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C1-Esterase Inhibitor (Human)

Class: Complement Inhibitors
Chemical Name: Human plasma protease C1 inhibitor (C1 esterase inhibitor) (N,O-glycosylated recombinant protein expressed in the mammary gland of transgenic rabbits), glycoform α
Molecular Formula: C2355H3745N613O728S17
CAS Number: 80295-38-1
Brands: Berinert, Cinryze

Medically reviewed by Drugs.com on Dec 23, 2020. Written by ASHP.

Introduction

Preparation of complement 1 (C1)-esterase inhibitor derived from pooled human plasma.

C1-esterase inhibitor is a naturally occurring inhibitor of certain serine proteases (e.g., C1 complement, kallikrein, coagulation factor XIIa, plasmin) involved in the complement, coagulation (contact), and fibrinolytic systems.

Uses for C1-Esterase Inhibitor (Human)

Hereditary Angioedema: Prevention of Angioedema Attacks

Routine prophylaxis against angioedema attacks in adults and adolescents with hereditary angioedema (HAE). Designated an orphan drug by FDA for this use.

One of several agents that may be considered for long-term prophylaxis of HAE attacks; other drugs include attenuated androgens (e.g., danazol) and antifibrinolytic agents (e.g., tranexamic acid).

Consider long-term prophylaxis in patients with HAE who have frequent or severe attacks of angioedema; individualize need for prophylactic therapy based on factors such as severity of disease, frequency of attacks, patient's quality of life, availability of resources, and patient response to on-demand therapy.

Hereditary Angioedema: Treatment of Acute Angioedema Attacks

Treatment of acute abdominal, facial, or laryngeal attacks of HAE in adults and adolescents. Designated an orphan drug by FDA for this use.

Recommended by US and international consensus guidelines as one of several options for treatment of acute HAE attacks; other drugs include ecallantide (plasma kallikrein inhibitor) and icatibant (bradykinin B2-receptor antagonist).

C1-Esterase Inhibitor (Human) Dosage and Administration

Administration

IV Administration

Administer by slow IV injection.

May be self-administered after appropriate training is provided. (See Advice to Patients.)

Do not mix with any other drug or solution. Administer via dedicated IV line.

Vials are for single use only; discard any unused portions.

Reconstitution of Cinryze

Allow vials of drug and diluent (sterile water for injection) to reach room temperature prior to reconstitution.

Reconstitute vial of Cinryzecontaining 500 units of C1-esterase inhibitor (human) with 5 mL of sterile water for injection using transfer set provided by manufacturer or another commercially available double-ended needle; vacuum will draw in the diluent. Do not use vials that lack a vacuum. Gently swirl until powder is completely dissolved. Resultant solution contains 100 units/mL and should be colorless to slightly blue, and free from visible particles. Reconstitute 2 vials to obtain a single 1000-unit dose.

Manufacturer recommends that silicone-free syringes be used for reconstitution and administration of Cinryze.

Administer within 3 hours of reconstitution.

Reconstitution of Berinert

Allow vials of drug and diluent (sterile water for injection) to reach room temperature prior to reconstitution.

Reconstitute vial of Berinert containing 500 units of C1-esterase inhibitor (human) with 10 mL of sterile water for injection using transfer set provided by manufacturer or another commercially available double-ended needle and vented filter spike. Gently swirl vial to ensure complete dissolution. Resultant solution should be colorless, clear, and free from visible particles.

Administer within 8 hours of reconstitution.

Rate of Administration

Cinryze: Administer IV over 10 minutes at a rate of approximately 1 mL/minute.

Berinert: Administer IV at a rate of approximately 4 mL/minute.

Dosage

Dosage of C1-esterase inhibitor (human) is expressed in international units (IU, units). One unit of C1-esterase inhibitor (human) is equivalent to the mean concentration of C1-esterase inhibitor present in 1 mL of normal fresh human plasma.

Pediatric Patients

Hereditary Angioedema
Routine Prophylaxis of Angioedema Attacks
IV

Cinryze: Adolescents 13–18 years of age: 1000 units every 3–4 days. Some clinicians recommend that the frequency of administration be individualized using the lowest possible frequency to prevent acute attacks.

