REMS: FDA approved a REMS for eculizumab under a combined REMS (Ultomiris and Soliris REMS) to ensure that the benefits outweigh the risks. The REMS may apply to one or more preparations of eculizumab and consists of the following: elements to assure safe use. See the FDA REMS page ([Web]). |
Eculizumab, a recombinant humanized IgG2/4 kappa monoclonal antibody, is a terminal complement inhibitor that binds specifically to the complement protein C5.1, 3, 4, 10, 16, 17, 19
Paroxysmal Nocturnal Hemoglobinuria
Eculizumab is used in the treatment of paroxysmal nocturnal hemoglobinuria (PNH) to reduce hemolysis,1, 3, 4 and has been designated an orphan drug by the US Food and Drug Administration (FDA) for use in this condition.2
The current indication for use of eculizumab in the treatment of PNH is based principally on the results of one randomized, double-blind, multicenter, placebo-controlled, efficacy study (TRIUMPH) and one noncomparative, open-label safety trial (SHEPHERD) in 184 transfusion-dependent adults with PNH.1, 3, 4 All patients treated with eculizumab received an initial dosage of 600 mg once weekly for 4 weeks, followed by a dose of 900 mg one week later (week 5), and then 900 mg every 2 weeks.1, 3, 4 In the TRIUMPH study, patients with PNH who had received at least 4 red blood cell transfusions during the 12 months prior to study entry were randomized to receive eculizumab or placebo for 26 weeks.1, 3 The SHEPHERD trial was conducted over a longer period (52 weeks) to further evaluate the safety of eculizumab and also included a broader range of PNH patients (i.e., those who had received at least one transfusion in the 24 months prior to study entry).1, 4 In both trials, patients were permitted to continue supportive therapies for PNH such as anticoagulants and systemic corticosteroids.1, 3
In these trials, treatment with eculizumab substantially reduced hemolysis as measured by a decrease in median serum LDH concentrations from 2,032-2,051 U/L at baseline to 239-269 U/L at the end of the study period.1, 3, 4, 6 In addition, other measures of hemolysis were favorably affected.3, 4 In the TRIUMPH study, the mean percentage of PNH type III erythrocytes increased from about 28% at baseline to 57% at 26 weeks in patients receiving eculizumab but remained unchanged in those receiving placebo.3 In the SHEPHERD trial, endogenous PNH erythrocyte mass after 52 weeks of treatment had increased by 44% over baseline.4
In addition to substantially reducing hemolysis, eculizumab also improved several measures of anemia in these studies.3, 4 Overall transfusion requirements decreased from a median of 8-9 units of packed red blood cells during the 6 or 12 months before treatment to 0 units of packed red blood cells during treatment.3, 4 Approximately 50% of patients receiving the drug achieved transfusion independence for the entire 6- or 12-month study period.1, 3, 4 Stabilization of hemoglobin concentrations (defined as hemoglobin concentrations maintained above the level requiring transfusion) was achieved in 49% of patients treated with eculizumab compared with 0% of those who received placebo in the TRIUMPH study.1, 3
Sustained responses to eculizumab have been observed in an open-label extension trial in 187 patients receiving the drug for periods of 10-54 months.1
PNH results from a somatic hematopoietic stem cell mutation; erythrocytes derived from the abnormal clone (known as PNH erythrocytes) are deficient in the complement inhibitor CD-59 and are susceptible to terminal complement-mediated intravascular hemolysis.1, 8, 9, 10 PNH is characterized by intravascular hemolysis with associated anemia, lethargy, hemoglobinuria, thrombosis, and smooth muscle dystonias (including esophageal spasms and dysphagia, abdominal pain, and erectile dysfunction).1, 8, 9, 10 The only curative treatment of PNH to date is stem cell transplantation.8, 10, 20 Eculizumab improves symptoms of PNH by reducing hemolysis, stabilizing hemoglobin concentrations, and reducing transfusion requirements.1, 3, 4, 6, 10, 16, 17
Atypical Hemolytic Uremic Syndrome
Eculizumab is used to inhibit complement-mediated thrombotic microangiopathy in patients with atypical hemolytic uremic syndrome (aHUS); the drug has been designated an orphan drug by the FDA for this use.1, 2, 22, 31
Although eculizumab has been used in some patients with hemolytic uremic syndrome caused by infection with Shiga toxin-producing Escherichia coli ,34 the drug currently is not FDA-labeled for the treatment of Shiga toxin-associated hemolytic uremic syndrome.1
