Prostin E2 (Dinoprostone)

PROSTIN® E2

Pharmacia & Upjohn

Dinoprostone

Prostaglandin

Action And Clinical Pharmacology: Orally administered dinoprostone stimulates the myometrium of the gravid uterus to contract in a manner that is similar to the contractions observed in the term uterus during spontaneous labor. Whether or not this action results from a direct or indirect effect of dinoprostone on the myometrium has not been determined with certainty.

Dinoprostone’s ability to stimulate gastrointestinal tract smooth muscle may be responsible for the nausea, vomiting and/or diarrhea that is sometimes associated with the use of dinoprostone.

I.V. administered dinoprostone is extremely rapidly distributed and metabolized in man. Within 1.5 minutes only about 3% of the administered dose remains in the blood as unchanged drug, whereas over 40% of the dose is present as the metabolite, 11a-hydroxy-9, 15-dioxoprost-5-enoic acid. At least 9 metabolites of dinoprostone have been identified in human blood and urine. Studies with these metabolites in the rat blood pressure assay and smooth muscle assays indicate a much lower level of activity than the parent compound. In the amount present from a therapeutic dose of dinoprostone in man, there is felt to be essentially no activity. Dinoprostone is cleared from the blood with a half-life of less than 1 minute and the metabolites with a half-life of less than 10 minutes.

Indications And Clinical Uses: As a uterine stimulant for induction of labor at or near term in:

1. Elective induction.

2. Indicated induction such as: postmaturity, hypertension, toxemia of pregnancy, premature rupture of amniotic membranes, Rh incompatibility, diabetes mellitus, intrauterine death, or fetal growth retardation.

Contra-Indications: Gynecological, obstetrical or medical conditions that preclude vaginal delivery. Hypersensitivity to dinoprostone. Do not use dinoprostone simultaneously with other oxytocics.

Dinoprostone is considered inappropriate in such conditions as: a) Patients with a history of cesarean section or prior major uterine surgery. b) Patients with cephalopelvic disproportion. c) Patients with fetal malpresentation. d) Patients with suspected or clinically evident pre-existing fetal distress. e) Patients with a prior history of difficult labor and/or traumatic delivery. f) Patients with overdistension of the uterus (multiple pregnancy, polyhydramnios). g) Patients with pre-existing uterine hypertonus. h) Circumstances that make it impossible for a responsible physician to be present. i) Grand multiparae with 6 or more previous term pregnancies.

Manufacturers’ Warnings In Clinical States: Dinoprostone, like other effective oxytocics, should be used with strict adherence to recommended dosages, by medically trained personnel in hospital surroundings that can provide immediate intensive care and facilities for immediate surgical intervention.

The sequential use of oxytocin immediately following dinoprostone has been carried out. It has been found that prostaglandins might potentiate the effect of oxytocin. Therefore, infusion of oxytocin should not be started until at least 1 hour has elapsed following the last oral dose of dinoprostone.

Reports of epileptic seizures with other forms of prostaglandin by routes other than oral 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, dinoprostone tablets should 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: In patients with a history of asthma, increased intraocular pressure, or glaucoma, dinoprostone should be used with caution.

During oral administration, uterine activity, fetal status and the progression of cervical dilatation should be carefully evaluated to detect possible evidence of unphysiological responses, e.g. hypertonus, sustained uterine contraction, or fetal distress. Uterine activity and the state of the fetus should be monitored throughout labor.

As with the use of any effective oxytocic agent, uterine rupture and/or cervical laceration should be borne in mind.

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 effects.

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

Adverse Reactions: The most frequent adverse reactions observed with the use of dinoprostone for the induction of labor are vomiting, with or without nausea and diarrhea. These adverse effects occur in about 21% of patients induced with a total dose of 0.5 to 3.0 mg (1 to 6 tablets) of dinoprostone in about 39% of patients induced with a total dose of 3.5 to 6.0 mg (7 to 12 tablets) of dinoprostone and in about 50% of patients induced with a total dose of more than 6.0 mg (more than 12 tablets) of dinoprostone.

Fetal heart rate changes were observed in 6.5% of patients induced with dinoprostone.

