Dinoprostone

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Gel, Vaginal:

Prepidil: 0.5 mg/3 g (3 g)

Insert, Vaginal:

Cervidil: 10 mg (1 ea)

Suppository, Vaginal:

Prostin E2: 20 mg (5 ea)

Pharmacology

Mechanism of Action

Dinoprostone (prostaglandin E₂) is an endogenous hormone found in low concentrations in most tissues of the body. When administered as an abortifacient, it stimulates uterine contractions similar to those seen during natural labor. When administered for labor induction, it relaxes the smooth muscle of the cervix allowing dilation and passage of the fetus through the birth canal.

Pharmacokinetics/Pharmacodynamics

Absorption

Vaginal suppository: Slow

Metabolism

Metabolized in the lungs; forms metabolites which are further metabolized in the liver and kidney

Excretion

Primarily urine; feces (small amounts)

Onset of Action

Uterine contractions: Vaginal suppository: Within 10 minutes

Time to Peak

Endocervical gel: 30-45 minutes

Duration of Action

Vaginal insert: 0.3 mg/hour over 12 hours; Vaginal suppository: Up to 2-3 hours

Half-Life Elimination

2.5-5 minutes

Use: Labeled Indications

Cervical ripening for labor induction:

Endocervical gel (Prepidil): Promote cervical ripening in patients at or near term in whom there is a medical or obstetrical indication for the induction of labor

Tablet (oral) (Prostin E₂; [Canadian product]): Elective induction of labor; when indications for induction of labor exist (eg, premature rupture of amniotic membranes, toxemia of pregnancy, Rh incompatibility, diabetes mellitus, hypertension, postmaturity, intrauterine death or fetal growth retardation)

Vaginal gel (Prostin E₂; [Canadian product]): Induction of labor in patients at or near term with singleton pregnancy, vertex presentation, and favorable induction features

Vaginal insert (Cervidil): Initiation and/or continuation of cervical ripening in patients at or near term in whom there is a medical or obstetrical indication for the induction of labor

Termination of intrauterine pregnancy: Suppositories (Prostin E2): Terminate pregnancy from 12th through 20th week of gestation; evacuate uterus in cases of missed abortion or intrauterine fetal death up to 28 weeks of gestation; manage benign hydatidiform mole (nonmetastatic gestational trophoblastic disease)

Contraindications

Generally, labor induction is contraindicated whenever spontaneous labor or vaginal delivery is contraindicated (ACOG 2009); manufacturer specific contraindications are listed by dosage form.

All dosage forms: Hypersensitivity to prostaglandins or any component of the formulation

Endocervical gel (Prepidil): Patients in whom oxytocic drugs are contraindicated including: History of cesarean section or major uterine surgery; presence of cephalopelvic disproportion; fetal distress when delivery is not imminent; unexplained vaginal bleeding during this pregnancy; history of difficult labor and/or traumatic delivery; ≥6 previous term pregnancies with nonvertex presentation; hyperactive or hypertonic uterine patterns; obstetric emergencies when surgical intervention would be favorable. Use is also contraindicated with placenta previa or when vaginal delivery is not indicated (eg, vasa previa, active herpes genitalia)

Canadian labeling (Prepidil):Additional contraindications (not in US labeling): History of epilepsy; fetal malpresentation; overdistention of the uterus (multiple pregnancies, polyhydramnios); ruptured amniotic membranes or suspected chorioamnionitis; concurrent use with other oxytocics

Suppository (Prostin E2): Acute pelvic inflammatory disease; active cardiac, pulmonary, renal, or hepatic disease

Tablet (oral) [Prostin E₂; Canadian product]: Patients in whom oxytocic drugs are generally contraindicated or where prolonged contractions of the uterus are considered inappropriate. Active cardiac, pulmonary, renal or hepatic disease; simultaneous use with other oxytocics; history of cesarean section or major uterine surgery; presence of cephalopelvic disproportion; history of difficult labor and/or traumatic delivery; ≥6 pregnancies; suspected or clinically evident preexisting fetal distress; overdistention of the uterus (multiple pregnancy, polyhydramnios); preexisting uterine hypertonus; situations where a responsible physician is unavailable; engagement of head not taken place; unexplained vaginal bleeding during this pregnancy; fetal malpresentation; gynecological, obstetrical or medical conditions that preclude vaginal delivery; pregnancy complicated by abnormal position of the placenta or umbilical cord; history of or existing pelvic inflammatory disease unless adequately treated