Efficacy and safety of eculizumab for the treatment of aHUS are based on the results of 5 single-arm studies, including 4 open label prospective studies in adults and pediatric patients and one retrospective study in pediatric patients 2 months to 17 years of age with the disease.1, 22, 31 In all of the studies, eculizumab was administered at a dosage of 900 mg once a week for 4 weeks, followed by a single 1200-mg dose approximately 1 week later, then 1200 mg every 2 weeks; dosage in pediatric patients weighing less than 40 kg was determined based on body weight.1, 22 All patients enrolled in the prospective studies were required to have ADAMTS13 activity level above 5%.1 Efficacy evaluations were based on thrombotic microangiopathy endpoints.1
Efficacy and safety of eculizumab in the treatment of aHUS were initially established in 2 prospective studies that included primarily adults with progressing thrombotic microangiopathy, long disease duration, and chronic kidney disease.1, 22 The first prospective study included 17 adults (median age 28 years; range 17-68 years) with progressing thrombotic microangiopathy despite plasma therapy who were not receiving chronic dialysis, and the second prospective study included 20 adults and adolescents (median age 28 years; range 13-63 years) who were receiving chronic plasma exchange or infusion but generally did not have evidence of ongoing thrombotic microangiopathy; patients on chronic dialysis were permitted in the second study.1, 22 In these studies, eculizumab substantially reduced complement-mediated thrombotic microangiopathic activity, as evidenced by a rapid (e.g., by 1 week) and sustained increase in mean platelet counts from baseline to 2 years, normalization of hematologic parameters (platelet counts and serum LDH concentrations), and absence of thrombotic microangiopathic events for at least 12 weeks in the majority of patients.1, 22 In addition, eculizumab treatment was associated with substantial improvements in renal function as indicated by increases in the estimated glomerular filtration rate from baseline to 26 weeks, which were maintained through 2 years, and reduced requirements for dialysis (i.e., 4 out of 5 patients in one of the studies who were dialysis dependent prior to treatment no longer required dialysis, and no patients in the second study required new dialysis).1, 22 Response to the drug was similar in patients with or without complement gene mutations, and earlier initiation of therapy was associated with greater improvement in the estimated glomerular filtration rate.1, 22
Results of the retrospective pediatric study generally were similar to those reported in the prospective studies; platelet normalization occurred in 89% of patients, hematologic normalization was observed in 42% of patients, and no patient required initiation of dialysis during eculizumab therapy.1 At the time of data analysis, the median duration of eculizumab treatment was 38 and 40 weeks in the prospective studies and 16-38 weeks in the pediatric study; however, most patients continued to receive the drug in extension studies with sustained clinical improvement.1, 22
Two additional prospective, open-label, phase 2 studies were conducted to further establish the efficacy and safety of eculizumab in patients with aHUS.1, 41, 42 The first study included 41 adults (median age 35 years; range 18-80 years) with severe aHUS who had signs of thrombotic microangiopathy.41 The second study was conducted in 22 pediatric patients (median age of 6.5 years (range 5 months to 17 years).42 In both studies, eculizumab reduced signs of complement-mediated thrombotic microangiopathic activity.1, 41, 42 Mean platelet counts increased from baseline by 1 week and were sustained through 26 weeks of treatment.1, 41, 42 Response to the drug was similar in patients with or without complement gene mutations.1 Eculizumab treatment also was associated with substantial improvements in renal function as indicated by increases in mean eGFR from baseline to 26 weeks.1, 41, 42 In the adult study, 20 out of 24 patients who required dialysis at baseline were able to discontinue dialysis during eculizumab treatment.1 In the pediatric study, the majority of patients who had CKD stage ≥2 at baseline had an improvement to CKD stage ≥1, and 9 out of 11 patients who required dialysis at baseline were able to discontinue dialysis during eculizumab treatment.1
