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MYSODELLE 200 MICROGRAMS VAGINAL DELIVERY SYSTEM

Active substance(s): MISOPROSTOL

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SUMMARY OF PRODUCT CHARACTERISTICS
1

NAME OF THE MEDICINAL PRODUCT
Mysodelle 200 micrograms vaginal delivery system.

2

QUALITATIVE AND QUANTITATIVE COMPOSITION
Mysodelle contains 200 micrograms misoprostol.
Misoprostol is released in vivo at a mean rate of approximately 7
micrograms/hour over a period of 24 hours. Drug release continues as long as
Mysodelle is in the vagina.
Excipients with known effect: 0.13 mg butylated hydroxyanisole per dose (see
Section 4.4).
For the full list of excipients, see Section 6.1.

3

PHARMACEUTICAL FORM
Vaginal delivery system.
The polymer insert is contained within a retrieval system consisting of an inert
woven polyester pouch and tail. The polymer insert is rectangular in shape
with radiused corners, is buff coloured, semi-transparent, non-biodegradable
and measures approximately 30 mm in length, 10 mm in width and 0.8 mm in
thickness. Mysodelle swells in the presence of moisture.

4

CLINICAL PARTICULARS

4.1

Therapeutic indications
Mysodelle is indicated for induction of labour in women with an unfavourable
cervix, from 36 weeks gestation, in whom induction is clinically indicated.

4.2

Posology and method of administration
Posology
Misodel 200 micrograms is a controlled release formulation that releases
misoprostol at a rate of approximately 7 micrograms/hour over a period of 24
hours.
The maximum recommended dose is one Misodel vaginal delivery system
(200 micrograms).
Remove Misodel:

-

At the onset of labour:
When contractions are rhythmic (3 or more in 10 minutes), firm and of
adequate quality and cause cervical change and/or at the latest when
cervical dilation is 4 cm


-

If excessive uterine contractions occur:
Tachysystole: more than 5 contractions in a 10-minute window, averaged
over a 30 minute window
Prolonged contractions: single contractions lasting 2 minutes or more
Hypertonic contractions: contractions are too frequent and a high resting
tone in the uterus.



If there is a clinical concern for the mother and/or baby



if 24 hours have elapsed since insertion.

If Misodel falls out, do not replace it.
In case of subsequent administration of oxytocin, a waiting period of at least
30 minutes is recommended following the removal of the vaginal delivery
system (see Section 4.5).
An unfavourable cervix (modified Bishop score ≤ 4) was an inclusion criteria
in the pivotal phase III clinical study
Paediatric population
The safety and efficacy of Misodel in pregnant women aged less than 18 years
has not been established.
No data are available.

Method of administration
Misodel should only be administered by trained obstetric personnel in a
hospital setting where facilities for continuous fetal and uterine monitoring is
available. The condition of the cervix should be assessed carefully before
Misodel is used. After insertion, uterine activity and fetal condition must be

carefully monitored by staff trained in cardiotocography interpretation.
Misodel should only be used in hospitals where facilities for emergency
Caesarean delivery are readily available.
Misodel is supplied in an individual aluminium foil sachet, and must be stored
in the freezer. No thawing is required prior to use.
There is a “tear mark” on one side of the foil sachet. Open the package along
the tear mark across the top of the sachet. Do not use scissors or other sharp
objects which may cut the retrieval system.
Place Misodel high in the posterior vaginal fornix (Figure a). To ensure that
Misodel remains in situ, it should be turned 90o so that it lies transversely in
the posterior fornix of the vagina (Figure b). Water-soluble lubricants may be
used to aid insertion when necessary.

Figure a.

Figure b.

Figure c.

