Agents for Acute Treatment of Hereditary Angioedema (HAE)
Agents for Hereditary Angioedema (HAE) Prophylaxis
Blood Coagulation Factors
For storage information, see the specific information within the How Supplied section.Injectable Administration
Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
Reconstitution, product administration, and administration set and needle handling must be done with caution. Place needles in a sharps container, and discard all equipment including any unused product in an appropriate container. C1 inhibitor, human is made from human plasma and may contain infectious agents such as viruses.
The health care professional should have immediate availability of epinephrine injection and other agents used in the treatment of severe anaphylaxis in the event of a serious allergic reaction. If a prior C1 inhibitor dose has been given, question the patient about any symptoms or signs of an adverse reaction after the previous dose. Depending on the adverse reaction, a subsequent dose may be contraindicated.
If self-administration is deemed appropriate for a patient, ensure that the patient/caregiver receives clear instructions and training on intravenous administration in the home or other appropriate setting and has demonstrated the ability to perform intravenous infusions. For Berinert, ensure that the patient/caregiver understands the importance of not treating any attack if it has progressed to a point that they would be unable to successfully prepare or administer Berinert. Advise patients to get immediate medical attention after Berinert receipt if they treated an acute laryngeal hereditary angioedema (HAE) attack because of the potential for airway obstruction. Also, advise patients who treat a suspected abdominal HAE attack to call their healthcare provider after administering Berinert to help exclude the possibility that another potentially serious medical cause may be responsible for their symptoms. Lastly, instruct patients/caregivers to record the lot number from the drug vial label every time they use the drug.
Berinert Administration Instructions
Ensure the C1 inhibitor and Sterile Water for Injection (diluent) vial are at room temperature.
Use either the Mix2Vial transfer set provided or a commercially available double-ended needle and vented filter spike to add 10 mL of Sterile Water for Injection to the C1 inhibitor vial. The diluent will automatically transfer into the C1 inhibitor vial.
Gently swirl the vial until all powder is dissolved. Do not shake the vial.
The reconstituted solution should be clear, colorless, and free from visible particles. Do not use if the solution is cloudy, discolored, or contains particulates.
Unscrew the transfer set.
Draw air into the empty, sterile, silicone-free syringe provided and inject air into the C1 inhibitor vial.
Keep the syringe plunger pressed and invert the system upside down. Pull the plunger back slowly to draw the concentrate into the syringe.
If the patients requires more than 1 vial per dose, use a new transfer set and silicone-free syringe for each C1 inhibitor vial.
Storage: Each vial is single use. Begin administration within 8 hours of reconstitution, provided the solution has been stored at a temperature of up to 30 degrees C (86 degrees F). Store solution in the vial. Do not refrigerate or freeze the reconstituted solution.
Berinert IV Infusion:
Administer via a separate infusion line. Do not mix with other medicinal products.
Use the silicone-free syringe provided in the administration kit.
Infuse intravenously at a rate of approximately 4 mL/minute.
Cinryze Administration Instructions
Bring the C1 inhibitor powder and Sterile Water for Injection (diluent) to room temperature before reconstitution, if refrigerated.
The diluent vial must be accessed prior to the vial of C1 inhibitor powder to prevent loss of vacuum. Use a Mix2Vial transfer device to add 5 mL of Sterile Water for Injection to the C1 inhibitor vial. The vacuum in the C1 inhibitor vial will draw the diluent into the vial.
Gently swirl the vial until all powder is dissolved. Do not shake or vigorously agitate the vial. Reconstituted solution should be colorless to slightly blue and free from visible particles. Do not use if the solution is turbid or discolored. Disconnect the diluent vial, but do not remove the clear end of the Mix2Vial transfer device from the Cinryze vial.
Each reconstituted vial has 5 mL of 100 International Units/mL of C1 inhibitor. One vial is used for a 500-International Unit dose and 2 vials are combined for a 1,000-International Unit dose; for higher doses, combine the content of the appropriate number of vials. Use a new unused Mix2Vial transfer set for each vial. Using a 10 mL silicone-free syringe, inject 5 mL of air into the clear end of the Mix2Vial transfer device and slowly withdraw the 5 mL of reconstituted solution. Using the same syringe, repeat the steps to obtain the second 5 mL from the other vial.
Storage: Use solution within 3 hours of reconstitution. Vials are for single use; discard any unused portion.
Cinryze IV Infusion:
Administer within 3 hours of reconstitution; the solution should be at room temperature.
Do not mix Cinryze with other materials.
Use a silicone-free syringe.
