Hemabate

Pronunciation

Generic Name: Carboprost Tromethamine
Class: Oxytocics
VA Class: HS875
Chemical Name: (5Z,9α,11α,13E,15S)-9,11,15-Trihydroxy-15-methyl-prosta-5,13-dien-1-oic acid
Molecular Formula: C21H36O5•C4H11NO3
CAS Number: 58551-69-2

Introduction

Stimulates uterine smooth muscle; synthetic derivative of prostaglandin F.1 10 11 19

Uses for Hemabate

Termination of Pregnancy

Termination of intrauterine pregnancy during the second trimester (weeks 13–20 of gestation, dated from the first day of the last menstrual period).1 14 15 16

Slideshow: View Frightful (But Dead Serious) Drug Side Effects

Used after failure of another method (e.g., in the event of premature rupture of membranes with loss of hypertonic abortifacients accompanied by inadequate uterine activity, when repeated intra-amniotic drug administration needed to expel fetus); used to induce abortion after membrane rupture.1

Postpartum Hemorrhage

Treatment of postpartum hemorrhage in the presence of uterine atony that has not responded to usual therapy (i.e., IV oxytocin, uterine massage, IM ergot alkaloids [unless contraindicated]).1 8 9 10 12 13 20

Hemabate Dosage and Administration

General

To minimize adverse GI effects, consider pretreatment use or concurrent administration of antiemetic and antidiarrheal agents.1 14 15

Administration

IM Administration

Administer by deep IM injection.1

For postpartum hemorrhage, has been administered directly into the uterine corpus.8

Dosage

Available as carboprost tromethamine; dosage is expressed in terms of carboprost.1

Closely adhere to recommended dosage.1 Dosage determined by uterine response.1

Adults

Termination of Pregnancy
IM

Initially, 250 mcg.1 15 Alternatively, initiate with test dose of 100 mcg.1 15

Subsequently, 250 mcg at 1.5- to 3.5-hour intervals depending on uterine response.1 15 After several 250-mcg doses, may increase dose to 500 mcg if uterine contractility is inadequate.1 15 Maximum total dose is 12 mg.1

Postpartum Hemorrhage
IM

Initially, 250 mcg; repeat every 15–90 minutes up to a maximum total dose of 2 mg.1 8 10 Single dose usually adequate.1 13 20 Clinician should determine the need for additional doses and dosing interval based on clinical events.1

Prescribing Limits

Adults

Termination of Pregnancy
IM

Maximum total dose is 12 mg; continuous administration for >2 days not recommended.1

Postpartum Hemorrhage
IM

Maximum total dose is 2 mg.1

Cautions for Hemabate

Contraindications

  • Known hypersensitivity to carboprost.1

  • Acute pelvic inflammatory disease.1

  • Active cardiac, pulmonary, renal, or hepatic disease.1

Warnings/Precautions

Warnings

Administer by qualified professional personnel in a hospital where intensive care and surgical facilities are immediately available.1

Considerations in Patients Undergoing Termination of Pregnancy

Carboprost does not affect the fetoplacental unit.1 Possibility exists that a previable fetus could exhibit transient signs of life following carboprost-induced abortion; carboprost is not indicated if the fetus has reached the stage of viability.1

If the pregnancy is not terminated with carboprost, complete abortion using another method.1

Risk of cervical trauma; examine each patient for cervical injuries after abortion is complete.1 14 Caution in patients with a compromised (scarred) uterus.1

Benzyl Alcohol in Neonates

Carboprost tromethamine injection contains as a preservative benzyl alcohol, which has been associated with toxicity (fatalities) in neonates.1 (See Pediatric Use under Cautions.)

