Eculizumab

Pronunciation: E-kue-LIZ-ue-mab
Class: Monoclonal antibody

Trade Names

Soliris
- Injection, solution, concentrate 10 mg/mL

Pharmacology

Inhibits terminal complement–mediated intravascular hemolysis in patients with paroxysmal nocturnal hemoglobinuria and complement-mediated thrombotic microangiopathy in patients with atypical hemolytic uremic syndrome by binding to complement protein C5.

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Pharmacokinetics

Absorption

C _max and C _min by week 26 are 194 and 97 mcg/mL, respectively, for patients with paroxysmal nocturnal hemoglobinuria.

Distribution

Vd is 7.7 (paroxysmal nocturnal hemoglobinuria) and 6.14 L (atypical hemolytic uremic syndrome).

Elimination

Half-life is 272 (paroxysmal nocturnal hemoglobinuria) and 291 h (atypical hemolytic uremic syndrome); Cl is 22 (paroxysmal nocturnal hemoglobinuria) and 14.6 mL/h (atypical hemolytic uremic syndrome).

Special Populations

Renal Function Impairment

Pharmacokinetics are not influenced by renal impairment.

Hepatic Function Impairment

Dedicated studies have not been conducted.

Elderly

Dedicated studies have not been conducted.

Children

Pharmacokinetics are not influenced by age.

Gender

Pharmacokinetics are not influenced by gender.

Race

Pharmacokinetics are not influenced by race.

Indications and Usage

Treatment of patients with paroxysmal nocturnal hemoglobinuria to reduce hemolysis; treatment of patients with atypical hemolytic uremic syndrome to inhibit complement-mediated thrombotic microangiopathy.

Contraindications

Unresolved Neisseria meningitidis infection; patients not currently vaccinated against N. meningitidis .

Dosage and Administration

Atypical hemolytic uremic syndrome
Adults

IV 900 mg every 7 days for the first 4 weeks, then 1,200 mg 7 days later for the fifth dose, then 1,200 mg every 14 days thereafter.

Children (younger than 18 y) IV Children 5 kg to less than 10 kg Induction

300 mg weekly for 1 dose.

Maintenance

300 mg at week 2, then 300 mg every 3 weeks.

Children 10 kg to less than 20 kg Induction

600 mg weekly for 1 dose.

Maintenance

300 mg at week 2, then 300 mg every 2 weeks.

Children 20 kg to less than 30 kg Induction

600 mg weekly for 2 doses.

Maintenance

600 mg at week 3, then 600 mg every 2 weeks.

Children 30 kg to less than 40 kg Induction

600 mg weekly for 2 doses.

Maintenance

900 mg at week 3, then 900 mg every 2 weeks.

Children at least 40 kg Induction

900 mg weekly for 4 doses.

Maintenance

1,200 mg at week 5, then 1,200 mg every 2 weeks.

Supplemental dosing Patients receiving plasmapheresis or plasma exchange

If most recent dose was 300 mg, administer 300 mg within 60 min after each plasmapheresis or plasma exchange session. If most recent dose was 600 mg or more, administer 600 mg within 60 min after each plasmapheresis or plasma exchange session.

Patients receiving fresh frozen plasma infusion

If most recent dose was 300 mg or more, administer 300 mg within 60 min prior to each unit of fresh frozen plasma infusion.

Paroxysmal nocturnal hemoglobinuria
Adults

IV 600 mg every 7 days for the first 4 weeks, then 900 mg 7 days later for the fifth dose, then 900 mg every 14 days thereafter.

General Advice

• Administer a meningococcal vaccine at least 2 weeks prior to starting eculizumab therapy and revaccinate according to current medical guidelines.
• Administer eculizumab at the recommended dosage time points, or within 2 days of these time points.
• Administer by IV infusion over 35 min via gravity feed, syringe-type pump, or infusion pump. Do not administer as an IV push or bolus injection.
• Dilute to a final administration concentration of 5 mg/mL by adding the appropriate amount of sodium chloride 0.9% or 0.45%, dextrose 5% in water, or Ringer's lactate injection.
• Ensure thorough mixing by gently inverting the infusion bag. Do not shake.
• Prior to administration, allow admixture to adjust to room temperature. Do not microwave or use heat source other than ambient air temperature.
• If an adverse reaction occurs during administration, slow or stop the infusion as needed. If the infusion is slowed, total infusion time should not exceed 2 h.

