Cervidil (Generic Name: dinoprostone)
By www.Drugs.com
Dosage Form: Vaginal insert
Rev. 5/06 Rx only
CERVIDIL DESCRIPTION: Dinoprostone vaginal insert is a thin, flat, polymeric slab which is rectangular in
shape with rounded corners contained within the pouch of an off-white knitted polyester retrieval system.
Each slab is buff colored, semitransparent and contains 10 mg of dinoprostone in a hydrogel insert. An
integral part of the knitted polyester retrieval system is a long tape designed to aid retrieval at the
end of the dosing interval or earlier if clinically indicated. The finished product is a controlled
release formulation which has been found to release dinoprostone in vivo at a rate of approximately 0.3 mg/hr.
The chemical name for dinoprostone (commonly known as prostaglandin E2 or PGE2) is 11α,
15S-dihydroxy-9-oxo-prosta-5Z,13E-dien-1-oic acid and the structural formula is represented below:
The molecular formula is C-20 H-32 O-5 and its molecular weight is 352.5. Dinoprostone occurs as a white
to off-white crystalline powder. It has a melting point within the range of 65° to 69°C.
Dinoprostone is soluble in ethanol and in 25% ethanol in water. Each insert contains 10 mg of dinoprostone
in 241 mg of a cross-linked polyethylene oxide/urethane polymer which is a semi-opaque, beige colored,
flat rectangular slab measuring 29 mm by 9.5 mm and 0.8 mm in thickness. The 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.
CERVIDIL - CLINICAL PHARMACOLOGY
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 (1-3). As with any local hormone, it is very rapidly metabolized
in the tissues of synthesis (the half-life estimated to be 2.5-5 minutes). The rate limiting step for
inactivation is regulated by the enzyme 15-hydroxyprostaglandin dehydrogenase (PGDH) (1,4). Any PGE2 that
escapes local inactivation is rapidly cleared to the extent of 95% on the first pass through the pulmonary
circulation (1,2).
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 labor (1,2). It is known that PGE2 stimulates the
production of PGF2α which in turn sensitizes the myometrium to endogenous or exogenously administered
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 labor, PGE2 plays an important role in cervical ripening without affecting uterine
contractions (5-7). This distinction serves as the basis for considering cervical ripening and induction
of labor, usually by the use of oxytocin (8-10), 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 (11-13). This process involves
activation of the enzyme collagenase which is responsible for digestion of some of the structural collagen
network of the cervix (1, 14). This is associated with a concomitant increase in the amount of hydrophilic
glycosaminoglycan, hyaluronic acid and a decrease in dermatan sulfate (1). Failure of the cervix to undergo
these natural physiologic changes, usually assessed by the method described by Bishop (15,16), prior to the
onset of effective uterine contractions, results in an unfavorable outcome for successful vaginal delivery
and may result in fetal compromise. It is estimated that in approximately 5% of pregnancies the cervix does
not ripen normally (17). In an additional 10-11% of pregnancies, labor must be induced for medical or
obstetric reasons prior to the time of cervical ripening (17).
The delivery rate of PGE2 in vivo is about 0.3 mg/hour over a period of 12 hours. The controlled release
of PGE2 from the hydrogel insert is an attempt to provide sufficient quantities of PGE2 to the local receptors
to satisfy hormonal requirements. In the majority of patients, these local effects are manifested by
changes in the consistency, dilatation and effacement of the cervix as measured by the Bishop score.
Although some patients experience uterine hyperstimulation as a result of direct PGE2 - or PGF2α -
mediated sensitization of the myometrium to oxytocin, systemic effects of PGE2 are rarely encountered.
The insert is fitted with a biocompatible retrieval system which facilitates removal at the conclusion of
therapy or in the event of an adverse reaction.
No correlation could be established between PGE2 release and plasma concentrations of PGEm. The relative
contributions of endogenously and exogenously released PGE2 to the plasma levels of the metabolite PGEm
could not be determined. Moreover, it is uncertain as to whether the measured concentrations of PGEm
reflect the natural progression of PGEm concentrations in blood as birth approaches or to what extent the
measured concentrations following PGE2 administration represent an increase over basal levels that might
be measured in control patients.
INDICATIONS & USAGE FOR CERVIDIL
Cervidil Vaginal Insert (dinoprostone, 10 mg) is indicated for the 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 labor.
CONTRAINDICATIONS
Cervidil is contraindicated in:
- Patients with known hypersensitivity to prostaglandins.
- Patients in whom there is clinical suspicion or definite evidence of fetal distress where delivery
is not imminent.
- Patients with 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, such as previous cesarean section or
major uterine surgery (see PRECAUTIONS and ADVERSE REACTIONS).
- Patients already receiving intravenous oxytocic drugs.
- Multipara with 6 or more previous term pregnancies.
WARNINGS
For hospital use only.
Cervidil should be administered only by trained obstetrical personnel in a hospital setting with
appropriate obstetrical care facilities.
PRECAUTIONS
1. General Precautions: 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 labor commences, the vaginal
insert should be removed. Cervidil should also be removed prior to amniotomy.
