001945 Oxytocin

HCFA JCODE(S): J2590; up to 10 units; IV, IM

DESCRIPTION

Note: This monograph contains complete prescribing information for the Injection as well as the Nasal Spray forms of oxytocin.

Injection:

Nasal Spray:

Oxytocin is one of the polypeptide hormones of the pituitary gland. The pharmacologic and clinical properties of oxytocin nasal solution, (nasal spray) are identical with the oxytocic and galactokinetic principle of the natural hormone.

Synthetic oxytocin has the formula C43H66N12012S2, with a molecular weight of 1007.19

Since oxytocin, a polypeptide, is subject to inactivation by the proteolytic enzymes of the alimentary tract, it is not absorbed from the gastrointestinal tract .

CLINICAL PHARMACOLOGY

Injection

Uterine motility depends on the formation of the contractile protein actomyosin under the influence of the Ca2+ -dependent phosphorylating enzyme myosin light-chain kinase. Oxytocin promotes contractions by increasing the intracellular Ca2+. Oxytocin has specific receptors in the myometrium and the receptor concentration increases greatly during pregnancy, reaching a maximum in early labor at term. The response to a given dose of oxytocin is very individualized and depends on the sensitivity of the uterus, which is determined by the oxytocin receptor concentration. However, the physician should be aware of the fact that oxytocin even in its pure form has inherent pressor and antidiuretic properties which may become manifest when large doses are administered. These properties are though to be due to the fact that oxytocin and vasopressin differ in regard to only two of the eight amino acids (see PRECAUTIONS.)

Oxytocin is distributed throughout the extracellular fluid. Small amounts of the drug probably reach the fetal circulation. Oxytocin has a plasma half-life of about 1 to 6 minutes which is decreased in late pregnancy and during lactation. Following intravenous administration of oxytocin, uterine response occurs almost immediately and subsides within 1 hour. Following intramuscular injection of the drug, uterine response occurs within 3 to 5 minutes and persists for 2 to 3 hours. Its rapid removal from plasma is accomplished largely by the kidney and the liver. Only small amounts are excreted in urine unchanged.

Nasal Spray

Oxytocin nasal spray acts specifically on the myoepithelial elements surrounding the alveoli of the breast, and making up the walls of the lactiferous ducts, causing their smooth muscle fibers to contract and thus force milk into the large ducts of the sinuses where it is more readily available to the baby. Oxytocin does not possess galactopoietic properties and its use is intended only for the purpose of milk ejection.

Pharmacokinetics:

INDICATIONS AND USAGE

Injection

IMPORTANT NOTICE

Elective induction of labor is defined as the initiation of labor in a pregnant individual who has no medical indications for induction. Since the available data are inadequate to evaluate the benefits-to-risks considerations. Oxytocin is not indicated for elective induction of labor.

Antepartum:

Postpartum:

Nasal Spray:

CONTRAINDICATIONS

Injection:

1.

Where there is significant cephalopelvic disproportion;

2.

In unfavorable fetal positions or presentations, such as transverse lies, which are undeliverable without conversion prior to delivery;

3.

In obstetrical emergencies where the benefit-to-risk ratio for either the fetus or the mother favors surgical intervention;

4.

In fetal distress where delivery is not imminent;

5.

Where adequate uterine activity fails to achieve satisfactory progress;

6.

Where the uterus is already hyperactive or hypertonic;

7.

In cases where vaginal delivery is contraindicated, such as invasive cervical carcinoma, active herpes genitalis, total placenta previa, vase previa, and cord presentation or prolapse of the cord;

8.

In patients with hypersensitivity to the drug.

Nasal Spray:

WARNINGS

Injection:

PRECAUTIONS

General

Injection

1.

All patients receiving intravenous oxytocin must be under continuous observation by trained personnel who have a thorough knowledge of the drug and qualified to identify complications. A physician qualified to manage any complications should be immediately available. Electric fetal monitoring provides the best means for early detection of overdosage (see OVERDOSAGE.) However, it must be born in mind that only intrauterine pressure recording can accurately measure the intrauterine pressure during contractions. A fetal scalp electrode provides a more dependable recording of the fetal heart rate than any external monitoring system.

2.

