Oxytocin Richter

Clear, colourless, sterile solution containing water for injections and ethanol.
Each ampoule of 1 mL contains 10 IU oxytocin.
The active substance is oxytocin.
Excipients/Inactive Ingredients: Acetic acid, chlorobutanol hemihydrate, ethanol, sodium hydroxide, water for injections.

Pharmacotherapeutic group: Systemic hormonal preparations, excl. sex hormones and insulins, Posterior pituitary lobe hormones, Oxytocin and analogues. ATC code: H01BB02.
Pharmacology: Pharmacodynamics: The pharmacological and clinical properties of oxytocin are identical to the natural hormone that is stored in the posterior lobe of the pituitary gland and released into the systemic circulation in response to suckling and labour.
The uterine myometrium contains receptors specific to oxytocin, which belong to the superfamily of G-protein-linked receptors. Oxytocin stimulates contraction of uterine smooth muscle more powerfully towards the end of pregnancy, during labour, and immediately postpartum. At these times, the oxytocin receptors in the myometrium are increased. Activation of receptors by oxytocin increases intracellular calcium concentrations by triggering its release from intracellular stores, thus leads to myometrial contractions.
When given in appropriate doses during pregnancy, oxytocin is capable of eliciting rhythmic contractions in upper segment of uterus, similar in frequency, force and duration of spontaneous motor activity (similar to that observed during spontaneous labour).
Being synthetic, oxytocin in Oxytocin-Richter does not contain vasopressin, but even in its pure form oxytocin possesses some weak intrinsic vasopressin-like antidiuretic activity.
Based on in vitro studies, prolonged exposure of oxytocin had been reported to cause desensitisation of oxytocin receptors probably due to down-regulation of oxytocin-binding sites, destabilisation of oxytocin receptors mRNA and internalisation of oxytocin receptors.
Pharmacokinetics: With intravenous injection given at doses appropriate for induction or enhancement of labour, the uterine response sets in gradually and usually reaches a steady state within 20 to 40 minutes. Following intramuscular injection, the myotonic effect on the uterus appears in 3-7 minutes and persists for 2-3 hours.
The corresponding plasma levels of oxytocin are comparable to those measured during spontaneous first-stage labour. For example, oxytocin plasma levels in 10 pregnant women at term receiving 4 milliunits per minute intravenous infusion were 2 to 5 microunits/mL. Upon discontinuation of the infusion, or following a substantial reduction in the infusion rate, e.g. in the event of overstimulation, uterine activity declines rapidly but may continue at an adequate lower level.
The steady-state volume of distribution determined in 6 healthy men after intravenous injection is 12.2 L or 0.17 L/kg. Plasma protein binding is negligible for oxytocin. It crosses the placenta in both directions. Oxytocin may be found in small quantities in monther's breast milk.
Plasma half-life of oxytocin ranges from 3 to 20 minutes. Most of the drug is rapidly metabolised by the liver and the kidney. Oxytocin is inactivated by enzymatic hydrolysis, primarily by enzyme oxytocinase. Oxytocinase is a glycoprotein aminopeptidase that is produced during pregnancy and appears in the plasma. It is produced from both the mother and the foetus. The metabolites are excreted in urine whereas less than 1% of the oxytocin is excreted unchanged in urine. The metabolic clearance rate amounts to 20 mL/kg/min in the pregnant woman.
Renal impairment: No studies have been performed in renally impaired patients. However, considering the excretion of oxytocin and its reduced urinary excretion because of anti-diuretic properties, the possible accumulation of oxytocin can result in prolonged action.
Hepatic impairment: No studies have been performed in hepatically impaired patients. Pharmacokinetic alteration in patients with impaired hepatic function is unlikely, since metabolising enzyme, oxytocinase is not confined to liver alone and the oxytocinase levels in placenta during the term has significantly increased. Therefore, biotransformation of oxytocin in impaired hepatic function may not result in substantial changes in metabolic clearance of oxytocin.

Antepartum: Induction of labour for medical reasons, e.g. in cases of post-term gestation, premature rupture of the membranes, pregnancy-induced hypertension (pre-eclampsia); Stimulation of labour in hypotonic uterine inertia; Early stages of pregnancy as adjunctive therapy for the management of incomplete, inevitable, or missed abortion.
Postpartum: During caesarean section, but following delivery of the child; Prevention and treatment of postpartum uterine atony and haemorrhage.

