Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2017 Publisher: Ferring Pharmaceuticals Ltd, Drayton Hall, Church Road, West Drayton, UB7 7PS, (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 Mysodelle.
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.
The phase III pivotal study, (Miso-Obs-303: The EXPEDITE study), was a double-blind, randomised, multicentre study conducted in the US with 1,358 pregnant women. The study compared the efficacy and safety of Mysodelle to the 10 mg dinoprostone vaginal delivery system (PROPESS). Nulliparous and parous women with an unfavourable cervix (modified Bishop score ≤ 4) were randomly assigned to receive Mysodelle or PROPESS® for up to 24 hours treatment. The co-primary efficacy endpoint of the study was time to vaginal delivery and the co-primary safety endpoint was the incidence of Caesarean deliveries.
Table 2 presents the key primary and secondary data endpoints from this study.
Table 2 Miso-Obs-303: The EXPEDITE Study Key Endpoint Results
| Mysodelle 200 mcg (N=678) | PROPESS 10mg (N=680) | p-value | |
|---|---|---|---|
| Median time to Vaginal Delivery of Neonate (hours)* | 21.5h** | 32.8h** | p < 0.001 |
| Nulliparous Subjects | 29.2 h (n=441) | 43.1 h (n=451) | p < 0.001 |
| Parous Subjects | 13.4 h (n=237) | 20.1 h (n=229) | p < 0.001 |
| Incidence of Caesarean Delivery (n%) | 176 (26.0%) | 184 (27.1%) | p = 0.646 |
| Nulliparous Subjects | 152 (34.5%) | 168 (37.3%) | p = 0.386 |
| Parous Subjects | 24 (10.1%) | 16 (7.0%) | p = 0.226 |
| Median time to Overall Delivery of the Neonate* (Vaginal and Caesarean) (h) | 18.3h† | 27.3h† | p < 0.001 |
| Overall Median time to Onset of Active Labour (hours)* | 12.1h†† | 18.6h†† | p < 0.001 |
| Overall number of Subjects who received Pre-delivery Oxytocin [n(%)] | 324 (48.1%) (N=674) | 497 (74.1%) (N=671) | p < 0.001 |
* Subjects who had a caesarean delivery, were discharged prior to delivery or withdrew consent during the first hospitalisation were censored using the longest time interval from study drug administration to caesarean delivery or to labour and delivery discharge (Kaplan Meier estimates).
** Summary of median time to vaginal delivery (only subjects who delivered vaginally): Mysodelle, 200 mcg: 16.6 h; PROPESS 10 mg: 25.1 h
† Summary of median time to any delivery: Mysodelle, 200 mcg: 18.2 h; PROPESS® 10 mg: 27.2 h
†† Summary of median time to onset of active labour: Mysodelle, 200 mcg: 12.0 h; PROPESS® 10 mg: 18.0 h
The European Medicines Agency has waived the obligation to submit results of clinical studies with Mysodelle 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 to inactive dinor and tetranor acid metabolites prior to excretion in the urine.
In non-pregnant women, the Mysodelle vaginal delivery system has a controlled mean in vivo release rate of approximately 7 micrograms/hour over a period of 24 hours. In a study of 24 pregnant women at term gestation, a median Cmax of 45.8 pg/mL with a median Tmax of 4 hours was observed. Median terminal half-life (after removal of the insert) was approximately 40 minutes.
The serum protein binding of misoprostol acid is less than 90% and concentration independent at therapeutic doses.
The active component in Mysodelle, misoprostol, revealed no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity and carcinogenicity.
No teratogenic effects of misoprostol were observed in rats at dosages up to 10 mg/kg/day. In rabbits, an increase in fetuses with extra ribs was observed at a dosage of 1 mg/kg/day, probably associated with maternal toxicity at this dose level. At near lethal dose levels to the fetal mice, various fetal defects were observed. There is evidence of a possible adverse effect of misoprostol on implantation and the No Observed Adverse Effect Level was found to be 0.4 mg/kg/day in fertility and early embryonic development studies in rats. The above mouse and rat findings are of no concern for Mysodelle as it is contraindicated for use prior to 36 weeks of gestation.
Peri/post natal toxicity studies in rats identified a no-effect dosage for effects of oral misoprostol on reproductive parameters to 1.0 mg/kg/day. By comparing exposure in rat and human kinetic studies, a safety factor of 20 is established for Mysodelle delivered as a 200 mcg dose in the form of a miniature version of the misoprostol vaginal delivery system.
There was no evidence of local irritation in the vagina or cervix following administration of Mysodelle to pregnant rats.
There are no hazards for humans regarding systemic toxicity for the hydrogel polymers, the polyester retrieval system and excipients based on conventional in vitro and in vivo testing and published toxicity data. Finally, the hydrogel polymers and polyester retrieval system are comprised of inert compounds with good local tolerability.
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