Carboprost Tromethamine

HEMABATE 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: 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. HEMABATE 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 HEMABATE 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, HEMABATE used in this manner has resulted in the cessation of life threatening bleeding and the avoidance of emergency surgical intervention.

1. Hypersensitivity (including anaphylaxis and angioedema) to HEMABATE Sterile Solution [ see ADVERSE REACTIONS, Post-marketing Experience ] 2. Acute pelvic inflammatory disease 3. Patients with active cardiac, pulmonary, renal or hepatic disease

HEMABATE Sterile Solution (carboprost tromethamine), like other potent oxytocic agents, should be used only with strict adherence to recommended dosages. HEMABATE should be used by medically trained personnel in a hospital which can provide immediate intensive care and acute surgical facilities. HEMABATE does not appear to directly affect the fetoplacental unit. Therefore, the possibility does exist that the previable fetus aborted by HEMABATE could exhibit transient life signs. HEMABATE is not indicated if the fetus in utero has reached the stage of viability. HEMABATE 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 HEMABATE is teratogenic, any pregnancy termination with HEMABATE 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.

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 HEMABATE Sterile Solution 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, HEMABATE should be used cautiously. As with any oxytocic agent, HEMABATE should be used with caution in patients with compromised (scarred) uteri. Abortion As with spontaneous abortion, a process which is sometimes incomplete, abortion induced by HEMABATE may be expected to be incomplete in about 20% of cases. Although the incidence of cervical trauma is extremely small, the cervix should always be carefully examined immediately post-abortion. Use of HEMABATE is associated with transient pyrexia that may be due to its effect on hypothalamic thermoregulation. Temperature elevations exceeding 2° F (1.1° C) were observed in approximately one-eighth of the patients who received the recommended dosage regimen. In all cases, temperature returned to normal when therapy ended. Differentiation of post-abortion endometritis from drug-induced temperature elevations is difficult, but with increasing clinical experience, the distinctions become more obvious and are summarized below: Endometritis pyrexia Pyrexia induced by HEMABATE 1. Time of onset: Typically, on third post-abortional day (38° C or higher). Within 1 to 16 hours after the first injection. 2. Duration: Untreated pyrexia and infection continue and may give rise to other pelvic infections. Temperatures revert to pretreatment levels after discontinuation of therapy without any other treatment. 3. Retention: Products of conception are often retained in the cervical os or uterine cavity. Temperature elevation occurs whether or not tissue is retained. 4. Histology: Endometrium is infiltrated with lymphocytes and some areas are necrotic and hemorrhagic. Although the endometrial stroma may be edematous and vascular, it is not inflamed. 5. The uterus: Often remains boggy and soft with tenderness over the fundus, and pain on moving the cervix on bimanual examination. Uterine involution normal and uterus is not tender. 6. Discharge: Often associated with foul-smelling lochia and leukorrhea. Lochia normal. 7. Cervical culture: The culture of pathological organisms from the cervix or uterine cavity after abortion alone does not warrant the diagnosis of septic abortion in the absence of clinical evidence of sepsis. Pathogens have been cultured soon after abortion in patients with no infections. Persistent positive culture with clear clinical signs of infections are significant in the differential diagnosis. 8. Blood count: Leukocytosis and differential white cell counts do not distinguish between endometritis and hyperthermia caused by HEMABATE since total WBC's may increase during infection and transient leukocytosis may also be drug-induced. Fluids should be forced in patients with drug-induced fever and no clinical or bacteriological evidence of intrauterine infection. Any other simple empirical measures for temperature reduction are unnecessary because all fevers induced by HEMABATE have been transient or self-limiting. Postpartum Hemorrhage Increased blood pressure. In the postpartum hemorrhage series, 5/115 (4%) of patients had an increase of blood pressure reported as a side effect. The degree of hypertension was moderate and it is not certain as to whether this was in fact due to a direct effect of HEMABATE or a return to a status of pregnancy associated hypertension manifest by the correction of hypovolemic shock. In any event the cases reported did not require specific therapy for the elevated blood pressure. Use in patients with chorioamnionitis. During the clinical trials with HEMABATE, chorioamnionitis was identified as a complication contributing to postpartum uterine atony and hemorrhage in 8/115 (7%) of cases, 3 of which failed to respond to HEMABATE. This complication during labor may have an inhibitory effect on the uterine response to HEMABATE similar to what has been reported for other oxytocic agents. Duff, Sanders, and Gibbs; The course of labor in term patients with chorioamnionitis; Am. J. Obstet. Gynecol.; vol. 147, no. 4, October 15, 1983 pp 391–395. Drug Interactions HEMABATE may augment the activity of other oxytocic agents. Concomitant use with other oxytocic agents is not recommended. Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenic bioassay studies have not been conducted in animals with HEMABATE due to the limited indications for use and short duration of administration. No evidence of mutagenicity was observed in the Micronucleus Test or Ames Assay. Pregnancy Teratogenic Effects Animal studies do not indicate that HEMABATE is teratogenic, however, it has been shown to be embryotoxic in rats and rabbits and any dose which produces increased uterine tone could put the embryo or fetus at risk. Pediatric Use Safety and effectiveness in pediatric patients have not been established.

The adverse effects of HEMABATE 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 HEMABATE. 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 HEMABATE 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 perforation Endometritis Weakness Hiccough Diaphoresis Dysmenorrhea-like 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 infection Dryness of mouth Leg cramps Hyperventilation Perforated uterus Respiratory distress Anxiety Hematemesis Chest pain Taste alterations Retained placental fragment Urinary tract infection Shortness of breath Septic shock Fullness of throat Torticollis Uterine sacculation Lethargy Faintness, light-headedness Hypertension Uterine rupture Tachycardia Pulmonary edema Endometritis from IUCD The most common complications when HEMABATE was utilized for abortion requiring additional treatment after discharge from the hospital were endometritis, retained placental fragments, and excessive uterine bleeding, occurring in about one in every 50 patients. Post-marketing experience Hypersensitivity reactions (e.g. Anaphylactic reaction, Anaphylactic shock, Anaphylactoid reaction, Angioedema).

HEMABATE may augment the activity of other oxytocic agents. Concomitant use with other oxytocic agents is not recommended.

Teratogenic Effects Animal studies do not indicate that HEMABATE is teratogenic, however, it has been shown to be embryotoxic in rats and rabbits and any dose which produces increased uterine tone could put the embryo or fetus at risk.

Safety and effectiveness in pediatric patients have not been established.