Consumer medicine information

Cervidil

Dinoprostone

BRAND INFORMATION

Brand name

Cervidil

Active ingredient

Dinoprostone

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Cervidil.

SUMMARY CMI

CERVIDIL®

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or midwife.

1. Why am I being given CERVIDIL?

CERVIDIL can be used to prepare the birth canal in women who require, and have favourable features for, induction of labour after 37 weeks of pregnancy have been completed. It helps the part of the birth canal, known as the cervix, to soften and open to allow the baby through. It contains the active ingredient dinoprostone.

There can be several reasons why you might need treatment with CERVIDIL. Ask your doctor if you would like to know more.

For more information, see Section 1. Why am I being given CERVIDIL? in the full CMI.

2. What should I know before I am given CERVIDIL?

CERVIDIL should not be used if you have ever had an allergic reaction to dinoprostone, urethane, or any of the ingredients listed at the end of the CMI.

There are several circumstances in which CERVIDIL should not be used or when it should only be used with additional caution.

Talk to your doctor if you have any other medical conditions or take any other medicines.

For more information, see Section 2. What should I know before I am given CERVIDIL? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with CERVIDIL and affect how it works. This includes aspirin and other NSAIDs.

Refer to Section 3. What if I am taking other medicines? in the full CMI for more information.

You must not be given CERVIDIL if you are being given, or will be given within the next 30 minutes, other medicines to make your womb contract or bring on (induce) labour, e.g. oxytocin.

4. How will I be given CERVIDIL?

  • CERVIDIL must only be used in a hospital setting by healthcare professionals trained in the care of women and babies during pregnancy and childbirth. Facilities for continuous monitoring of you and your baby must be available.
  • While you are lying down, your doctor or midwife will place one pessary next to the cervix in your vagina.
  • The active ingredient dinoprostone will be released from CERVIDIL until it is removed by your doctor or midwife, up to a maximum of 24 hours after it was first given to you.

More information can be found in Section 4. How will I be given CERVIDIL? in the full CMI.

5. What should I know while using CERVIDIL?

Things you should do
  • Tell your doctor or midwife if you experience any nausea or vomiting or if you feel unwell in other ways. They may decide to remove the pessary if you have adverse effects.
Things you should not do
  • Do not remove the pessary yourself. CERVIDIL should only be inserted and removed by trained healthcare professionals.

For more information, see Section 5. What should I know while using CERVIDIL? in the full CMI.

6. Are there any side effects?

CERVIDIL may contribute to increased or abnormal contractions of the womb, with possible effects on the progress of your labour, or on you or your baby. The effects on you or your baby may depend on the strength of your contractions. For more information, see Section 6. Are there any side effects? in the full CMI.

Use of CERVIDIL may also contribute to other risks of having labour induced, including heavy vaginal bleeding, inflammation of the membranes lining the inside of the womb, or the risk of a serious condition affecting blood clotting, known as Disseminated Intravascular Coagulation (DIC).

Other side effects can include headache, decrease in blood pressure, itching, swelling or feeling of burning in the genitals, fever, abdominal pain, nausea, vomiting, or diarrhoea. Allergic reactions, including anaphylaxis, have also been reported.



FULL CMI

CERVIDIL®

Active ingredient: dinoprostone

Consumer Medicine Information (CMI)

This leaflet provides important information about using CERVIDIL. You should also speak to your doctor or midwife if you would like further information or if you have any concerns or questions about being given CERVIDIL.

Where to find information in this leaflet:

1. Why am I being given CERVIDIL?
2. What should I know before I am given CERVIDIL?
3. What if I am taking other medicines?
4. How will I be given CERVIDIL?
5. What should I know while using CERVIDIL?
6. Are there any side effects?
7. Product details

1. Why am I being given CERVIDIL?

CERVIDIL can be used to prepare the birth canal in women who require, and have favourable features for, induction of labour after 37 weeks of pregnancy have been completed. It helps the part of the birth canal known as the cervix to soften and open to allow the baby through.

There can be several reasons why you might need treatment with CERVIDIL. Ask your doctor if you would like to know more.

CERVIDIL contains the active ingredient dinoprostone, also known as Prostaglandin E2 or PGE2. PGE2 also occurs naturally in the body and has an important role during childbirth.

CERVIDIL comes in the form of a pessary (vaginal insert) which is placed in the vagina before the start of labour.

