Consumer medicine information

Cervidil

Dinoprostone

BRAND INFORMATION

Brand name

Cervidil Pessary

Active ingredient

Dinoprostone

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Cervidil.

What is in this leaflet

This leaflet answers some common questions about CERVIDIL. It does not contain all the available information. It does not take the place of talking to your doctor or midwife.

All medicines have risks and benefits. Your doctor has weighed the risks of you being given CERVIDIL against the benefits he/she expects it will have for you.

If you have any concerns about being given this medicine, ask your doctor or midwife.

Keep this leaflet in a safe place.

You may need to read it again.

What CERVIDIL is used for

CERVIDIL is for women who have a normal pregnancy and are near their due date for delivery. It is used to prepare for induction of labour.

CERVIDIL is a pessary (vaginal insert) containing dinoprostone, also known as Prostaglandin E2 or PGE2. Prostaglandin E2 also occurs naturally in the body. Prostaglandin E2 is important for the changes that take place before labour begins.

CERVIDIL is used to prepare the cervix (the neck of the womb, at the top of the birth canal) to allow the baby to pass through. This process is called "cervical ripening".

This medicine is available only with a doctor's prescription.

Your doctor may have prescribed CERVIDIL for another purpose.

Ask your doctor or midwife if you have any questions about why CERVIDIL has been prescribed for you.

How it works

CERVIDIL works by:

  • softening and opening the cervix (neck of the womb)
  • setting off contractions (in the body of the womb)
  • releasing dinoprostone continuously to the cervix at the appropriate rate.

This allows softening and opening of the cervix to progress.

When the doctor decides no further dinoprostone is required, the pessary (vaginal insert) is removed by pulling on the withdrawal tape.

Before you are given CERVIDIL

Your doctor will decide if CERVIDIL is suitable for you.

CERVIDIL should be administered only by trained personnel, in hospital, with appropriate obstetrical care and facilities for the required monitoring.

When you must not be given it

You must not be given CERVIDIL if you have an allergy to dinoprostone or any of the ingredients (e.g. urethane) listed at the end of this leaflet.

Symptoms of an allergic reaction may include:

  • shortness of breath, wheezing or difficulty breathing
  • swelling of the face, lips, tongue or other parts of the body
  • rash, itching or hives on the skin.

You must not be given CERVIDIL if:

  • you are carrying more than one baby
  • your labour has already started
  • your waters have broken
  • there is any reason why you should not have a vaginal delivery, for example, genital herpes
  • the baby's head is not well down in the pelvis
  • the baby is not in the normal position for birth, or
  • if it is suspected, or tests show, your baby is unwell or not growing, or
  • the head of the baby is too big or the size of your pelvis is too small for normal delivery, or
  • you have contractions that are unusually strong and/or long (known as "hypertonic contractions" or "hyperstimulation of the uterus").

You must not be given CERVIDIL if you have had any of the following:

  • previous surgical operation on the womb, for example, a caesarean section, or
  • surgery to the neck of the womb (cervix), or
  • previous rupture of the cervix
  • any vaginal discharge or unexplained vaginal bleeding during the current pregnancy.

You must not be given CERVIDIL if you have untreated pelvic inflammatory disease
(also known as PID); usually caused by an infection of the internal female sex organs; it may result in, for example, pain and tenderness of the stomach and fever.

You should not be given CERVIDIL:

  • if the packaging is torn or shows signs of tampering
  • after the expiry date (EXP) printed on the pack.

If you are not sure whether you should be given CERVIDIL, talk to your doctor.

Taking other medicines

Tell your doctor or midwife if you are taking/using any other medicines, including any that you buy without a prescription from your pharmacy, supermarket or health food shop. Some medicines and CERVIDIL may interfere with each other.

Your doctor or midwife may have more information on medicines to be careful with or avoid while using CERVIDIL.

You must not be given CERVIDIL if you are being given, or are to be given intravenously within the next thirty minutes, medicines to make the muscles of your womb contract or bring labour, e.g. oxytocin.

