ATC Class:G02AD02
VA Class:HS875
Dinoprostone, the naturally occurring prostaglandin E2, stimulates uterine smooth muscle and also produces cervical dilation and softening.
Dinoprostone suppositories are used intravaginally to induce abortion during the second trimester of pregnancy (beyond the 12th week of gestation). Continuous IV infusion of a dilute solution of oxytocin usually is used in conjunction with dinoprostone administration to shorten the induction-to-abortion time and reduce the number of dinoprostone doses required and the number of adverse effects. The mean induction-to-abortion time following intravaginal administration of dinoprostone with IV infusion of oxytocin in second trimester pregnancies is 12-14 hours; abortion occurs in about 90% of patients within 30 hours after the initial dose of dinoprostone.
When abortion fails to occur, the presence of uterine malformations or abnormalities (e.g., extrauterine pregnancy, ovarian cyst) should be considered; surgical intervention may be necessary. IV infusion of dilute solutions of oxytocin also has been used to induce abortion when the patient has failed to abort within 24-36 hours of dinoprostone administration, or after membranes have ruptured because intravaginal dinoprostone often is not effective then. Additional infusion of dilute oxytocin solution or curettage may be used if the placenta fails to abort spontaneously within 1 hour after delivery of the fetus; however, some clinicians maintain that oxytocin may hinder, rather than assist in, expulsion of the placenta. Because concurrent use of oxytocin and dinoprostone may produce uterine contractions of such intensity that cervical laceration may be more likely to occur, patients should be carefully monitored.
For inducing second-trimester abortions between the 12th and 16th week of gestation, most clinicians recommend dilatation and evacuation or intravaginal dinoprostone. Although some clinicians recommend dilatation and evacuation or, as a second choice, intra-amniotic hypertonic abortifacients for abortions beyond the 16th week of gestation, other clinicians have preferred intra-amniotic dinoprost tromethamine, but the latter agent is no longer commercially available in the US. Abortion should not be deferred until after the 16th week for purposes of administering intra-amniotic abortifacients. There are no well-controlled studies comparing intravaginal dinoprostone suppositories to dilatation and evacuation or to intra-amniotic abortifacients for second trimester abortions beyond the 16th week of gestation. Although intravaginal dinoprostone suppositories reportedly have a slightly shorter mean induction-to-abortion time than does intra-amniotic dinoprost (12-14 hours vs 20-24 hours), the intravaginal method also is associated with higher incidences of vomiting and diarrhea. In addition, the fact that prostaglandin abortifacients, unlike hypertonic abortifacients, are not feticidal and that some live births may occur late in the second trimester should be considered. It also is possible that previable fetuses may exhibit transient signs of life following dinoprostone-induced abortion. The manufacturer of the vaginal suppositories states that dinoprostone should not be used if the fetus has reached a stage of viability in utero .
Intravaginal dinoprostone suppositories also are used to evacuate the uterus in cases of missed abortion, intrauterine fetal deaths of up to 28 weeks of gestational age, and benign hydatidiform mole. In these instances, the drug produces successful evacuation in 80-100% of patients in a mean time of about 10 hours. In cases of missed abortion or suspected intrauterine fetal death, the death of the fetus should be documented by a negative pregnancy test for chorionic gonadotropin activity, absence of fetal heart sounds, or radiograph before inducing abortion with dinoprostone.
Intravaginal dinoprostone suppositories also have been used to induce abortion during the first trimester of pregnancy†, but dilatation and evacuation is more satisfactory under most conditions.
Dinoprostone has been administered IV†, intra-amniotically†, or extra-amniotically† to induce abortion during the second trimester and intravaginally to dilate the cervix prior to dilatation and evacuation†, but these methods are usually accompanied by an unacceptable incidence of adverse effects. The drug has been used orally† or intravaginally with some success for the induction of labor at term†.