The pessary is held within a pouch attached to a withdrawal tape. Pouch and tape are made of knitted polyester yarn.

When placed in the vagina, the pessary takes up some of the moisture there. This allows the active ingredient, dinoprostone, to be released at a constant rate until the pessary is removed by your doctor or midwife by pulling the withdrawal tape.

CERVIDIL must only be used in a hospital setting by healthcare professionals trained in the care of women and babies during pregnancy and childbirth. Facilities for continuous monitoring of you and your baby must be available.

Ask your doctor or midwife if you have any questions about why this medicine has been prescribed for you. Your doctor may have prescribed CERVIDIL for another reason.

2. What should I know before I am given CERVIDIL?

Warnings

CERVIDIL should not be used if:

  • you are allergic to dinoprostone, or any of the ingredients (e.g. urethane) listed at the end of this leaflet
    Always check the ingredients to make sure you can use this medicine.
  • you have had previous womb surgery, including caesarean section, or rupture of the cervix or the womb
  • you have had unexplained vaginal bleeding during this pregnancy
  • you are carrying more than one baby
  • there is any reason why you should not have a vaginal delivery, e.g., active genital herpes or if the placenta is blocking the birth canal
  • your baby's head is too big, or the size of your pelvis is too small for a vaginal delivery
  • your baby is not in the normal position for birth, including
    - if your baby is in a breech position (not head down into the pelvis)
  • you have untreated pelvic inflammatory disease (an infection in the womb, ovaries, tubes and/or cervix)
  • it is suspected, or tests show, your baby is unwell or not growing.

Your doctor will not give you CERVIDIL or will remove it after it has been given to you:

  • if your contractions are too strong or prolonged
  • if your baby becomes distressed
  • once labour starts
  • if you experience nausea or vomiting, if your blood pressure drops, or if you have an elevated heart rate
  • if, following insertion your cervix still hasn't softened and opened enough in 24 hours
  • if you need to be given a medicine such as oxytocin to help your labour progress.

There is limited experience of using CERVIDIL if your waters have already broken. Your doctor will remove CERVIDIL after it has been given to you if your waters break or are going to be broken by the doctor.

Check with your doctor if you:

  • had difficulties or unusually strong or prolonged contractions delivering a previous baby
  • have had more than three full term deliveries
  • have or have had any other medical conditions, such as:
    - problems with your heart or blood pressure
    - glaucoma (raised pressure in the eye)
    - epilepsy
    - asthma
    - liver, lung or kidney disease
  • are 35 years or older or younger than 18 years of age
  • have had complications during this pregnancy, e.g. gestational diabetes, low blood pressure, thyroid problems, or if your pregnancy has passed 40 weeks
  • take any medicines for any other condition (see Section 3. What if I am taking other medicines?).

You will be examined carefully before being given CERVIDIL to determine if CERVIDIL is the right treatment for you. This will include a vaginal examination to check the condition of your cervix and whether the membranes around the baby are intact.

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Pregnancy and breastfeeding

CERVIDIL is used to help start the birth process provided that 37 weeks of pregnancy have been completed. CERVIDIL should not be used at other phases of pregnancy.

The use of CERVIDIL during breastfeeding has not been investigated. A small amount of the active ingredient in CERVIDIL may pass into breastmilk for a short time but this should not hinder breastfeeding. No effects on the breastfed newborn have been observed.

3. What if I am taking other medicines?

Tell your doctor or midwife if you are taking any other medicines, including any medicines, vitamins or supplements that you buy without a prescription from your pharmacy, supermarket or health food shop.

You must not be given CERVIDIL if you are being given, or will be given within the next 30 minutes, other medicines to make your womb contract or bring on (induce) labour, e.g. oxytocin.

You should also stop taking aspirin or any other non-steroidal anti-inflammatory drugs (known as NSAIDs) before CERVIDIL is used. Some examples of NSAIDs are naproxen, diclofenac and ibuprofen.

Check with your doctor or midwife if you are not sure about what medicines, vitamins or supplements you are taking and if these could affect CERVIDIL.

4. How will I be given CERVIDIL?

How much you will be given

  • CERVIDIL is given as one pessary placed into the vagina once only.
  • Dinoprostone is slowly released from the CERVIDIL pessary while it remains in place.
  • Use of a second pessary is not recommended as the effects of a second dose have not been studied.