Treatment of Angioedema Attacks
IV

Berinert: Adolescents 13–18 years of age: 20 units/kg. Do not administer doses <20 units/kg; efficacy of 10-unit/kg dose not established.

Adults

Hereditary Angioedema
Routine Prophylaxis of Angioedema Attacks
IV

Cinryze: 1000 units every 3–4 days. Other dosing frequencies (e.g., every 5–7 days) have been used. Some clinicians recommend that frequency of administration be individualized using the lowest possible frequency to prevent acute attacks.

Treatment of Angioedema Attacks
IV

Berinert: 20 units/kg. Do not administer doses <20 units/kg; efficacy of 10-unit/kg dose not established.

Cautions for C1-Esterase Inhibitor (Human)

Contraindications

  • Known life-threatening hypersensitivity (e.g., anaphylaxis) to C1-esterase inhibitor (human) or any ingredient in the formulation.

Warnings/Precautions

Warnings

Thrombotic Events

Risk of thromboembolic events (e.g., MI, cerebrovascular accident, DVT, PE); reported in association with recommended as well as with higher than recommended (e.g., ≥100 units/kg) doses.

Closely monitor patients with known risk factors for thrombosis.

Risk of Transmissible Agents in Plasma-derived Preparations

Potential vehicle for transmission of human viruses (e.g., HIV, hepatitis A virus [HAV], HBV, HCV, parvovirus B19) or other infectious agents (e.g., Creutzfeldt-Jakob disease [CJD]). Risk substantially reduced with current donor screening practices and viral inactivating procedures; however, possibility of disease transmission still exists.

Although cases of suspected viral transmission (including HCV) have been reported with use of Berinert outside the US, manufacturer states no causal relationship to the drug has been established since introduction of a pasteurization step in 1985.

Weigh risks of viral infection against benefits of therapy. Some experts recommend that patients who receive long-term treatment with blood products be vaccinated against hepatitis A and hepatitis B. Report any suspected infections thought to be associated with C1-esterase inhibitor (human) to the manufacturer.

Laryngeal Attacks

Because of potential for airway obstruction, patients who self-administer C1-esterase inhibitor (human) for treatment of a laryngeal attack should seek immediate medical attention in an appropriate healthcare facility after the drug is administered.

Immunogenicity

Potential for immunogenicity with use of all therapeutic proteins, including C1-esterase inhibitor (human). Development of noninhibitory antibodies to C1-esterase inhibitor (human) reported in clinical trials; however, clinically important effects not observed.

Sensitivity Reactions

Hypersensitivity

Risk of severe hypersensitivity reactions (e.g., hives, urticaria, chest tightness, wheezing, hypotension, anaphylaxis). If hypersensitivity occurs, discontinue drug immediately and initiate appropriate treatment. Because symptoms of hypersensitivity can resemble acute attacks of hereditary angioedema, carefully consider treatment method. Epinephrine should be available for immediate use.

Specific Populations

Pregnancy

Category C.

Lactation

Not known whether C1-esterase inhibitor (human) is distributed into milk. Use with caution and only if clearly needed.

Pediatric Use

Safety and efficacy of Cinryze not established in neonates, infants, and children <13 years of age; use in adolescents 13–18 years of age supported by data from approval study.

Safety and efficacy of Berinert not established in pediatric patients ≤12 years of age, although used successfully for the treatment of acute HAE attacks in a limited number of children as young as 6 years of age.

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether geriatric patients respond differently than younger patients.

Hepatic Impairment

Pharmacokinetics not evaluated in patients with hepatic impairment.

Renal Impairment

Pharmacokinetics not evaluated in patients with renal impairment.

Common Adverse Effects

Headache, nausea, rash, vomiting, dysgeusia, abdominal pain.

Interactions for C1-Esterase Inhibitor (Human)

No formal drug interaction studies to date.

C1-Esterase Inhibitor (Human) Pharmacokinetics

Absorption

Onset

Plasma concentrations of C1-esterase inhibitor increase immediately (i.e., within 1 hour) following IV administration; C4 levels subsequently rise 2–24 hours later, indicating consumption of C1-esterase inhibitor and stabilization of the complement activation system.

