Dinoprostone (Monograph)

Brand names: Cervidil, Prepidil, Prostin E2
Drug class: Oxytocics
- Abortifacient Agents
ATC class: G02AD02
VA class: HS875
Chemical name: (5Z, 11a, 13E, 15S)-11,15-Dihydroxy-9-oxo-prosta-5,13-dien-1-oic acid
Molecular formula: C₂₀H₃₂O₅
CAS number: 363-24-6

Introduction

Stimulates uterine smooth muscle and also produces cervical dilation and softening; prostaglandin E₂.

Uses for Dinoprostone

Termination of Pregnancy

Termination of intrauterine pregnancy during the second trimester (12–20th week of gestation, dated from the first day of the last menstrual period).

For termination of pregnancy, has been used in conjunction with oxytocin to reduce the dinoprostone dose and number of adverse effects associated with dinoprostone.

Evacuation of uterine contents in cases of missed abortion, intrauterine fetal death up to 28 weeks of gestational age, or nonmetastatic gestational trophoblastic disease (benign hydatidiform mole).

Labor Induction (Cervical “Ripening”)

Treatment to improve cervical inducibility (cervical “ripening”) in pregnant women at or near term with a medical or obstetrical need for labor induction.

Postpartum Hemorrhage

Has been used in the management of postpartum hemorrhage^{† [off-label]}.

Dinoprostone Dosage and Administration

Administration

Vaginal Administration

Administer intravaginally as a vaginal suppository (Prostin E2), cervical gel (Prepidil), or vaginal insert (Cervidil).

Vaginal Suppositories

Allow suppository to reach room temperature just prior to administration.

Remove the foil wrapper and insert the suppository high into the posterior vaginal fornix. Patient should remain supine for 10 minutes following each insertion. May require the use of a diaphragm to prevent displacement of the suppository from the paracervical area.

Cervical Gel

Allow the gel to reach room temperature just prior to administration; do not use a water bath or other source of external heat (e.g., microwave oven) to facilitate the warming process.

Consult the manufacturer’s instructions for proper assembly of the syringe and catheter.

Administer the cervical gel (supplied in a syringe) through a shielded catheter into the cervical canal. Select the proper size catheter based on the degree of effacement; if no effacement is present, use the 20-mm catheter; for 50% effacement, use the 10-mm catheter.

Place patient in a dorsal position and visualize the cervix using a speculum. Using sterile technique, introduce the gel via the catheter into the cervical canal, just below the level of the internal os. Remove the catheter. Patient should remain supine for at least 15–30 minutes to minimize leakage from the cervical canal.

Vaginal Insert

Keep frozen until use.

After removal from the protective package (tear at designated mark), place the vaginal insert transversely in the posterior fornix of the vagina. May use a small amount of water-soluble lubricant to assist insertion; excess contact or coating with lubricant may prevent optimal swelling and release of dinoprostone from the insert. Patient should remain supine for 2 hours following insertion. If patient is ambulatory, ensure that the vaginal insert remains in place.

Use the knitted polyester retrieval system to aid in drug retrieval at the end of the dosing interval. Upon removal of the insert, ensure that the slab is removed. If the slab is not found in the retrieval system, perform a vaginal examination to remove the slab.

Formulation Considerations

Dinoprostone vaginal suppositories and any preparation made extemporaneously from dinoprostone vaginal suppositories should not be used at term for cervical “ripening”; dinoprostone cervical gel and vaginal insert are used at or near term to improve cervical inducibility.

Dinoprostone vaginal suppositories should not be used for extemporaneous preparation of any other dosage form.

Dosage

Adults

Termination of Pregnancy

Intravaginal

Vaginal suppositories: 20 mg every 3–5 hours until abortion occurs; adjust the dosing intervals according to abortifacient progress, uterine contractility, and patient tolerance.

Vaginal suppositories: Initial dose of 5 mg, repeated as needed, when used for intrauterine fetal death at >24 weeks’ gestational age. (See Prescribing Limits.)

Induction of Labor (Cervical “Ripening”)

Intravaginal

Cervical gel: Initially, 0.5 mg (2.5 mL of gel). If there is no cervical and/or uterine response to the initial dose, administer another 0.5-mg dose after 6–12 hours. Clinician should determine the need for additional doses and the dosing intervals.

Vaginal insert: 1 insert delivering dinoprostone 0.3 mg/hour for 12 hours. Remove after 12 hours, at the onset of active labor, or if uterine hyperstimulation develops.

Postpartum Hemorrhage† [off-label]

Intravaginal or Rectal

Vaginal suppositories: 20 mg every 2 hours has been used.

Prescribing Limits

Adults

Termination of Pregnancy

Intravaginal Vaginal suppositories

Intravaginal Vaginal suppositories: Use for >2 days notrecommended.

Vaginal suppositories: Initially 5 mg; repeat as needed when used for intrauterine fetal death at >24 weeks, gestational age. Use of 20-mg dose may result in uterine rupture.

Intravaginal

Cervical gel: Maximum cumulative dose is 1.5 mg (7.5 mL)/24 hours.

Cautions for Dinoprostone

Contraindications

• Known hypersensitivity to prostaglandins or any ingredient in the formulation.

• Dinoprostone vaginal suppositories are contraindicated in patients with acute pelvic inflammatory disease and in those with active cardiac, pulmonary, renal, or hepatic disease.

