Dosage Forms
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)
Pharmacology
Mechanism of Action
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.
Pharmacokinetics/Pharmacodynamics
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: Adolescents and Adults: 0.05 L/kg
Onset of Action
Berinert: Onset of symptom relief: 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)
Cinryze: Increased plasma C1 inhibitor levels observed ~1 hour or less
Time to Peak
Cinryze: ~4 hours; Haegarda: 59 hours
Duration of Action
Time to complete resolution of HAE symptoms: Berinert: Median: 8.4 hours
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: Adolescents and Adults: 69 hours
Use in Specific Populations
Special Populations: Children
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
Use: Labeled Indications
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 adolescents with HAE.
Contraindications
History of anaphylactic or life-threatening hypersensitivity reactions to C1 inhibitor (human) or any component of the formulation
Dosage and Administration
Dosing: Adult
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 2,500 units (≤100 units/kg) every 3 or 4 days may be considered based on individual patient response.
Haegarda: SubQ: 60 units/kg every 3 or 4 days.
HAE attacks (abdominal, facial or laryngeal), treatment (Berinert): IV: 20 units/kg
Dosing: Geriatric
Refer to adult dosing.
Dosing: Pediatric
Note: Products are not interchangeable.
Hereditary angioedema (HAE) attacks; routine prophylaxis:
Cinryze: Note: If used for preprocedural prophylaxis, administer as close as possible to the beginning of the procedure (WAO/EEACI [Maurer 2018]).
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 (Lumry 2013)
Children ≥12 years and Adolescents: IV: 1,000 units every 3 to 4 days; if an adequate response is not achieved, doses up to 2,500 units (≤100 units/kg/dose) every 3 to 4 days may be considered
Haegarda: Children ≥12 years and Adolescents: SubQ: 60 units/kg/dose every 3 or 4 days. A lower dose of 40 units/kg/dose has been studied; however, it appears to have a lower response rate (Longhurst 2017); Note: For long-term prophylaxis, SubQ administration may provide greater convenience as well as improved steady-state plasma concentrations (compared to IV administration) (Longhurst 2017; WAO/EEACI [Maurer 2018])
Hereditary angioedema (HAE) attacks (abdominal, facial or laryngeal); treatment:
Berinert: Children ≥5 years and Adolescents: IV: 20 units/kg
Cinryze: Limited data available: Children ≥6 years and Adolescents: IV: 1,000 units; may repeat dose in 1 hour if needed (Lumry 2013)
Reconstitution
Allow vial and diluent (SWFI) to come to room temperature prior to reconstitution. Reconstitute each vial with 5 mL (Cinryze 500 units), 10 mL (Berinert 500 units), 4 mL (Haegarda 2,000 units), 6 mL (Haegarda 3,000 units), or 3 mL (Berinert 1,500 units [Canadian product]) of SWFI using a double-ended transfer needle or the provided transfer set. A silicone-free syringe may be required for reconstitution (refer to manufacturer's labeling). Do not use product if there is no vacuum in the vial. After combining with diluent, gently swirl vial (do not shake) until the powder is completely dissolved. Reconstituted product should be clear and colorless or slightly blue (Cinryze only); do not use if turbid, discolored, or contains particles. The provided filter needle or transfer set should be used to withdraw the reconstituted product. Remove filter needle and attach reconstituted solution to infusion set or appropriate needle for infusion. Do not mix with other medicinal products.
Administration
IV:
Berinert (500 units): Administer intravenously at ~4 mL/minute by a separate infusion line.
Berinert (1,500 units) [Canadian product]: Administer intravenously by slow injection by a separate infusion line.
Cinryze (500 units): Administer intravenously at 1 mL/minute (as a guideline, administer 1,000 units over 10 minutes and 500 units over 5 minutes)
SubQ:
Haegarda (2,000 or 3,000 units): For SubQ injection only in the abdominal area or other SubQ injection sites. Rotate injection sites.
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 (HAE) attack and self-administering should be informed to seek immediate medical attention following treatment (potential for airway obstruction to occur).
A silicone-free syringe may be required for administration (refer to manufacturer's labeling).
Storage
Berinert: Store intact vials at 2°C to 30°C (36°F to 86°F); do not freeze. Store in original carton; protect from light. Use within 8 hours of reconstitution (Canadian labeling recommends immediate use after reconstitution); do not refrigerate or freeze reconstituted solution. Discard any unused product.
Cinryze: Store intact vials at 2°C to 25°C (36°F to 77°F); do not freeze. Store in original carton; protect from light. Use within 3 hours of reconstitution; do not refrigerate or freeze reconstituted solution. Discard any unused product.
Haegarda: Store intact vials at ≤30°C (86°F); do not freeze. Store in original carton; protect from light. Use within 8 hours of reconstitution; do not refrigerate or freeze reconstituted solution. Discard any unused product.
Drug Interactions
Androgens: May enhance the thrombogenic effect of C1 inhibitors. Monitor therapy
Estrogen Derivatives: May enhance the thrombogenic effect of C1 inhibitors. Monitor therapy
Progestins: May enhance the thrombogenic effect of C1 inhibitors. Monitor therapy
Adverse Reactions
>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
Warnings/Precautions
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.
Monitoring Parameters
Signs/symptoms of hypersensitivity reactions and thrombotic events.
Pregnancy
Pregnancy Considerations
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; Fox 2017; 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. Women with HAE should be monitored closely during pregnancy and for at least 72 hours after delivery (WAO/EEACI [Maurer 2018]).
Patient Education
- Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)
- Patient may experience injection site irritation, stuffy nose, sore throat, nausea, vomiting, or bad taste. Have patient report immediately to prescriber signs of blood clots (numbness or weakness on one side of the body; pain, redness, tenderness, warmth, or swelling in the arms or legs; change in color of an arm or leg; chest pain; shortness of breath; fast heartbeat; or coughing up blood), signs of severe cerebrovascular disease (change in strength on one side is greater than the other, difficulty speaking or thinking, change in balance, or vision changes), severe dizziness, passing out, severe headache, mouth discoloration, or fast heartbeat (HCAHPS).
- Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.
Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.
