CERVIDIL

5 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 ) 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) ] 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. 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 Trial 1 (101-103) and Trial 2 (101-003) evaluated the dinoprostone insert only, without the use of a retrieval system , Trial 2 , and Trial 3 Trial 3 (101-801) evaluated the dinoprostone insert with the retrieval system. Trials 1 and 2 CERVIDIL (N=320) Placebo (N=338) Uterine tachysystole with fetal distress 2.8% 0.3% Uterine tachysystole without fetal distress 4.7% 0% Fetal distress without uterine tachysystole - 3.8% 1.2% Trial 3 CERVIDIL (N=102) Placebo (N=104) Uterine tachysystole with fetal distress 2.9% 0% Uterine tachysystole -without fetal distress 2% 0% Fetal distress without uterine tachysystole 2.9% 1% 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. 6.2 Postmarketing Experience 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

<table width="85%" ID="t1"><caption>Table 1. Common Adverse Reactions (&#x2265; 2%) in Pregnant Patients Near Term Gestation in Trial 1<footnote ID="fn1">Trial 1 (101-103) and Trial 2 (101-003) evaluated the dinoprostone insert only, without the use of a retrieval system</footnote>, Trial 2<footnoteRef IDREF="fn1"/>, and Trial 3<footnote ID="fn2">Trial 3 (101-801) evaluated the dinoprostone insert with the retrieval system.</footnote></caption><col width="33%" align="left" valign="middle"/><col width="34%" align="center" valign="middle"/><col width="33%" align="center" valign="middle"/><tbody><tr><td styleCode="Rrule"/><td styleCode="Rrule" colspan="2"><content styleCode="underline bold">Trials 1<footnoteRef IDREF="fn1"/>and 2</content><footnoteRef IDREF="fn1"/></td></tr><tr styleCode="Botrule"><td styleCode="Rrule"/><td><content styleCode="bold">CERVIDIL (N=320)</content></td><td styleCode="Rrule"><content styleCode="bold">Placebo (N=338)</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Uterine tachysystole with fetal distress</td><td styleCode="Rrule">2.8%</td><td styleCode="Rrule">0.3%</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Uterine tachysystole without fetal distress</td><td styleCode="Rrule">4.7%</td><td styleCode="Rrule">0%</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Fetal distress without uterine tachysystole -</td><td styleCode="Rrule">3.8%</td><td styleCode="Rrule">1.2%</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"/><td styleCode="Rrule"/><td styleCode="Rrule"/></tr><tr><td styleCode="Lrule Rrule"/><td styleCode="Rrule" colspan="2"><content styleCode="bold"><content styleCode="underline">Trial 3</content></content><footnoteRef IDREF="fn2"/></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"/><td><content styleCode="bold">CERVIDIL (N=102)</content></td><td styleCode="Rrule"><content styleCode="bold">Placebo (N=104)</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Uterine tachysystole with fetal distress</td><td styleCode="Rrule">2.9%</td><td styleCode="Rrule">0%</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Uterine tachysystole -without fetal distress</td><td styleCode="Rrule">2%</td><td styleCode="Rrule">0%</td></tr><tr><td styleCode="Lrule Rrule">Fetal distress without uterine tachysystole</td><td styleCode="Rrule">2.9%</td><td styleCode="Rrule">1%</td></tr></tbody></table>