Dinoprostone (Cervidil) is a naturally occurring prostaglandin E2. It stimulates uterine contractions and is used in the induction of labor, postpartum hemorrhage, and termination of pregnancy.

Dinoprostone Uses:

• Cervical ripening for labor induction:

  • Endocervical gel (Prepidil): 
    • Encourage cervical ripening in those sufferers at or near term in whom there is a medical or obstetrical manifestation for the induction of labor.
  • Tablet (oral) (Prostin E-2; [Canadian product]):
    • Elective induction of labor; when indications for induction of labor available (eg, Toxemia of pregnancy, Rh incompatibility, diabetes mellitus, hypertension, postmaturity, premature rupture of amniotic membranes, intrauterine death, or fetal growth retardation)
  • Vaginal gel (Prostin E-2; [Canadian product]):
    • Induction of labor in sufferer at or near term with a singleton pregnancy, vertex presentation, and favorable induction features
  • Vaginal insert (Cervidil):
    • starting and/or continuation of cervical ripening in sufferer at or near term in whom there is a medical or obstetrical manifestation 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)

Dinoprostone (Cervidil) Dose in Adults

Note: In the USA, dinoprostone is existed as an endocervical gel (Prepidil), suppository (Prostin E2), and insert (Cervidil). Additional dosage forms and products with similar names but different indications also exist in Canada. The pharmacokinetic properties vary by dosage form and are, therefore, not interchangeable. When the incorrect dosage form was used medication errors have occurred.

Dinoprostone (Cervidil) Dose in the Termination of intrauterine pregnancy:

• Vaginal suppository (Prostin E2):
  • Put 20 mg (1 suppository) high in the vagina, repeat at the time intervals of 3- to 5-hour until abortion occurs; continued administration > 2 days is not considered.

Dinoprostone (Cervidil) Dose in the Cervical ripening:

• Endocervical gel (Prepidil):
  • Using a catheter with gel, Put 0.5 mg into the cervical canal.
  • May repeat every 6 hours if required.
  • The maximum cumulative dose: 1.5 mg per 24 hours
• Tablet (oral) [Prostin E-2, Canadian product]:
  • Induction:
    • Starter: 0.5 mg and then repeat 0.5 mg dose after 1 hour;
    • give additional 0.5 mg dose on an hourly basis as required for satisfactory uterine response.
    • Maintain the patient at the lowest effective dose.
    • Note: If the induction of regular contractions fails after 8 hours, alternative treatment should be recommended.
    • If an intact tablet is vomited by the patient during therapy then repeat the dose. Following 2 successive doses even if the patient vomits intact tablets, stop therapy until the next scheduled dose.
    • If a partial tablet is vomited out by the patient or if no tablet is visible, carry on with the next regularly scheduled dose.
  • Parity 2 or more than 2 times or Bishop Score of 6 or more than 6:
    • Examine half-hourly throughout induction (discontinue hourly dose for excessive uterine activity)
  • Multiparous or Nulliparous and resistant to induction (Bishop Score less than 6):
    • If inadequate response after 2 hours of therapy may increase the 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 sometimes stop the hourly dose to assess the need for further dosing
• Vaginal gel [Prostin E-2, Canadian product]:
  • Initial: Using a prefilled syringe, Put 1 mg into the posterior fornix of the vaginal canal;
  • may give 1 additional dose of 1 to 2 mg 6 hours later if required.
• Vaginal insert (Cervidil):
  • Put 10 mg transversely into the posterior fornix of the vagina (to be removed at the onset of active labor or after 12 hours).

Dinoprostone (Cervidil) Dose in Childrens

Females of reproductive age: Refer to adult dosing.

Dinoprostone Pregnancy Risk Category: X

• Animal reproduction studies have shown that adverse events can be observed.
• These effects are unlikely to occur in humans if administered after organogenesis.
• However, prolonged increases in uterine tone could increase the risk of adverse events for the fetus.
• In 3 to 4 percent to 4% of infants who were exposed to Cervidil in their utero, there was no fetal distress. In a 3-year follow up study, no adverse effects on psychomotor or physical function were found in exposed infants.
• 17 percent of Prepidil gel-treated infants experienced abnormal fetal heart beats.
• Administration of the endocervical jelly has also been associated with fetal acidosis, intrauterine foetal sepsis, and deceleration.
• Prostin E oral tablet and vaginal gel have been associated with stillbirths, abnormal fetal beat rate and fetal distress.
• Dinoprostone can be used to terminate a pregnancy. However, it is not considered to be feticidal.
• It is used to end a pregnancy because of its ability to stimulate uterine cramps. Do not use if your fetus is at the stage of viability.
• If dinoprostone is used to terminate a pre-viable pregnancy, it may cause transient signs. You should not terminate a failed pregnancy with dinoprostone.

