Cervidil - Product Information
|Form:||Vaginal (e.g., douche, pessary, etc.)|
|Ingredients:||dinoprostone, hydrogel polymer, macrogol 8000, dicyclohexylmethane-4,4’diisocyanate, 1,2,6-hexanetriol, polyester retrieval system|
Summary Product Information
|Route of |
|Dosage Form / |
|Clinically Relevant Nonmedicinal |
|Vaginal||10 mg||Hydrogel Polymer |
Polyester Retrieval system
Indications and Clinical Use
Cervdil (dinoprostone) is indicated for:
- Initiation and/or continuation of cervical ripening in patients at or near term in whom there is a medical or obstetrical indication for the induction of labour.
Geriatrics (> 65 years of age)
Cervidil has not been studied in this patient population and is not recommended for use.
Pediatrics (< 18years of age)
Cervidil has not been studied in this patient population and is not recommended for use.
Description of Vaginal Insert
CERVIDIL is a thin, flat, semi-transparent polymeric slab which is rectangular in shape with rounded corners contained within a knitted polyester retrieval system, as illustrated below.
Each insert contains 10 mg dinoprostone (prostaglandin E2) dispersed throughout its matrix, and releases approximately 0.3 mg/hour PGE2 over a 12 hour period. The reservoir of 10 mg dinoprostone serves to maintain constant release.
The retrieval system consists of a one-piece knitted polyester pouch and withdrawal tape. This ensures easy and reliable removal of the insert when the patient’s requirement for PGE2 has been fulfilled or an obstetric event makes it necessary to stop further drug administration.
CERVIDIL is contraindicated in:
- Patients who are hypersensitive to this drug or to any ingredient in the formulation or component of the container. For a complete listing, see the Dosage Forms, Composition and Packaging section of the product monograph.
- Patients in whom there is clinical suspicion or definite evidence of fetal distress where delivery is not imminent;
- Patients with placenta previa or unexplained vaginal bleeding during this pregnancy;
- Patients in whom there is evidence or strong suspicion of marked cephalopelvic disproportion;
- Patients in whom oxytocic drugs are contraindicated or when prolonged contraction of the uterus may be detrimental to fetal safety or uterine integrity (previous cesarean section or major uterine surgery);
- Multipara with 6 or more previous term pregnancies;
- Patients with a history of difficult labour and/or traumatic delivery;
- Patients with overdistension of uterus (multiple pregnancy, polyhydramnios);
- Patients with fetal malpresentation;
- Patients with a history of epilepsy whose seizures are poorly controlled;
- CERVIDIL should not be used simultaneously with other oxytocics; (See Warnings)
- CERVIDIL should not be used when there is a history of, or current pelvic inflammatory disease, unless adequate prior treatment has been instituted.
Warnings and Precautions
Serious Warnings and Precautions
For Hospital Use Only
Cervidil should be administered only by trained obstetrical personnel in a hospital setting with appropriate obstetrical care facilities.
Since prostaglandins potentiate the effect of oxytocin, CERVIDIL must be removed before oxytocin administration is initiated and the patient's uterine activity carefully monitored for uterine hyperstimulation.
If uterine hyperstimulation is encountered or if labour commences, the vaginal insert should be removed. CERVIDIL should also be removed prior to amniotomy. The vaginal insert should be removed if there is evidence of maternal systemic adverse PGE2 effects such as nausea, vomiting, hypotension or tachycardia.
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.
Caution should be exercised in the administration of CERVIDIL for cervical ripening in patients with a history of previous uterine hypertonicity, glaucoma, or a history of childhood asthma, even though there have been no asthma attacks in adulthood or unexplained genital bleeding during the current pregnancy.
Women aged 35 and over (occasionally also younger women), women with complications during pregnancy and women at gestational age above 40 weeks, have a higher risk for developing disseminated intravascular coagulation (DIC). These factors may enhance the risk of disseminated intravascular coagulation in women with pharmacologically induced labour.
Therefore, dinoprostone should be used with caution in these women. In the immediate post-partum phase the physician should look carefully for early signs of developing DIC (e.g. fibrinolysis).