When you will be given CERVIDIL

  • You will be given CERVIDIL when you have completed at least 37 weeks of pregnancy and before your labour has started.
  • CERVIDIL is used to help start the birth process. There can be several reasons why you might need help to start this process. Ask your doctor or midwife if you would like to know more.

How you are given CERVIDIL

CERVIDIL must only be used in a hospital setting by healthcare professionals trained in the care of women and babies during pregnancy and childbirth. Facilities for continuous monitoring of you and your baby must be available.

Your doctor or midwife will place one pessary next to the cervix in your vagina. You should not do this yourself. Your doctor or midwife will coat the pessary with a small amount of lubricating jelly before putting it in place. Enough of the withdrawal tape will be left outside the vagina, so that the pessary can be easily pulled out when it is time to remove it.

You should be lying down during this procedure and you will have to stay that way for about 30 minutes after the pessary is put in.

When placed in position, the pessary takes up some of the moisture there. This allows the dinoprostone to be slowly released.

When CERVIDIL will be removed

Your doctor or midwife will decide how long CERVIDIL needs to be kept in place, depending on your progress. CERVIDIL can be left in place for a maximum of 24 hours.

For example, they may remove the CERVIDIL pessary if:

  • your uterus is contracting too strongly
  • your labour has started
  • your waters have broken
  • your doctor wants to use a different medicine to help your womb contract, e.g. oxytocin
  • you or your baby is experiencing adverse effects.

Your doctor or midwife will remove the pessary by gently pulling the withdrawal tape.

On removal from the vagina the pessary will have swollen to 2-3 times of its original size and will be pliable.

5. What should I know while using CERVIDIL?

Things you should do

CERVIDIL can be left in place for a maximum of 24 hours depending on your progress. Whilst the pessary remains in place, you will be examined regularly amongst other things for:

  • opening of your cervix
  • uterine contractions
  • the continuing health of you and your baby.

Tell your doctor or midwife if you experience any nausea or vomiting or if you feel unwell in other ways. They may decide to remove the pessary if you have adverse effects.

Things you should not do

Do not remove the pessary yourself. CERVIDIL should only be inserted and removed by trained healthcare professionals.

Looking after your medicine

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

Getting rid of any unwanted medicine

The used pessary will be disposed of by the hospital as clinical waste.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

See the information below and, if you need to, ask your doctor or midwife if you have any further questions about side effects.

Tell your doctor or midwife if you notice any of the following and they worry you:

  • headache
  • itching
  • feeling of burning in the genitals
  • fever
  • abdominal pain
  • nausea
  • vomiting
  • diarrhoea.

These side effects are not usually serious but can become serious. Talk to your doctor or midwife if you have any concerns.

Some side effects will be monitored by your healthcare team, for example:

  • discoloured amniotic fluid
  • decrease in blood pressure
  • slow progress of the birthing process
  • slow shrinking of the womb after delivery
  • swelling of the genitals.

Some side effects can be serious, for example:

  • increased or abnormal contractions of the womb which may or may not affect the baby
  • placenta detaches from the wall of the womb before the baby is delivered
  • heavy bleeding from the vagina following delivery
  • hypersensitivity reaction and severe allergic reactions (anaphylactic reaction), which can include: difficult breathing, shortness of breath, weak or rapid pulse, dizziness, redness of skin and rash
  • Disseminated Intravascular Coagulation (DIC), a rare condition which affects blood clotting and can lead to serious bleeding, possibly from multiple sites
  • anaphylactoid syndrome of pregnancy, a rare condition caused when the amniotic fluid that surrounds the baby in the womb passes into the mother's bloodstream during delivery and blocks a blood vessel. This can lead to shortness of breath, low blood pressure, anxiety, chills, seizures, coma, bleeding and fluid in the lungs.

Possible effects on your baby:

  • signs of distress, e.g. heart rate faster or slower than normal
  • depressed Apgar score (measures how well the baby is doing immediately after birth)
  • difficulty breathing after birth
  • jaundice (yellowing of skin and eyes).

These are very serious side effects, which can be life-threatening. They need urgent medical attention.

Your doctor and midwife will monitor you and remove the CERVIDIL pessary if your contractions become too strong. If contractions become too strong, there are risks to both the mother and baby, e.g. tearing of the womb and fetal distress which in very severe cases can result in loss of the baby.

Tell your doctor or midwife if you notice anything else that may be making you feel unwell.