Dinoprostone208, 209, 210, 211 (cervical gel and vaginal inserts)201, 202, 203, 204, 205, 206, 207 are used to improve cervical inducibility (cervical “ripening”)201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211 near or at term in pregnant women with a medical or obstetric need for labor induction;212, 213, 216, 217, 218, 219, 220 in some cases, induction with oxytocin may not be necessary following administration of dinoprostone. Efficacy of intracervival or intravaginal dinoprostone in cervical ripening has been shown to be superior to placebo or no therapy and similar to that of misoprostol.220 The manufacturer of dinoprostone vaginal suppositories warns that neither the commercially available vaginal suppositories nor formulations prepared extemporaneously from the suppositories should be used for cervical ripening or any other purpose in a woman with a term pregnancy.200
Pelvic adequacy and other maternal and fetal conditions must be evaluated carefully whenever induction of labor is considered.212, 220 Dinoprostone in association with induction of labor should not be used when the benefit-to-risk ratio for the mother or child favors surgical intervention.212
Dinoprostone also has been used IV† and by intranasal inhalation† as a bronchodilator in patients with bronchial asthma, but the inconsistency of the drug's bronchial smooth muscle effects precludes its use in these patients.
Dinoprostone Vaginal Suppositories
Dinoprostone vaginal suppositories are administered intravaginally. Before removing the foil wrapping, dinoprostone suppositories should be allowed to warm to room temperature. Dinoprostone suppositories should be inserted high into the posterior vaginal fornix, and patients should remain supine for 10 minutes following each insertion. A diaphragm may be used to prevent displacement of dinoprostone from the paracervical area but may make monitoring of cervical ripening difficult.
The manufacturer warns that the commercially available dinoprostone vaginal suppositories should not be used for extemporaneous preparation of any other dosage form of the drug.
Dinoprostone cervical gel (supplied in a syringe) is administered intravaginally via a shielded catheter into the cervical canal.212 The manufacturer's instructions should be consulted for proper assembly of the syringe and catheter.212 Prior to administration, the gel should be allowed to warm to room temperature (15-30°C); however, use of a water bath or other source of direct external heat (e.g., microwave radiation) is not recommended.212 The selection of a proper size catheter should be based on the degree of effacement; if no effacement is present the, 20-mm catheter should be used while with 50% of cervical effacement the 10-mm catheter should be used.212
When administering dinoprostone cervical gel, the patient should be in a dorsal position and a speculum should be used to visualize the cervix.212 Using sterile technique, dinoprostone gel should be administered via the catheter (provided by the manufacturer) into the cervical canal, just below the level of the internal os.212 Extra-amniotical administration of the gel has been associated with uterine hyperstimulation.212 Contents of a syringe should be used by one patient only and after administration of the gel, the catheter should be removed and the patient should remain in the supine position for at least 15-30 minutes to minimize leakage from the cervical canal.212 The catheter (usually still contaning a small amount of gel), the syringe, and any unused wrapping material should be discarded after administration.212
Dinoprostone vaginal inserts are administered intravaginally.213 The vaginal insert should be placed transversely in the posterior fornix of the vagina immediately after removal from the foil wrapping and patients should remain supine for 2 hours following insertion.213 The vaginal insert should always be used with the knitted polyester retrieval system, designed to aid retrieval at the end of the dosage interval.213 A small amount of water-soluble lubricant may be used to assist insertion.213 However, excess contact or coating with the lubricant may prevent optimal swelling and release of dinoprostone from the vaginal insert.213
Dinoprostone Vaginal Suppositories
The usual dosage of dinoprostone for second trimester abortions and for evacuation of the uterus in cases of missed abortion, intrauterine fetal death, and benign hydatidiform mole is 20 mg every 2-3 hours until abortion occurs or membranes rupture. However, the manufacturer and some clinicians recommend initial intervals of 3-5 hours between doses with subsequent adjustment of these intervals according to the progress of the abortion, uterine contractility, and patient tolerance. Concurrent IV infusion of a dilute solution of oxytocin usually is started 1 hour after the first dose of dinoprostone, usually at a rate of 10-100 milliunits of oxytocin per minute.
In patients who fail to respond within 24-36 hours after the initial dinoprostone dose, several treatment alternatives are possible. If abortion appears imminent, additional IV infusion of a dilute oxytocin solution may be given. Alternatively, dinoprostone administration can be continued or other appropriate abortion methods (e.g., dilatation and evacuation) may be used. Continuation of dinoprostone for longer than 2 days is not recommended.
