Cervidil

Labor Inducers

Hazardous Drugs Classification
NIOSH 2016 List: Group 3
NIOSH (Draft) 2020 List: Table 2
Observe and exercise appropriate precautions for handling, preparation, administration, and disposal of hazardous drugs.
Use double chemotherapy gloves and protective gown. Eye/face and respiratory protection may be needed during preparation and administration.

Vaginal suppositories (e.g., Prostin E2):
Before removing foil wrapper, allow vaginal suppository to warm to room temperature. Once warmed, remove from wrapper and insert high into the posterior vaginal fornix.
Patients should remain supine for 10 minutes after each insertion.
Do not use dinoprostone vaginal suppositories to prepare extemporaneous preparations of any other dosage forms.
Wash hands thoroughly following administration.[41180]
 
Endocervical gel (Prepidil):
Prior to administration, allow gel to warm to room temperature (59 to 86 degrees F; 15 to 30 degrees C); do not warm forcefully.
Caution should be exercised to prevent contact with skin.
Use the contents of 1 syringe for 1 patient only.
To prepare the product for use, 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.
The 20 mm endocervical catheter should be used if no effacement is present.
The 10 mm catheter should be used if the cervix is 50% 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.
The patient should be in a dorsal position with the cervix visualized using a speculum.
Using sterile technique, insert catheter into the cervical canal just below the level of the internal os.
Administer the contents of the syringe by gentle expulsion and remove the catheter. Do not attempt to administer the small amount of gel remaining in the catheter.
The patient should remain recumbent for at least 15 to 30 minutes following insertion to ensure proper efficacy and minimize leakage from the cervical canal.
Wash hands thoroughly following administration.[41179]
 
Vaginal insert (Cervidil):
The vaginal insert must be kept frozen until ready for use; do NOT warm prior to vaginal insertion.
The vaginal insert 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. Do not use scissors or other sharp objects to open. This could result in cutting the knitted polyester pouch that serves as the retrieval system for the polymeric slab (contains active ingredient). An integral part of the knitted polyester retrieval system is a long tape designed to aid in the retrieval of the insert at the end of the dosing interval or earlier if clinically indicated.
The insertion of the vaginal insert does not require sterile conditions.
Position vaginal insert securely between the index and middle fingers. Place insert transversely in the posterior fornix of the vagina immediately after removal from the package. Do not use vaginal insert without its retrieval system. If necessary, use a minimal amount of water-miscible lubricant to assist vaginal insertion. Do not permit excess contact or coating with the lubricant, as this could prevent the release of dinoprostone from the vaginal insert. Insertion does not require sterile conditions.
Tuck some of the excess retrieval system into the vagina to avoid movement of the vaginal insert away from the proper position; however, leave a small amount of the retrieval system outside the vagina to aid in retrieval.
The patient should remain recumbent for 2 hours following insertion; but thereafter may be ambulatory. However, ensure that the vaginal insert remains in place.
Removal: To remove the vaginal insert, pull tape slowly from the vagina. It is essential to ensure that the slab has been removed. Visualization of the knitted polyester retrieval system as well as the slab is necessary to ensure proper removal. If the slab is not contained within the polyester retrieval system, a vaginal exam should be performed and the slab removed manually.
Discard the vaginal insert once used.[41178]

cervical laceration / Early / 0-1.0
disseminated intravascular coagulation (DIC) / Delayed / 0-1.0
myocardial infarction / Delayed / Incidence not known
amniotic fluid embolism / Early / Incidence not known
uterine rupture / Early / Incidence not known
bronchospasm / Rapid / Incidence not known
anaphylactoid reactions / Rapid / Incidence not known
angioedema / Rapid / Incidence not known

hypotension / Rapid / 0-10.0
fetal distress / Delayed / 2.8-3.8
hot flashes / Early / Incidence not known
hypertension / Early / Incidence not known
chest pain (unspecified) / Early / Incidence not known
vaginal pain / Early / Incidence not known
wheezing / Rapid / Incidence not known
dyspnea / Early / Incidence not known
blurred vision / Early / Incidence not known
uterine contractions / Early / Incidence not known