aHUS is a rare, life-threatening variant of thrombotic microangiopathy caused by abnormalities of the alternative complement pathway; these abnormalities lead to complement activation and subsequent endothelial cell injury and dysfunction.38, 39 The microvascular injury caused by aHUS manifests as microangiopathic hemolytic anemia, thrombocytopenia, thrombosis, and ischemic damage to organs, primarily the kidneys.39 Options for management of aHUS include supportive care (e.g., packed RBCs for anemia, fluid and electrolytes, management of hypertension and renal impairment), plasma exchange or infusion, and complement inhibitors.38, 39 Plasma therapy has been the standard treatment for aHUS; however, some patients do not respond or require prolonged therapy.39 Complement inhibitor therapy may provide an alternative option to plasma therapy and in some cases may be preferred.38, 40
Eculizumab is used for treatment of generalized myasthenia gravis in adults who are anti-acetylcholine receptor (anti-AChR) antibody positive.1, 43 The drug has been designated an orphan drug by FDA for the treatment of myasthenia gravis.2
Efficacy of eculizumab for the treatment of generalized myasthenia gravis was established in a 26-week randomized, multicenter, double-blind, placebo-controlled study (REGAIN).1, 43 The study included 125 adults with anti-AChR antibody-positive generalized myasthenia gravis, a Myasthenia Gravis Foundation of America (MGFA) clinical classification of class II-IV, and a Myasthenia Gravis-Activities of Daily Living (MG-ADL) scale total score ≥6.1, 43 Patients were randomized to receive eculizumab or placebo for 26 weeks.1, 43 The primary efficacy endpoint was change from baseline in MG-ADL total score at week 26.1 Key secondary outcomes included change in Quantitative Myasthenia Gravis (QMG) scale total score from baseline to week 26, and the proportion of patients considered QMG responders (≥5-point improvement in total QMG score) and MG-ADL responders (≥3-point improvement in MG-ADL score).1, 43
Baseline characteristics were similar between the eculizumab and placebo groups.1 Over 95% of patients were receiving acetylcholinesterase inhibitors at study entry and approximately 50% of patients in each group had been previously treated with at least 3 immunosuppressant therapies.1 The least-square mean change in MG-ADL score from baseline to week 26 was substantially reduced with eculizumab (-4.2) compared with placebo (-2.3).1 The least-square mean change in QMG total score was also greater with eculizumab compared to placebo (-4.6 versus -1.6, respectively).1 For both endpoints, the proportion of responders was consistently greater in the eculizumab group compared with placebo.1
Generalized myasthenia gravis is a chronic, antibody-mediated disease that affects the post-synaptic neuromuscular junctions of skeletal muscles.44 Up to 85% of cases are caused by antibodies that target and bind to the post-synaptic AChR, causing receptor internalization and complement activation, which lead to formation of membrane attack complexes and post-synaptic membrane damage.44, 45 Myasthenia gravis manifests with generalized muscle weakness that can affect ocular, bulbar, respiratory, axial, and limb muscles.46 Conventional therapy for generalized myasthenia gravis includes the use of immunosuppressive agents, removal of antibodies by plasma exchange, and, in some cases, thymectomy.47 Complement inhibitors (e.g., eculizumab, ravulizumab) may play a role in the treatment of AChR-positive generalized myasthenia gravis by reducing deposition of complement and membrane attack complexes at the neuromuscular junction.44, 45 International experts recommend consideration of eculizumab for the treatment of severe, refractory anti-AChR antibody-positive generalized myasthenia gravis; the specific place in therapy for ravulizumab remains to be determined.47
Neuromyelitis Optica Spectrum Disorder
Eculizumab is used for the treatment of adults with neuromyelitis optica spectrum disorder (NMOSD) who are anti-aquaporin-4 (AQP4) antibody positive.1, 48 Eculizumab has been designated an orphan drug by FDA for the treatment of neuromyelitis optica.2
Efficacy of eculizumab for the treatment of NMOSD was established in a randomized, double-blind, placebo-controlled study (PREVENT) that enrolled 143 adults with anti-AQP4 antibody positive NMOSD.1, 48 Eligibility criteria included a history of at least 2 relapses in the last 12 months or 3 relapses in the last 24 months, with at least 1 relapse in the 12 months prior to study entry; an Expanded Disability Status Scale (EDSS) score ≤7; stable dosages of immunosuppressive therapy in patients receiving such therapy; and no more than 20 mg per day of concurrent corticosteroid usage.1 Eculizumab was administered at the recommended dosage regimen.1
