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HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use CERVIDIL safely and effectively. See full prescribing information for CERVIDIL.
CERVIDIL®^ (dinoprostone) vaginal insert Initial U.S. Approval: 1977
----------------------------INDICATIONS AND USAGE-------------------------- CERVIDIL is a prostaglandin analog indicated for the initiation and/or continuation of cervical ripening in pregnant women at or near term in whom there is a medical or obstetrical indication for the induction of labor. (1)
----------------------DOSAGE AND ADMINISTRATION----------------------
- Administer a single vaginal insert (10 mg) for up to 12 hours of use (approximately 0.3 mg of dinoprostone is released per hour) (2.1)
- Remove upon onset of active labor or 12 hours after insertion. (2.1)
- Carefully monitor for uterine activity, fetal status and the progression of cervical dilatation and effacement. (2.1)
- CERVIDIL should be administered only by trained obstetrical personnel in a hospital setting with appropriate obstetrical care facilities (2.2).
- See full prescribing information for complete preparation, administration, and removal instructions. (2.2, 2.3) ---------------------DOSAGE FORMS AND STRENGTHS--------------------- Vaginal Insert: 10 mg of dinoprostone contained within a knitted polyester pouch retrieval system. (3)
-------------------------------CONTRAINDICATIONS----------------------------- CERVIDIL is contraindicated for:
- Known hypersensitivity to prostaglandins (4)
- Evidence or clinical suspicion of fetal distress, where delivery is not imminent (4)
- Unexplained vaginal bleeding in the current pregnancy (4)
- Evidence or clinical suspicion of marked cephalopelvic disproportion (4)
- Contraindication to induction of labor (4)
- Concurrent use with intravenous oxytocic agents (4)
- History of previous cesarean section or other uterine surgery (such as myomectomy) (4)
- Conditions under which prolonged contraction of the uterus may be detrimental to fetal safety. (4)
- Six or more previous term pregnancies (4) -----------------------WARNINGS AND PRECAUTIONS-----------------------
- Disseminated Intravascular Coagulation: Assess for evolving fibrinolysis in the immediate post-partum period. (5.2)
- Amniotic Fluid Embolism Syndrome: Carefully monitor patients for clinical signs of hypotension, hypoxemia and respiratory failure, DIC, coma or seizures. Provide supportive care. (5.3)
- Uterine Tachysystole and Uterine Hypersystole/Hypertonicity: Monitor uterine activity; remove vaginal insert. (5.4)
- History of Glaucoma: Consider non-prostaglandin cervical ripening procedures. (5.5) ------------------------------ADVERSE REACTIONS------------------------------ The most common adverse reactions (≥ 2 %) are uterine tachysystole without fetal distress, uterine tachysystole with fetal distress, and fetal distress without uterine tachysystole. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact FERRING PHARMACEUTICALS, INC. at 1 888-FERRING (1-888-337-7464) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. ------------------------------DRUG INTERACTIONS------------------------------- Oxytocic Agents: May augment the activity of oxytocic agents; concomitant use of intravenous oxytocic agents is contraindicated (4, 7.1). Remove vaginal insert at least 30 minutes before administering an oxytocic agent. (7.1) See 17 for PATIENT COUNSELING INFORMATION. Revised: 1/
FULL PRESCRIBING INFORMATION: CONTENTS*
1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 2.1 Dosage Instructions 2.2 Preparation and Administration Instructions 2.3 Removal Instructions 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 For Hospital Use Only 5.2 Disseminated Intravascular Coagulation 5.3 Amniotic Fluid Embolism Syndrome 5.4 Uterine Tachysystole and Uterine Hypersystole/Hypertonicity 5.5 Glaucoma 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 6.2 Postmarketing Experience 7 DRUG INTERACTIONS 7.1 Oxytocic Agents
8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation 8.4 Pediatric Use 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 14 CLINICAL STUDIES 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION *Sections or subsections omitted from the full prescribing information are not listed.
FULL PRESCRIBING INFORMATION
1 INDICATIONS AND USAGE
CERVIDIL is indicated for the initiation and/or continuation of cervical ripening in pregnant women at or near term in whom there is a medical or obstetrical indication for the induction of labor.
2 DOSAGE AND ADMINISTRATION
2.1 Dosage Instructions
Administer one CERVIDIL insert (10 mg) intravaginally for use up to 12 hours (approximately 0.3 mg of dinoprostone is released per hour) [see Dosage and Administration (2.2)].
Monitor uterine activity, fetal status, and the progression of cervical dilatation and effacement with the use of CERVIDIL. Remove CERVIDIL 12 hours after insertion with the onset of active labor, prior to an amniotomy, occurrence of uterine tachysystole, uterine hypersystole/hypertonicity, or fetal distress [see Warnings and Precautions (5.4)]. Remove CERVIDIL at least 30 minutes prior to administering an oxytocic agent [see Warnings and Precautions (5.4) and Drug Interactions (7)].
2.2 Preparation and Administration Instructions
CERVIDIL should be administered only by trained obstetrical personnel in a hospital setting with appropriate obstetrical care facilities.
