METHYLERGOMETRINE

METHYLERGOMETRINE

0.125 mg tablet

0.2 mg/mL Ampule

CATEGORY: Oxytocic

BRAND NAME: Methergin

FORMULATION

Each sugar-coated tablet contains: 0.125 mg methylergometrine hydrogen maleate.

Each mL of ampule contains: 0.2 mg methylergometrine hydrogen maleate.

INDICATIONS

• Active managements of the third stage of labor (as a means to promote separation of the placenta and to reduce blood loss).

• Treatment of uterine atony/hemorrhage occurring during and after the third stage of labor, in association with Cesarean section or following abortion.

• Treatment of subinvolution of the uterus, lochiometra, puerperal bleeding.

• Methylergometrine is not recommended during breast-feeding (see 'Use during pregnancy and lactation').

DOSAGE AND ADMINISTRATION

Active management of the third stage of labor.

• 0.5 to 1 mL (0.1 to 0.2 mg) slowly I.V. (see 'Special warnings and special precautions for use') following delivery of the anterior shoulder or, at the latest, immediately after delivery of the child. Expulsion of the placenta, usually separated by the first strong contraction following Methylergometrine, should be manually assisted by applying fundal pressure. For delivery under general anesthesia, the recommended dose is 1 mL (0.2 mg).

Treatment of uterine atony / hemorrhage

• 1 mL (0.2 mg) I.M. Or 0.5 to 1 mL (0.1 to 0.2 mg) slowly I.V. (see 'Special warnings and special precautions for use'). May be repeated every 2 to 4 hours, if necessary, up to five doses within 24 hours.

Treatment of subinvolution, lochiometra, puerperal bleeding

• 0.125 to 0.25 mg P.O. (1 to 2 tablets or 0.5 to 1 mL of the oral solution), or 0.5 to 1 mL (0.1 to 0.2 mg) S.C. or I.M., up to 3 times daily.

CONTRAINDICATIONS

Pregnancy; first stage of labor; second stage of labor before crowning of the head (Methylergometrine must not be used for induction or enhancement of labor); sever hypertension; pre-eclampsia and eclampsia; occlusive vascular disease (including ischemic heart disease); sepsis; known hypersensitivity to ergot alkaloids or any other component of the formulation.

PRECAUTIONS

In breech presentation and other abnormal presentations Methylergometrine should not be given before delivery of the child is completed, and in multiple birth not before the last child has been delivered. Active management of the third stage of labor requires obstetric supervision. Intravenous injections must be given slowly over a period of no less than 60 seconds with careful monitoring of blood pressure. Intra- or periarterial injection must be avoided.

Caution should be exercised in the presence of mild to moderate hypertension (severe hypertension is a contraindication) or impaired hepatic or renal function.

INTERACTIONS

Methylergometrine may enhance the vasoconstrictor/vasopressor effects of the other drugs such as sympathomimetics (including those in local anesthetics) or other ergot alkaloids. Therefore, the concomitant use of bromocriptine and methylergometrine in the puerperium is not recommended. No adverse interactions are know to occur with the concurrent administration of methylergometrine and oxytocin. For prevention and treatment of uterine hemorrhage by I.M. injection, it may be advantageous to combine the two uterotonic principles, since oxytocin has a very short latent period where as methylergometrine possesses a prolonged duration of action. Anesthetics like halothan and methoxyfluran may reduce the oxytocic potency of methylergometrine.

USE DURING PREGNANCY AND LACTATION

The use of methylergometrine in pregnancy is contraindicated because of its potent uterotonic activity. Methylergometrine has been reported to reduce milk secretion and to be excreted in the breast milk (see 'Pharmacokinetic properties'). There have been isolated reports of intoxication in breast-fed infants whose mothers were receiving the drug for several days. One more of the following symptoms were observed (and disappeared upon withdrawal of the medication): elevated blood pressure, bradycardia or tachycardia, vomiting diarhhea, restlessness, clonic cramps. In view of the possible side effects for the child and the reduction of the mild yield methylergometrine is not recommended for use during breast-feeding.

EFFECTS ON ABILITY TO DRIVE AND USE MACHINES

Not known. However, caution should be exercised when driving or operating machines, especially at the start of treatment.

ADVERSE EFFECTS

Frequency estimates:

very common ≥ 10%;

common ≥ 1% to <10%;

uncommon ≥ 0.1% to <1%;

rare ≥ 0.01% <0.1%

very rare <0.01%

Central nervous system

-Common: headache

-Uncommon: dizziness; convulsions

-Very rare: hallucinations

Cardiovascular system

-Common: hypertension

-Uncommon: chest pain; hypotension

-Rare: bradycardia; tachycardia; palpitations; peripheral vasospastic reactions

-Very rare: myocardial infarction

Gastrointestinal tract

-Uncommon: nausea; vomiting

Skin and appendages

-Common: skin eruptions

-Uncommon: increased sweating

Urogenital tract

-Common: abdominal pain (caused by uterine contractions)

Miscellaneous

Very rare: anaphylactic reactions

OVERDOSE

Symptoms: Nausea; vomiting; hypertension or hypotension; numbness, tingling and pain in the extremities; respiratory depression; convulsions; coma.

