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  • CLASSES

    Agents for Acute Treatment of Hereditary Angioedema (HAE)
    Inhibitors of The Kallikrein-kinin-system

    DEA CLASS

    Rx

    DESCRIPTION

    Recombinant protein kallikrein inhibitor
    Used for treatment of acute attacks of hereditary angioedema
    Only administer in settings with appropriate medical support/supplies readily available to treat anaphylaxis

    COMMON BRAND NAMES

    Kalbitor

    HOW SUPPLIED

    Kalbitor Subcutaneous Inj Sol: 1mL, 10mg

    DOSAGE & INDICATIONS

    For the treatment of acute attacks of hereditary angioedema (HAE).
    Subcutaneous dosage
    Adults, Adolescents, and Children >= 12 years

    30 mg subcutaneously administered as three 10-mg (1 mL) injections. If the attack persists, an additional 30 mg dose may be administered within a 24-hour period. The efficacy of ecallantide in children and adolescents 12 to 15 years of age is extrapolated from efficacy in patients 16 years of age or older and from pharmacokinetic data demonstrating similar drug exposure in adolescents and adults.

    MAXIMUM DOSAGE

    Adults

    30 mg/dose subcutaneously. May repeat once within 24 hour period.

    Geriatric

    30 mg/dose subcutaneously. May repeat once within 24 hour period.

    Adolescents

    30 mg/dose subcutaneously. May repeat once within 24 hour period.

    Children

    12 years: 30 mg/dose subcutaneously. May repeat once within 24 hour period.
    < 12 years: Safety and efficacy have not been established.

    Infants

    Safety and efficacy have not been established.

    Neonates

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.

    Renal Impairment

    Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

    ADMINISTRATION

     
    Ecallantide should only be administered by a health care professional with appropriate medical support to manage anaphylaxis and hereditary angioedema.

    Injectable Administration
    Subcutaneous Administration

    Using aseptic technique, withdraw 1 mL (10 mg) of ecallantide from the vial using a large bore needle. Change the needle on the syringe to a needle suitable for subcutaneous injection (27 gauge recommended).
    Inject ecallantide into the skin of the abdomen, thigh, or upper arm.
    Repeat the procedure for each of the three vials of ecallantide (30 mg total dose). The injection site for each of the three injections may be in the same or different anatomic location (abdomen, thigh, or upper arm). There is no need for site rotation. Individual injections should be separated by at least 2 inches and away from the anatomical site of attack.
    The same directions for administration apply if an additional dose of ecallantide is required within 24 hours. Different injection sites or the same anatomical location as used for the first dose may be used.
    Ecallantide is a clear, colorless solution. Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit. If there is particulate matter or discoloration, the vial should not be used.

    STORAGE

    Kalbitor:
    - Do not freeze
    - Product must be used within 14 days after removal from refrigeration to room temperature (77 degrees F)
    - Protect from light
    - Refrigerate (between 36 and 46 degrees F)

    CONTRAINDICATIONS / PRECAUTIONS

    Ecallantide hypersensitivity, requires an experienced clinician, serious hypersensitivity reactions or anaphylaxis

    Do not administer ecallantide to a patient who has known ecallantide hypersensitivity. Potentially serious hypersensitivity reactions or anaphylaxis have occurred. Observe patients for an appropriate period of time after administration. During clinical trials, hypersensitivity reactions occurred within the first hour after dosing. Given the similarity in hypersensitivity symptoms and acute hereditary angioedema symptoms, monitor patients closely if a hypersensitivity reaction occurs. Ecallantide administration requires an experienced clinician with appropriate medical support to manage anaphylaxis and hereditary angioedema. Patients administered ecallantide may develop antibodies to ecallantide. Patients who seroconvert to anti-ecallantide antibodies may be at a higher risk of a hypersensitivity reaction.[37780]

    Geriatric

    In general, ecallantide dose selection for a geriatric patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

    Pregnancy

    The available data from the pharmacovigilance database for ecallantide have not identified a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes with use during pregnancy. In an animal reproductive study, increased early fetal deaths resulting in decreased live fetuses were observed after treatment during the period of organogenesis at an intravenous dose approximately 1.6 times the maximum recommended human dose (MRHD) in the presence of maternal toxicity. There were no effects on embryofetal survival or structural abnormalities in other animal studies after treatment during the period of organogenesis with intravenous doses up to approximately 1.1 and 6 times the MRHD or with subcutaneous doses up to 2.4 times the MRHD. In a pre- and post-natal development animal study, there were no effects on pup survival and development with subcutaneous doses up to approximately 2.7 times the MRHD.

