CARBOPROST TROMETHAMINE

Carboprost tromethamine injection, USP Sterile Solution, an oxytocic, contains the tromethamine salt of the (15S)-15 methyl analogue of naturally occurring prostaglandin F2α in a 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. 7-(3α,5α-dihydroxy-2ß-[(3S)-3-hydroxy-3-methyl- trans -1-octenyl]-1α-cyclopentyl]- cis -5-heptenoic acid compound with 2-amino-2-(hydroxymethyl)-1,3-propanediol 3. (15S)-9α,11α,15-trihydroxy-15-methylprosta- cis -5, trans -13-dienoic acid tromethamine salt 4. (15S)-15-methyl PGF2α-THAM The structural formula is represented below: The molecular formula is C 25 H 47 O 8 N. The molecular weight of carboprost tromethamine is 489.64. It is a white to slightly off-white crystalline powder. It generally melts between 95° and 105° C, depending on the rate of heating. Carboprost tromethamine dissolves readily in water at room temperature at a concentration greater than 75 mg/mL. Each mL of carboprost tromethamine injection, USP Sterile Solution contains carboprost tromethamine 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. chemical-structure

Carboprost tromethamine injection Sterile Solution 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: Failure of expulsion of the fetus during the course of treatment by another method; Premature rupture of membranes in intrauterine methods with loss of drug and insufficient or absent uterine activity; Requirement of a repeat intrauterine instillation of drug for expulsion of the fetus; 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.

1. Abortion and Indications 1–4 An initial dose of 1 mL of Carboprost tromethamine injection Sterile Solution (containing the equivalent of 250 micrograms of carboprost) is to be administered deep in the muscle with a tuberculin syringe. Subsequent doses of 250 micrograms should be administered at 1½ to 3½ hour intervals depending on uterine response. An optional test dose of 100 micrograms (0.4 mL) may be administered initially. The dose may be increased to 500 micrograms (2 mL) if uterine contractility is judged to be inadequate after several doses of 250 micrograms (1 mL). The total dose administered of carboprost tromethamine should not exceed 12 milligrams and continuous administration of the drug for more than two days is not recommended. 2. For Refractory Postpartum Uterine Bleeding: An initial dose of 250 micrograms of carboprost tromethamine injection Sterile Solution (1 mL of Carboprost tromethamine injection) is to be given deep, intramuscularly. In clinical trials it was found that the majority of successful cases (73%) responded to single injections. In some selected cases, however, multiple dosing at intervals of 15 to 90 minutes was carried out with successful outcome. The need for additional injections and the interval at which these should be given can be determined only by the attending physicians as dictated by the course of clinical events. The total dose of carboprost tromethamine injection USP should not exceed 2 milligrams (8 doses). Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

1. Hypersensitivity (including anaphylaxis and angioedema) to Carboprost tromethamine injection Sterile Solution [ see ADVERSE REACTIONS, Post-marketing Experience] 2. Acute pelvic inflammatory disease 3. Patients with active cardiac, pulmonary, renal or hepatic disease WARNINGS Carboprost tromethamine injection Sterile Solution (carboprost tromethamine), like other potent oxytocic agents, should be used only with strict adherence to recommended dosages. Carboprost tromethamine injection 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 injection 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 injection is teratogenic, any pregnancy termination with Carboprost tromethamine injection 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.

The adverse effects of Carboprost tromethamine Sterile Solution are generally transient and reversible when therapy ends. The most frequent adverse reactions observed are related to its contractile effect on smooth muscle. In patients studied, approximately two-thirds experienced vomiting and diarrhea, approximately one-third had nausea, one-eighth had a temperature increase greater than 2° F, and one-fourteenth experienced flushing. The pretreatment or concurrent administration of antiemetic and antidiarrheal drugs decreases considerably the very high incidence of gastrointestinal effects common with all prostaglandins used for abortion. Their use should be considered an integral part of the management of patients undergoing abortion with carboprost tromethamine injection. Of those patients experiencing a temperature elevation, approximately one-sixteenth had a clinical diagnosis of endometritis. The remaining temperature elevations returned to normal within several hours after the last injection. Adverse effects observed during the use of carboprost tromethamine injection for abortion and for hemorrhage, not all of which are clearly drug related, in decreasing order of frequency include: Vomiting Nervousness Diarrhea Nosebleed Nausea Sleep disorders Flushing or hot flashes Dyspnea Chills or Shivering Tightness in chest Coughing Wheezing Headaches Posterior cervical Endometritis perforation Hiccough Weakness Dysmenorrhea-like Diaphoresis Pain Dizziness Paresthesia Blurred vision Backache Epigastric pain Muscular pain Excessive thirst Breast tenderness Twitching eyelids Eye pain Gagging, retching Drowsiness Dry throat Dystonia Sensation of choking Asthma Thyroid storm Injection site pain Syncope Tinnitus Palpitations Vertigo Rash Vaso-vagal syndrome Upper respiratory Dryness of mouth infection Hyperventilation Leg cramps Respiratory distress Perforated uterus Hematemesis Anxiety Taste alteration Chest pain Urinary tract infection Retained placental Septic shock fragment Torticollis Shortness of breath Lethargy Fullness of throat Hypertension Uterine sacculation Tachycardia Faintness, light- Pulmonary edema headedness Endometritis from Uterine rupture IUCD