Carboprost Tromethamine

CARBOPROST TROMETHAMINE- carboprost tromethamine injection, solution
Amneal Pharmaceuticals LLC

DESCRIPTION

Carboprost tromethamine injection, USP, an oxytocic, contains the tromethamine salt of the (15S)-15 methyl analogue of naturally occurring prostaglandin F2α in a sterile solution suitable for intramuscular injection.

Carboprost tromethamine, is the established name for the active ingredient in carboprost tromethamine injection, USP. Four other chemical names are:

1. (15S)-15-methyl prostaglandin F2α tromethamine salt

2. (Z)-7-[(1R,2R,3R,5S)-3,5-dihydroxy-2-[(E)-(3S)-3-hydroxy-3-methyl-1-octenyl]cyclopentyl]-5-heptenoic acid compound with 2-amino-2-(hydroxymethyl)-1,3-propanediol (1:1)

3. Prosta-5,13-dien-1-oic acid, 9,11,15-trihydroxy-15-methyl-, (5Z,9α,11α,13E,15S)-,compound with 2-amino-2-(hydroxy-methyl)-1,3-propanediol (1:1)

The structural formula is represented below:

structure
(click image for full-size original)

The molecular formula is C21 H36 O5 .C4 H11 NO3 . The molecular weight of carboprost tromethamine, USP is 489.64. It is a white to off-white crystalline powder. It generally melts between 95° and 105° C, depending on the rate of heating.

Carboprost tromethamine, USP dissolves readily in water at room temperature at a concentration greater than 75 mg/mL.

Each mL of carboprost tromethamine injection, USP contains carboprost tromethamine, USP equivalent to 250 mcg of carboprost, 83 mcg tromethamine, 9 mg sodium chloride, and 9.45 mg benzyl alcohol added as preservative. When necessary, pH is adjusted with sodium hydroxide and/or hydrochloric acid. The solution is sterile.

CLINICAL PHARMACOLOGY

Carboprost tromethamine administered intramuscularly stimulates in the gravid uterus myometrial contractions similar to labor contractions at the end of a full term pregnancy. Whether or not these contractions result from a direct effect of carboprost on the myometrium has not been determined. Nonetheless, they evacuate the products of conception from the uterus in most cases.

Postpartum, the resultant myometrial contractions provide hemostasis at the site of placentation.

Carboprost tromethamine also stimulates the smooth muscle of the human gastrointestinal tract. This activity may produce the vomiting or diarrhea or both that is common when carboprost tromethamine is used to terminate pregnancy and for use postpartum. In laboratory animals and also in humans carboprost tromethamine can elevate body temperature. With the clinical doses of carboprost tromethamine used for the termination of pregnancy, and for use postpartum, some patients do experience transient temperature increases.

In laboratory animals and in humans large doses of carboprost tromethamine can raise blood pressure, probably by contracting the vascular smooth muscle. With the doses of carboprost tromethamine used for terminating pregnancy, this effect has not been clinically significant. In laboratory animals and also in humans carboprost tromethamine can elevate body temperature. With the clinical doses of carboprost tromethamine used for the termination of pregnancy, some patients do experience temperature increases. In some patients, carboprost tromethamine may cause transient bronchoconstriction.

Drug plasma concentrations were determined by radioimmunoassay in peripheral blood samples collected by different investigators from 10 patients undergoing abortion. The patients had been injected intramuscularly with 250 micrograms of carboprost at two hour intervals. Blood levels of drug peaked at an average of 2,060 picograms/mL one-half hour after the first injection then declined to an average concentration of 770 picograms/mL two hours after the first injection just before the second injection. The average plasma concentration one-half hour after the second injection was slightly higher (2,663 picograms/mL) than that after the first injection and decreased again to an average of 1,047 picograms/mL by two hours after the second injection. Plasma samples were collected from 5 of these 10 patients following additional injections of the prostaglandin. The average peak concentrations of drug were slightly higher following each successive injection of the prostaglandin, but always decreased to levels less than the preceding peak values by two hours after each injection.
Five women who had delivery spontaneously at term were treated immediately postpartum with a single injection of 250 micrograms of carboprost tromethamine. Peripheral blood samples were collected at several times during the four hours following treatment and carboprost tromethamine levels were determined by radioimmunoassay. The highest concentration of carboprost tromethamine was observed at 15 minutes in two patients (3,009 and 2,916 picograms/mL), at 30 minutes in two patients (3,097 and 2,792 picograms/mL), and at 60 minutes in one patient (2,718 picograms/mL).

INDICATIONS AND USAGE

Carboprost tromethamine injection is indicated for aborting pregnancy between the 13th and 20th weeks of gestation as calculated from the first day of the last normal menstrual period and in the following conditions related to second trimester abortion:

1. Failure of expulsion of the fetus during the course of treatment by another method;

2. Premature rupture of membranes in intrauterine methods with loss of drug and insufficient or absent uterine activity;

3. Requirement of a repeat intrauterine instillation of drug for expulsion of the fetus;

4. Inadvertent or spontaneous rupture of membranes in the presence of a previable fetus and absence of adequate activity for expulsion.

Carboprost tromethamine injection is indicated for the treatment of postpartum hemorrhage due to uterine atony which has not responded to conventional methods of management. Prior treatment should include the use of intravenously administered oxytocin, manipulative techniques such as uterine massage and, unless contraindicated, intramuscular ergot preparations. Studies have shown that in such cases, the use of carboprost tromethamine injection has resulted in satisfactory control of hemorrhage, although it is unclear whether or not ongoing or delayed effects of previously administered ecbolic agents have contributed to the outcome. In a high proportion of cases, carboprost tromethamine injection used in this manner has resulted in the cessation of life threatening bleeding and the avoidance of emergency surgical intervention.

CONTRAINDICATIONS

1. Hypersensitivity (including anaphylaxis and angioedema) to carboprost tromethamine injection [see ADVERSE REACTIONS, Post-marketing Experience].

2. Acute pelvic inflammatory disease.

3. Patients with active cardiac, pulmonary, renal or hepatic disease.

WARNINGS

Carboprost tromethamine, like other potent oxytocic agents, should be used only with strict adherence to recommended dosages. Carboprost tromethamine should be used by medically trained personnel in a hospital which can provide immediate intensive care and acute surgical facilities.

Carboprost tromethamine does not appear to directly affect the fetoplacental unit. Therefore, the possibility does exist that the previable fetus aborted by carboprost tromethamine could exhibit transient life signs. Carboprost tromethamine is not indicated if the fetus in utero has reached the stage of viability. Carboprost tromethamine should not be considered a feticidal agent.

Evidence from animal studies has suggested that certain other prostaglandins have some teratogenic potential. Although these studies do not indicate that carboprost tromethamine is teratogenic, any pregnancy termination with carboprost tromethamine that fails should be completed by some other means.

This product contains benzyl alcohol. Benzyl alcohol has been reported to be associated with a fatal “Gasping Syndrome” in premature infants.

PRECAUTIONS

General

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 carboprost tromethamine injection can cause similar bone effects.

In patients with a history of asthma, hypo- or hypertension, cardiovascular, renal, or hepatic disease, anemia, jaundice, diabetes, or epilepsy, carboprost tromethamine should be used cautiously.

As with any oxytocic agent, carboprost tromethamine should be used with caution in patients with compromised (scarred) uteri.

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