SOLIRIS

Eculizumab is a monoclonal antibody indicated for the treatment of paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic uremic syndrome (aHUS), anti-acetylcholine receptor antibody positive generalized myasthenia gravis, and anti-aquaporin-4 (AQP4) antibody positive neuromyelitis optica spectrum disorder (NMOSD). During clinical trials in patients with PNH, treatment with eculizumab has been shown to stabilize hemoglobin concentrations without blood transfusions, reduce the number of necessary blood transfusions, decrease LDH concentrations (a biochemical marker of hemolysis), decrease the number of PNH attacks, and improve quality of life including the symptom of fatigue. A reduction in blood transfusions and stabilization in hemoglobin concentrations have been demonstrated in patients receiving eculizumab for up to 64 weeks in duration. In patients with aHUS, treatment with eculizumab prevents complement-mediated thrombotic microangiopathy (TMA). Three clinical studies have evaluated the safety and efficacy of eculizumab for the treatment of aHUS. During these studies, patients receiving eculizumab experienced a reduction in terminal complement activity as indicated by increased mean platelet counts over baseline. In a 26-week placebo-controlled trial of patients with generalized myasthenia gravis, patients receiving eculizumab had a greater improvement in the Myasthenia Gravis-Specific Activities of Daily Living scale from baseline to week 26. Patients receiving eculizumab also reported a greater change from baseline to week 26 in the Quantitative Myasthenia Gravis score, a categorical scale assessing muscle weakness. In a randomized, double-blind, placebo-controlled trial, eculizumab significantly reduced the time to relapse in patients with anti-AQP4 positive NMOSD, with a relative risk reduction of 94%. There is an increased risk of meningococcal infections in patients receiving eculizumab; immunization with meningococcal vaccines is required prior to eculizumab administration unless the risks of delaying treatment outweigh the risks of developing a meningococcal infection.

General Administration Information
For storage information, see the specific product information within the How Supplied section.

Route-Specific Administration

Injectable Administration
-Visually inspect the solution for particulate matter or discoloration prior to infusion.
Intravenous Administration
-For intravenous infusion after dilution only; do NOT administer via IV push or bolus.

Preparation of IV infusion:
-Withdraw the required amount of eculizumab from the vial into a sterile syringe. Transfer the dose to an infusion bag.
-Dilute to a final concentration of 5 mg/mL by adding the appropriate amount of 0.9% Sodium Chloride, 0.45% Sodium Chloride, Dextrose 5% in Water, or Ringer's injection to the infusion bag. The volume of diluent required will be equal to the volume of drug.-The final infusion volume for eculizumab 300 mg is 60 mL.
-The final infusion volume for eculizumab 600 mg is 120 mL.
-The final infusion volume for eculizumab 900 mg is 180 mL.
-The final infusion volume for eculizumab 1,200 mg is 240 mL.

-Once the diluent is added, gently invert the infusion bag to ensure thorough mixing of eculizumab and the diluent. Do NOT shake.
-Discard any amount of eculizumab that is remaining in the vial; eculizumab does not contain a preservative.
-Allow the admixture to come to room temperature (18 to 25 degrees C or 64 to 77 degrees F) prior to administration. Do not heat in a microwave or with any other heat source other than ambient air temperature.
-Storage: Once mixed, the IV infusion solution is stable for 24 hours under refrigeration (2 to 8 degrees C or 36 to 46 degrees F) or at room temperature (18 to 25 degrees C or 64 to 77 degrees F). Do not freeze.

Administration of IV infusion:
-Administer the dose via IV infusion over 35 minutes in adults and infuse IV over 1 to 4 hours in pediatric patients using gravity feed, a syringe-type pump, or an infusion pump.
-Infuse repeat doses at the recommended intervals, or within 2 days of these intervals.
-Monitor for allergic reactions during the infusion. and for 1 hour after the completion of the infusion. If an allergic reaction occurs, the infusion can be stopped or slowed. If it is slowed, the total infusion time should not exceed 2 hours for adults.

