Active treatment of the third stage of childbirth (placenta delivery) – in order to promote the detachment of the placenta and reduce hemorrhaging.

Treatment of uterine atonia and hemorrhaging during and after placental delivery in the case of a cesarean section or after an abortion.

Treatment of uterine subinvolution, lochiometra, delayed puerperal hemorrhaging.

Posology

General population

Active treatment of placental delivery:

The intramuscular (IM) is the recommended route of administration. When administered intravenously (IV), the dose should be injected slowly over a period of not less than 60 seconds (see section 4.4).

The recommended dosage of Methergin is: 1 ml (0.2 mg) im or from 0.5 to 1 ml (0.1 to 0.2 mg) injected by slow intravenous administration after successful disengagement of the front shoulder or, at the latest, immediately after the escape of the fetus. The expulsion of the placenta, which usually comes off the first contraction induced by violent Methergin, should be manually facilitated through pressure exerted on the bottom of the uterus.

In case of delivery under general anesthesia, the recommended dose is 1 ml (0.2 mg) with a slow intravenous injection.

Treatment of uterine atonia/hemorrhaging:

The intramuscular (IM) is the recommended route of administration. When administered intravenously (IV), the dose should be injected slowly over a period of not less than 60 seconds (see section 4.4).

The recommended dosage of Methergin is: 1 ml (0.2 mg) im or 0.5 to 1 ml (0.1 to 0.2 mg) injected by slow intravenous administration (see section 4.4). If necessary, the administration can be repeated every 2-4 hours up to a maximum of 5 doses within 24 hours.

Treatment of uterine subinvolution, lochiometra, delayed puerperal hemorrhaging:

The recommended dosage of Methergin is: 1 or 2 tablets (0.125 to 0.25 mg) orally, or from 0.5 to 1 ml (0.1 to 0.2 mg) im up to 3 times a day and usually up to 5 days Administer 0.125-0.25 mg orally (1 or 2 tablets) or 0.5-1 ml (0.1-0.2 mg) intramuscularly up to three times a day.

Special Populations

Renal / hepatic impairment

In the presence of impaired hepatic or renal impairment (see section 4.4), we must exercise caution.

General recommendations on the administration

For breech and other abnormal presentations, Methergin should not be given before the complete discharge of the fetus and multiple births not before the release of the last fetus.

Active treatment of the third stage of labor requires supervision midwife. The intramuscular injection is the recommended route of administration. Intravenous injections should be made slowly over a period of not less than 60 seconds, with careful monitoring of blood pressure.

You should avoid injections intra-or peri-arterial.

Breastfeeding

During breast-feeding are possible side effects for the baby and the reduction of milk secretion. Women should not breast-feed during treatment with Methergin and at least 12 hours after the last dose. The milk secreted during this period should be eliminated (see section 4.6).

Hypertension and hepatic or renal impairment

Use with caution in the presence of mild or moderate hypertension (severe hypertension is a contraindication) or in patients with hepatic or renal impairment.

Coronary artery disease

The patients with coronary artery disease or with risk factors for coronary artery disease (eg. Smoking, obesity, diabetes, hypercholesterolemia) can be more susceptible to the development of myocardial ischemia and infarction associated with vasospasm induced by methylergometrine (see section 4.8).

Medication errors

It has been reported accidental administration to infants. In these cases of accidental overdose have been reported in the newborn symptoms such as shortness  of  breath,  convulsions,  cyanosis,  oliguria  and  peripheral vasocostriction. Furthermore, encephalopathy has been reported in infants presenting with signs and symptoms such as irritability, agitation and lethargy. Treatment should be symptomatic, and in severe cases it was necessary to support the respiratory and cardiovascular systems. In the absence of adequate treatment have been reported fatal cases (see section 4.9).

The patient should be informed to store the medicine separately from other medicines to be administered to neonates.