To improve cervical inducibility (cervical “ripening”) near or at term in pregnant women with medical or obstetric need for labor induction, the usual dosage of dinoprostone cervical gel is 0.5 mg (2.5 mL of Prepidil® gel).212 If the desired response is obtained with the use of the gel, the manufacturer recommends an interval of 6-12 hours before administration of IV oxytocin.212 (See Drug Interactions.) If there is no cervical and/or uterine response to the initial dose of dinoprostone cervical gel, a second 0.5-mg dose may be given after 6-12 hours.212, 220 The need for additional doses and corresponding dosing intervals should be determined by the clinician.212 The maximum recommended cumulative dose of dinoprostone cervical gel during a 24-hour period is 1.5 mg (7.5 mL of Prepidil® gel).212, 220
To improve cervical inducibility (cervical “ripening”) near or at term in pregnant women with medical or obstetric need for labor induction, the usual dosage of dinoprostone vaginal inserts is 10 mg (1 insert; designed to deliver about 0.3 mg of the drug per hour over 12 hours).213 Dinoprostone vaginal inserts should be removed upon onset of active labor or 12 hours after insertion.213
Most of dinoprostone's adverse effects are related to the contractile effects of the drug on GI, vascular, bronchial, and uterine smooth muscle. Since dinoprostone, like dinoprost, is metabolized rapidly, discontinuing administration of the drug and supportive therapy are usually adequate treatments for serious adverse effects.
Hyperstimulation (defined as a series of single uterine contractions lasting 2 minutes or longer or occurrence of 5 or more contractions in 10 minutes that may be accompanied by evidence of fetal intolerance to such a contraction pattern as demonstrated by late deceleration or fetal bradycardia) has been reported in 5 or at least 1% of women receiving dinoprostone vaginal inserts or cervical gel, respectively. 212, 213, 220 Fetal depression, fetal acidosis, and premature rupture of membranes have been reported with use of dinoprostone cervical gel.212 In addition, intrauterine fetal sepsis has been associated with extra-amniotic intrauterine administration of dinoprostone.212
Adverse GI effects are the most frequent adverse reactions of dinoprostone. In patients premedicated with antiemetics (e.g., prochlorperazine) and antidiarrhea agents (e.g., diphenoxylate with atropine), one or more episodes of nausea and vomiting occur in about 60% of patients and diarrhea occurs in 15-40% of patients. The incidence of adverse GI effects is increased when patients are not premedicated with antiemetics and antidiarrhea agents. Abdominal pain also may occur.213
Vasomotor and vasovagal symptoms, including transient reductions in diastolic blood pressure of greater than 20 mm Hg, dizziness, syncope or a fainting sensation, flushing or hot flashes, and cardiac arrhythmias have been reported. Bronchospasm, wheezing, dyspnea, pain and tightness of the chest, and coughing have occurred. In one 38-year-old patient with severe hypertension and preeclampsia, severe chest pain, dyspnea, acute hypotension, vascular collapse, and myocardial infarction occurred 1 hour after the administration of dinoprostone for intrauterine fetal death at 32 weeks' gestation. Myocardial infarction has occurred following dinoprostone administration in at least one other woman with underlying cardiovascular disease.
Temperature elevations in excess of 1.1°C occur in 50-70% of patients within 15-45 minutes and persist for up to 6 hours following a dose of the drug. In contrast to fever secondary to endometritis, dinoprostone-induced fever may occur earlier, whether or not abortion is incomplete, and without an endometrial inflammatory reaction or uterine subinvolution. Because dinoprostone-induced fever is self-limiting and transient, it may be treated by sponging the patient with water or alcohol and increasing oral fluid intake, provided there is no clinical or bacteriologic evidence of intrauterine infection. Aspirin does not appear to be useful for dinoprostone-induced fever.
Cervical laceration and trauma have occurred during dinoprostone-induced abortion. These effects have occurred most commonly in primigravida patients and in those receiving concomitant IV oxytocin. Uterine rupture also has occurred. Placentas may be retained in some patients undergoing abortion with dinoprostone; when abortion is delayed, the risk of retained placenta with resultant hemorrhage, fever, and infection, including endometritis, is increased.
