Dinoprostone

Class: Oxytocics
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
Brands: Cervidil, Prepidil, Prostin E2

Introduction

Stimulates uterine smooth muscle and also produces cervical dilation and softening; prostaglandin E2.a 200 213 214

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).a e 200

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

Slideshow: Fact or Fiction? The Top 15 Osteoarthritis Myths

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).a e 200

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.212 213 216 217 218 219 220 h

Postpartum Hemorrhage

Has been used in the management of postpartum hemorrhage.g

Dinoprostone Dosage and Administration

Administration

Vaginal Administration

Administer intravaginally as a vaginal suppository (Prostin E2), cervical gel (Prepidil), or vaginal insert (Cervidil).200 212 213

Vaginal Suppositories

Allow suppository to reach room temperature just prior to administration.200

Remove the foil wrapper and insert the suppository high into the posterior vaginal fornix.200 a Patient should remain supine for 10 minutes following each insertion.200 May require the use of a diaphragm to prevent displacement of the suppository from the paracervical area.a

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.212

Consult the manufacturer’s instructions for proper assembly of the syringe and catheter.212

Administer the cervical gel (supplied in a syringe) through a shielded catheter into the cervical canal.212 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.212

Place patient in a dorsal position and visualize the cervix using a speculum.212 Using sterile technique, introduce the gel via the catheter into the cervical canal, just below the level of the internal os.212 Remove the catheter.212 Patient should remain supine for at least 15–30 minutes to minimize leakage from the cervical canal.212

Vaginal Insert

Keep frozen until use.d

After removal from the protective package (tear at designated mark),d place the vaginal insert transversely in the posterior fornix of the vagina.213 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.213 Patient should remain supine for 2 hours following insertion.213 If patient is ambulatory, ensure that the vaginal insert remains in place.d

Use the knitted polyester retrieval system to aid in drug retrieval at the end of the dosing interval.213 Upon removal of the insert, ensure that the slab is removed.d If the slab is not found in the retrieval system, perform a vaginal examination to remove the slab.d

Formulation Considerations

Dinoprostone vaginal suppositories and any preparation made extemporaneously from dinoprostone vaginal suppositories should not be used at term for cervical “ripening”;200 dinoprostone cervical gel and vaginal insert are used at or near term to improve cervical inducibility.212 213

Dinoprostone vaginal suppositories should not be used for extemporaneous preparation of any other dosage form.200

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.a 200

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

Induction of Labor (Cervical “Ripening”)
Intravaginal

Cervical gel: Initially, 0.5 mg (2.5 mL of gel).212 If there is no cervical and/or uterine response to the initial dose, administer another 0.5-mg dose after 6–12 hours.212 220 Clinician should determine the need for additional doses and the dosing intervals.212

Vaginal insert: 1 insert delivering dinoprostone 0.3 mg/hour for 12 hours.213 Remove after 12 hours, at the onset of active labor, or if uterine hyperstimulation develops.213 d

Postpartum Hemorrhage
Intravaginal or Rectal

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

Prescribing Limits

Adults

Termination of Pregnancy
Intravaginal Vaginal suppositories

Intravaginal Vaginal suppositories: Use for >2 days notrecommended.200

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

Intravaginal

Cervical gel: Maximum cumulative dose is 1.5 mg (7.5 mL)/24 hours.212 220

Cautions for Dinoprostone

Contraindications

  • Known hypersensitivity to prostaglandins or any ingredient in the formulation.200 212 213

  • Dinoprostone vaginal suppositories are contraindicated in patients with acute pelvic inflammatory disease and in those with active cardiac, pulmonary, renal, or hepatic disease.200

  • 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).212 213

  • Dinoprostone cervical gel and vaginal inserts are contraindicated in patients with placenta previa or unexplained vaginal bleeding during the current pregnancy.212 213

  • Dinoprostone cervical gel is contraindicated when vaginal delivery is not indicated (e.g., vasa previa, active genital herpes infection).212

  • The manufacturer of dinoprostone vaginal inserts states that this preparation is contraindicated in patients receiving IV oxytocic therapy.213

Warnings/Precautions

Warnings

Administer by qualified professional personnel in a hospital where intensive care and surgical facilities are immediately available.a 200 212

Considerations in Patients Undergoing Termination of Pregnancy

Dinoprostone does not affect the fetoplacental unit.200 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.200 If pregnancy is terminated because of late fetal intrauterine death, confirm fetal death prior to administration of dinoprostone.200

If the pregnancy is not terminated with dinoprostone, complete abortion by another method.200

Confirm pregnancy termination for pregnancy diagnosed as missed abortion.200

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.220 212 213

Use with caution in patients with ruptured membranes.c d

Carefully select patients; evaluate both maternal and fetal condition before dinoprostone use.212 213 220 (See Contraindications.)

