Mefnil

Uses

Mefnil is used for:

• As a medical alternative to surgical termination of intra-uterine pregnancy
• Softening and dilatation of the cervix uteri prior to surgical pregnancy termination
• Preparation for the action of prostaglandin analogues in the termination of pregnancy for medical reasons
• Labour induction for the expulsion of a dead fetus (fetal death in utero).

Mefnil is also used to associated treatment for these conditions: Hyperglycemia, Pregnancy Termination

How Mefnil works

The anti-progestational activity of mifepristone results from competitive interaction with progesterone at progesterone-receptor sites. Based on studies with various oral doses in several animal species (mouse, rat, rabbit and monkey), the compound inhibits the activity of endogenous or exogenous progesterone. The termination of pregnancy results.

In the treatment of Cushing's syndrome, Mefnil blocks the binding of cortisol to its receptor. It does not decrease cortisol production but reduces the effects of excess cortisol, such as high blood sugar levels.

Dosage

Mefnil dosage

As a medical alternative to surgical termination of intra-uterine pregnancy in early pregnancy: 600 mg Mefnil in a single oral dose followed 36-48 hrs later, by the administration of a prostaglandin analogue Misoprostol 400 mcg orally (up to 49 days) or Gemeprost 1 mg vaginally (up to 63 days).

Softening and dilatation of the cervix uteri prior to surgical pregnancy termination: 200 mg Mefnil, followed 36-48 hrs later (but not beyond) by a surgical termination of pregnancy.

Preparation for the action of prostaglandin analogues in the termination of pregnancy for medical reasons (to reduce the doses of prostaglandin): 600 mg of Mefnil taken in a single oral dose, 36-48 hrs prior to scheduled prostaglandin administration which will be repeated as often as indicated.

Labour induction for expulsion of a dead fetus (fetal death in utero): 600 mg of Mefnil in a single oral daily dose for 2 consecutive days. Mefnil alone leads to expulsion in about 60%. Labour should be induced by the usual methods if it has not started within 72 hrs following the first administration of Mefnil.

There are no precautions for timing in relation to food.

Side Effects

It is very common for women to experience uterine contractions or cramping (10-45%) in the hours following prostaglandin intake. Bleeding increases with gestational age. Heavy bleeding occurs in about 5% of cases and from 0-1.4% may require haemostatic curettage. Uterine rupture, hypotension, skin rashes, urticaria, hot flashes and dizziness have been uncommonly reported.

Toxicity

Nearly all of the women who receive mifepristone will report adverse reactions, and many can be expected to report more than one such reaction. About 90% of patients report adverse reactions following administration of misoprostol on day three of the treatment procedure. Side effects include more heavy bleeding than a heavy menstrual period, abdominal pain, uterine cramping, nausea, vomiting, and diarrhea.

Precaution

Mefnil is available only in single dose packaging. Administration must be under the supervision of a qualified physician. There are no data on the safety and efficacy of Mefnil in women with chronic medical conditions such as cardiovascular, hypertensive, hepatic, respiratory or renal disease; insulin-dependent diabetes mellitus; severe anemia or heavy smoking. Women who are more than 35 years of age and who also smoke 10 or more cigarettes per day should be treated with caution because such patients were generally excluded from clinical trials of Mefnil. Although there is no clinical evidence, the effectiveness of Mefnil may be lower if Misoprostol is administered more than two days after Mefnil administration.

Interaction

ketoconazole, itraconazole, erythromycin and grapefruit juice may inhibit its metabolism (increasing serum levels of mifepristone). Furthermore, rifampicin, dexamethasone, St John's Wort and certain anticonvulsants (phenytoin, phenobarbital, carbamazepine) may induce mifepristone metabolism (lowering serum levels of Mefnil). Based on invitro inhibition information, co-administration of mifepristone may lead to an increase in serum levels of drugs that are CYP3A4 substrates.