Plasma Concentrations

Peak plasma concentrations attained in approximately 4 hours following a single 1000-unit dose of Cinryze.

Distribution

Extent

Not known whether C1-esterase inhibitor is distributed into milk.

Elimination

Half-life

Cinryze: Mean half-life about 56 hours (range 11–108 hours) following a single 1000-unit dose in asymptomatic patients.

Berinert: Following administration of single doses (500–1500 units) in patients with mild to severe HAE, half-life approximately 18 hours in adults and 17 hours in pediatric patients 6–13 years of age.

Difference in half-life observed between Cinryze and Berinert may be due to differences in patient populations evaluated (e.g., asymptomatic versus symptomatic).

Special Populations

Limited data on Berinert suggest that half-life of C1-esterase inhibitor (human) may be decreased and clearance increased in pediatric patients <12 years of age compared with adults; clinical importance of such findings not known.

Stability

Storage

Parenteral

Powder for Injection

2–25°C; do not freeze. Store in original container and protect from light.

May store reconstituted solutions at room temperature for up to 3 hours (Cinryze) or up to 8 hours (Berinert); do not refrigerate or freeze.

Actions

  • Naturally occurring serine protease inhibitor that principally regulates the activation of the complement and intrinsic coagulation (e.g., contact system) pathways. Also plays a role in the fibrinolytic system.

  • Regulates contact system activation by inhibiting plasma kallikrein and coagulation factor XIIa; such actions prevent formation of bradykinin, the presumed mediator of increased vascular permeability in HAE.

  • Blocks both the spontaneous activation of C1 complement and formation of activated C1 complement, suppressing the classical complement pathway.

  • Also exhibits inhibitory effects on plasmin.

  • Binds to and forms irreversible complexes with target protease; the complexes are then inactivated and removed from circulation.

  • Preparation of highly purified C1-esterase inhibitor derived from pooled human plasma. Undergoes a series of viral reduction steps (e.g., pasteurization, precipitation, nanofiltration, chromatography) to reduce risk of viral transmission.

Advice to Patients

  • Importance of discussing potential risks and benefits of therapy with the patient prior to prescribing or administering the drug.

  • Importance of clinicians providing clear instructions and training on proper IV administration technique to patients self-administering C1-esterase inhibitor (human). Advise patients to record the lot number of the C1-esterase inhibitor (human) vial used each time they self-administer the drug.

  • Importance of patients not starting self-administration if an HAE attack has progressed to a point where the patient or caregiver is unable to successfully prepare or administer the drug.

  • After self-administering the drug to treat an acute laryngeal attack of HAE, importance of seeking immediate medical attention in an appropriate healthcare facility because of the potential for airway obstruction during such attacks.

  • After self-administering the drug to treat a suspected abdominal HAE attack, importance of contacting clinician to rule out the possibility of other potentially serious causes.

  • Risk of transmission of human viruses (i.e., HAV, HBV, HCV, HIV, parvovirus B19) and other infectious agents (i.e., causative agent for Creutzfeldt-Jakob disease). Advise patient that current donor screening and viral inactivating procedures have reduced, but not completely eliminated, the risk of disease transmission.

  • Importance of discontinuing therapy and immediately informing clinician if any signs or symptoms of hypersensitivity (e.g., rash, hives, chest tightness, wheezing, hypotension, anaphylaxis) occur.

  • Risk of thrombotic events; advise patients to immediately report any signs and symptoms of thrombosis (e.g., new-onset swelling and pain in the limbs or abdomen; new-onset chest pain; shortness of breath; loss of sensation or motor ability; altered consciousness, vision, or speech).

  • Advise patients to bring an adequate supply of C1-esterase inhibitor (human) while traveling and to consult a clinician prior to travel.

  • Advise patients to bring their drug with them when visiting a healthcare provider or facility for an acute HAE attack.

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.

  • Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

C1-esterase Inhibitor

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

For injection, for IV infusion

500 units

Berinert

CSL Behring

Cinryze

Viro Pharma

AHFS DI Essentials™. © Copyright 2021, Selected Revisions January 2, 2014. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

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