Eculizumab

Class: Complement Inhibitors
ATC Class: L04AA25
VA Class: BL500
Chemical Name: Disulfide with human-mouse monoclonal 5G.1.1 light chain anti-(human complement C5 α-chain) (human-mouse monoclonal 5G1.1 heavy chain) immunoglobulin dimer
CAS Number: 219685-50-4
Brands: Soliris

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  Risk of serious meningococcal infection.^{1 10}

  
  


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  Vaccinate patients with a meningococcal vaccine at least 2 weeks prior to first dose of eculizumab; revaccinate according to current vaccination guidelines.^{1 5} (See Meningococcal Vaccination under Dosage and Administration and also see Infectious Complications under Cautions.)

  
  


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  Monitor patients during therapy for early manifestations of meningococcal infection.¹ Evaluate suspected infections immediately and initiate appropriate antibiotic treatment if indicated.¹

  
  

REMS:

FDA approved a REMS for eculizumab to ensure that the benefits of a drug outweigh the risks. The REMS may apply to one or more preparations of eculizumab and consists of the following: medication guide and elements to assure safe use. See the FDA REMS page () or the ASHP REMS Resource Center ().

Introduction

Terminal complement inhibitor; a recombinant humanized immunoglobulin IgG_2/4 kappa monoclonal antibody.^{1 3 4 10 16 17 19}

Uses for Eculizumab

Paroxysmal Nocturnal Hemoglobinuria

Treatment of paroxysmal nocturnal hemoglobinuria (PNH) to reduce hemolysis (designated an orphan drug by FDA for this use).^{1 2 3 4 10 16 17}

Improves symptoms of PNH by reducing hemolysis, stabilizing hemoglobin concentrations, and reducing transfusion requirements.^{1 3 4 6 10 16 17} Reduced fatigue and improved quality of life also reported.^{1 3 6} Only curative treatment of PNH to date is stem cell transplantation.^{8 10 20}

Eculizumab Dosage and Administration

General

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  Distribute medication guide to every patient prior to first dose and before each subsequent infusion.^{1 21}

  
  

Meningococcal Vaccination

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  Assess vaccination status prior to initiating therapy.¹ Ensure patients are vaccinated against Neisseria meningitidis at least 2 weeks before first dose of eculizumab and revaccinated thereafter based on current immunization guidelines. ^{1 6} (See Infectious Complications under Cautions.)

  
  


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  CDC recommends vaccination with meningococcal (groups A, C, Y and W-135) polysaccharide diphtheria toxoid conjugate vaccine (MCV4) for adults ≤55 years of age, and meningococcal polysaccharide combined vaccine (MPSV4) for adults >55 years of age.⁵ Use of a conjugated quadrivalent vaccine strongly recommended by the manufacturer.^{1 6}

  
  

Risk Minimization Plan

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  A risk minimization plan has been developed to monitor adverse events associated with eculizumab, including meningococcal infections.^{6 11 12 13} (See Boxed Warning and also see Infectious Complications under Cautions.)

  
  


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  Patients being treated with eculizumab will automatically be enrolled in a registry (Soliris Safety Registry) established to monitor long-term safety of the drug.^{6 12 13} Enrollment in a separate Global PNH Patient Registry that monitors the natural history and management of PNH is optional.^{6 10 14} For additional information, consult registry website at .¹⁴

  
  


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  Eculizumab is available through a flexible distribution program.^{6 7} Drug can be obtained through the Soliris OneSource Program, a manufacturer-sponsored support service that facilitates access to therapy; patient education, reimbursement support, and coordination of care also provided.⁷ Information about the Soliris OneSource Program available at 888-SOLIRIS (888-765-4747) or at .⁷

  
  

Administration

IV Administration

For solution and drug compatibility information, see Compatibility under Stability.

Administer by IV infusion using gravity flow or a controlled-infusion device (e.g., infusion pump or syringe pump).¹ Do not administer by rapid IV injection such as IV push or bolus.¹

Allow solution to warm to room temperature before administering to patient.¹ Do not heat (e.g., in a microwave).¹

Monitor patients for hypersensitivity or infusion-related reactions during and for 1 hour following each infusion.¹ Slow infusion rate or discontinue therapy if adverse reaction occurs.¹ (See Hypersensitivity Reactions under Cautions.)