Storage/Stability

Store vials under refrigeration, between 36° and 46°F, until time of use. Protect from light. Do not freeze. Admixed solution is stable for 24 h between 36° and 46°F and at room temperature. Discard unused portion.

Drug Interactions

None well documented.

Adverse Reactions

Cardiovascular

Hypertension (47%); tachycardia (40%).

CNS

Headache (44%); insomnia (24%); fatigue (18%); vertigo (15%).

EENT

Nasal congestion (40%); nasopharyngitis (23%); pharyngolaryngeal pain (20%).

GI

Diarrhea, vomiting (40%); nausea (24%); abdominal pain (20%); constipation (7%).

Genitourinary

UTI (24%).

Hematologic

Anemia (35%); leukopenia (24%).

Musculoskeletal

Back pain (19%); pain in extremity (15%); myalgia (7%).

Respiratory

Cough (60%); upper respiratory tract infection (40%); respiratory tract infection, sinusitis (7%).

Miscellaneous

Pyrexia (80%); peripheral edema (18%); infections (14%); herpes simplex infections (7%); flu-like illness (5%); serious and/or fatal meningococcal infection (postmarketing).

Precautions

Warnings Life-threatening and fatal meningococcal infections have occurred in patients treated with eculizumab. Meningococcal infection may become rapidly life-threatening or fatal if not recognized and treated early. Immunize patients with a meningococcal vaccine according to current medical guidelines for patients with complement deficiencies at least 2 weeks prior to administering the first dose of eculizumab. Monitor patients for early signs of meningococcal infections and evaluate immediately if infection is suspected. Eculizumab is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS).

Monitor Monitor patients with paroxysmal nocturnal hemoglobinuria for serious hemolysis and other reactions for at least 8 weeks after discontinuing treatment. Monitor patients with atypical hemolytic uremic syndrome for thrombotic microangiopathy for at least 12 weeks after discontinuing treatment. Monitor for early signs and symptoms of meningococcal infections and evaluate immediately if an infection is suspected. Monitor patient for at least 1 h following completion of the infusion for signs and symptoms of infusion reaction.

Pregnancy

Category C .

Lactation

Undetermined. Immunoglobulin G is excreted in human milk; therefore, it is expected that eculizumab will be present in human milk.

Children

Safety and efficacy not established for the treatment of paroxysmal nocturnal hemoglobinuria. Safety and efficacy for the treatment of atypical hemolytic uremic syndrome appear similar in pediatric and adult patients.

Discontinuation of therapy

Patients with paroxysmal nocturnal hemoglobinuria who discontinue treatment with eculizumab may be at increased risk for serious hemolysis, while patients with atypical hemolytic uremic syndrome may be at increased risk for thrombotic microangiopathy. If thrombotic microangiopathy complications occur, consider reinitiation of treatment, plasmapheresis, plasma exchange, fresh frozen plasma infusion, and/or appropriate organ-specific measures.

Immunogenicity

As with all proteins, there is a potential for immunogenicity.

Infection

Risk of infection, especially with encapsulated bacteria, is increased. Use with caution in patients with systemic infection.

Infusion reactions

As with any protein product, anaphylaxis or other hypersensitivity reactions may occur. Interrupt treatment and administer medical therapy if a severe infusion reaction occurs.

Overdosage

Symptoms

No cases reported.

Patient Information

• Advise patient to read the Medication Guide before using product for the first time and with each treatment.
• Inform patient of the need to receive meningococcal vaccination at least 2 weeks prior to starting therapy.
• Educate patients about signs and symptoms of meningococcal infection and advise them to seek immediate medical attention if they experience the following: confusion, fever and rash, fever of 103°F or higher, headache and fever, headache with nausea or vomiting, headache with stiff neck or stiff back, muscle aches with flu-like symptoms, or eyes sensitive to light.
• Instruct patient to carry the provided patient safety card at all times.
• Inform patients with paroxysmal nocturnal hemoglobinuria of the risk of serious hemolysis when treatment is discontinued, and that they need to be monitored for at least 8 weeks after completion of treatment.
• Inform patients with atypical hemolytic uremic syndrome that there is a potential for thrombotic microangiopathy complications when treatment is discontinued, and that they need to be monitored for 3 months after completion of treatment.
• Inform patients that there may be an increased risk of other types of infections, particularly those due to encapsulated bacteria. Inform patients or caregivers of children receiving treatment for atypical hemolytic uremic syndrome that their child should be vaccinated against Streptococcus pneumoniae and Haemophilus influenzae type b.

Copyright © 2009 Wolters Kluwer Health.