Preparation and Administration Instructions
- Keep CERVIDIL frozen until ready for use. Do not warm CERVIDIL prior to vaginal insertion.
- Tear open the individually-wrapped foil package containing CERVIDIL along the tear mark. Never open the package using scissors or other sharp objects because this may damage the knitted polyester retrieval system. Do not cut the retrieval system and do not use CERVIDIL unless its retrieval system is intact.
- Immediately after opening the package, insert CERVIDIL transversely, in the posterior fornix of the vagina (see Figure 1). 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 release of dinoprostone from the vaginal insert. Insertion does not require sterile conditions.
- Unexplained vaginal bleeding in the current pregnancy
- Evidence or clinical suspicion of marked cephalopelvic disproportion
- Conditions for which induction of labor is contraindicated
- Conditions for which oxytocic drugs are contraindicated
- Previous cesarean section or other uterine surgery expected to affect uterine integrity (such as myomectomy)
- Conditions under which prolonged contraction of the uterus may be detrimental to fetal safety
- Concurrent use with intravenous oxytocic agents [see Warnings and Precautions (5.4) and Drug Interactions (7)]
- Six or more previous term pregnancies
5 WARNINGS AND PRECAUTIONS
5.1 For Hospital Use Only
CERVIDIL should be administered in a hospital setting with an obstetrical care facility.
5.2 Disseminated Intravascular Coagulation
CERVIDIL should be used with caution in women at high risk of postpartum disseminated intravascular coagulation (DIC). Physiologic or pharmacologic induction of labor, including the use of CERVIDIL, is associated with an increased risk of DIC during the postpartum period. Women aged 30 years or older, those with complications during pregnancy and those with a gestational age over 40 weeks have an increased risk of DIC during the postpartum period. As soon as possible, assess for an evolving fibrinolysis in the immediate post-partum period. Therapy consisting of prompt removal of the source of procoagulant material, replacement of depleted clotting factors and, in some cases, anti-coagulation with heparin should be instituted promptly.
5.3 Amniotic Fluid Embolism Syndrome
The use of dinoprostone-containing products, including CERVIDIL, can result in inadvertent disruption and subsequent embolization of antigenic tissue causing the development of Amniotic Fluid Embolism Syndrome, a rare and often fatal obstetric condition.
Carefully monitor patients for clinical signs of Amniotic Fluid Embolism Syndrome including hypotension, hypoxemia and respiratory failure, DIC, coma or seizures and provide supportive care as needed.
5.4 Uterine Tachysystole and Uterine Hypersystole/Hypertonicity
The use of CERVIDIL may cause uterine tachysystole with or without fetal heart rate changes (see Table 1). While using CERVIDIL, carefully monitor uterine activity, fetal status and the progression of cervical dilatation and effacement. Remove CERVIDIL with any evidence of uterine tachysystole, uterine hypersystole/hypertonicity, fetal distress, or if labor commences. CERVIDIL is contraindicated when prolonged contraction of the uterus is detrimental to fetal safety or uterine integrity, such as previous cesarean section or major uterine surgery, because of the risk of uterine rupture and obstetrical complications (e.g., need for hysterectomy and the occurrence of fetal or neonatal death). Prostaglandins, including CERVIDIL, may potentiate the effect of oxytocin [see Drug Interactions (7)]. Remove CERVIDIL at least 30 minutes before
administration of an oxytocic agent is initiated and continue to carefully monitor uterine activity. Remove CERVIDIL prior to amniotomy or following rupture of membranes because the higher vaginal pH that occurs with rupture of membranes may result in higher release rate of dinoprostone.
5.5 Glaucoma Prostaglandins, including CERVIDIL, can lead to raised intraocular pressure and constriction of pupils. Consider non-prostaglandin cervical ripening procedures in patients with Glaucoma.
6 ADVERSE REACTIONS
The following adverse reactions are described, or described in greater detail, in other sections:
- Disseminated Intravascular Coagulation [see Warnings and Precautions (5.2)]
- Amniotic Fluid Embolism [see Warnings and Precautions (5.3)]
- Uterine Tachysytole and Uterine Hypersystole/Hypertonicity [see Warnings and Precautions (5.4)]
6.1 Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
In placebo-controlled trials of 658 pregnant women (320 CERVIDIL-treated women and 338 placebo-treated women), the following treatment related adverse reactions (see Table 1) occurred at an incidence greater than 2% (and greater than that reported in the placebo group) in the CERVIDIL group [see Clinical Studies (14)].
Table 1. Common Adverse Reactions (≥ 2%) in Pregnant Patients Near Term Gestation in Trial 1^1 , Trial 2^1 , and Trial 3^2
Trials 1 1 and 2 1 CERVIDIL (N=320) Placebo (N=338) Uterine tachysystole with fetal distress
Uterine tachysystole without fetal distress
Fetal distress without uterine tachysystole - 3.8%^ 1.2% Trial 3^2 CERVIDIL (N=102) Placebo (N=104) Uterine tachysystole with fetal distress
data with CERVIDIL use in pregnant women do not show a clear association with adverse developmental outcomes. Relevant animal reproduction data with dinoprostone is not available.
