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  • CLASSES

    Labor Inducers

    DEA CLASS

    Rx

    DESCRIPTION

    Prostaglandin F2-alpha analogue; oxytocic; abortifacient and refractory postpartum uterine bleeding treatment; sales restricted to hospitals only.

    COMMON BRAND NAMES

    Hemabate

    HOW SUPPLIED

    Hemabate Intramuscular Inj Sol: 1mL, 250mcg

    DOSAGE & INDICATIONS

    For pregnancy termination.
    For pregnancy termination between weeks 13—20 gestation dated from the first day of the last menstrual period.
    Intramuscular dosage
    Adults

    100 mcg (0.4 mL) optional test dose may be administered initially; 250 mcg (1 mL) by deep IM injection repeated every 1.5—3.5 hours, depending on uterine response, is recommended. May increase the dose to 500 mcg (2 mL) IM if inadequate uterine contraction persists after several doses. Do not exceed the 12 mg (48 mL) Maximum Dosage Limit; administration for more than 48 hours is not recommended.

    For second trimester pregnancy termination in women with intact intrauterine membranes.
    NOTE: Also see above for women in weeks 13—20 of gestation.
    Intra-amniotic dosage†
    Adults

    1.5 mg intra-amniotic injection, repeated once at 24 hours, if necessary, resulted in abortion in 43 of 61 study patients within 24 hours and in all 61 study patients within 48 hours; all women were between 12 and 24 weeks gestation. Alternately, a 2.5 mg single intra-amniotic injection resulted in abortion within 24 hours in 23 of 26 patients of 17—24 weeks gestation.

    For second trimester pregnancy termination when there is failure of expulsion of the fetus during the course of treatment by another method.
    Intramuscular dosage
    Adults

    100 mcg (0.4 mL) optional test dose may be administered initially; 250 mcg (1 mL) by deep IM injection repeated every 1.5—3.5 hours, depending on uterine response, is recommended. May increase the dose to 500 mcg (2 mL) IM if inadequate uterine contraction persists after several doses. Do not exceed the 12 mg (48 mL) Maximum Dosage Limit; administration for more than 48 hours is not recommended.

    For second trimester pregnancy termination with the premature rupture of membranes in intrauterine methods with loss of drug and insufficient or absent uterine activity.
    Intramuscular dosage
    Adults

    100 mcg (0.4 mL) optional test dose may be administered initially; 250 mcg (1 mL) by deep IM injection repeated every 1.5—3.5 hours, depending on uterine response, is recommended. May increase the dose to 500 mcg (2 mL) IM if inadequate uterine contraction persists after several doses. Do not exceed the 12 mg (48 mL) Maximum Dosage Limit; administration for more than 48 hours is not recommended.

    For second trimester pregnancy termination when there is a requirement of a repeat intrauterine instillation of drug for expulsion of the fetus.
    Intramuscular dosage
    Adults

    100 mcg (0.4 mL) optional test dose may be administered initially; 250 mcg (1 mL) by deep IM injection repeated every 1.5—3.5 hours, depending on uterine response, is recommended. May increase the dose to 500 mcg (2 mL) IM if inadequate uterine contraction persists after several doses. Do not exceed the 12 mg (48 mL) Maximum Dosage Limit; administration for more than 48 hours is not recommended.

    For second trimester pregnancy termination when there is an inadvertent or spontaneous rupture of membranes in the presence of a previable fetus and absence of adequate activity for expulsion.
    Intramuscular dosage
    Adults

    100 mcg (0.4 mL) optional test dose may be administered initially; 250 mcg (1 mL) by deep IM injection repeated every 1.5—3.5 hours, depending on uterine response, is recommended. May increase the dose to 500 mcg (2 mL) IM if inadequate uterine contraction persists after several doses. Do not exceed the 12 mg (48 mL) Maximum Dosage Limit; administration for more than 48 hours is not recommended.

    For the treatment of postpartum bleeding due to uterine atony that is unresponsive to conventional management.
    NOTE: Conventional management includes oxytocin IV, uterine massage, uterine manipulation, and ergot preparations IM or IV, as appropriate.
    Intramuscular dosage
    Adults

    250 mcg (1 mL) IM is advised; if hemostasis is inadequate, additional doses may be administered every 15—90 minutes as determined by the attending physician. Do not exceed the Maximum Dosage Limit of 2 mg (8 mL).

    Intramyometrial dosage†
    Adults

    250 mcg (1 mL) by intramyometrial injection; if hemostasis is inadequate, repeat dose once at 5 minutes. Treatment failure after 2 doses necessitated surgical intervention in 2 of 5 women with postpartum hemorrhage following cesarean section.