During 3 prospective, single-arm studies in 78 adults and adolescents with atypical hemolytic uremic syndrome (aHUS), neoplasms that were benign or malignant (including cysts and polyps) occurred in 10% of patients treated with eculizumab.

During eculizumab clinical trials in patients with paroxysmal nocturnal hemoglobinuria (PNH), fatigue was reported in 12% of patients compared to 2% of patients receiving placebo. Anemia was reported in 2% of patients in a single-arm study. During 3 prospective, single-arm studies in 78 adults and adolescents with atypical hemolytic uremic syndrome (aHUS), anemia (26%), leukopenia (15%), fatigue (13%), and asthenia (17%) occurred. During a placebo-controlled trial in patients with neuromyelitis optica spectrum disorder, leukopenia (5% eculizumab vs. 2% placebo), lymphopenia (5% vs. 0%), and asthenia (5% vs. 2%) were reported.

Gastrointestinal adverse reactions reported during placebo-controlled clinical trials of eculizumab in patients with paroxysmal nocturnal hemoglobinuria (PNH) or generalized myasthenia gravis (gMG) include abdominal pain (8% eculizumab vs. 5% placebo), nausea/vomiting (16% vs. 11%), and constipation (7% vs. 5%). Diarrhea (15%) and nausea (10%) were also reported in a long-term extension study of patients with gMG. During 3 prospective, single-arm studies in 78 adults and adolescents with atypical hemolytic uremic syndrome (aHUS), diarrhea (37%), vomiting (30%), nausea (23%), and abdominal pain (19%) occurred. During a single-arm, prospective trial in 22 pediatric patients, abdominal pain (32%), diarrhea (32%), vomiting (27%), and dyspepsia (14%) occurred. In a retrospective study of adult and pediatric patients with aHUS, diarrhea (32%), and vomiting (21%) were observed in pediatric patients. During a placebo-controlled trial of patients with neuromyelitis optica spectrum disorder, diarrhea (16% eculizumab vs. 15% placebo), constipation (9% vs. 6%), and decreased appetite (5% vs. 2%) were reported.

During clinical trials, antibodies to eculizumab were detected in 2% to 3% in the paroxysmal nocturnal hemoglobinuria (PNH) population, 3% of the atypical hemolytic uremic syndrome (aHUS) population, 0% of the myasthenia gravis population, and 2% of the neuromyelitis optica spectrum disorder (NMOSD) population. A correlation between response to treatment and antibody formation was not found.

The most commonly reported adverse reaction during clinical trials of eculizumab in patients with paroxysmal nocturnal hemoglobinuria (PNH) was headache, at a rate of 44% compared to 27% with placebo. Headache was also reported in 26% of patients receiving eculizumab for myasthenia gravis during a long-term extension study. During 3 prospective, single-arm studies in 78 adults and adolescents with atypical hemolytic uremic syndrome (aHUS), headache occurred in 41% of patients. During a single-arm, prospective trial in 22 pediatric patients, headache occurred in 18% of patients. During a placebo-controlled trial of patients with neuromyelitis optica spectrum disorder, dizziness (15% eculizumab vs. 13% placebo) and paresthesias (8% vs. 6%) were reported.

Hypersensitivity reactions, including anaphylactoid reactions, are possible during eculizumab treatment. During clinical trials, no patients experienced infusion-related reactions requiring drug discontinuation. Monitor the patient for at least 1 hour after completion of the infusion for signs or symptoms of an infusion-related reaction. If an adverse reaction occurs during the administration of eculizumab, the infusion may be stopped or slowed at the physician's discretion. If the infusion is slowed, the total infusion time should not exceed 2 hours in adults. Interrupt eculizumab infusion and initiate appropriate supportive measures if signs of cardiovascular instability or respiratory compromise occur. During clinical trials, 1 patient experienced nausea/vomiting and a headache during the infusion with dizziness and shivering occurring the next day. During 3 prospective, single-arm studies in 78 adults and adolescents with atypical hemolytic uremic syndrome (aHUS), rash (14%) and pruritus (10%) occurred. During a single-arm, prospective trial in 22 pediatric patients, rash occurred in 18% of patients. During a placebo-controlled trial of patients with neuromyelitis optica spectrum disorder, alopecia was observed in 5% of patients who received eculizumab (n = 96) vs. 4% of patients who received placebo (n = 47).