Uterine activity, fetal status and the progression of cervical dilatation and effacement should be carefully monitored whenever the dinoprostone vaginal insert is in place. Any evidence of uterine hyperstimulation, sustained uterine contractions, fetal distress, or other fetal or maternal adverse reactions, should be a cause for consideration of removal of the insert. The possibility of uterine rupture and/or cervical laceration should be born in mind where hypertonic myometrial contractions are sustained.
Cephalopelvic relationships should be carefully evaluated before the use of CERVIDIL.
Prolonged treatment of newborn infants with prostaglandin E1 can induce proliferation of bone. There is no evidence that short term administration of prostaglandin E2 can cause similar bone effects.
Patients with severe renal disease and/or severe hepatic disease accompanied by metabolic aberrations should be dosed with caution.
Carcinogenesis and Mutagenesis
Long-term carcinogenicity and fertility studies have not been conducted with CERVIDIL (dinoprostone vaginal insert). No evidence of mutagenicity has been observed with prostaglandin E2 in the Unscheduled DNA Synthesis Assay, the Micronucleus Test, or Ames Assay.
Animal studies indicate that the prostaglandins may be teratogenic. No effect would be expected clinically, when used as indicated, since CERVIDIL (dinoprostone vaginal insert) is administered after the period of organogenesis. Any dose of the drug that produces sustained increased uterine tone could put the embryo or fetus at risk.
Cervidil is not indicated for use during early or other phases of pregnancy or during lactation.
Monitoring and Laboratory Tests
After insertion, the patient should remain supine and monitored for 2 hours for any evidence of uterine hyperstimulation, change in fetal heart rate or maternal blood pressure or heart rate.
If any of these changes occur, removal of Cervidil should be considered.
Adverse Drug Reaction Overview
Clinical Trial Adverse Drug Reactions
Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.
CERVIDIL is well tolerated. In placebo-controlled trials in which 658 women were entered and 320 received active therapy (218 without retrieval system, 102 with retrieval system), the following events were reported.
|Controlled Studies1||Study 101-8012|
|Uterine hyperstimulation |
with fetal distress
|Uterine hyperstimulation |
without fetal distress
|Fetal Distress without uterinehyperstimulation||3.8%||1.2%||2.9%||1.0%|
|1Controlled Studies (with and without retrieval system) |
2Controlled Study (with retrieval system)
Drug related fever, nausea, vomiting, diarrhea, and abdominal pain were noted in less than 1% of patients who received CERVIDIL.
The following table outlines the frequency of reported adverse events:
|Adverse Events (MedDRA Preferred Term)|
|Pregnancy, puerperium and perinatal conditions||Abnormal labour affecting fetus |
Fetal heart rate disorder
Fetal distress syndrome
|Nausea, vomiting, diarrhea|
|Blood and lymphatic |
and breast disorders
and perinatal conditions
|Disseminated intravascular coagulation |
An increased risk of post-partum disseminated intravascular coagulation has been reported in patients whose labour was induced by pharmacological means, either with dinoprostone or oxytocin.The frequency of this adverse event, however, appears to be rare (<1 per 1,000 pregnancies).
Very rare cases of anaphylactic reactions have been reported with the use of dinoprostone.
In Study 101-801 (with the retrieval system) all 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.
Five minute Apgar scores were 7 or above in 98.2% (646/658) of studied neonates whose mothers participated in placebo-controlled studies with CERVIDIL. A 3 year pediatric follow-up study in 121 infants whose mothers received PGE2, found no significant differences from a control group on physical examination or psychomotor evaluation.
Post-Market Adverse Drug Reactions
In post marketing experience reports, uterine rupture has been reported rarely in association with the use of Cervidil (see Warning and Precautions and Contraindications sections).
CERVIDIL may augment the activity of oxytocic agents and their concomitant use is not recommended. A dosing interval of at least 30 minutes is recommended for the sequential use of oxytocin following the removal of the dinoprostone vaginal insert. No other drug interactions have been identified.
Dosage and Administration
To remove Cervidil from the packaging, first tear the foil along the top of the sachet. Do not use scissors or sharp implements to cut the foil as this may damage the product. Use the retrieval system to gently pull the product out of the sachet.