After the vaginal delivery system has been inserted, the withdrawal tape may
be cut with scissors always ensuring there is sufficient tape outside the vagina
to allow removal.
The patient is to remain in bed for 30 minutes after insertion, but may be
ambulatory thereafter. Take care not to inadvertently remove Misodel during
toileting and vaginal examinations.
Removal
Misodel is removed by gently pulling the tail of the retrieval system (Figure c).
The vaginal delivery system should NEVER be removed from the retrieval
system.
Misodel is a controlled release formulation that swells in the presence of
moisture, causing drug release to occur. During insertion, Misodel will swell
to 2-3 times its original size and be pliable. After removal, ensure that the
entire product (insert and retrieval system) has been removed from the vagina.
4.3

Contraindications
Mysodelle is contraindicated:

4.4



When there is hypersensitivity to the active substance or to any of the
excipients listed in Section 6.1



When labour has started



When there is suspicion or evidence of fetal compromise prior to induction
(e.g., failed non-stress or stress test, meconium staining or diagnosis or
history of non-reassuring fetal status)



When oxytocic drugs and/ or other labour induction agents are being given
(see section 4.4)



When there is suspicion or evidence of uterine scar resulting from previous
uterine or cervical surgery, e.g. caesarean delivery



When there is uterine abnormality (e.g. bicornate uterus)



When there is placenta praevia or unexplained vaginal bleeding after 24
weeks gestation with this pregnancy



When there is fetal malpresentation



When there are signs or symptoms of chorioamnionitis, unless adequate
prior treatment has been instituted



Before week 36 of gestation.

Special warnings and precautions for use
Misodel can cause excessive uterine tachysystole that may not respond to
tocolytic treatment and that may not subside before delivery. Misodel 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
MISODEL.
In women with pre-eclampsia, evidence or suspicion of fetal compromise
should be ruled out (refer to Section 4.3). Pregnant women with severe preeclampsia 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 (MisoObs-303; The EXPEDITE Study).
Misodel has not been studied in women whose membranes have been ruptured
for more than 48 hours prior to the insertion of Misodel.
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 Misodel before oxytocin administration is initiated. Wait at least 30
minutes after removing Misodel before initiating oxytocin (see Sections 4.2,
4.3 and 4.5).
Misodel has only been studied in singleton pregnancies with cephalic
presentation. No studies in multiple pregnancies have been performed.
Misodel has not been studied in women with more than 3 previous vaginal
deliveries after 24 weeks gestation.
Misodel should be used only when induction of labour is clinically indicated.
Misodel should be used with caution in patients with modified bishop score
(mBS) >4.
A second dose of Misodel 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.
4.5

Interaction with other medicinal products and other forms of interaction
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.

4.6

Fertility, pregnancy and lactation
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 breastfeeding. With Mysodelle, no effects on the breastfed newborns have been
observed in the clinical development programme.

4.7

Effects on ability to drive and use machines
Not relevant.

4.8

Undesirable effects
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, foetal heart rate
disorder and abnormal labour affecting foetus.

Table 1: Adverse Reactions observed in Clinical Studies
System Organ
Class
Nervous system
disorders
Cardiac disorders

Very common
(≥1/10)

Common
(≥1/100 to <1/10)

Uncommon
(≥1/1,000 to <1/100)
Hypoxic-ischaemic
encephalopathy

Foetal heart rate
disorder†

Respiratory,
thoracic and
mediastinal
disorders

Neonatal respiratory
depression
Transient tachypnoea
of the newborn

Gastrointestinal
disorders

Nausea
Vomiting

Skin and
subcutaneous
tissue disorders

Rash

Pregnancy,
puerperium and
perinatal
conditions

Meconium in
amniotic fluid
Uterine contractions
abnormal
Abnormal labour
affecting foetus

Reproductive
system and breast
disorders
Investigations

Antepartum haemorrhage
Foetal acidosis

Postpartum
haemorrhage

Premature separation of
placenta

Uterine hypertonus

Pruritus genital

Apgar score low

Injury, poisoning
and procedural
complications

Blood pressure increased
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.

