Methylergonovine Maleate Injection, USP

Mechanism of Action

Methylergonovine maleate acts directly on the smooth muscle of the uterus and increases the tone, rate, and amplitude of rhythmic contractions. Thus, it induces a rapid and sustained tetanic uterotonic effect which shortens the third stage of labor and reduces blood loss.

Pharmacodynamics

The onset of action after IV administration is immediate; after IM administration, 2-5 minutes, and after oral administration, 5-10 minutes.

Pharmacokinetics

Pharmacokinetic studies following an IV injection have shown that methylergonovine is rapidly distributed from plasma to peripheral tissues within 2-3 minutes or less. The bioavailability after oral administration was reported to be about 60% with no accumulation after repeated doses. During delivery, with intramuscular injection, bioavailability increased to 78%. Ergot alkaloids are mostly eliminated by hepatic metabolism and excretion, and the decrease in bioavailability following oral administration is probably a result of first-pass metabolism in the liver.

Bioavailability studies conducted in fasting healthy female volunteers have shown that oral absorption of a 0.2 mg methylergonovine tablet was fairly rapid with a mean peak plasma concentration of 3243 ± 1308 pg/mL observed at 1.12 ± 0.82 hours. A delayed gastrointestinal absorption (T_max about 3 hours) of methylergonovine maleate tablet might be observed in postpartum women during continuous treatment with this oxytocic agent.

For a 0.2 mg intramuscular (IM) injection, a mean peak plasma concentration of 5918 ± 1952 pg/mL was observed at 0.41 ± 0.21 hours. The extent of absorption of the tablet, based upon methylergonovine plasma concentrations, was found to be equivalent to that of the IM solution given orally, and the extent of oral absorption of the IM solution was proportional to the dose following administration of 0.1, 0.2, and 0.4 mg. When given intramuscularly, the extent of absorption of methylergonovine maleate solution was about 25% greater than the tablet. The volume of distribution (Vd_ss/F) of intramuscularly administered methylergonovine was calculated to be 56.1 ± 17.0 liters, and the plasma clearance (CLp/F) was calculated to be 14.4 ± 4.5 liters per hour. The decline of plasma level of intramuscularly administered methylergonovine was biphasic with a mean elimination half-life of 3.39 hours (range 1.5 to 12.7 hours).

This drug should not be administered I.V. routinely because of the possibility of inducing sudden hypertensive and cerebrovascular accidents. If I.V. administration is considered essential as a lifesaving measure, methylergonovine maleate should be given slowly over a period of no less than 60 seconds with careful monitoring of blood pressure. Intra-arterial or periarterial injection should be strictly avoided.

Caution should be exercised in the presence of impaired hepatic or renal function.

Patients with coronary artery disease or risk factors for coronary artery disease (e.g., smoking, obesity, diabetes, high cholesterol) may be more susceptible to developing myocardial ischemia and infarction associated with methylergonovine-induced vasospasm.

Risk of Adverse Reactions or Reduced Therapeutic Effect Due to Drug Interactions

The concomitant use of Methylergonovine Maleate and certain drugs may result in potentially significant drug interactions, some of which may lead to adverse reactions or reduced therapeutic effect of Methylergonovine Maleate or the concomitant drug. (see CONTRAINDICATION and DRUG INTERACTION)

Inadvertent administration of Methylergonovine Maleate Injection to newborn infants has been reported. In these cases of inadvertent neonatal exposure, symptoms such as respiratory depression, convulsions, cyanosis and oliguria have been reported. Usual treatment is symptomatic. However, in severe cases, respiratory and cardiovascular support is required.

Methylergonovine Maleate Injection has been administered instead of vitamin K and Hepatitis B vaccine, medications which are routinely administered to the newborn. Due to the potential for accidental neonatal exposure, Methylergonovine Maleate Injection should be stored separately from medications intended for neonatal administration.

Caution should be exercised in the presence of sepsis, obliterative vascular disease. Also use with caution during the second stage of labor. The necessity for manual removal of a retained placenta should occur only rarely with proper technique and adequate allowance of time for its spontaneous separation.

No long-term studies have been performed in animals to evaluate carcinogenic potential. The effect of the drug on mutagenesis or fertility has not been determined.

Use of Methylergonovine Maleate is contraindicated during pregnancy because of its uterotonic effects. (See INDICATIONS AND USAGE)

Animal reproductive studies have not been conducted with Methylergonovine Maleate. It is not known whether Methylergonovine Maleate can cause fetal harm or can affect reproductive capacity.

The uterotonic effect of methylergonovine maleate is utilized after delivery to assist involution and decrease hemorrhage, shortening the third stage of labor. Caution should be exercised during the second stage of labor. The necessity for manual removal of a retained placenta should occur only rarely with proper technique and adequate allowance of time for its spontaneous separation.

Mothers should not breast-feed during treatment with Methylergonovine Maleate Injection and at least 12 hours after administration of the last dose. Milk secreted during this period should be discarded. Methylergonovine Maleate may produce adverse effects in the breast-feeding infant. Methylergonovine Maleate may also reduce the yield of breast milk

Safety and effectiveness in pediatric patients have not been established.

Clinical studies of methylergonovine maleate did not include sufficient number of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in response between the elderly and younger patients. In general dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

No studies have been performed in subjects with hepatic impairment. Methylergometrine is mostly eliminated by hepatic metabolism and excretion. Use with caution in patients with hepatic impairment.

No studies have been performed in subjects with renal impairment. Renal excretion contributes to the elimination of methylergometrine and its metabolites. Use with caution in patients with renal impairment.

The following adverse drug reactions have been derived from post-marketing experience with Methylergonovine Maleate Injection via spontaneous case reports. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency which is therefore categorized as not known.

Cerebrovascular accident, paraesthesia

Ventricular fibrillation, ventricular tachycardia, angina pectoris, atrioventricular block

1 mL, 0.2 mg, after delivery of the anterior shoulder, after delivery of the placenta, or during the puerperium. May be repeated as required, at intervals of 2-4 hours.

1 mL, 0.2 mg, administered slowly over a period of no less than 60 seconds (See WARNINGS.)