Hereditary angioedema (HAE) attacks, prophylaxis: Note: Have on-demand therapy available for all patients (breakthrough attacks may occur) (WAO/EEACI [Maurer 2018])
Guideline recommendations:
Short-term/pre-procedural prophylaxis (off-label dose): Cinryze: IV: 20 units/kg or 1,000 units as close as possible to the start of the procedure (WAO/EEACI [Maurer 2018])
Long-term prophylaxis (off-label dose): Haegarda: SUBQ: 40 or 60 units/kg twice weekly; adjust dose based on patient response. Note: SUBQ administration may provide more convenient administration as well as improved steady state plasma concentrations (compared to IV administration) (WAO/EEACI [Maurer 2018]; Longhurst 2017)
Manufacturer's labeling:
Long-term prophylaxis:
Cinryze: IV: 1,000 units every 3 to 4 days; if response is not adequate, doses up to 2,000 units (not exceeding 80 units/kg) every 3 or 4 days may be considered based on individual patient response. Note: Prior to March 2022, the manufacturer's labeling stated that if response was not adequate, doses up to 2,500 units every 3 or 4 days could be considered; however, internal standardization of international units made them reduce this to 2,000 units.
Haegarda: SUBQ: 60 units/kg every 3 or 4 days.
Hereditary angioedema attacks, treatment (Berinert [labeled use]; Cinryze [off-label use]):
Note: To minimize morbidity and mortality, should be self-administered (or administered by a caregiver) at the onset of an attack whenever possible (US HAEA [Busse 2021]).
Berinert: IV: 20 units/kg once as soon as possible after symptom onset. Some experts recommend rounding up the dose to utilize a full vial (500 units/vial) as follows (Craig 2009; Riedl 2016; Zanichelli 2015; Zuraw 2022; manufacturer's labeling):
Weight ≤50 kg: 1,000 units.
Weight >50 kg and ≤75 kg: 1,500 units.
Weight >75 kg and ≤100 kg: 2,000 units.
Weight >100 kg: 2,500 units; single doses up to 3,500 units have been reported.
Repeat dosing : A clinical response is usually observed within ~1 to 2 hours of the initial dose; after ~1 to 2 hours, a second dose may be given if symptoms worsen, but this is rarely needed (Craig 2009; Riedl 2016; Zanichelli 2015; Zuraw 2022; manufacturer's labeling).
Cinryze: IV: 1,000 units once as soon as possible after symptom onset; if symptoms do not resolve or show improvement after 1 hour, administer a second dose of 1,000 units (Zuraw 2010).
There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).
There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).
(For additional information see "C1 inhibitor, concentrate from human plasma: Pediatric drug information")
Note: Products are not interchangeable and product-specific dosing is necessary; use caution.
Hereditary angioedema (HAE) attacks; prophylaxis:
Short-term prophylaxis: Limited data available: Note: If used for preprocedural prophylaxis, administer as close as possible to the beginning of the procedure (WAO/EEACI [Maurer 2018]).
Berinert: Children and Adolescents: IV: 15 to 30 units/kg; administer within 6 hours or immediately prior to significant medical, surgical, or dental procedure (Ajewole 2021; Farkas 2017; Sabharwal 2017; US HAEA [Busse 2021]; WAO/EEACI [Maurer 2018]; Berinert UK prescribing information).
Cinryze:
Children ≥2 to <12 years and weighing 10 to 25 kg: IV: 500 units; administer within 24 hours of the procedure (Cinryze European Medicines Agency 2022).
Children ≥2 to <12 years and weighing >25 kg and Adolescents: IV: 1,000 units; administer within 24 hours of the procedure (Cinryze European Medicines Agency 2022).
Long-term prophylaxis: Note: For long-term prophylaxis, C1 inhibitor therapy is considered first line and subcutaneous administration may provide greater convenience as well as improved steady-state plasma concentrations (compared to IV administration) (US HAEA [Busse 2021]; WAO/EEACI [Maurer 2018]).