Consider removing dinoprostone vaginal insert if sustained uterine contractions, fetal distress, or other fetal or maternal adverse effects occur.213 Remove the insert if uterine hyperstimulation develops or labor starts.213 Remove the insert before amniotomy.213

General Precautions

Musculoskeletal Effects

Proliferation of long bones reported in neonates receiving long-term therapy with alprostadil (prostaglandin E1).200 a i No evidence that short-term administration of dinoprostone has similar effects on bone.200 a

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.200 212 213 a b

Fever

Transient fever (i.e., temperature elevations >1.1°C) reported.200 When used for termination of pregnancy, may be difficult to distinguish drug-induced temperature elevations from post-abortion endometritis.200

Specific Populations

Pregnancy

Category C.200 212 213

Pediatric Use

Safety and efficacy not established in children.200 212 213 Safety and efficacy in adolescents expected to be the same as in adults.213

Hepatic Impairment

Use with caution.200 212

Dinoprostone vaginal suppositories are contraindicated in patients with active hepatic disease.200

Renal Impairment

Use with caution.200 212

Dinoprostone vaginal suppositories are contraindicated in patients with active renal disease.200

Common Adverse Effects

Dinoprostone vaginal suppositories: Vomiting, transient fever, diarrhea, nausea, headache, chills, transient DBP decreases of >20 mm Hg.200

Dinoprostone cervical gel or vaginal insert: Uterine hyperstimulation, fetal heart rate abnormality, adverse GI effects, back pain, fever.212 213

Interactions for Dinoprostone

Specific Drugs

Drug

Interaction

Comments

Oxytocic agents (e.g., oxytocin)

May increase activity of other oxytocic agents200 212 213

Concomitant use not recommended200 212 213

Dinoprostone cervical gel: Allow an inteval of 6–12 hours between administration of the cervical gel and initiation of IV oxytocin212 220

Dinoprostone vaginal insert: Wait ≥30 minutes between removal of dinoprostone vaginal insert and initiation of IV oxytocin213 220

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.a

Dinoprostone cervical gel: Peak plasma concentrations achieved in 30–45 minutes.212

Dinoprostone vaginal insert: A controlled-release preparation designed to release 0.3 mg of dinoprostone per hour for 12 hours.213

Onset

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

Duration

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

Distribution

Extent

Widely distributed in the mother.a

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.a

Elimination Route

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

Half-life

2.5–5 minutes.213

Stability

Storage

Vaginal

Gel

2–8°C.212

Insert

-20°C to -10°C.213 Protect from moisture and humidity.213

Suppositories

Do not exceed -20°C.200

Actions

  • Elicits pharmacologic responses usually produced by endogenous prostaglandin E2.200 212 213

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

  • Produces local cervical effects including softening, effacement, and dilation.212 213 214

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

Advice to Patients

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.200 212 213

  • Importance of informing patients of other important precautionary information.200 212 213 (See Cautions.)

Preparations

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

Dinoprostone

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Vaginal

Gel

0.5 mg/3 g

Prepidil

Pfizer

Insert

10 mg

Cervidil

Forest

Suppositories

20 mg

Prostin E2

Pfizer

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions January 1, 2008. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

200. Pharmacia & Upjohn Company. Prostin E2 (dinoprostone vaginal suppository) prescribing information (dated 1999 Aug). In: Physician’s desk reference. 55th ed. Montvale, NJ: Medical Economics Company Inc; 2001:2638-9.

201. Rayburn W, Gosen R, Ramadei C et al. Outpatient cervical ripening with prostaglandin E2 gel in uncomplicated postdate pregnancies. Am J Obstet Gynecol. 1988; 158:1417-23. [IDIS 310426] [PubMed 3289398]

202. Nager CW, Key TC, Moore TR. Cervical ripening and labor outcome with preinduction intracervical prostaglandin E2 (Prepidil) gel. J Perinatol. 1987; 7:189-93. [PubMed 3504454]

203. Trofatter KF Jr, Bowers D, Gall SA et al. Preinduction cervical ripening with prostaglandin E2 (Prepidil) gel. Am J Obstet Gynecol. 1985; 153:268-71. [IDIS 207501] [PubMed 3901764]

204. Neilson DR Jr, Prins RP, Bolton RN et al. A comparison of prostaglandin E2 gel and prostaglandin F gel for preinduction cervical ripening. Am J Obstet Gynecol. 1983; 146:526-32. [IDIS 172356] [PubMed 6344644]

205. Lorenz RP, Botti JJ, Chez RA et al. Variations of biologic activity of low-dose prostaglandin E2 on cervical ripening. Obstet Gynecol. 1984; 64:123-7. [IDIS 187151] [PubMed 6377145]

206. Prins RP, Bolton RN, Mark C III et al. Cervical ripening with intravaginal prostaglandin E2 gel. Obstet Gynecol. 1983; 61:459-62. [IDIS 168236] [PubMed 6572335]

