Key points from the evidence

The content of this evidence summary was up-to-date in March 2014. See summaries of product characteristics (SPCs), British national formulary (BNF) or the MHRA or NICE websites for up-to-date information.

Summary

In a randomised controlled trial of 1358 women, the misoprostol vaginal delivery system (controlled-release vaginal insert) statistically significantly reduced the time to vaginal delivery and reduced the need for oxytocin compared with the dinoprostone controlled-release vaginal insert. The rate of caesarean delivery was similar in both treatment groups, but the pre-specified criterion for non-inferiority to dinoprostone was not met. Overall, there were no significant differences between the treatment groups in the proportions of women or neonates who experienced adverse events, although there were some statistically significant differences in individual adverse events. For example, uterine hyperstimulation was significantly more common in women receiving the misoprostol vaginal insert.

Effectiveness

  • In the study, compared with the dinoprostone vaginal insert, the misoprostol vaginal insert statistically significantly reduced:

    • the median time to vaginal delivery by 11.3 hours (p<0.001)

    • the median time to any delivery (vaginal or caesarean) by 9.0 hours (p<0.001)

    • the median time to active labour by 6.5 hours (p<0.001), and

    • the need for oxytocin by 26% (p<0.001).

Safety

  • In the study, the rate of caesarean delivery was similar in both treatment groups (26–27%; p=0.65) but the pre-specified criterion for non-inferiority to dinoprostone was not met.

  • Uterine tachysystole with fetal heart rate changes or tachysystole requiring intervention was 3 times higher with misoprostol compared with dinoprostone (13.3% compared with 4.0%, p<0.001).

  • The summary of product characteristics states that the most common adverse events are abnormal uterine contractions, fetal heart rate disorder, abnormal labour affecting the fetus and meconium in the amniotic fluid.

Patient factors

  • Prolonged labour is associated with higher infection rates, greater use of antibiotics and oxytocin, and increased maternal distress.

  • The time to delivery is important to women undergoing induction of labour, as are other outcomes such as the time to active labour.

Resource implications

  • The cost of the misoprostol controlled-release vaginal insert is expected to be about £93. The costs of the dinoprostone vaginal gel, tablet and controlled-release insert range from £13.28 to £30.00.

  • Prolonged labour is associated with more demands on hospital resources.

  • Health economic analyses of the misoprostol vaginal insert are expected to be published later in 2014.

Key points

In November 2013, a UK marketing authorisation was granted for the misoprostol controlled-release vaginal delivery system (Mysodelle) for the induction of labour in women with an unfavourable cervix, from 36 weeks' gestation, in whom induction is clinically indicated. The manufacturer has advised that the UK launch is expected in quarter 4, 2014 (Ferring Pharmaceuticals: personal communication, January 2014).

Currently, only short-acting oral preparations of misoprostol are available and none is licensed for the induction of labour in the UK. In practice, oral misoprostol tablets are sometimes administered vaginally to induce labour. The tablets must be cut or made into suspension to achieve lower doses. Use of the oral preparations in this way is off-label.

EXPEDITE was a phase III, double-blind, randomised multicentre study that compared the efficacy and safety of a 200 microgram misoprostol controlled-release vaginal insert and a 10 mg dinoprostone controlled-release vaginal insert in 1358 women undergoing induction of labour. The study found that the median time to vaginal delivery (the primary efficacy outcome) was statistically significantly reduced by 11.3 hours in women who received misoprostol compared with dinoprostone. The median time from study drug administration to vaginal delivery was 21.5 hours (95% confidence interval [CI] 20.0 to 23.4 hours) for the misoprostol vaginal insert and 32.8 hours (95% CI 30.2 to 34.9 hours) for the dinoprostone vaginal insert (p<0.001).

Statistically significant improvements were also seen in the 3 key secondary efficacy end points. The median time to any delivery (vaginal or caesarean) was reduced by 9.0 hours (p<0.001); the median time to active labour was reduced by 6.5 hours (p<0.001); and the proportion of women requiring pre-delivery oxytocin was reduced by 26% (p<0.001) in women receiving the misoprostol vaginal insert compared with the dinoprostone vaginal insert.