Cinryze:
Children 6 to 11 years: IV: 500 units every 3 to 4 days; if inadequate response, may increase dose to 1,000 units every 3 to 4 days (US HAEA [Busse 2021]; manufacturer's labeling).
Children ≥12 years and Adolescents: IV: 1,000 units every 3 to 4 days; if an adequate response is not achieved, doses up to 2,000 units (≤80 units/kg/dose) every 3 to 4 days may be considered (US HAEA [Busse 2021]; manufacturer's labeling). Note: Prior to March 2022, the manufacturer's labeling stated that if response was not adequate, doses up to 2,500 units every 3 or 4 days could be considered; however, internal restandardization of international units by the manufacturer equated to the reduced dose of 2,000 units.
Haegarda: Children ≥6 years and Adolescents: SUBQ: 60 units/kg/dose every 3 or 4 days; in trials, the youngest patient recruited was 8 years of age (Levy 2020; manufacturer's labeling). A lower dose of 40 units/kg/dose has been studied; however, it appears to have a lower response rate (Levy 2020; Longhurst 2017).
Hereditary angioedema (HAE) attacks (abdominal, facial or laryngeal); treatment:
Berinert: Limited data in ages <5 years: Children and Adolescents: IV: 20 units/kg (US HAEA [Busse 2021]; manufacturer's labeling).
Cinryze: Limited data available:
Children ≥2 years:
10 to 25 kg: IV: 500 units; may repeat dose in 1 hour if needed (Cinryze European Medicines Agency 2022).
>25 kg: IV: 1,000 units; may repeat dose in 1 hour if needed (Cinryze European Medicines Agency 2022; Lumry 2013).
Adolescents IV: 1,000 units; may repeat dose in 1 hour if needed; may repeat sooner if treating laryngeal attacks or if initiation of treatment has been delayed (Cinryze European Medicines Agency 2022).
There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).
There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).
Refer to adult dosing.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Kit, Intravenous:
Berinert: 500 units
Solution Reconstituted, Intravenous [preservative free]:
Cinryze: 500 units (1 ea)
Solution Reconstituted, Subcutaneous:
Haegarda: 2000 units (1 ea); 3000 units (1 ea)
No
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Kit, Intravenous:
Berinert: 500 units, 1500 units
Solution Reconstituted, Intravenous:
Cinryze: 500 units (1 ea)
Solution Reconstituted, Subcutaneous:
Haegarda: 2000 units (1 ea); 3000 units (1 ea)
Assistance with procurement and reimbursement of Cinryze is available for health care providers and patients through the CINRYZESolutions program (telephone: 1-877-945-1000) or at http://www.cinryze.com/Cinryze_Solutions/Default.aspx
IV:
Berinert (500 unit vial): Administer intravenously at ~4 mL/minute by a separate infusion line. Use a silicone-free syringe for administration.
Berinert (1,500 unit vial) [Canadian product]: Administer intravenously by slow injection by a separate infusion line.
Cinryze: Administer intravenously at 1 mL/minute (as a guideline, administer 1,000 units over 10 minutes and 500 units over 5 minutes). Use of a silicone-free syringe for administration is recommended.
SUBQ:
Haegarda: For SUBQ injection only in the abdominal area or other SUBQ injection sites. Rotate injection sites. Use a silicone-free syringe for administration.
Self-administration: Following patient training and instructions on self-administration, patient may self-administer treatment (Berinert) or prophylaxis (Cinryze, Haegarda) therapy. Epinephrine should be available during self-administration in the event of an acute, severe hypersensitivity reaction. Patient suffering from an acute laryngeal hereditary angioedema attack and self-administering should be informed to seek immediate medical attention following treatment (potential for airway obstruction to occur).
Parenteral:
IV:
Berinert: A silicone-free syringe is recommended for administration. Administer IV at recommended infusion rate: 4 mL/minute (200 units/minute); use within 8 hours of reconstitution; discard any unused product.
Cinryze: A silicone-free syringe is recommended for administration. Administer IV at recommended infusion rate: 1 mL/minute; use within 3 hours of reconstitution; discard any unused product.
