RUCONEST

General Administration Information
For storage information, see the specific product information within the How Supplied section.

Route-Specific Administration

Injectable Administration
-Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
Intravenous Administration
Reconstitution
-Allow vial 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).
-Each vial of C1 esterase inhibitor, recombinant is for single use only; discard partially used vials.
-Storage: Use reconstituted product immediately or within 8 hours if stored at 2-8 degrees C (36-46 degrees F). Do not freeze reconstituted solution.

IV Push
-Administer by slow IV injection over approximately 5 minutes.
-Do not mix with other medicinal products. Administer by a separate infusion line.
-Patients may self-administer C1 esterase inhibitor, recombinant upon recognition of an HAE attack, after appropriate training under the guidance of a healthcare professional.

The safety of C1 esterase inhibitor, recombinant was evaluated in 17 adolescent patients treated for 52 HAE attacks prior to FDA approval. Approximately half of the patients experienced adverse reactions; however, none were reported as serious.

Severe hypersensitivity reactions, including anaphylactoid reactions, may occur. The signs and symptoms of hypersensitivity reactions may include hives, generalized urticaria, tightness of the chest, wheezing, hypotension, and/or anaphylaxis during or after injection. Discontinue C1 esterase inhibitor, recombinant and initiate appropriate treatment should symptoms occur. Rash (unspecified) has been reported in patients receiving C1 esterase inhibitor, recombinant during post-marketing experience.

Serious arterial and venous thromboembolic (TE) events (i.e., thromboembolism) have been reported at the recommended dose of plasma derived C1 esterase inhibitor products in patients with risk factors such as the presence of an indwelling venous catheter, history of thromboembolic disease, underlying arteriosclerosis, use of oral contraceptives or certain androgens, obesity, and immobility. Monitor patients with known risk factors for TE events during and after administration.

Because C1 esterase inhibitor, recombinant is a therapeutic protein, there is a potential for immunogenicity and antibody formation with administration. At least 10% of subjects formed a specific antibody response to C1 esterase inhibitor, recombinant after 5 treated HAE attacks. Observed antibody formation was not associated with adverse clinical findings.

The most commonly reported adverse reactions (>= 2%) in pre-marketing clinical trials of C1 esterase inhibitor, recombinant were headache (9%), nausea, and diarrhea. Additionally, the most common adverse events (occurring in at least 2 patients) reported in adolescent patients who received C1 esterase inhibitor, recombinant in clinical trials included headache, abdominal pain, and oropharyngeal pain. Other adverse reactions reported in >= 2% of patients in clinical trials included angioedema, sneezing, erythema marginatum, skin burning sensation, back pain, elevated C-reactive protein, elevated fibrin D-dimer, vertigo, and lipoma.

Effectiveness of C1 esterase inhibitor, recombinant has not been established in HAE patients with laryngeal attacks.

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. Hypersensitivity reactions can occur during or after administration. Because hypersensitivity reactions can be severe and may have symptoms similar to hereditary angioedema attacks, treatment methods should be carefully considered.

Serious arterial and venous thromboembolic events have occurred at recommended doses of C1 esterase inhibitor products in patients with risk factors. Patients with an indwelling venous catheter/access device, history of thromboembolic disease, underlying arteriosclerosis, morbid obesity, immobility, and patients receiving oral contraceptives or certain androgens are at increased risk. Monitor patients with known risk factors for thromboembolic events during and after administration.

Description: C1 esterase inhibitor, recombinant is approved for the treatment of acute angioedema attacks in adolescents and adults with hereditary angioedema (HAE). Effectiveness is not established in HAE patients with laryngeal attacks. HAE is a rare genetic disorder that presents as acute, recurrent attacks of soft tissue skin swelling, abdominal pain, and potentially life-threatening upper airway obstruction. Patients with HAE have low concentrations of endogenous or functional C1 inhibitor, which is a plasma protein that maintains the natural regulation of the contact, complement, and fibrinolytic systems. C1 esterase inhibitor, recombinant is a analog of human C1 esterase inhibitor and is obtained from the milk of rabbits expressing the gene encoding for human C1 esterase inhibitor; therefore, it is contraindicated in patients with a history of allergy to rabbits or rabbit-derived products. C1 esterase inhibitor, recombinant is FDA-approved in pediatric patients as young as adolescents.

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

Maximum Dosage Limits:
-Neonates
Safety and efficacy have not been established.
-Infants
Safety and efficacy have not been established.
-Children
Safety and efficacy have not been established.
-Adolescents
50 International Units/kg/dose (Max: 4200 International Units/dose) IV; Max 2 doses per 24 hours.

Patients with Hepatic Impairment Dosing
Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.

Patients with Renal Impairment Dosing
Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

*non-FDA-approved indication

Monograph content under development

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 a pharmacokinetic study in 12 asymptomatic patients with hereditary angioedema (HAE), clearance was nonlinear (decreasing with increasing dose) over a dose range of 25-100 International Units/kg.


-Route-Specific Pharmacokinetics
Intravenous Route
The following pharmacokinetic parameters were calculated using data from 12 asymptomatic patients (ages not specified) with HAE who received 50 International Units/kg IV C1 esterase inhibitor, recombinant :
Cbaseline = 0.18 +/- 0.12 International Units/mL
Cmax = 1.2 +/- 0.2 International Units/mL
Tmax = 0.31 +/- 0.1 hours
AUC = 3.3 +/- 1 International Units x hr/mL
CL = 1207 +/- 414 mL/hour
t1/2 = 2.4 +/- 0.6 hours
Vss = 3 +/- 0.9 L