fever / Early / 0-92.0
chills / Rapid / 0-79.0
nausea / Early / 0-71.0
vomiting / Early / 0-66.0
diarrhea / Early / 0-40.0
headache / Early / 0-33.0
shivering / Rapid / 10.0-10.0
back pain / Delayed / 1.0-10.0
muscle cramps / Delayed / 10.0
abdominal pain / Early / Incidence not known
syncope / Early / Incidence not known
dizziness / Early / Incidence not known
diaphoresis / Early / Incidence not known
flushing / Rapid / Incidence not known
musculoskeletal pain / Early / Incidence not known
arthralgia / Delayed / Incidence not known
mastalgia / Delayed / Incidence not known
paresthesias / Delayed / Incidence not known
weakness / Early / Incidence not known
cough / Delayed / Incidence not known
rash / Early / Incidence not known
ocular pain / Early / Incidence not known

Administration of dinoprostone, given its oxytocic effects, requires a specialized care setting (a hospital) that can provide immediate intensive care and acute surgical facilities and requires an experienced clinician to oversee the use of monitoring of dinoprostone for termination of pregnancy or labor induction/cervical ripening. The dinoprostone vaginal suppositories have a specific boxed warning regarding these parameters, since the possibility does exist that the previable fetus aborted by dinoprostone could exhibit transient life signs, one of several possible events that requires specialized care by the clinician. Dinoprostone use is contraindicated in patients with a known dinoprostone hypersensitivity or sensitivity to product excipients. Dinoprostone use carries a risk of serious hypersensitivity reactions or anaphylaxis. Anaphylactoid reactions, anaphylaxis, and angioedema have been noted to occur with dinoprostone. Onset of these reported reactions occurred within minutes to hours after initiation with dinoprostone. Watch for signs and symptoms of local and systemic hypersensitivity. If a hypersensitivity reaction is suspected, if possible remove the dinoprostone from the patient, assess for potential causes of the event, and institute symptomatic and supportive therapy. Dinoprostone should also be used with strict adherence to recommended dosages. Because of the serious nature of the possible adverse reactions associated with dinoprostone use (e.g., clinically significant decreases in blood pressure, elevations in body temperature, nausea, vomiting, diarrhea, and headache), the use of dinoprostone requires continual monitoring of maternal and fetal status.

Cervidil, Prepidil

Rx

Synthetic form of prostaglandin E2; has oxytocic actions; use requires specialized care facilities and monitoring
Vaginal suppositories used clinically to induce abortion or to evacuate uterine contents following intrauterine fetal death, missed abortion, or benign hydatidiform mole
Endocervical gel or vaginal inserts are used for cervical ripening during labor in term pregnancies

Insert one 20-mg suppository high into the vagina. An additional suppository should be inserted vaginally at 3 to 5 hour intervals until abortion occurs. Administration time within the 3 to 5 hour interval should be determined by clinical progress, uterine contractility response, and by patient tolerance. Continuous administration for more than 2 days (48 hours) is not recommended.

0.5 mg (2.5 mL) endocervically; may repeat dose every 6 hours as needed. Max: 1.5 mg/day (7.5 mL/day). If the desired response is obtained, the recommended interval before giving oxytocin is 6 to 12 hours.

10 mg (1 insert) intravaginally for up to 12 hours (approximately 0.3 mg/hour is released). Monitor uterine activity, fetal status, and the progression of cervical dilatation and effacement. Remove the insert 12 hours after insertion, 30 minutes before administering an oxytocic agent, with the onset of labor, and prior to an amniotomy, occurrence of uterine tachysystole, uterine hypersystole/hypertonicity, or fetal distress.

Dinoprostone suppositories are contraindicated for use in patients with hepatic impairment.

Specific guidelines for dosage adjustments in renal impairment are not available; dinoprostone suppositories are considered contraindicated for use.

