Prostin Vaginal Gel (Dinoprostone)

PROSTIN® E2 Vaginal Gel

Pharmacia & Upjohn

Dinoprostone

Prostaglandin

Action And Clinical Pharmacology: Dinoprostone is a synthetic analogue of Prostaglandin E2 (PGE2). The major clinical application of PGE2 relates to its effect on uterine smooth muscle. This property has led to its obstetrical use for term labor induction and preterm evacuation of uterine contents (for fetal death in utero, hydatidiform mole and abortion). Similarly, this effect on other smooth muscle beds results in prominent dose-related side effects of nausea, vomiting and abdominal cramping. It also acts as a vasodilator and may be associated with modest hypotension. Changes that occur in the cervix during pharmacologically induced softening, effacement and dilatation (collectively referred to as cervical ripening) appear to involve more than smooth muscle contraction. While a small amount of smooth muscle is found in this structure, the body of the cervix is composed mainly of fibrous connective tissue and surrounding collagenous matrix.

Although the exact mechanisms are not fully understood, it is theorized that the pharmacologic action of PGE2 is related to its ability to regulate intracellular cyclic 3, 5-adenosine monophosphate (cAMP) levels and cellular membrane calcium ion transport. In many tissues, PGE2 appears to stimulate the syntheses of cAMP by activating the enzyme, adenylate cyclase. It has been proposed that the prostaglandins are released by hormonal stimulation and, in turn, stimulate the enzyme. It should be noted, however, that some effects of prostaglandins are independent of cAMP and are mediated through that of cGMP.

In controlled clinical trials of 964 patients (484 on dinoprostone vaginal gel; 480 on oxytocin), 67% of PGE2 treated patients and 67% of oxytocin treated patients had achieved satisfactory labor at 12 hours while 69% of PGE2 treated patients and 68% of oxytocin treated patients were successfully induced. There was a trend toward fewer cesarean sections in the PGE2 treated group.

Indications And Clinical Uses: For the induction of labor in term or near term pregnant women who have favorable induction features, a singleton pregnancy and a vertex presentation.

Contra-Indications: Dinoprostone should not be used in patients with known hypersensitivity to dinoprostone or any other constituents of the gel (colloidal silicon dioxide and triacetin).

Labor should not be induced in patients who have any of the following: Patients in whom oxytocic drugs are generally contraindicated or where prolonged contractions of the uterus are considered inappropriate. These include the following situations: patients with a history of cesarean section or major uterine surgery; patients with cephalopelvic disproportion; patients with a history of difficult labor and/or traumatic delivery; grand multiparae with 6 or more previous term pregnancies; patients with suspected or clinically evident pre-existing fetal distress; patients with overdistention of the uterus (multiple pregnancy, polyhydraminos); patients with pre-existing uterine hypertonus; circumstances that make it impossible for a responsible physician to be present.

Patients with ruptured membranes; engagement of the head has not taken place; patients with unexplained vaginal bleeding during this pregnancy; patients with fetal malpresentation; patients with gynecological, obstetrical or medical conditions that preclude vaginal delivery.

Dinoprostone vaginal gel should not be used simultaneously with other oxytocics (see Precautions).

Manufacturers’ Warnings In Clinical States: Dinoprostone like other effective oxytocic agents, should be used with strict adherence to recommended dosages, by medically trained personnel in hospital surroundings with appropriate obstetrical care facilities.

The sequential use of oxytocin less than 12 hours following dinoprostone vaginal gel has not been carried out. Therefore, infusion of oxytocin should not be started until 12 to 24 hours has elapsed following the use of dinoprostone vaginal gel.

Reports of epileptic seizures with other forms of prostaglandins have been published. The association of prostaglandin with seizures has not been conclusively proven. One epileptic patient under poor control, when treated with dinoprostone tablets, did experience a grand mal seizure. Therefore, it is recommended that dinoprostone vaginal gel be used in known epileptics only when their epilepsy is under good control and then only with maximum care and observation on the part of the physician in charge. Elective induction of labor should not be employed in these patients.