Use of dinoprostone while breastfeeding

• Breast milk contains endogenous PGE.

Dinoprostone Dose in renal disease:

No dosage recommendations have been mentioned, however, in active renal impairment, the use of vaginal gel, suppository, and tablets are contraindicated.

Dinoprostone Dose in Liver disease:

No dosage recommendations have been mentioned, however, certain forms such as vaginal gel, suppository, and tablets are contraindicated in active liver disease.

Side effects of Dinoprostone Endocervical gel:

• Central nervous system:

  • Localized warm feeling

• Gastrointestinal:

  • Gastrointestinal distress

• Genitourinary:

  • Uterine contractions

• Neuromuscular & skeletal:

  • Back pain

Side effects of Dinoprostone Suppository:

• 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
  • Back Pain
  • Leg Cramps
  • Muscle Cramps
  • Myalgia
  • Neck Stiffness
  • Tremor
  • Weakness

• Ophthalmic:

  • Blurred Vision
  • Eye Pain

• Otic:

  • Auditory Impairment

• Respiratory:

  • Cough
  • Dyspnea
  • Laryngitis
  • Pharyngitis
  • Wheezing

• Miscellaneous:

  • Fever

Side effects of Dinoprostone Tablets [Canadian Product]:

• Cardiovascular:

  • Amniotic Fluid Embolism
  • Cardiac Arrest Central Nervous System: Malaise

• Gastrointestinal:

  • Vomiting

• Genitourinary:

  • Hypertonic Uterine Contractions
  • Cervical Dilation
  • Placental Abruption
  • Uterine Contractions
  • Uterine Rupture

• Hypersensitivity:

  • Hypersensitivity Reaction

• Neuromuscular & Skeletal:

  • Back Pain

• Respiratory:

  • Asthma

Side effects of Vaginal Gel [Canadian Product]:

• Cardiovascular:

  • Cardiac Arrest

• Central Nervous System:

  • Localized Warm Feeling

• Gastrointestinal:

  • Diarrhea
  • Nausea
  • Vomiting

• Genitourinary:

  • Hypertonic Uterine Contractions
  • Uterine Contractions
  • Uterine Rupture

• Hypersensitivity:

  • Hypersensitivity Reaction Including
    • Anaphylaxis
    • Anaphylactic Shock
    • And Nonimmunologic Anaphylaxis

• Neuromuscular & Skeletal:

  • Back Pain

• Miscellaneous:

  • Fever

Vaginal Insert:

Less Common Side Effects Of Dinoprostone (Cervidil):

• Genitourinary:

  • Hypertonic Uterine Contractions

Contraindications to Dinoprostone (Cervidil):

Labor induction is generally contraindicated when spontaneous labor or vaginal birth is not possible. The manufacturer-specific contraindications are listed by the dosage form. Endocervical gel (Prepidil):

• Patients who are not a good candidate for oxytocic medications include:
  • History of major uterine or cesarean sections;
  • presence of cephalopelvic disproportion
  • Fetal distress during pregnancy that is not imminent
  • Unsuspected vaginal bleeding in this pregnancy
  • History of difficult labor or traumatic delivery; >=6 pregnancies in the past with nonvertex presentations;
  • Hyperactive or hypertonic patterns in the uterine;
  • When surgical intervention is possible in obstetric emergencies.
  • It is not recommended for use in conjunction with vaginal delivery.

Canadian labeling (Prepidil),: Additional contraindications not in US labeling

• Fetal malpresentation;
• Overdistention Epilepsy history of the uterus (polyhydramnios multiple pregnancies);
• Possible ruptured amniotic membranes, or suspected chorioamnionitis
• Concurrent use with other oxytocics

Suppository (Prostin E2)

• Acute pelvic inflammation disease
• Pulmonary, renal, active or hepatic diseases

Tablet (oral) [Prostin E-2 Canadian product]