Recommended Dosage: Posology: Dosage must be adjusted to meet the individual requirements of each patient on the basis of maternal and foetal response.
The following dosage information is based upon the various regimens and indications in general use.
Induction or enhancement of labour: Oxytocin should not be started for 6 hours following administration of vaginal prostaglandins. Oxytocin should be administered as an intravenous (IV) drip infusion or, preferably, by means of a variable-speed infusion pump. For drip infusion it is recommended that 5 IU of Oxytocin be added to 500 mL of a physiological electrolyte solution (such as sodium chloride 0.9%). For patients in whom infusion of sodium chloride must be avoided, 5% dextrose solution may be used as the diluent (see Precautions). To ensure even mixing, the bottle or bag must be turned upside down several times before use.
The initial infusion rate should be set at 1 to 4 milliunits/minute (2 to 8 drops/minute). It may be gradually increased at intervals not shorter than 20 minutes and increments of not more than 1-2 milliunits/minute, until a contraction pattern similar to that of normal labour is established. In pregnancy near term this can often be achieved with an infusion of less than 10 milliunits/minute (20 drops/minute), and the recommended maximum rate is 20 milliunits/minute (40 drops/minute). In the unusual event that higher rates are required, as may occur in the management of foetal death in utero or for induction of labour at an earlier stage of pregnancy, when the uterus is less sensitive to oxytocin, it is advisable to use a more concentrated Oxytocin solution, e.g., 10 IU in 500 mL
When using a motor-driven infusion pump which delivers smaller volumes than those given by drip infusion, the concentration suitable for infusion within the recommended dosage range must be calculated according to the specifications of the pump.
The frequency, strength, and duration of contractions as well as the foetal heart rate must be carefully monitored throughout the infusion. Once an adequate level of uterine activity is attained, aiming for 3 to 4 contractions every 10 minutes, the infusion rate can often be reduced. In the event of uterine hyperactivity and/or foetal distress, the infusion must be discontinued immediately.
If, in women who are at term or near term, regular contractions are not established after the infusion of a total amount of 5 IU, it is recommended that the attempt to induce labour be ceased; it may be repeated on the following day, starting again from a rate of 1 to 4 milliunits/minute (see Contraindications).
In women given Oxytocin for induction or enhancement of labour, the infusion should be continued at an increased rate during the third stage of labour and for the next few hours thereafter.
Incomplete, inevitable, or missed abortion: 5 IU by IV infusion (5 IU diluted in physiological electrolyte solution and administered as an IV drip infusion or, preferably, by means of a variable-speed infusion pump over 5 minutes), if necessary followed by IV infusion at a rate of 20 to 40 milliunits/minute.
Caesarean section: 5 IU by IV infusion (5 IU diluted in physiological electrolyte solution and administered as an IV drip infusion or, preferably, by means of a variable-speed infusion pump over 5 minutes) immediately after delivery.
Prevention of postpartum uterine haemorrhage: Within one minute of the delivery of the baby, the abdomen should be palpated to rule out the presence of an additional baby(s) and 10 units of oxytocin should be administered IM. Oxytocin is preferred because it is effective two to three minutes after injection, has minimal side effects and can be used in all women.
The usual dose is 5 IU by IV infusion (5 IU diluted in physiological electrolyte solution and administered as an IV drip infusion or, preferably, by means of a variable-speed infusion pump over 5 minutes) after delivery of the placenta.
Treatment of postpartum uterine haemorrhage: 10 units of oxytocin should be administered IM, then an IV infusion should be started. The infusion of IV fluids should happen as described as follows.
5 IU by IV infusion (5 IU diluted in physiological electrolyte solution and administered as an IV drip infusion or, preferably, by means of a variable-speed infusion pump over 5 minutes), followed in severe cases by IV infusion of a solution containing 5 to 20 IU of oxytocin in 500 mL of an electrolyte-containing diluent, run at the rate necessary to control uterine atony.
For atonic uterus: Intramuscular administration: 5 units of oxytocin can be given after delivery of the placenta.
Special populations: Paediatric population: No studies have been performed in paediatric patients.
Elderly patients: No studies have been performed in elderly patients (65 years old and over).
Renal impairment: Studies have not been performed in patients with renal failure.
Hepatic impairment: Studies have not been performed in patients with liver failure.
Route of Administration: Intravenous infusion (drip method) or intramuscular injection.

Overdose: The fatal dose of oxytocin has not been established. Oxytocin is subject to inactivation by proteolytic enzymes of the alimentary tract. Hence it is not absorbed from the intestine and is not likely to have toxic effects when ingested. The symptoms and consequences of overdosage are those mentioned under sections Precautions and Adverse Reactions. In addition, as a result of uterine overstimulation, placental abruption and/or amniotic fluid embolism have been reported.
Treatment: When signs or symptoms of overdosage occur during continuous IV administration of oxytocin, the infusion must be discontinued at once and oxygen should be given to the mother. In cases of water intoxication, it is essential to restrict fluid intake, promote diuresis, correct electrolyte imbalance, and control convulsions that may eventually occur. In the case of coma, a free airway should be maintained with routine measures normally employed in the nursing of the unconscious patient.