Baseline characteristics of the study population were similar between the eculizumab and placebo groups; 91% of patients were women.1, 48 During the trial, 76% of patients continued to receive their previous immunosuppressive therapies.1 The primary end point was the time to first adjudicated on-trial relapse, which was significantly longer in patients receiving eculizumab than in those receiving placebo; adjudicated relapse occurred in 3% of patients in the eculizumab group and 43% of patients in the placebo group, for a relative risk reduction of 94%1, 48 Similar improvements were observed with eculizumab regardless of concomitant treatment.1
NMOSD is a rare and severe autoimmune neuroinflammatory disease of the CNS that typically causes acute attacks of transverse myelitis, optic neuritis, and brainstem encephalitis.49, 51 Most patients with NMOSD have IgG autoantibodies directed against AQP4, the most abundant water channel in the CNS.49, 51 These autoantibodies play a central role in the pathogenesis of NMOSD by activating the complement cascade, resulting in enhanced local inflammation and cytotoxicity.50, 51 Without treatment, patients with NMOSD develop significant disability from recurrent attacks.50, 51
There is no known cure for NMOSD; the main goals of treatment are to treat acute attacks promptly and effectively, and prevent future attacks to minimize disability progression.50 The Neuromyelitis Optica Study Group (NEMOS) has published guidelines on the treatment of NMOSD.50 The guidelines state that acute attacks must be treated as soon as possible with high-dose glucocorticoid therapy and/or apheresis.50 Long-term immunotherapy must be offered to patients with AQP4-IgG-positive NMOSD after the first attack.50 Drugs that have demonstrated efficacy for this use include eculizumab, ravulizumab, inebilizumab, rituximab, and satralizumab, and the guidelines state that long-term immunotherapy should be initiated with one of these monoclonal antibodies when these treatments are available and accessible.50 There are no head-to-head studies demonstrating superiority of one drug over another; therefore, choice of therapy should be based on disease severity, comorbidities, patient age, family planning, adherence, patient and physician preferences, and drug-related factors (mechanism, onset of action, adverse effects, safety, route of administration, cost, availability).50
Eculizumab is administered by IV infusion using gravity flow or a controlled-infusion device (e.g., infusion pump or syringe pump).1 The drug must not be administered by rapid IV injection, such as IV “push” or “bolus.”1
Vials should be refrigerated at 2-8°C in original carton and protected from light.1 Prior to administration, solutions of eculizumab should be allowed to warm to room temperature (18-25°C); heat sources (e.g., microwave) other than ambient air temperature should not be used.1 Admixed solutions of eculizumab are stable for 24 hours at 2—8°C and at room temperature.1
Patients should be monitored for infusion-related reactions during and for at least 1 hour following each infusion.1 If an adverse reaction occurs, the infusion rate should be slowed or treatment discontinued.1
Commercially available eculizumab concentrate for IV infusion must be diluted prior to administration.1
The appropriate amount of eculizumab should be withdrawn from the vial, added to an infusion bag, and diluted 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 300-mg dose, 30 mL of the concentrate for injection (containing 10 mg/mL) should be withdrawn and added to 30 mL of diluent in an infusion bag to achieve a final admixture volume of 60 mL (i.e., 5 mg of eculizumab per mL).1 In the same manner, doses of 600, 900, or 1200 mg of eculizumab should be prepared by withdrawing 60, 90, or 120 mL of the concentrate, and adding to 60, 90, or 120 mL, respectively, of diluent to achieve final admixture volumes of 120 mL (for 600-mg doses), 180 mL (for 900-mg doses), or 240 mL (for 1200-mg doses).1, 6 The diluted solution should be gently inverted to ensure complete mixing.1
Vials of eculizumab are for single use only; any unused portions of the vial should be discarded after preparing a dose.1
IV infusions of eculizumab should be administered over 35 minutes in adults and 1—4 hours in pediatric patients; if the infusion must be slowed due to adverse effects, the total infusion time should not exceed 2 hours in adults.1
Paroxysmal Nocturnal Hemoglobinuria
For the treatment of paroxysmal nocturnal hemoglobinuria (PNH) in adults, the recommended dosage of eculizumab is 600 mg once a week for the first 4 weeks, followed by a dose of 900 mg 1 week later (week 5), then 900 mg every 2 weeks thereafter.1, 6 Doses should be administered at these 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 dosing interval (i.e., from 14 to 12 days) to achieve optimal reduction in hemolysis (as determined by reduction in LDH concentrations).1