After removal from the patient, ensure that the entire product (vaginal delivery system and retrieval system) has been removed from the vagina.
Recommended Dose and Dosage Adjustment
The dosage of dinoprostone in the vaginal insert is 10 mg designed to be released at approximately 0.3 mg/hour over a 12 hour period. CERVIDIL should be removed upon onset of active labour or 12 hours after insertion.
One CERVIDIL is placed transversely in the posterior fornix of the vagina immediately after removal from its foil package. The insertion of the vaginal insert does not require sterile conditions. The vaginal insert must not be used without its retrieval system. There is no need for previous warming of the product. A minimal amount of K-Y® jelly (or other water-miscible lubricant) may be used to assist in insertion of CERVIDIL. Care should be taken not to permit excess contact or coating with the lubricant and thus prevent optimal swelling and release of dinoprostone from the vaginal insert. Patients should remain in the supine position for 2 hours following insertion, but thereafter may be ambulatory.
CERVIDIL is used as a single dosage in a single application. Overdosage is usually manifested by uterine hyperstimulation which may be accompanied by fetal distress and is responsive to removal of the insert. 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
Action and Clinical Pharmacology
Mechanism of Action
Dinoprostone (PGE2) is a naturally-occurring biomolecule. It is found in low concentrations in most tissues of the body and functions as a local hormone. As with any local hormone, it is very rapidly metabolized in the tissues of synthesis. The rate limiting step for inactivation is regulated by the enzyme 15-hydroxyprostaglandin dehydrogenase (PGDH). Any PGE2 that escapes local inactivation is rapidly cleared to the extent of 95% on the first pass through the pulmonary circulation.
In pregnancy, PGE2 is secreted continuously by the fetal membranes and placenta and plays an important role in the final events leading to the initiation of labour. It is known that PGE2 stimulates the production of PGF2α which in turn sensitizes the myometrium to endogenous or exogenously administrated oxytocin. Although PGE2 is capable of initiating uterine contractions and may interact with oxytocin to increase uterine contractility, the available evidence indicates, that in the concentrations found during the early part of labour, PGE2 plays an important role in cervical ripening without affecting uterine contractions. This distinction serves as the basis for considering cervical ripening and induction of labour, usually by the use of oxytocin, as two separate processes.
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 fibers 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. This is associated with a concomitant increase in the amount of hydrophilic glycosaminoglycan, hyaluronic acid, and a decrease in dermatan sulfate. Failure of the cervix to undergo these natural physiologic changes, usually assessed by the method described by Bishop, prior to the onset of effective uterine contractions, results in an unfavourable outcome for successful vaginal delivery and may result in fetal compromise. It is estimated that in approximately 5% of the pregnancies the cervix does not ripen normally. In an additional 10-11% of pregnancies, labour must be induced for medical or obstetric reasons prior to the time of cervical ripening.
Pharmacotherapeutic group: oxytocics.
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 marked relaxation of the cervical smooth muscle fibres 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
PGE2 is rapidly metabolised primarily in the tissue of synthesis.
No correlation could be established between PGE2 release and plasma concentrations of its metabolite, PGEm. The relative contributions of endogenously and exogenously released PGE2 to the plasma levels of the metabolite PGEm could not be determined.
The reservoir of 10 mg dinoprostone serves to maintain a controlled and constant release. The release rate is approximately 0.3 mg per hour over 12 hours in women with intact membranes whereas release is higher and more variable in women with premature rupture of membranes.
Cervidil 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
Storage and Stability
Store in a freezer between -20oC and -10oC
Dosage Forms, Composition and Packaging
CERVIDIL (dinoprostone 10 mg vaginal insert) is available in a carton containing 1 insert within a retrieval system, enclosed in foil (aluminium/polyethylene) pack.
Each insert contains 10 mg of dinoprostone in 236 mg of a cross-linked polyethylene oxide/urethane polymer which is a semi-transparent, beige coloured, flat, 0.8 mm thick rectangular slab measuring 29 mm by 9.5 mm. The insert and its retrieval system, is made of polyester yarn, are non-toxic and when placed in a moist environment, absorbs water, swells, and releases dinoprostone.