Medication with aspirin and other non-steroidal anti-inflammatory drugs (known as NSAIDs) should be stopped before administration of CERVIDIL. Some examples of NSAIDs are Naprosyn and Voltaren.

Tell your doctor or midwife if you have allergies to:

  • any other medicines
  • any other substances, such as foods, preservatives or dyes.

Before you are given CERVIDIL tell your doctor or midwife if you are over 35 years of age or if you have had any medical conditions, especially the following:

  • lung, liver or kidney problems
  • asthma
  • epilepsy (convulsions or fits)
  • unexplained genital bleeding during current pregnancy
  • glaucoma (raised pressure in the eye)
  • abnormally strong contractions of your womb during previous labour, or
  • previous excessively short labour and delivery time
  • heart or blood pressure problems
  • previous complications during pregnancy
  • you have had more than three full term deliveries.
  • gestational diabetes
  • your pregnancy is past 40 weeks gestation.

When CERVIDIL must be removed

The pessary (vaginal insert) should be removed immediately:

  • if contractions are considered too sustained or excessive, or
  • if labour commences.

It should also be removed

  • prior to amniotomy
  • after the waters break (spontaneous rupture of the membranes)
  • if there is any suggestion of maternal or fetal complications, or
  • if unwanted side-effects occur
  • if, after 24 hours the cervix has not changed adequately for delivery.

How CERVIDIL is given

How much is given

CERVIDIL is given as one pessary (vaginal insert) inserted once only. Each CERVIDIL insert contains 10 mg dinoprostone.

Over the maximum recommended usage period of 24 hours, the insert gradually releases dinoprostone.

Over the maximum recommended usage period of 24 hours, the insert gradually releases about 0.3 mg of dinoprostone per hour.

How it is given

CERVIDIL must only be given under the supervision of a doctor.

CERVIDIL is inserted into the vagina. The pouch containing the active ingredient is positioned up at the top of the vagina behind the cervix. This is called the "posterior fornix" (See Figure 1).

The tape for withdrawal hangs from the entrance to the vagina.

Before CERVIDIL is used, careful assessment of the cervix is necessary.

After insertion of CERVIDIL the following must be monitored regularly:

  • changes in the cervix
  • presence or absence of contractions
  • frequency, duration and strength of contractions
  • baby's health.

If there is any suggestion of maternal or fetal complications, or if adverse effects occur, the CERVIDIL pessary (vaginal insert) should be removed. This is done by gently pulling on the withdrawal tape, until the whole device is removed from the vagina.

Administration

CERVIDIL looks like a small slim tampon, with a very long attached tape. CERVIDIL must not be used without this tape, which is used to withdraw the pessary (vaginal insert).

Your doctor or midwife will coat the CERVIDIL with a little lubricating jelly before putting it in your vagina. The tampon-like end, which holds the medicine, is placed behind the neck of the womb (cervix), in the area known as the "posterior fornix" of the vagina. The medicine gradually passes from the device into the upper vagina. The continuing concentration of medicine in the fluids around the cervix causes the cervix to become softer and gradually open.

The attached withdrawal tape is left hanging out of the entrance to your vagina. Your doctor or midwife can therefore easily pull out the CERVIDIL pessary (vaginal insert) when it is time to do so, or if it needs to be removed for any reason.

While you are being given CERVIDIL

Things you must do

You will be lying down while CERVIDIL is put in. You should remain lying down for at least 30 minutes afterwards. Your doctor or midwife will advise you when you can get up again. The pessary (vaginal insert) should be left in place for no longer than 24 hours.

While the pessary (vaginal insert) is in place, you will be checked frequently. Examples of what is being checked include but are not limited to:

  • the neck of the womb (cervix)
  • the strength and frequency of any contractions
  • the health of your unborn baby.

Removal

The pessary (vaginal insert) is removed by gently pulling the withdrawal tape.