Atypical Hemolytic Uremic Syndrome
For the treatment of atypical hemolytic uremic syndrome (aHUS) in patients 18 years of age or older, the recommended dosage of eculizumab is 900 mg once a week for 4 weeks as an induction regimen; a dose of 1200 mg should then be given 1 week later (at week 5), followed by 1200 mg every 2 weeks thereafter for maintenance therapy.1 Doses should be administered at these recommended time points, or within 2 days of each time point, to achieve maximum benefit.1
Dosage recommendations for the treatment of aHUS in pediatric patients (2 months of age or older) are based on body weight.1 In patients weighing 40 kg or more, an induction dosage of 900 mg of eculizumab once a week for the first 4 weeks is recommended, followed by a dose of 1200 mg at week 5, then 1200 mg every 2 weeks thereafter for maintenance therapy.1 In patients weighing 30 kg to less than 40 kg, an induction dosage of 600 mg of eculizumab once a week for 2 weeks is recommended, followed by a dose of 900 mg at week 3, then 900 mg every 2 weeks thereafter.1 In patients weighing 20 kg to less than 30 kg, an induction dosage of 600 mg of eculizumab once a week for the first 2 weeks is recommended, followed by a dose of 600 mg at week 3, then 600 mg every 2 weeks thereafter.1 In patients weighing 10 kg to less than 20 kg, an induction dose of 600 mg of eculizumab is recommended, followed by a dose of 300 mg at week 2, then 300 mg every 2 weeks thereafter.1 In patients weighing 5 kg to less than 10 kg, an induction dose of 300 mg of eculizumab is recommended, followed by a dose of 300 mg at week 2, then 300 mg every 3 weeks thereafter.1 Doses should be administered at these recommended time points, or within 2 days of each time point, to achieve maximum benefit.1, 31
Supplemental doses of eculizumab are recommended in patients receiving concomitant plasma therapy with plasmapheresis, plasma exchange, or fresh frozen plasma infusion because clearance of the drug may be increased with these interventions; the additional amount of drug that should be given is determined by the most recent dose of eculizumab administered.1 A supplemental dose of 300 mg (in patients whose most recent dose was 300 mg) or 600 mg (in patients whose most recent dose was 600 mg or higher) should be administered within 60 minutes after each plasmapheresis or plasma exchange session.1 In patients receiving fresh frozen plasma in whom the most recent eculizumab dose was 300 mg or more, an additional dose of 300 mg should be administered 60 minutes prior to each unit of fresh frozen plasma infused.1
The optimal duration of eculizumab therapy in patients with aHUS is not known.29, 32, 33 Because of the chronic nature of aHUS and some evidence suggesting that treatment discontinuance may result in a return of disease manifestations, long-term (e.g., at least 1 year) therapy may be beneficial; some experts recommend lifelong therapy.1, 22, 28, 29, 32, 33, 37
For the treatment of generalized myasthenia gravis in adults, the recommended dosage of eculizumab is 900 mg once a week for the first 4 weeks; a dose of 1200 mg should then be given 1 week later (at week 5), followed by 1200 mg every 2 weeks thereafter for maintenance therapy.1 Doses should be administered at these recommended time points, or within 2 days of each time point, to achieve maximum benefit.1
Supplemental doses of eculizumab are recommended in patients receiving concomitant plasma therapy with plasmapheresis, plasma exchange, or fresh frozen plasma infusion because clearance of the drug may be increased with these interventions; the additional amount of drug that should be given is determined by the most recent dose of eculizumab administered.1 A supplemental dose of 300 mg (in patients whose most recent dose was 300 mg) or 600 mg (in patients whose most recent dose was 600 mg or higher) should be administered within 60 minutes after each plasmapheresis or plasma exchange session.1 In patients receiving fresh frozen plasma in whom the most recent eculizumab dose was 300 mg or more, an additional dose of 300 mg should be administered 60 minutes prior to each unit of fresh frozen plasma infused.1
Neuromyelitis Optica Spectrum Disorder
For the treatment of neuromyelitis optica spectrum disorder (NMOSD) in adults, the recommended dosage of eculizumab is 900 mg once a week for the first 4 weeks; a dose of 1200 mg should then be given 1 week later (at week 5), followed by 1200 mg every 2 weeks thereafter for maintenance therapy.1 Doses should be administered at these recommended time points, or within 2 days of each time point, to achieve maximum benefit.1