Cervidil is contraindicated when prolonged contraction of the uterus may be detrimental to fetal safety
and uterine integrity. Therefore, Cervidil should not be administered to patients with a history of previous
cesarean section or uterine surgery given the potential risk for uterine rupture and associated obstetrical
complications.
Caution should be exercised in the administration of Cervidil for cervical ripening in patients with
ruptured membranes, in cases of non-vertex or non-singleton presentation, and in patients with a history
of previous uterine hypertony, glaucoma, or a history of childhood asthma, even though there have been
no asthma attacks in adulthood.
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.
2. Drug Interactions: 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.
3. Carcinogenesis, Mutagenesis, Impairment of Fertility: 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.
4. Pregnancy, Teratogenic Effects: Pregnancy 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 (dinoprostone) Vaginal Insert is administered after the period of organogenesis.
Prostaglandin E2 has been shown to be embryotoxic in rats and rabbits, and any dose that produces sustained
increased uterine tone could put the embryo or fetus at risk.
5. Pediatric Use: The safety and efficacy of Cervidil has been established in women of a reproductive
age and women who are pregnant. Although safety and efficacy has not been established in pediatric patients,
safety and efficacy are expected to be the same for adolescents.
ADVERSE REACTIONS
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.
Table 1 Total Cervidil – Treated Drug Related Adverse Events
1Controlled Studies (with and without retrieval system) |
2Controlled Study (with retrieval system) |
|
Controlled Studies1
|
|
Active |
Placebo |
Uterine hyperstimulation
with fetal distress |
2.8% |
0.3% |
Uterine hyperstimulation
without fetal distress |
4.7% |
0% |
Fetal Distress without
uterine hyperstimulation |
3.8% |
1.2% |
| N |
320 |
338 |
|
STUDY 101-8012
|
|
Active |
Placebo |
Uterine hyperstimulation
with fetal distress |
2.9% |
0% |
Uterine hyperstimulation
without fetal distress |
2.0% |
0% |
Fetal Distress without
uterine hyperstimulation |
2.9% |
1.0% |
| N |
102
|
104 |
In Postmarketing Experience Reports, uterine rupture has been reported in association with the use of Cervidil.
Drug related fever, nausea, vomiting, diarrhea, and abdominal pain were noted in less than 1% of patients
who received Cervidil.
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.
Five minute Apgar scores were 7 or above in 98.2% (646/658) of studied neonates whose mothers received
Cervidil. In a report of a 3 year pediatric follow-up study in 121 infants, 51 of whose mothers received
Cervidil, there were no deleterious effects on physical examination or psychomotor evaluation (18).
DRUG ABUSE & DEPENDENCE
No drug abuse or dependence has been seen with the use of Cervidil.
OVERDOSAGE
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.
CERVIDIL DOSAGE & ADMINISTRATION
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 labor or 12 hours after
insertion.
Cervidil is supplied in an individually wrapped aluminum/polyethylene package with a "tear mark"
on one side of the package. The package should only be opened by tearing the aluminum package along the
tear mark. The package should never be opened with scissors or other sharp objects which may compromise
or cut the knitted polyester pouch that serves as the retrieval system for the polymeric slab.
Cervidil must be kept frozen until use, and is administered by placing one unit 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 water-miscible
lubricant may be used to assist insertion of Cervidil. Care should be taken not to permit excess contact
or coating with the lubricant which could prevent optimal swelling and release of dinoprostone from the
vaginal insert. Patients should remain in the recumbent position for 2 hours following insertion, but
thereafter may be ambulatory. If the patient is ambulatory, care should be taken to ensure the vaginal
insert remains in place. If uterine hyperstimulation is encountered or if labor commences, the vaginal
insert should be removed. Cervidil should also be removed prior to amniotomy.
Upon removal of Cervidil, it is essential to ensure that the slab has been removed, as it will continue
delivering the active ingredient. This is accomplished by visualizing the knitted polyester retrieval
system and confirming that it contains the slab. In the rare instance that the slab is not contained
within the polyester retrieval system, a vaginal exam should be performed to remove the slab.
HOW IS CERVIDIL SUPPLIED
Cervidil (NDC 0456-4123-63) contains 10 mg dinoprostone. The product is wound and enclosed in an
aluminum/polyethylene pack. Cervidil is stored in a freezer: between -20°C and -10°C (-4°F
and 14°F). Cervidil is packed in foil and is stable when stored in a freezer for a period of
three years. Vaginal inserts exposed to high humidity will absorb moisture from the air and thereby
alter the release characteristics of dinoprostone. Once used, the vaginal insert should be discarded.
CLINICAL STUDIES
Table 2 Efficacy of Cervidil in Double Blind Studies
|
|
Primip/Nullip |
Multip |
|
| Parameter |
Study # |
Cervidil |
Placebo |
Cervidil |
Placebo |
P-Value |
Treatment success was defined as Bishop score
increase at 12 hours of≥ 3, vaginal delivery within 12 hours or Bishop score at 12 hours≥ 6.
