DINOPROSTONE
DESCRIPTION:
CERVIPRIME Gel contains dinoprostone as the naturally occurring form of
prostaglandin E2 (PGE2) and is designated chemically as (5Z, 11alpha, 13E, 15S)
- 11,15 - Dihydroxy-9-oxo- prosta-5, 13-dien-1-oic acid. The molecular formula
is C20H32O5 and the molecular weight is 352.5. Dinoprostone occurs as a white to
off- white crystalline powder with a melting point within the range of 65 deg to
69 deg C. It is soluble in ethanol, in 25+ACU- ethanol in water, and in water to the
extent of 130 mg/100 mL. The active constituent of CERVIPRIME Gel is dinoprostone
0.5 mg/3 g (2.5 mL gel)+ADs- other constituents are colloidal silicon dioxide NF
(240 mg/3 g) and triacetin USP (2760 mg/3 g).
ACTIONS/CLINICAL PHARMACOLOGY:
CERVIPRIME Gel (dinoprostone) administered endocervically may stimulate the
myometrium of the gravid uterus to contract in a manner similar to contractions
seen in the term uterus during labor. Whether or not this action results from a
direct effect of dinoprostone on the myometrium has not been determined.
Dinoprostone is also capable of stimulating smooth muscle of the
gastrointestinal tract in humans. This activity may be responsible for the
vomiting and/or diarrhea that is occasionally seen when dinoprostone is used for
preinduction cervical ripening.
In laboratory animals, and also in humans, large doses of dinoprostone can lower
blood pressure, probably as a result of its effect on smooth muscle of the
vascular system. With the doses of dinoprostone used for cervical ripening this
effect has not been seen. In laboratory animals, and also in humans,
dinoprostone can elevate body temperature+ADs- however, with the dosing used for
cervical ripening this effect has not been seen.
In addition to an oxytocic effect, there is evidence suggesting that this agent
has a local cervical effect in initiating softening, effacement, and dilation.
These changes, referred to as cervical ripening, occur spontaneously as the
normal pregnancy progresses toward term and allow evacuation of uterine contents
by decreasing cervical resistance at the same time that myometrial activity
increases. While not completely understood, biochemical changes within the
cervix during natural cervical ripening are similar to those following PGE2-
induced ripening. Further, it has been shown that these changes can take place
independent of myometrial activity+ADs- however, it is quite likely that PGE2
administered endocervically produces effacement and softening by combined
contraction-inducing and cervical-ripening properties. There is evidence to
suggest that the changes that take place within the cervix are due to collagen
degradation resulting from collagenase secretion as a response, at least in
part, to PGE2.
Using an unvalidated assay, the following information was determined. When
CERVIPRIME Gel was administered endocervically to women undergoing preinduction
ripening, results from measurement of plasma levels of the metabolite 13,14-
dihydro- 15-keto-PGE2 (DHK-PGE2) showed that PGE2 was relatively rapidly
absorbed and the Tmax was 0.5 to 0.75 hours. Plasma mean Cmax for gel-treated
subjects was 433 51 pg/mL versus 137 24 pg/mL for untreated controls. In
those subjects in which a clinical response was observed, mean Cmax was 484
57 pg/mL versus 213 69 pg/mL in nonresponders and 219 92 pg/mL in
control subjects who had positive clinical progression toward normal labor.
These elevated levels in gel-treated subjects appear to be largely a result of
absorption of PGE2 from the gel rather than from endogenous sources.
PGE2 is completely metabolized in humans. PGE2 is extensively metabolized in the
lungs, and the resulting metabolites are further metabolized in the liver and
kidney. The major route of elimination of the products of PGE2 metabolism is the
kidneys.
INDICATIONS AND USAGE:
CERVIPRIME Gel is indicated for ripening an unfavorable cervix in pregnant women
at or near term with a medical or obstetrical need for labor
induction.