Herpes simplex infection (7% to 8% eculizumab vs. 0% to 2% placebo), sinusitis (7% vs. 0%), nasopharyngitis (23% vs. 18%), cough (12% vs. 9%), fever (2% to 7% vs. 3%), and respiratory tract infection (7% vs. 2%) were reported more commonly in subjects receiving eculizumab vs. placebo during clinical trials in persons with paroxysmal nocturnal hemoglobinuria (PNH) or generalized myasthenia gravis (gMG). In addition, symptoms consistent with influenza-like illness were also reported more commonly (5% vs. 2%) with eculizumab. Nasopharyngitis (24%) and upper respiratory tract infection (11%) were also reported in a long-term extension study of persons with gMG. During 3 prospective, single-arm studies in 78 adults and adolescents with atypical hemolytic uremic syndrome (aHUS), bronchitis (12%), nasopharyngitis (27%), gastroenteritis (12%), upper respiratory tract infection (19%), urinary tract infection (22%), cough (23%), and fever (21%) occurred. During a single-arm, prospective trial in 22 pediatric subjects, upper respiratory infection (32%), nasopharyngitis (27%), rhinitis (18%), urinary tract infection (18%), catheter site infection (14%), cough (36%), fever (50%), and oropharyngeal pain (14%) occurred. In a retrospective study of adult and pediatric subjects with aHUS, upper respiratory tract infection and/or nasopharyngitis (32%), cough (26%), fever (47%), and nasal congestion (21%) occurred in pediatric subjects. During a placebo-controlled trial of persons with neuromyelitis optica spectrum disorder, upper respiratory tract infection (29% eculizumab vs. 13% placebo), nasopharyngitis (21% vs. 19%), influenza (11% vs. 4%), pharyngitis (10% vs. 6%), bronchitis (9% vs. 6%), conjunctivitis (9% vs. 9%), cystitis (8% vs. 2%), hordeolum (7% vs. 0%), sinusitis (6% vs. 0%), cellulitis (5% vs. 2%), and oropharyngeal pain (7% vs. 4%) were reported. In PNH clinical studies, 2 subjects experienced meningococcal sepsis. Both subjects had previously received a meningococcal vaccine. In clinical studies among subjects without PNH, meningococcal meningitis occurred in 1 unvaccinated subject. Meningococcal sepsis occurred in 1 previously vaccinated subject enrolled in the retrospective aHUS study during the post-study follow-up period. The use of eculizumab increases susceptibility to encapsulated bacteria infection, especially those caused by N. meningitidis but also S. pneumoniae, H. influenzae, and to a lesser extent, N. gonorrhoeae. Additionally, fungal infection with Aspergillus sp. has occurred in persons with immunosuppression and neutropenia. Serious infections with Neisseria species, other than N. meningitidis, including disseminated gonococcal infections, have been reported. With the postmarketing use of eculizumab, Neisseria gonorrhoeae, Neisseria meningitidis, Neisseria sicca/subflava, and Neisseria spp. unspecified infections have been reported. Ensure persons are appropriately vaccinated. Closely monitor for early signs and symptoms of meningococcal infection and evaluate immediately if infection is suspected. Instruct persons to seek immediate medical care if these signs and symptoms occur. Promptly treat known infections. Meningococcal infection may become rapidly life-threatening or fatal if not recognized and treated early. Consider interruption of eculizumab in persons who are being treated for a serious meningococcal infection, depending on the risks of interrupting treatment in the disease being treated.

