SYNTOCINON Concentrate for solution for infusion Ref.[27701] Active ingredients: Oxytocin

Syntocinon must only be administered as an i.v. infusion and never by i.v. 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

Syntocinon 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 syndrome

Syntocinon 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 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 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 Impairment

Caution 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.

Excipients

The medicine contains 4.7mg of alcohol (ethanol) in per 1 ml which is equivalent to 4.7 mg/ml (0.47% w/v). The amount in one dose (1ml) of this medicine is equivalent to less than 1 ml beer or 1 ml wine.

The small amount of alcohol in this medicine will not have any noticeable effects.

This medicine contains less than 1 mmol sodium (23 mg) per1 ml, that is to say essentially ‘sodium-free’.

Interaction resulting in a concomitant use not recommended

Prostaglandins and their analogues

Prostaglandins 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 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 section 4.4 Special warnings and precautions for use).

Interactions to be considered

Inhalation anaesthetics

Inhalation 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/Sympathomimetics

Oxytocin may enhance the vasopressor effects of vasoconstrictors and sympathomimetics, even those contained in local anaesthetics.

Caudal anaesthetics

When given during or after caudal block anaesthesia, oxytocin may potentiate the pressor effect of sympathomimetic vasoconstrictor agents.

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.

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

Lactation

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 Syntocinon because of the targeted indications

Infertility

Not applicable for Syntocinon because of the targeted indications.

Syntocinon can induce labour, therefore caution should be exercised when driving or operating machines. Women with uterine contractions should not drive or use machines.

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 i.v. 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 i.v. bolus injection of oxytocin at doses amounting to several IU may result in acute short-lasting hypotension accompanied with flushing and reflex tachycardia (see section 4.4 Special warnings and precautions for use). These rapid haemodynamic changes may result in myocardial ischaemia, particularly in patients with pre-existing cardiovascular disease. Rapid i.v. 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 section 4.4 Special warnings and precautions for use).

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 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:

Table 2. Adverse drug reactions in foetus/neonate:

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 Yellow Card Scheme (www.mhra.gov.uk/yellowcard) or search for MHRA Yellow Card in the Google Play or Apple App Store.

Syntocinon should not be infused via the same apparatus as blood or plasma, because the peptide linkages are rapidly inactivated by oxytocin-inactivating enzymes. Syntocinon is incompatible with solutions containing sodium metabisulphite as a stabiliser.