How long it is used for

Your doctor or midwife will remove the pessary (vaginal insert) when you no longer need it or after 24 hours.

For example, they may remove it because:

  • your labour has started
  • your doctor wants to use a different medicine to help your womb (uterus) contract e.g. oxytocin
  • your waters have broken
  • your uterus is contracting too strongly
  • your baby is starting to get distressed.

OVERDOSAGE

Your medical attendants will be alert for any signs of overdose. Your doctor, midwife or pharmacist have information on how to recognise and treat an overdose. Initial treatment of overdose is removal of the pessary (vaginal insert). Other treatment is also available.

Contact the Poisons Information Centre on 131 126 for further advice on overdose management.

Side effects

Tell your doctor or midwife as soon as possible if you do not feel well while you are being given CERVIDIL.

All medicines can have side effects. Sometimes they are serious, most of the time they are not.

In most people, CERVIDIL helps prepare the cervix (neck of womb) for birth. It may have unwanted side effects in a few people.

Tell your doctor or midwife immediately if you notice any of the following:

  • headache
  • dizziness
  • itching
  • bleeding, possibly from multiple sites of your body
  • fever
  • nausea or vomiting
  • very strong or very frequent contractions of the womb
  • bluish coloration of the fingers
  • sudden bruising.

The above list includes serious side effects. Your doctor may decide to remove the CERVIDIL pessary (vaginal insert) if these side effects occur.

Tell your doctor or midwife if you notice any other side effects.

Rarely, rupture of the womb has been reported in association with the use of CERVIDIL. However, most of these patients should not have been given CERVIDIL. See the section beginning "When you must not be given it" above.

Do not be alarmed by this list of possible side effects.

You may not experience any of them.

Ask your doctor or midwife to answer any questions you may have.

Product description

What it looks like

The CERVIDIL pessary (vaginal insert) is:

  • a thin, flat rectangle, with rounded corners
  • slightly thicker than a large postage stamp
  • beige in colour
  • contained within a pouch
  • made so that, when the pouch becomes moist, the active ingredient (dinoprostone) comes out very slowly. The pouch forms one end of a long tape
  • pouch and tape are made of knitted polyester (off-white in colour)
  • tape allows withdrawal of the insert at the end of dosing.

NOTE: After recommended use, when CERVIDIL is removed from the vagina, the tampon-like end will have become larger. It absorbs fluid and becomes 2-3 times its original size.

Ingredients

The active ingredient in CERVIDIL is dinoprostone.

The active ingredient is within a plastic (polyurethane) sustained release insert which contains:

  • hexanetriol/macrogol 8000/ isocyanate cross-linked hydrogel copolymer.

The insert is held within a pouch in continuity with a withdrawal tape. Pouch and tape are made of knitted polyester yarn.

Presentation

CERVIDIL is in an aluminium/polyethylene foil sachet, each containing 1 pessary (vaginal insert).

Storage

CERVIDIL is kept in a freezer and removed immediately before use. It is stored in the hospital.

Disposal

The used pessary (vaginal insert) should be disposed of as clinical waste.

Sponsor

Ferring Pharmaceuticals Pty Ltd
Suite 2, Level 1, Building 1
20 Bridge Street
Pymble, NSW 2073, Australia.

AUST R 81391 - CERVIDIL dinoprostone 10 mg pessary sachet

This leaflet was prepared in January 2018.

#37784-v2B.

CERVIDIL® is a registered trademark of Ferring B.V.

® = Registered trademark

BRAND INFORMATION

Brand name

Cervidil Pessary

Active ingredient

Dinoprostone

Schedule

S4

 

1 Name of Medicine

Dinoprostone (prostaglandin E2).

6.7 Physicochemical Properties

Chemical structure.

The structural formula is represented below:

CAS number.

