Q. What is the clinical indication for eculizumab?

On June 27, 2019, eculizumab, or Soliris, became the first FDA approved treatment for anti-aquaporin-4 (AQP4) antibody positive neuromyelitis optica spectrum disorder (NMOSD) in adults. Eculizumab had previously been FDA approved for treatment of paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic uremic syndrome (aHUS), and anti-acetylcholine receptor antibody positive generalized myasthenia gravis (gMG).

Q. What is the mechanism of action of eculizumab?

Histologic studies in NMO lesions have shown pronounced complement activation, eosinophilic infiltration, and vascular fibrosis that differ from prototypical multiple sclerosis lesions. The pathophysiology of NMOSD is primarily a humoral immune system mediated attack on AQP4. Eculizumab is a humanized monoclonal antibody that inhibits the terminal complement protein C5 to prevent its cleavage into C5a and C5b. The exact mechanism for its efficacy in NMOSD is unknown, but is believed to be related to inhibition of the formation of the membrane attack complex mediated by C5b.

Q. What did the clinical trials of eculizumab in neuromyelitis optica show?

Eculizumab was first studied in 14 AQP4 antibody positive neuromyelitis optica patients in an open-label trial. This trial showed positive findings in reducing relapses as well as an improvement in median EDSS scores compared with pretreatment.

Because of these results, a subsequent randomized, double-blinded, placebo-controlled phase III time-to-event trial over 4 years, Prevention of Relapses in Neuromyelitis Optica (PREVENT), was performed. The majority of patients in both the eculizumab (78%) and placebo (72%) groups continued on prior immunotherapy including glucocorticoids, azathioprine, and mycophenolate mofetil. A significantly smaller proportion of patients in the eculizumab group experienced an adjudicated relapse compared with the placebo group (3% vs 43%). Change from baseline in disability measures including EDSS, modified Rankin scale, and Hauser Ambulation Index did not significantly differ between the two groups.

Q. How is eculizumab administered in AQP4 antibody positive NMOSD?

Eculizumab is supplied in 300 mg vials (30 mL of a 10 mg/mL solution) and is administered via intravenous infusion over 35 minutes. We suggest administration at an infusion center to allow for patient monitoring given the relative newness of the medication for this indication.

Dosing regimen consists of:

  • 900 mg per dose, once weekly for the first 4 weeks, followed by
  • 1200 mg for the fifth dose 1 week later, followed by
  • 1200 mg per dose every 2 weeks afterwards

Q. When does dosing adjustments need to be made?

Supplemental dosing is required in patients undergoing plasma exchange as it can increase the clearance of eculizumab by approximately 250-fold. An additional 600 mg per each plasma exchange session is recommended to be given within 60 minutes after each plasma exchange session.

Q. What are the pharmacokinetics of eculizumab?

The half-life of eculizumab ranges from 270 to 414 hours. Steady state is achieved 4 weeks after starting eculizumab treatment. Age, race, and renal function do not affect pharmacokinetics of eculizumab.

Q. What are the pharmacodynamics of eculizumab?

While the PREVENT trial did not pharmacodynamics of eculizumab in APQ4 antibody positive NMOSD patients, pharmacodynamics of eculizumab has been studied in other disease states. An inverse relationship appear to exist between eculizumab concentration and C5 complement blockade. Increased dose of eculizumab has also been shown to correlate with longer period of complement activity suppression. One study in patients with hemolytic anemia found that increasing the dose from 2mg/kg to 4mg/kg to 8mg/kg led to increased drug effect from 2 days, to 7-14 days, to 11-21 days.

Q. What are the major adverse effects of eculizumab?

Headache, nausea, and dizziness were the most common side effects reported in the open label trial of eculizumab in APQ4 antibody positive neuromyelitis optica patients. In the PREVENT trial, upper respiratory tract infections, headache, and nasopharyngitis were the most common side effects. With the exception of upper respiratory tract infections, percentages of patients experiencing these effects were comparable in the eculizumab group and the placebo group. Other side effects such as nausea, diarrhea, urinary tract infection, limb pain, and vomiting were also seen in both groups.

  Eculizumab group* Placebo group+
Upper respiratory tract infection 29% 13%
Headache 23% 23%
Nasopharyngitis 21% 19%
Nausea 17% 26%
Diarrhea 16% 15%
Urinary tract infection 14% 21%
Limb pain 11% 21%
Vomiting 10% 17%
*78% patients continued on prior immunotherapy: 17% glucocorticoids alone, 39% azathioprine, 18% mycophenolate mofetil, 5% other
+72% patients continued on prior immunotherapy: 23% glucocorticoids alone, 28% azathioprine, 17% mycophenolate mofetil, 4% other

Although no cases of meningococcal infection were reported in the PREVENT trial, eculizumab’s mechanism of action increases risk of infection, especially from encapsulated bacteria. Eculizumab is thus contraindicated in patients with unresolved serious Neisseria meningitidis infection and patients who are not currently vaccinated against . Because of this risk, providers must enroll in a Risk Evaluation and Mitigation Strategy (REMS) program to prescribe eculizumab.

