Cervidil (Dinoprostone)

CERVIDIL™

Ferring

Dinoprostone

Prostaglandin

Action And Clinical Pharmacology: Dinoprostone (PGE2) is a naturally occurring biomolecule. It is found in low concentrations in most tissues of the body and functions as a local hormone. As with any local hormone, it is very rapidly metabolized in the tissues of synthesis. The rate limiting step for inactivation is regulated by the enzyme 15-hydroxyprostaglandin dehydrogenase (PGDH). Any PGE2 that escapes local inactivation is rapidly cleared to the extent of 95% on the first pass through the pulmonary circulation.

In pregnancy, PGE2 is secreted continuously by the fetal membranes and placenta and plays an important role in the final events leading to the initiation of labor. It is known that PGE2 stimulates the production of PGF2 which in turn sensitizes the myometrium to endogenous or exogenously administrated oxytocin. Although PGE2 is capable of initiating uterine contractions and may interact with oxytocin to increase uterine contractility, the available evidence indicates, that in the concentrations found during the early part of labor, PGE2 plays an important role in cervical ripening without affecting uterine contractions. This distinction serves as the basis for considering cervical ripening and induction of labor, usually by the use of oxytocin, as two separate processes.

PGE2 plays an important role in the complex set of biochemical and structural alterations involved in cervical ripening. Cervical ripening involves a marked relaxation of the cervical smooth muscle fibers of the uterine cervix which must be transformed from a rigid structure to a softened, yielding and dilated configuration to allow passage of the fetus through the birth canal. This process involves activation of the enzyme collagenase, which is responsible for digestion of some of the structural collagen network of the cervix. This is associated with a concomitant increase in the amount of hydrophilic glycosaminoglycan, hyaluronic acid, and a decrease in dermatan sulfate. Failure of the cervix to undergo these natural physiologic changes, usually assessed by the method described by Bishop, prior to the onset of effective uterine contractions, results in an unfavorable outcome for successful vaginal delivery and may result in fetal compromise. It is estimated that in approximately 5% of the pregnancies the cervix does not ripen normally. In an additional 10 to 11% of pregnancies, labor must be induced for medical or obstetric reasons prior to the time of cervical ripening.

Clinical Studies: Treatment success in 3 double-blind, placebo-controlled studies was defined as Bishop score increase at 12 hours of ³3, vaginal delivery within 12 hours or Bishop score at 12 hours ³6. Results in a total of 603 (283 active, 320 placebo) qualified patients demonstrated success rates of 69.4% and 71.7% for primips and multips, respectively compared to placebo values of 29.7% for both groups.

Of the 658 patients evaluable for safety in the double-blind trials (320 active, 338 placebo), 9 patients (2.8%) who received the active insert experienced maternal hyperstimulation associated with fetal distress, while 15 patients (4.7%) experienced hyperstimulation without fetal distress. Removal of the insert resulted in relief of the symptomatology and in no case was there evidence of a neonatal adverse event.

Indications And Clinical Uses: For the 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.

Contra-Indications: Patients with known hypersensitivity to prostaglandins. Patients in whom there is clinical suspicion or definite evidence of fetal distress where delivery is not imminent. Patients with unexplained vaginal bleeding during this pregnancy. Patients in whom there is evidence or strong suspicion of marked cephalopelvic disproportion. Patients in whom oxytocic drugs are contraindicated or when prolonged contraction of the uterus may be detrimental to fetal safety or uterine integrity (previous cesarean section or major uterine surgery). Multipara with 6 or more previous term pregnancies. Patients with a history of difficult labor and/or traumatic delivery. Patients with overdistention of uterus (multiple pregnancy, polyhydramnios). Patients with ruptured membranes. Patients with fetal malpresentation. Patients with a history of epilepsy whose seizures are poorly controlled. Dinoprostone vaginal insert should not be used simultaneously with other oxytocics (see Warnings). Dinoprostone vaginal insert should not be used when there is a history of, or current pelvic inflammatory disease, unless adequate prior treatment has been instituted.

Manufacturers’ Warnings In Clinical States: For hospital use only. Dinoprostone vaginal insert should be administered only by trained obstetrical personnel in a hospital setting with appropriate obstetrical care facilities.

Precautions: General: Since prostaglandins potentiate the effect of oxytocin, dinoprostone vaginal insert must be removed before oxytocin administration is initiated and the patient’s uterine activity carefully monitored for uterine hyperstimulation.

If uterine hyperstimulation is encountered or if labor commences, the vaginal insert should be removed. Dinoprostone vaginal insert should also be removed prior to amniotomy. The vaginal insert should be removed if there is evidence of maternal systemic adverse PGE2 effects such as nausea, vomiting, hypotension or tachycardia.

Caution should be exercised in the administration of dinoprostone for cervical ripening in patients with a history of previous uterine hypertonicity, glaucoma, or a history of childhood asthma, even though there have been no asthma attacks in adulthood.