Headache, chills, and shivering occur in about 10% of patients receiving dinoprostone. Other adverse reactions occasionally reported, all of which have not been definitely related to dinoprostone, include, in order of decreasing incidence: backache, joint inflammation or pain (new or exacerbated), vaginal pain, vaginitis, vulvitis, weakness, muscle cramps or pain, nocturnal leg cramps, breast tenderness, blurred vision, rash, myalgia, stiff neck, dehydration, tremor, paresthesia, hearing impairment, urine retention, pharyngitis, laryngitis, diaphoresis, eye pain, skin discoloration, and tension. Seizures were reported in one patient receiving intra-amniotic dinoprostone but have not been reported in patients receiving the drug intravaginally.
Animal studies indicate that prostaglandins of the E and F series can induce bone proliferation after several weeks of high dosages. Such effects also have been observed in neonates who received prolonged therapy with alprostadil (prostaglandin E1). However, there is no evidence to date that short-term administration of dinoprostone is associated with similar effects on bone.
Precautions and Contraindications
Dinoprostone should be used only by medically trained personnel in a hospital where intensive care and surgical facilities are immediately available. Patients should be informed of the benefits and risks of dinoprostone-induced abortions. A complete medical history and physical examination should be performed prior to administration of the drug.
Patients with cervical laceration with resultant retention of the placenta and severe hemorrhage may require blood tranfusions. These hazards can be minimized if dinoprostone is not administered to patients with a history of pelvic surgery resulting in through-and-through incisions, uterine fibroids, or cervical stenosis. Because cervical trauma can occur without symptoms, each patient should be carefully examined after the abortion is completed to detect any cervical injuries.
Caution should be exercised when administering dinoprostone to 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 intraocular pressure, anemia, jaundice, or cardiovascular, renal, or hepatic disease.
Animal studies indicate that the prostaglandins may be teratogenic; therefore, if the pregnancy is not terminated with dinoprostone, the abortion should be completed by another method.
While the manufacturer of dinoprostone vaginal suppositories states that they should not be used in a woman at term pregnancy,200 the drug is used as a cervical gel or a vaginal insert at or near term to improve cervical inducibility and thus facilitate subsequent labor induction efforts.212, 213 Because such use at or near term involves administration of the drug after the period of organogenesis, no adverse effect on fetal development would be expected.212 However, any dose of the drug that produces sustained increased uterine tone could place the embryo or fetus at risk of other complications.212
During endocervical administration of dinoprostone cervical gel and administration of dinoprostone vaginal inserts, uterine activity, fetal status, and character of the cervix (i.e., dilation and effacement) should be carefully monitored either by auscultation or electronic fetal monitoring to detect possible complications (e.g., hypertonus, sustained uterine contractility, fetal distress.)212, 213, 220 In women with a history of hypertonic uterine contractility or tetanic uterine contractions, uterine activity and fetal status should be continuously monitored.212
Safety and efficacy of dinoprostone in children have not been established.200, 212, 213
IV infusion of 500 mL of 10% alcohol injection over a period of 1 hour has been reported to inhibit uterine activity that had been initiated and maintained by IV dinoprostone.
Since dinoprostone may increase activity of oxytocic agents, concomitant use of dinoprostone and oxytocics is not recommended.200, 212, 213 At least 30 minutes should elapse between removal of dinoprostone vaginal insert and initiation of oxytocin therapy,213, 220 while an interval of 6-12 hours is recommended for the sequential administration of oxytocin after the use of dinoprostone cervical gel.212, 220
Dinoprostone stimulates uterine and GI smooth muscle. Although it is believed that the drug exerts its uterine effects via direct myometrial stimulation, the exact mode of this and other actions has not been fully elucidated. Other mechanisms proposed include regulation of cellular membrane calcium transport and of intracellular concentrations of cyclic 3',5'-adenosine monophosphate.
Contractions produced in the gravid uterus by dinoprostone are similar to those occurring in the term uterus during spontaneous labor. Dinoprostone increases the amplitude and frequency of uterine contractions throughout pregnancy, but uterine response to the drug increases with the duration of pregnancy. In early pregnancy, the uterus is more responsive to dinoprostone than to oxytocin. Dinoprostone-induced uterine contractions are usually sufficient to cause evacuation of both the fetus and the placenta; however, abortion may be incomplete in 30-40% of patients.