Self-administration: Following patient or caregiver training and instructions on self-administration, patient or caregiver may self-administer treatment (Berinert) or prophylaxis (Cinryze) therapy. Epinephrine should be available during self-administration in the event of an acute, severe hypersensitivity reaction. Any patient suffering from an acute laryngeal hereditary angioedema attack and self-administering should be informed to seek immediate medical attention following treatment (potential for airway obstruction to occur).
SUBQ: Haegarda: A silicone-free syringe is recommended for administration. Administer SUBQ in the abdominal area or other SUBQ injection sites. Rotate injection sites. Use within 8 hours of reconstitution; discard any unused product.
Self-administration: Following patient training and instructions on self-administration, patient may self-administer prophylaxis therapy. Epinephrine should be available during self-administration in the event of an acute, severe hypersensitivity reaction.
Hereditary angioedema:
Berinert: Treatment of acute abdominal, facial, or laryngeal attacks of hereditary angioedema (HAE) in adults and pediatric patients.
Cinryze: Routine prophylaxis against angioedema attacks in adults, adolescents, and pediatric patients ≥6 years of age with HAE.
Haegarda: Routine prophylaxis against angioedema attacks in adults and pediatric patients ≥6 years of age with HAE.
Hereditary angioedema attacks, treatment
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.
>10%:
Central nervous system: Headache (17%)
Dermatological: Skin rash (21%)
Local: Injection site reaction (35%)
Respiratory: Nasopharyngitis (19%)
1% to 10%:
Dermatologic: Pruritus (8%)
Gastrointestinal: Nausea (≥5%), dysgeusia (5%), vomiting (8%)
Hypersensitivity: Hypersensitivity reaction (7%)
Immunologic: Antibody development (9%)
Miscellaneous: Fever (>5%)
<1%, postmarketing, and/or case reports: Anaphylaxis, arterial thromboembolism, chills, erythema at injection site, infusion site reaction, injection site pain, shock, thrombosis, venous thromboembolism
History of anaphylactic or life-threatening hypersensitivity reactions to C1 inhibitor (human) or any component of the formulation
Concerns related to adverse effects:
• Hypersensitivity: Severe hypersensitivity reactions (eg, urticaria, hives, tightness of the chest, wheezing, hypotension, anaphylaxis) may occur during or after administration. Signs/symptoms of hypersensitivity reactions may be similar to the attacks associated with hereditary angioedema, therefore, consideration should be given to treatment methods. In the event of acute or severe hypersensitivity reactions, discontinue treatment immediately.
• Thrombotic events: Serious arterial and venous thromboembolic events have been reported at recommended intravenous doses and when used off-label at doses higher than recommended. Risk factors may include the presence of an indwelling venous catheter/access device, prior history of thrombosis, underlying atherosclerosis, use of oral contraceptives or certain androgens, morbid obesity, and immobility. Consider potential risk of thrombosis with use, and closely monitor patients with preexisting risks for thrombotic events.
Dosage form specific issues:
• Human plasma: Product of human plasma; may potentially contain infectious agents (eg, viruses, the variant Creutzfeldt-Jakob disease [vCJD] agent and, theoretically, the Creutzfeldt-Jakob disease [CJD] agent) that could transmit disease. Screening of donors, as well as testing and/or inactivation or removal of certain viruses, reduces the risk. Infections thought to be transmitted by this product should be reported to the manufacturer.
Other warnings/precautions:
• Self-administration: Due to the potential for airway obstruction, patients suffering from an acute laryngeal hereditary angioedema (HAE) attack and self-administering should be informed to immediately seek medical attention following treatment.
None known.
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
Androgens: May enhance the thrombogenic effect of C1 inhibitors. Risk C: Monitor therapy
Estrogen Derivatives: May enhance the thrombogenic effect of C1 inhibitors. Risk C: Monitor therapy
C1 esterase inhibitor is endogenous to human plasma. Information is available following maternal administration for the prevention and treatment of hereditary angioedema (HAE) attacks, and use has not been associated with adverse pregnancy outcomes due to C1 inhibitor (human) (Baker 2013; Brooks 2020; Fox 2017; Levy 2020; Martinez-Saguer 2010).
