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Oct.04.2022

Dinoprostone, Prostaglandin E2

Indications/Dosage

Labeled

  • cervical ripening induction
  • hydatidiform mole
  • intrauterine fetal death
  • pregnancy termination

Off-Label

    † Off-label indication

    For evacuation of the uterine contents in the cases of missed abortion or intrauterine fetal death, second trimester pregnancy termination, or benign hydatidiform mole

    Vaginal dosage (vaginal suppository)

    Adult females

    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.[41180]

    For cervical ripening induction in women at or near term with a medical or obstetrical need for labor induction

    Endocervical dosage (gel)

    Adults

    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.[41179]

    Vaginal dosage (vaginal insert)

    Adults

    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.[41178]

    Therapeutic Drug Monitoring

    Maximum Dosage Limits

    • Adults

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

    • Elderly

      Safety and efficacy have not been established.

    • Adolescents

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

    • Children

      Safety and efficacy have not been established.

    Patients with Hepatic Impairment Dosing

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

    Patients with Renal Impairment Dosing

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

    † Off-label indication
    Revision Date: 10/04/2022, 06:49:19 PM

    References

    41178 - Cervidil (dinoprostone) vaginal insert package insert. Parsippany, NJ, Ferring Pharmaceuticals, Inc.; 2020 Jan.41179 - Prepidil Gel (dinoprostone) cervical gel package insert. New York, NY: Pfizer Inc.; 2019 Dec.41180 - Prostin E2 (dinoprostone) suppository package insert. New York, NY: Pharmacia and Upjohn Company; 2018 Oct.

    How Supplied

    Dinoprostone Vaginal gel

    Prepidil 0.5mg/3g Vaginal Gel (00009-3359) (Pfizer Inc.) null

    Dinoprostone Vaginal insert

    Cervidil 10mg Vaginal Insert (00456-4123) (Allergan USA, Inc.) (off market)Cervidil 10mg Vaginal Insert package photo

    Dinoprostone Vaginal insert

    Cervidil 10mg Vaginal Insert (00456-4123) (Ferring Pharmaceuticals Inc) null

    Dinoprostone Vaginal insert

    Cervidil 10mg Vaginal Insert (55566-2800) (Ferring Pharmaceuticals Inc) null

    Dinoprostone Vaginal Suppository

    Prostin E-2 20mg Vaginal Suppository (00009-0827) (Pfizer Inc.) (off market)

    Description/Classification

    Description

    Dinoprostone is a synthetic preparation of naturally occurring prostaglandin E2. Dinoprostone is administered endocervically or vaginally; the drug has oxytocic actions. Dinoprostone vaginal suppositories (Prostin E2) are used clinically to induce abortion in the second trimester of pregnancy and to evacuate the contents of the uterus following intrauterine fetal death, missed abortion, or benign hydatidiform mole.[41180] The endocervical gel (Prepidil) and the removable vaginal insert (Cervidil) are used for cervical ripening.[41179][41178] Use of any dosage form requires trained obstetrical personnel in a hospital setting with appropriate surgical, emergency, and obstetrical care facilities.

    Classifications

    • Genito-urinary System and Sex Hormones
      • Other Gynecologicals
        • Labor Inducers
    Revision Date: 07/16/2020, 04:46:11 PM

    References

    41178 - Cervidil (dinoprostone) vaginal insert package insert. Parsippany, NJ, Ferring Pharmaceuticals, Inc.; 2020 Jan.41179 - Prepidil Gel (dinoprostone) cervical gel package insert. New York, NY: Pfizer Inc.; 2019 Dec.41180 - Prostin E2 (dinoprostone) suppository package insert. New York, NY: Pharmacia and Upjohn Company; 2018 Oct.

    Administration Information

    General Administration Information

    For storage information, see the specific product information within the How Supplied section.