363-24-6.
Molecular formula: C20H32O5. Molecular weight: 352.5.
The chemical name for dinoprostone (commonly known as prostaglandin E2 or PGE2) is 11alpha-5Sdihydroxy-9-oxo-prosta-5Z,13E-dien-1-oic acid. It is a white to off-white crystalline powder. It has a melting point within the range of 65°C to 69°C. Dinoprostone is soluble in ethanol and in 25% ethanol in water.

2 Qualitative and Quantitative Composition

Each pessary (vaginal insert) contains 10 mg of dinoprostone and releases a mean dose of approximately 0.3 mg per hour of dinoprostone over 24 hours. The dinoprostone is dispersed throughout a matrix consisting of 241 mg of hexanetriol/macrogol 8000/isocyanate cross-linked hydrogel copolymer, which is a semiopaque, beige coloured, flat rectangular pessary (vaginal insert) measuring 29 mm by 9.5 mm and 0.8 mm in thickness.

3 Pharmaceutical Form

Cervidil is a thin, flat, polymeric pessary (vaginal insert) which is rectangular in shape with rounded corners. The pessary (vaginal insert) is contained within the pouch of an off-white knitted polyester retrieval system designed to aid retrieval at the end of the dosing interval. The pessary (vaginal insert) and its retrieval system, made of polyester yarn, are non-toxic and when placed in a moist environment, absorb water, swell, and release dinoprostone.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Prostaglandin E2 (PGE2) is a naturally occurring compound found in low concentrations in most tissues of the body. It functions as a local hormone.
PGE2 plays an important role in the complex set of biochemical and structural alterations involved in cervical ripening. Cervical ripening involves a marked relaxation of the cervical smooth muscle fibres of the uterine cervix which must be transformed from a rigid structure to a softened, yielding and dilated configuration to allow passage of the fetus through the birth canal. This process involves activation of the enzyme collagenase which is responsible for digestion of some of the structural collagen network of the cervix.

Clinical trials.

Trials involving insertion of Cervidil for up to 12 hours.

Three randomised, double-blind placebo controlled studies have been conducted in which Cervidil was inserted for up to 12 hours. If successful cervical ripening was achieved at the end of the 12-hour period amniotomy was performed (if necessary) and oxytocin infusion commenced (if necessary, after waiting at least 30 minutes from removal of the pessary). Studies 101-003 and 101-103 involved the pessary (vaginal insert) alone, whereas study 101-801 used the pessary (vaginal insert) fitted with retrieval system to facilitate rapid and reliable retrieval of the pessary (vaginal insert). Pharmacokinetic studies had demonstrated that there was no significant difference between the PGE2 release characteristics of the "netted" and "unnetted" versions of the pessary (vaginal insert).
All three studies involved patients with singleton pregnancies and cephalic presentation, for whom there were medical or obstetrical grounds for the induction of labour and who had a Bishop score of 4 or less. Patients had to be in at least the 37th week of gestation. On randomisation, patients were stratified according to whether they were primiparous or multiparous.
The efficacy of Cervidil as demonstrated in these studies is shown in Table 4.

Trials involving insertion of Cervidil for up to 24 hours.

Miso-Obs-004 and Miso-Obs-303.