207. Ulmsten U, Wingerup L, Andersson KE. Comparison of prostaglandin E2 and intravenous oxytocin for induction of labor. Obstet Gynecol. 1979; 54:581-4. [IDIS 107185] [PubMed 503385]

208. Dingfelder JR, Brenner WE, Hendricks CH et al. Reduction of cervical resistance by prostaglandin suppositories prior to dilatation for induced abortion. Am J Obstet Gynecol. 1975; 122:25-30. [PubMed 1130444]

209. Jagani N, Schulman H, Fleischer A et al. Role of prostaglandin-induced cervical changes in labor induction. Obstet Gynecol. 1984; 63:225-9. [IDIS 181001] [PubMed 6582419]

210. Buchanan D, Macer J, Yonekura ML. Cervical ripening with prostaglandin E2 vaginal suppositories. Obstet Gynecol. 1984; 63:659-63. [IDIS 184594] [PubMed 6585733]

211. Lagrew DC, Freeman RK. Management of postdate pregnancy. Am J Obstet Gynecol. 1986; 154:8-13. [PubMed 3946506]

212. Pharmacia & Upjohn Company. Prepidil Gel (dinoprostone cervical gel) prescribing information (dated 1999 Apr). In: Physician’s desk reference. 55th ed. Montvale, NJ: Medical Economics Company Inc; 2001:2637-8.

213. Forest Pharmaceuticals. Cervidil (dinoprostone vaginal insert) prescribing information (dated 2000 Feb). In: Physician’s desk reference. 55th ed. Montvale, NJ: Medical Economics Company Inc; 2001:1261-3.

214. Bryman I, Norstrom A, Lindblom B. Has cervical smooth muscle any physiological role in the human? Acta Physiol Hung. 1985; 65:327-30.

215. MacLennan AH, Katz M, Creasy R. The morphologic characteristics of cervical ripening induced by the hormones relaxin and prostaglandin F2 alpha in a rabbit model. Am J Obstet Gynecol. 1985; 152(6 pt 1):691-6. [PubMed 3861093]

216. Sadaty A, Pagano M, Greer C et al. A randomized trial of vaginal prostaglandin E(2) gel and dinoprostone vaginal insert for induction of labor at term. Prim Care Update Ob Gyns. 1998; 5:183. [PubMed 10838343]

217. Warke HS, Saraogi RM, Sanjwalla SM. Prostaglandin E2 gel In ripening of cervix in induction of labour. J Postgrad Med. 1999; 45:105-9. [PubMed 10734347]

218. Wieland D, Friedman F Jr. Comparing two dinoprostone agents for preinduction cervical ripening at term: a randomized trial. J Reprod Med. 1999; 44:724-8. [IDIS 435924] [PubMed 10483544]

219. McKenna DS, Costa SW, Samuels P. Prostaglandin E2 cervical ripening without subsequent induction of labor. Obstet Gynecol. 1999; 94:11-4. [IDIS 430673] [PubMed 10389710]

220. American College of Obstetricians and Gynecologists (ACOG) Committee on Practice Bulletins. Induction of labor. Practice Bulletin No. 10. Washington, DC: American College of Obstetricians and Gynecologists; 1999 Nov.

a. AHFS Drug Information 2007. McEvoy GK, ed. Dinoprostone. Bethesda, MD: American Society of Health-System Pharmacists; 2007: 3267-9.

b. Pharmacia and UpJohn. Prostin E2 (dinoprostone) vaginal suppository prescribing information. New York, NY; 2006 Apr..

c. Pharmacia and UpJohn . Prepidil (dinoprostone) cervical gel prescribing information. New York, NY; 2006 Nov.

d. Forest Pharmaceuticals, Inc. Cervidil (dinoprostone) vaginal insert prescribing information. St Louis, MO; 2006 May.

e. Stubblefield PG, Carr-Ellis S, Borgatta L. Methods for induced abortion. Obstet Gynecol. 2004; 104:174-85. [PubMed 15229018]

f. Ramsey PS, Savage K, Lincoln T, Owen J. Vaginal misoprostol versus concentrated oxytocin and vaginal PGE2 for second-trimester labor induction. Obstet Gynecol. 2004; 104:138-45. [PubMed 15229013]

g. American College of Obstetricians and Gynecologists (ACOG) Committee Practice Bulletin. Postpartum hemorrhage. Practice Bulletin No. 76. Washington, DC: American College of Obstetricians and Gynecologists; 2006 Oct.

h. Briggs GG, Wan SR. Drug therapy during labor and delivery, part 2. Am J Health-Syst Pharm. 2006; 63:1131-9. [PubMed 16754739]

i. Pharmacia. Prostin VR Pediatric (alprostadil) injection prescribing information. Kalamazoo, MI; 2002 Aug.

Hide
(web5)