Limited evidence suggests that co-administration of NSAIDs on the day of prostaglandin administration does not adversely influence the effects of Mefnil or the prostaglandin on cervical ripening or uterine contractility and does not reduce the clinical efficacy of medical termination of pregnancy.

Food Interaction

• Avoid grapefruit products. Grapefruit inhibits the metabolism of mifepristone through the CYP3A4 pathway causing increased serum levels of mifepristone.
• Take with food. Taking mifepristone with meals has been shown to increase serum levels of mifepristone.

[Moderate] ADJUST DOSING INTERVAL: Food may significantly increase the plasma concentrations of mifepristone.

GENERALLY AVOID: Grapefruit juice may increase the plasma concentrations of mifepristone.

The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit.

Because pharmacokinetic interactions involving grapefruit juice are often subject to a high degree of interpatient variability, the extent to which a given patient may be affected is difficult to predict.

MANAGEMENT: When mifepristone is used daily to control hyperglycemia secondary to hypercortisolism in patients with endogenous Cushing's syndrome, it should be taken with food to achieve consistent plasma drug levels.

Patients should be advised to avoid consuming grapefruit or grapefruit juice during treatment with mifepristone, as it may cause increased adverse effects such as headache, dizziness, fatigue, nausea, vomiting, cramping, diarrhea, hypokalemia, adrenal insufficiency, vaginal bleeding, arthralgia, peripheral edema, and hypertension.

Because mifepristone is eliminated slowly from the body, the interaction with grapefruit juice may be observed for a prolonged period.

Mefnil Drug Interaction

Major: heparin, methylergonovine, promethazine, oxytocinModerate: losartan, testosterone, tamsulosinUnknown: amphetamine / dextroamphetamine, amphetamine / dextroamphetamine, multivitamin, dextran, low molecular weight, cabergoline, aspirin, acetaminophen / aspirin / caffeine, acetaminophen, omeprazole, levothyroxine, ascorbic acid, cholecalciferol, cetirizine

Mefnil Disease Interaction

Major: organ transplant, vaginal bleedingModerate: cardiovascular disease, hepatic impairment, long QT, renal impairment

Elimination Route

The absolute bioavailability of a 20 mg oral dose is 69%

Half Life

18 hours

Elimination Route

Fecal: 83%; Renal: 9%.

Pregnancy & Breastfeeding use

Pregnancy: Mefnil is indicated for use in the termination of pregnancy (through 49 days’ pregnancy) and has no other approved indication for use during pregnancy.

Lactation: It is not known whether Mefnil is excreted in human milk. Many hormones with a similar chemical structure, however, are excreted in breast milk. Since the effects of Mefnil on infants are unknown, breast-feeding women should consult with their health care provider to decide if they should discard their breast milk for a few days following administration of the medications.

Contraindication

Mefnil must not be administered if there is doubt as to the existence or age of the pregnancy or if an extra-uterine pregnancy is suspected. An ultrasound scan and/or measurement of Beta-hCG must be performed before administration. For first trimester abortions, Mefnil is contraindicated if the pregnancy is beyond 49 days of amenorrhoea when used with Misoprostol, or beyond 63 days of amenorrhoea when used with Gemeprost. Mefnil should never be prescribed in patients with chronic adrenal failure, known allergy to Mefnil or to any component of the product, severe asthma uncontrolled by corticosteroid therapy, porphyrias and renal failure, liver failure or malnutrition, or during breast feeding. Mefnil is a lipophilic compound and may theoretically be excreted in the mother\'s breast milk, however no data is available.

Special Warning

Use in children: Safety and effectiveness in pediatric patients have not been established.

Acute Overdose

Single doses of Mefnil up to 2 gm caused no unwanted reaction. In the event of massive ingestion, signs of adrenal failure might occur. Acute intoxication may require admission to hospital and if relevant treatment with dexamethasone.

Storage Condition

Store at 25° C.

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