The efficacy of the Cervidil pessary (vaginal insert) in cervical ripening when insertion for up to 24 hours was permitted has been studied in two Phase III trials: Miso-Obs-303 and Miso-Obs-004. Both studies were double-blind, randomised, active-controlled trials in pregnant subjects requiring cervical ripening and induction of labour, where Cervidil dinoprostone vaginal insert (DVI) was used as an active comparator for misoprostol vaginal insert 200 micrograms (MVI 200) [Miso-Obs-303], 100 micrograms (MVI 100) or 50 micrograms (MVI 50) [Miso-Obs-004]. Intravenous oxytocin was permitted, when required, 30 minutes following removal of the study drug assuming no contraindications and active labour not present.
The primary efficacy endpoint of Miso-Obs-004 and Miso-Obs-303 was time to vaginal delivery.
The secondary efficacy endpoints of Miso-Obs-004 were cervical ripening based on success on the composite modified Bishop score at 12 hours: proportion of vaginal deliveries within 12 and 24 hours; need for oxytocin in the first and/or second stages of labour; and time to onset of active labour in the first and/or second stages of labour.
The secondary efficacy endpoints of Miso-Obs-303 were time to any delivery (vaginal or caesarean); time to active labour; proportion of subjects with pre-delivery oxytocin; proportion of subjects with vaginal delivery within 12 hours; proportion of subjects with any delivery within 24 hours; proportion of subjects with any delivery within 12 hours; proportion of subjects with vaginal delivery within 24 hours; proportion of subjects with vaginal delivery; and proportion of subjects with cervical ripening success at 12 hours.
MISODEL (MVI 200), but not MVI 100 or MVI 50, is registered in Australia for induction of labour in women with an unfavourable cervix, from 36 weeks’ gestation in whom induction is clinically indicated and in a hospital where continuous electronic fetal monitoring is available.
An overview of these trials is presented in Table 5.
Approximately 60% of the women in these two Phase III trials required cervical ripening to continue beyond 12 hours and a total of 302 women had the insert in situ for 24 hours during the two trials (83 in Miso-Obs-004 and 219 in Miso-Obs-303). Table 6 shows the efficacy results in both trials, where results for the DVI group are consistent in these two Phase III trials.
A total of 8.38% and 11.7% of subjects in the DVI groups delivered vaginally within 12 hours which increased to 33.97% and 42.7% by 24 hours in the Miso-Obs-303 and Miso-Obs-004 trials, respectively. There were 66.0% and 59.6% of subjects in the DVI groups who achieved the composite endpoint for cervical ripening at 12 hours in Miso-Obs-303 and Miso-Obs-004 trials, respectively. In Miso-Obs-303, the percentage of subjects in the DVI group with cervical ripening success increased to 86.8% at 24 hours.

5.2 Pharmacokinetic Properties

Cervidil releases PGE2 to the cervical tissue continuously at a rate which allows cervical ripening to progress until complete (mean dose of approximately 0.3 mg per hour over 24 hours), and with the facility to remove the PGE2 source when the clinician decides that no further PGE2 is required.
Dinoprostone is established as a successful agent for cervical ripening and induction of labour. Dinoprostone initiates labour by a process which may be more akin to spontaneous labour than that produced by forewater amniotomy followed by oxytocin infusion. Local application of dinoprostone (endocervical and vaginal) has proved to be clinically superior to intravenous administration, avoiding gastrointestinal side effects.

Distribution.

Using equilibrium dialysis, studies indicate that dinoprostone is approximately 73% bound to human plasma albumin.

Metabolism.

Dinoprostone is rapidly metabolised in the lungs, kidneys and liver. Approximately 90% of dinoprostone is metabolised in the first pass. In man, three metabolites of dinoprostone have been identified in plasma, 13,14-dihydro-15-keto GE2 (the primary metabolite), 11 alpha-hydroxy-9 15- diketoprost-5-enoic acid and 11 alpha-hydroxy-9,15-dioxyprost -5-13-dienoic acid.

Excretion.

Dinoprostone is eliminated from the circulation very rapidly. Studies indicate that the half-life of dinoprostone is less than one minute.
The plasma concentration of dinoprostone and its metabolites is low after intravaginally administered PGE2. The plasma half-life for dinoprostone is less than 1 minute and for its primary metabolite less than 10 minutes. Animal studies have shown that this metabolite (15-keto-13,14-dihydro-PGE2) is about half as active as the mother substance. Dinoprostone is metabolised in the lung and is excreted via the urine.

5.3 Preclinical Safety Data

Genotoxicity.

No evidence of mutagenicity has been observed with PGE2 in the Micronucleus Test, or Ames Test. PGE2 did induce chromosomal aberrations in Chinese hamster lung fibroblasts in culture but only at an unphysiologically high concentration.
Long term clinical use of chemically related polymers such as those used in the hydrogel and retrieval system has not identified any concerns regarding genotoxicity.