These studies were not designed with the power to show differences in cesarean section rates between
Cervidil and placebo groups and none were noted. |
| Treatment Success* |
101-103 (N=81) |
65% |
28% |
87% |
29% |
<0.001 |
101-003
(N=371) |
68% |
24% |
77% |
24% |
<0.001 |
101-801
(N=206) |
72% |
48% |
55% |
41% |
0.003 |
| Time to Delivery (hours) |
|
|
|
|
|
|
| Average Median |
101-103 (N=81) |
33.7
25.7 |
48.6
34.5 |
14.0
12.3 |
28.6
24.6 |
0.001 |
| Average Median |
101-801
(N=206) |
31.1
25.5 |
51.8
37.2 |
52.3
20.8 |
45.9
27.4 |
<0.001 |
| Time to Onset of Labor (hrs) |
|
|
|
|
|
|
| Average Median |
101-103 (N=81) |
19.9
12.0 |
39.4
19.2 |
6.8
6.9 |
22.4
18.3 |
<0.001 |
References
- Physiology of Labor In: Williams Obstetrics. Eds. Pritchard, J. A., MacDonald, P. C., and Gant, N.F. Appleton-Century-Crofts, Conn, Pp 295-321, (1985).
- Rall, T. W. and Schliefer, L. S. Oxytocin, prostaglandin, ergot alkaloids, and other drugs; tocolytics agents, In: The Pharmacological Basis of Therapeutics. Eds. Gilman, A.G., Goodman, L.S., Rall, T.W., and Murad, F. MacMillan, Publ. Co., New York, Pp. 926-945, (1985).
- Casey, M.L. and MacDonald, P.C. The initiation of labor in women: Regulation of phospholipid and arachidonic acid metabolism and of prostaglandin production. Semin. Perinat. 10:270-275, (1986).
- Casey, M.L., MacDonald, P.C. and Mitchell, M.D. Stimulation of Prostaglandin E2 production in amnion cells in culture by a substance(s) in human fetal urine. Biochem. Biophys. Res. Comm. 114:1056, (1983).
- Olson, C.M., Lye, S.J., Skinner, K. and Challis, J.R.G. Prostanoid concentrations in maternal/fetal plasma and amniotic fluid and intrauterine tissue prostanoid output in relation to myometrial contractility during the onset of Endocrinology, 116: 389-397, (1985).
- Ledger, W.L., Ellwood, D.A., and Taylor, M.J. Cervical softening in late pregnant sheep by infusion of Prostaglandin E2 into cervical artery. J. Reprod. Fert. 69, 511-515, (1983).
- Olson, D.M., Lye, S.J., Skinner, K. and Challis, J.R.G. Early changes in prostaglandin concentrations in ovine maternal and fetal plasma, amniotic fluid and from dispersed cells of intrauterine tissues before the onset of ACTH-induced pre-term labor. J. Reprod. Fert., 71: 45-55, (1984).
- Caldero-Garcia, R. and Posiero, J. Oxytocin and the contractility of the human uterus, Ann, N. Y. Acad. Sci. 75:813, (1959).
- Posiero, J. and Noriega-Guerra, L. Dose-response relationships in uterine effects of oxytocin infusion. Oxytocin. Eds., Caldero-Garcia, R. and Heller, J. Pergamon Press, New York, (1961).
- Cibils, L. Enhancement of induction of labor. In: Risks in the Practice of Modern Obstetrics. Aldjem, S. Ed. Mosby Publishing, St. Louis, (1972).
- Bryman, I., Lindblom, B., and Norstrom, A. Extreme sensitivity of cervical musculature to prostaglandin E2 in early pregnancy. Lancet, 2:1471, (1982).
- Thiery, M. Induction of labor with prostaglandins. In: Human Parturition. Eds. Keirse, M.J.N.C., Anderson, A.B.M., and Gravenhorst, J.B. Martinus Nijhoff Publ., Boston, 155-164, (1979).
- Thiery, M. and Amy, J.J. Induction of labor with prostaglandins. In:Advances in Prostaglandin Research. Prostaglandin and Reproduction, Karim, S.M.M., Ed., MTP, Lancaster, Pp. 149-228, (1975).
- MacLennan, A.H., Katz, M., and Creasey, R. The morphologic characteristics of cervical ripening induced by the hormones relaxin and prostaglandin F2 in a rabbit model. Am. J. Obstet. Gynecol, 152:910696, (1985).
- Bishop, E. Elective induction of labor. Obstet & Gynecol, 5: 519-527, (1955).
- Bishop, E. Pelvic scoring for elective induction. Obstet & Gynecol. 24: 266-268, (1969).
- Thiery, M. Preinduction cervical ripening. In: Obstetrics and Gynecology Annual, Vol. 12, Ed. Wynn, R. M. Appleton-Century-Crofts, New York, Pp. 103-146, (1983).
- MacKenzie, I.; Information on File: Controlled Therapeutics (Scotland).
Mfg by:
Controlled Therapeutics
East Kilbride, Scotland, G74 5PB
Made in the U.K.
Distributed by: FOREST PHARMACEUTICALS, INC., Subsidiary of Forest Laboratories, Inc., St. Louis, MO 63045 USA
|
VBAC and Prostaglandin Induction
