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]

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]