In EXPEDITE, the rate of caesarean delivery (the primary safety end point) was similar in the misoprostol and dinoprostone groups (26.0% compared with 27.1%; difference −1.10%, 95% CI −5.79% to 3.59%; p=0.65). However, non-inferiority of the misoprostol vaginal insert to the dinoprostone vaginal insert could not be concluded because the upper limit of the 95% CI (3.59%) exceeded the pre-specified non-inferiority margin (2.71%).

Overall, there were no statistically significant differences between the treatment groups in the proportions of women or neonates who experienced adverse events, although there were some statistically significant differences in individual adverse events. The rate of uterine tachysystole with category II (indeterminate, requiring evaluation and surveillance) and category III (abnormal and requiring prompt evaluation) fetal heart rate changes or tachysystole requiring intervention (uterine hyperstimulation) was 3 times higher with misoprostol vaginal inserts compared with dinoprostone vaginal inserts (13.3% compared with 4.0%; relative risk 3.34, 95% CI 2.20 to 5.07; p<0.001). However, rates of fetal heart rate category II and category III patterns were not statistically significantly different between the misoprostol and dinoprostone vaginal inserts.

Tocolysis use and meconium in the amniotic fluid were seen more often in the misoprostol group (both p<0.05). Arrested labour, chorioamnionitis, and intrapartum and postpartum intravenous or intramuscular antibiotic use were more common in the dinoprostone group (all p<0.05). There was no significant difference between the groups in the rate of admission to neonatal intensive care.

The EXPEDITE study was well designed and well reported, and allocation was concealed. However, the inclusion and exclusion criteria limit the generalisability of the results. For example, women aged under 18 years, women with multiple pregnancies or more than 3 previous vaginal deliveries, and women with fetal malpresentation were not included. In addition, the study was too small to assess the likelihood of rare, serious adverse perinatal and maternal complications. Post-marketing surveillance will be very important to detect potential adverse effects.

The misoprostol vaginal insert is expected to cost about £93. This is more than the costs for dinoprostone vaginal gel, tablet and controlled-release inserts, which range from £13.28 to £30.00. Although there is evidence that misoprostol reduces the median time to delivery compared with dinoprostone, it is not known whether this will have economic benefits for obstetric units by reducing the use of resources (for example, staffing) and the total cost of inducing labour, compared with current management. Health economic analyses of the misoprostol vaginal insert are expected to be published later in 2014.

The NICE clinical guideline on induction of labour (NICE clinical guideline 70) states that misoprostol (a prostaglandin E1) should only be offered as a method of induction of labour to women who have had an intrauterine fetal death or in the context of a clinical trial. If induction of labour is clinically justified, NICE states that vaginal prostaglandin E2 (dinoprostone gel, tablet or controlled-release insert) is the preferred method, unless there are specific clinical reasons for not using it (in particular the risk of uterine hyperstimulation). The results of EXPEDITE suggest that the risk of uterine hyperstimulation is higher with the misoprostol vaginal insert than with the dinoprostone vaginal insert.

Key evidence

Wing DA, Brown R, Plante LA et al. (2013) Misoprostol vaginal insert and time to vaginal delivery: a randomized controlled trial. Obstetrics & Gynecology 122: 201–9

Update

The following information has become available since this ESNM was produced.

November 2014: Availability of misoprostol vaginal delivery system

The misoprostol vaginal delivery system has been launched in the UK as Mysodelle 200 micrograms vaginal delivery system. The cost of Mysodelle (excluding VAT) is £465.00 for 5 delivery systems. Cost taken from MIMS, November 2014.

About this evidence summary

'Evidence summaries: new medicines' provide summaries of key evidence for selected new medicines, or for existing medicines with new indications or formulations, that are considered to be of significance to the NHS. The strengths and weaknesses of the relevant evidence are critically reviewed within this summary to provide useful information for those working on the managed entry of new medicines for the NHS, but this summary is not NICE guidance.