Vaginal gel [Prostin E₂; Canadian product]: Simultaneous use with other oxytocics; history of cesarean section or major uterine surgery; presence of cephalopelvic disproportion; history of difficult labor and/or traumatic delivery; ≥6 term pregnancies; suspected or clinically evident preexisting fetal distress; overdistention of the uterus (multiple pregnancy, polyhydramnios); preexisting uterine hypertonus; situations where a responsible physician is unavailable; engagement of head not taken place; unexplained vaginal bleeding during this pregnancy; fetal malpresentation; gynecological, obstetrical or medical conditions that preclude vaginal delivery; pregnancy complicated by abnormal position of the placenta or umbilical cord; ruptured amniotic membranes or suspected chorioamnionitis

Vaginal insert (Cervidil): Patients in whom oxytocic drugs are contraindicated; history of cesarean section or major uterine surgery; presence of cephalopelvic disproportion; fetal distress when delivery is not imminent; unexplained vaginal bleeding during this pregnancy; patients already receiving IV oxytocic drugs; ≥6 previous term pregnancies

Canadian labeling (Cervidil): Additional contraindications (not in US labeling): Placenta previa; history of difficult labor and/or traumatic delivery; overdistention of the uterus (multiple pregnancies, polyhydramnios); fetal malpresentation; history of uncontrolled epilepsy; history of or existing pelvic inflammatory disease unless adequately treated

Dosage and Administration

Dosing: Adult

Note: In the United States, dinoprostone is available as an endocervical gel (Prepidil), insert (Cervidil), and suppository (Prostin E2). Additional dosage forms and products with similar names but different indications are also available in Canada. The pharmacokinetic properties vary by dosage form and are, therefore, not interchangeable. Medication errors have occurred when the incorrect dosage form was used (Institute for Safe Medication Practices [ISMP] 2013).

Termination of intrauterine pregnancy: Vaginal suppository (Prostin E2): Insert 20 mg (1 suppository) high in vagina, repeat at 3- to 5-hour intervals until abortion occurs; continued administration for longer than 2 days is not advisable

Cervical ripening:

Endocervical gel (Prepidil): Using catheter supplied with gel, insert 0.5 mg into the cervical canal. May repeat every 6 hours if needed. Maximum cumulative dose: 1.5 mg/24 hours

Tablet (oral) [Prostin E₂, Canadian product]:

Induction: Initial: 0.5 mg and then repeat 0.5 mg dose 1 hour later; may give additional 0.5 mg dose on an hourly basis as needed for satisfactory uterine response. Maintain patient at the lowest effective dose. Note: Failure to induce regular contractions after 8 hours indicates failed induction and alternative management of patient should be considered. If patient vomits an intact tablet during therapy repeat dose. If patient vomits intact tablets following 2 successive doses, withhold therapy until next scheduled dose. If patient vomits a partial tablet or if no tablet is visible, continue at next regularly scheduled dose.

Parity ≥2 times or Bishop Score of ≥6: Administer 0.5 mg hourly throughout induction (discontinue hourly dose for excessive uterine activity)

Nulliparous or multiparous and resistant to induction (Bishop Score <6): If inadequate response after 2 hours of therapy may increase dose in 0.5 mg increments at hourly intervals up to a maximum single dose of 1.5 mg.

Maintenance of labor: 0.5 mg dose; may occasionally withhold hourly dose to assess need for further dosing

Vaginal gel [Prostin E₂, Canadian product]: Initial: Using prefilled syringe, insert 1 mg into the posterior fornix of the vaginal canal; may give 1 additional dose of 1 to 2 mg 6 hours later if needed.

Vaginal insert (Cervidil): Insert 10 mg transversely into the posterior fornix of the vagina (to be removed at the onset of active labor or after 12 hours).