Dilution

Must dilute eculizumab concentrate for injection prior to administration.¹

Withdraw appropriate dose of eculizumab from vial, add to infusion bag, and dilute with 5% dextrose, 0.9% sodium chloride, 0.45% sodium chloride, or Ringer's injection to provide a final concentration of 5 mg/mL.^{1 6}

To prepare a 600-mg dose, withdraw 60 mL of the concentrate for injection (containing 10 mg/mL) and add to 60 mL of diluent in an infusion bag to achieve a final admixture volume of 120 mL (i.e., 5 mg of eculizumab per mL).^{1 6} To prepare a 900-mg dose, withdraw 90 mL of the concentrate for injection (containing 10 mg/mL) and add to 90 mL of diluent in an infusion bag to achieve a final admixture volume of 180 mL (i.e., 5 mg of eculizumab per mL).^{1 6}

Gently invert diluted solution to mix completely; do not shake.¹

Vials are for single use only.¹ Discard any unused portion after preparing dose.¹

Rate of Administration

Administer by IV infusion over 35 minutes; if infusion must be slowed due to adverse effects, do not exceed 2 hours total infusion time.¹

Dosage

Adults

Paroxysmal Nocturnal Hemoglobinuria

IV

Initially, 600 mg every 7 days for 4 weeks, followed by one dose of 900 mg 7 days later (week 5), then 900 mg every 14 days thereafter.^{1 6}

Doses should be administered at the recommended time points, or within 2 days of each time point, to achieve maximum benefit.^{1 16 17} A few patients have required a decrease in the recommended dosage interval (i.e., from 14 to 12 days) to achieve optimal reduction in hemolysis (as determined by reduction in LDH levels).¹

Prescribing Limits

Adults

Paroxysmal Nocturnal Hemoglobinuria

IV

Total infusion time beyond 2 hours not recommended.¹

Cautions for Eculizumab

Contraindications

Active, severe N. meningitidis infection.¹

Patients not currently vaccinated against N. meningitidis.¹

Warnings/Precautions

Warnings

Infectious Complications

Eculizumab increases susceptibility to infections caused by encapsulated bacteria, particularly meningococcal infections.^{1 10} Serious infections (e.g., meningococcal sepsis) reported in some patients receiving eculizumab.^{1 6} Do not initiate therapy in patients with active meningococcal infections or in those not immunized against N. meningitidis.¹ (See Boxed Warning.) Use caution in patients with other systemic infections.¹

Patients must be vaccinated against N. meningitidis at least 2 weeks prior to the first dose of eculizumab and revaccinated thereafter according to current vaccination guidelines.^{1 5 6} Vaccination may not prevent meningococcal infection; cases of meningococcal septicemia reported in patients treated with eculizumab despite immunization.^{1 6 10}

Monitor for manifestations of infection during therapy; strongly consider discontinuance in patients who develop serious infection, and initiate appropriate antibiotic treatment.¹

Hemolysis

Possible risk of serious hemolysis following treatment discontinuance due to eculizumab-induced increase in PNH erythrocytes.^{1 6 10}

Monitor patients ≥8 weeks after discontinuing therapy for manifestations of serious hemolysis, consisting of elevated serum LDH concentrations with any of the following: >25% absolute decrease in PNH clone size (in the absence of transfusional dilution) in ≤1 week; hemoglobin concentration <5 g/dL or decrease in hemoglobin of >4 g/dL in ≤1 week; angina; altered mental status; 50% increase in S_cr; or thrombosis.¹

Treatment of serious hemolysis may consist of packed RBCs transfusion, exchange transfusion (if PNH erythrocytes are >50% of total RBCs by flow cytometry), anticoagulation, corticosteroids, or reinitiation of eculizumab.^{1 6 9}

Hypersensitivity Reactions

Infusion reactions requiring discontinuance of eculizumab not observed during clinical trials, but hypersensitivity or anaphylaxis possible with all protein products.^{1 6}

Monitor for infusion-related reactions during treatment; if hypersensitivity or other serious reaction develops, interrupt eculizumab infusion and initiate appropriate treatment.¹

General Precautions

Thrombosis Prevention and Management

High risk of venous thrombosis (potentially life-threatening or fatal) in patients with PNH.^{4 8 18 20} Effects of withdrawing anticoagulant therapy in patients receiving eculizumab not established.¹ Treatment with eculizumab should not affect concomitant anticoagulant management.¹

Immunogenicity

Low titers of antibodies to eculizumab reported infrequently; relationship between development of antibodies and clinical response not observed.^{1 3 6}

Laboratory Monitoring

Serum LDH concentrations and flow cytometry may be used to monitor response to therapy (e.g., hemolysis, PNH erythrocytes).^{1 10} In a few patients in clinical studies, a reduction in LDH levels was maintained only after a decrease in the eculizumab dosage interval from 14 to 12 days.^{1 6}

Following withdrawal of therapy, monitor serum LDH concentrations and other parameters to detect serious hemolysis.^{1 6} (See Hemolysis under Cautions.)

