METHYLERGONOVINE: 160 Adverse Event Reports & Safety Profile

DESCRIPTION Methylergonovine maleate is a semi-synthetic ergot alkaloid used for the prevention and control of postpartum hemorrhage. Methylergonovine maleate is available in tablets for oral ingestion containing 0.2 mg methylergonovine maleate.

Active

Ingredient: methylergonovine maleate USP, 0.2 mg.

Inactive

Ingredients: acacia, gelatin, lactose monohydrate, methylparaben, microcrystalline cellulose, povidone, propylparaben, corn starch, 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 C 20 H 25 N 3 O 2 ·C 4 H 4 O 4 M.W.

455.50 FDA approved dissolution test specifications differ from USP. formula

INDICATIONS AND USAGE Following delivery of the 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.

DOSAGE AND ADMINISTRATION 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 to 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.

CONTRAINDICATIONS Hypertension; toxemia; pregnancy; and hypersensitivity.

ADVERSE REACTIONS Clinical trials experience Common Adverse Reactions 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.

Rare Adverse Reactions

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. Post marketing Experience The following adverse drug reactions have been derived from post-marketing experience with methylergonovine maleate 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 To report SUSPECTED ADVERSE REACTIONS, contact Rising Pharma Holdings, Inc. at 1-844-874-7464 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

WARNINGS 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 have 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.

PRECAUTIONS General 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.

Drug

Interactions CYP 3A4 Inhibitors (e.g., Macrolide Antibiotics and Protease Inhibitors) There have been rare reports of serious adverse events in connection with the coadministration of certain ergot alkaloid drugs (e.g., dihydroergotamine and ergotamine) and potent CYP 3A4 inhibitors, resulting in vasospasm leading to cerebral ischemia and/or ischemia of the extremities. Although there have been no reports of such interactions with methylergonovine alone, strong and moderate CYP 3A4 inhibitors should not be co-administered with methylergonovine. Examples of some of the strong CYP 3A4 inhibitors include saquinavir, grapefruit juice, nefazodone, macrolide antibiotics (e.g., troleandomycin, clarithromycin), HIV protease or reverse transcriptase inhibitors (e.g., ritonavir, indinavir, nelfinavir) or azole antifungals (e.g., ketoconazole, itraconazole, voriconazole). Moderate inhibitors include fluconazole, fluvoxamine and clotrimazole. Weak CYP 3A4 inhibitors should be administered with caution. Weak inhibitors include chlorzoxazone, cilostazol, and ranitidine. These lists are not exhaustive, and the prescriber should consider the effects on CYP 3A4 of other agents being considered for concomitant use with methylergonovine. CYP3A4 inducers Drugs (e.g. nevirapine, rifampin) that are strong inducers of CYP3A4 are likely to decrease the pharmacological action of Methylergonovine Maleate Injection. Beta-blockers Caution should be exercised when Methylergonovine Maleate Injection is used concurrently with beta-blockers. Concomitant administration with beta-blockers may enhance the vasoconstrictive action of ergot alkaloids.

Anesthetics

Anesthetics like halothane and methoxyflurane may reduce the oxytocic potency of Methylergonovine Maleate Injection. Glyceryl trinitrate and other antianginal drugs Methylergonovine maleate produces vasoconstriction and can be expected to reduce the effect of glyceryl trinitrate and other antianginal drugs. No pharmacokinetic interactions involving other cytochrome P450 isoenzymes are known. Caution should be exercised when Methylergonovine Maleate Injection is used concurrently with other vasoconstrictors, ergot alkaloids, or prostaglandins. Carcinogenesis, Mutagenesis, Impairment of Fertility 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.

Pregnancy

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. Labor and Delivery 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.

Nursing Mothers

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.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

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.

Hepatic

Impairment 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.

Renal

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.

Drug Interactions CYP 3A4 Inhibitors (e.g., Macrolide Antibiotics and Protease Inhibitors) There have been rare reports of serious adverse events in connection with the coadministration of certain ergot alkaloid drugs (e.g., dihydroergotamine and ergotamine) and potent CYP 3A4 inhibitors, resulting in vasospasm leading to cerebral ischemia and/or ischemia of the extremities. Although there have been no reports of such interactions with methylergonovine alone, strong and moderate CYP 3A4 inhibitors should not be co-administered with methylergonovine. Examples of some of the strong CYP 3A4 inhibitors include saquinavir, grapefruit juice, nefazodone, macrolide antibiotics (e.g., troleandomycin, clarithromycin), HIV protease or reverse transcriptase inhibitors (e.g., ritonavir, indinavir, nelfinavir) or azole antifungals (e.g., ketoconazole, itraconazole, voriconazole). Moderate inhibitors include fluconazole, fluvoxamine and clotrimazole. Weak CYP 3A4 inhibitors should be administered with caution. Weak inhibitors include chlorzoxazone, cilostazol, and ranitidine. These lists are not exhaustive, and the prescriber should consider the effects on CYP 3A4 of other agents being considered for concomitant use with methylergonovine. CYP3A4 inducers Drugs (e.g. nevirapine, rifampin) that are strong inducers of CYP3A4 are likely to decrease the pharmacological action of Methylergonovine Maleate Injection. Beta-blockers Caution should be exercised when Methylergonovine Maleate Injection is used concurrently with beta-blockers. Concomitant administration with beta-blockers may enhance the vasoconstrictive action of ergot alkaloids.

Anesthetics

Anesthetics like halothane and methoxyflurane may reduce the oxytocic potency of Methylergonovine Maleate Injection. Glyceryl trinitrate and other antianginal drugs Methylergonovine maleate produces vasoconstriction and can be expected to reduce the effect of glyceryl trinitrate and other antianginal drugs. No pharmacokinetic interactions involving other cytochrome P450 isoenzymes are known. Caution should be exercised when Methylergonovine Maleate Injection is used concurrently with other vasoconstrictors, ergot alkaloids, or prostaglandins.