Other side effects not listed here may occur in some people.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop using any of your medicines.

7. Product details

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

What CERVIDIL contains

Active ingredient
(main ingredient)		Dinoprostone
Other ingredients
(inactive ingredients)

The active ingredient is contained in a plastic (polyurethane) sustained release pessary made of:

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


The pessary is held within a pouch attached to a withdrawal tape. Pouch and tape are made of knitted polyester yarn.

Do not take this medicine if you are allergic to any of these ingredients.

What CERVIDIL looks like

The CERVIDIL pessary is a small piece of plastic in the shape of a rectangle with rounded corners, contained in a knitted retrieval system (in the pouch with the withdrawal tape). The plastic piece is a hydrogel polymer which swells in the presence of moisture to release dinoprostone. The retrieval system has a long tape which allows the doctor or midwife to remove it when necessary.

CERVIDIL contains 10 mg dinoprostone as a pessary in an aluminium/polyethylene foil sachet. Each sachet contains 1 pessary (AUST R 81391).

Who distributes CERVIDIL

CERVIDIL is distributed in Australia by:

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

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

This leaflet was prepared in September 2022.

DOCS#37784-v4E

Published by MIMS December 2022

BRAND INFORMATION

Brand name

Cervidil

Active ingredient

Dinoprostone

Schedule

S4

 

1 Name of Medicine

Dinoprostone (prostaglandin E2, PGE2).

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 semi-opaque, 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.

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.

4.2 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 administration of other uterotonic medicines, e.g. oxytocin.
7. If there has been insufficient cervical ripening in 24 hours.
Upon 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.

4.3 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 uterotonic medicines 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. Who have had previous uterine cervix surgery or rupture of the cervix.
c. With cephalopelvic disproportion.
d. With fetal malpresentation.
e. With suspicion or evidence of fetal distress (e.g. abnormal cardiotocography).
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 units with facilities for continuous fetal and uterine monitoring.
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, uterine activity, fetal condition and the progression of cervical dilatation and effacement, must be monitored carefully and regularly by qualified healthcare personnel. If there is any suggestion of maternal or fetal complications, or if adverse effects occur, the pessary (vaginal insert) should be removed.
Uterine rupture has been reported in association with the use of Cervidil, mainly in patients with contraindicated conditions (see Section 4.3 Contraindications). Therefore, Cervidil 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.
If uterine contractions are prolonged or excessive, there is a possibility of uterine hypertonus or rupture and the vaginal insert should be removed immediately.
As with other uterotonic medicines, the possibility of uterine rupture should be considered in the presence of excessive uterine activity or unusual uterine pain.
Prostaglandins potentiate the uterotonic effect of uterotonic medicines. Cervidil must be removed at least 30 minutes before administration of other uterotonic medicines (e.g. oxytocin) is initiated (also see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions), and the patient's uterine activity monitored carefully 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.
A second dose of Cervidil is not recommended, as the effects of a second dose have not been studied.
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.
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.
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.
Cervidil should be used with caution in patients who have had more than three full term deliveries.
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 DIC in women with pharmacologically induced labour (also see Section 4.8 Adverse Effects (Undesirable Effects)). Therefore, dinoprostone 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 that, as with other labour induction methods, use of dinoprostone may result in inadvertent abruption of placenta and subsequent embolisation 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 uterotonic medicines. Concurrent use of Cervidil in patients receiving other uterotonic medicines is not recommended. A waiting period of at least 30 minutes is recommended before sequential use of other uterotonic medicines (e.g. oxytocin) following the removal of Cervidil (also see Section 4.4 Special Warnings and Precautions for Use).
Medication with non-steroidal anti-inflammatory medicines, including aspirin, should be stopped before administration of Cervidil.

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.
Cervidil 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.

4.7 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.

4.8 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 (misoprostol 200 micrograms vaginal insert) (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 DIC has been reported in patients whose labour was induced by pharmacological means, either with dinoprostone or oxytocin.
In post-marketing 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.

4.9 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).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

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 3 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 3 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 3 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.

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.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

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).

6.6 Special Precautions for Disposal

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

6.7 Physicochemical Properties

Chemical structure.

The structural formula is represented below:
Molecular formula: C20H32O5. Molecular weight: 352.5.

CAS number.

363-24-6.
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.

7 Medicine Schedule (Poisons Standard)

(S4) Prescription Only Medicine.

Summary Table of Changes