    For the treatment of refractory hemorrhagic cystitis†.
    NOTE: Consider premedication to minimize bladder spasms (oxybutynin 5—10 mg PO with or without belladonna; opium suppositories).
    Intravesicular dosage†
    Adults

    0.8 mg/dL in 50 mL of saline instilled into the bladder for 60 minutes every 6 hours for 4 doses led to hematuria resolution in 4 of 13 patients with refractory, grade 3 or 4 hemorrhagic cystitis after bone marrow transplantation; a bladder irrigation of 0.02% hydrocortisone in saline was used between carboprost instillations. Elevation of the carboprost dose to 1 mg/dL in 50 mL of saline using the same protocol resulted in resolution of hematuria in an additional 5 patients.
    Investigators recommend treatment for 48 hours after resolution of hematuria or for a total of 7 days with an additional 7 day treatment duration at the previously effective dose if hematuria recurs after therapy discontinuation.

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    Maximum dosage limits are indication specific. 12 mg IM total dose, up to a maximum recommended duration of 48 hours for pregnancy termination; 2 mg IM for postpartum bleeding.

    Elderly

    Safety and efficacy have not been established.

    Adolescents

    Safety and efficacy have not been established.

    Children

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Carboprost tromethamine is contraindicated for use in patients with hepatic impairment.

    Renal Impairment

    Carboprost tromethamine is contraindicated for use in patients with renal impairment.

    ADMINISTRATION

    For storage information, see the specific product information in the How Supplied section.

    Injectable Administration

    Administer only by medically trained personnel in a hospital that can provide immediate and intensive medical and surgical care.
    Use with strict adherence to recommended dosages. Each ml of Hemabate contains carboprost tromethamine equivalent to 250 mcg of carboprost.
    Inspect visually prior to administration. Discard the solution if particulate matter or discoloration is seen.

    Intramuscular Administration

    Inject deeply into a large muscle such as the deltoid muscle.
    Aspirate prior to injection to avoid injecting into a blood vessel.

    Other Injectable Administration

    Intramyometrial Injection:
    NOTE: Carboprost tromethamine is not approved by the FDA for intramyometrial administration.
    May be administered directly into the uterus following cesarean section.
    Aspirate prior to injection to avoid injecting into a blood vessel.
     
    Intra-amniotic Injection:
    NOTE: Carboprost tromethamine is not approved by the FDA for intra-amniotic administration.
    Use ultrasound or equivalent to allow visualization of the amniotic cavity for administration.
     
    Intravesicular Administration:
    NOTE: Carboprost tromethamine is not approved by the FDA for intravesicular administration.
    Dilute appropriate dose in 50 mL of saline.
    Evacuate blood clots by hand irrigation immediately prior to dose administration.
    Instill dose then clamp bladder irrigation line for 60 minutes.
    Instruct patient to change positions every 15 minutes during therapy.
    Resume bladder irrigation after draining carboprost.
    Use intravesicular dilution within 1 hour of preparation.

    STORAGE

    Hemabate:
    - Refrigerate (between 36 and 46 degrees F)

    CONTRAINDICATIONS / PRECAUTIONS

    Incomplete abortion, trauma

    Use carboprost tromethamine with strict adherence to recommended dosages. Further, use of carboprost tromethamine is restricted to administration by qualified personnel in a hospital setting where emergency measures may be taken, if necessary. Carboprost tromethamine-induced termination may be expected to result in an incomplete abortion in approximately 20 percent of cases, necessitating further care and completion by another mechanism. Cervical laceration or other drug related adverse events may require acute care. Because cervical trauma can be asymptomatic, the cervix should be carefully examined following completion of the carboprost tromethamine-induced abortion.

    Benzyl alcohol hypersensitivity

    Carboprost tromethamine is contraindicated in patients with known carboprost tromethamine hypersensitivity or hypersensitivity any excipients. The Hemabate brand of carboprost tromethamine contains benzyl alcohol as a preservative and should be avoided in patients with benzyl alcohol hypersensitivity.

    Infection

    Carboprost tromethamine is contraindicated in patients with acute pelvic inflammatory disease; treat patients with this type of infection as medically indicated to allow full recovery prior to the initiation of abortion procedures.

    Caesarean section, surgery

    As compromised (scarred) uteri may increase the risk of uterine rupture and associated complications, use carboprost tromethamine with caution in patients with a history of caesarean section or major uterine surgery. Use of laminaria tents and/or conservative uterine stimulation in at risk patients may decrease the risk of rupture.

    Chorioamnionitis

    During the clinical trials with carboprost tromethamine, 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 carboprost tromethamine therapy. Chorioamnionitis during labor may have an inhibitory effect on the uterine response to carboprost tromethamine similar to what has been reported for other oxytocic agents.

    Cardiac disease, hypertension

    Use of carboprost tromethamine is contraindicated in patients with active cardiac disease. Carboprost tromethamine may stimulate vascular smooth muscle and may cause hypertension. Cautious use of carboprost in patients with hypertension may be advisable. Patients with cardiac disease were excluded from most trials, so data from the patient population are limited.