Q. What pretesting and monitoring labs are recommended for eculizumab?

Prior to starting: complete blood count with differential, comprehensive metabolic panel. Monitoring labs: complete blood count with differential, comprehensive metabolic panel. Although urinalysis and lactate dehydrogenase (LDH) are monitored for patients with paroxysmal nocturnal hematuria, this is not necessary for AQP4 antibody positive NMOSD. A Mayo Clinic Eculizumab monitoring panel (ECUMP) for C5 function and C5 antigen is available to determine the impact of eculizumab on the complement system but as no specific guidelines are available for its use with AQP4 antibody positive NMO, it is not currently recommended.

As leukopenia, lymphopenia, and transaminitis were noted with eculizumab for other indications, we suggest routine monitoring labs as above. A reduction in absolute lymphocyte count less than 0.5k/µL or an elevation of AST or ALT greater than 2 times the upper limit of normal should prompt discontinuation of therapy.

Q. What vaccines are recommended prior to starting eculizumab?

Required: Meningococcal vaccines (serogroups ACWY and B)
All patients are recommended to receive meningococcal vaccination at least 2 weeks prior to starting eculizumab. Both MenACWY and MenB vaccines are required to cover ACWY and B serogroups. There are two MenACWY vaccine products, Menactra® and Menveo®. These products are interchangeable within the MenACWY series, however Menactra must be separated by 4 weeks from the Pneumococcal conjugate vaccine (Prevnar-13). Therefore, we recommend Menveo for the MenACWY “primary series” at 0 and 8 weeks to prevent the Prevnar13/Menactra interaction.

There are two MenB vaccine products available: MenB-4 (Bexsero®) and MenB-FHbp (Trumenba®). Bexsero is a 2-dose series administered at least 1 month apart. Trumenba® is a 3-dose series administered at 0, 1-2, and 6 months. Dose 3 not needed if dose 2 is administered at least 6 months after dose 1. Bexsero and Trumenba are not interchangeable (the same product should be used for all doses in series). Trumenba is not available on formulary at the Cleveland Clinic.

Vaccination reduces but does not eliminate the risk of meningococcal infections. A review of eculizumab recipients in the United States from 2008 to 2016 identified 16 cases of meningococcal disease with eleven cases caused by nongroupable Neisseria meningitidis not impacted by vaccination. Fourteen patients had received at least one dose of vaccine. All cases had meningococcemia. Six patients had meningitis.

Recommended: Streptococcus pneumoniae and Haemophilus influenzae type b (Hib)
In previously unvaccinated patients, consider vaccine administration for other encapsulated organisms. This is due to a theoretical increased risk of infection while on eculizumab. The Advisory Committee on Immunization Practices (ACIP) recommend pneumococcal (for all patients) and Hib (for children 12-59 months) vaccination for patients with complement deficiencies; the only ACIP recommendation specific to eculizumab is meningococcal.

We recommend initiation of vaccination series at least 2 weeks prior to the first eculizumab dose to optimize immune response.

  1. Haemophilus influenzae type b (ActHIB®)
  2. Pneumococcal conjugate vaccine (Prevnar-13; PCV13)
  3. Pneumococcal polysaccharide vaccine (Pneumovax-23; PPSV23)

Recommended vaccination administration schedule
Refer to CDC/ACIP for further guidance. Your institution/facility may have alternative brand names for the vaccinations suggested below on formulary.

Pre-Dose Vaccinations for Duration of Eculizumab Therapy1
≥ 2 weeks prior to first dose F
8-12 weeks 1 year 2-3 years 5 years Booster Every 2-3 years Booster Every 5 years After age 65
MenACWY (Menveo)
MenB (Bexsero)2
- Hib (ActHIB)1 - PCV131
MenACWY (Menveo)
MenB (Bexsero)2
- PPSV233
MenB (Bexsero)1 MenB (Bexsero)1 MenB (Bexsero)1
MenACWY (Menactra)
MenB (Bexsero) MenACWY (Menactra) PPSV233
1These recommendations presume no history of vaccination. Refer to CDC/ACIP guidance for catch-up vaccination for patients with a history of meningococcal, pneumococcal, or Hib vaccination.
2MenB(Bexsero) minimum age: 10 years old
3PPSV23 minimum age: 2 years old

If unable to administer MenACWY and MenB vaccinations at least 2 weeks prior to first dose of eculizumab, administer vaccines with the first dose. Antimicrobial prophylaxis is recommended to prevent meningococcal disease for a minimum of 2 weeks following vaccination