• Oxytocic drugs should not be used in patients who are pregnant or have prolonged contractions.
• Renal, active cardiopulmonary, or hepatic diseases
• History of hard labor and traumatizing deliveries;
• Use with other oxytocics simultaneously
• presence of cephalopelvic disproportion
• History of major uterine or cesarean sections;
• 6 or more pregnancies
• Clinically manifested preexisting fetal distress
• Pre-existing uterine hypertonus
• Overdistention of uterus (multiple pregnancies and polyhydramnios);
• Unsuspected vaginal bleeding in this pregnancy
• fetal malpresentation;
• The abnormal position of the umbilical cord or placenta can cause pregnancy complications.
• Engagement of the head has not occurred
• Situations in which a competent physician is not available
• Medical conditions, such as gynecological or obstetrical issues, that prevent vaginal birth;
• If not properly treated, history or current pelvic inflammatory disease

Vaginal gel [Prostin E-2; Canadian product]:

• Use with other oxytocics simultaneously
• Cephalopelvic disproportionment;
• History of hard labor and traumatizing deliveries;
• History of major uterine or cesarean sections;
• 6 or more pregnancies with multiple term;
• Preexisting preexisting clinically obvious fetal distress may be suspected or confirmed.
• Overdistention of uterus (multiple pregnancies and polyhydramnios);
• Engagement of the head has not occurred
• Pre-existing uterine hypertonus
• Situations in which a competent physician is not available
• Unsuspected vaginal bleeding in this pregnancy
• fetal malpresentation;
• Medical conditions, such as gynecological or obstetrical issues, that prevent vaginal birth;
• Fragmented amniotic membranes, suspected chorioamnionitis pregnancy and abnormal position of the umbilical cord or placenta can lead to ruptured or engorged amniotic membranes.

Insert vaginal (Cervidil).

• Patients for whom oxytocic medications are contraindicated
• History of major uterine or cesarean sections;
• Undiagnosed vaginal bleeding in this pregnancy
• Cephalopelvic disproportionment;
• Fetal distress during pregnancy that is not imminent
• Patients already receiving IV oxytocic medications;
• 6 or more previous pregnancies

Canadian labeling (Cervidil), Additional contraindications not in US labeling:

• Overdistention of uterus (polyhydramnios; multiple pregnancies);
• Previa placenta
• History of difficult labor or traumatic births;
• fetal malpresentation;
• History of uncontrolled epilepsy
• If not properly treated, history or current pelvic inflammatory disease

Warnings and precautions

• Anaphylactoid pregnancy syndrome:

  • The anaphylactoid Syndrome of Pregnancy (rare) may result from the intracervical placing of the vaginal gel, endocervical gel or vaginal insert.

• Disseminated intravascular coagulation

  • Postpartum DIC is reported to be used for labor induction.
  • Women over 30 years old, pregnant women who have been gestating for more than 40 weeks or with complications during pregnancy may be at greater risk.

• Hypersensitivity reactions

  • Angioedema and anaphylaxis, which can be life-threatening, have been reported.
  • Within minutes or hours of therapy being initiated, reactions can begin.

• Cardiovascular disease

  • Patients with heart disease should be cautious.
  • Some dosage forms' manufacturer labels are contraindicated for use in active cardiovascular disease (refer the contraindications field).

• Epilepsy:

  • Patients with epilepsy should be cautious.

• Glaucoma:

  • Glaucoma patients should be cautious

• Hepatic impairment

  • Patients with hepatic impairment should be cautious; some dosage forms (eg vaginal gels, suppository tablets) are not recommended for use in patients with active hepatic disease.

• Pulmonary disease

  • Patients who have had asthma in the past should be cautious when using it. Some dosage forms, such as tablet, vaginal gel, or suppository, are not recommended for patients with active pulmonary disease.

• Renal impairment

  • It was used with caution by patients with impaired renal function.
  • Some dosage forms, such as tablet or vaginal gel suppository, are labeled by the manufacturer to indicate that they should not be used in active renal disease.

Dinoprostone: Drug Interaction

Note: Drug Interaction Categories:

• Risk Factor C: Monitor When Using Combination
• Risk Factor D: Consider Treatment Modification
• Risk Factor X: Avoid Concomitant Use

Risk Factor D (Consider therapy modifications)
Oxytocin	Oxytocin's toxic/adverse effects may be increased by dinoprostone. In particular, the oxytocic effect may be increased. Management: It is not recommended to use dinoprostone with oxytocin. Monitor uterine activity carefully if used in a sequence. After removing the dinoprostone vaginal insert, and between 6 and 12 hours after applying dinoprostone gel, administer oxytocin.
Risk Factor X (Avoid Combination)
Carbetocin	Dinoprostone could increase the toxic/adverse effects of Carbetocin. Carbetocin's oxytocic effects could be increased.
Carboprost Tromethamine	Oxytocic Agents may have an adverse/toxic effect that can be increased. Particularly, the oxytocic effect may be increased.