Articaine; Epinephrine: (Major) Oxytocics have inherent vasopressor properties; hypertensive episodes have been reported in laboring women during induction with oxytoxin. Because epinephrine is a vasopressor, concomitant use may result in severe, prolonged hypertension. In addition, epinephrine, secondary to beta2-receptor agonism, can interfere with the oxytocic action of drugs such as dinoprostone or oxytocin.
Bupivacaine; Epinephrine: (Major) Oxytocics have inherent vasopressor properties; hypertensive episodes have been reported in laboring women during induction with oxytoxin. Because epinephrine is a vasopressor, concomitant use may result in severe, prolonged hypertension. In addition, epinephrine, secondary to beta2-receptor agonism, can interfere with the oxytocic action of drugs such as dinoprostone or oxytocin.
Carboprost Tromethamine: (Major) Carboprost tromethamine may augment the activity of other oxytocics. Augmentation can result in uterine hypertonus with subsequent uterine rupture, particularly in the absence of adequate cervical dilation. The concurrent use of carboprost tromethamine and other oxytocic drugs is not recommended.
Epinephrine: (Major) Oxytocics have inherent vasopressor properties; hypertensive episodes have been reported in laboring women during induction with oxytoxin. Because epinephrine is a vasopressor, concomitant use may result in severe, prolonged hypertension. In addition, epinephrine, secondary to beta2-receptor agonism, can interfere with the oxytocic action of drugs such as dinoprostone or oxytocin.
Lidocaine; Epinephrine: (Major) Oxytocics have inherent vasopressor properties; hypertensive episodes have been reported in laboring women during induction with oxytoxin. Because epinephrine is a vasopressor, concomitant use may result in severe, prolonged hypertension. In addition, epinephrine, secondary to beta2-receptor agonism, can interfere with the oxytocic action of drugs such as dinoprostone or oxytocin.
Methylergonovine: (Contraindicated) Concomitant use of dinoprostone with other oxytocics can result in uterine hypertonus with subsequent uterine rupture, particularly in the absence of adequate cervical dilation. The concurrent use of dinoprostone and other oxytocic drugs is considered contraindicated; following the removal of the dinoprostone vaginal insert, an interval of at least 30 minutes is recommended prior to the use of another oxytocic agent. These products should be used sequentially only under adequate obstetric supervision and the patient should be monitored closely for adverse effects.
Oxytocin: (Contraindicated) Dinoprostone is contraindicated in patients receiving intravenous oxytocic agents. Following dinoprostone use, a specific wash-out period is recommended before the use of oxytocin; see specific product information for the specific recommendations as they differ. These products should be used sequentially only under adequate obstetric supervision. Following the removal of the dinoprostone vaginal insert, an interval of at least 30 minutes is recommended prior to the use of another oxytocic agent. For the sequential use of oxytocin following dinoprostone gel administration, a dosing interval of 6 to 12 hours is recommended. Concomitant use of dinoprostone vaginal suppositories with other oxytocic agents is also not recommended. Serious side effects may occur if these agents are used concurrently. There is a risk of severe uterine hypertony occurring, with possible uterine rupture or cervical laceration.
Prilocaine; Epinephrine: (Major) Oxytocics have inherent vasopressor properties; hypertensive episodes have been reported in laboring women during induction with oxytoxin. Because epinephrine is a vasopressor, concomitant use may result in severe, prolonged hypertension. In addition, epinephrine, secondary to beta2-receptor agonism, can interfere with the oxytocic action of drugs such as dinoprostone or oxytocin.

Cervidil Vaginal Insert ER: 10mg
Prepidil Vaginal Gel: 0.5mg, 3g
Prostin E2 Vaginal Supp: 20mg

Dependent on indication for use and dosage formulation selected for therapy.

Safety and efficacy have not been established.

Dependent on indication for use and dosage formulation selected for therapy.

Safety and efficacy have not been established.

