Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2020 Publisher: Norgine Pharmaceuticals Limited, Norgine House, Widewater Place, Moorhall Road, Harefield, Uxbridge, UB9 6NS, UK
Pharmacotherapeutic group: Other gynaecologicals, oxytocics, prostaglandins
ATC-code: G02AD06
Misoprostol is a synthetic analogue of Prostaglandin E1 (PGE1), a naturally occurring oxytocic compound. Prostaglandins of the F and E series have been shown to increase collagenase activity in rabbit uterine cervix fibroblasts in vitro and to cause cervical ripening and uterine contraction in vivo. These pharmacodynamic effects are considered to be the mechanism of action relevant for the clinical effect of Angusta
PGE analogues also have a number of other effects, e.g. relaxation of bronchial and tracheal muscles, increase of mucus secretion and decrease of acid and pepsin secretion in the stomach, increase of renal blood flow, increase of circulating concentrations of adrenocorticotropic hormone and prolactin. These pharmacodynamic effects are considered to be of no clinical importance with the short treatment.
Knowledge about efficacy and safety is based on meta-analyses of 4 clinical studies where 637 women were exposed to the dosing regimen, oral misoprostol 20-25 µg 2-hourly.
| Comparator | Number of studies | Exposure to oral misoprostol 20 or 25 µg 2-hourly |
|---|---|---|
| Oxytocin | 2 | 169 women |
| Dinoprostone1 | 2 (one double-blind) | 468 women (365 in double-blind study) |
1 Dinoprostone administered vaginally
In three of the trials (596 women), the main inclusion criterion was term pregnancy. For one trial (41 women), the main inclusion criterion was term pregnancy and Prelabour Rupture of Membranes (PROM). The double-blind trial, Dodd 2006 is considered pivotal and is described in detail in the following.
Dodd 2006 was a randomised double-blind, double-dummy, active-controlled (vaginal dinoprostone gel) study (N=365/376). Women at term pregnancy (> 36 weeks + 6 days) with singleton pregnancies in cephalic presentation without complications and Bishop score <7 were eligible. The primary endpoints were vaginal delivery not achieved within 24 hours, uterine hyperstimulation with fetal heart rate change (FHR) and caesarean sections.
There was no statistically significant difference between oral misoprostol and vaginal dinoprostone with regards to vaginal delivery not achieved within 24 hours (oral misoprostol 168/365 (46.0%) v dinoprostone 155/376 (41.2%); relative risk 1.12, 95% confidence interval 0.95 to 1.32; P = 0.134).
There was a lower (not statistically significant) risk in the oral misoprostol group for uterine hyperstimulation with fetal heart rate changes, caesarean section and low Apgar score. There was a statistically significant lower risk of uterine hyperstimulation without fetal heart rate changes in women treated with oral misoprostol. There was no difference in the secondary outcomes such as neonatal cord pH and blood loss.
Knowledge about efficacy and safety is based on meta-analyses of 23 clinical trials where 2,515 women were exposed to the dosing regimen, oral misoprostol 50 µg 4-hourly.
| Comparator | Number of studies | Exposure to oral misoprostol 50 µg 4-hourly |
|---|---|---|
| Placebo | 3 (two double-blind) | 247 women (97 in double-blind studies) |
| Oxytocin | 2 | 91 women |
| Dinoprostone1 | 3 | 155 women |
| Vaginal misoprostol | 10 (three double-blind) | 867 women (215 in double-blind studies) |
| Other comparators2 | 5 (one double-blind) | 1155 women (32 in double-blind study) |
1 Dinoprostone administered vaginally or intracervically
2 Titrated oral misoprostol, higher dose oral misoprostol, combinations of oxytocin and PGE gel and Foley Catheter
The main inclusion criterion in all three placebo controlled trials was PROM.
In one study comparing against oxytocin, the main inclusion criterion was PROM (55 women) and in the other study the main inclusion criterion was term pregnancy (36 women).
All three studies comparing against dinoprostone (administered vaginally or intracervically) were open label studies. In one study, the main inclusion criterion was PROM (31 patients) whereas the main inclusion criterion was term pregnancy (124 women) for the other two studies.