 

Monitoring parameters:

Gel, insert:

• Uterine activity,
• Fetal heart rate progression of cervical dilation and effacement

Tablet:

• Uterine activity;
• excessive uterine activity is contractions more than  5 per 10 minutes and the internal tonus consistently more than  15 mmHg.

Suppository:

• Confirmation of fetal death

How to administer Dinoprostone (Cervidil)?

Note:

• In the USA, 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.

Endocervical gel (Prepidil):

• Just prior to use bring it to room temperature.
• Stop to force the warming process (eg microwave, water bath).
• Restrict contact with skin while handling; wash hands completely with soap and water after consideration.
• The patient should be supine in the dorsal position for cervical ripening.
• The appropriate catheter length should be dependent on the degree of effacement;10 mm if 50 percent effaced; 20 mm for no effacement.
• The patient should remain supine for 15 to 30 minutes following consideration.
• The manufacturer recommends waiting 6 to 12 hours after dinoprostone gel consideration before initiating oxytocin.

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

• Administer with a small amount of water.
• The use of oxytocin should be restricted until 1 or more than 1 hour after consideration of the last oral tablet.

Vaginal gel [Prostin E-2, Canadian product]:

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

Vaginal insert (Cervidil):

• Keep frozen until use.
• Only open the 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 put transversely in the posterior fornix of the vagina.
• A water-miscible lubricant may be used to facilitate(avoid excessive use of lubricant which could prevent optimal swelling and release of dinoprostone from the vaginal insert).
• Patients should remain in the horizontal position for 2 hours after putting, but thereafter may be ambulatory (ensure the vaginal put remains in place).
• Do not use it without a retrieval system.
• The manufacturer recommends waiting 30 or more than 30 minutes after removing the dinoprostone vaginal insert before initiating oxytocin.

Vaginal suppository (Prostin E2):

• Put high into the vagina after removal from its foil package.
• Bring to room temperature just prior to use.
• The patient should remain weak for 10 minutes following insertion.

Mechanism of action of Dinoprostone (Cervidil):

• Endogenous hormones such as prostaglandin E-2 (dinoprostone) are found in very low levels in the majority of tissues.
• It is an abortion inducer that stimulates uterine contractions in a manner similar to natural labor. It is used to induce labor.

The onset of action (uterine contractions):

• Vaginal suppository: Within 10 minutes

Duration:

• Vaginal insert: 0.3 mg per hour over 12 hours;
• Vaginal suppository: Up to 2 to 3 hours

Absorption: Vaginal suppository:

• Slow

Metabolism:

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

Half-life elimination:

• 2.5 to 5 minutes

Time to peak, plasma:

• Endocervical gel: 30 to 45 minutes

Excretion:

• Primarily urine;
• feces (small amounts)

International Brand Names of Dinoprostone:

• Cervidil
• Prepidil
• Prostin E2
• Cervidil
• Cerviprime
• Cerviprost
• Dinoglandin E2
• Glandin E2
• Minprostin
• Minprostin E(2)
• Prandin E2
• Prepidil
• Primigyn
• Primiprost
• Prolisina E2
• Propess
• Propess Vag SR
• Prostaglandina E2
• Prostarmon E
• Prostenon
• Prostin E2
• Prostin E2 Vaginal Cream
• Prostin E2 Vaginal Gel
• Prostin VR
• Prostine

Dinoprostone Brand Names in Pakistan:

Dinoprostone Injection 5 mg/ml
Prostin F2 Alpha	Pfizer Laboratories Ltd.

Dinoprostone Gel 1 mg
Glandin-E2	Nabiqasim Industries (Pvt) Ltd.

Dinoprostone Gel 2 mg
Glandin-E2	Nabiqasim Industries (Pvt) Ltd.

Dinoprostone Tabs 3 mg
Gynaid	Wilsons Pharmaceuticals

Dinoprostone Vaginal Tablets 3 mg
Dinoprose-E2	Himont Pharmaceuticals (Pvt) Ltd.
Glandin-E2	Nabiqasim Industries (Pvt) Ltd.
Preglan E2	Platinum Pharmaceuticals (Pvt.) Ltd.
Prostin E2	Pfizer Laboratories Ltd.
Vprestone-2	Hansel Pharmacueutical Pvt (Ltd)