Dinoprostone also appears to produce local cervical effects including softening, effacement, and dilation.212, 213, 214, 215 The exact mechanism of action of dinosprostone in the improvement of cervical inductibility (cervical “ripening”) has not been elucidated.212, 213 It has been suggested that the marked relaxation of the cervical smooth muscle occurring during cervical ripening may be associated with collagen degradation caused by secretion of the enzyme collagenase as a partial response to locally administered dinoprostone.212, 213, 215
Dinoprostone causes stimulation of the circular smooth muscle of the GI tract, increasing GI motility; this effect is responsible for the adverse GI effects of the drug. When inhaled intranasally, dinoprostone has caused bronchodilation in patients with elevated airway resistance and has reversed dinoprost-induced bronchoconstriction in normal patients. Conversely, intranasal inhalation or IV injection of dinoprostone also has produced bronchoconstriction in normal and asthmatic patients. Large doses of dinoprostone may cause vasodilation, but resultant reductions in blood pressure are not usually clinically important.
Dinoprostone increases body temperature, but the precise mechanism of prostaglandin-induced temperature alteration has not been established.
Following vaginal insertion of dinoprostone suppositories, most of the drug slowly diffuses into the maternal blood; a small amount is absorbed directly by the uterus through the cervix or local lymphatic or vascular channels. Diaphragms which prevent displacement of the drug from the paracervical area may enhance local absorption. Plasma concentrations of dinoprostone do not appear to be related to the uterine activity produced by the drug. In most first and second trimester pregnancies, slight uterine contractions begin within 10 minutes and contractions continue for 2-3 hours following vaginal insertion of a dinoprostone suppository.
Dinoprostone cervical gel is rapidly absorbed and peak plasma concentrations of the drug are achieved in 30-45 minutes.212 The commercially available 10-mg dinorpostone vaginal inserts are designed to release 0.3 mg of the drug per hour over 12 hours.213 Plasma concentrations of dinoprostone do not appear to be related to the amount of drug released from the inserts.213 In addition, the relative contribution of endogenously secreted and exogenously administered prostaglandin E2 to plasma prostaglandin metabolite concentrations is not known.213
Dinoprostone is widely distributed in the mother and is rapidly metabolized in the maternal lungs, kidneys, spleen, and other tissues, primarily by oxidation of the side chains to at least 9 inactive metabolites. The drug and its metabolites are excreted principally in urine but small amounts are excreted in feces.
Dinoprostone, the naturally occurring prostaglandin E2, is prepared synthetically for commercial use. Dinoprostone occurs as a white, crystalline powder and is slightly soluble in water and soluble in alcohol. The drug has a pKa of 4.6. Dinoprostone is commercially available as a cervical gel (Prepidil®), vaginal insert (Cervidil®), and vaginal suppository (Prostin E2®).200, 212, 213, 220
Commercially available dinoprostone vaginal suppositories should be stored at temperatures not exceeding -20°C. The vaginal inserts should be stored between -20°C and -10°C and protected from moisture and humidity since the release characteristics of the inserts may be altered when exposed to high humidity.213 Under such storage conditions, the inserts are stable for 3 years.213 The cervical gel is stable for 24 months when stored under continuous refrigeration between 2-8°C.212
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.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Vaginal | Gel | 0.5 mg/3 g | ||
Insert | 10 mg | |||
Suppositories | 20 mg | Pfizer |
Only references cited for selected revisions after 1984 are available electronically.
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. [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. [PubMed 3901764]
204. Neilson DR Jr, Prins RP, Bolton RN et al. A comparison of prostaglandin E2 gel and prostaglandin F2α gel for preinduction cervical ripening. Am J Obstet Gynecol . 1983; 146:526-32. [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. [PubMed 6377145]
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207. Ulmsten U, Wingerup L, Andersson KE. Comparison of prostaglandin E2 and intravenous oxytocin for induction of labor. Obstet Gynecol . 1979; 54:581-4. [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. [PubMed 6582419]
210. Buchanan D, Macer J, Yonekura ML. Cervical ripening with prostaglandin E2 vaginal suppositories. Obstet Gynecol . 1984; 63:659-63. [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. [PubMed 10483544]
219. McKenna DS, Costa SW, Samuels P. Prostaglandin E2 cervical ripening without subsequent induction of labor. Obstet Gynecol . 1999; 94:11-4. [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.