Propess
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
PROPESS10 mg vaginal delivery system
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each vaginal delivery system consists of a non-biodegradable polymeric drug delivery device containing 10 mg dinoprostone (Prostaglandin E2) dispersed throughout its matrix.
For the full list of excipients, see section 6.1
3 PHARMACEUTICAL FORM
Vaginal delivery system
PROPESS is presented as a thin, flat semi-transparent polymeric vaginal delivery system which is rectangular in shape with rounded corners contained within a knitted polyester retrieval system.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Initiation of cervical ripening in patients, at term (from 37 completed weeks of gestation).
4.2 Posology and method of administration
Posology
One vaginal delivery system is administered high into the posterior vaginal fornix.
The vaginal delivery system should be removed after 24 hours irrespective of whether cervical ripening has been achieved.
A dosing interval of at least 30 minutes is recommended for the sequential use of oxytocin following the removal of the vaginal delivery system.
Paediatric population
The safety and efficacy of PROPESS in pregnant woman aged less than 18 years has not been established. No data are available.
Method of administration
Administration
PROPESS should be removed from the freezer in direct connection with the insertion. No thawing is required prior to use.
There is a “tearmark” on 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.
The vaginal delivery system should be inserted high into the posterior vaginal fornix using only small amounts of water soluble lubricants to aid insertion. 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. No attempt should be made to tuck the end of the tape into the vagina as this may make retrieval more difficult.
The patient should be recumbent for 20 minutes to 30 minutes after insertion. As dinoprostone will be released continuously over a period of 24 hours, it is important to monitor uterine contractions and fetal condition at frequent regular intervals.
Removal
The vaginal delivery system can be removed quickly and easily by gentle traction on the retrieval tape.
It is necessary to remove the vaginal delivery system to terminate drug administration when cervical ripening is judged to be complete or for any of the reasons listed below.
Onset of labour. For the purposes of induction of labour with PROPESS, the onset of labour is defined as the presence of regular painful uterine contractions occurring every 3 minutes irrespective of any cervical change. There are two important points to note:
Once regular, painful contractions have been established with PROPESS they will not reduce in frequency or intensity as long as PROPESS remains in situ because dinoprostone is still being administered.
Patients, particularly multigravidae, may develop regular painful contractions without any apparent cervical change. Effacement and dilatation of the cervix may not occur until uterine activity is established. Because of this, once regular painful uterine activity is established with PROPESS in situ, the vaginal delivery system should be removed irrespective of cervical state to avoid the risk of uterine hyperstimulation.
Spontaneous rupture of the membranes or amniotomy.
Any suggestion of uterine hyperstimulation or hypertonic uterine contractions.
Evidence of fetal distress.
Evidence of maternal systemic adverse dinoprostone effects such as nausea, vomiting, hypotension or tachycardia.
At least 30 minutes prior to starting an intravenous infusion of oxytocin, as there is a much greater risk of hyperstimulation if the dinoprostone source is not removed before administration of oxytocin.
The opening on one side of the retrieval device is present only to allow the manufacturer to enclose the vaginal delivery system into the retrieval device during manufacture. The vaginal delivery system should NEVER be removed from the retrieval device.
On removal of the product from the vagina, the vaginal delivery system will have swollen to 2-3 times its original size and be pliable.
4.3 Contraindications
PROPESS should not be used or left in place:
When labour has started.
When oxytocic drugs and/or other labour induction agents are being given.
When strong prolonged uterine contractions would be inappropriate such as in patients:
who have had previous major uterine surgery, e.g. caesarean section, myomectomy etc (see sections 4.4 and 4.8)
with cephalopelvic disproportion
with fetal malpresentation
with suspicion or evidence of fetal distress
who have had previous major surgery (e.g. other than biopsies and cervical abrasion) or rupture of the uterine cervix
When there is current pelvic inflammatory disease, unless adequate prior treatment has been instituted.
When there is hypersensitivity to dinoprostone or to any of the excipients listed in section 6.1.
When there is placenta previa or unexplained vaginal bleeding during the current pregnancy.
4.4 Special warnings and precautions for use
The condition of the cervix should be assessed carefully before PROPESS is used. After insertion, uterine activity and fetal condition must be monitored regularly. PROPESS must only be used if facilities for continuous fetal and uterine monitoring are available. If there is any suggestion of maternal or fetal complications or if adverse effects occur, the vaginal delivery system should be removed from the vagina.