    Hazardous Drugs Classification

    • NIOSH 2016 List: Group 3 [63664]
    • 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.[63664] [67506] [67507]

    Route-Specific Administration

    Intravaginal 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]

    Clinical Pharmaceutics Information

    From Trissel's 2‚Ñ¢ Clinical Pharmaceutics Database
    Revision Date: 04/20/2022, 04:27:05 PMCopyright 2004-2023 by Lawrence A. Trissel. All Rights Reserved.

    References

    41178 - Cervidil (dinoprostone) vaginal insert package insert. Parsippany, NJ, Ferring Pharmaceuticals, Inc.; 2020 Jan.41179 - Prepidil Gel (dinoprostone) cervical gel package insert. New York, NY: Pfizer Inc.; 2019 Dec.41180 - Prostin E2 (dinoprostone) suppository package insert. New York, NY: Pharmacia and Upjohn Company; 2018 Oct.63664 - CDC National Institute for Occupational Safety and Health (NIOSH). NIOSH List of Antineoplastic and Other Hazardous Drugs in Healthcare Settings 2016. DHHS (NIOSH) Publication Number 2016-161, September 2016. Available on the World Wide Web at https://www.cdc.gov/niosh/docs/2016-161/pdfs/2016-161.pdf?id=10.26616/NIOSHPUB201616167506 - American Society of Health-System Pharmacists. ASHP guidelines on handling hazardous drugs. Am J Health-Syst Pharm. 2018; 75:1996-2031.67507 - NIOSH [2016]. NIOSH Alert: Preventing Occupational Exposures to Antineoplastics and Other Hazardous Drugs in Health Care Settings. U.S. Department of Health and Human Services, Public Health Service, Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health, DHHS (NIOSH) Publication No. 2016-161.

    Adverse Reactions

    Mild

    • abdominal pain
    • arthralgia
    • back pain
    • chills
    • cough
    • diaphoresis
    • diarrhea
    • dizziness
    • fever
    • flushing
    • headache
    • mastalgia
    • muscle cramps
    • musculoskeletal pain
    • nausea
    • ocular pain
    • paresthesias
    • rash
    • shivering
    • syncope
    • vomiting
    • weakness

    Moderate

    • blurred vision
    • chest pain (unspecified)
    • dyspnea
    • fetal distress
    • hot flashes
    • hypertension
    • hypotension
    • uterine contractions
    • vaginal pain
    • wheezing

    Severe

    • amniotic fluid embolism
    • anaphylactoid reactions
    • angioedema
    • bronchospasm
    • cervical laceration
    • disseminated intravascular coagulation (DIC)
    • myocardial infarction
    • uterine rupture

    Among 25 women who received dinoprostone, prostaglandin E2 20 mg suppository every 3 hours, 71% had nausea.[32756] In other trials with the vaginal suppository, approximately two-thirds experienced vomiting, approximately two-fifths had diarrhea, and approximately one-third had nausea.[41180] In contrast, < 1% of dinoprostone vaginal insert recipients had nausea, vomiting, diarrhea, or abdominal pain.[41178] The vomiting and/or diarrhea that is occasionally seen when dinoprostone is used for preinduction cervical ripening is likely due to the contractile effect of dinoprostone on smooth muscle; the reactions are usually transient and reversible once dinoprostone administration ceases. The pretreatment or concurrent administration of antiemetic and antidiarrheal drugs considerably decreases the incidence of gastrointestinal effects common with all prostaglandins used for abortion; consider such co-therapies as an integral part of patient care.[32757]

    Approximately 10% of dinoprostone, prostaglandin E2 suppository recipients had transient diastolic blood pressure decreases of > 20 mmHg, and 2 cases of myocardial infarction after the use of dinoprostone have been reported in patients with a history of cardiovascular disease. Of note, large doses of another prostaglandin carboprost tromethamine can raise blood pressure, probably by contracting the vascular smooth muscle; the most frequent adverse reactions observed with the use of dinoprostone for abortion are related to its contractile effect on smooth muscle. Clinically significant effects on blood pressure have not been noted with dinoprostone doses used for terminating pregnancy, but cautious use of dinoprostone is advised for patients with a history of hypotension or hypertension. Other adverse events that may be related to dinoprostone-induced vasomotor and vasovagal effects include flushing, hot flashes, dizziness, syncope, lightheadedness, chest pain (unspecified), diaphoresis, and cardiac arrhythmias.[32757] [41180]