Infuse intravenously at 1 mL/minute.
If self-administration is deemed appropriate for a patient, ensure that the patient/caregiver receives clear instructions and training on subcutaneous administration in the home or other appropriate setting and has demonstrated the ability to perform subcutaneous injections.
Haegarda Administration Instructions
Both the C1 inhibitor vial and the diluent need to be at room temperature before reconstitution. Use either the Mix2Vial transfer set provided with Haegarda or a commercially available double-ended needle and vented filter spike. If the same patient is to receive more than 1 vial of Haegarda, the contents of multiple vials may be pooled in a single silicone-free syringe. Use a new unused Mix2Vial transfer set for each Haegarda vial.
After removing the flip caps and wiping the stoppers with an alcohol swab, peel away the lid to open the Mix2Vial transfer set package.
Place diluent vial on a flat surface and hold the vial tightly. Grip the Mix2Vial transfer set together with the clear package, and push the plastic spike at the blue end of the Mix2Vial transfer set firmly through the center of the stopper of the diluent vial. Carefully remove the clear package without removing the Mix2Vial transfer set or touching the exposed end of the device.
With the C1 inhibitor vial on a flat surface, invert the diluent vial with the Mix2Vial transfer set attached and push the plastic spike of the transparent adapter firmly through the center of the stopper of the C1 inhibitor vial. The diluent will automatically transfer into the C1 inhibitor vial.
Gently swirl the vial until all powder is dissolved. Do not shake. Reconstituted solution should be colorless, clear, and free from visible particles. Do not use if the solution is turbid or discolored.
With 1 hand, grasp the C1 inhibitor side of the Mix2Vial transfer set, and with the other hand grasp the blue diluent side of the Mix2Vial transfer set. Unscrew the set into 2 pieces.
Draw air into an empty, sterile silicone-free syringe. While the C1 inhibitor vial is upright, screw the syringe to the Mix2Vial transfer set and inject air into the C1 inhibitor vial.
While keeping the syringe plunger pressed, invert the system upside down and draw the concentrate into the syringe by pulling the plunger back slowly.
Disconnect the filled syringe by unscrewing it from the Mix2Vial transfer set.
Storage: Each vial is only for single use; no preservative is present. Reconstituted product must be used immediately or within 8 hours of reconstitution and must be stored at room temperature. Do not freeze or refrigerate the solution. Discard any unused portion.
Haegarda Subcutaneous Injection:
The solution should be at room temperature before administration to the patient, and the solution must be administered to the patient within 8 hours of reconstitution.
Do not mix Haegarda with other medicinal products.
Use a silicone-free syringe.
Attach the syringe containing the reconstituted Haegarda solution to a hypodermic needle or subcutaneous infusion set.
Inject in the abdominal area or other subcutaneous injection sites; rotate injection sites.
Administer by subcutaneous injection. Adapt the administration rate to the comfort level of the patient.
anaphylactic shock / Rapid / Incidence not known
pulmonary embolism / Delayed / Incidence not known
stroke / Early / Incidence not known
thrombosis / Delayed / Incidence not known
myocardial infarction / Delayed / Incidence not known
erythema / Early / 2.0-2.0
antibody formation / Delayed / Incidence not known
injection site reaction / Rapid / 3.0-31.0
headache / Early / 7.0-19.0
nausea / Early / 18.0-18.0
pharyngitis / Delayed / 3.5-11.0
rash / Early / 3.5-10.0
vomiting / Early / 10.0-10.0
abdominal pain / Early / 7.0-7.0
fever / Early / 5.0-5.0
dizziness / Early / 2.0-5.0
dysgeusia / Early / 4.7-4.7
infection / Delayed / 1.8-3.5
influenza / Delayed / 3.5-3.5
pruritus / Rapid / 2.0-2.0
chills / Rapid / Incidence not known
Common Brand Names
Berinert, Cinryze, HAEGARDA
Plasma-derived concentrate of C1 esterase inhibitor
Used for the prevention or treatment of angioedema attacks in patients with hereditary angioedema
Not effective for patients with autoantibody-mediated acquired C1 inhibitor deficiency and high titer monoclonal anti-C1 inhibitor antibody concentrations
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.
There are no drug interactions associated with C1 Inhibitor, Human products.