Musculoskeletal adverse reactions including back pain (19% vs. 9%), musculoskeletal pain (15% vs. 8%), myalgia (7% vs. 2%), and pain in extremity (7% vs. 2%) were reported during placebo-controlled eculizumab clinical trials in patients with paroxysmal nocturnal hemoglobinuria (PNH) or generalized myasthenia gravis (gMG). Arthralgia (12%) was also reported in a long-term extension study of patients with gMG. During 3 prospective, single-arm studies in 78 adults and adolescents with atypical hemolytic uremic syndrome (aHUS), arthralgia (13%) and back pain (10%) occurred. During a single-arm, prospective trial in 22 pediatric patients, muscle spasms occurred in 14% of patients. During a placebo-controlled trial in patients with neuromyelitis optica spectrum disorder, back pain (15% eculizumab vs. 13% placebo), arthralgia (11% vs. 11%), musculoskeletal pain (6% vs. 0%), and muscle cramps or spasms (5% vs. 4%) were reported.

Peripheral edema has been reported in clinical trials of eculizumab (8% and 23% of patients with atypical hemolytic uremic syndrome and myasthenia gravis, respectively vs. 5% placebo).

Eculizumab increases the number of paroxysmal nocturnal hemoglobinuria (PNH) cells. Accordingly, patients with PNH who discontinue treatment may be at increased risk for serious hemolysis. Monitor patients treated for PNH for hemolysis for at least 8 weeks after eculizumab discontinuation. Monitor patients with atypical hemolytic-uremic syndrome for signs and symptoms of thrombotic microangiopathy (TMA) for at least 12 weeks after eculizumab discontinuation. Clinical signs and symptoms of TMA include changes in mental status, seizures, angina, dyspnea, or thrombosis. In addition, laboratory parameters may identify a TMA complication. The occurrence of 2, or repeated measurement of any one of the following: a decrease in platelet count by 25% or more compared to baseline or the peak platelet count during eculizumab treatment; an increase in serum creatinine by 25% or more compared to baseline or nadir during eculizumab treatment; or, an increase in serum LDH by 25% or more over baseline or nadir during treatment. If serious TMA complications occur, consider restarting eculizumab, plasma therapy (plasmapheresis, plasma exchange, or fresh frozen plasma), or appropriate organ-specific supportive measures. During aHUS clinical studies, 18 patients discontinued therapy. TMA complications occurred following a missed dose in 5 patients; eculizumab was reinitiated in 4 of these 5 patients.

During 3 prospective, single-arm studies in 78 adults and adolescents with atypical hemolytic uremic syndrome (aHUS), hypertension including accelerated hypertension and malignant hypertension occurred in 33% of patients. Hypotension was reported in 17% of patients. During a single-arm, prospective trial in 22 pediatric patients, hypertension occurred in 18% of patients. In a retrospective study of adult and pediatric patients with aHUS, sinus tachycardia was observed in 21% of pediatric patients.

During 3 prospective, single-arm studies in 78 adults and adolescents with atypical hemolytic uremic syndrome (aHUS), insomnia occurred in 14% of patients who received eculizumab.

During 3 prospective, single-arm studies in 78 adults and adolescents with atypical hemolytic uremic syndrome (aHUS), renal impairment (18%) and proteinuria (10%) occurred in patients who received eculizumab.

During 3 prospective, single-arm studies in 78 adults and adolescents with atypical hemolytic uremic syndrome (aHUS), hypokalemia occurred in 12% of patients who received eculizumab.

During a placebo-controlled trial of patients with neuromyelitis optica spectrum disorder, cataracts were observed in 6% of patients who received eculizumab (n = 96) vs. 4% of patients who received placebo (n = 47).