When properly administered, oxytocin should stimulate uterine contractions similar to those seen in normal labor. Overstimulation of the uterus by improper administration can be hazardous to both mother and fetus. Even with proper administration and adequate supervision, hypertonic contractions can occur in patients whose uteri are hypersensitive to oxytocin. This fact must be considered by the physician in exercising his judgement regarding patient selection.

3.

Except in unusual circumstances, oxytocin should not be administered in the following conditions: fetal distress, partial placenta previa, prematurity, borderline cephalopelvic disproportion, and major surgery on the cervix or uterus including cesarean section, overdistention of the uterus, grand multiparity, or past history of uterine sepsis or of traumatic delivery. Because of the variability of the combinations of factors which may be present in the conditions listed above, the definition of "unusual circumstances" must be left to the judgment of the physician. The decision can only be made by carefully weighing the potential benefits which oxytocin can provide in a given case against rare but definite potential for the drug to produce hypertonicity or tetanic spasm.

4.

Maternal deaths due to hypertensive episodes, subarachnoid hemorrhage, rupture of the uterus, fetal deaths due to various cases have been reported associated with the use of parenteral oxytocic drugs for induction of labor or the augmentation in the first and second stages of labor

5.

Oxytocin has been shown to have an intrinsic antidiuretic effect, acting to increase water reabsorption from the glomerular filtrate. Consideration should, therefore, be given to the possibility of water intoxication, particularly when oxytocin is administered continuously by infusion and the patient is receiving fluids by mouth.

6.

When oxytocin is used for induction or reinforcement of already existent labor, patients should be carefully selected. Pelvic adequacy must be considered and maternal and fetal conditions evaluated before the drug is administered.

Carcinogenesis, Mutagenesis, and Impairment of Fertility

There are no animal or human studies on the carcinogenicity and mutagenicity of this drug, nor is there any information on its effect on fertility.

Injection

Pregnancy, Teratogenic Effects:

Nonteratogenic Effects:

Nasal Spray

Pregnancy Category X:

Labor and Delivery

See INDICATIONS AND USAGE.

Nasal Spray:

Information for the Patient

The squeeze bottle should be held in an upright position when administering the drug to the nose and the patient should be in an sitting position rather than lying down. If preferred, the solution can be instilled in drop form by inverting the squeeze bottle and exerting very gentle pressure on its walls.

Nursing Mothers

While harmful effects on the newborn have not been reported, it should be noted that Oxytocin nasal solution, (nasal spray) is intended to be used only for initial milk propulsion and ejection during the first week postpartum, and not for continued use. Caution shall be exercised when oxytocin nasal solution, (nasal spray) is administered to a nursing mother since oxytocin is known to be excreted in human milk.

DRUG INTERACTIONS

Injection:

ADVERSE REACTIONS

Injection:

Excessive dosage or hypersensitivity to the drug may result in uterine hypertonicity, spasm, tetanic contraction, or rupture of the uterus.

The possibility of increased blood loss and afibrinogenemia should be kept in mind when administering the drug.

Severe water intoxication with convulsions and coma has occurred, associated with a slow oxytocin infusion over a 24-hour period. Maternal death due to oxytocin-induced water intoxication has been reported.

The following adverse reactions have been reported in the fetus or infant: Due to induced uterine motility: Bradycardia, Premature ventricular contractions and other arrhythmias, Permanent CNS or brain damage, Fetal death. Due to use of oxytocin in the mother: Low Apgar scores at five minutes, Neonatal jaundice, Neonatal retinal hemorrhage.

Nasal Spray:

One case each of seizure and "psychotic state" are the most severe reactions reported. No other reactions have been described.3

DRUG ABUSE AND DEPENDENCE

Nasal Spray:

OVERDOSAGE

Injection:

Nasal Spray:

DOSAGE AND ADMINISTRATION

Injection

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.

The dosage of oxytocin is determined by uterine response. The following dosage information is based upon the various regimens and indications in general use.

Induction or Stimulation of Labor

Intravenous infusion (drip method) is the only acceptable method of parenteral administration of oxytocin for the induction or stimulation of labor. Accurate control of the rate of infusion flow is essential and is best accomplished by an infusion pump. It is convenient to piggyback the oxytocin infusion on a physiologic electrolyte solution, permitting the oxytocin infusion to be stopped abruptly without interrupting the electrolyte infusion. This is done in the following way.

Preparation:

a.