Interactions

The ergot alkaloids are substrates of CYP3A4. Concomitant use of Methergin with  potent  CYP3A4  inhibitors  such  as  macrolide  antibiotics  (eg. Troleandomycin, erythromycin, clarithromycin) or protease inhibitors of HIV reverse transcriptase (eg. Ritonavir, indinavir, nelfinavir, delavirdine) or azolinici antifungals (eg. ketoconazole, itraconazole, voriconazole), should be avoided, as this may result in exposure to high methylergometrine and then ergot toxicity (vasospasm and ischemia of the extremities and other tissues) (see section 4.5).

It is not recommended the concomitant use of Methergin with bromocriptine during puerperium and prostaglandins (see section 4.5).

Caution must be exercised in the concomitant use of Methergin with less potent CYP3A4 inhibitors (eg. Cimetidine, delavirdine, grapefruit juice, quinupristin, dalfopristin), or drugs with vasoconstrictor / vasopressor such as the triptans (5HT1B receptor agonists / 1D), the sympathomimetics, or other ergot alkaloids or beta-blockers (see section 4.5).

Important information about some of the ingredients

Methergin 0.125 mg coated tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or malabsorption of glucose / galactose malabsorption should not take this medicine. Methergin 0.125 mg coated tablets contain sucrose. Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption, or sucrase- isomaltase insufficiency should not take this medicine.

The ergot alkaloids are substrates of CYP3A4

Interactions resulting from concomitant use not recommended

Inhibitors of CYP3A4

The concomitant use of Methergin and potent CYP3A inhibitors, such as macrolide antibiotics (e.g.: troleandomycin, erythromycin, clarithromycin), HIV protease or reverse transcriptase inhibitors (e.g..: ritonavir, indinavir, nelfinavir, delavirdine), or azoline antimycotics (e.g..: ketoconazole, itraconazole, voriconazole), should be avoided because it could cause highed methlergometrine exposure and therefore ergot toxicity (vasospasms and ischemia of the extremities and other tissues) (see section 4.4).

Bromocriptine

Concomitant use of bromocriptine and Methergin during the puerperium is not recommended as the methylergometrine may increase the effect of other vasoconstrictive ergot alkaloids (see section 4.4).

Prostaglandins

Prostaglandins (eg. sulprostone, dinoprostone, misoprostol) facilitate the contraction of the myometrium, and Methergin may potentiate the action of prostaglandins on the uterus and vice versa. Concomitant use with these drugs is not recommended (see section 4.4).

Interactions to take into account

Less potent CYP3A4 inhibitors

Caution is required when Methergin is used together with less potent CYP3A inhibitors (eg. cimetidine, delavirdine, grapefruit juice, quinupristin, dalfopristin), as it can produce a highed exposure to methylergometrine.

Vasoconstrictors, triptans, sympathomimetics and other ergot alkaloids

Caution is required when Methergin is used simukltaneously with other vasoconstrictors or ergot alkaloids. Methylergometrine can increase the vasoconstrictive/vasopressor effects of other drugs such as the tryptanes (agonists of the 5HT1B/1D receptor), sympathomimetics (including those present in local anesthetics), or other ergot alkaloids (see section 4.4).

Beta-blockers

Caution must be exercised when Methergin is used simultaneously with beta- blockers. Co-administration of beta-blockers may potentiate the action of vasoconstrictive ergot alkaloids (see section 4.4).

Anesthetics

Anesthetics such as halothane and methoxyflurane may reduce the power of oxytocic Methergin (see section 4.2).

Inducers of CYP3A4

It is probable that drugs potent CYP3A4 inducers (eg.  nevirapine, rifampin) reduce the pharmacologic action of Methergin.

Glyceryl trinitrate and other antianginal drugs

The methylergometrine caises vasoconstriction and can reduce the effect of glyceryl trinitrate and other antianginal drugs.

Pregnancy

The use of Methergin during pregnancy is contraindicated because of its potent uterotonic activity.

