine bleeding. The usual dose is 5 IU administered by intravenous infusion (5 IU diluted in physiological electrolyte solution and administered as i.v. drip infusion, preferably using an infusion pump with variable flow rate over more than 5 minutes) immediately after delivery of the placenta. In women who have received oxytocin for induction or stimulation of labor, oxytocin infusion should be continued with increased rate throughout the third stage of labor and for several hours after delivery.

Treatment of postpartum uterine bleeding. 5 IU may be administered by intravenous infusion (5 IU diluted in physiological electrolyte solution and administered as i.v. drip infusion, preferably using an infusion pump with variable flow rate over more than 5 minutes); in severe cases, followed by continuous 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.

Special Populations

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.

Elderly patients. Studies in elderly patients (aged 65 years and older) have not been conducted.

Children. Not to be used in children.

Overdose.

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

Symptoms and consequences of overdose are described in the sections "Special Warnings and Precautions for Use" and "Adverse Reactions." In addition, cases of placental abruption and/or amniotic fluid embolism due to excessive uterine stimulation have been reported.

Treatment. Upon the first signs or symptoms of overdose during prolonged intravenous infusion of oxytocin, administration should be stopped immediately and oxygen should be administered to the patient. In case of water intoxication, fluid intake should be restricted, diuresis stimulated, electrolyte imbalances corrected, and seizures monitored and managed if they occur. In case of coma, airway patency should be maintained using standard measures typically applied in the care of unconscious patients.

Adverse reactions.

Due to differences in uterine sensitivity, in some cases even doses considered low may cause uterine spasm. When oxytocin is administered intravenously for induction or stimulation of labor, excessively high doses may lead to excessive uterine stimulation, which can result in fetal distress, asphyxia, or fetal death, and in the mother — to uterine hypertonus, tonic seizures, soft tissue injury, or uterine rupture.

Rapid intravenous administration by bolus injection of several international units (IU) of oxytocin may cause acute, short-term arterial hypotension accompanied by hyperemia and reflex tachycardia. Such sudden hemodynamic changes may provoke myocardial ischemia, particularly in patients with pre-existing cardiovascular disorders. Rapid intravenous bolus injection of several IU of oxytocin may also cause QT interval prolongation.

In individual cases, pharmacological induction of labor using uterotonic medicinal products, including oxytocin, may increase the risk of postpartum disseminated intravascular coagulation syndrome (see section "Special precautions").

Cases of water intoxication due to hyponatremia in both mother and infant have been reported following prolonged administration of high-dose oxytocin together with large volumes of electrolyte-free solutions (see section "Special precautions"). The combined antidiuretic effect of oxytocin and intravenous fluid administration may lead to hypervolemia, resulting in hemodynamic acute pulmonary edema without hyponatremia (see section "Special precautions").

Symptoms of water intoxication include:

1. Headache, anorexia, nausea, vomiting, abdominal pain.
2. Lethargy, drowsiness, unconsciousness, epileptic-like convulsions.
3. Low electrolyte concentration in blood.

Adverse reactions in Tables 1 and 2 are classified according to frequency of occurrence, starting with the most frequent, using the following categories: very common (≥ 1/10); common (≥ 1/100, < 1/10); uncommon (≥ 1/1,000, < 1/100); rare (≥ 1/10,000, < 1/1,000); very rare (≥ 1/100,000, < 1/10,000), including isolated cases; frequency not known (cannot be estimated from available data). Adverse reactions listed in the tables below are based on clinical trial data and post-marketing reports.

Adverse reactions observed during post-marketing use of oxytocin are derived from spontaneous reports and published literature. Since these reactions were reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency; hence, the frequency is listed as "not known."

Adverse drug reactions are listed by organ system classes according to MedDRA. Within each organ system class, adverse reactions are listed in order of decreasing severity.

Table 1

Adverse reactions in postpartum women

Table 2

Adverse reactions in the fetus/newborn

Reporting of suspected adverse reactions

Reporting adverse reactions after marketing authorization of a medicinal product is of great importance. It enables continuous monitoring of the benefit-risk balance of the use of this medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, are encouraged to report all cases of suspected adverse reactions and lack of efficacy of the medicinal product via the automated pharmacovigilance information system at the following link: https://aisf.dec.gov.ua.

Shelf life. 2 years.

Storage conditions. Store at 2–8 °C in a place protected from light. Do not freeze. Keep out of reach and sight of children.

Incompatibilities.

This medicinal product should not be administered using the same system as blood or plasma infusions, as oxytocin-inactivating enzymes rapidly deactivate the peptide bonds.

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

Packaging. 1 ml in a vial; 10 vials in a plastic blister pack in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

S TERIL-GENE LIFE SCIENCES (P) LTD / Steril-Gene Life Sciences (P) Ltd.

Address of the manufacturer and location of its business operations.

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