OXYTOCIN

OXYTOCIN

FORMULATION

Active Component 1 ampule (1 mL)

Synthetic oxytocin 5 IU/mL

10 IU/mL

DRUG CATEGORY: Synthetic oxytocin, for stimulation of uterine contractions

BRAND NAME: Syntocinon®

PROPERTIES

The active principle of synthetic oxytocin is a synthetic nonapetide identical with oxytocin, a hormone released by the posterior lobe of the pituitary. It exerts a stimulatory effect on the smooth musculature of the uterus, particularly towards the end of pregnancy, during labor, after delivery and in the peurperium, i.e. at times when the number of specific oxytocin receptors in the myometrium is increased.

When given by low-dose IV infusion, synthetic oxytocin elicits rhytmic uterine contractions that are indistinguishable in frequency, force and duration from those observed during spontaneous labor. At higher infusion dosages, or when given by single injection, the drug is capable of causing sustained tetanic uterine contractions.

In addition to its effects on the uterus, oxytocin contracts the myoepithelial cells surrounding the mammary alveoli, thereby causing milk ejection and facilitating breast-feeding.

Being synthetic oxytocin, it does not contain vasopressin, but even in its pure form oxytocin possesses some weak intrinsic vasopressin-like anti-diuretic activity.

Another pharmacological effect observed with high doses of oxytocin, particularly when administered by rapid i.v. bolus injection, consists in a transient direct relaxing effect on vascular smooth muscle, resulting in brief hypotension, flushing and reflex tachycardia.

PHARMACOKINETICS

When administered by IV or IM injection for prevention or treatment of post-partum hemorrhage, synthetic oxytocin acts rapidly with a latency period of less that 1 minute by IV injection, and of 2 to 4 minutes by IM route. The oxytocin response lasts for 30 to 60 minutes after IM administration and possibly less after IV injection. When synthetic oxytocin is given continuous IV infusion at doses appropriate for induction or enhancement of labor, the uterine response sets in gradually and reaches a steady state usually within 20 to 40 minutes. The corresponding plasma levels of oxytocin are comparable with those measured during spontaneous first-stage labor. Upon discontinuation of the infusion or following a substantial reduction in the infusion rate e.g. in case of overstimulation, uterine activity declines rapidly but may continue on an adequate lower level. The relative ease with which the rate and force of uterine contractions can be regulated by the IV infusion of synthetic oxytocin is due to the short half-life of oxytocin. Values reported by various investigators range from 3 to 17 minutes. Plasma protein binding is very low. Removal of oxytocin from plasma is accomplished mainly by the liver and the kidneys. Less that 1% of a given dose is excreted unchanged in the urine. The apparent volume of distribution is approximately 300 mL/kg in men: and the metabolic clearance rate amounts to about 20ml/kg per minute in men as well as in pregnant women. The extent to which oxytocin crosses the placenta or passes into breast milk is not known.

INDICATIONS

• Induction of labor for medical reasons e.g. in cases of post-term gestation, premature rupture of the membranes, pregnancy-induced hypertension (pre-eclampsia)
• Enhancement of labor in selected cases of uterine inertia
• During cesarean section, following the delivery of a child
• Prevention and treatment of post-partum uterine atony and hemorrhage
• Treatment of puerperal bleeding, subinvolution of the uterus and lochiometr, as an alternative to uterotonic ergot alkaloids for women in whom these drugs should be avoided

Synthetic oxytocin may also be indicated in early stages of pregnancy as an adjunctive therapy for the management of incomplete, inevitable or missed abortion.

DOSAGE AND ADMINISTRATION

Induction or enhancement of labor

Synthetic oxytocin should be administered as as IV drip infusion or, preferably, by means of a variable-speed infusion pump. For drip infusion it is recommended the 5 IU of synthetic oxytocin be added to 500ml of physiologic electrolyte solution. 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 mU/min (2 to 8 drops/min). It may be gradually increased at intervals not shorter than 20 minutes until a contraction pattern similar to that of normal labor is established. In pregnancy near term, this can be often be achieved with an infusion of less than 10mU/min (20 drops/min), and the recommended maximum rate is 2 mU/min (40 drops/min). In the unusual event that higher rates are required, as may occur in the management of fetal death in utero or for induction of labor at an earlier stage of pregnancy when the uterus is less sensitive to oxytocin, it is advisable to use a more concentrated synthetic oxytocin solution, e.g. 10IU in 500ml.