Specific Populations

Pregnancy

Category C.¹

Lactation

Not known whether eculizumab is distributed into human milk.¹ (See Extent under Pharmacokinetics.) Caution if used in nursing women.¹

Pediatric Use

Safety and efficacy not established in children <18 years of age.¹

Geriatric Use

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

Common Adverse Effects

Headache,^{1 3 4 21} nasopharyngitis,^{1 3 4} back pain,^{1 3 21} nausea,^{1 3 4 21} fatigue,¹ cough,¹ herpes simplex infections,¹ sinusitis,¹ respiratory tract infection,¹ constipation,¹ myalgia,¹ pain in extremity,¹ influenza-like illness.¹

Interactions for Eculizumab

No formal drug interaction studies to date.¹

Eculizumab Pharmacokinetics

Absorption

Plasma Concentrations

Plasma concentrations ≥35 mcg/mL required to block complement.^{16 17}

Duration

Complement activity inhibited for ≤2 weeks following single dose.¹⁹

Reduction of hemolysis (as determined by reduction in LDH concentrations) maintained at least 52 weeks in open-label study.^{1 17}

Distribution

Extent

Human IgG crosses placenta and is distributed into milk.¹ Potential exists for eculizumab to cross placenta and distribute into milk.¹

Elimination

Metabolism

Metabolic fate of immunoglobulins not well characterized; catabolized in various tissues via diffuse cellular processes.¹⁵

Elimination Route

Minimal excretion in urine expected due to large molecular size.^{1 15} Small quantities of immunoglobulin found in bile.¹⁵

Half-life

Approximately 272 hours.¹

Stability

Storage

Parenteral

Injection

2–8°C.¹ Do not freeze or shake.¹ Store in manufacturer's carton and protect from light.¹

Following dilution, stable for 24 hours at 2–8°C or at room temperature.¹

Single-use vials do not contain preservative.¹ Discard unused portions.¹

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

Solution Compatibility¹

Compatible
Dextrose 5% in water
Sodium chloride 0.45 or 0.9%
Ringer's injection

Actions

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  IgG_2/4 kappa immunoglobulin containing human framework (i.e., variable and constant regions) and murine complementarity-determining regions.¹

  
  


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  Hemolysis in PNH results from a genetic deficiency of glycosylphosphatidylinositol (GPI)-linked complement inhibitor CD-59 on the surface of RBCs (PNH erythrocytes), which renders such erythrocytes sensitive to persistent terminal complement-mediated destruction.^{1 4 8 9 10 18 20}

  
  


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  Eculizumab prevents destruction of PNH erythrocytes that lack complement protection with CD-59 by binding specifically and with high affinity to complement protein C5, preventing activation of terminal complement components (cleavage to C5a and C5b and subsequent formation of C5b–C9 terminal complement complex).^{1 3 10 19}

  
  

Advice to Patients

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  Importance of patients fully understanding risks and benefits of therapy prior to initiation.^{1 21}

  
  


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  Risk of serious meningococcal infections and other systemic infections.^{1 21} Importance of immunization against meningococcal infections at least 2 weeks prior to first dose and revaccination as recommended while on therapy.^{1 6 21} Advise patients that vaccination may not prevent infection; importance of informing clinician immediately if manifestations of meningococcal infection (moderate to severe headache with nausea, vomiting, fever, stiff neck or back; temperature ≥103°F; fever with rash; confusion; severe muscle aches with flu-like symptoms; light sensitivity) develop.^{1 21}

  
  


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  Notify clinician immediately if a dose is missed.^{1 21} Discontinuance of therapy may cause sudden hemolysis; importance of monitoring for hemolysis for ≥8 weeks following treatment discontinuance.^{1 21}

  
  


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  Importance of reading medication guide provided by manufacturer before each infusion.^{1 21} Advise patients to carry patient safety card (describing symptoms requiring immediate medical attention) at all times.^{1 21}

  
  


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  Importance of women informing their clinicians if they are or plan to become pregnant or plan to breast-feed.^{1 21}

  
  


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  Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as concomitant illnesses.^{1 21}

  
  


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  Importance of informing patients of other important precautionary information.^{1 21} (See Cautions.)

  
  

Preparations

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

Eculizumab

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Parenteral	For injection, concentrate, for IV infusion only	10 mg/mL (300 mg)	Soliris (preservative-free)	Alexion

Disclaimer

This report on medications is for your information only, and is not considered individual patient advice. Because of the changing nature of drug information, please consult your physician or pharmacist about specific clinical use.