Treatment: Elimination of orally ingested drug by administration of high doses of activated charcoal. Symptomatic treatment under close monitoring of the cardiovascular and the respiratory system. If sedation is required, benzodiazepines may be used. In case of severe arteriospasm, vasodilators should be administered, e.g. sodium nitroprusside, phentolamine or dihydralazine. In the event of coronary constriction, appropriate anti-anginal treatment should be provided (e.g. nitrates).

PHARMACODYNAMICS

Methylergometrine, a synthetic derivative of the naturally occurring alkaloid ergometrine is a potent and specific uterotonic agent. It acts directly on the smooth muscle of the uterus and increases the basal tone, frequency and amplitude of the rhythmic contractions. Compared with other ergot alkaloids, its effects on cardiovascular and central nervous systems are less pronounced. The stronger and selective oxytocic effect of the methylergometrine results from its specific pattern of actions as partial agonist and antagonist at serontoninergic, dopaminergic and α-adrenergic receptors. Nevertheless, this does not totally preclude from vvasoconstrictory complications. (see 'Undesirable effects').

PHARMACOKINETICS

The onset of action of methylergometrine occurs 30 to 60 seconds after I.V., 2 to 5 minutes after I.M., and 5 to 10 minutes after oral administration, and lasts for 4 to 6 hours.

Absorption

Studies conducted in fasted healthy female volunteers have shown that oral absorption of a 0.2 mg methylergometrine tablet was fairly rapid with a mean peak plasma concentration (C_max) of 3243±1308 pg/mL observed at 1.12±0.82 hours (t_max). For a 0.2 mg I.M. injection, C_max was 5918±1952 pg/mL and t_max0.41±0.21 hours. The bioavailability of the tablet was equivalent to that of the I.M. solution given orally and dose proportional following administration of 0.1, 0.2 and 0.4 mg. After I.M. injection, the extent of the absorption was about 25% greater than after oral administration. A delayed gastrointestinal absorption (t_max about 3 hours) was observed in postpartum women during continuous treatment with methylergometrine tablets.

Distribution

Following I.V. injection, methylergometrine is rapidly distributed from plasma to peripheral tissues within 2 to 3 minutes or less. In healthy female volunteers the distribution volume is 56.1±17.0 liters. It is unknown whether the drug crosses the blood-brain barrier.

Metabolism

Methylergometrine is metabolized mainly in the liver. The metabolic pathways has been investigated in humans. In vitro studies show N-demethylation and hydroxylation of the phenyl ring.

Elimination

In healthy female volunteers the plasma clearance is 14.4±4.5 liters per hour and the mean elimination half-life 3.29±1.31 hours. A study in male volunteers has shown that only about 3% of an oral dose is eliminated as parent drug in the urine. The drug is mainly eliminated with the bile into the feces. During continuous treatment the drug is also secreted into the milk. A milk-plasma ratio of about 0.3 was found.

PRECLINICAL SAFETY DATA

Acute toxicity

The LD₅₀ values determined after single oral treatments were 140 and 93 mg/kg in the mouse and the rat. After single I.V. treatments the LD₅₀ values were 85, 23, 2 and 45 mg/kg in the mouse, rat, rabbit and guinea pig.

Subacute / chronic toxicity

No results from long-term toxicity studies with methylergometrine are available.

Reproduction toxicity

No studies have been performed to assess the reproduction toxicity of methylergometrine.

Mutagenic and carcinogenic potential

The effect of methylergometrine on mutagenesis and carcinogenesis has not been determined.

INCOMPATIBILITIES

None known.

SHELF LIFE

Methylergometrine sugar-coated tablets: 5 years.

Methylergometrine ampule: 3 years if stored at 2-8^oC; the ampules may be stored for 14 days out of a refrigerator but not above 25^oC

SPECIAL PRECAUTIONS FOR STORAGE

Methylergometrine sugar-coated tablets: no special precautions.

Methylergometrine ampules: protect from light; store in a refrigerator (2-8^oC); the ampules may be stored for 14 days out of a refrigerator but not above 25^oC. Methylergometrine should be kept out of the reach of children.

INSTRUCTIONS FOR USE AND HANDLING

Methylergometrine ampules: the ampules may be stored for 14 days out of a refrigerator but not above 25^oC.