Three of the studies comparing against vaginal misoprostol were double blind studies (215 women were exposed). In one double-blind study, the main inclusion criterion was PROM (51 women). In the two other double-blind studies, the main inclusion criterion was term pregnancy (164 women). The remaining seven studies were open label studies with the main inclusion criterion being term pregnancy (652 women).
An additional 5 studies (1155 women) compared to various comparators such as titrated misoprostol, higher dose misoprostol, combinations of oxytocin and PGE gel; and Foley Catheter. These trials are supportive for safety, only.
The double-blind trials Bennett 1998 and Levy 2007 are considered pivotal and are described in detail in the following.
Bennett 1998 was a randomized double-blind active controlled (vaginal misoprostol) study (N=104/102) comparing oral to vaginal use of 50 μg of misoprostol administered every 4 hours in women at term with intact membranes. The study stratified for low (<7) or high (≥7) Bishop score. The primary endpoint was time from induction to vaginal birth. Other endpoints were frequency of excessive uterine activity resulting in abnormal fetal heart rate (FHR), neonatal morbidity (as measured by cord blood acid-base analysis and ACOG criteria for birth asphyxia), caesarean birth, maternal gastrointestinal side effects, and patient satisfaction.
Time from induction to delivery was statistically significantly shorter with vaginal misoprostol than with oral misoprostol (14.1 hours vs 17.9 hours, p=0.004).
For other outcomes, such as risk of uterine hyperstimulation with fetal heart rate changes and caesarean section, there was a lower (not statistically significant) risk in the oral misoprostol group. There was a statistically significantly lower risk of uterine hyperstimulation without fetal heart rate changes in the oral misoprostol group.
Levy 2007 was a double-blind study (N=64/66) investigating the 50 µg 4-hourly posology against placebo in women with prelabour rupture of membranes (PROM). The primary endpoint was delivery within 24 hours from PROM.
The time to delivery was statistically significantly shortened with oral misoprostol compared to placebo with only a slight (not statistically significant) increase in the frequency of uterine hyperstimulation. For other safety outcomes, such as risk of caesarean section, there appeared to be a lower risk in the oral misoprostol group (not statistically significant). No neonates had an Apgar score less than 7 at 5 min.
The clinical study (AZ-201) supports the safety and efficacy of Angusta for induction of labour.
The European Medicines Agency has waived the obligation to submit results of clinical studies with Angusta in all subsets of the paediatric population in labour induction, in the granted indication (see section 4.2 for information on paediatric use).
Misoprostol, an ester, is rapidly metabolised to its active metabolite misoprostol acid. Only misoprostol acid is detectable in plasma. The acid is further metabolised by beta fatty acid oxidation to inactive dinor and tetranor acid metabolites prior to excretion in the urine.
After oral administration of Angusta, misoprostol is rapidly absorbed, with peak plasma levels of the active metabolite (misoprostol acid) occurring after approximately 30 minutes. The mean plasma elimination half-life of misoprostol acid is approximately 45 minutes.
The dose normalized AUC following 25 and 50 µg misoprostol (Angusta) were not statistically significantly different. Mean±SD were 107.8±53.16 and 128.1±45.60 h∙pg/ml, respectively.
The serum protein binding of misoprostol acid is less than 90% and concentration independent at therapeutic doses.
Administration of misoprostol with food does not change the bioavailability of misoprostol acid, but reduces the maximum plasma concentration due to a slower absorption rate.
There are studies showing a trend towards higher Cmax, AUC and t½ in patients with renal or hepatic impairment. See sections 4.2, 4.3 and 4.4
Published literature on misoprostol studies of safety pharmacology, acute and repeated dose toxicity, mutagenicity, carcinogenicity and reproductive toxicity reveals no special hazard for humans.
In humans, misoprostol exposure in early pregnancy (failed, early medication pregnancy termination) has been associated with multiple congenital defects. Since teratogenicity studies do not confirm direct teratogenic effects of misoprostol, these malformations are thought to be due to vascular disruption and disturbed blood supply to the developing embryo secondary to uterine contractions caused by misoprostol administered for medication pregnancy termination.
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