Supplemental doses of eculizumab are recommended in patients receiving concomitant plasma therapy with plasmapheresis, plasma exchange, or fresh frozen plasma infusion because clearance of the drug may be increased with these interventions; the additional amount of drug that should be given is determined by the most recent dose of eculizumab administered.1 A supplemental dose of 300 mg (in patients whose most recent dose was 300 mg) or 600 mg (in patients whose most recent dose was 600 mg or higher) should be administered within 60 minutes after each plasmapheresis or plasma exchange session.1 In patients receiving fresh frozen plasma in whom the most recent eculizumab dose was 300 mg or more, an additional dose of 300 mg should be administered 60 minutes prior to each unit of fresh frozen plasma infused.1
Serious Meningococcal Infections
A boxed warning regarding the risk of serious meningococcal infections is included in the prescribing information for eculizumab.1 The drug increases the risk of serious infections caused by Neisseria meningitidis .1 Life-threatening and fatal meningococcal infections have occurred in both vaccinated and unvaccinated patients treated with complement inhibitors.1 These infections may quickly become life-threatening or fatal if not recognized and treated early.1
Complete or update vaccination for meningococcal bacteria (for serogroups A, C, W, Y, and B) at least 2 weeks prior to the first dose of eculizumab, unless the risks of delaying therapy outweigh the risk of developing a serious infection.1 Comply with the most current Advisory Committee on Immunization Practices (ACIP) recommendations for patients receiving a complement inhibitor.1 Revaccinate patients according to ACIP recommendations with consideration of the duration of eculizumab therapy.1 Of note, ACIP recommends an administration schedule that differs from the vaccine prescribing information.1 If urgent therapy with eculizumab is indicated in a patient who is not up to date with meningococcal vaccines, provide the patient with antibacterial drug prophylaxis and administer these vaccines as soon as possible.1 Because the optimal durations and drug regimens for prophylaxis have not been studied in unvaccinated or vaccinated patients receiving eculizumab, weigh the benefits and risks of eculizumab treatment and antibacterial drug prophylaxis against the risks for serious infections caused by Neisseria meningitidis .1
Vaccination does not eliminate the risk of serious encapsulated bacterial infections, despite development of antibodies following vaccination.1 Monitor patients closely for early signs and symptoms of serious meningococcal infection.1 Evaluate patients immediately if an infection is suspected and promptly treat confirmed infections.1 Consider interruption of eculizumab therapy in patients undergoing treatment for serious meningococcal infection.1
Because of the risk of meningococcal infections, eculizumab is available only through a restricted Risk Evaluation and Mitigation Strategy (REMS) program called Ultomiris and Soliris REMS.1 (See REMS under Dosage and Administration.)
Other Warnings and Precautions
Eculizumab blocks terminal complement activation and therefore may increase susceptibility to infections, especially those caused by encapsulated bacteria such as Neisseria meningitidis , Streptococcus pneumoniae , Haemophilus influenzae , and, to a lesser extent, Neisseria gonorrhoeae .1, 10, 27, 31, 35, 36 Children receiving eculizumab may be at increased risk of developing serious Streptococcus pneumoniae and H. influenzae type B (Hib) infections.1
Vaccinate patients for the prevention of Streptococcus pneumoniae and Hib infections in accordance with current ACIP guidelines.1 Patients receiving eculizumab are at increased risk of infections due to these organisms even if they develop antibodies following vaccination.1
Complications Following Treatment Discontinuance
In patients with paroxysmal nocturnal hemoglobinuria (PNH), serious hemolysis due to a drug-induced increase in PNH erythrocytes is possible following discontinuance of eculizumab therapy.1, 6, 10 Patients receiving eculizumab for the treatment of PNH should be monitored for at least 8 weeks after discontinuance of therapy for manifestations of hemolysis.1