CONTRAINDICATIONS:
Endocervically administered CERVIPRIME Gel is not recommended for the following:
a. Patients in whom oxytocic drugs are generally contraindicated or where
prolonged contractions of the uterus are considered inappropriate, such as:
-- cases with a history of cesarean section or major uterine surgery
-- cases in which cephalopelvic disproportion is present
-- cases in which there is a history of difficult labor and/or traumatic
delivery
-- grand multiparae with six or more previous term pregnancies cases with non-
vertex presentation
-- cases with hyperactive or hypertonic uterine patterns
-- cases of fetal distress where delivery is not imminent
-- in obstetric emergencies where the benefit-to- risk ratio for either the
fetus or the mother favors surgical intervention
b. Patients with hypersensitivity to prostaglandins or constituents of the gel.
c. Patients with placenta previa or unexplained vaginal bleeding during this
pregnancy.
d. Patients for whom vaginal delivery is not indicated, such as vasa previa or
active herpes genitalia.
WARNINGS:
FOR HOSPITAL USE ONLY
Dinoprostone, as with other potent oxytocic agents, should be used only with
strict adherence to recommended dosages. Dinoprostone should be administered by
physicians in a hospital that can provide immediate intensive care and acute
surgical facilities.
PRECAUTIONS:
1. GENERAL PRECAUTIONS:
During use, uterine activity, fetal status, and character of the cervix
(dilation and effacement) should be carefully monitored either by auscultation
or electronic fetal monitoring to detect possible evidence of undesired
responses, eg, hypertonus, sustained uterine contractility, or fetal distress.
In cases where there is a history of hypertonic uterine contractility or tetanic
uterine contractions, it is recommended that uterine activity and the state of
the fetus should be continuously monitored. The possibility of uterine rupture
should be borne in mind when high-tone myometrial contractions are sustained.
Feto-pelvic relationships should be carefully evaluated before use of CERVIPRIME
Gel (see CONTRAINDICATIONS).
Caution should be exercised in administration of CERVIPRIME Gel in patients with:
-- asthma or history of asthma
-- glaucoma or raised intraocular pressure
Caution should be taken so as not to administer CERVIPRIME Gel above the level of
the internal os. Careful vaginal examination will reveal the degree of
effacement which will regulate the size of the shielded endocervical catheter to
be used. That is, the 20 mm endocervical catheter should be used if no
effacement is present, and the 10 mm catheter should be used if the cervix is
50+ACU- effaced. Placement of CERVIPRIME Gel into the extra-amniotic space has been
associated with uterine hyperstimulation.
As CERVIPRIME Gel is extensively metabolized in the lung, liver, and kidney, and
the major route of elimination is the kidney, CERVIPRIME Gel should be used with
caution in patients with renal and hepatic dysfunction.
2. PATIENTS WITH RUPTURED MEMBRANES:
Caution should be exercised in the administration of CERVIPRIME Gel in patients
with ruptured membranes. The safety of use of CERVIPRIME Gel in these patients has
not been determined.
3. DRUG INTERACTIONS:
CERVIPRIME Gel may augment the activity of other oxytocic agents and their
concomitant use is not recommended. For the sequential use of oxytocin following
CERVIPRIME Gel administration, a dosing interval of 6-12 hours is recommended.
4. CARCINOGENESIS, MUTAGENESIS, IMPAIRMENT OF FERTILITY:
Carcinogenic bioassay studies have not been conducted in animals with CERVIPRIME
Gel due to the limited indications for use and short duration of administration.
No evidence of mutagenicity was observed in the Micronucleus Test or Ames Assay.
5. PREGNANCY, TERATOGENIC EFFECTS:
PREGNANCY CATEGORY C
Prostaglandin E2 produced an increase in skeletal anomalies in rats and rabbits.
No effect would be expected clinically, when used as indicated, since CERVIPRIME
Gel is administered after the period of organogenesis. CERVIPRIME Gel 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. See
statements under General Precautions.
DRUG INTERACTIONS:
CERVIPRIME Gel may augment the activity of other oxytocic agents and their
concomitant use is not recommended. For the sequential use of oxytocin following
CERVIPRIME Gel administration, a dosing interval of 6-12 hours is recommended.