Lactation

It was reported that methylergometrine reduces milk secretion and is excreted in breast milk (see paragraphs 5.1-5.2). Have been isolated cases of intoxication in breast-fed infants whose mothers had taken the drug for several days. Were observed (and then disappeared after discontinuation of treatment) one or more of the following symptoms: increased blood pressure, tachycardia or bradycardia, vomiting, diarrhea, agitation and seizures.

In view of possible side effects for the baby and the reduction of milk production, we do not recommend the use of Methergin during lactation.

Women should not breast-feed during treatment with Methergin and for at least

12 hours after the last dose. The milk secreted during this period should be eliminated (see section 4.4).

Fertility

There are no data on fertility in light of the current indications of the product.

Methylergometrine can cause dizziness and convulsions. It is therefore necessary to pay particular attention when driving vehicles or using machinery.

The adverse reactions (table 1) are listed by system organ classes in MedDRA. Within each system-organ class, adverse reactions are ranked by frequency, the most frequent reactions first. Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. In addition, for each reaction is also given the category corresponding frequency using the following convention (CIOMS III):   very common (≥1/10); common (≥1/100, <1/10); uncommon (≥1/1000, <1/100); rare (≥1/10.000, <1/1000); very rare (<1/10.000),not known (the frequency cannot be established on the basis of available data).

Table 1

Adverse reactions from post-marketing spontaneous reports and literature cases

(frequency not known)

Because these reactions are reported voluntarily from a population of uncertain abundance, it is not possible to reliably estimate their frequency which is then categorized as not known. Adverse reactions are listed by system organ classes in MedDRA.  Within each class, adverse reactions are arranged in order of decreasing seriousness.

Nervous system disorders

Cerebrovascular accident, paraesthesia.

Cardiac disorders

Ventricular fibrillation, ventricular tachycardia, angina pectoris, atrioventricular block.

--To reports any side effect(s):

·         Saudi Arabia:

--Saudi Food and Drug Authority National Pharmacovigilance Center (NPC):

o Fax: +966-11-205-7662

o Call NPC at +966-11-2038222, Exts: 2317-2356-2340.

o Toll free phone: 8002490000

o SFDA call center: 19999

o E-mail: npc.drug@sfda.gov.sa

o Website: https://ade.sfda.gov.sa

--Patient Safety Department Novartis Consulting AG - Saudi Arabia:

o Toll Free Number: 8001240078

o Phone: +966112658100

o Fax: +966112658107

o Email: adverse.events@novartis.com

·         Other GCC States:

-- Please contact the relevant competent authority.

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

Treatment: Eliminate the drug ingested orally by administering high doses of active carbon.

Symptomatic    treatment          includes           careful cardiovascular  and      respiratory monitoering. If sedation is required, the benzodiazepines can be used.

In  the  case  of  arterial  spasm,  a  vasodilator  such  as  sodium  nitroprusside, phentolamine or dihydralazine should be administered. In the case of coronary constriction, appropriate anti-anginal treatment (e.g. nitrates) should be given.

Medication errors

It has been reported accidental administration to infants.  In these cases of accidental  overdose  in  the  neonate  have  been  reported  symptoms  such  as shortness  of  breath,  convulsions,  cyanosis,  oliguria  and  peripheral vasocostriction. Furthermore, encephalopathy has been reported in infants presenting with signs and symptoms such as irritability, agitation and lethargy. Treatment should be symptomatic; in severe cases were required respiratory support and cardiovascular systems. In the absence of proper treatment, have been reported fatal cases (see section 4.4).

- Pharmacotherapeutic group: oxytocics - Ergot alkaloids. ATC code: G02AB01.

 Mechanism of action:

Methylergometrine, a semi-synthetic derivate of the natural ergometrine alkaloid, is a potent and specific uterotonic agent.