When using a motor-driven infusion pump which delivers smaller volumes that 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 contraction, as well as fetal heart rate must be carefully monitored throughout the infusion. Once an adequate uterine activity is attained, the infusion rater can often be reduced. In the event of uterine hyperactivity and/or fetal 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 5IU, it is recommended that the attempt to induce labor should be ceased; it may be repeated on the following day, starting again from a rate of 1 to 4 mU/min.

Note: inadvertent paravenous infusion of oxytocin is not harmful.

Cesarean section

5 IU intramuscularly or by slow IV injection immediately after delivery.

Prevention of post-partum uterine hemorrhage

The usual dose is 5 IU slowly IV or 5 to 10 IU IM after delivery of the placenta. In women given synthetic oxytocin for induction or enhancement of labor, the infusion should be continued at an increased rate during the third stage of labor and for the nest few hours thereafter.

Treatment of post-partum uterine hemorrhage

5 IU slowly IV or 5 to 10 IU IM followed in sever cases by intravenous infusion of a solution containing 5 to 20 IU of oxytocin in 500 ml of a non-hydrating diluent, run at the rate necessary to control uterine atony.

Puerperal bleeding, sub-involution of the uterus, lochiometra

2 to 5 IU IM repeated according to individual needs.

Incomplete, inevitable or missed abortion

5 IU slowly IV or 5 to 10 IU IM, if necessary followed by IV infusion at a rate of 20 to 40 mU/min or higher.

CONTRAINDICATIONS

Hypersensitivity to the drug. Hypertonic uterine contractions, fetal distress when delivery is not imminent. Any condition in which, for fetal or maternal reasons, spontaneous labor in inadvisable and/or vaginal delivery is contraindicated: e.g. significant cephalopelvic disproportion, fetal malpresentation; placenta praevia and vasa praevia, placental abruption, cord presentation or prolapse; overdistension, polyphydramnios; or impaired resistance of the uterus to rupture as in multiple pregnancy, grand multiparity and in the presence of a uterine scan resulting from a major surgery including classical cesarean section.

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

PRECAUTIONS

The induction of labor by means of oxytocin should be attempted only when strictly indicated for medical reasons, rather than for convenience. Administration should only be under hospital conditions and qualified medical supervision. When given for induction and enhancement of labor, synthetic oxytocin must be administered only as an IV infusion, and never by SC, IM or IV bolus injection. Careful monitoring of fetal heart rate and uterine motility (frequency, strength, and duration of contractions) is essential, so that the dosage may be adjusted to individual response. When synthetic oxytocin is given for induction or enhancement of labor, 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 with a history of lower-uterine-segment cesarean section.

In the case of fetal death in utero, and/or in the presence of meconium-stained amniotic fluid, tumultuous labor must be avoided, at it may cause amniotic fluid embolism.

Becaused oxytocin possesses a sligh 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 invevitable or missed abortion, or in the management of post-partum hemorrhage, may cause water intoxication associated with hyponatraemia. To avoid this rare complication, 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 liquid should be kept low (by infusing oxytocin at a higher concentration than recommended for the induction or enhancement of labor 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.

When synthetic oxytocin is used for prevention or treatment of uterine hemorrhage, rapid IV injection should be avoided, as it may cause an acute short-lasting drop in blood pressure.

INTERACTIONS

Prostaglandins may potentiate the uterotonic effect of oxytocin and vice versa; therefore concomitant administration requires very careful monitoring.

Some inhalation anesthetics. e.g. cyclopropane or halothane, may enhance the hypotensive effect of oxytocin and reduce its oxytocin action. Their concurrent use with oxytocin has also been reported to cause cardiac rhythm disturbances.

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

SIDE EFFECTS

When oxytocin is used by IV infusion for the induction or enhancement of labor, its administration at too high doses results in uterine overstimulation which may cause fetal distress, asphyxia and death, or may lead to hypertonicity, tetanic contractions or rupture of the uterus.

Water intoxication associated with maternal and neonatal hyponatremia 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'). 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.

With either mode of administration, oxytocin may occasionally cause nausea, vomiting or cardiac arrhythmias. In a few cases, skin rashes and anaphylactoid reactions associated with dyspnea, hypotension or shock have been reported.

OVERDOSAGE

The symptoms and consequences of overdosage are those mentioned under 'Side effects'. In addition placental abruption and/or amniotic fluid embolism as a result of uterine overstimulation have been reported.

Treatment:When signs or symptoms of overdosage occur during continuous IV administration of synthetic oxytocin, the infusion must be discontinued at once and oxygen should be given to the mother. In case of water intoxication, it is essential to restrict fluid intake, promote diuresis, correct electrolyte imbalance, and control convulsions that may eventually occur by judicious use of diazepam.

STORAGE

Protect from light; store in a refrigerator (2-8^oC).