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  • CLASSES

    Agents for Acute Treatment of Hereditary Angioedema (HAE)
    Blood Coagulation Factors

    DEA CLASS

    Rx

    DESCRIPTION

    Recombinant analog of human C1 esterase inhibitor obtained from the milk of rabbits expressing the encoded gene for human C1 esterase inhibitor
    For the treatment of acute angioedema attacks in adolescents and adults
    Contraindicated in patients with a history of allergy to rabbits or rabbit-derived products

    COMMON BRAND NAMES

    RUCONEST

    HOW SUPPLIED

    RUCONEST Intravenous Inj Pwd F/Sol: 2100U

    DOSAGE & INDICATIONS

    For the treatment of acute attacks of hereditary angioedema (HAE).
    NOTE: Effectiveness was not established in HAE patients with laryngeal attacks.
    Intravenous dosage
    Adults

    50 International Units/kg/dose (Max: 4200 International Units/dose) as a slow IV injection over approximately 5 minutes. If the attack symptoms persist, an additional (second) dose can be administered. No more than 2 doses should be administered within a 24 hour period.

    Adolescents

    50 International Units/kg/dose (Max: 4200 International Units/dose) as a slow IV injection over approximately 5 minutes. If the attack symptoms persist, an additional (second) dose can be administered. No more than 2 doses should be administered within a 24 hour period.

    For angioedema prophylaxis† in patients with hereditary angioedema.
    Intravenous dosage
    Adults

    50 International Units/kg/dose (Max: 4,200 International Units/dose) IV once or twice weekly.

    Adolescents

    50 International Units/kg/dose (Max: 4,200 International Units/dose) IV once or twice weekly.

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    50 International Units/kg/dose (Max: 4200 International Units/dose); Max 2 doses per 24 hours.

    Geriatric

    50 International Units/kg/dose (Max: 4200 International Units/dose); Max 2 doses per 24 hours.

    Adolescents

    50 International Units/kg/dose (Max: 4200 International Units/dose); Max 2 doses per 24 hours.

    Children

    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

    Injectable Administration

    NOTE: Patients may self-administer C1 esterase inhibitor, recombinant upon recognition of an HAE attack, after appropriate training under the guidance of a healthcare professional.
    For intravenous injection only.
    Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.

    Intravenous Administration

    Reconstitution:
    Allow solution and diluent to come to room temperature.
    Using aseptic technique, slowly add 14 ml of sterile water for injection to each C1 esterase inhibitor, recombinant vial. Swirl the vial slowly to mix and avoid foaming.
    If the same patient is to receive more than one vial, the contents of multiple vials may be pooled into a single administration device (i.e., syringe).
    Use reconstituted product immediately or within 8 hours stored at 2—8 degrees C (36—46 degrees F). Do not freeze reconstituted solution.
    Each vial of C1 esterase inhibitor, recombinant is for single use only; discard partially used vials.
    Intravenous administration:
    Administer by slow IV injection over approximately 5 minutes.
    Do not mix with other medicinal products. Administer by a separate infusion line.

    STORAGE

    RUCONEST:
    - Discard unused portion. Do not store for later use.
    - Do not freeze
    - Protect from light
    - Store between 36 to 77 degrees F
    - Store in original container

    CONTRAINDICATIONS / PRECAUTIONS

    Leporine protein hypersensitivity

    C1 esterase inhibitor, recombinant is contraindicated in patients with a history of allergy to rabbits or rabbit-derived products (leporine protein hypersensitivity). It is also contraindicated in patients with a history of life-threatening immediate hypersensitivity reactions to C1 esterase inhibitor preparations, including anaphylaxis. Because severe hypersensitivity reactions may occur and may have symptoms similar to hereditary angioedema attacks, treatment methods should be carefully considered.

    Arteriosclerosis, obesity, thromboembolic disease

    Patients with an indwelling venous catheter/access device, thromboembolic disease, underlying arteriosclerosis, use of oral contraceptives or certain androgens, morbid obesity, and immobility have an increased risk of developing serious arterial and venous thromboembolic events at the recommended dose of plasma derived C1 esterase inhibitor products. Monitor patients with known risk factors for thromboembolic events during and after administration.

    Pregnancy

    C1 esterase inhibitor, recombinant is classified in FDA pregnancy category B. There are no adequate and well-controlled studies in pregnant women. An effect on embryo-fetal development could not be excluded in animal studies at doses up to 12.5 times the human dose of 50 International Units/kg. According to the manufacturer, C1 esterase inhibitor, recombinant should be used during pregnancy only if clearly needed. According to a consensus panel, plasma-derived human C1 esterase inhibitor concentrate is preferred for acute treatment, short-term prophylaxis, or long-term prophylaxis during pregnancy. Also, C1 esterase inhibitor should be available during labor and delivery if not administered prophylactically; prophylaxis is advised before forceps or vacuum extraction or cesarean section and may be warranted in other deliveries based on HAE symptoms during the pregnancy and/or during previous deliveries. Among 29 pregnancies, the efficacy of C1 esterase inhibitor treatment was consistent before, during, and after pregnancy; all patients received prophylactic C1 esterase inhibitor immediately before delivery. No abortions or drug-related abnormalities were noted.

    Breast-feeding

    According to the manufacturer, caution should be exercised when C1 esterase inhibitor, recombinant is administered during breast-feeding. It is not known if C1 esterase inhibitor, recombinant is excreted in human milk. According to a consensus panel, human plasma-derived C1 esterase inhibitor is considered to be the therapy of choice for both treatment and prophylaxis of maternal hereditary angioedema during lactation. 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.