General Precautions

Musculoskeletal Effects

Proliferation of long bones reported in neonates receiving long-term therapy with alprostadil (prostaglandin E1).1 22 No evidence that short-term administration of carboprost has similar effects on bone.1

Concomitant Diseases

Caution in patients with history of asthma, seizure disorders, diabetes, or anemia.1 24

Fever

Transient fever (i.e., temperature elevations >1.1°C) reported in approximately 12.5% of patients.1 When used for termination of pregnancy, may be difficult to distinguish drug-induced temperature elevations from post-abortion endometritis.1

Cardiovascular Effects

Increased BP reported.1 13 20 Increase in BP was observed in 4% of women receiving the drug for postpartum hemorrhage in 1 study; specific treatment for hypertension was not needed.1 13

Caution in patients with hypertension, hypotension, or cardiovascular disease.1

Chorioamnionitis

Chorioamnionitis may contribute to postpartum uterine atony and hemorrhage; individuals with chorioamnionitis experiencing postpartum hemorrhage have failed to respond to carboprost.1 8 9 10 12 13

Specific Populations

Pregnancy

Category C.1

Pediatric Use

Not indicated in pediatric patients.1

Large amounts of benzyl alcohol (i.e., 100–400 mg/kg daily) have been associated with toxicity (fatal “gasping syndrome”) in neonates;1 2 3 4 5 6 7 each mL of carboprost tromethamine injection contains 9.45 mg of benzyl alcohol.1

Hepatic Impairment

Caution in patients with hepatic disease, including jaundice.1 Contraindicated in patients with active hepatic disease.1

Renal Impairment

Caution in patients with renal disease.1 Contraindicated in patients with active renal disease.1

Common Adverse Effects

Vomiting,1 10 14 15 18 20 diarrhea,1 10 13 14 15 18 nausea,1 13 20 fever,1 20 flushing.1 14 15

Interactions for Hemabate

May increase activity of other oxytocic agents; concomitant use not recommended.1

Hemabate Pharmacokinetics

Absorption

Bioavailability

Rapidly absorbed following IM administration; peak plasma concentrations attained in 20–30 minutes.1 11 21

Onset

When used for postpartum hemorrhage, increase in uterine tone and decreased bleeding noted after about 45 minutes.13

Elimination

Metabolism

Metabolized principally via ω-oxidation and to limited extent via ω-oxidation to a number of metabolites.19 Metabolized more slowly than naturally occurring prostaglandin F.11 15 17 19 21

Elimination Route

Excreted in urine (83%), mainly as metabolites.19

Stability

Storage

Parenteral

Injection

2–8°C.1

Actions

  • Elicits pharmacologic responses usually produced by endogenous prostaglandin F; more potent and has longer duration of activity on the uterus than prostaglandin F.15 17 18

  • Increases the amplitude and frequency of uterine contractions throughout pregnancy; uterine response to the drug increases with the duration of pregnancy.23

  • After delivery, uterine contractions impede uterine blood flow.1

  • Produces cervical dilation.15

  • Produces contraction of vascular smooth muscle; may result in increased BP.1 10 20

  • Causes stimulation of the smooth muscle of the GI tract, increasing GI motility.1 18

  • Stimulates transient bronchoconstriction in some patients.1 12

Advice to Patients

  • Importance of women informing clinicians if they plan to breast-feed.1

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.1

  • Importance of informing patients of other important precautionary information.1 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Carboprost Tromethamine

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

Injection

250 mcg (of carboprost)/mL

Hemabate (with benzyl alcohol)

Pfizer

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions January 1, 2008. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

1. Pharmacia & Upjohn. Hemabate (carboprost tromethamine) injection prescribing information. New York, NY; 2006 Mar.

2. American Academy of Pediatrics Committee on Fetus and Newborn and Committee on Drugs. Benzyl alcohol: toxic agent in neonatal units. Pediatrics. 1983; 72:356-8. [IDIS 175725] [PubMed 6889041]

3. Anon. Benzyl alcohol may be toxic to newborns. FDA Drug Bull. 1982; 12(2):10-11.

4. Centers for Disease Control. Neonatal deaths associated with use of benzyl alcohol. MMWR. 1982; 31:290-1. [IDIS 150868] [PubMed 6810084]