    Hypotension

    As carboprost tromethamine may elicit vaso-vagal syndrome, use with caution in patients with a history of hypotension.

    Asthma, pulmonary disease

    Use of carboprost tromethamine is contraindicated in patients with active pulmonary disease. Carboprost tromethamine may stimulate bronchial smooth muscle and may cause bronchospasm. Cautious use of carboprost in patients with asthma may be advisable. Patients with pulmonary disease were excluded from most trials, so data from the patient population are limited.

    Anemia, diabetes mellitus, hepatic disease, jaundice, renal disease, seizure disorder

    Carboprost tromethamine is contraindicated for use in patients with active renal disease or hepatic disease. Further, cautious use of carboprost tromethamine is recommended in patients with a history of anemia, diabetes mellitus, jaundice, or epilepsy or other seizure disorder. Patients with these conditions were excluded from most trials, so data from the patient populations are limited.

    Children, infants, neonates

    The safety and effectiveness of carboprost tromethamine in children, infants, and neonates have not been established. Early study did include patients as young as 12 years of age, but data are limited. An accidental exposure of carboprost tromethamine 250 mcg IM in a newborn resulted in hypertension and elevations of both respiration and pulse rate within 15 minutes. Bronchospasm was treated with albuterol and oxygen; 10% dextrose IV was administered. Subsequently, fever, diarrhea, and dystonic movements or seizures were reported. The neonate's symptomatology resolved within 18 hours with patient discharge 24 hours after carboprost tromethamine injection. All neurological and developmental tests were normal at 3 months.

    Pregnancy

    Carboprost tromethamine is categorized in FDA pregnancy risk category C. Carboprost tromethamine is embryotoxic in rats and rabbits; any dose that produces increased uterine tone could put the embryo or fetus at risk. Although not specifically proven of carboprost tromethamine, animal studies suggest that some prostaglandins have teratogenic potential. As such, any cases of incomplete abortion should be completed by another mechanism. Carboprost tromethamine is not indicated for pregnancy termination once the fetus in utero has reached the stage of viability. Carboprost tromethamine does not appear to directly affect the fetoplacental unit and should not be considered a feticidal agent. The previable fetus may exhibit transient life signs post-abortion.

    Breast-feeding

    It is not known if carboprost tromethamine is excreted into human breast milk. Because many drugs are excreted in human milk, breast-feeding mothers should receive carboprost tromethamine therapy with caution.

    ADVERSE REACTIONS

    Severe

    cervical laceration / Early / 0-1.0
    hematemesis / Delayed / Incidence not known
    uterine rupture / Early / Incidence not known
    bronchospasm / Rapid / Incidence not known
    pulmonary edema / Early / Incidence not known
    anaphylactic shock / Rapid / Incidence not known
    angioedema / Rapid / Incidence not known
    anaphylactoid reactions / Rapid / Incidence not known
    torticollis / Delayed / Incidence not known

    Moderate

    hot flashes / Early / 1.0-10.0
    wheezing / Rapid / 0-1.0
    dyspnea / Early / 0-1.0
    hypertension / Early / Incidence not known
    palpitations / Early / Incidence not known
    sinus tachycardia / Rapid / Incidence not known
    chest pain (unspecified) / Early / Incidence not known
    blurred vision / Early / Incidence not known
    thyrotoxicosis / Delayed / Incidence not known
    dystonic reaction / Delayed / Incidence not known

    Mild

    chills / Rapid / 2.0-39.0
    fever / Early / 11.0-23.0
    flushing / Rapid / 1.0-10.0
    cough / Delayed / 1.0-10.0
    back pain / Delayed / 1.0-10.0
    headache / Early / 1.0-10.0
    shivering / Rapid / 2.0-2.0
    nausea / Early / 10.0
    diarrhea / Early / 10.0
    vomiting / Early / 10.0
    muscle cramps / Delayed / 10.0
    dysmenorrhea / Delayed / 10.0
    epistaxis / Delayed / Incidence not known
    abdominal pain / Early / Incidence not known
    xerostomia / Early / Incidence not known
    syncope / Early / Incidence not known
    vertigo / Early / Incidence not known
    tinnitus / Delayed / Incidence not known
    dizziness / Early / Incidence not known
    diaphoresis / Early / Incidence not known
    hyperventilation / Early / Incidence not known
    rash (unspecified) / Early / Incidence not known
    injection site reaction / Rapid / Incidence not known
    weakness / Early / Incidence not known
    paresthesias / Delayed / Incidence not known
    mastalgia / Delayed / Incidence not known
    musculoskeletal pain / Early / Incidence not known
    insomnia / Early / Incidence not known
    ocular pain / Early / Incidence not known
    drowsiness / Early / Incidence not known
    anxiety / Delayed / Incidence not known
    lethargy / Early / Incidence not known