It acts directly on the smooth musculature of the uterus by increasing its basal tone, and the frequency and amplitude of rythmic contractions. Its effects on the central nervous system and cardiovascular apparatus are less pronounced than those of other ergot alkaloids.

- Pharmacodynamic effects.

The potent and selective oxytocic effect of methylergometrine is a result of its specific mechanism of action and as a partial agonist and antagonist of serotoninergic, dopaminergic and -adrenergic receptors. However, this does not completely preclude the possibility of complications due to vasoconstriction (see 4.8).

For the prevention and treatment of bleeding uterine by im injection, can be considered the association of Methergin and oxytocin, as oxytocin presents a very short latency period, while the methylergometrine possesses a prolonged duration of action.

Methergin acts 30-60 seconds after administration, 2-5 minutes after administration, and 5-10 minutes after oral administration, and its duration of action is 4-6 hours.

Absorption: Studies of fasting healthy female volunteers have shown that the oral absorption of a 0.2 mg tablet is quite rapid, and leads to mean peak plasma concentrations (Cmax) of 3243+1308 pg/ml in 1.12+0.82 hours (tmax). After the intramuscular injection of 0.2 mg, Cmax is 5918+1952 pg/ml andl tmax 0.41+0.21 hours. The bioavailability of the tablets is equivalent to that of the injectable solution administered orally, and is dose-dependent after the administration of 0.1, 0.2 and 0.4 mg.

After an intramuscular injection, absorption is 25% greater than after oral administration. Delayed gastrointestinal absorption has been observed in post- partum patients receiving continuous treatment with Methergin tablets (a tmax of about 3 hours).

Distribution: After intravenous administration, methylergometrine is rapidly distributed from the plasma to the peripheral tissues within 2-3 minutes or even less. In healthy female volunteers distribution volume is 56.1+17.0 litres. It is not known whether the drug crosses the blood/brain barrier.

Biotransformation: Methylergometrine is mainly metabolised in the liver. Its metabolic pathway has not been studied in humans. In vitro studies have shown the N-demethylation and hydroxylisation of the phenyl ring.

Elimination:   Plasma   clearance in   healthy   female   volunteers   is   14.4+4.5 litres/hour, and the the mean elimination half-life is 3.29+1.31 hours. A study of male volunteers has shown that only 3% of an oral dose is eliminated as unchanged drug in urine. The methylergometrine is also excreted in breast milk. After 1 h after administration of a single dose of 250 micrograms of methylergonovine, the ratio of concentrations milk / plasma was 0.18 + 0.03. The half-life of methylergometrine reported in milk was 2.3 + 0.3 h.

Linearity / non-linearity: The bioavailability of the tablet is shown to be proportional to the dose.

Studies of bioavailability/bioequivalence:  the bioavailability of the tablet is shown to be equivalent to that of the solution i.m. administered orally.

The genotoxic potential of methylergometrine has not been determined. There are no available studies that have evaluated the carcinogenic potential of methylergonovine. Have not been performed standard studies on fertility and reproductive toxicity in animals methylergometrine.

METHERGIN 0.2 mg/ml injectable solution

Maleic acid, sodium chloride, water for injectable preparations.

METHERGIN 0.125 mg coated tablets

Maleic acid, gelatine, stearic acid, talc, maize starch, lactose monohydrate, red iron oxide, anhydrous colloidal silica, gum arabic, sucrose.

None  known.

Methergin 0.2 mg/ml injectable solution:

Store at a temperature of between 2°C and 8°C. Do not freeze.

Keep ampoules in the outer carton to protect against the light.

Do not store at a temperature of more 25°C for longer than two weeks.

Methergin 0.125 mg coated tablets:

This medicine does not require any special storage conditions.

METHERGIN 0.2 mg/ml injectable solution

Glass ampoule - 5 ampoules of 1 ml

METHERGIN 0.125 mg coated tablets

Blister - 30 coated tablets

No particular instructions