    Breast-feeding

    There are no data on the presence of ecallantide in human breast milk, the effects on the breast-fed infant, or the effects on milk production. Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for ecallantide and any potential adverse effects on the breast-fed child from ecallantide or the underlying maternal condition.

    ADVERSE REACTIONS

    Severe

    serious hypersensitivity reactions or anaphylaxis / Rapid / Incidence not known

    Moderate

    antibody formation / Delayed / 20.2-20.2
    wheezing / Rapid / Incidence not known
    erythema / Early / Incidence not known
    chest pain (unspecified) / Early / Incidence not known
    hypotension / Rapid / Incidence not known

    Mild

    headache / Early / 16.0-16.0
    nausea / Early / 13.0-13.0
    fatigue / Early / 12.0-12.0
    diarrhea / Early / 11.0-11.0
    infection / Delayed / 8.0-8.0
    injection site reaction / Rapid / 7.0-7.0
    vomiting / Early / 6.0-6.0
    pharyngitis / Delayed / 6.0-6.0
    pruritus / Rapid / 5.0-5.0
    abdominal pain / Early / 5.0-5.0
    fever / Early / 5.0-5.0
    rash / Early / 3.0-3.0
    urticaria / Rapid / 2.0-2.0
    nasal congestion / Early / Incidence not known
    flushing / Rapid / Incidence not known
    sneezing / Early / Incidence not known
    throat irritation / Early / Incidence not known
    rhinorrhea / Early / Incidence not known

    DRUG INTERACTIONS

    There are no drug interactions associated with Ecallantide products.

    PREGNANCY AND LACTATION

    Pregnancy

    The available data from the pharmacovigilance database for ecallantide have not identified a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes with use during pregnancy. In an animal reproductive study, increased early fetal deaths resulting in decreased live fetuses were observed after treatment during the period of organogenesis at an intravenous dose approximately 1.6 times the maximum recommended human dose (MRHD) in the presence of maternal toxicity. There were no effects on embryofetal survival or structural abnormalities in other animal studies after treatment during the period of organogenesis with intravenous doses up to approximately 1.1 and 6 times the MRHD or with subcutaneous doses up to 2.4 times the MRHD. In a pre- and post-natal development animal study, there were no effects on pup survival and development with subcutaneous doses up to approximately 2.7 times the MRHD.

    There are no data on the presence of ecallantide in human breast milk, the effects on the breast-fed infant, or the effects on milk production. Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for ecallantide and any potential adverse effects on the breast-fed child from ecallantide or the underlying maternal condition.

    MECHANISM OF ACTION

    Ecallantide is a potent, selective, reversible inhibitor of kallikrein that blocks the production of kallikrein, a precursor to bradykinin. Ecallantide binds to the protease plasma kallikrein and blocks its binding site, preventing the conversion of high molecular weight kininogen to bradykinin. People with hereditary angioedema (HAE) have mutations to C1-esterase inhibitor (C1-INH) located on chromosome 11q. C1-INH, a serine protease, is the primary regulator of the kallikrein-kinin cascade, but is also involved in complement and intrinsic coagulation, fibrinolysis, hypotension, and pain and inflammation pathways. A deficiency in C1-INH causes an increase in the production of kallikrein, and thus, bradykinin. The edema and swelling of HAE attacks are thought to be due to the excessive production of bradykinin. Because ecallantide is selective for the kallikrein-kinin pathway, ecallantide should not affect other pathways regulated by C1-INH.
     
    In regard to the investigational use of ecallantide for the prevention of blood loss during cardiothoracic surgery, ecallantide's inhibition of kallikrein production may be very beneficial. Kallikrein liberates bradykinin, which causes local leakage of fluid from the blood vessels into the tissues. Ecallantide helps reduce bradykinin liberation and may reduce both blood transfusions associated with on-pump cardiothoracic surgery and systemic inflammatory effects. Contact activation of the inflammatory cascade is one of the inherent risks of on-pump cardiothoracic surgery. Blood loss and the systemic inflammatory response syndrome may occur when the patient's blood comes into contact with the artificial surface of the cardiopulmonary bypass machine and tubing.

    PHARMACOKINETICS

    Ecallantide is administered subcutaneously. After administration, the mean elimination half-life of ecallantide was approximately 2 hours. Plasma clearance was 153 +/- 20 mL/min and the volume of distribution was 26.4 +/- 7.8 L. Ecallantide is a small protein with a molecular weight of 7054 Da. Renal elimination of ecallantide has been observed in treated subjects.

    Subcutaneous Route

    After the subcutaneous administration of a single 30 mg dose of ecallantide to healthy subjects, the maximum plasma concentration, 586 +/- 106 ng/mL, was observed 2—3 hours after the dose.