C1-Esterase Inhibitor (Human)

Class: Complement Inhibitors
Brands: Cinryze

Introduction

Complement 1 (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.^{1 2 4 5 6 7 8 10 11 12 19}

Uses for C1-Esterase Inhibitor (Human)

Hereditary Angioedema: Prevention of Angioedema Attacks

Used for routine prophylaxis against angioedema attacks in adults and adolescents with hereditary angioedema (HAE).^{1 2 4 8 18} Designated an orphan drug by the FDA.³

Long-term prophylaxis recommended in patients with HAE who have frequent or severe attacks of angioedema.^{2 5 6 11 12 13 15 16 19} Consider C1-esterase inhibitor (human) when standard prophylactic regimens (e.g., attenuated androgens, antifibrinolytic agents) are ineffective, not tolerated, or contraindicated.^{5 8 9 11 12 13}

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Hereditary Angioedema: Treatment of Acute Angioedema Attacks

Although C1-esterase inhibitor concentrates generally are considered treatment of choice for acute attacks of HAE†, C1-esterase inhibitor (Cinryze ) currently is approved in the US only for prevention of such events.^{6 8 14 18 19}

C1-Esterase Inhibitor (Human) Dosage and Administration

Administration

IV Administration

Administer by IV infusion.¹

May be self-administered; however, patients should not attempt to self-administer unless appropriate training is provided by a clinician.¹

Do not mix with any other drug or solution.¹

Vials are for single use only; discard any unused portions.¹

Reconstitution

Allow vials of drug and diluent (sterile water for injection) to reach room temperature prior to reconstitution; protect unreconstituted drug from light.¹

Reconstitute vial containing 500 units of C1-esterase inhibitor (human) with 5 mL of sterile water for injection using a double-ended transfer needle; vacuum will draw in the diluent.¹ Do not use vials that lack a vacuum.¹ Gently swirl until powder is completely dissolved.¹ Resultant solution contains 100 units/mL.¹ Discard the reconstituted solution if turbid or discolored.¹ Prepare a total of 2 vials to obtain a single 1000-unit dose.¹ Use filter needle to withdraw reconstituted contents of both vials into a syringe; remove filter needle and replace with another suitable needle or infusion set prior to administration.¹ Observe proper aseptic technique since the drug contains no preservatives.¹ Administer within 3 hours of reconstitution.¹

Rate of Administration

Infuse IV over 10 minutes at a rate of approximately 1 mL/minute.¹

Dosage

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.^{1 5 8}

Pediatric Patients

Hereditary Angioedema

Routine Prophylaxis of Angioedema Attacks

Adolescents 13–18 years of age: 1000 units every 3–4 days.^{1 20} Some clinicians recommend that the frequency of administration be individualized using the lowest possible frequency to prevent acute attacks.⁵

Adults

Hereditary Angioedema

Routine Prophylaxis of Angioedema Attacks

1000 units every 3–4 days.¹ Other dosing frequencies (e.g., every 5–7 days) have been used.^{5 9 13 15} Some clinicians recommend that frequency of administration be individualized using the lowest possible frequency to prevent acute attacks.⁵

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.¹

Warnings/Precautions

Warnings

Thrombotic Events

Risk of thrombosis with high doses.^{1 17} Serious thromboembolic events, including death, reported in neonates, infants, and children receiving excessive doses up to 500 units/kg of C1-esterase inhibitor (human).^{1 17}

Risk of Transmissible Agents in Plasma-derived Preparations

Potential vehicle for transmission of human viruses (e.g., HIV, hepatitis A virus [HAV], hepatitis B virus [HBV], hepatitis C virus [HCV], parvovirus B19) or other infectious agents (e.g., Creutzfeldt-Jakob disease [CJD]).^{1 9 12 13} Risk substantially reduced with current donor screening practices and viral inactivating procedures; however, possibility of disease transmission still exists.^{1 12 15 19} No cases of parvovirus B19, HBV, HCV, or HIV reported to date with currently available C1-esterase inhibitor (human).^{1 5 8 15}