ADVERSE REACTIONS:
CERVIPRIME Gel is generally well-tolerated. In controlled trials, in which 1731
women were entered, the following events were reported at an occurrence of
+AD4-/+AD0-1+ACU-:
PGE2 Control+ACo-
Adverse Reaction (N+AD0-884) (N+AD0-847)
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MATERNAL N (+ACU-) N (+ACU-)
Uterine contractile abnormality 58 (6.6) 34 (4.0)
Any gastrointestinal effect 50 (5.7) 22 (2.6)
Back pain 27 (3.1) 0 (0)
Warm feeling in vagina 13 (1.5) 0 (0)
Fever 12 (1.4) 10 (1.2)
FETAL
Any fetal heart rate abnormality 150 (17.0) 123 (14.5)
Bradycardia 36 (4.1) 26 (3.1)
Deceleration
Late 25 (2.8) 18 (2.1)
Variable 38 (4.3) 29 (3.4)
Unspecified 19 (2.1) 19 (2.2)
------------------------------------------------------------------------------------------------------------------------------------------
+ACo- placebo gel or no treatment
----------------------------------------------------------------------------
In addition, in other trials amnionitis and intrauterine fetal sepsis have been
associated with extra-amniotic intrauterine administration of PGE2. Uterine
rupture has been reported in association with the use of CERVIPRIME Gel
intracervically. Additional events reported in the literature, associated by the
authors with the use of CERVIPRIME Gel, included premature rupture of membranes,
fetal depression (1 min Apgar+ADw-7), and fetal acidosis (umbilical artery pH+ADw-7.15).
DRUG ABUSE AND DEPENDENCE:
No drug abuse or drug dependence has been seen with the use of CERVIPRIME Gel.
OVERDOSAGE:
Overdosage with CERVIPRIME Gel may be expressed by uterine hypercontractility and
uterine hypertonus. Because of the transient nature of PGE2-induced myometrial
hyperstimulation, nonspecific, conservative management was found to be effective
in the vast majority of the cases+ADs- ie, maternal position change and
administration of oxygen to the mother. Bta-adrenergic drugs may be used as a
treatment of hyperstimulation following the administration of PGE2 for cervical
ripening.
DOSAGE AND ADMINISTRATION:
NOTE: USE CAUTION IN HANDLING THIS PRODUCT TO PREVENT CONTACT WITH SKIN. WASH
HANDS THOROUGHLY WITH SOAP AND WATER AFTER ADMINISTRATION.
CERVIPRIME Gel should be brought to room temperature (59 deg to 86 deg F+ADs- 15 deg
to 30 deg C) just prior to administration. Do not force the warming process by
using a water bath or other source of external heat (eg, microwave oven).
To prepare the product for use, remove the peel- off seal from the end of the
syringe. Then remove the protective end cap (to serve as plunger extension) and
insert the protective end cap into the plunger stopper assembly in the barrel of
syringe. Choose the appropriate length shielded catheter (10 mm or 20 mm) and
aseptically remove the sterile shielded catheter from the package. Careful
vaginal examination will reveal the degree of effacement which will regulate the
size of the shielded endocervical catheter to be used. That is, the 20 mm
endocervical catheter should be used if no effacement is present, and the 10 mm
catheter should be used if the cervix is 50+ACU- effaced. Firmly attach the catheter
hub to the syringe tip as evidenced by a distinct click. Fill the catheter with
sterile gel by pushing the plunger assembly to expel air from the catheter prior
to administration to the patient. Proper assembly of the dosing apparatus is
shown below.
To properly administer the product, the patient should be in a dorsal position
with the cervix visualized using a speculum. Using sterile technique, introduce
the gel with the catheter provided into the cervical canal just below the level
of the internal os. Administer the contents of the syringe by gentle expulsion
and then remove the catheter. The gel is easily extrudable from the syringe. Use
the contents of one syringe for one patient only. No attempt should be made to
administer the small amount of gel remaining in the catheter. The syringe,
catheter, and any unused package contents should be discarded after use.
Following administration of CERVIPRIME Gel, the patient should remain in the
supine position for at least 15-30 minutes to minimize leakage from the cervical
canal. If the desired response is obtained from CERVIPRIME Gel, the recommended
interval before giving intravenous oxytocin is 6-12 hours. If there is no
cervical/uterine response to the initial dose of CERVIPRIME Gel, repeat dosing may
be given. The recommended repeat dose is 0.5 mg dinoprostone with a dosing
interval of 6 hours. The need for additional dosing and the interval must be
determined by the attending physician based on the course of clinical events.
The maximum recommended cumulative dose for a 24-hour period is 1.5 mg of
dinoprostone (7.5 mL CERVIPRIME Gel).