    Use of dinoprostone, prostaglandin E2 is associated with transient fever that may be due to its effect on hypothalamic thermoregulation.[41180] Among 25 recipients of dinoprostone suppositories 20 mg every 3 hours until abortion, 79% had chills, and 92% had fever.[32756] Among other suppository recipients, 50% had temperature elevations in excess of 2 degrees F, and 10% had shivering and chills. In all cases, temperature returned to normal on dinoprostone discontinuation; temperature usually reverts to baseline 2—6 hours after dinoprostone discontinuation or suppository removal. In contrast to the suppository, fever was noted in < 1% of dinoprostone vaginal insert recipients and in 1.4% of dinoprostone gel recipients.[41178] [41179] In regard to dinoprostone use for pregnancy termination, differentiation of post-abortion endometritis from drug-induced temperature elevations is difficult. Determining the time of onset may help discern the fever cause; dinoprostone-induced fever usually occurs within 15—45 minutes of suppository administration while endometritis-induced temperature elevations typically present on day 3 after the abortion procedure. Uterine and other physical findings consistent with endometritis include incomplete evacuation of the uterus, histology consistent with endometrial inflammation, foul-smelling lochia and leukorrhea, and uterine tenderness. Force fluids in patients with drug-induced fever and no clinical or bacteriological evidence of an infectious process; no other simple empirical measures for temperature reduction are necessary, as fever is transient or self-limiting.[32757]

    Use of dinoprostone, prostaglandin E2 suppositories for pregnancy termination may cause a cervical laceration. For example, posterior cervical perforation has been noted with another prostaglandin carboprost tromethamine. As cervical trauma can be asymptomatic, carefully examine the cervix immediately after the completion of dinoprostone-induced abortion. Take corrective measures as necessary.[32757]

    Uterine contraction is a common and expected effect of dinoprostone, prostaglandin E2. Among 25 women who received a 20 mg suppository every 3 hours until delivery, 88% had uterine muscle cramps and 33% had headache.[32756] Headache was also noted in 10% of other suppository recipients, and arthralgia, mastalgia, back pain, leg cramps, musculoskeletal pain, paresthesias, vaginal pain, weakness, and cramping similar to dysmenorrhea have been observed.[41180] Back pain was also noted among 3.1% of 884 dinoprostone vaginal gel recipients.[41179]

    According to the manufacturers of dinoprostone vaginal gel and insert, during post-marketing surveillance, an increased risk of post-partum disseminated intravascular coagulation (DIC) has been reported in patients whose labor was induced by dinoprostone. The frequency of this adverse event appears to be rare; reported in < 1 per 1000 labors in patients receiving the vaginal gel (Prepidil). Risk factors for DIC include pregnant females 30 years or older, those with complications during pregnancy, and those with a gestational age over 40 weeks. Therefore, use dinoprostone with considerable caution in these groups, and monitor carefully for the possibility of fibrinolysis in the post-partum period.[41178] [41179]

    The intravaginal placement of dinoprostone vaginal gel and vaginal insert (Prepidil and Cervidil, respectively) may result in inadvertent disruption and subsequent embolization of antigenic tissue causing in rare circumstances the development of anaphylactoid syndrome of pregnancy (amniotic fluid embolism).[41178] [41179]

    Uterine rupture or perforation is a potentially life-threatening adverse event that has been noted among women who received dinoprostone; prostaglandin E2 for pregnancy termination and for cervical ripening. Consider uterine rupture if high-tone myometrial contractions are sustained. Cautious use of the suppositories is advised for women with compromised (scarred) uteri.[41180] Of note, the vaginal insert and the vaginal gel are contraindicated for use by women with a previous cesarean section.[41179] [41178] Among women who had various induction methods for pregnancy termination, the incidence of uterine rupture was 3.8% among women with a prior cesarean as compared with 0.2% of women without such a history.[54356] Use of laminaria tents and/or conservative uterine stimulation in at risk patients may decrease the risk of rupture.[32763]