Weigh risks of viral infection against benefits of therapy.^{1 12} Some experts recommend that patients who receive long-term treatment with blood products be vaccinated against hepatitis A and hepatitis B.^{12 13} Report any suspected infections thought to be associated with C1-esterase inhibitor (human) to the manufacturer at 877-945-1000.¹

Sensitivity Reactions

Hypersensitivity

Risk of severe hypersensitivity reactions (e.g., hives, urticaria, chest tightness, wheezing, hypotension, anaphylaxis).¹ If hypersensitivity occurs, discontinue drug immediately and initiate appropriate treatment.¹ Because symptoms of hypersensitivity can resemble acute attacks of hereditary angioedema, carefully consider treatment method.¹ Epinephrine should be available for immediate use.¹

Specific Populations

Pregnancy

Category C.¹

Lactation

Not known whether C1-esterase inhibitor (human) is distributed into milk.¹ Use with caution.¹

Pediatric Use

Safety and efficacy not established in neonates, infants, and children <13 years of age.^{1 20}

Use in adolescents 13–18 years of age supported by data from approval study.^{1 20}

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether geriatric patients respond differently than younger patients.¹

Common Adverse Effects

Upper respiratory tract infection, sinusitis, rash, headache.^{1 8}

Interactions for C1-Esterase Inhibitor (Human)

No formal drug interaction studies to date.¹

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.^{1 5 6 8 15}

Plasma Concentrations

Peak plasma concentrations attained in approximately 4 hours following a single 1000-unit dose.^{1 8}

Distribution

Extent

Not known whether C1-esterase inhibitor is distributed into milk.¹

Elimination

Half-life

Mean half-life about 56 hours (range 11–108 hours) following a single 1000-unit dose.^{1 8}

Stability

Storage

Parenteral

Powder for Injection

2–25°C; do not freeze.¹ Store in original container and protect from light.¹

Store reconstituted solution at 20–25°C for up to 3 hours.¹

Actions

• Naturally occurring serine protease inhibitor that principally regulates the activation of the complement and intrinsic coagulation (e.g., contact system) pathways.^{1 2 4 5 6 7 8 10 11 12 19} Also plays a role in the fibrinolytic system.^{1 2 6 8 12}

• 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.^{1 2 4 5 6 7 10 11 12 13}

• Blocks both the spontaneous activation of C1 complement and formation of activated C1 complement, suppressing the classical complement pathway.^{1 6 7 12}

• Also exhibits inhibitory effects on plasmin.^{4 11 12}

• Binds to and forms irreversible complexes with target protease; the complexes are then inactivated and removed from circulation.^{1 6 7 8 11}

• Preparation of highly purified C1-esterase inhibitor derived from pooled human plasma.^{1 8 19} Undergoes a series of viral reduction steps (e.g., pasteurization, precipitation, nanofiltration) to reduce risk of viral transmission.^{1 8 19}

Advice to Patients

Importance of discussing potential risks and benefits of therapy with patient prior to prescribing or administering the drug.¹

Importance of using C1-esterase inhibitor (human) only for the condition prescribed.¹

Advise patients not to attempt to self-administer the drug unless appropriate training has been provided by a clinician.^{1 9}

Advise patients to notify a clinician inmediately, if swelling is not controlled following treatment with C1-esterase inhibitor (human).¹

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).^{1 12} Advise patient that current donor screening and viral inactivating procedures have reduced, but not completely eliminated the risk of disease transmission.¹

Advise patients not to use C1-esterase inhibitor (human) if they have experienced life-threatening immediate hypersensitivity reactions (e,g., anaphylaxis).¹ Importance of discontinuing therapy and immediately informing clinician if any symptoms of hypersensitivity (e.g., rash, hives, swelling of the face, chest tightness, fast heartbeat, wheezing, breathing difficulty, turning blue [lips, gum], low BP, faintness, anaphylaxis) occur.¹

Advise patients to bring an adequate supply of C1-esterase inhibitor (human) while traveling and to consult a clinician prior to travel.¹

Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.¹

Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.¹

Importance of informing patients of other important precautionary information.¹ (See Cautions.)

Preparations

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