The experience of PROPESS in patients with ruptured membranes is limited. Therefore, PROPESS should be used with caution in those patients. Since the release of dinoprostone from the insert can be affected in the presence of amniotic fluid, special attention should be given to uterine activity and fetal condition.
PROPESS should be used with caution in patients with a previous history of uterine hypertonus, glaucoma or asthma.
Medication with non-steroidal anti-inflammatory drugs, including acetylsalicylic acid, should be stopped before administration of dinoprostone.
If uterine contractions are prolonged or excessive, there is possibility of uterine hypertonus or rupture and the vaginal delivery system should be removed immediately.
Uterine rupture has been reported in association with the use of PROPESS, mainly in patients with contra-indicated conditions (see section 4.3). Therefore, PROPESS should not be administered to patients with a history of previous caesarean section or uterine surgery given the potential risk for uterine rupture and associated obstetrical complications.
PROPESS should be used with caution when there is a multiple pregnancy. No studies in multiple pregnancy have been performed.
PROPESS should be used with caution when the woman has had more than three full term deliveries. No studies in woman with more than three full term deliveries have been performed.
A second dose of PROPESS is not recommended, as the effects of a second dose have not been studied.
The use of the product in patients with diseases which could affect the metabolism or excretion of dinoprostone, e.g. lung, liver or renal disease, has not been specifically studied. The use of the product in such patients is not recommended.
Women aged 35 and over, women with complications during pregnancy, such as gestational diabetes, arterial hypertension and hypothyroidism, and women at gestational age above 40 weeks have a higher post-partum risk for developing disseminated intravascular coagulation (DIC). These factors may additionally enhance the risk of disseminated intravascular coagulation in women with pharmacologically induced labour (see section 4.8). Therefore, dinoprostone and oxytocin should be used with caution in these women. In the immediate post-partum phase the physician should look out carefully for early signs of a developing DIC (e.g fibrinolysis).
The Clinician should be alert that, as with other labour induction methods, use of dinoprostone may result in inadvertent abruption of placenta and subsequent embolization of antigenic tissue causing in rare circumstances the development of Anaphylactoid Syndrome of Pregnancy (Amniotic Fluid Embolism).
4.5 Interaction with other medicinal products and other forms of interaction
No dedicated interaction studies have been performed with PROPESS.
Prostaglandins potentiate the uterotonic effect of oxytocic drugs. Therefore, PROPESS should not be used concurrently with the use of oxytocic drugs.
4.6 Fertility, pregnancy and lactation
Pregnancy
.
PROPESS should not be used during pregnancy prior to 37 completed weeks of gestation.
Breast-feeding
No studies have been performed to investigate the amount of dinoprostone in colostrum or breast milk following the use of PROPESS.
Dinoprostone may be excreted in colostrum and breast milk, but the level and duration is expected to be very limited and should not hinder breastfeeding. No effects on the breastfed newborns have been observed in the clinical studies conducted with PROPESS.
4.7 Effects on ability to drive and use machines
Not relevant.
4.8 Undesirable effects
Summary of safety profile:
The most commonly reported adverse drug reactions in placebo-controlled and active comparator efficacy clinical trials (N=1116) were “foetal heart rate disorder” (6,9%), “uterine contractions abnormal” (6,2%) and “abnormal labour affecting foetus” (2.6 %).
The table below displays the main ADRs distributed by system organ classes (SOC) and frequency. Further, the ADRs seen during post-marketing experience are mentioned with unknown frequency.
Adverse reactions observed in clinical studies are presented according to their incidence, post authorisation reported adverse reactions are presented in the column frequency unknown.