    ADVERSE REACTIONS

    Severe

    angioedema / Rapid / Incidence not known
    anaphylactoid reactions / Rapid / Incidence not known
    thromboembolism / Delayed / Incidence not known

    Moderate

    hypotension / Rapid / Incidence not known
    wheezing / Rapid / Incidence not known
    antibody formation / Delayed / Incidence not known

    Mild

    headache / Early / 9.0-9.0
    vertigo / Early / 3.0-3.0
    back pain / Delayed / 3.0-3.0
    sneezing / Early / 2.0-2.0
    diarrhea / Early / 2.0-2.0
    nausea / Early / 2.0-2.0
    urticaria / Rapid / Incidence not known
    rash / Early / Incidence not known
    abdominal pain / Early / Incidence not known

    DRUG INTERACTIONS

    There are no drug interactions associated with C1 Esterase Inhibitor, Recombinant products.

    PREGNANCY AND LACTATION

    Pregnancy

    C1 esterase inhibitor, recombinant is classified in FDA pregnancy category B. There are no adequate and well-controlled studies in pregnant women. An effect on embryo-fetal development could not be excluded in animal studies at doses up to 12.5 times the human dose of 50 International Units/kg. According to the manufacturer, C1 esterase inhibitor, recombinant should be used during pregnancy only if clearly needed. According to a consensus panel, plasma-derived human C1 esterase inhibitor concentrate is preferred for acute treatment, short-term prophylaxis, or long-term prophylaxis during pregnancy. Also, C1 esterase inhibitor should be available during labor and delivery if not administered prophylactically; prophylaxis is advised before forceps or vacuum extraction or cesarean section and may be warranted in other deliveries based on HAE symptoms during the pregnancy and/or during previous deliveries. Among 29 pregnancies, the efficacy of C1 esterase inhibitor treatment was consistent before, during, and after pregnancy; all patients received prophylactic C1 esterase inhibitor immediately before delivery. No abortions or drug-related abnormalities were noted.

    According to the manufacturer, caution should be exercised when C1 esterase inhibitor, recombinant is administered during breast-feeding. It is not known if C1 esterase inhibitor, recombinant is excreted in human milk. According to a consensus panel, human plasma-derived C1 esterase inhibitor is considered to be the therapy of choice for both treatment and prophylaxis of maternal hereditary angioedema during lactation. 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

    C1 esterase inhibitor is a normal constituent of human blood that functions as a serine protease inhibitor. C1 esterase inhibitor regulates the fibrinolytic system, the complement system, and the contact system (intrinsic coagulation pathway). For example, C1 esterase inhibitor binds to and inactivates proteases that activate the complement system such as C1r, C1s, and mannan-binding, lectin-associated proteases. C1 esterase inhibitor also binds to and inactivates proteases that activate the contact system such as factor XIIa and plasma kallikrein. Lastly, C1 esterase inhibitor binds to and inactivates proteases that activate the fibrinolytic system such as tissue plasminogen activator and plasmin. C1 esterase inhibitor is known as a suicide inhibitor: binding of C1 esterase inhibitor and the protease inactivates both and consumes the C1 esterase inhibitor. Patients with hereditary angioedema (HAE) already have a low baseline C1 esterase inhibitor concentration. The average C1 esterase inhibitor concentration is approximately 30% of normal. So, activation of any protease that is inactivated by C1 esterase inhibitor leads to consumption of the C1 esterase inhibitor to the extent that activation of the complement and contact systems becomes completely unregulated.
     
    During HAE attacks, contact system activation leads to bradykinin generation. Bradykinin interacts with the Bk2 receptor on endothelial cells and mediates an increase in vascular permeability. The release of vasoactive mediators during a HAE attack appears to be associated with fibrinolytic system activation. In fact, during an attack, contact system and fibrinolytic system activation are strictly correlated. Specifically, a significant correlation was found between plasma plasmin-alpha2-antiplasmin (PAP) complex concentrations and cleaved high molecular weight kininogen. Contact system activation was demonstrated by cleaved high molecular weight kininogen. During attacks, a significant increase in PAP complexes occurs as compared with baseline concentrations during remission, which implies that attacks are characterized by plasmin generation. As expected, a significant increase in plasmin concentrations occurs during an attack. Plasma tissue plasminogen activator concentrations were normal during both remission and attacks, so fibrinolysis activation during an attack appears to occur independent of the release of tissue plasminogen activator.
     
    C1 esterase inhibitor suppresses contact system activation by inactivating plasma kallikrein and factor XIIa, which may modulate vascular permeability by preventing bradykinin generation. Administration of C1 esterase inhibitor increases plasma levels of functional C1 esterase inhibitor activity.

    PHARMACOKINETICS

    C1 inhibitor esterase, recombinant is administered intravenously. During hereditary angioedema attacks, classical complement activation occurs because of depletion of C1 inhibitor. As a result of unregulated complement activation, C4 and C2 concentrations fall.
     

    Intravenous Route

    Among asymptomatic patients with hereditary angioedema, the mean Cmax was 1.2 International Units/ml and was reached at approximately 20 minutes. The elimination half-life was approximately 2.5 hours after administration of C1 esterase inhibitor 50 International Units/kg. The plasma C1INH activity levels is increased to greater than 0.7 International Units/ml (the lower limit of normal) in HAE patients following a dose of 50 International Units/kg. Clearance is nonlinear over the dose range of 25—100 International Units/kg.