• Dinoprostone cervical gel and vaginal inserts are contraindicated in patients with contraindications to oxytocic agents and when prolonged contractions of the uterus are inappropriate (e.g., previous cesarean section, previous major uterine surgery, history of difficult labor and/or traumatic delivery, marked cephalopelvic disproportion, unfavorable fetal position, ≥6 previous term pregnancies, fetal distress when delivery is not imminent, hyperactive or hypertonic uterus, obstetric emergencies where maternal or fetal risk-to-benefit ratio favors surgery).

• Dinoprostone cervical gel and vaginal inserts are contraindicated in patients with placenta previa or unexplained vaginal bleeding during the current pregnancy.

• Dinoprostone cervical gel is contraindicated when vaginal delivery is not indicated (e.g., vasa previa, active genital herpes infection).

• The manufacturer of dinoprostone vaginal inserts states that this preparation is contraindicated in patients receiving IV oxytocic therapy.

Warnings/Precautions

Warnings

Administer by qualified professional personnel in a hospital where intensive care and surgical facilities are immediately available.

Considerations in Patients Undergoing Termination of Pregnancy

Dinoprostone does not affect the fetoplacental unit. Possibility exists that a previable fetus could exhibit transient signs of life following dinoprostone-induced abortion; dinoprostone is not indicated if the fetus has reached the stage of viability. If pregnancy is terminated because of late fetal intrauterine death, confirm fetal death prior to administration of dinoprostone.

If the pregnancy is not terminated with dinoprostone, complete abortion by another method.

Confirm pregnancy termination for pregnancy diagnosed as missed abortion.

Considerations in Patients Undergoing Induction of Labor (Cervical “Ripening”)

Monitor uterine contractions, fetal status (e.g., heart rate), and progression of cervical dilation and effacement of the cervix to avoid complications.

Use with caution in patients with ruptured membranes.

Carefully select patients; evaluate both maternal and fetal condition before dinoprostone use. (See Contraindications.)

Consider removing dinoprostone vaginal insert if sustained uterine contractions, fetal distress, or other fetal or maternal adverse effects occur. Remove the insert if uterine hyperstimulation develops or labor starts. Remove the insert before amniotomy.

General Precautions

Musculoskeletal Effects

Proliferation of long bones reported in neonates receiving long-term therapy with alprostadil (prostaglandin E₁). No evidence that short-term administration of dinoprostone has similar effects on bone.

Concomitant Diseases

Caution in patients with cervicitis, infected endocervical lesions, acute vaginitis, compromised (scarred) uterus, asthma or a history of asthma, hypertension or hypotension, seizure disorders, diabetes mellitus, glaucoma, increased IOP, anemia, jaundice, or cardiovascular, renal, or hepatic disease.

Fever

Transient fever (i.e., temperature elevations >1.1°C) reported. When used for termination of pregnancy, may be difficult to distinguish drug-induced temperature elevations from post-abortion endometritis.

Specific Populations

Pregnancy

Category C.

Pediatric Use

Safety and efficacy not established in children. Safety and efficacy in adolescents expected to be the same as in adults.

Hepatic Impairment

Use with caution.

Dinoprostone vaginal suppositories are contraindicated in patients with active hepatic disease.

Renal Impairment

Use with caution.

Dinoprostone vaginal suppositories are contraindicated in patients with active renal disease.

Common Adverse Effects

Dinoprostone vaginal suppositories: Vomiting, transient fever, diarrhea, nausea, headache, chills, transient DBP decreases of >20 mm Hg.

Dinoprostone cervical gel or vaginal insert: Uterine hyperstimulation, fetal heart rate abnormality, adverse GI effects, back pain, fever.

Drug Interactions

Specific Drugs

Dinoprostone Pharmacokinetics

Absorption

Bioavailability

Absorbed systemically following vaginal administration as dinoprostone suppositories; a small amount of drug is absorbed directly by the uterus through the cervix or local lymphatic or vascular channels.

Dinoprostone cervical gel: Peak plasma concentrations achieved in 30–45 minutes.

Dinoprostone vaginal insert: A controlled-release preparation designed to release 0.3 mg of dinoprostone per hour for 12 hours.

Onset

Dinoprostone vaginal suppositories: Slight uterine contractions begin within 10 minutes (first and second trimester pregnancies).

Duration

Dinoprostone vaginal suppositories: Contractions continue for 2–3 hours (first and second trimester pregnancies).

Distribution

Extent

Widely distributed in the mother.

Elimination

Metabolism

Rapidly metabolized in the maternal lungs, kidneys, spleen, and other tissues, primarily by oxidation of the side chains to at least 9 inactive metabolites.

Elimination Route

Drug and its metabolites excreted principally in urine; small amounts excreted in feces.

Half-life

2.5–5 minutes.

Stability

Storage

Vaginal

Gel

2–8°C.

Insert

-20°C to -10°C. Protect from moisture and humidity.

Suppositories

Do not exceed -20°C.

Actions

• Elicits pharmacologic responses usually produced by endogenous prostaglandin E₂.

• Increases the amplitude and frequency of uterine contractions throughout pregnancy; uterine response to the drug increases with the duration of pregnancy.

• Produces local cervical effects including softening, effacement, and dilation.

• Causes stimulation of the circular smooth muscle of the GI tract, increasing GI motility.

Advice to Patients

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.

• Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

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.

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