POM: Prescription only medicine
This information is intended for use by health professionals
Excipient(s) with known effect:Ethanol 5.000mgFor the full list of excipients, see section 6.1.
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
Renal impairmentNo studies have been performed in renally impaired patients.
Hepatic impairmentNo studies have been performed in hepatically impaired patients.
Paediatric populationNo studies have been performed in paediatric patients.
Elderly populationNo studies have been performed in elderly patients (65 years old and over).
Induction of labourThe 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 disordersSyntocinon should be used with caution in patients who have a pre-disposition to myocardial ischaemia due to pre-existing cardiovascular disease (such as hypertrophic cardiomyopathy, valvular heart disease and/or ischaemic heart disease including coronary artery vasospasm), to avoid significant changes in blood pressure and heart rate in these patients.
QT syndromeSyntocinon 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 section 4.5 Interaction with other medicinal products and other forms of interaction).When Syntocinon 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 the 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 post partum 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 deathIn 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 intoxicationBecause oxytocin possesses slight antidiuretic activity, its prolonged i.v. 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 i.v. 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 ImpairementCaution should be exercised in patients with severe renal impairment because of possible water retention and possible accumulation of oxytocin (see section 5.2 Pharmacokinetics).
Anaphylaxis in women with latex allergy
There have been reports of anaphylaxis following administration of oxytocin in women with a known 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.
Prostaglandins and their analoguesProstaglandins and its analogues facilitate contraction of the myometrium hence oxytocin can potentiate the uterine action of prostaglandins and analogues and vice versa (see section 4.3 Contraindications).
Drugs prolonging the QT intervalOxytocin 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 section 4.4 Special warnings and precautions for use).Interactions to be considered
Inhalation anaestheticsInhalation anaesthetics (e.g. cyclopropane, halothane, sevoflurane, desflurane) 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.
Vasoconstrictors/SympathomimeticsOxytocin may enhance the vasopressor effects of vasoconstrictors and sympathomimetics, even those contained in local anaesthetics.
Caudal anaestheticsWhen given during or after caudal block anaesthesia, oxytocin may potentiate the pressor effect of sympathomimetic vasoconstrictor agents.
Water intoxicationWater 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 Section 4.4 Special warnings and precautions for use). The combined antidiuretic effect of oxytocin and the i.v. fluid administration may cause fluid overload leading to a haemodynamic form of acute pulmonary oedema without hyponatraemia (see section 4.4. Special warnings and precautions for use).Symptoms of water intoxication include:1. Headache, anorexia, nausea, vomiting and abdominal pain. 2. Lethargy, drowsiness, unconsciousness and grand-mal type seizures.3. 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, < 1/10); uncommon (≥ 1/1,000, < 1/100); rare (≥ 1/10,000, < 1/1,000); very rare (< 1/10,000), including isolated reports; not known (cannot be estimated from the available data).The ADRs tabulated below are based on clinical trial results as well as postmarketing reports.The adverse drug reactions derived from post-marketing experience with Syntocinon 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. Table 1 Adverse drug reactions in mother
|System organ class||Adverse drug reaction|
|Immune system disorders||Rare: Anaphylactic/Anaphylactoid reaction associated with dyspnoea, hypotension or Anaphylactic/Anaphylactoid shock|
|Nervous system disorders||Common: Headache|
|Cardiac disorders||Common Tachycardia, bradycardia Uncommon: Arrhythmia Not known: Myocardial ischaemia, Electrocardiogram QTc prolongation|
|Vascular disorders||Not known: Hypotension, haemorrhage|
|Gastrointestinal disorders||Common: Nausea, vomiting|
|Skin and subcutaneous tissue disorders||Rare: Rash|
|Pregnancy, puerperium and perinatal conditions||Not known: Uterine hypertonus, tetanic contractions of uterus, rupture of the uterus|
|Metabolism and nutrition disorders||Not known: Water intoxication, maternal hyponatraemia|
|Respiratory, thoracic and mediastinal disorders||Not known: acute pulmonary oedema|
|General disorders and administration site conditions||Not known: Flushing|
|Blood and lymphatic system disorders||Not known: disseminated intravascular coagulation|
|Skin and subcutaneous tissue disorders||Not Known: Angioedema|
|System organ class||Adverse drug reaction|
|Pregnancy, puerperium and perinatal conditions||Not known: foetal distress syndrome, asphyxia and death|
|Metabolism and nutrition disorders||Not known: Neonatal hyponatraemia|
Mechanism of actionOxytocin is a cyclic nonapeptide that is obtained by chemical synthesis. This synthetic form is identical to the natural hormone that is stored in the posterior pituitary and released into the systemic circulation in response to suckling and labour.Oxytocin stimulates the smooth muscle of the uterus, more powerfully towards the end of pregnancy, during labour, and immediately postpartum. At these times, the oxytocin receptors in the myometrium are increased. The oxytocin receptors are G-proteins coupled receptors. Activation of receptor by oxytocin triggers release of calcium from intracellular stores and thus leads to myometrial contraction.Oxytocin elicits rhythmic contractions in upper segment of uterus, similar in frequency, force and duration to those observed during labour.Being synthetic, oxytocin in Syntocinon 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.
Plasma levels and onset/duration of effectIntravenous infusion. When Syntocinon is given by continuous i.v. infusion 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. 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 a 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.
AbsorptionPlasma levels of oxytocin following intravenous infusion at 4 milliunits per minute in pregnant women at term were 2 to 5 microunits/mL.
DistributionThe steady-state volume of distribution determined in 6 healthy men after i.v. 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 mother's breast milk.
Biotransformation/MetabolismOxytocinase is a glycoprotein aminopeptidase that is produced during pregnancy and appears in the plasma. It is capable of degrading oxytocin. It is produced from both the mother and the foetus. Liver and kidney plays a major role in metabolising and clearing oxytocin from the plasma. Thus, liver, kidney and systemic circulation contribute to the biotransformation of oxytocin.
EliminationPlasma half-life of oxytocin ranges from 3 to 20 min. 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 impairmentNo 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 impairmentNo 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.
|Date of First Authorisation: Date of Last Renewal:||03 October 1977 22 March 2005|