Patients with atypical hemolytic uremic syndrome (aHUS) may experience a return of thrombotic microangiopathic symptoms following discontinuance of eculizumab therapy and should be monitored for at least 12 weeks following drug discontinuance.1, 28, 32 In clinical studies, such complications occurred in some patients who missed a dose of the drug.1, 22 Manifestations of thrombotic microangiopathy can include mental status changes, seizures, angina, dyspnea, and thrombosis.1 In addition, the occurrence of 2 of the following laboratory changes or a repeat occurrence of any one of the changes may indicate the development of thrombotic microangiopathy: a decrease in platelet count by 25% or more compared with either baseline or the peak platelet count during eculizumab treatment; an increase in serum creatinine concentration by 25% or more compared with either baseline or the nadir value during eculizumab treatment; or an increase in serum LDH concentration by 25% or more compared with either baseline or the nadir value during eculizumab treatment.1 If manifestations of thrombotic microangiopathy occur after eculizumab is discontinued, reinitiation of the drug, plasma therapy, and/or supportive measures should be considered.1
Thrombosis Prevention and Management
Patients with PNH have a high risk of venous thrombosis, which can be life-threatening or fatal.4, 8, 18, 20 The effects of withdrawing anticoagulant therapy in patients receiving eculizumab have not been established; therefore, treatment with eculizumab should not affect concomitant anticoagulant management.1
Infusion reactions requiring discontinuance of eculizumab were not observed during clinical trials, but hypersensitivity reactions, including anaphylaxis, are possible with all therapeutic proteins.1, 6 Patients should be monitored for infusion-related reactions during treatment; if manifestations of cardiovascular instability or respiratory compromise occur, the infusion should be interrupted and appropriate treatment instituted.1
Antibodies to eculizumab were detected in approximately 2-3% of patients with PNH, aHUS, or NMOSD who received eculizumab in clinical studies.1 Low titers of neutralizing antibodies were detected in 1.2% of patients with PNH and 1% of patients with aHUS who received eculizumab; neutralizing antibodies were not detected in patients with NMOSD.1 No apparent relationship has been observed between the development of antibodies and clinical response in either of the indications.1
Limited data in pregnant women receiving eculizumab have not identified any concerns of adverse developmental outcomes.1
There are disease-associated risks to the mother and fetus.1 Untreated PNH in pregnancy is associated with adverse maternal outcomes (e.g., worsening cytopenias, thrombotic events, infections, bleeding, miscarriages, increased maternal mortality) and adverse fetal outcomes (e.g., fetal death, premature delivery).1 Similarly, untreated aHUS in pregnancy is associated with adverse maternal outcomes (e.g., preeclampsia, preterm delivery) and adverse fetal/neonatal outcomes (e.g., intrauterine growth restriction, fetal death, low birth weight).1
In animal reproduction studies, increased rates of developmental abnormalities and increased rate of dead and moribund offspring were observed.1
Detectable levels of eculizumab have not been found in human milk; however, maternal IgG is known to be present in human milk.1 There is insufficient information to inform the effect of eculizumab on the breast-fed infant.1 There are no data on the effects of eculizumab on milk production.1 Consider the developmental and health benefits of breastfeeding along with the mother's clinical need for eculizumab and any potential adverse effects on the breast-fed child from the drug or underlying maternal condition.1
Safety and efficacy of eculizumab for the treatment of PNH, myasthenia gravis, or NMOSD have not been established in pediatric patients.1
A total of 47 pediatric patients 2 months to 17 years of age were included in the principal efficacy studies of eculizumab for the treatment of aHUS.1 Safety and efficacy of the drug in these pediatric patients were similar to those in adults.1
Pediatric patients receiving eculizumab should receive appropriate vaccinations for the prevention of Neisseria meningitidis , Streptococcus pneumoniae , and Haemophilus influenzae type b (Hib) infections.1
There is insufficient experience in patients 65 years of age or older to determine whether geriatric patients respond differently than younger patients.1
Renal impairment is not likely to affect the pharmacokinetics of eculizumab.1
Adverse effects reported in at least 10% of patients and at a higher incidence than placebo in the PNH clinical studies include headache, nasopharyngitis, back pain, and nausea.1
Adverse effects reported in at least 20% of patients (total incidence from 2 studies) in the single-arm prospective aHUS studies include headache, diarrhea, hypertension, upper respiratory infection, abdominal pain, vomiting, nasopharyngitis, anemia, cough, peripheral edema, nausea, urinary tract infections, and pyrexia.1 h