Precautions: Prior to and during the use of labor inducing agents including dinoprostone vaginal gel, uterine activity, fetal status and the character of the cervix (dilation and effacement) should be carefully monitored to detect possible evidence of undesired responses. These include hypertonus, sustained uterine contractility or fetal distress.

As with other effective oxytocic agents, it is recommended, during labor induction with dinoprostone vaginal gel, that continuous electronic monitoring of uterine activity and fetal heart rate be employed; particularly in cases where there is a known history of hypertonic uterine contractility or tetanic uterine contractions.

Cephalopelvic relationships should be carefully evaluated before the use of labor inducing agents, including dinoprostone vaginal gel.

Dinoprostone vaginal gel for labor induction should be used with caution in patients with compromised cardiovascular, hepatic or renal function and in patients with asthma or glaucoma.

Dinoprostone vaginal gel is an intravaginal product. Not to be used intracervically.

Consistent with treatment with any labor inducing agent, patients who develop uterine hypertonus or hypercontractility or in whom nonreassuring fetal heart patterns develop should be managed in a manner that addresses the welfare of the fetus and mother.

As with any oxytocic agent, the possibility of uterine rupture and/or cervical laceration should be considered in the presence of excessive uterine activity or unusual uterine pain, or where high-tone myometrial contractions are sustained.

In approximately 54% of 484 patients treated in controlled clinical trials with dinoprostone vaginal gel for labor induction, the membranes were artificially ruptured after administration of the gel.

Animal studies lasting several weeks at high doses have shown that prostaglandins of the E and F series can induce proliferation of bone. Such effects have also been noted in newborn infants who have received prostaglandin E1 during prolonged treatment. There is no evidence that short-term administration of dinoprostone can cause similar bone effect.

Drug Interactions: Dinoprostone vaginal gel, like all prostaglandins, may potentiate the uterine response to oxytocin. The response to oxytocin may be accentuated in the presence of exogenous prostaglandin therapy.

Adverse Reactions: In clinical trials of 965 patients treated with dinoprostone compared to placebo (26 patients) and oxytocin (739 patients).

Symptoms And Treatment Of Overdose: Symptoms and Treatment: No cases of overdose have been reported. Should an overdose occur, any of the listed adverse reactions would be anticipated. Treatment of overdosage must be symptomatic at this time, since clinical studies with prostaglandin antagonists have not progressed to the point where recommendations may be made.

Dosage And Administration: For intravaginal use only. Not to be used intracervically.

For the induction of labor in term or near term pregnant women who have favorable induction features, a singleton pregnancy and a vertex presentation: an initial dose of 1 mg of dinoprostone vaginal gel placed into the posterior fornix of the vaginal canal is recommended. A dose of 1 or 2 mg of the gel may be repeated, once, 6 hours later depending upon the patient’s response to the initial dose.

Patients should remain in a lateral or supine position for 30 minutes after administration to prevent leakage of the gel.

Dinoprostone vaginal gel prefilled syringes contain overfill and are designed to deliver a dose of 1 or 2 mg of dinoprostone.

The syringe should be assembled by following the sequence in the diagram (see package insert).

Method of Assembly: Remove syringe from sterile package. Remove peel-off seal from end of syringe. Remove protective end cap (to serve as plunger extension). Insert protective end cap into plunger stopper assembly in barrel of syringe. Administer syringe contents.

Availability And Storage: Each syringe of semi-translucent viscous vaginal gel contains: dinoprostone 1 or 2 mg/3 g (2.5 mL). Nonmedicinal ingredients: colloidal silicon dioxide and triacetin gel. The contents of one syringe (a single dose container/closure system) to be used for one patient. Discard after use. The gel has a shelf life of 36 months when stored at 2 to 8°C, under continuous refrigeration.

PROSTIN® E2 Vaginal Gel Pharmacia & Upjohn Dinoprostone Prostaglandin

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