Label: METHYLERGONOVINE MALEATE tablet

Methylergonovine Maleate is a semi-synthetic ergot alkaloid used for the prevention and control of postpartum hemorrhage.

Methylergonovine Maleate Tablets, USP is available in tablets for oral ingestion containing 0.2 mg methylergonovine maleate.

Tablets

Active ingredient: Methylergonovine maleate, USP, 0.2 mg.

Inactive ingredients: acacia, corn starch, gelatin, lactose monohydrate, methylparaben, microcrystalline cellulose, povidone, propylparaben, stearic acid, and tartaric acid.

Chemically, methylergonovine maleate is designated as ergoline-8-carboxamide, 9, 10-didehydro-N-[1-(hydroxymethyl) propyl]-6-methyl-, [8β(S)]-, (Z)-2-butenedioate (1:1) (salt). Its structural formula is:

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. The onset of action after I.V. administration is immediate; after I.M. administration, 2-5 minutes, and after oral administration, 5-10 minutes

Pharmacokinetic studies following an I.V. 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. For a 0.2 mg intramuscular 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 I.M. solution given orally, and the extent of oral absorption of the I.M. 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 (Vdss/F) of 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 plasma level decline was biphasic with a mean elimination half-life of 3.39 hours (range 1.5 to 12.7 hours). A delayed gastrointestinal absorption (Tmax about 3 hours) of methylergonovine maleate tablet might be observed in postpartum women during continuous treatment with this oxytocic agent.

Following delivery of placenta, for routine management of uterine atony, hemorrhage and subinvolution of the uterus. For control of uterine hemorrhage in the second stage of labor following delivery of the anterior shoulder.

Hypertension; toxemia; pregnancy; and hypersensitivity.

General

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 presence of impaired hepatic or renal function.

Breast-feeding

Mothers should not breast-feed during treatment with Methylergonovine Maleate Tablets, USP. Milk secreted during this period should be discarded. Methylergonovine Maleate Tablets, USP may produce adverse effects in the breast-feeding infant. Methylergonovine Maleate Tablets, USP may also reduce the yield of breast milk. Mothers should wait at least 12 hours after administration of the last dose of Methylergonovine Maleate Tablets, USP before initiating or resuming breast feeding.

Coronary artery disease

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.

Medication errors

Inadvertent administration of Methylergonovine Maleate Tablets, USP 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 Tablets, USP 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 should be stored separately from medications intended for neonatal administration.

The most common adverse reaction is hypertension associated in several cases with seizure and/or headache. Hypotension has also been reported. Abdominal pain (caused by uterine contractions), nausea and vomiting have occurred occasionally. Rarely observed reactions have included: acute myocardial infarction, transient chest pains, vasoconstriction, vasospasm, coronary arterial spasm, bradycardia, tachycardia, dyspnea, hematuria, thrombophlebitis, water intoxication, hallucinations, leg cramps, dizziness, tinnitus, nasal congestion, diarrhea, diaphoresis, palpitation, rash, and foul taste

There have been rare isolated reports of anaphylaxis, without a proven causal relationship to the drug product

Postmarketing Experience

The following adverse drug reactions have been derived from post-marketing experience with Methylergonovine Maleate Tablets, USP 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

Nervous system disorders

Cerebrovascular accident, paraesthesia

Cardiac disorders

Ventricular fibrillation, ventricular tachycardia, angina pectoris, atrioventricular block

Methylergonovine maleate has not been associated with drug abuse or dependence of either a physical or psychological nature.

Symptoms of acute overdose may include: nausea, vomiting, oliquria, abdominal pain, numbness, tingling of the extremities, rise in blood pressure, in severe cases followed by hypotension, respiratory depression, hypothermia, convulsions, and coma.

Because reports of overdosage with methylergonovine maleate are infrequent, the lethal dose in humans has not been established. The oral LD50 (in mg/kg) for the mouse is 187, the rat 93, and the rabbit 4.5. Several cases of accidental methylergonovine maleate injection in newborn infants have been reported, and in such cases 0.2 mg represents an overdose of great magnitude. However, recovery occurred in all but one case following a period of respiratory depression, hypothermia, hypertonicity with jerking movements, and convulsions.

Also, several children 1-3 years of age have accidentally ingested up to 10 tablets (2 mg) with no apparent ill effects. A postpartum patient took 4 tablets at one time in error and reported paresthesias and clamminess as her only symptoms.

Treatment of acute overdosage is symptomatic and includes the usual procedures of:

1. removal of offending drug by inducing emesis, gastric lavage, catharsis, and supportive diuresis.
2. maintenance of adequate pulmonary ventilation, especially if convulsions or coma develop.
3. correction of hypotension with pressor drugs as needed.
4. control of convulsions with standard anticonvulsant agents.
5. control of peripheral vasospasm with warmth to the extremities if needed.

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

Intramuscularly

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.

Intravenously

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

Orally

One tablet, 0.2 mg, 3 or 4 times daily in the puerperium for a maximum of 1 week.

White, round, biconvex compressed tablets debossed with "n" on one side and "01" on the other side. Available in bottles of 7, 12, 28 and 100 tablets.

Bottles of 7 .....................................NDC  43386-140-07

Bottles of 12 ...................................NDC  43386-140-12

Bottles of 28....................................NDC  43386-140-28

Bottles of 100 ................................NDC  43386-140-01

STORE AND DISPENSE

Tablets: Store below 25°C (77°F); in tight, light-resistant container.

Manufactured by:

Novel Laboratories, Inc.

Somerset, NJ 08873

Manufactured for:

Lupin Pharmaceuticals, Inc.

Baltimore, MD  21202

PI1400000206

Rev. 10/2017

NDC 43386-140-01

Rx Only

Methylergonovine Maleate Tablets, USP

0.2 mg

100 Tablets

NDC 43386-140-28

Rx Only

Methylergonovine Maleate Tablets, USP

0.2 mg

28 Tablets

NDC 43386-140-12

Rx Only

Methylergonovine Maleate Tablets, USP

0.2 mg

12 Tablets

NDC 43386-140-07

Rx Only

Methylergonovine Maleate Tablets, USP

0.2 mg

7 Tablets