The most frequently reported adverse effect in at least 10% of patients with generalized myasthenia gravis is musculoskeletal pain.1
The most frequently reported adverse effects in at least 10% of patients with NMOSD include upper respiratory infection, nasopharyngitis, diarrhea, back pain, dizziness, influenza, arthralgia, pharyngitis, and contusion.1
No formal drug interaction studies have been conducted to date with eculizumab.1
Plasma Exchange, Plasmapheresis, or Fresh Frozen Plasma
Concomitant use of eculizumab with plasma exchange, plasmapheresis, or fresh frozen plasma can reduce serum eculizumab concentrations.1 Administer a supplemental dose of eculizumab.1
Concomitant use of eculizumab with neonatal Fc receptor blockers may lower systemic exposure and reduce effectiveness of eculizumab.1 Closely monitor for reduced effectiveness of eculizumab.1
Eculizumab is a recombinant humanized immunoglobulin G2/4 kappa (IgG2/4 kappa) monoclonal antibody.1 The drug binds specifically and with high affinity to the complement protein C5, preventing activation of terminal complement components.1, 10 Eculizumab prevents the cleavage of complement protein C5 into C5a and C5b, thereby blocking subsequent formation of the C5b-C9 terminal complement complex (also referred to as the membrane attack complex).1, 10
Patients with paroxysmal nocturnal hemoglobinuria (PNH) have a somatic hematopoietic stem cell mutation that results in deficient synthesis of glycosylphosphatidylinositol (GPI), a glycolipid that links many proteins to the cell surface.8, 9, 10 Blood cells derived from this abnormal clone (known as PNH cells) have partial or complete (type II or III cells, respectively) deficiency of GPI-linked proteins, including the GPI-linked complement inhibitor CD-59.1, 8, 9, 10 CD-59 inhibits formation of the C5b-C9 terminal complement complex; deficiency of CD-59 on PNH erythrocytes is thought to result in increased susceptibility of these cells to complement-mediated hemolysis.1, 8, 9, 10
In patients with atypical hemolytic uremic syndrome (aHUS), an acquired or inherited defect in regulation of the alternative complement pathway results in uncontrolled terminal complement activation; chronic, uncontrolled activation of the complement system leads to platelet activation, endothelial cell damage, thrombotic microangiopathy, and damage to multiple organ systems (e.g., CNS, kidneys, heart, GI tract).1, 22, 31 Eculizumab blocks formation of terminal complement, thereby inhibiting terminal complement-mediated intravascular hemolysis in patients with PNH and complement-mediated thrombotic microangiopathy in patients with aHUS.1, 10
The precise mechanism by which eculizumab exerts its therapeutic effect in generalized myasthenia gravis patients is unknown, but is presumed to involve reduction of terminal complement complex C5b-9 deposition at the neuromuscular junction.1 The precise mechanism by which eculizumab exerts its therapeutic effect in neuromyelitis optica spectrum disorder (NMOSD) is unknown, but is thought to involve inhibition of aquaporin-4-antibody induced terminal complement C5b-9 deposition.1
Eculizumab plasma concentrations ≥35 mcg/mL are required to block complement.16, 17 Following administration of a single dose, complement activity is inhibited for up to 2 weeks.19 Reduction of hemolysis (as determined by reduction in LDH concentrations) was maintained at least 52 weeks in open-label study.1, 17 The metabolic fate of immunoglobulins such as eculizumab is not well characterized but is likely to involve catabolism in various tissues via diffuse cellular processes.15 Minimal excretion of eculizumab is expected in urine due to its large molecular size.1, 15 Small quantities of immunoglobulin have been found in bile.15
Eculizumab exhibits linear pharmacokinetics over the dose range of 600 to 1200 mg.1 Following initiation of eculizumab therapy, steady-state concentrations are achieved in 4 weeks with an accumulation ratio of approximately 2-fold.1 The half-life of the drug is approximately 270 to 414 hours.1 Plasma exchange or infusion increases clearance by approximately 250-fold and reduces half-life to 1.26 hours.1 The pharmacokinetics of eculizumab are not affected by age, sex, or race.1
Additional Information
The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.
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.
Eculizumab is available only through a restricted distribution program (see REMS under Dosage and Administration).1
AHFS® Drug Information. © Copyright, 1959-2025, Selected Revisions February 10, 2025. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.
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