Eculizumab is contraindicated in persons with unresolved meningococcal infection. Eculizumab increases the risk of serious, life-threatening, or fatal infections caused by meningococcal bacteria in any serogroup, including non-groupable strains. Complete or update meningococcal vaccination (for serogroups A, C, W, Y, and B) at least 2 weeks prior to administration of the first dose of eculizumab, according to current Advisory Committee on Immunization Practices (ACIP) recommendations for persons receiving a complement inhibitor. Revaccinate considering the duration of eculizumab therapy. Note that ACIP recommends an administration schedule in persons receiving complement inhibitors that differs from the administration schedule in the vaccine prescribing information. If urgent eculizumab therapy is indicated in persons who are not up to date with meningococcal vaccines according to ACIP recommendations, administer meningococcal vaccine(s) as soon as possible and provide antibacterial medication prophylaxis. The optimal durations and medication regimens for antibacterial medication prophylaxis and their efficacy have not been studied in persons receiving complement inhibitors, including eculizumab. Consider the benefits and risks of treatment with eculizumab in addition to the benefits and risks of antibacterial medication prophylaxis in unvaccinated or vaccinated persons against the known risks for serious infections caused by N. meningitidis. Closely monitor for early signs and symptoms of meningococcal infection and evaluate immediately if infection is suspected. Instruct persons to seek immediate medical care if these signs and symptoms occur. Promptly treat known infections. Meningococcal infection may become rapidly life-threatening or fatal if not recognized and treated early. Consider interruption of eculizumab in persons who are being treated for a serious meningococcal infection, depending on the risks of interrupting treatment in the disease being treated. The use of eculizumab increases susceptibility to encapsulated bacteria infection, especially those caused by N. meningitidis but also S. pneumoniae, H. influenzae, and to a lesser extent, N. gonorrhoeae. Additionally, fungal infection with Aspergillus sp. has occurred in persons with immunosuppression and neutropenia. Infants and children treated with eculizumab may be at increased risk of developing serious S. pneumoniae and H. influenzae type b (Hib) infections; administer vaccinations for the prevention of pneumococcal infection and Hib infection according to ACIP guidelines. Vaccination does not eliminate the risk for infections due to these organisms, despite development of antibodies after vaccination.

Monitor patients being treated for paroxysmal nocturnal hemoglobinuria after discontinuing eculizumab for at least 8 weeks to detect hemolysis. After discontinuing eculizumab, monitor patients with atypical hemolytic-uremic syndrome for signs and symptoms of thrombotic microangiopathy (TMA) complications for at least 12 weeks. Clinical signs and symptoms of TMA include changes in mental status, seizures, angina, dyspnea, or thrombosis. In addition, the following changes in laboratory parameters may identify a TMA complication: occurrence of 2, or repeated measurement of any 1 of the following: a decrease in platelet count by 25% or more compared to baseline or the peak platelet count during eculizumab treatment; an increase in serum creatinine by 25% or more compared to baseline or nadir during eculizumab treatment; or, an increase in serum lactate dehydrogenase by 25% or more over baseline or nadir during eculizumab treatment. If TMA complications occur after eculizumab discontinuation, consider reinstitution of eculizumab treatment, plasma therapy [plasmapheresis, plasma exchange, or fresh frozen plasma infusion (PE/PI)], or appropriate organ-specific supportive measures.

