MYSODELLE Vaginal delivery system Ref.[7775] Active ingredients: Misoprostol

Mysodelle can cause excessive uterine tachysystole that may not respond to tocolytic treatment and that may not subside before delivery. Mysodelle can also cause excessive uterine stimulation if left in place after onset of active labour (see section 4.9).

Therefore, immediate removal of the vaginal delivery system should take place (see section 4.2):

• At the onset of labour: rhythmic, firm contractions of adequate quality that cause cervical change, and/or at the latest when cervical dilation is 4 cm, since excessive uterine contractions can occur.
• If prolonged or excessive uterine contractions occur
• If there is a clinical concern for the mother and/or baby
• When 24 hours have elapsed since insertion

Being prepared to administer tocolytic therapy is recommended and should this be needed, it can be administered without delay after removal of MYSODELLE.

In women with pre-eclampsia, evidence or suspicion of fetal compromise should be ruled out (refer to Section 4.3). Pregnant women with severe pre-eclampsia marked by Haemolytic anaemia; Elevated Liver enzymes; Low Platelet count (HELLP) syndrome, other end organ affliction or CNS findings other than mild headache were not studied in the pivotal Phase III trial (Miso-Obs-303; The EXPEDITE Study).

Mysodelle has not been studied in women whose membranes have been ruptured for more than 48 hours prior to the insertion of Mysodelle.

For women with positive Group B Streptococcus status requiring prophylactic antibiotics, careful consideration should be given regarding timing of antibiotic therapy in order to achieve adequate protection for the neonates. In the pivotal Phase III study (Miso-Obs-303; The EXPEDITE Study), the shortest observed time to any delivery was 2.95 hours.

Remove Mysodelle before oxytocin administration is initiated. Wait at least 30 minutes after removing Mysodelle before initiating oxytocin (see Sections 4.2, 4.3 and 4.5).

Mysodelle has only been studied in singleton pregnancies with cephalic presentation. No studies in multiple pregnancies have been performed. Mysodelle has not been studied in women with more than 3 previous vaginal deliveries after 24 weeks gestation.

Mysodelle should be used only when induction of labour is clinically indicated.

Mysodelle should be used with caution in patients with modified bishop score (mBS) >4.

A second dose of Mysodelle is not recommended, as the effects of a second dose have not been studied.

An increased risk of post-partum disseminated intravascular coagulation has been described in patients whose labour has been induced by any physiological or pharmacological method.

Butylated hydroxyanisole is used as an antioxidant in the cross-linked hydrogel polymer. It is only present in trace amounts in the final drug product. Butylated hydroxyanisole can cause skin reactions (e.g. contact dermatitis), or irritation to the eyes and mucous membranes.

No interaction studies have been performed with Mysodelle.

Concurrent use of oxytocic drugs or other labour induction agents is contraindicated due to the potential of increased uterotonic effects (see Sections 4.2, 4.3 and 4.4).

Other prostaglandin-containing products were given to subjects if needed in the clinical trials following removal of Mysodelle without apparent ill effect. A one-hour waiting period following removal of Mysodelle was utilised prior to allowing these products.

Fertility

From fertility and early embryonic development studies in rats, there is evidence of a possible adverse effect of misoprostol on implantation, however this is not relevant for the indicated clinical use of Mysodelle (see Section 5.3).

Pregnancy

Mysodelle has been studied in pregnant women ≥ 36 weeks gestation.

Mysodelle should not be used prior to 36 weeks of gestation (see Section 4.3).

Breast-feeding

No studies have been performed to investigate the amount of misoprostol acid in colostrum or breast milk following the use of Mysodelle.

Misoprostol acid has been detected in human milk following oral administration of misoprostol in tablet form.

After removal of Mysodelle, the median half-life in plasma of misoprostol acid is approximately 40 minutes. After five half-lives, i.e., approximately 3 hours, the misoprostol acid levels in the maternal plasma are negligible. Misoprostol acid may be excreted in colostrum and breast milk, but the level and duration is expected to be very limited and should not hinder breast-feeding. With Mysodelle, no effects on the breastfed newborns have been observed in the clinical development programme.

Not relevant.

Clinical Studies Experience.

Summary of the safety profile

The adverse reaction profile in Table 1 is based upon five clinical studies conducted with Misodel in 874 pregnant women at term gestation. The most common adverse reactions are uterine contractions abnormal (with/without foetal heart rate disorder), foetal heart rate disorder and abnormal labour affecting foetus.

Table 1: Adverse Reactions observed in Clinical Studies

Very common (≥1/10)
Common (≥1/100 to <1/10)
Uncommon (≥1/1,000 to <1/100)

Nervous system disorders

Uncommon: Hypoxic-ischaemic encephalopathy

Cardiac disorders

Very common: Foetal heart rate disorder†

Respiratory, thoracic and mediastinal disorders

Common: Neonatal respiratory depression, Transient tachypnoea of the newborn

Gastrointestinal disorders

Uncommon: Nausea, Vomiting

Skin and subcutaneous tissue disorders

Uncommon: Rash

Pregnancy, puerperium and perinatal conditions

Very common: Meconium in amniotic fluid, Uterine contractions abnormal, Abnormal labour affecting foetus

Common: Foetal acidosis, Postpartum haemorrhage, Uterine hypertonus

Uncommon: Antepartum haemorrhage, Premature separation of placenta

Reproductive system and breast disorders

Uncommon: Pruritus genital

Investigations

Common: Apgar score low

Uncommon: Blood pressure increased

Injury, poisoning and procedural complications

Uncommon: Uterine rupture

† The term foetal heart rate disorder covers different types of non reassuring foetal heart rates.

In the pivotal Misodel study (Miso-Obs-303: The EXPEDITE Study), neonates were followed for the first month after delivery for hospital admission or emergency room visits. No adverse reactions were reported following hospital discharge.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme, website: www.mhra.gov.uk/yellowcard.

Not applicable.