Data
Human Data
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 CERVIDIL.
Clinical Considerations Fetal/Neonatal Adverse Reactions When CERVIDIL was removed for fetal distress, there was a return to normal rhythm and there were no neonatal sequelae. Remove CERVIDIL in the event of persistent tachysystole with or without fetal heart rate changes, and follow established institutional protocols in management of patients.
8.2 Lactation
Risk Summary
Concomitant administration of CERVIDIL is not indicated in breastfeeding women. There is no information on the effects of maternal CERVIDIL administration on the breastfed child. Insufficient information is available on the effects of maternal CERVIDIL administration on milk production.
8.4 Pediatric Use The safety and effectiveness of CERVIDIL have not been established in pregnant girls.
11 DESCRIPTION
CERVIDIL (dinoprostone) vaginal insert contains dinoprostone, a prostaglandin analog. Each vaginal insert contains 10 mg of dinoprostone in 241 mg of a cross-linked polyethylene oxide/urethane polymer (hydrogel polymer) that is semi-opaque, beige colored, flat, rectangular in shape with rounded corners and measuring 29 mm by 9.5 mm by 0.8 mm. The vaginal insert is contained within a pouch of an off-white knitted polyester yarn retrieval system. When placed in a moist environment, the yarn absorbs water, swells, and releases the enclosed dinoprostone. The knitted polyester retrieval system has a long tape-like end that is designed to aid retrieval of CERVIDIL at the end of the dosing interval or earlier if clinically indicated. The finished product is a controlled-release formulation that has been found to release dinoprostone in vivo at a rate of approximately 0.3 mg per hour.
The chemical name for dinoprostone (known as prostaglandin E 2 or PGE 2 ) is 11α,15S dihydroxy-9-oxo-prosta-5Z,13E-dien-1-oic acid and the structural formula is represented below:
COOH
HO
O
HO
The molecular formula is C20H (^) 32O 5 and its molecular weight is 352.47. Dinoprostone occurs as a white to off-white crystalline powder. It has a melting point within the range of 65o^ to 69oC. Dinoprostone is soluble in ethanol and in 25% ethanol in water.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Dinoprostone is found in low concentrations in most tissues of the body and functions as a local hormone. In pregnancy, dinoprostone is secreted continuously by the fetal membranes and placenta and plays an important role in the final events leading to the initiation of labor including cervical ripening. Dinoprostone stimulates the production of prostaglandin F2α (PGF2α), which sensitizes the myometrium to endogenous or exogenously administered oxytocin. Available evidence indicates that dinoprostone, in the concentrations found during the early part of labor, plays an important role in cervical ripening without affecting uterine contractions.
In most patients, local effects of CERVIDIL on the cervix include changes in the tissue consistency, dilatation and effacement. Some women experience systemic effects, including uterine tachysystole, and uterine hypersystole/hypertonicity, as a result dinoprostone or PGF2α mediated sensitization of the myometrium to oxytocin [see Warnings and Precautions (5.4)].
12.2 Pharmacodynamics
No specific pharmacodynamic studies were conducted with CERVIDIL.
12.3 Pharmacokinetics
The delivery rate of dinoprostone from CERVIDIL in vivo is approximately 0.3 mg/per hour over a period of 12 hours. Dinoprostone is metabolized in the tissues of synthesis with the half- life estimated to be 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 CERVIDIL 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.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Storage and Handling
Store in a freezer between -20°C and -10°C (-4°F and 14°F). CERVIDIL, enclosed in its aluminum/polyethylene pack, is stable when stored in a freezer for a period of three years. Vaginal inserts exposed to high humidity will absorb moisture from the air and thereby alter the release characteristics of dinoprostone.
17 PATIENT COUNSELING INFORMATION
Administration Advise the woman to remain in the recumbent position for 2 hours following CERVIDIL insertion and to inform her health care provider immediately if CERVIDIL does not remain in place [see Dosage and Administration (2.2)].
Disseminated Intravascular Coagulation Inform women that the use of CERVIDIL is associated with an increased risk of disseminated intravascular coagulation (DIC) during the postpartum period [see Warnings and Precautions (5.2)].
Amniotic Fluid Embolism Syndrome Inform women that the use of CERVIDIL can result in inadvertent disruption and subsequent embolization of antigenic tissue causing the development of Amniotic Fluid Embolism Syndrome, a rare and often fatal obstetric condition [see Warnings and Precautions (5.3)].
Frequent or Prolonged Uterine Contractions Inform women that the use of CERVIDIL may cause frequent or prolonged contractions [see Warnings and Precautions (5.4 )]. This might result in disruption of blood flow through the placenta and to the fetus.
Glaucoma Inform women that CERVIDIL can lead to raised intraocular pressure and constriction of pupils [see Warnings and Precautions (5.5)].
Manufactured for: Ferring Pharmaceuticals, Inc. Parsippany, NJ 07054
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