Oxytocin injection is contraindicated in any of the following conditions: in cases of foetal distress where delivery is not imminent; hypertonic uterine contractions, mechanical obstruction to delivery; hypersensitivity to the active substance or to any of the excipients listed in Description.
Oxytocin should not be used for induction or augmentation of labour in any condition in which, for foetal or maternal reasons, spontaneous labour is inadvisable, and/or vaginal delivery is contraindicated, such as: significant cephalopelvic disproportion; foetal malpresentation (e.g. positions which are undeliverable without conversion prior to delivery like transverse lies); placenta previa, vasa praevia; cord presentation or prolapse; overdistension or impaired resistance of he uterus to rupture as in multiple pregnancy; polyhydramnios; grand multiparity; in the presence of a uterine scar resulting from major surgery including classical caesarean section.
Oxytocin should not be used for prolonged periods in patients with: oxytocin resistant uterine inertia; severe preeclamptic toxaemia; severe maternal cardiovascular disorders.
Oxytocin must not be administered within 6 hours after vaginal prostaglandins have been given (see Interactions).

Oxytocin-Richter must only be administered as an intravenous infusion and never by intravenous bolus injection, as it may cause an acute short-lasting hypotension accompanied with flushing and reflex tachycardia.
Induction of labour: The induction of labour by means of oxytocin should be attempted only when strictly indicated for medical reasons. Administration should only be under hospital conditions and qualified medical supervision.
Cardiovascular disorders: Oxytocin should be used with caution in patients who have a predisposition to myocardial ischemia due to pre-existing cardiovascular disease (such as hypertrophic cardiomyopathy, valvular heart disease and/or ischemic heart disease including coronary artery vasospasm), to avoid significant changes in blood pressure and heart rate in these patients.
QT syndrome: Oxytocin should be given with caution to patients with known 'long QT syndrome' or related symptoms and to patients taking drugs that are known to prolong the QTc interval (see Interactions).
When Oxytocin-Richter is given for induction and enhancement of labour: Foetal distress and foetal death: Administration of oxytocin at excessive doses results in uterine overstimulation which may cause foetal distress, asphyxia and death, or may lead to hypertonicity, tetanic contractions or rupture of uterus. Careful monitoring of foetal heart rate and uterine motility (frequency, strength and duration of contractions) is essential, so that the dosage may be adjusted to individual response.
Particular caution is required in the presence of borderline cephalopelvic disproportion, secondary uterine inertia, mild or moderate degrees of pregnancy-induced hypertension or cardiac disease, and in patients above 35 years of age or with a history of lower-uterine-segment caesarean section.
Disseminated intravascular coagulation: In rare circumstances, the pharmacological induction of labour using uterotonic agents, including oxytocin increases the risk of postpartum disseminated intravascular coagulation (DIC). The pharmacological induction itself and not a particular agent is linked to such risk. This risk is increased in particular if the woman has additional risk factors for DIC, such as being 35 years of age or over, complications during pregnancy and gestational age more than 40 weeks. In these women, oxytocin or any other alternative drug should be used with care, and the practitioner should be alerted by signs of DIC.
Intrauterine death: In the case of foetal death in utero, and/or in the presence of meconium-stained amniotic fluid, tumultuous labour must be avoided, as it may cause amniotic fluid embolism.
Water intoxication: Because oxytocin possesses slight antidiuretic activity, its prolonged IV administration at high doses in conjunction with large volumes of fluid, as may be the case in the treatment of inevitable or missed abortion or in the management of postpartum haemorrhage, may cause water intoxication associated with hyponatraemia. The combined antidiuretic effect of oxytocin and the IV fluid administration may cause fluid overload leading to a haemodynamic form of acute pulmonary oedema without hyponatraemia. To avoid these rare complications, the following precautions must be observed whenever high doses of oxytocin are administered over a long time: an electrolyte-containing diluent must be used (not dextrose); the volume of infused fluid should be kept low (by infusing oxytocin at a higher concentration than recommended for the induction or enhancement of labour at term); fluid intake by mouth must be restricted; a fluid balance chart should be kept, and serum electrolytes should be measured when electrolyte imbalance is suspected.
Renal impairment: Caution should be exercised in patients with severe renal impairment because of possible water retention and possible accumulation of oxytocin (see Pharmacology: Pharmacodynamics under Actions).
Anaphylaxis in women with latex allergy: There have been reports of anaphylaxis following administration of oxytocin in women with latex allergy. Due to the existing structural homology between oxytocin and latex, latex allergy/intolerance may be an important predisposing risk factor for anaphylaxis following oxytocin administration.
Excipients: This medicinal product contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially 'sodium-free'.
This medicinal product contains small amounts of ethanol (alcohol), less than 100 mg per dose.
Effects on ability to drive and use machines: Oxytocin can induce labour; therefore, caution should be exercised when driving or operating machines. Women with uterine contractions should not drive or use machines.

