WARNINGS AND PRECAUTIONS

Clinical Trials Experie nce

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 1¹, Trial 2¹, and Trial 3²

¹Trial 1 (101-103) and Trial 2 (101-003) evaluated the dinoprostone insert only, without the use of a retrieval system

²Trial 3 (101-801) evaluated the dinoprostone insert with the retrieval system.

Drug related fever, nausea, vomiting, diarrhea, and abdominal pain occurred in less than 1% of CERVIDIL-treated patients.

In Trial 3 (with the retrieval system) cases of tachysystole uterine hyperstimulation reversed within 2 to 13 minutes of removal of CERVIDIL. Tocolytics were required in one of the five cases.

DRUG INTERACTIONS

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 E₂ or PGE₂) is 11α,15S- dihydroxy-9-oxo-prosta-5Z,13E-dien-1-oic acid and the structural formula is represented below

The molecular formula is C₂₀H₃₂O₅ 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.

DOSAGE AND ADMINISTRATION

CLINICAL PHARMACOLOGY

Pre parathion and Administration Instructions

·         Tuck some of the excess retrieval system into the vagina to avoid movement of CERVIDIL away from the proper position; however, leave a small amount of the retrieval system outside the vagina to aid in retrieval.

·         Instruct women to remain in a recumbent position during insertion of CERVIDIL and for 2 hours afterward. Women may be ambulatory 2 hours after insertion; however, ensure that the insert remains in place.

NONCLINICAL TOXICOLOGY

DOSAGE FORMS AND STRENGTHS

Vaginal Insert: 10 mg of dinoprostone (release rate approximately 0.3 mg/hour up to 12 hours) in a hydrogel polymer. The insert is beige-colored, semi-opaque, thin, flat, and rectangular in shape with rounded corners, measuring 29 mm by 9.5 mm by 0.8 mm, contained within an off- white knitted polyester pouch retrieval system (see Figure 2).

CLINICAL STUDIES

The effectiveness and safety of CERVIDIL for the induction of cervical ripening was evaluated in 658 pregnant women (320 CERVIDIL-treated women and 338 placebo-treated women) at or near term in three randomized, double-blind, placebo-controlled trials (Trials 1, 2, and 3).

Efficacy outcomes included percentage with treatment success (defined as vaginal delivery within 12 hours, Bishop Score ≥ 6 in the 12-hour observation period, or ≥ 3 increase in the Bishop score in the 12-hour observation period), time to delivery, and time to onset of labor. Table 2 presents efficacy outcomes from Trials 1, 2, and 3.

Table 2:    Efficacy Outcome s in Pregnant Wome n in Trials 1¹, 2,¹ and 3² for CERVIDIL Ripe ning, Inte nt-to-Tre at Population

*Treatment success was defined as vaginal delivery within 12 hours, Bishop score ≥ 6 in the 12-hour observation period, or ≥ 3 increase in the

Bishop score in the 12-hour observation period.

¹Trial 1 and Trial 2 evaluated the dinoprostone insert only, without the use of a retrieval system.

²Trial 3 evaluated the dinoprostone insert with the retrieval system

CONTRAINDICATIONS

CERVIDIL is contraindicated in patients with:

•   Known hypersensitivity to prostaglandins [see Adverse Reactions (6.2)]

•   Evidence or clinical suspicion of fetal distress where delivery is not imminent•   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

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.

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/hypertonic ity, 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

Removal Instructions

·         To retrieve, locate the retrieval system and pull it gently until CERVIDIL is fully removed.

Upon removal of CERVIDIL, it is essential to perform a visual inspection to ensure that the slab has been removed, as it will continue delivering the active ingredient

For Hospital Use Only

CERVIDIL should be administered in a hospital setting with an obstetrical care facility.

Disseminate d 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.

Amniotic Fluid Embolism Syndrome

The use of dinoprostone-conta ining 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.

Uterine Tachysystole and Uterine Hype rsystole/Hype rtonicity

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.

Glaucoma

Prostaglandins, including CERVIDIL, can lead to raised intraocular pressure and constriction of pupils. Consider non-prostaglandin cervical ripening procedures in patients with Glaucoma.

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/Hypertonic ity [see Warnings and Precautions (5.4)]

Postmarketing Expe rie nce

The following adverse reactions have been identified during postapproval use of CERVIDIL or other dinoprostone products. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Blood and lymphatic system disorders: Disseminated Intravascular Coagulation

Cardiovascular disorders: Myocardial Infarction in women with a history of myocardial infarction

Immune system disorders: Hypersensitivity Nervous system disorders: Headache

Pregnancy, puerperium and perinatal conditions: Amniotic fluid embolism

Reproductive system: reports of uterine rupture have been reported in association with use of CERVIDIL. Some required a hysterectomy and others resulted in subsequent fetal or neonatal death. Uterine hypertonus

Vascular disorders: Hypotension

Oxytocic Agents

CERVIDIL is contraindicated in patients receiving intravenous oxytocic agents because CERVIDIL may augment the activity of oxytocic agents. A dosing interval of at least 30 minutes is recommended for the sequential use of an oxytocic agent following the removal of CERVIDIL.

USE IN SPECIFIC POPULATIONS

Risk Summary
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. Fetal, neonatal, and maternal risks are discussed throughout the labeling. Limited available

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 institutiona l protocols in management of patients.

 

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.

Pe diatric Use

The safety and effectiveness of CERVIDIL have not been established in pregnant girls.

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 F_{2α (}PGF_2α), 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/hypertonic ity, as a result dinoprostone or PGF_2α mediated sensitization of the myometrium to oxytocin [see Warnings and Precautions (5.4)].

Pharmacodynamics

No specific pharmacodynamic studies were conducted with CERVIDIL.

Pharmacokine tics

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-hydroxyprosta glandin 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 (PGE_m). The relative contributions of endogenously and exogenously released dinoprostone to the plasma levels of the metabolite PGE_m is not known.

Carcinoge nesis, Mutagenesis, Impairme nt of Fe rtility

Long-term carcinogenicity and fertility studies have not been conducted with dinoprostone. No evidence of mutagenicity has been observed with dinoprostone in the Unscheduled DNA Synthesis Assay, the Micronucleus Test, or the bacteria reverse mutation (Ames) test.

HOW SUPPLIED/STORAGE AND HANDLING

How Supplied

CERVIDIL vaginal insert contains 10 mg dinoprostone in a hydrogel polymer (NDC 0456-4123- 63). The vaginal insert is beige-colored, semi-opaque, thin, flat, and rectangular in shape with rounded corners, measuring 29 mm by 9.5 mm by 0.8 mm, and is contained within an off-white knitted polyester pouch retrieval system.

CERVIDIL is enclosed in an aluminum/polyethylene pack.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.

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)].