Carcinogenicity.

Long-term carcinogenicity studies have not been conducted with Cervidil.
Exposure to PGE2 at the dosage and administration recommended for induction of labour is not considered to be of concern with regard to potential carcinogenicity.

4 Clinical Particulars

4.1 Therapeutic Indications

Cervical ripening in patients, at or near term, who have favourable induction features and in whom there is a medical or obstetrical indication for induction of labour.

4.3 Contraindications

Cervidil should not be used or left in place in the following conditions.
1. When there is known hypersensitivity to dinoprostone or any other constituent of the pessary (vaginal insert) (e.g. urethane).
2. When the patient is carrying more than one fetus or the fetus is in a nonvertex presentation.
3. When labour has started.
4. When oxytocic drugs and/or other labour inducing agents are being given or if they are to be given intravenously within 30 minutes.
5. When strong prolonged uterine contractions would be inappropriate such as in patients:
a. Who have had previous major uterine surgery, e.g. caesarean section or myomectomy (see Section 4.4 Special Warnings and Precautions for Use; Section 4.8 Adverse Effects (Undesirable Effects)).
b. With cephalopelvic disproportion.
c. With fetal malpresentation.
d. With suspicion or evidence of fetal distress (e.g. abnormal cardiotocography).
e. Who have had previous cervical surgery or rupture of the cervix.
6. When there is current pelvic inflammatory disease, unless adequate prior treatment has been instituted.
7. Where vaginal delivery is not indicated, e.g. placenta praevia or active herpes genitalis.
8. When there has been unexplained vaginal bleeding during the pregnancy.
9. When there is abnormal cardiotocography or suspected fetal compromise.
10. In the presence of any suggestion of uterine hyperstimulation or hypertonic uterine contractions.

4.4 Special Warnings and Precautions for Use

For hospital use only.

Cervidil should be administered only by trained obstetrical personnel in a hospital setting with appropriate obstetrical care facilities.
The condition of the cervix should be assessed carefully before Cervidil is used.
Use with caution in patients with cervical (Bishop) scores of 8 or more.
After insertion, Cervidil should be positioned transversely into the posterior fornix of the vagina (Figure 1). Incorrect positioning of the pessary (vaginal insert) could lead to the loss of device from the vagina and consequent lack of efficacy, due to insufficient exposure of the cervix to the appropriate sustained concentrations of prostaglandin.
The experience of Cervidil in patients with ruptured membranes is limited. Therefore, Cervidil 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.
After insertion, uterine activity, fetal condition and the progression of cervical dilatation and effacement must be monitored regularly. Cervidil 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 pessary (vaginal insert) should be removed.
Since prostaglandins potentiate the effect of oxytocin, Cervidil must be removed before oxytocin administration is initiated (also see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions) and the patient's uterine activity carefully monitored for uterine hyperstimulation.
If uterine hyperstimulation is encountered or if labour commences, the pessary (vaginal insert) should be removed immediately. Cervidil should also be removed prior to amniotomy.
If uterine contractions are prolonged or excessive, there is a 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 Cervidil, mainly in patients with contra-indicated conditions.
Cervidil should be used with caution in patients with compromised cardiovascular function.
Cervidil should be used with caution in patients with a previous history of uterine hypertony, glaucoma, epilepsy or asthma.
Cervidil should be used with caution in patients who have had more than three full term deliveries.
Medication with nonsteroidal anti-inflammatory drugs, including aspirin, should be stopped before administration of PGE2.
A second dose of Cervidil is not recommended, as the effects of a second dose have not been studied.
As with other oxytocic agents, the possibility of uterine rupture should be considered in the presence of excessive uterine activity or unusual uterine pain.
Women aged 35 and over, women with complications during pregnancy, such as gestational diabetes, arterial hypotension and hypothyroidism, and women at gestational age above 40 weeks have a higher postpartum risk of developing disseminated intravascular coagulation (DIC). These factors may additionally enhance the risk of disseminated intravascular coagulation in women with pharmacologically induced labour (also see Section 4.8 Adverse Effects (Undesirable Effects)). Therefore, dinoprostone and oxytocin should be used with caution in these women. In the immediate postpartum phase the physician should continue to monitor for early signs of a developing DIC (e.g. fibrinolysis).
The clinician should be alert to 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).