Pregnancy: Based on the wide experience with this drug and its chemical structure and pharmacological properties, it is not expected to present a risk of foetal abnormalities when used as indicated (for induction or augmentation of labour).
One study has shown that treatment of rats with oxytocin in early pregnancy at doses considered sufficiently in excess of the maximum recommended human dose caused embryonic loss. No standard reproductive performance studies with oxytocin are available.
Breastfeeding: Oxytocin may be found in small quantities in mother's breast milk. However, oxytocin is not expected to cause harmful effects in the newborn, because it passes into the alimentary tract where it undergoes rapid inactivation.
Females and males of reproductive potential: Not applicable for Oxytocin-Richter because of the targeted indications.
Infertility: Not applicable for Oxytocin-Richter because of the targeted indications.

As there is a wide variation in uterine sensitivity, uterine spasm may be caused in some instances by what are normally considered to be low doses. When oxytocin is used by IV infusion for the induction or enhancement of labour, administration at too high doses results in uterine overstimulation which may cause foetal distress, asphyxia, and death, or may lead to hypertonicity, tetanic contractions, soft tissue damage or rupture of the uterus.
Rapid IV bolus injection of oxytocin at doses amounting to several IU may result in acute short-lasting hypotension accompanied with flushing and reflex tachycardia (see Precautions). These rapid haemodynamic changes may result in myocardial ischaemia, particularly in patients with pre-existing cardiovascular disease. Rapid IV bolus injection of oxytocin at doses amounting to several IU may also lead to QTc prolongation.
In rare circumstances the pharmacological induction of labour using uterotonic agents, including oxytocin, increases the risk of postpartum disseminated intravascular coagulation (see Precautions).
Water intoxication: Water intoxication associated with maternal and neonatal hyponatraemia has been reported in cases where high doses of oxytocin together with large amounts of electrolyte free fluid have been administered over a prolonged period of time (see Precautions). The combined antidiuretic effect of oxytocin and the IV fluid administration may cause fluid overload leading to a haemodynamic form of acute pulmonary oedema without hyponatraemia (see Precautions).
Symptoms of water intoxication include: Headache, anorexia, nausea, vomiting and abdominal pain; Lethargy, drowsiness, unconsciousness and grand mal type seizures; Low blood electrolyte concentration.
Undesirable effects (Tables 1 and 2) are ranked under heading of frequency, the most frequent first, using the following convention: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000), including isolated reports; not known (cannot be estimated from the available data. The ADRs tabulated as follows are based on clinical trial results as well as post-marketing reports.
The adverse drug reactions derived from post-marketing experience with oxytocin are via spontaneous case reports and literature cases. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency which is therefore categorised as not known. Adverse drug reactions are listed according to system organ classes in MedDRA. Within each system organ class, ADRs are presented in order of decreasing seriousness. (See Tables 1 and 2.)

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Reporting of suspected adverse reactions: Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system.

Interaction resulting in a concomitant use is not recommended: Prostaglandins and their analogues: Prostaglandins and their analogues facilitate contraction of the myometrium, hence oxytocin can potentiate the uterine action of prostaglandins and analogues and vice versa (see Contraindications).
Drugs prolonging the QT interval: Oxytocin should be considered as potentially arrhythmogenic, particularly in patients with other risk factors for Torsades de Pointes such as drugs which prolong the QT interval or in patients with history of long QT syndrome (see Precautions).
Interactions to be considered: Caudal anaesthetics: When given during or after caudal block anaesthesia, oxytocin may potentiate the pressor effect of sympathomimetic vasoconstrictor agents.
Vasoconstrictors/Sympathomimetics: Oxytocin may enhance the vasopressor effects of vasoconstrictors and sympathomimetics, even those contained in local anaesthetics.
Inhalation anaesthetics: Inhalation anaesthetics (e.g. cyclopropane, halothane, sevoflurane, desflurane, enflurane) have a relaxing effect on the uterus and produce a notable inhibition of uterine tone and thereby, may diminish the uterotonic effect of oxytocin. Their concurrent use with oxytocin has also been reported to cause cardiac rhythm disturbances.

Incompatibilities: It can be mixed with Sodium lactate intravenous infusion (Infusio natrii lactici salina), with Sodium chloride intravenous infusion (Infusio natrii chlorati) and with Glucose intravenous infusion (Infusio glucosi). The mixed pharmaceutical product must be used within maximum 8 hours.
(The compatibility tests were performed with 500 mL solutions for infusion.)
Any unused product or waste material should be disposed of in accordance with local requirements.

Store in a refrigerator (2°C to 8°C).
Shelf life: 3 years.

Drugs Acting on the Uterus

H01BB02 - oxytocin ; Belongs to the class of oxytocin and analogues. Used in posterior pituitary lobe hormone preparations.

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