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  • CLASSES

    Inhibitors of The Kallikrein-kinin-system

    BOXED WARNING

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

    There is a risk of serious hypersensitivity reactions or anaphylaxis with ecallantide therapy. Ecallantide use requires an experienced clinician with appropriate medical support to manage anaphylaxis and hereditary angioedema. Healthcare professionals should be aware of the similarity of symptoms between hypersensitivity reactions and hereditary angioedema and patients should be monitored closely.Do not administer ecallantide to a patient with known ecallantide hypersensitivity. 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.

    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, risk of serious hypersensitivity reactions or anaphylaxis

    There is a risk of serious hypersensitivity reactions or anaphylaxis with ecallantide therapy. Ecallantide use requires an experienced clinician with appropriate medical support to manage anaphylaxis and hereditary angioedema. Healthcare professionals should be aware of the similarity of symptoms between hypersensitivity reactions and hereditary angioedema and patients should be monitored closely.Do not administer ecallantide to a patient with known ecallantide hypersensitivity. 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.

    Pregnancy

    Ecallantide is classified as FDA pregnancy category C. There are no adequate and well-controlled studies of ecallantide in pregnant women. Ecallantide was shown to cause developmental toxicity in rats and should be used during pregnancy only when clearly needed. No information is available on the effects of ecallantide during labor and obstetric delivery.

    Breast-feeding

    According to the manufacturer, it is not known whether ecallantide is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when administering ecallantide to a woman who is breast-feeding her infant. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally administered drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    Children, infants, neonates

    The safety and efficacy of ecallantide have not been established in neonates, infants, or children under 12 years of age. The efficacy of ecallantide in children and adolescents 12—15 years of age is extrapolated from efficacy in patients >= 16 years of age and from pharmacokinetic data demonstrating similar drug exposure in adolescents and adults.

    Geriatric

    Clinical trials did not include a sufficient number of geriatric patients aged 65 years and over to determine if they respond differently to ecallantide than younger patients. Dose selection for elderly patients should be cautious and generally begin at the lower end of the dosing range due to the greater frequency of comorbid conditions in this population.

    ADVERSE REACTIONS

    Severe

    anaphylactic shock / Rapid / 4.0-4.0

    Moderate

    antibody formation / Delayed / 20.2-20.2
    chest pain (unspecified) / Early / Incidence not known
    wheezing / Rapid / Incidence not known
    hypotension / Rapid / Incidence not known
    erythema / Early / 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 (unspecified) / Early / 3.0-3.0
    urticaria / Rapid / 2.0-2.0
    throat irritation / Early / Incidence not known
    rhinorrhea / Early / Incidence not known
    nasal congestion / Early / Incidence not known
    sneezing / Early / Incidence not known
    flushing / Rapid / Incidence not known

    DRUG INTERACTIONS

    There are no drug interactions associated with Ecallantide products.

    PREGNANCY AND LACTATION

    Pregnancy

    Ecallantide is classified as FDA pregnancy category C. There are no adequate and well-controlled studies of ecallantide in pregnant women. Ecallantide was shown to cause developmental toxicity in rats and should be used during pregnancy only when clearly needed. No information is available on the effects of ecallantide during labor and obstetric delivery.

    According to the manufacturer, it is not known whether ecallantide is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when administering ecallantide to a woman who is breast-feeding her infant. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally administered drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    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.