The standard solution for infusion of oxytocin is prepared by adding the contents of one 1-ml ampoule containing 10 units of oxytocin to 1000 ml of 0.9% aqueous sodium chloride or Ringer's lactate. The combined solution containing 10 milliunits (mU) of oxytocin/ml is rotated in the infusion bottle for thorough mixing. The same concentration can be obtained by mixing the contents of one 0.5 ml ampoule, containing 5 units of oxytocin, with 500 ml of electrolyte solution.

b.

Establish the infusion with a separate bottle of physiologic electrolyte solution not containing oxytocin.

c.

Attach (piggyback) the oxytocin-containing bottle with the infusion pump to the infusion line as close to the infusion site as possible.

Administration:

Studies of the concentrations of oxytocin in the maternal plasma during oxytocin infusion have shown that infusion rates up to 6 mU/min give the same oxytocin levels that are found in spontaneous labor. At term, higher infusion rates should be given with great care, and rates exceeding 9-10 mU/min are rarely required. Before term, when the sensitivity of the uterus is lower because of a lower concentration of oxytocin receptors, a higher infusion rate may be required.

Monitoring:

a.

Electronically monitor the uterine activity and the fetal heart rate throughout the infusion of oxytocin. Attention should be given to tonus, amplitude and frequency of contractions and to the fetal heart rate in relation to uterine contractions. If uterine contractions become too powerful, the infusion can be abruptly stopped and oxytocic stimulation of the uterine musculature will soon wane. (see PRECAUTIONS.)

b.

Discontinue the infusion of oxytocin immediately in the event of uterine and hyperactivity and/or fetal distress. Administer oxygen to the mother, who preferably should be put in a lateral position. The condition of mother and fetus should immediately be evaluated by the responsible physician and appropriate steps taken.

Control of Postpartum Uterine Bleeding

Intravenous infusion (drip method):

Intramuscular Administration:

Treatment of Incomplete, Inevitable or Elective Abortion

Intravenous infusion of 10 units of oxytocin added to 500 ml of a physiologic saline solution or 5% dextrose in-water solution may help the uterus contract after a suction or sharp curettage for an incomplete, inevitable or elective abortion.

Subsequent to intra-amniotic injection of hypertonic saline, professionals, urea, etc, for midtrimester elective abortion, the injection-to-abortion time may be shortened by infusion of oxytocin at the rate of 10 to 20 milliunits (20 to 40 drops) per minute. The total dose should not exceed 30 units in a 12-hour period due to the risk of water intoxication.

Nasal Spray

One spray into one or both nostrils two to three minutes before nursing or pumping of breasts.

Nasal Spray

1.

U.S.P. XXI, p. 777,

2.

Goodman and Gilman: The Pharmacological Basis of Therapeutics. Sixth Ed., 937-8.

3.

Data collected by the Medical Services Department, Sandoz Pharmaceuticals Corporation.

4.

Boglin, N.E.: The use of intranasal oxytocin for the induction of labor. Zbl. Gynak. 85: 193-199 (Feb 9) 1963.

5.

Sandoz Overdosage Manual, 1984, Syntocinon Injection.

Injection

1.

Seitchik J, Castillo M: Oxytocin augmentation of dysfunctional labor. I. Clinical Data. Am J Obstet Gynecol 1982; 144:889-905.

2.

Seitchik j, Castillo M: Oxytocin augmentation of dysfunctional labor. II. Multuparous patients.Am J Obstet Gynecol 1983; 145:777-780.

3.

Fuchs A, Goeschen K, Husslein P, et al: Oxytocin and the initiation of human parturition. III. Plasma concentrations of oxytocin and 13, 14-dihydro-15-keto-prostaglandin F2α in spontaneous and oxytocin-induced labor at term. Am J Obstet Gynecol 1983; 145:497-502.

4.

Seitchik J, Amico J, et al: Oxytocin augmentation of dysfunctional labor. IV. Oxytocin pharmacokinetics. Am J Obstet Gynecol 1984; 150:225- 228.

5.

American College of Obstetricians and Gynecologists: ACOG Technical Bulletin Number 110-November 1987: Induction and augmentation of labor.

HOW SUPPLIED

Injection:

Nasal Spray:

(Injection, Parke-Davis, 5/94, 4160G069)

(Nasal Spray, Sandoz, 7/88, St-ZZ13)