    Respiratory effects associated with dinoprostone, prostaglandin, E2 use include dyspnea, chest tightness, cough, and wheezing. Dinoprostone vaginal suppositories are contraindicated for use by patients with active pulmonary disease; use all dinoprostone formulations with caution in patients with a history of asthma or other bronchospasm.[41178] [41179] [41180]

    Serious hypersensitivity reactions, including anaphylactoid reactions, anaphylaxis, and angioedema have been noted postmarketing experience with dinoprostone.[41179] [41180] Onset of these reported reactions occurred within minutes to hours after initiation with dinoprostone. Rash (unspecified) has been observed with dinoprostone, prostaglandin E2 administration.[41180] 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.[41179] [41180]

    Blurred vision and ocular pain have been noted with dinoprostone, prostaglandin E2.[41180] Cautious use of dinoprostone is advised for patients with glaucoma or raised intraocular pressure.[41179]

    The use of the dinoprostone vaginal insert may cause uterine tachysystole (excessively frequent uterine contractions) with or without fetal heart rate changes. In placebo-controlled trials, 2.8% to 2.9% of women who received the vaginal insert experienced uterine tachysystole with fetal distress compared to 0% to 0.3% of women who received placebo. During these trials, 2% to 4.7% of treated women experienced uterine tachysystole without fetal distress compared to 0% of women who received placebo. Also, 2.9% to 3.8% of women who received the vaginal insert experienced fetal distress without uterine tachysystole vs. 1% to 1.2% of the women who received placebo. In the cases of uterine tachysystole, uterine hyperstimulation reversed within 2 to 13 minutes of removal of the vaginal insert, using the retrieval system. Tocolytics were required in one of the 5 cases. When the vaginal insert was removed for fetal distress, there was a return to a normal rhythm and there were no neonatal sequelae. During use of the vaginal insert, carefully monitor uterine activity, fetal status, and the progression of cervical dilatation and effacement. Remove the vaginal insert with any evidence of persistent tachysystole with or without fetal heart rate changes, uterine hypersystole/hypertonicity, fetal distress, or if labor commences.[41178]

    Revision Date: 07/16/2020, 05:10:45 PM

    References

    32756 - Borgida AF, Rodis JF, Hanlon W, et al. Second-trimester abortion by intramuscular 15-methyl-prostaglandin F2alpha or intravaginal prostaglandin E2 suppositories: a randomized trial. Obstet Gynecol 1995;85:697-700.32757 - Hemabate (carboprost tromethamine injection, USP) package insert. New York, NY: Pfizer, Inc.; 2013 Dec.32763 - Baxi L. Midtrimester pregnancy termination. Am J Obstet Gynecol 1997;176:952. Letter.41178 - Cervidil (dinoprostone) vaginal insert package insert. Parsippany, NJ, Ferring Pharmaceuticals, Inc.; 2020 Jan.41179 - Prepidil Gel (dinoprostone) cervical gel package insert. New York, NY: Pfizer Inc.; 2019 Dec.41180 - Prostin E2 (dinoprostone) suppository package insert. New York, NY: Pharmacia and Upjohn Company; 2018 Oct.54356 - Chapman SJ, Crispens M, Owen J, et al. Complications of midtrimester pregnancy termination The effect of prior cesarean delivery termination. Am J Obstet Gynecol 1996;175:889-92.

    Contraindications/Precautions

    Absolute contraindications are italicized.