Uterine activity, fetal status and the progression of cervical dilatation and effacement should be carefully monitored whenever the dinoprostone vaginal insert is in place. Any evidence of uterine hyperstimulation, sustained uterine contractions, fetal distress, or other fetal or maternal adverse reactions, should be a cause for consideration of removal of the insert. The possibility of uterine rupture and/or cervical laceration should be borne in mind where hypertonic myometrial contractions are sustained.

Cephalopelvic relationships should be carefully evaluated before the use of dinoprostone vaginal insert.

Prolonged treatment of newborn infants with prostaglandin E1 can induce proliferation of bone. There is no evidence that short-term administration of prostaglandin E2 can cause similar bone effects.

Patients with severe renal disease and/or severe hepatic disease accompanied by metabolic aberrations should be dosed with caution.

Drug Interactions: Dinoprostone may augment the activity of oxytocic agents and their concomitant use is not recommended. A dosing interval of at least 30 minutes is recommended for the sequential use of oxytocin following the removal of the dinoprostone vaginal insert. No other drug interactions have been identified.

Dependence Liability: No drug abuse or dependence has been seen with the use of the dinoprostone vaginal insert.

Carcinogenicity: Long-term carcinogenicity and fertility studies have not been conducted with dinoprostone vaginal insert. No evidence of mutagenicity has been observed with prostaglandin E2 in the Unscheduled DNA Synthesis Assay, the Micronucleus Test, or Ames Assay.

Pregnancy: Animal studies indicate that the prostaglandins may be teratogenic. No effect would be expected clinically, when used as indicated, since dinoprostone is administered after the period of organogenesis. Any dose of the drug that produces sustained increased uterine tone could put the embryo or fetus at risk.

Adverse Reactions: Dinoprostone is well tolerated. In placebo-controlled trials in which 658 women were entered and 320 received active therapy (218 without retrieval system, 102 with retrieval system).

Drug related fever, nausea, vomiting, diarrhea, and abdominal pain were noted in less than 1% of patients who received dinoprostone.

In Study 101 to 801 (with the retrieval system) all cases of hyperstimulation reversed within 2 to 13 minutes of removal of the product. Tocolytics were required in 1 of the 5 cases.

In cases of fetal distress, when product removal was thought advisable, there was a return to normal rhythm and no neonatal sequelae.

Five-minute Apgar scores were 7 or above in 98.2% (646/658) of studied neonates whose mothers participated in placebo-controlled studies with dinoprostone vaginal insert. A 3-year pediatric follow-up study in 121 infants whose mothers received PGE2, found no significant differences from a control group on physical examination or psychomotor evaluation.

Symptoms And Treatment Of Overdose: Symptoms and Treatment: Dinoprostone vaginal insert is used as a single dosage in a single application. Overdosage is usually manifested by uterine hyperstimulation which may be accompanied by fetal distress and is responsive to removal of the insert. Other treatment must be symptomatic, since to date, clinical experience with prostaglandin antagonists is insufficient.

The use of beta-adrenergic agents should be considered in the event of undesirable increased uterine activity.

Dosage And Administration: The dosage of dinoprostone in the vaginal insert is 10 mg designed to be released at approximately 0.3 mg/h over a 12-hour period. The vaginal insert should be removed upon onset of active labor or 12 hours after insertion.

One vaginal insert is placed transversely in the posterior fornix of the vagina immediately after removal from its foil package. The insertion of the vaginal insert does not require sterile conditions. The vaginal insert must not be used without its retrieval system. There is no need for previous warming of the product. A minimal amount of K-Y jelly (or other water-miscible lubricant) may be used to assist in insertion of the vaginal insert. Care should be taken not to permit excess contact or coating with the lubricant and thus prevent optimal swelling and release of dinoprostone from the vaginal insert. Patients should remain in the supine position for 2 hours following insertion, but thereafter may be ambulatory.

Availability And Storage: Each vaginal insert contains: dinoprostone 10 mg (prostaglandin E2) dispersed throughout its matrix described as 236 mg of a cross-linked polyethylene oxide/urethane polymer which is a semi-transparent, beige colored, flat, 0.8 mm thick rectangular slab with rounded corners measuring 29 mm by 9.5 mm, releasing approximately 0.3 mg/h PGE2 over a 12-hour period. The reservoir of 10 mg dinoprostone serves to maintain constant release. The retrieval system consists of a one-piece knitted polyester pouch and withdrawal tape. This ensures easy and reliable removal of the insert when the patient’s requirement for PGE2 has been fulfilled or an obstetric event makes it necessary to stop further drug administration. The insert and its retrieval system, made of polyester yarn, are nontoxic and when placed in a moist environment, absorb water, swell, and release dinoprostone. Cartons of 1. The retrieval system is wound around the insert and the product is enclosed in an aluminum sleeve which is contained in a foil (aluminum/polyethylene) pack. Vaginal inserts exposed to high humidity will absorb moisture from the air and thereby alter the release characteristics of dinoprostone. Once used, the vaginal insert should be discarded. Store in a freezer between -20 and -10°C.

CERVIDIL Ferring Dinoprostone Prostaglandin

Connected Diseases :

Clinical Medicine

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