Use in the elderly.

No data available.

Paediatric use.

The safety and efficacy of Cervidil in pregnant women aged less than 18 years has not been established. No data are available.

Renal, pulmonary and hepatic impairment.

The use of Cervidil in patients with diseases which could affect the metabolism or excretion of PGE2, e.g. liver, lung or kidney disease, has not been specifically studied. The use of Cervidil in such patients is not recommended.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

No dedicated interaction studies have been performed with Cervidil.
Prostaglandins potentiate the uterotonic effect of oxytocic drugs. Concurrent use of Cervidil in patients receiving oxytocics is not recommended. A waiting period of at least 30 minutes is recommended before sequential use of oxytocin following the removal of the dinoprostone pessary (vaginal insert) (also see Section 4.4 Special Warnings and Precautions for Use). No other drug interactions have been identified.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Fertility studies have not been conducted with Cervidil.
(Category C)
Prostaglandin E2 has produced an increase in skeletal anomalies in rats and rabbits. No effect would be expected clinically, when used as indicated, since Cervidil is administered after the period of organogenesis. Prostaglandin E2 has been shown to be embryotoxic in rats and rabbits. Specific fetotoxicity studies of this dose form of PGE2 have not been conducted. However, an increase in stillbirths was noted when PGE2 containing pessary (vaginal insert) were used in studies in pregnant rats. There has been idiosyncratic sensitivity of the uterus resulting in anoxia. Any dose that produces sustained increased uterine tone could put the embryo or fetus at risk.
The product is for the initiation and/or continuation of cervical ripening in pregnant patients at term (from 37 completed weeks) only where labour induction is indicated. Cervidil is not indicated for use during early or other phases of pregnancy.
Cervidil is not indicated for use during lactation.
No studies have been performed to investigate the amount of dinoprostone in colostrum or breast milk following the use of Cervidil.
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.

4.8 Adverse Effects (Undesirable Effects)

Cervidil is well tolerated.
Table 1 presents adverse events reported in the Phase-3 study (Miso-Obs-303) that compared MISODEL (n=678) to 10 mg dinoprostone vaginal insert (DVI) (n=680) in women at term or near term gestation.
(See Table 2.)
In study 101-801, five minute Apgar scores were below 7 in 1.8% (646/658) of studied neonates whose mothers received Cervidil for up to 12 hours. In Miso-Obs-303, where Cervidil was inserted up to 24 hours, five minute Apgar scores of below 7 were reported in neonates of 1% of participants.
In a report of a 3 year paediatric follow-up study in 121 infants, 51 of whose mothers received Cervidil for up to 12 hours, there were no deleterious effects on physical examination or psychomotor evaluation.

Postmarketing experience.

(See Table 3.)
An increased risk of post-partum disseminated intravascular coagulation (DIC) has been reported in patients whose labour was induced by pharmacological means, either with dinoprostone or oxytocin.
In Postmarketing Experience Reports, uterine rupture has been reported in association with the use of Cervidil.

Influence of removal of Cervidil on adverse events.

In study 101-801 (with the retrieval system) cases of hyperstimulation reversed within 2 to 13 minutes of removal of the product. Tocolytics were required in one of the five cases.
In cases of fetal distress, when product removal was thought advisable, there was a return to normal rhythm and no neonatal sequelae.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration 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 at www.tga.gov.au/reporting-problems.

4.2 Dose and Method of Administration

Administration.