Dosing: Pediatric

Females of reproductive age: Refer to adult dosing.

Administration

Note: In the United States, dinoprostone is available as an endocervical gel (Prepidil), insert (Cervidil), and suppository (Prostin E2). Additional dosage forms and products with similar names but different indications are also available in Canada. The pharmacokinetic properties vary by dosage form and are, therefore, not interchangeable. Medication errors have occurred when the incorrect dosage form was used (Institute for Safe Medication Practices [ISMP] 2013).

Endocervical gel (Prepidil): Bring to room temperature just prior to use. Do not force the warming process (eg, water bath, microwave). Avoid contact with skin while handling; wash hands thoroughly with soap and water after administration. For cervical ripening, patient should be supine in the dorsal position. The appropriate catheter length should be based on degree of effacement; 20 mm for no effacement; 10 mm if 50% effaced. Patient should remain supine for 15-30 minutes following administration. The manufacturer recommends waiting 6-12 hours after dinoprostone gel administration before initiating oxytocin.

Tablet (oral) [Prostin E₂,Canadian product]: Administer with small amount of water. Use of oxytocin should be avoided until ≥1 hour after administration of the last oral tablet.

Vaginal gel [Prostin E₂, Canadian product]: For intravaginal use only (not for intracervical use). Using prefilled syringe, dose is placed in the posterior fornix of the vagina. Patient should remain in lateral or supine position for 30 minutes to prevent leakage. Syringe contains overfill and is designed to deliver a dose of 1 mg or 2 mg dinoprostone. Syringe is for single use only. Use of oxytocin should be avoided for 12-24 hours after administration of vaginal gel.

Vaginal insert (Cervidil): Keep frozen until use; product does not need warmed prior to use. Only open package along the tear mark; do not open with sharp objects which may compromise or cut the knitted polyester pouch which is the retrieval system for the polymeric slab. To use, remove from the foil package and immediately place one vaginal insert transversely in the posterior fornix of the vagina. A water miscible lubricant may be used to facilitate insertion (avoid excessive use of lubricant which could prevent optimal swelling and release of dinoprostone from the vaginal insert). Patients should remain in the recumbent position for 2 hours after insertion, but thereafter may be ambulatory (ensure the vaginal insert remains in place). Do not use without retrieval system. Ensure complete removal of system at completion of therapy. The manufacturer recommends waiting ≥30 minutes after removing the dinoprostone vaginal insert before initiating oxytocin.

Vaginal suppository (Prostin E2): Insert high into vagina after removal from its foil package. Bring to room temperature just prior to use. Patient should remain supine for 10 minutes following insertion.

Storage

Endocervical gel should be stored under refrigeration at 2°C to 8°C (36°F to 46°F).

Suppositories must be kept frozen; store in freezer not above -20°C (-4°F).

Tablets (oral) [Canadian product]: Store under refrigeration at 2°C to 8°C (36°F to 46°F). Discard unused tablets 90 days after bottle is opened.

Vaginal gel [Canadian product]: Store under refrigeration at 2°C to 8°C (36°F to 46°F).

Vaginal insert should be stored in freezer between -20°C and -10°C (-4°F and 14°F).

Drug Interactions

Carbetocin: Dinoprostone may enhance the adverse/toxic effect of Carbetocin. Specifically, Carbetocin oxytocic effects may be enhanced. Avoid combination

Carboprost Tromethamine: May enhance the adverse/toxic effect of Oxytocic Agents. Specifically, oxytocic effects may be enhanced. Avoid combination

Oxytocin: Dinoprostone may enhance the adverse/toxic effect of Oxytocin. Specifically, oxytocic effects may be enhanced. Management: Concomitant use of dinoprostone and oxytocin is not recommended. If used sequentially, monitor uterine activity closely. Administer oxytocin 30 minutes after removing dinoprostone vaginal insert and 6 to 12 hours after the application of dinoprostone gel. Consider therapy modification

Adverse Reactions

Endocervical gel:

1% to 10%:

Central nervous system: Localized warm feeling (vagina; 2%)

Gastrointestinal: Gastrointestinal distress (6%)

Genitourinary: Uterine contractions (abnormal 7%)