Berinert/Cinryze Intravenous Inj Pwd F/Sol: 500U
HAEGARDA Subcutaneous Inj Pwd F/Sol: 2000U, 3000U
20 International Units/kg IV for Berinert; 2,500 International Units (Max: 100 International Units/kg) IV every 3 days for Cinryze; 60 International Units/kg subcutaneously twice weekly (no sooner than every 3 days) for Haegarda.Geriatric
20 International Units/kg IV for Berinert; 2,500 International Units (Max: 100 International Units/kg) IV every 3 days for Cinryze; 60 International Units/kg subcutaneously twice weekly (no sooner than every 3 days) for Haegarda.Adolescents
20 International Units/kg IV for Berinert; 2,500 International Units (Max: 100 International Units/kg) IV every 3 days for Cinryze; 60 International Units/kg subcutaneously twice weekly (no sooner than every 3 days) for Haegarda.Children
12 years: 20 International Units/kg IV for Berinert; 2,500 International Units (Max: 100 International Units/kg) IV every 3 days for Cinryze; 60 International Units/kg subcutaneously twice weekly (no sooner than every 3 days) for Haegarda.
6 to 11 years: 20 International Units/kg IV for Berinert; 1,000 International Units IV every 3 days for Cinryze; 60 International Units/kg subcutaneously twice weekly (no sooner than every 3 days) for Haegarda.
1 to 5 years: 20 International Units/kg IV for Berinert; safety and efficacy of Cinryze and Haegarda have not been established.
Safety and efficacy have not been established.Neonates
Safety and efficacy have not been established.
Mechanism Of Action
C1 inhibitor is a normal constituent of human blood that functions as a serine protease inhibitor. C1 inhibitor regulates the fibrinolytic system, the complement system, and the contact system (intrinsic coagulation pathway). For example, C1 inhibitor binds to and inactivates proteases that activate the complement system such as C1r, C1s, and mannan-binding, lectin-associated proteases. C1 inhibitor also binds to and inactivates proteases that activate the contact system such as factor XIIa and plasma kallikrein. Lastly, C1 inhibitor binds to and inactivates proteases that activate the fibrinolytic system such as tissue plasminogen activator and plasmin. C1 inhibitor is known as a suicide inhibitor: binding of C1 inhibitor and the protease inactivates both and consumes the C1 inhibitor. Patients with hereditary angioedema (HAE) already have a low baseline C1 inhibitor concentration. The average C1 inhibitor concentration is approximately 30% of normal. So, activation of any protease that is inactivated by C1 inhibitor leads to consumption of the C1 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.
Administration of C1 inhibitor suppresses contact system activation by inactivating plasma kallikrein and factor XIIa, which may modulate vascular permeability by preventing bradykinin generation.
C1 inhibitor, human is administered via the intravenous or subcutaneous routes. 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 baseline C1 inhibitor concentration was 0.31 +/- 0.2 International Units/mL and reached a maximum of 0.68 +/- 0.08 International Units/mL 3.9 hours after a 1,000 International Unit IV dose of Cinryze. Intravenous administration of C1 inhibitor, human increases the plasma concentration of C1 inhibitor within 1 hour. After a 1,000 International Unit IV dose of Cinryze, the mean half-life of functional C1 inhibitor was 56 +/- 36 hours (range, 11 to 108 hours). Biological activity was demonstrated by a subsequent increase in plasma C4 concentrations from a baseline average of 8.1 mg/mL to 8.6 mg/mL 12 hours after a dose. After a single Berinert dose of 500 to 1,500 International Units IV, the half-life ranged from 7.4 to 22.8 hours.Subcutaneous Route
After twice weekly 60 International Units/kg subcutaneous dosing, the half-life was 69 hours (95% CI, 24 to 251 hours). Additional PK parameters included a mean bioavailability of 42.7%, clearance of 1.03 mL/kg/hour, Vd of 0.05 L/kg, and Tmax of 59 hours.
Pregnancy And Lactation
C1 inhibitor, human should only be administered during pregnancy if clearly needed. No harmful effects on 34 neonates and no delivery complications were noted among 20 pregnant women who received human C1 inhibitor with repeated doses up to 3,500 International Units per attack. According to a consensus panel, plasma-derived human C1 inhibitor concentrate is preferred for acute treatment, short-term prophylaxis, or long-term prophylaxis during pregnancy. Also, C1 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 hereditary angioedema symptoms during the pregnancy and/or during previous deliveries. Among 29 pregnancies, the efficacy of C1 inhibitor treatment was consistent before, during, and after pregnancy; all patients received prophylactic C1 inhibitor immediately before delivery. No abortions or drug-related abnormalities were noted.
It is not known if C1 inhibitor, human is excreted in human milk. However, the large molecular weight (105 kD) reduces the risk of excretion in human milk. Use caution when human C1 inhibitor is given to a breast-feeding woman. 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.