    • caesarean section
    • cardiac disease
    • cephalopelvic disproportion
    • fetal distress
    • hepatic disease
    • herpes infection
    • multiparity
    • placenta previa
    • pulmonary disease
    • renal disease
    • uterine atony
    • vaginal bleeding
    • amniotic fluid embolism
    • anemia
    • angioedema
    • asthma
    • bleeding
    • breast-feeding
    • cervicitis
    • children
    • diabetes mellitus
    • disseminated intravascular coagulation (DIC)
    • fibrinolysis
    • glaucoma
    • hypertension
    • hypotension
    • incomplete abortion
    • increased intraocular pressure
    • infants
    • infection
    • jaundice
    • labor
    • pregnancy
    • pregnancy testing
    • premature rupture of membranes (PROM)
    • requires a specialized care setting
    • requires an experienced clinician
    • seizure disorder
    • serious hypersensitivity reactions or anaphylaxis
    • surgery
    • vaginitis

    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.[41178] [41179] [41180] 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.[41180] 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.[41180] 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.[41178] Because prostaglandins potentiate the effects of oxytocin, the concurrent use of dinoprostone and other oxytocic drugs is not recommended for any indication.[41178] [41179] [41180] 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.[41178] [41179]

    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.[41180] [41178] [41179] 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.[41180] 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.[41180] [41178] [41179] 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.[41180] [41178] [41179]

    The placement of dinoprostone endocervical and vaginal products, respectively) may result in inadvertent disruption and subsequent embolization of antigenic tissue causing in rare circumstances the development of anaphylactoid syndrome of pregnancy (amniotic fluid embolism).[41178] [41179]

    Pregnant females 30 years or older, those with complications during pregnancy, and those with a gestational age greater than 40 weeks have been shown to have an increased risk of post-partum disseminated intravascular coagulation (DIC). Patients within these groups may also have an increased risk associated with labor induction. Therefore, use endocervical and vaginal dinoprostone for cervical ripening with considerable caution in these groups and monitor carefully for the possibility of fibrinolysis in the post-partum period.[41178] [41179]

    Dinoprostone suppositories for pregnancy termination are contraindicated in patients with active cardiac disease, pulmonary disease, renal disease, or hepatic disease.[41180] Use dinoprostone with caution in patients with hypotension; transient diastolic blood pressure decreases of greater than 20 mmHg have been reported during use of dinoprostone vaginal suppositories in up to 10% of patients, and hypotension has been reported with products for cervical ripening in postmarketing surveillance. In patients with asthma or a history of asthma, glaucoma or increased intraocular pressure, hypertension, cardiac disease, renal disease, hepatic disease, jaundice, anemia, diabetes mellitus, or history of seizure disorder, dinoprostone endocervical or vaginal cervical ripening agents should be used with caution. Prostaglandins have the ability to influence these disease states. Dinoprostone is extensively metabolized in the lung, liver, and kidney, and the major route of elimination is the kidney.[41178] [41179]

    Dinoprostone use for cervical ripening is contraindicated when prolonged contraction of the uterus may be detrimental to fetal safety and uterine integrity. Factors that contraindicate the use of dinoprostone for cervical ripening at term can reflect possible maternal or fetal problems. Cephalopelvic disproportion or signs of fetal distress contraindicate use. Certain maternal problems contraindicate use of dinoprostone for cervical ripening such as a history of difficult labor (prolonged contraction of the uterus) or traumatic delivery, grand multiparity (delivery of 6 or more live infants), previous history of caesarean section or major uterine surgery, or any hyperactive or hypertonic uterine patterns (uterine atony). Such maternal problems may increase the risk of uterine rupture and associated fetal and maternal complications. Cautious use is warranted in patients with premature rupture of membranes (PROM), in cases of non-vertex or non-singleton presentation, and in patients with a history of uterine hypertony when administering dinoprostone vaginal products for cervical ripening.[41178] [41179] The use of the vaginal insert may also cause uterine tachysystole with or without fetal heart rate changes. While using the vaginal insert, carefully monitor uterine activity, fetal status and the progression of cervical dilatation and effacement. Remove the vaginal insert with any evidence of uterine tachysystole, uterine hypersystole/hypertonicity, fetal distress, or if labor commences. Prostaglandins, including the vaginal insert, may potentiate the effect of oxytocin. Remove the vaginal insert at least 30 minutes before administration of an oxytocic agent is initiated and continue to carefully monitor uterine activity. Remove the vaginal insert prior to amniotomy or following rupture of membranes because the higher vaginal pH that occurs with rupture of membranes may result in a higher release rate of dinoprostone from the insert.[41178]