Neuromuscular & skeletal: Back pain (3%)

<1%, postmarketing and/or case reports: Amnionitis, amniotic fluid embolism (anaphylactoid syndrome of pregnancy), disseminated intravascular coagulation (postpartum), hypersensitivity reaction (including anaphylaxis, anaphylactic shock, and anaphylactoid reaction), premature rupture of membranes, uterine rupture (with intracervical administration)

Suppository:

Frequency not defined:

Cardiovascular: Cardiac arrhythmia, chest pain, chest tightness, hypotension, syncope

Central nervous system: Chills, dizziness, headache, paresthesia, shivering, tension

Dermatologic: Diaphoresis, skin discoloration, skin rash

Endocrine & metabolic: Dehydration, hot flash

Gastrointestinal: Diarrhea, endometritis, nausea, vomiting

Genitourinary: Breast tenderness, urinary retention, uterine rupture, vaginal pain, vaginismus, vaginitis, vulvitis

Neuromuscular & skeletal: Arthralgia, arthritis (new or exacerbated), back pain, leg cramps (nocturnal), muscle cramps, myalgia, neck stiffness, tremor, weakness

Ophthalmic: Blurred vision, eye pain

Otic: Auditory impairment

Respiratory: Cough, dyspnea, laryngitis, pharyngitis, wheezing

Miscellaneous: Fever

<1%, postmarketing and/or case reports: Myocardial infarction

Tablets (oral) [Canadian product]:

Frequency not always defined:

Cardiovascular: Amniotic fluid embolism (pulmonary), cardiac arrest

Central nervous system: Malaise (transient vasovagal symptoms)

Gastrointestinal: Vomiting (with or without nausea/diarrhea: 21% to 50%; dose dependent)

Genitourinary: Hypertonic uterine contractions (3%), cervical dilation (rapid), placental abruption, uterine contractions (abnormal), uterine rupture

Hypersensitivity: Hypersensitivity reaction (including anaphylaxis, anaphylactic shock, and nonimmunologic anaphylaxis [formerly known as anaphylactoid reaction])

Neuromuscular & skeletal: Back pain

Respiratory: Asthma

<1%, postmarketing and/or case reports: Bronchospasm, chills, disseminated intravascular coagulation, dizziness, dyspnea, fever, flushing, headache, hiccups, hypertension, hypotension, postpartum hemorrhage, skin rash, tachycardia

Vaginal gel [Canadian product]:

Frequency not always defined:

Cardiovascular: Cardiac arrest

Central nervous system: Localized warm feeling (vagina)

Gastrointestinal: Diarrhea, nausea, vomiting

Genitourinary: Hypertonic uterine contractions (3%), uterine contractions (abnormal), uterine rupture

Hypersensitivity: Hypersensitivity reaction (including anaphylaxis, anaphylactic shock, and nonimmunologic anaphylaxis [formerly known as anaphylactoid reaction])

Neuromuscular & skeletal: Back pain

Miscellaneous: Fever

<1%, postmarketing and/or case reports: Disseminated intravascular coagulation

Vaginal insert:

1% to 10%:

Genitourinary: Hypertonic uterine contractions (without fetal distress 2% to 5%, with fetal distress 3%)

<1% postmarketing and/or case reports: Abdominal pain, amniotic fluid embolism (anaphylactoid syndrome of pregnancy), diarrhea, disseminated intravascular coagulation (postpartum), fever, hypersensitivity reaction, hypotension, nausea, uterine rupture, vomiting

Warnings/Precautions

Concerns related to adverse effects:

• Anaphylactoid syndrome of pregnancy: Intracervical placement of endocervical gel, vaginal gel or vaginal insert may lead to anaphylactoid syndrome of pregnancy (rare).
• Disseminated intravascular coagulation (DIC): Postpartum DIC has been reported following dinoprostone for labor induction. Risk may be increased in women ≥30 years of age, gestation age >40 weeks, or women with pregnancy complications.
• Hypersensitivity reactions: Serious life-threatening hypersensitivity reactions, including anaphylaxis and angioedema, have been noted. Onset of reactions may occur within minutes to hours following initiation of therapy.