5. Gershanik J, Boecler B, Ensley H et al. The gasping syndrome and benzyl alcohol poisoning. N Engl J Med. 1982; 307:1384-8. [IDIS 160823] [PubMed 7133084]

6. Menon PA, Thach BT, Smith CH et al. Benzyl alcohol toxicity in a neonatal intensive care unit: incidence, symptomatology, and mortality. Am J Perinatol. 1984; 1:288-92. [PubMed 6440575]

7. Anderson CW, Ng KJ, Andresen B et al. Benzyl alcohol poisoning in a premature newborn infant. Am J Obstet Gynecol. 1984; 148:344-6. [IDIS 181207] [PubMed 6695984]

8. American College of Obstetricians and Gynecologists (ACOG) Committee on Practice Bulletins. Postpartum hemorrhage. Practice Bulletin No. 76. Obstet Gynecol. 2006; 108:1039-47. [PubMed 17012482]

9. Oleen MA, Mariano JP. Controlling refractory atonic postpartum hemorrhage with Hemabate sterile solution. Am J Obstet Gynecol. 1990; 16:205-8.

10. Briggs GG, Wan SR. Drug therapy during labor and delivery, part 2. Am J Health-Syst Pharm. 2006; 63:1131-9. [PubMed 16754739]

11. Bygdeman M. Pharmacokinetics of prostaglandins. Best Pract Res Clin Obstet Gynaecol. 2003; 17:707-16. [PubMed 12972009]

12. Dildy GA. Postpartum hemorrhage: new management options. Clin Obstet Gynecol. 2002; 45:330-44. [PubMed 12048393]

13. Hayashi RH, Castillo MS, Noah ML. Management of severe postpartum hemorrhage with prostaglandin F analogue. Obstet Gynecol. 1984; 63:806-8. [PubMed 6610143]

14. World Health Organization task force on the use of prostaglandins for regulation of fertility. Prostaglandins and abortion. I. Intramuscular administration of 15-methyl prostaglandin Ffor induction of abortion in weeks 10 to 20 of pregnancy. Am J Obstet Gynecol. 1977; 129:593-6. [PubMed 920759]

15. Schwallie PC, Lamborn KR. Induction of abortion by intramuscular administration of (15S)-15-methyl PGF2α: an overview of 815 cases. J Reprod Med. 1979; 23:289-93. [PubMed 392084]

16. Stubblefield PG, Carr-Ellis S, Borgatta L. Methods for induced abortion. Obstet Gynecol. 2004; 104:174-85. [PubMed 15229018]

17. Bygdeman M, Swahn ML. Uterine contractility during pregnancy and the effect of abortifacient drugs. Bailliere’s Clin Obstet Gynecol. 1990; 4:249-61.

18. Karim SMM, Sharma SD. Termination of second trimester pregnancy with 15 methyl analogues of prostaglandins E2 and F. J Obstet Gynaecol Br Commonw. 1972; 79:737-43. [PubMed 5070889]

19. Hansson G, Granström E. Metabolism of 15-methyl-prostaglandin F2α in the cynomologus monkey and the human female. Biochem Med. 1977; 18:420-39. [PubMed 413545]

20. Buttino L, Garite TJ. The use of 15 methyl F2α prostaglandin (prostin 15M) for the control of postpartum hemorrhage. Am J Perinatol. 1986; 3:241-3. [PubMed 3487334]

21. Bergström S, Greén K, Bygdeman M. Metabolism and pharmaco-kinetics of 15 methyl PGF and its ester after administration via various routes. Prostaglandins. 1976; 12 (Suppl):17-26.

22. Pharmacia. Prostin VR Pediatric (alprostadil) injection prescribing information. Kalamazoo, MI; 2002 Sep.

23. AHFS Drug Information 2007. McEvoy GK, ed. Dinoprostone. Bethesda, MD: American Society of Health-System Pharmacists; 2007: 3267-9.

24. Pfizer, Morris Plains, NJ: Personal communication.

Hide
(web3)