There are insufficient data on eculizumab use in human pregnancy to inform a drug-associated risk of major birth defects and miscarriage. Eculizumab, a recombinant IgG molecule (humanized anti-C5 antibody), is expected to cross the placenta. A pooled analysis of prospectively and retrospectively collected data of more than 300 women with live births following exposure to eculizumab have not raised safety concerns. However, due to the limited sample size, these data cannot definitively exclude any drug-associated rusk during pregnancy. Animal studies using a mouse analogue of the eculizumab molecule (murine anti-C5 antibody) showed increased rates of developmental abnormalities and an increased rate of dead and moribund offspring at doses 2 to 8 times the human dose. Advise pregnant women of the potential risk to the fetus. The manufacturer's disease registries collect pregnancy outcomes in women exposed to eculizumab during pregnancy. To enroll or obtain information, contact www.pnhregistry.com or www.ahusregistry.com, or call 215-616-3558. A healthy male infant was delivered at 38 weeks gestation to a woman who had taken eculizumab for paroxysmal nocturnal hemoglobinuria (PNH) throughout the entire pregnancy. The infant was developing normally at 9 months of age. Two additional healthy babies were born to women who received eculizumab throughout their pregnancies. In both women, therapeutic serum eculizumab concentrations were noted at delivery, and no eculizumab was detected in the cord blood. Three additional women delivered healthy babies after eculizumab receipt during early pregnancy: eculizumab was stopped at gestation weeks 5, 14, and 4. Lastly, 4 healthy babies (2 sets of twins) were born to women who received eculizumab later in pregnancy (week 30 in 1 mother and week 27 in the other). In 1 mother, therapeutic serum eculizumab concentrations were noted at delivery, and low concentrations were noted in the cord blood of both twins, but cord drug concentrations were within the background concentrations for the assay and insufficient to block complement.

There is no information regarding the presence of eculizumab in human milk, the effects on the breast-fed infant, or the effects on milk production. IgG is excreted in human milk, so it is expected that eculizumab will be present in human milk. However, published data suggest that antibodies in human milk do not enter the neonatal and infant circulation in substantial amounts. Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for eculizumab and any potential adverse effects on the breast-fed child from eculizumab or the underlying maternal condition. In a small study, excretion of the drug in breast milk was evaluated in a eculizumab-treated lactating mother. The drug was not detected during the analysis on postpartum days 1, 2, 3, 9, and 10.

General Dosing Information
-Vaccinate persons against meningococcal infection (serogroups A, C, W, Y, and B) at least 2 weeks prior to initiation of eculizumab according to the most current Advisory Committee on Immunization Practices (ACIP) recommendations for persons receiving a complement inhibitor.
-If urgent eculizumab therapy is indicated in persons who are not up to date with meningococcal vaccines according to ACIP recommendations, administer meningococcal vaccine(s) as soon as possible and provide antibacterial medication prophylaxis.
-A supplemental dose of eculizumab is required in the setting of plasmapheresis or plasma exchange and in persons receiving fresh frozen plasma infusions.

For the reduction of hemolysis in patients with paroxysmal nocturnal hemoglobinuria (PNH):
Intravenous dosage:
Adults: 600 mg IV infusion every 7 days for the first 4 weeks, followed by a single dose of 900 mg IV infusion 7 days after the fourth dose, and then 900 mg IV infusion every 14 days. In clinical trials, eculizumab stabilized hemoglobin concentrations without blood transfusions in approximately 49% of treated patients and reduced the number of blood transfusions; the drug also improved quality of life scores and fatigue. DURATION OF TREATMENT: A reduction in blood transfusions, stabilization in hemoglobin concentrations, and reduced exacerbation rates have been demonstrated in patients receiving eculizumab for up to 64 weeks in duration. A duration of therapy is not defined; following discontinuation of therapy, monitor patients for at least 8 weeks to detect the development of hemolysis.