Uterine hypertonus occurred in 3.1% of patients. It is usually manageable by the temporary discontinuation of dinoprostone, a reduction in the dose of dinoprostone and the administration of oxygen. In the rare instance where these measures are not effective, prompt delivery is indicated.

Other adverse effects reported in less than 1% of patients include the following: headache, hypertension, hypotension, postpartum hemorrhage, fever, dizziness, chills, hiccough, flushing, tachycardia, dyspnea, bronchospasm, rash. The relationship of these adverse effects to dinoprostone therapy has not been established.

Symptoms And Treatment Of Overdose: Symptoms: No cases of accidental or intentional overdosage with dinoprostone tablets have been reported. Should such overdosage occur in nonpregnant patients it would be expected that nausea and vomiting and possibly diarrhea would occur.

Hyperpyrexia may occur. Pregnant patients should be carefully observed for severe uterine hypercontractility.

Treatment: Because of dinoprostone’s extremely short duration of action once it is absorbed, no specific treatment to counteract drug effect need be taken. However, vomiting should be induced (if not already occurring) to remove any unabsorbed drug from the stomach.

In one published report, the i.v. infusion of 500 mL of 10% ethanol/hour for 1 hour inhibited uterine activity initiated and maintained by an infusion of either prostaglandin F2-a or E2 when given simultaneously with the prostaglandin.

Dosage And Administration: An initial 0.5 mg (1 tablet) dose should be given followed in one hour by a second dose of 0.5 mg (1 tablet). All subsequent doses should be given hourly. The lowest dosage that will produce satisfactory uterine response should be used. All doses should be taken with a small amount of water.

For patients with a parity of 2 or greater, and those with a Bishop Score of 6 or greater, 0.5 mg should be administered hourly and maintained throughout the induction (unless excessive uterine activity dictates elimination of the hourly dose). In nulliparous or multiparous patients who are historically resistant to induction (Bishop Score of 0 to 5), an increment in individual doses may be justified. If satisfactory labor has not been initiated in these patients after 2 hours of dinoprostone administration, subsequent doses may be increased by 0.5 mg increments at each hourly interval. A single dose should never exceed 1.5 mg (3 tablets).

Once labor has been initiated (regardless of the dose), 0.5 mg (1 tablet) should be given hourly for maintenance of the progress of labor. It may, however, prove reasonable to occasionally eliminate this maintenance dose to determine if labor will progress without additional medication.

If vomiting occurs at any time during the treatment period, examine the vomitus for the presence of an intact dinoprostone tablet. If one is found, the dose should be repeated at once. If only a part or parts of the tablet is (are) seen (this is considered as evidence of tablet disintegration) or, if no tablet is seen in the vomitus, the dose should not be repeated and the next dose should be given only at the scheduled time. If 2 successive doses are vomited and an intact tablet is seen each time the patient should be allowed to rest until the next scheduled dose. The effectiveness of medication to treat the nausea and/or vomiting which may occur with the use of dinoprostone has not been determined.

Uterine activity is considered excessive if the frequency of contractions is greater than 5 per 10 minutes and/or the internal tonus consistently exceeds 15 mm Hg. In this event, dinoprostone administration should be stopped to allow stabilization and evaluation. Note: The i.v. administration of 10% ethyl alcohol may reverse the effect of dinoprostone.

If dinoprostone fails to elicit regular uterine contraction by the end of 8 hours, the case should be classified as a failed induction. Subsequent management is left to the physician’s discretion.

The total treatment period with dinoprostone should not, in any instance, exceed 18 hours.

SuppliedSupplied: Available to hospitals only. Each white rectangular compressed tablet imprinted “U” on one side and “76” on the other side contains: dinoprostone 0.5 mg. Nonmedicinal ingredients: cornstarch, lactose, magnesium stearate, microcrystalline cellulose and silicon dioxide. Gluten-free. Glass bottles of 10. Tablets are stable for at least 2 years if stored under normal refrigeration (4°C). Once bottle is opened, use tablets within 90 days.

PROSTIN® E2 Pharmacia & Upjohn Dinoprostone Prostaglandin

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