|
System organ class |
Common (≥ 1/100 and < 1/10) |
Uncommon (≥ 1/1000 and ≤ 1/100) |
Not known: frequency cannot be estimated from the available data |
|
Blood and lymphatic system disorders |
|
|
Disseminated intravascular coagulation |
|
Immune system disorders |
|
|
Anaphylactic reaction Hypersensitivity |
|
Nervous system disorders |
|
Headache |
|
|
Cardiac disorders |
Foetal heart rate disorder 1* |
|
|
|
Vascular disorders |
|
Hypotension |
|
|
Respiratory, thoracic and mediastinal disorders |
|
Neonatal respiratory distress related conditions |
|
|
Gastrointestinal disorders |
|
|
Abdominal pain, Nausea, vomiting, diarrhoea |
|
Hepatobiliary disorders |
|
Neonatal hyperbilirubinaemia |
|
|
Skin and subcutaneous tissue disorders |
|
Pruritus |
|
|
Pregnancy, puerperium and perinatal conditions |
Abnormal labour affecting foetus 2* Uterine contractions abnormal 4* Meconium in amniotic fluid |
Postpartum haemorrhage, Premature separation of placenta, Apgar score low Arrested labour Chorioamnionitis Uterine atony |
Anaphylactoid syndrome of pregnancy Foetal distress syndrome 3* |
|
Reproductive system and breast disorders |
|
Vulvovaginal burning sensation |
Genital oedema |
|
General disorders and administration site conditions |
|
Febrile disorders |
|
|
Injury, poisoning and procedural complications |
|
|
Uterine rupture |
in good condition at birth. h. (observed in the clinical studies conducted. and should not hinder breastfeeding. No effects on t1* “Foetal heart rate disorder” was in clinical studies reported as “foetal heart rate abnormalities”, “foetal bradycardia”, “foetal tachycardia”, “unexplained absence of normal variability”, “foetal heart rate decreased”, “foetal heart rate deceleration”, “early or late decelerations”, “variable decelerations”, “prolonged decelerations”.
2* “Abnormal labour affecting foetus” as expression for hyperstimulation syndrome was in clinical studies reported as “uterine tachysystole” combined with “late decelerations”, “foetal bradycardia”, or “prolonged decelerations ”
3* “Foetal distress syndrome” was also reported as “foetal acidosis” , “pathological CTG”, “foetal heart rate abnormalities”, “intrauterine hypoxia” or “threatening asphyxia”. The term itself is unspecific, has a low positive predictive value and is often associated with an infant who is in good condition at birth.
4* “Uterine contractions abnormal” were reported as “uterine hyperstimulation” and “uterine hypertonus”.
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 national reporting system> <[to be completed nationally]>.
4.9 Overdose
Overdosage or hypersensitivity may lead to hyperstimulation of the uterine muscle with or without foetal distress. If foetal distress occurs, remove PROPESS immediately and manage in accordance with local protocol.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: oxytocics, ATC-code: G02AD02
Prostaglandin E2(PGE2) is a naturally occurring compound found in low concentrations in most tissues of the body. It functions as a local hormone.
Prostaglandin E2 plays an important role in the complex set of biochemical and structural alterations involved in cervical ripening. Cervical ripening involves a transformation of the uterine cervix which must be transformed from a rigid structure to a soft, dilated configuration to allow passage of the fetus through the birth canal. This process involves activation of the enzyme collagenase which is responsible for the breakdown of the collagen.
Local administration of dinoprostone to the cervix results in cervical ripening which then induces the subsequent events which complete labour.
5.2 Pharmacokinetic properties
PGE2is rapidly metabolised primarily in the tissue of synthesis. Any which escapes local inactivation is rapidly cleared from the circulation with a half-life generally estimated as 1-3 minutes.
No correlation could be established between PGE2release and plasma concentrations of its metabolite, PGEm. The relative contributions of endogenously and exogenously released PGE2to the plasma levels of the metabolite PGEmcould not be determined.
The reservoir of 10mg dinoprostone serves to maintain a controlled and constant release. The release rate is approximately 0.3mg per hour over 24 hours in women with intact membranes whereas release is higher and more variable in women with premature rupture of membranes. PROPESS releases dinoprostone to the cervical tissue continuously at a rate which allows cervical ripening to progress until complete, and with the facility to remove the dinoprostone source when the clinician decides that cervical ripening is complete or labour has started, at which point no further dinoprostone is required.
5.3 Preclinical safety data
Preclinical studies have demonstrated that dinoprostone is a locally acting substance which is rapidly inactivated and thus it has no significant systemic toxicity.
The hydrogel and polyester polymers are inert compounds with good local tolerability.
Reproduction toxicity, genotoxic or carcinogenic effects of the polymers have not been investigated but systemic exposure is negligible.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Crosslinked polyethylene glycol (hydrogel)
Polyester yarn
6.2 Incompatibilities
Not applicable
6.3 Shelf life
3 years
6.4 Special precautions for storage
Store in a freezer. Store in the original container in order to protect from moisture.
6.5 Nature and contents of container
PROPESS vaginal delivery systems are presented in individual, sealed aluminium/polyethylene laminate sachets in packs of 5 vaginal delivery systems.
6.6 Special precautions for disposal
PROPESS should be removed from the freezer in direct connection with the insertion.
After usage, the whole product should be disposed of as clinical waste.