    Dinoprostone suppositories are contraindicated in patients with acute pelvic inflammatory disease (PID) infection.[41180] Following suppository use for pregnancy termination, patients should be examined for cervical trauma. Cervical laceration with resultant bleeding may require blood transfusions, so dinoprostone should be administered only by qualified personnel in a hospital setting where emergency measures may be taken, if necessary.[41180] Dinoprostone products should be used with caution in the presence of cervicitis, infected endocervical lesions, or acute vaginitis.[41178] [41179] [41180] Dinoprostone use for cervical ripening is contraindicated in patients who have placenta previa or who have had unexplained vaginal bleeding during the course of the current pregnancy. Dinoprostone should not be used if the patient has any other condition contraindicating a vaginal delivery such as vasa previa or genital herpes infection.[41178] [41179]

    Dinoprostone would not normally be prescribed except for short-term use in a patient who is currently breast-feeding.[41178] [41179] [41180] Prostaglandins are a normal component of breast milk; it is not known if dinoprostone appears in breast milk following vaginal use. However, the patient who receives limited administration of dinoprostone for the purpose of cervical ripening and induction of labor is probably able to breast-feed the newborn in the post-partum period without concern. However, use of the drug in the early post-partum period may suppress lactation and thus the drug should be avoided in women who desire to breast-feed; dinoprostone has been used orally off-label for inhibition of post-partum lactation and reduction of engorgement.[47327]

    Dinoprostone (prostaglandin E2) is not indicated for use in prepubertal children and infants. The safety and efficacy of dinoprostone vaginal inserts for cervical ripening have been established in women of a reproductive age and women who are pregnant. Although safety and efficacy have not been established in pediatric patients, safety and efficacy are expected to be the same for adolescent females as for adult women.[41178] Safety and efficacy of dinoprostone suppositories and dinoprostone endocervical gel have not been established in pediatric patients.[41180] [41179]

    Revision Date: 07/16/2020, 11:19:38 AM

    References

    41178 - Cervidil (dinoprostone) vaginal insert package insert. Parsippany, NJ, Ferring Pharmaceuticals, Inc.; 2020 Jan.41179 - Prepidil Gel (dinoprostone) cervical gel package insert. New York, NY: Pfizer Inc.; 2019 Dec.41180 - Prostin E2 (dinoprostone) suppository package insert. New York, NY: Pharmacia and Upjohn Company; 2018 Oct.47327 - England MJ, Tjallinks A, Hofmeyr J, et al. Suppression of lactation. A comparison of bromocriptine and prostaglandin E2. J Reprod Med. 1988;33:630-632.

    Mechanism of Action

    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.[41180]
    • 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.[41179][41178]
    • 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.[41180][41179][41178]
    Revision Date: 07/10/2017, 10:58:21 AM

    References

    41178 - Cervidil (dinoprostone) vaginal insert package insert. Parsippany, NJ, Ferring Pharmaceuticals, Inc.; 2020 Jan.41179 - Prepidil Gel (dinoprostone) cervical gel package insert. New York, NY: Pfizer Inc.; 2019 Dec.41180 - Prostin E2 (dinoprostone) suppository package insert. New York, NY: Pharmacia and Upjohn Company; 2018 Oct.

    Pharmacokinetics

    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.[41178] Specific pharmacokinetic data for dinoprostone endocervical gel and vaginal suppository products are not available.[41179][41180]

     

    Affected Cytochrome P450 isoenzymes and drug transporters: None

    Route-Specific Pharmacokinetics

    Other Route(s)

    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.[41180]

    Revision Date: 07/16/2020, 04:41:20 PM

    References

    41178 - Cervidil (dinoprostone) vaginal insert package insert. Parsippany, NJ, Ferring Pharmaceuticals, Inc.; 2020 Jan.41179 - Prepidil Gel (dinoprostone) cervical gel package insert. New York, NY: Pfizer Inc.; 2019 Dec.41180 - Prostin E2 (dinoprostone) suppository package insert. New York, NY: Pharmacia and Upjohn Company; 2018 Oct.