Dinoprostone can exerts its effects throughout pregnancy, but the uterus and cervix exhibit an increased response to dinoprostone as pregnancy progresses.
Effects during pregnancy termination or uterine evacuation: Although the exact mechanism of dinoprostone's oxytocic effect is unknown, it is believed to involve the regulation of calcium transport across the cellular membrane as well as regulation of the concentration of cyclic 3', 5'-adenosine monophosphate within the cell. As a result of these actions, dinoprostone induces uterine contractions via stimulation of uterine smooth muscle (myometrium). Dinoprostone-induced uterine contractions are similar to those produced by the body during spontaneous labor. Increases in the amplitude and frequency of uterine contractions reduces cervical tone, which produces cervical dilation. The myometrial contractions induced by the vaginal administration of dinoprostone suppositories are sufficient to produce evacuation of the products of conception from the uterus in the majority of cases.
Effects when used for cervical ripening: Dinoprostone cervical insert or endocervical gel promotes cervical ripening by stimulating local receptors. The process of cervical ripening includes activation of the collagenase enzyme responsible for digestion of some of the structural collagen network of the cervix. Breakdown of the collagen network is associated with an increase in hydrophilic glycosaminoglycan and hyaluronic acid, and a decrease in dermaten sulfate. Clinically, dinoprostone produces a marked relaxation of the cervical smooth muscle fibers of the uterine cervix.
Other body effects observed: Dinoprostone is also capable of stimulating the smooth muscle of the gastrointestinal (GI) tract; nausea, vomiting and/or diarrhea is not uncommon during use. Dinoprostone-induced elevations in body temperature (transient pyrexia) also can occur in patients receiving the drug, but temperatures return to normal following its discontinuance. The exact mechanism by which fever occurs is unknown. Finally, large doses of dinoprostone can lower blood pressure in animals and in humans, probably as a consequence of its effect on the smooth muscle of the vascular system. With the doses of dinoprostone used for terminating pregnancy or cervical ripening, this effect has not been clinically significant for most patients.

Dinoprostone is administered intravaginally. Dinoprostone distributes widely throughout the body and is metabolized extensively on first pass through the lungs (about 95%). The delivery rate of dinoprostone from the vaginal insert in vivo is approximately 0.3 mg/per hour over a period of 12 hours. The metabolites are then further metabolized by the spleen, kidneys, and other tissues to inactive metabolites, which are excreted primarily by the kidneys. Dinoprostone's half-life is approximately 2.5 to 5 minutes. The rate-limiting step for inactivation is regulated by the enzyme 15-hydroxyprostaglandin dehydrogenase (PGDH). Any dinoprostone that escapes local inactivation is cleared to the extent of 95% on the first pass through the pulmonary circulation. No correlation could be established between the release of dinoprostone from the vaginal insert and plasma concentrations of metabolite of dinoprostone (PGEm). The relative contributions of endogenously and exogenously released dinoprostone to the plasma levels of the metabolite PGEm is not known. Specific pharmacokinetic data for dinoprostone endocervical gel and vaginal suppository products are not available.
 
Affected Cytochrome P450 isoenzymes and drug transporters: None

Vaginal Route (Vaginal suppository)
The majority of a vaginally inserted dose of dinoprostone enters the maternal circulation, while a small amount is absorbed directly by the uterus via the cervix or lymphatic system. Plasma concentrations do not correlate with the extent of uterine activity. Minimal uterine contractions begin within 10 minutes of administration, followed by stronger contractions that can continue for 2 to 3 hours. The mean time required for abortion or expulsion is approximately 17 hours.

Dinoprostone is approved for both termination of pregnancy and also for cervical ripening prior to delivery at term. Contraindications reflect the indication for which dinoprostone is used. Animal studies suggest that some prostaglandins are teratogenic. When a pregnancy diagnosed as missed abortion is electively interrupted with intravaginal administration of dinoprostone, confirmation of intrauterine fetal death should be obtained in respect to negative pregnancy testing for human chorionic gonadotropic (HCG) activity. When a pregnancy with late fetal intrauterine death is interrupted with intravaginal administration of dinoprostone, confirmation of intrauterine fetal death should be obtained prior to treatment. Dinoprostone suppositories are not indicated if the fetus in utero has reached the stage of viability. Dinoprostone does not appear to directly affect the fetoplacental unit. Therefore, the possibility does exist that the previable fetus aborted by dinoprostone could exhibit transient life signs. When dinoprostone is used for termination of pregnancy, the termination should be completed by another mechanism if there is a failed or incomplete abortion. In a report of a 3-year pediatric follow-up study, there were no deleterious effects noted on physical examination or psychomotor evaluation of 51 infants born following maternal treatment with the vaginal insert. Because prostaglandins potentiate the effects of oxytocin, the concurrent use of dinoprostone and other oxytocic drugs is not recommended for any indication. Concurrent use of intravenous oxytocics is particularly not recommended; sequential use of oxytocin, following dinoprostone cervical ripening, may be considered in selected circumstances. The patient's uterine activity should be carefully monitored for uterine hyperstimulation. Remove dinoprostone cervical ripening products in cases of uterine hyperstimulation, if labor commences, and prior to amniotomy.