The American Society of Health-System Pharmacists, Inc. and Drugs.com represent that the information provided hereunder was formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. and Drugs.com make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to such information and specifically disclaims all such warranties. Users are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and the information is provided for informational purposes only. The entire monograph for a drug should be reviewed for a thorough understanding of the drug's actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. and Drugs.com do not endorse or recommend the use of any drug. The information is not a substitute for medical care.

AHFS Drug Information. © Copyright, 1959-2011, Selected Revisions October 27, 2011. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. Alexion Pharmaceuticals, Inc. Soliris (eculizumab) concentrated solution for intravenous infusion prescribing information. Chesire, CT; 2007 June.

2. 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 (). Accessed 2007 Jul 11.

3. Hillmen P, Young NS, Schubert J et al. The complement inhibitor eculizumab in paroxysmal nocturnal hemoglobinuria. N Engl J Med. 2006; 355:1233-43. [PubMed 16990386]

4. Young NS, Antonioli E, Rotoli B et al. Safety and efficacy of the terminal complement inhibitor eculizumab in patients with paroxysmal nocturnal hemoglobinuria: SHEPHERD phase III clincial study results. Paper presented at American Society of Hematology Annual Meeting. Orlando, FL: 2006 Dec 9.

5. Centers for Disease Control and Prevention. Prevention and control of meningococcal disease recommendations of the advisory committee on immunization practices (ACIP). MMWR. 2005;54 (No. RR-7):1-21.

6. Alexion Pharmaceuticals, Cheshire, CT: Personal communication.

7. The Soliris (eculizumab) OneSource Program for Healthcare Professionals and Patients. Soliris website. Available at: . Accessed 2007 July 25.

8. Hillmen P, Lewis SM, Bessler M et al. Natural history of paroxysmal nocturnal hemoglobinuria. N Engl J Med. 1995; 333:1253-8. [PubMed 7566002]

9. Parker C, Omine M, Richards S et al. Diagnosis and management of paroxysmal nocturnal hemoglobinuria. Blood. 2005; 106:3699-709. [PubMed 16051736]

10. Hill A, Richards SJ, Hillmen P. Recent developments in the understanding and management of paroxysmal nocturnal hemoglobinuria. Br J Haematol. 2007; 137:181-92. [PubMed 17408457]

11. US Food and Drug Administration. FDA approves first-of-its-kind drug to treat rare blood disorder. FDA News. P07-47. 2007 Mar 16. Available at: . Accessed 2007 Jul 5.

12. Pazdur R. Approval letter for eculizumab (application number 125166). Rockville, MD: US Food and Drug Administration; 2007 Mar 16. From FDA website ().

13. Alexion Pharmaceuticals. FDA approves Alexion's Soliris for all patients with PNH: first therapy approved for this rare and life-threatening blood disease. Cheshire, CT; 2007 Mar 16. Press release from website ().

14. PNH Source. PNHSource website. Available at: . Accessed 2007 Aug 15.

15. Lobo ED, Hansen RJ, Balthasar JP. Antibody pharmacokinetics and pharmacodynamics. J Pharm Sci. 2004; 93:2645-68. [PubMed 15389672]

16. Hillmen P, Hall C, Marsh JCW et al. Effect of eculizumab on hemolysis and transfusion requirements in patients with paroxysmal nocturnal hemoglobinuria. N Engl J Med. 2004; 350:552-59. [PubMed 14762182]

17. Hill A, Hillmen P, Richards SJ et al. Sustained response and long-term safety of eculizumab in paroxysmal nocturnal hemoglobinuria. Blood. 2005; 106:2559-65. [PubMed 15985537]

18. In: Lee RG, Bithell TC, Foerster J et al, eds. Winthrobe's clinical hematology. 9th ed. Malver, PA: Lea and Febiger; 1993:1232-44.

19. Anon. Eculizumab: 5G1.1, h5G1.1, long-acting anti-C5 monoclonal antibody 5G1-1, long-acting anti-C5 monoclonal antibody 5G1.1. Drugs R D. 2007; 8:61-8.

20. Socie G, Jean-Yves M, de Gramont A et al. Paroxysmal nocturnal haemoglobinuria: long term follow-up and prognostic factors. Lancet. 1996; 348:573-77. [PubMed 8774569]

21. Alexion Pharmaceuticals, Inc. Soliris (eculizumab) medication guide. Chesire, CT; 2007 Jun.

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