    Pregnancy/Breast-feeding

    incomplete abortion, labor, pregnancy, pregnancy testing

    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.[41178] [41179] [41180] 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.[41180] 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.[41180] 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.[41178] Because prostaglandins potentiate the effects of oxytocin, the concurrent use of dinoprostone and other oxytocic drugs is not recommended for any indication.[41178] [41179] [41180] 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.[41178] [41179]

    breast-feeding

    Dinoprostone would not normally be prescribed except for short-term use in a patient who is currently breast-feeding.[41178] [41179] [41180] Prostaglandins are a normal component of breast milk; it is not known if dinoprostone appears in breast milk following vaginal use. However, the patient who receives limited administration of dinoprostone for the purpose of cervical ripening and induction of labor is probably able to breast-feed the newborn in the post-partum period without concern. However, use of the drug in the early post-partum period may suppress lactation and thus the drug should be avoided in women who desire to breast-feed; dinoprostone has been used orally off-label for inhibition of post-partum lactation and reduction of engorgement.[47327]

    Revision Date: 07/16/2020, 11:19:38 AM

    References

    41178 - Cervidil (dinoprostone) vaginal insert package insert. Parsippany, NJ, Ferring Pharmaceuticals, Inc.; 2020 Jan.41179 - Prepidil Gel (dinoprostone) cervical gel package insert. New York, NY: Pfizer Inc.; 2019 Dec.41180 - Prostin E2 (dinoprostone) suppository package insert. New York, NY: Pharmacia and Upjohn Company; 2018 Oct.47327 - England MJ, Tjallinks A, Hofmeyr J, et al. Suppression of lactation. A comparison of bromocriptine and prostaglandin E2. J Reprod Med. 1988;33:630-632.

    Interactions

    Level 1 (Severe)

    • Ergonovine
    • Methylergonovine
    • Oxytocin

    Level 2 (Major)

    • Articaine; Epinephrine
    • Bupivacaine; Epinephrine
    • Carboprost Tromethamine
    • Epinephrine
    • Lidocaine; Epinephrine
    • Prilocaine; Epinephrine
    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. [5861] 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. [5861] 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. [9600] 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. [5861] Ergonovine: (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. [41178] [41179] [41180] [4719] 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. [5861] 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. [41178] [41179] [41180] [4719] 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. [41178] [41179] [47239] 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. [5861]
    Revision Date: 11/05/2022, 02:33:00 AM

    References

    4719 - Cervidil® (dinoprostone vaginal insert) package insert. St. Louis, MO: Forest Laboratories, Inc.; 1997 Jul.5861 - Pitocin® (oxytocin injection, USP) package insert. Rochester, MI: Monarch Pharmaceuticals; 2003 Jan.9600 - Hemabate (carboprost tromethamine injection, USP) package insert. New York, NY: Pfizer, Inc.; 2013 Dec.41178 - Cervidil (dinoprostone) vaginal insert package insert. Parsippany, NJ, Ferring Pharmaceuticals, Inc.; 2020 Jan.41179 - Prepidil Gel (dinoprostone) cervical gel package insert. New York, NY: Pfizer Inc.; 2019 Dec.41180 - Prostin E2 (dinoprostone) suppository package insert. New York, NY: Pharmacia and Upjohn Company; 2018 Oct.47239 - Pitocin (oxytocin injection) package insert. Chestnut Ridge, NY; Par Pharmaceutical, Inc.: 2021 May.

    Monitoring Parameters

    • pelvic exam

    US Drug Names

    • Cervidil
    • Prepidil
    • Prostin E2
    ;