    DRUG INTERACTIONS

    Dinoprostone, Prostaglandin E2: (Major) Carboprost tromethamine may augment the activity of other oxytocics. Augmentation can result in uterine hypertonus with subsequent uterine rupture, particularly in the absence of adequate cervical dilation. The concurrent use of carboprost tromethamine and other oxytocic drugs is not recommended.
    Ergonovine: (Major) Carboprost tromethamine may augment the activity of other oxytocics. Augmentation can result in uterine hypertonus with subsequent uterine rupture, particularly in the absence of adequate cervical dilation. The concurrent use of carboprost tromethamine and other oxytocic drugs is not recommended.
    Methylergonovine: (Major) Carboprost tromethamine may augment the activity of other oxytocics. Augmentation can result in uterine hypertonus with subsequent uterine rupture, particularly in the absence of adequate cervical dilation. The concurrent use of carboprost tromethamine and other oxytocic drugs is not recommended.
    Oxytocin: (Major) Carboprost tromethamine may augment the activity of other oxytocics. Augmentation can result in uterine hypertonus with subsequent uterine rupture, particularly in the absence of adequate cervical dilation. The concurrent use of carboprost tromethamine and other oxytocic drugs is not recommended.

    PREGNANCY AND LACTATION

    Pregnancy

    Carboprost tromethamine is categorized in FDA pregnancy risk category C. Carboprost tromethamine is embryotoxic in rats and rabbits; any dose that produces increased uterine tone could put the embryo or fetus at risk. Although not specifically proven of carboprost tromethamine, animal studies suggest that some prostaglandins have teratogenic potential. As such, any cases of incomplete abortion should be completed by another mechanism. Carboprost tromethamine is not indicated for pregnancy termination once the fetus in utero has reached the stage of viability. Carboprost tromethamine does not appear to directly affect the fetoplacental unit and should not be considered a feticidal agent. The previable fetus may exhibit transient life signs post-abortion.

    It is not known if carboprost tromethamine is excreted into human breast milk. Because many drugs are excreted in human milk, breast-feeding mothers should receive carboprost tromethamine therapy with caution.

    MECHANISM OF ACTION

    Carboprost tromethamine has stimulatory effects on uterine, gastrointestinal, and possibly other smooth muscle. Administration results in myometrial contractions in the gravid uterus similar to labor contractions at the end of a full term pregnancy. Carboprost tromethamine-induced uterine contractions will usually cause complete evacuation of the uterus; however, abortion may be incomplete in as many as 20 percent of patients receiving the drug. Postpartum, the resultant myometrial contractions provide hemostasis at the site of placentation. Common adverse reactions associated with carboprost tromethamine use (i.e., vomiting and/or diarrhea) are the result of smooth muscle stimulation of the human gastrointestinal tract. In laboratory animals and in humans, large doses of carboprost tromethamine can raise blood pressure, probably by contracting the vascular smooth muscle; this effect has not been clinically significant with the doses of carboprost tromethamine used for terminating pregnancy. In susceptible patients, carboprost tromethamine may cause transient bronchoconstriction.

    PHARMACOKINETICS

    Carboprost tromethamine is administered by intramuscular injection; off-label administration methods studied include intra-amniotic injection, intramyometrial injection, and intravesicular administration. The estimated plasma half-life of endogenous prostaglandin F2-alpha is 15 seconds due to rapid inactivation at the site of carbon 15. The structure of carboprost tromethamine contains an additional methyl group at carbon 15, which blocks similar metabolism. Carboprost, thus, has a longer half-life of 8 minutes. The longer half-life of carboprost makes the analogue more suitable for IM administration as compared with the endogenous prostaglandin.Carboprost tromethamine is inactivated by beta-oxidation with subsequent urinary elimination of the major metabolite.
     
    In a clinical trial of 25 patients at 14—24 weeks gestation who received a regimen of carboprost tromethamine 250 mcg IM injections every 3 hours, the mean time to delivery of the fetus was 21.2 +/-11.2 hours. In a clinical trial of 815 cases of carboprost tromethamine-induced abortion conducted between 6 and 27 weeks of gestation, the investigators noted that the amount of medication required for fetal expulsion increased with gestational age and that time to abortion increased with gravidity, parity, and gestational age.

    Intramuscular Route

    Following IM injection of carboprost tromethamine, time to peak plasma concentration was measured to be between 15 and 60 minutes. In a pharmacokinetic study of 5 patients undergoing abortion, the average peak concentrations of drug were slightly higher following each successive IM injection of the prostaglandin, but the concentrations always decreased to concentrations less than the preceding peak values by two hours after each injection.