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Ruconest

Generic Name: C1-Esterase Inhibitor (Recombinant)
Class: Complement Inhibitors
CAS Number: CAS-80295-38-1

Introduction

Biosynthetic (recombinant DNA-origin) preparation of complement 1 (C1)-esterase inhibitor.1 9 15 31

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 6 7 10 12 19 23

Uses for Ruconest

Hereditary Angioedema

Treatment of acute angioedema attacks in patients with hereditary angioedema (HAE).1 9 15 31 Designated an orphan drug by FDA for this use.3

Clinical studies were conducted principally in patients with abdominal, facial, or peripheral angioedema; efficacy in patients with laryngeal HAE attacks not established.1 37

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).8 11 24 26 27 29 34 36

Ruconest Dosage and Administration

Administration

IV Administration

Administer by slow IV injection.1

Initiate therapy under supervision of a qualified healthcare professional experienced in the treatment of HAE.1 May be self-administered after appropriate training is provided.1

Do not mix or administer 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.1

Reconstitute vial containing 2100 units of C1-esterase inhibitor (recombinant) with 14 mL of sterile water for injection.1 Add diluent slowly to avoid forceful impact on the powder.1 Gently swirl vial to ensure complete dissolution.1 Resultant solution contains 150 units/mL.1 If more than 1 vial is required to obtain a dose, may pool reconstituted contents of multiple vials into a single administration device (i.e., syringe).1

Administer reconstituted solutions immediately or within 8 hours if stored at 2–8°C.1

Rate of Administration

Administer by IV injection over approximately 5 minutes.1

Dosage

Dosage of C1-esterase inhibitor (recombinant) is expressed in international units (IU, units).1 One unit of C1-esterase inhibitor (recombinant) is equivalent to the C1-esterase-inhibiting activity present in 1 mL of pooled normal plasma.1 35

Pediatric Patients

Hereditary Angioedema
Treatment of Acute Angioedema Attacks
IV

Adolescents 13–17 years of age: 50 units/kg (up to 4200 units) for patients weighing <84 kg; 4200 units in patients weighing ≥84 kg.1

May administer a second dose if attack symptoms persist.1

Adults

Hereditary Angioedema
Treatment of Acute Angioedema Attacks
IV

50 units/kg (up to 4200 units) for patients weighing <84 kg; 4200 units in patients weighing ≥84 kg.1

May administer a second dose if attack symptoms persist.1

Prescribing Limits

Pediatric Patients

Hereditary Angioedema
Treatment of Acute Angioedema Attacks
IV

Adolescents 13–17 years of age: Maximum 4200 units per dose; do not exceed 2 doses within a 24-hour period.1

Adults

Hereditary Angioedema
Treatment of Acute Angioedema Attacks
IV

Maximum 4200 units per dose; do not exceed 2 doses within a 24-hour period.1

Cautions for Ruconest

Contraindications

  • Known hypersensitivity to rabbits or rabbit-derived products.1 16

  • Known life-threatening immediate hypersensitivity, including anaphylaxis, to C1-esterase inhibitor preparations.1

Warnings/Precautions

Thrombotic Events

Risk of thromboembolic events.1 28 Reported with plasma-derived C1-esterase inhibitor at recommended doses in patients with underlying risk factors (e.g., presence of indwelling venous catheter/access device, history of thrombosis, underlying atherosclerosis, use of oral contraceptives or certain androgens, morbid obesity, immobility).1 28

Clinical studies to date have not suggested an increased thrombotic risk with C1-esterase inhibitor (recombinant).15 22 32 37

Closely monitor patients with known risk factors for thromboembolism.1

Immunogenicity

Potential for immunogenicity with use of all therapeutic proteins, including C1-esterase inhibitor (recombinant).1 Development of non-neutralizing antibodies to C1-esterase inhibitor (recombinant) reported in clinical trials; however, clinically important effects not observed.1 37

Sensitivity Reactions

Hypersensitivity

Risk of severe hypersensitivity reactions (e.g., urticaria, chest tightness, wheezing, hypotension, anaphylaxis).1 (See Contraindications under Cautions.) Anaphylaxis was reported in an individual with preexisting allergy to rabbit protein.1 37

If hypersensitivity occurs, discontinue drug immediately and initiate appropriate treatment.1 Because symptoms of hypersensitivity can resemble acute attacks of HAE, carefully consider treatment method.1

Specific Populations

Pregnancy

Category B.1

No adequate and well-controlled studies in pregnant women.1 30 Animal studies suggest a possibility of adverse embryofetal effects.1

Lactation

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

Pediatric Use

Safety and efficacy not established in pediatric patients <13 years of age; use of the drug in adolescents 13–17 years of age is supported by data from approval studies.1 25

Geriatric Use

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

Hepatic Impairment

Pharmacokinetics not evaluated in patients with hepatic impairment.1

Renal Impairment

Pharmacokinetics not evaluated in patients with renal impairment.1

Common Adverse Effects

Headache,17 18 20 21 32 nausea,21 32 diarrhea.18 21 32

Interactions for Ruconest

No formal drug interaction studies to date.1 9

Ruconest Pharmacokinetics

Absorption

Plasma Concentrations

Peak plasma concentrations attained in approximately 0.3 hours following a single 50-unit/kg dose in asymptomatic patients.1 32

Distribution

Extent

Not known whether distributed into human milk.1

Elimination

Half-life

Approximately 2.5 hours following a 50-unit/kg dose in asymptomatic patients.1 32