Cervidil should be removed from the freezer immediately prior to the insertion. No thawing is required prior to use. To remove Cervidil from the packaging, first tear the foil along the tear mark across the top of the sachet. Do not use scissors or sharp instruments to cut the foil as this may damage the product. Use the retrieval tape to gently pull the product out of the sachet.
The pessary (vaginal insert) should be inserted immediately after removal from the freezer and its foil package; however, controlled periods of time of up to one month at 2-8°C can be allowed within the shelf life of the product. Cervidil must not be used without its retrieval system.
One pessary (vaginal insert) should be inserted high into the posterior vaginal fornix using only small amounts of water soluble lubricants to aid insertion (see Figure 1). After Cervidil 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 30 minutes after insertion. As PGE2 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 pessary (vaginal insert) can be removed quickly and easily by gentle traction on the retrieval tape. After removal ensure that the entire product, pessary (vaginal insert) and retrieval system, has been removed from the vagina.
It is necessary to remove the pessary (vaginal insert) to terminate drug administration when cervical ripening is judged to be complete or for any of the reasons listed below.
1. Onset of labour. For the purposes of induction of labour with Cervidil, 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.
i. Once regular, painful contractions have been established with Cervidil, they will not reduce in frequency or intensity as long as Cervidil remains in situ because PGE2 is still being administered, nor will they reduce if Cervidil is removed because the woman is in labour.
ii. 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 Cervidil in situ, the pessary (vaginal insert) should be removed irrespective of cervical state to avoid the risk of uterine hyperstimulation.
2. Spontaneous rupture of the membranes or amniotomy.
3. Any suggestion of uterine hyperstimulation or hypertonic uterine contractions.
4. Evidence of fetal distress.
5. Evidence of maternal systemic adverse PGE2 effects such as nausea, vomiting, hypotension or tachycardia.
6. At least 30 minutes prior to starting an intravenous infusion of oxytocin.
7. If there has been insufficient cervical ripening in 24 hours.
On removal of the product from the vagina, the pessary (vaginal insert) will have swollen to 2-3 times its original size and be pliable. The whole product should be disposed of as clinical waste.

4.7 Effects on Ability to Drive and Use Machines

The effects of Cervidil on a person's ability to drive and use machines were not assessed as part of its registration.

4.9 Overdose

Cervidil is used as a single dosage in a single application. Overdosage is usually manifested by uterine hyperstimulation which may or may not be accompanied by fetal distress. If fetal distress occurs, remove the pessary (vaginal insert) immediately and manage in accordance with local protocol. Other treatment must be symptomatic since, to date, clinical experience with prostaglandin antagonists is insufficient.
The use of beta-adrenergic agents should be considered in the event of undesirable increased uterine activity, if removal does not diminish the undesirable uterine activity.
For information on the management of overdose, contact the Poisons Information Centre on 131126 (Australia).

7 Medicine Schedule (Poisons Standard)

S4.

6 Pharmaceutical Particulars

6.1 List of Excipients

See Section 2 Qualitative and Quantitative Composition.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.
See Section 4.5 Interactions with Other Medicines and Other Forms of Interactions.

6.3 Shelf Life

3 years.

6.4 Special Precautions for Storage

Store in a freezer below -18°C. The pessary (vaginal insert) should be inserted immediately after removal from the freezer and its foil package, however, controlled periods of time of up to one month at 2 to 8°C can be allowed within the shelf life of the product.
Pessaries (vaginal inserts) exposed to high humidity will absorb moisture from the air and thereby alter the release characteristics of dinoprostone. Once used, the pessary (vaginal insert) should be discarded.

6.5 Nature and Contents of Container

Cervidil is presented in an individual, sealed aluminium/polyethylene laminate sachet containing 1 pessary (vaginal insert).
The hydrogel polymer of Cervidil is prepared with polyethylene glycol 8000, dicyclohexyl methane-4, 4'-diisocyanate and 1,2,6-Hexanetriol.

6.6 Special Precautions for Disposal

After usage, the whole product should be disposed of as clinical waste.

Summary Table of Changes