Dinoprostone

Cervidil is a vaginal insert containing 10 mg dinoprostone. The product is wound and enclosed in an aluminium/polyethylene pack and supplied as follows:

NDC 55566- 2800-1     Box of 1

Store 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.

REFERENCES

19. De Abajo FJ et al. Labor induction with dinoprostone or oxytocin and postpartum disseminated intravascular coagulation: a hospital-based case-control study. Am J Obs Gynecol, 2004, 191: 1637- 1643.

Manufactured For: Ferring Pharmaceuticals Inc.Parsippany,NJ 07054.Revised: Aug 2016.

Dinoprostone is a prescription medication used to soften and dilate the cervix (known medically as cervical ripening) for the induction of labor in pregnant women who are at or near term. This medication is a synthetic version of prostaglandin E2, a naturally occuring hormone important for preparing the cervix during labor.

Dinoprostone comes as a vaginal insert, suppository, and as a gel that is inserted into the vagina. It is administered by a healthcare professional.

Common side effects include strong uterine contractions, headache, and nausea.

You should not be treated with this medication if you are allergic to prostaglandins, or if you have:

• active genital herpes with a vaginal lesion;
• placenta previa (the placenta is below the fetus in your uterus); or
• if your water has broken.

Be sure your doctor knows your entire pregnancy history, especially:

• if you have ever had a C-section or major surgery on your uterus;
• if you have ever had a baby born in a breech position (not head-first); or
• if you have ever had a difficult labor or delivery of a previous child.

To make sure you can safely use dinoprostone topical, tell your doctor if you have any of these other conditions:

• kidney disease;
• liver disease;
• glaucoma;
• a history of asthma;
• if you are 30 years or older; or
• if your pregnancy is at full term (40 weeks).

Specific Drugs

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Dinoprostone Vaginal Insert 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.

1. General Precautions

Since prostaglandins potentiate the effect of oxytocin, Dinoprostone Vaginal Insert 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. Dinoprostone Vaginal Insert should also be removed prior to amniotomy.

Dinoprostone Vaginal Insert is contraindicated when prolonged contraction of the uterus may be detrimental to fetal safety and uterine integrity. Therefore, Dinoprostone Vaginal Insert 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, including the need for hysterectomy and the occurrence of fetal or neonatal death.

Caution should be exercised in the administration of Dinoprostone Vaginal Insert 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. With any evidence of uterine hyperstimulation, sustained uterine contractions, fetal distress, or other fetal or maternal adverse reactions, the vaginal insert should be removed. An increased risk of post-partum disseminated intravascular coagulation has been described in patients whose labor was induced by physiologic means, either with Dinoprostone or oxytocin.

2. Drug Interactions

Dinoprostone Vaginal Insert 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 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

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 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 Dinoprostone Vaginal Insert 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.

Dinoprostone Vaginal Insert 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.

Drug related fever, nausea, vomiting, diarrhea, and abdominal pain were noted in less than 1% of patients who received Dinoprostone Vaginal Insert.

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 Dinoprostone Vaginal Insert. In a report of a 3 year pediatric follow-up study in 121 infants, 51 of whose mothers received Dinoprostone Vaginal Insert, there were no deleterious effects on physical examination or psychomotor evaluation (18).

Post-marketing surveillance

Immune System Disorders: Hypersensitivity

Blood and lymphatic system disorders: Disseminated Intravascular Coagulation (See Warnings Section)

Reproductive system: Reports of uterine rupture have been reported in association with use of Dinoprostone Vaginal Insert some required a hysterectomy and some resulted in subsequent fetal or neonatal death.

Vascular Disorders: Hypotension

Pregnancy, Puerperium and Perinatal Conditions: Amniotic fluid embolism

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. Dinoprostone Vaginal Insert should be removed upon onset of active labor or 12 hours after insertion.

Dinoprostone Vaginal Insert is supplied in an individually wrapped aluminium/polyethylene package with a "tear mark" on one side of the package. The package should only be opened by tearing the aluminium 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.

Dinoprostone Vaginal Insert 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 Dinoprostone Vaginal Insert. 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. Dinoprostone Vaginal Insert should also be removed prior to amniotomy.

Upon removal of Dinoprostone Vaginal Insert, 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.

Females of reproductive age: Refer to adult dosing.

Endocervical gel should be stored under refrigeration at 2°C to 8°C (36°F to 46°F).

Suppositories must be kept frozen; store in freezer not above -20°C (-4°F).

Tablets (oral) [Canadian product]: Store under refrigeration at 2°C to 8°C (36°F to 46°F). Discard unused tablets 90 days after bottle is opened.

Vaginal gel [Canadian product]: Store under refrigeration at 2°C to 8°C (36°F to 46°F).

Vaginal insert should be stored in freezer between -20°C and -10°C (-4°F and 14°F).

VAGINAL SUPPOSITORY:
-A 20 mg suppository should be inserted high into the vagina; the patient should remain in the supine position for 10 minutes following insertion
-Additional intravaginal administration of each subsequent suppository should be at 3 to 5 hour intervals until abortion occurs. Within the recommended intervals administration time should be determined by abortifacient progress, uterine contractility response, and by patient tolerance.
-Continuous administration for more than 2 days is not recommended.
-The manufacturer product information should be consulted for instructions relating to product preparation and proper administration.

Uses:
-For the termination of pregnancy from the 12th through the 20th gestational week as calculated from the first day of the last normal menstrual period
-For evacuation of the uterine contents in the management of missed abortion or intrauterine fetal death up to 28 weeks of gestational age as calculated from the first day of the last normal menstrual period
-For the management of nonmetastatic gestational trophoblastic disease (benign hydatidiform mole)