Exhibits nonlinear clearance.1

Elimination half-life has been reported to be shorter than that of plasma-derived C1-esterase inhibitor due to differences in glycosylation.15 22 31 34

Stability

Storage

Parenteral

Powder for Injection

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

May store reconstituted solutions at 2–8°C for up to 8 hours; do not freeze.1

Actions

  • Serine protease inhibitor that principally regulates the activation of the complement and intrinsic coagulation (e.g., contact system) pathways.1 2 6 7 8 10 12 19 22 23 31 34 Also plays a role in the fibrinolytic system.2 6 10 12 14 19 31 34

  • 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 6 7 8 9 10 12 13 32 33

  • 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.8 12 23

  • Binds to and forms irreversible complexes with target protease, which are then inactivated and removed from circulation.1 6 7 9 22 32

  • Biosynthetic (recombinant DNA origin) preparation of human C1-esterase inhibitor produced from the milk of transgenic (genetically modified) rabbits.1 37 Undergoes a series of viral reduction steps (e.g., pasteurization, precipitation, nanofiltration, chromatography) to reduce risk of viral transmission.1 8 15 37

  • Structurally and functionally similar to plasma-derived C1-esterase inhibitor.1 8 32

Advice to Patients

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

  • Importance of instructing patients to read the manufacturer's product information and instructions for use.1

  • Importance of patients immediately informing a clinician if any signs or symptoms of hypersensitivity (e.g., urticaria, chest tightness, wheezing, hypotension, anaphylaxis) occur during or after administration of C1-esterase inhibitor (recombinant).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.

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

C1-Esterase Inhibitor (Recombinant)

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

For injection, for IV use

2100 units

Ruconest

Salix

AHFS DI Essentials. © Copyright 2016, Selected Revisions January 29, 2016. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. Salix Pharmaceuticals, Inc. Ruconest (C1 inhibitor [recombinant]) prescribing information. Raleigh, NC; 2015 Feb.

2. Zuraw BL. Hereditary angioedema. N Engl J Med. 2008; 359:1027-36. [PubMed 18768946]

3. Food and Drug Administration. Orphan designations pursuant to Section 526 of the Federal Food and Cosmetic Act as amended by the Orphan Drug Act (P.L. 97-414). Rockville, MD. From FDA web site.

4. ViroPharma. Cinryze (C1 inhibitor, human) prescribing information. Exton, PA; 2014 Feb.

5. CSL Behring. Berinert (C1 esterase inhibitor, human) prescribing information. Kankakee, IL; 2015 Feb.

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21. Moldovan D, Reshef A, Fabiani J et al. Efficacy and safety of recombinant human C1-inhibitor for the treatment of attacks of hereditary angioedema: European open-label extension study. Clin Exp Allergy. 2012; 42:929-35. [PubMed 22909164]

22. Plosker GL. Recombinant human c1 inhibitor (conestat alfa): in the treatment of angioedema attacks in hereditary angioedema. BioDrugs. 2012; 26:315-23. [PubMed 22946752]

23. Relan A, Bakhtiari K, van Amersfoort ES et al. Recombinant C1-inhibitor: effects on coagulation and fibrinolysis in patients with hereditary angioedema. BioDrugs. 2012; 26:43-52. [PubMed 22171564]

24. Thomas MC, Shah S. New treatment options for acute edema attacks caused by hereditary angioedema. Am J Health Syst Pharm. 2011; 68:2129-38. [PubMed 22058099]

25. Farkas H, Csuka D, Zotter Z et al. Treatment of attacks with plasma-derived C1-inhibitor concentrate in pediatric hereditary angioedema patients. J Allergy Clin Immunol. 2013; 131:909-11. [PubMed 23063583]

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27. Zuraw BL, Bernstein JA, Lang DM et al. A focused parameter update: hereditary angioedema, acquired C1 inhibitor deficiency, and angiotensin-converting enzyme inhibitor-associated angioedema. J Allergy Clin Immunol. 2013; 131:1491-3. [PubMed 23726531]

28. Gandhi PK, Gentry WM, Bottorff MB. Thrombotic events associated with C1 esterase inhibitor products in patients with hereditary angioedema: investigation from the United States Food and Drug Administration adverse event reporting system database. Pharmacotherapy. 2012; 32:902-9. [PubMed 23033229]

29. Longhurst H, Cicardi M. Hereditary angio-oedema. Lancet. 2012; 379:474-81. [PubMed 22305226]

30. Caballero T, Farkas H, Bouillet L et al. International consensus and practical guidelines on the gynecologic and obstetric management of female patients with hereditary angioedema caused by C1 inhibitor deficiency. J Allergy Clin Immunol. 2012; 129:308-20. [PubMed 22197274]

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33. Varga L, Farkas H. rhC1INH: a new drug for the treatment of attacks in hereditary angioedema caused by C1-inhibitor deficiency. Expert Rev Clin Immunol. 2011; 7:143-53. [PubMed 21426252]

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36. Craig T, Aygören-Pürsün E, Bork K et al. WAO Guideline for the Management of Hereditary Angioedema. World Allergy Organ J. 2012; 5:182-99. [PubMed 23282420]

37. US Food and Drug Administration. Summary Basis for Regulatory Action: BLA# BL-125495/0. From FDA website.

38. van Doorn MB, Burggraaf J, van Dam T et al. A phase I study of recombinant human C1 inhibitor in asymptomatic patients with hereditary angioedema. J Allergy Clin Immunol. 2005; 116:876-83. [PubMed 16210064]

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