4.9

Overdose
There is no experience with the use of more than one application of
Mysodelle. The controlled release formulation and ability to remove
Mysodelle thereby stopping misoprostol delivery limits the risk of overdose.
Accidentally leaving Mysodelle in place after onset of active labour may lead
to symptoms of prostaglandin overdose (excessive uterine stimulation). If this
occurs, remove Mysodelle and manage in accordance with local protocol.

5

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties
Pharmacotherapeutic group: Other gynaecologicals, oxytocics, prostaglandins,
ATC-code: G02AD06.
Mechanism of action
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 Misodel.
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.
Clinical efficacy and safety
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 Misodel 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 Misodel 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
Misodel
200 mcg
(N=678)

PROPESS®
10mg
(N=680)

p-value

21.5h**

32.8h**

p < 0.001

Nulliparous Subjects

29.2 h (n=441)

43.1 h (n=451)

p < 0.001

Parous Subjects
Incidence of Caesarean
Delivery (n %)

13.4 h (n=237)
176 (26.0%)

20.1 h (n=229)
184 (27.1%)

p < 0.001
p = 0.646

Nulliparous Subjects

152 (34.5%)

168 (37.3%)

p = 0.386

Parous Subjects
Median time to Overall
Delivery of the Neonate*
(Vaginal and Caesarean) (h)
Overall Median time to
Onset of Active Labour
(hours)*
Overall number of Subjects
who received Pre-delivery
Oxytocin [n (%)]

24 (10.1%)

16 (7.0%)

p = 0.226

18.3h†

27.3h†

p < 0.001

12.1h††

18.6h††

p < 0.001

324 (48.1%)
(N=674)

497 (74.1%)
(N=671)

p < 0.001

Median time to Vaginal
Delivery of Neonate (hours)*

* 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): Misodel, 200 mcg: 16.6 h;
PROPESS® 10 mg: 25.1 h
† Summary of median time to any delivery: Misodel, 200 mcg: 18.2 h; PROPESS® 10 mg: 27.2 h
†† Summary of median time to onset of active labour: Misodel, 200 mcg: 12.0 h; PROPESS® 10 mg: 18.0 h

Paediatric population
The European Medicines Agency has waived the obligation to submit results
of clinical studies with Misodel in one or more subsets of the paediatric
population in labour induction, in the granted indication (See Section 4.2 for
information on paediatric use).
5.2

Pharmacokinetic properties
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.

5.3

Preclinical safety data
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.

6

PHARMACEUTICAL PARTICULARS

6.1

List of excipients
Cross-linked hydrogel polymer (comprised of macrogol, 1,2,6- hexanetriol
and dicyclohexyl-methane-4,4’-diisocyanate).
Butylated Hydroxyanisole

Polyester retrieval system (knitted polyester yarn)

6.2

Incompatibilities
Not applicable.

6.3

Shelf life
3 years.

6.4

Special precautions for storage
Store in a freezer (-10 to -25°C). No thawing is required prior to use.

6.5

Nature and contents of container
1 x 200 micrograms vaginal delivery system
5 x 200 micrograms vaginal delivery system
5 x 200 micrograms vaginal delivery system (multipack).
Each vaginal delivery system is contained within an individual foil sachet
produced from an aluminium foil laminate strip containing a desiccant and
packed in a carton.
Not all pack sizes may be marketed.

6.6

Special precautions for disposal
Mysodelle should be removed from the freezer and taken out of the laminated
aluminium foil sachet just prior to insertion.
Any unused medical product or waste material should be disposed of in
accordance with local requirements. The whole product should be disposed
following removal.

7

MARKETING AUTHORISATION HOLDER

Ferring Pharmaceuticals Ltd
Drayton Hall
Church Road
West Drayton
UB7 7PS, (UK)

8

MARKETING AUTHORISATION NUMBER(S)
PL 03194/0112

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
01/11/2013

10

DATE OF REVISION OF THE TEXT
10/11/2017

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Source: Medicines and Healthcare Products Regulatory Agency

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