Disease related concerns:

• Cardiovascular disease: Use caution in patients with cardiovascular disease; manufacturer labeling for some dosage forms contraindicate use in active cardiovascular disease (refer to contraindications field).
• Epilepsy: Use with caution in patients with epilepsy.
• Glaucoma: Use caution in patients with glaucoma.
• Hepatic impairment: Use caution in patients with hepatic impairment; manufacturer labeling for some dosage forms (eg, suppository, tablet, vaginal gel) contraindicate use in active hepatic disease.
• Pulmonary disease: Use caution in patients with a history of asthma; manufacturer labeling for some dosage forms (eg, suppository, tablet, vaginal gel) contraindicate use with active pulmonary disease.
• Renal impairment: Use caution in patients with renal impairment; manufacturer labeling for some dosage forms (eg, suppository, tablet, vaginal gel) contraindicate use in active renal disease.

Dosage form specific issues:

• Endocervical gel: Prepidil: Use caution with ruptured membranes.
• Suppository: Prostin E2: When used for termination of pregnancy, dinoprostone is not considered feticidal, but is used to terminate pregnancy due to its ability to stimulate uterine contractions; do not use if fetus has reached the stage of viability. Transient pyrexia and decreased blood pressure may be observed with treatment. Use caution with history of hypotension or hypertension; cardiovascular disease; anemia; jaundice; diabetes; compromised uteri; cervicitis, endocervical infections or acute vaginitis. Measures should be taken to ensure complete abortion. Commercially available suppositories should not be used for extemporaneous preparation of any other dosage form of drug. Do not use for cervical ripening or other indications in patients with term pregnancy.
• Vaginal gel [Prostin E₂; Canadian product]: For intravaginal use only; not for intracervical use.
• Vaginal insert: Cervidil: Use caution with ruptured membranes; nonvertex or nonsingleton pregnancy or previous uterine hypertony. Must be removed prior to administration of oxytocin, in case of hyperstimulation or if labor begins, fetal distress, maternal distress (eg, hypotension, nausea, tachycardia, vomiting), and prior to amniotomy.

Other warnings/precautions:

• Experienced personnel: [US Boxed Warning]: Dinoprostone should be used only by medically-trained personnel in a hospital with strict adherence to recommended doses.

Monitoring Parameters

Gel, insert: Fetal heart rate, uterine activity, progression of cervical dilation and effacement

Tablet: Uterine activity; excessive uterine activity is contractions > 5 per 10 minutes and/or the internal tonus consistently > 15 mmHg.

Suppository: Confirmation of fetal death

Pregnancy

Pregnancy Considerations

Adverse events have been observed in animal reproduction studies. Although these effects would not be expected in humans when administered after the period of organogenesis, a sustained increase in uterine tone may have increased risks of adverse events to the fetus.

Fetal distress without corresponding maternal uterine hyperstimulation was observed in 3% to 4% of infants exposed to Cervidil in utero. No adverse effects on physical or psychomotor function were observed in a 3 year follow-up study of exposed infants. Abnormal fetal heart rates were observed in 17% of infants exposed to Prepidil gel in utero. Deceleration, intrauterine fetal sepsis, fetal depression and fetal acidosis have also been reported with administration of the endocervical gel. Stillbirths, abnormal fetal heart rate and fetal distress have been reported with administration of Prostin E₂ vaginal gel and oral tablets [Canadian product].

When used for termination of pregnancy, dinoprostone is not considered feticidal, but is used to terminate pregnancy due to its ability to stimulate uterine contractions; do not use if fetus has reached the stage of viability. A previable fetus may show transient life signs if aborted by dinoprostone. Failed pregnancy termination with dinoprostone should be completed by another method.

Patient Education

What is this drug used for?

• It is used to get your cervix ready for childbirth.
• It is used to end a pregnancy.
• It is used to treat certain tumors in the uterus.
• It may be given to you for other reasons. Talk with the doctor.

Frequently reported side effects of this drug

• Diarrhea
• Headache
• Chills
• Nausea
• Vomiting

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• Severe dizziness
• Passing out
• Severe abdominal pain
• Signs of a significant reaction like wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.