Adults Pediatrics2
Amoxicillin 875 mg PO BID x 2 weeks Amoxicillin 10 mg/kg/dose (max 250 mg) PO BID x 2 weeks
Azithromycin 500 mg PO QD x 2 weeks Ciprofloxacin 10 mg/kg/dose (max 500 mg) PO BID x 2 weeks
Ciprofloxacin 500 mg PO QD x 2 weeks Azithromycin 5 mg/kg/dose (max 250 mg) PO QD x 2 weeks
Cefdinir 300 mg PO BID x 2 weeks1 2use oral liquid or round to nearest tablet size
1Cefdinir is a last-line option for meningococcal prophylaxis in patients unable to tolerate oral penicillins, fluoroquinolones, or macrolides

Q. Is antimicrobial prophylaxis indicated during treatment?

Meningococcal disease in patients receiving eculizumab despite vaccination has been reported, therefore clinicians may consider recommending antimicrobial prophylaxis for the duration of treatment:

  1. Adults: penicillin VK 250 mg orally twice daily or azithromycin 250 mg orally daily for penicillin allergic patients
  2. Pediatrics: amoxicillin 10 mg/kg (max 250 mg) orally twice a day or azithromycin 5 mg/kg (max 250 mg) orally daily

The effectiveness, safety, or risk for development of penicillin-resistant meningococcal infections have not been established.

Q. What is the effect on pregnancy and breastfeeding?

Safety of eculizumab during pregnancy and lactation has not been studied in NMOSD patients and is thus not routinely used in this population. Limited data for other clinical indications of eculizumab have not identified specific adverse developmental outcomes. One study of pregnant patients with paroxysmal nocturnal hemoglobinuria, for example, found that all 69 children met developmental milestones for vision, hearing, locomotion, fine-motor skills, behavior, and physical health. Only one child had slightly delayed speech. Eculizumab in concentration below therapeutic range has been detected in cord blood in patients on treatment for paroxysmal nocturnal hemoglobinuria. One study examining 10 breast milk samples found no detectable eculizumab.

Q. How does eculizumab compare to other therapies for antibody positive NMOSD?

There are no head to head clinical trials comparing different therapies for antibody positive NMOSD.

Prior to the FDA approved medications for AQP4 antibody positive NMOSD, treatments included rituximab, azathioprine, and mcyophenolate mofetil. Factors that may influence selecting a therapy can include route of administration, FDA approval, frequency of administration (every 2 weeks for eculizumab versus every 6 months for anti-CD20 therapies), healthcare costs (greater than $500,000/year for eculizumab), and potential comparative efficacy.

While eculizumab can be given as a first line treatment, given the above factors, we would suggest use of eculizumab in patients who have experienced failure or intolerance with other treatments.

While eculizumab was only studied in adult patients with AQP4 antibody positive NMOSD, it has been used in the pediatric population safely for its other indication. Unlike satralizumab and inebilizumab, the other two FDA-approved medications for AQP4 antibody positive NMOSD, eculizumab has also been used in patients older than 65. Though the numbers are limited (15 in PNH, 4 in aHUS, 26 in gMG, and 6 in NMOSD), no age related differences in medication effects were noted. Unlike inebilizumab, which carries a warning for fetal harm, there have not been similar adverse effects noted with eculizumab based on limited case reports and case series.

Q. How should patients be switched from one therapy to eculizumab?

We suggest checking absolute lymphocyte count and immunoglobulin levels for patients on other therapies prior to initiating eculizumab to ensure levels are > 0.5k/µL and in a normal range respectively. Transfusions of IV immunoglobulins can be considered in patients who have hypogammaglobulinemia prior to initiation of eculizumab.


CDC. ACIP Altered Immunocompetence, CDC: 2020. https://www.cdc.gov/vaccines/hcp/acip-recs/general-recs/immunocompetence.html

FDA drug info: Eculizumab: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/125166s431lbl.pdf

Kelly et al. Eculizumab in pregnant patients with paroxysmal nocturnal hemoglobinuria. New England Journal of Medicine. 2015, 373(111):1032-1039.

Lucchinetti CF et al. A role for humoral mechanisms in the pathogenesis of Devic’s neuromyelitis optica. Brain. 2002: 125: 1450-1461.

McNamara LA, Topaz N, Wang X, et al. High risk for invasive meningococcal disease among patients receiving eculizumab (Soliris) despite receipt of meningococcal vaccine. CDC Morbidity and Mortality Weekly Report. 2017;66(27):734-7.

Miyasaka et al. Pregnancy outcomes of patients with paroxysmal nocturnal hemoglobinuria treated with eculizumab: a Japanese experience and updated review. Int J Hematol. 2016:103(6):703-712

Pittock et al. Eculizumab in AQP4-IgG-positive relapsing neuromyelitis optica spectrum disorders: an open-label pilot study. Lancet. 2013, 12(6). 554-562.

Pittock et al. Eculizumab in Aquaporin-4-positive Neuromyelitis Optica Spectrum Disorder. New England Journal of Medicine. 2019, 281. 614-625

Wignsma et al. Pharmacology, pharmacokinetics and pharmacodynamics of eculizumab, and possibilities for an individualized approach to eculizumab. Clinical Pharmacokinetics. 2019, 58(7): 859-874.