C1 inhibitor (human) is the preferred treatment for HAE during pregnancy and may be used for acute attacks, short-term prophylaxis, and long-term prophylaxis. Pre-procedural prophylaxis before uncomplicated natural delivery is not mandatory; however, C1 inhibitor (human) should be immediately available for on-demand use. Pre-procedural prophylaxis is recommended before labor and delivery when symptoms have been recurring frequently during the third trimester and the patient's history includes genital edema caused by mechanical trauma; during forceps delivery or vacuum extraction; before a caesarean section; before surgery or general anesthesia when intubation is required; and before interventions such as chorionic villus sampling, amniocentesis, and induced surgical abortion. Patients with HAE should be monitored closely during pregnancy and for at least 72 hours after delivery (WAO/EEACI [Maurer 2018]).
It is not known if C1 inhibitor (human) is present in breast milk following maternal administration; however, C1 esterase inhibitor is endogenous to human plasma.
According to the manufacturer, the decision to breastfeed during therapy should consider the risk of infant exposure, the benefits of breastfeeding to the infant, and benefits of treatment to the mother. Lactation may increase the frequency of attacks, and patients should be monitored closely. C1 inhibitor (human) is the preferred treatment for HAE during lactation (WAO/EEACI [Maurer 2018]).
Signs/symptoms of hypersensitivity reactions and thrombotic events.
C1 inhibitor, one of the serine proteinase inhibitors found in human blood, plays a role in regulating the complement and intrinsic coagulation (contact system) pathway, and is also involved in the fibrinolytic and kinin pathways. C1 inhibitor therapy in patients with C1 inhibitor deficiency, such as HAE, is believed to suppress contact system activation via inactivation of plasma kallikrein and factor XIIa, thus preventing bradykinin production. Unregulated bradykinin production is thought to contribute to the increased vascular permeability and angioedema observed in HAE.
Onset of action: Cinryze: Increased plasma C1 inhibitor levels observed ~1 hour or less.
Onset of symptom relief: Berinert: Median: 15 minutes per attack; Cinryze: Pediatric patients 6 to 17 years: Median: 30 minutes per attack; for the majority of patient unequivocal symptom relief reported within 1 hour (range: 15 to 135 minutes) (Lumry 2013).
Duration of action: Time to complete resolution of hereditary angioedema (HAE) symptoms: Berinert: Median: 8.4 hours.
Distribution:
Berinert: Vss: Children and Adolescents (6 to 13 years, n=5): 0.02 L/kg (range: 0.017 to 0.026 L/kg); Adults: 0.018 L/kg (range: 0.011 to 0.028 L/kg).
Haegarda: Vd: Children ≥8 years, Adolescents, and Adults: 0.05 L/kg.
Bioavailability: Haegarda: Children ≥8 years, Adolescents, and Adults: 42.7%.
Half-life elimination:
Berinert:
Children and Adolescents (6 to 13 years, n=5): 22 hours (range: 20 to 24 hours).
Adults (following a single dose): 22 hours (range: 17 to 24 hours).
Cinryze: Adults: 56 hours (range: 11 to 108 hours).
Haegarda: Children ≥8 years, Adolescents, and Adults: 69 hours.
Time to peak: Cinryze: ~4 hours; Haegarda: Children ≥8 years, Adolescents, and Adults: 59 hours.
Pediatric:
Cinryze: Compared to adults, children 7 to 11 years of age showed a 30% higher mean AUC and Cmax at a 1,000 unit dose level.
Haegarda: Compared to adults, children (8 to <12 years) and adolescents (12 to <18 years) showed a 11% and 10% higher weight-adjusted clearance, respectively.
Kit (Berinert Intravenous)
500 unit (per each): $4,098.90
Solution (reconstituted) (Cinryze Intravenous)
500 unit (per each): $3,512.16
Solution (reconstituted) (Haegarda Subcutaneous)
2000 unit (per each): $2,465.18
3000 unit (per each): $3,697.78
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