Source: Health Products Regulatory Authority (ZA) Revision Year: 2021 Publisher: Ranbaxy Pharmaceuticals (Pty) Ltd, 14 Lautre Road, Stormill Ext.1, Roodepoort, Johannesburg
Category and class: A 21.12 Hormones and antihormones and oral hypglycaemics – Hormone inhibitors.
Pharmacotherapeutic group: Other sex hormone and modulator of the genital system/antiprogestogen
ATC code: G03XB51
Mifepristone is a synthetic steroid with an anti-progestational action as a result of competition with progesterone at the progesterone receptors.
At doses ranging from 3 to 10 mg/kg orally, it inhibits the action of endogenous or exogenous progesterone in different animal species (rat, mouse, rabbit and monkey). This action is manifested in the form of pregnancy termination in rodents.
In women at doses of greater than or equal to 1 mg/kg, mifepristone antagonises the endometrial and myometrial effects of progesterone. During pregnancy it sensitises the myometrium to the contraction-inducing action of prostaglandins. The maximum effect is achieved when prostaglandin was administered 36 to 48 hours after mifepristone.
Mifepristone induces softening and dilatation of the cervix; softening and dilatation has been shown to be detectable from 24 hours after administration of mifepristone and increases to a maximum at approximately 36-48 hours after administration.
Mifepristone binds to the glucocorticoid receptor. In animals at doses of 10 to 25 mg/kg it inhibits the action of dexamethasone. In man the antiglucocorticoid action is manifested at a dose equal to or greater than 4,5 mg/kg by a compensatory elevation of ACTH and cortisol. Glucocorticoid bioactivity (GBA) may be depressed for several days following a single administration of 200 mg mifepristone for termination of pregnancy. The clinical implications of this are unclear, however vomiting and nausea may be increased in susceptible women.
Mifepristone has a weak anti-androgenic action which only appears in animals during prolonged administration of very high doses.
Pharmacotherapeutic group: Oxycytotoxics/prostaglandins
ATC code: G02AD06
Misoprostol is a synthetic analogue of prostaglandin E1. At the recommended dosages, misoprostol induces contractions of the smooth muscle in the myometrium and laxation of the uterine cervix. The uterotonic properties of misoprostol should facilitate cervical opening and evacuation of the product of conception.
When administered vaginally, the increase in uterine tonus begins after about 20 minutes and reaches its maximum after 46 minutes. Uterine contractility increases continuously for four hours after vaginal administration. Vaginal administration of misoprostol induces far more powerful and regular contractions than does oral administration.
In the event of an early termination of pregnancy, the combination of a prostaglandin analogue used in a sequential regimen after mifepristone leads to the expulsion of the conceptus. In clinical trials, the success rate is around 95 % when 200 mg mifepristone is combined with misoprostol 0,8 mg vaginally up to 63 days of amenorrhoea.
The table shows the outcome of treatment with regard to complete abortion, incomplete/missed abortion and continuing pregnancy by duration of amenorrhea from the pivotal study performed by the WHO.
| Days of amenorrhoea | Complete abortion | Incomplete abortion | Missed abortion | Continuing pregnancy | Undetermined outcome | |||||
|---|---|---|---|---|---|---|---|---|---|---|
| N | % | N | % | N | % | N | % | N | % | |
| <49 | 214 | 95,5 | 5 | 2.2 | 0 | 0 | 2 | 0,9 | 3 | 1,3 |
| 50-57 | 227 | 93,0 | 11 | 4,5 | 0 | 0 | 0 | 0 | 6 | 2,5 |
| >57-<63 | 249 | 92,2 | 15 | 5,6 | 0 | 0 | 0 | 0 | 6 | 2,5 |
After oral administration of a single dose of 600 mg mifepristone is rapidly absorbed. The peak concentration of 1,98 mg/L is reached after 1,30 hours (means of 10 subjects).
There is a non-linear dose response with doses of 100 mg and beyond. After a distribution phase, elimination is at first slow, the concentration decreasing by a half between about 12 and 72 hours, and then more rapid, giving an elimination half-life of 18 hours. With radioreceptorassay techniques, the terminal half-life is of up to 90 hours, including all metabolites of mifepristone able to bind to progesterone receptors.
After administration of low doses of mifepristone (20 mg orally or intravenously), the absolute bioavailability is 69%.
In plasma mifepristone is 98% bound to plasma proteins: albumin and principally alpha-1-acid glycoprotein (AAG), to which binding is saturable. Due to this specific binding, volume of distribution and plasma clearance of mifepristone are inversely proportional to the plasma concentration of AAG.
N-Demethylation and terminal hydroxylation of the 17-propynyl chain are primary metabolic pathways of hepatic oxidative metabolism.
Mifepristone is mainly excreted in faeces. After administration of a 600 mg labelled dose, 10% of the total radioactivity is eliminated in the urine and 90% in the faeces.
On vaginal administration, the plasma concentrations of misoprostol acid (i.e. its pharmacologically active metabolite) peak in 1-2 hours and then decline slowly, resulting in the sustained plasma levels up to 4 hours.
The liver is the primary site of metabolism and less than 1% of misoprostol acid is excreted in the urine.
The rate and extent of absorption of the misoprostol vaginal tablets in the MEDABON CO formulation is approximately 70% higher when compared to a marketed misoprostol formulation.
The metabolites of misoprostol acid are inactive and the majority of the dose is excreted as metabolites to misoprostol and misoprostol acid in the urine.
The serum protein binding of misoprostol acid is approximately 90% and is concentration independent at therapeutic doses.
No further information of relevance available.
© All content on this website, including data entry, data processing, decision support tools, "RxReasoner" logo and graphics, is the intellectual property of RxReasoner and is protected by copyright laws. Unauthorized reproduction or distribution of any part of this content without explicit written permission from RxReasoner is strictly prohibited. Any third-party content used on this site is acknowledged and utilized under fair use principles.