For the treatment of patients with atypical hemolytic-uremic syndrome (aHUS) to prevent complement-mediated thrombotic microangiopathy:
Intravenous dosage:
Adults: 900 mg IV infusion every 7 days for the first 4 weeks, followed by a single dose of 1,200 mg IV infusion 7 days after the fourth dose, and then 1,200 mg IV infusion every 14 days. LIMITS OF USE: Not indicated for patients with Shiga toxin E. coli related hemolytic uremic syndrome (STEC-HUS). DURATION OF TREATMENT: A duration of therapy is not defined; following discontinuation, monitor patients for at least 12 weeks to detect signs and symptoms of TMA complications, including changes in mental status, seizures, angina, dyspnea, and thrombosis. Laboratory parameters indicating TMA complications include repeated measurements of any of the following: decreased platelet count by 25% or more compared to baseline or peak levels during eculizumab therapy; increase in serum creatinine by 25% or more compared to baseline or nadir during eculizumab therapy; or increase in serum LDH by 25% or more over baseline or nadir during eculizumab therapy. If TMA complications are detected after discontinuation, consider initiating plasma exchange or plasmapheresis, infusing fresh frozen plasma, restarting eculizumab therapy, or beginning appropriate organ-specific supportive care.
Children and Adolescents 40 kg or more: 900 mg IV infusion every 7 days for the first 4 weeks, followed by a single dose of 1,200 mg IV infusion 7 days after the fourth dose, and then 1,200 mg IV infusion every 14 days. Studies evaluating the safety and efficacy of eculizumab for aHUS included a total of 25 pediatric patients (ages 2 months to 17 years). LIMITS OF USE: Not indicated for patients with Shiga toxin E. coli related hemolytic uremic syndrome (STEC-HUS). DURATION OF TREATMENT: A duration of therapy is not defined; following discontinuation, monitor patients for at least 12 weeks to detect signs and symptoms of TMA complications. If TMA complications are detected after discontinuation, consider initiating plasma exchange or plasmapheresis, infusing fresh frozen plasma, restarting eculizumab therapy, or beginning appropriate organ-specific supportive care.
Children and Adolescents 30 to 39 kg: 600 mg IV infusion every 7 days for the first 2 weeks, followed by a single dose of 900 mg IV infusion given 7 days after the second dose, and then 900 mg IV infusion every 14 days. Studies evaluating the safety and efficacy of eculizumab for aHUS included a total of 25 pediatric patients (ages 2 months to 17 years). LIMITS OF USE: Not indicated for patients with Shiga toxin E. coli related hemolytic uremic syndrome (STEC-HUS). DURATION OF TREATMENT: A duration of therapy is not defined; following discontinuation, monitor patients for at least 12 weeks to detect signs and symptoms of TMA complications. If TMA complications are detected after discontinuation, consider initiating plasma exchange or plasmapheresis, infusing fresh frozen plasma, restarting eculizumab therapy, or beginning appropriate organ-specific supportive care.
Children and Adolescents 20 to 29 kg: 600 mg IV infusion every 7 days for the first 3 weeks, then 600 mg IV infusion every 14 days. Studies evaluating the safety and efficacy of eculizumab for aHUS included a total of 25 pediatric patients (ages 2 months to 17 years). LIMITS OF USE: Not indicated for patients with Shiga toxin E. coli related hemolytic uremic syndrome (STEC-HUS). DURATION OF TREATMENT: A duration of therapy is not defined; following discontinuation, monitor patients for at least 12 weeks to detect signs and symptoms of TMA complications. If TMA complications are detected after discontinuation, consider initiating plasma exchange or plasmapheresis, infusing fresh frozen plasma, restarting eculizumab therapy, or beginning appropriate organ-specific supportive care.
Children and Adolescents 10 to 19 kg: 600 mg IV infusion single dose; then 7 days after first dose, give 300 mg IV infusion. Thereafter, give 300 mg every 14 days. Studies evaluating the safety and efficacy of eculizumab for aHUS included a total of 25 pediatric patients (ages 2 months to 17 years). LIMITS OF USE: Not indicated for patients with Shiga toxin E. coli related hemolytic uremic syndrome (STEC-HUS). DURATION OF TREATMENT: A duration of therapy is not defined; following discontinuation, monitor patients for at least 12 weeks to detect signs and symptoms of TMA complications. If TMA complications are detected after discontinuation, consider initiating plasma exchange or plasmapheresis, infusing fresh frozen plasma, restarting eculizumab therapy, or beginning appropriate organ-specific supportive care.
Infants and Children older than 2 months and 5 to 9 kg: 300 mg IV infusion every 7 days for the first 2 weeks, then 300 mg IV infusion every 21 days (3 weeks). Studies evaluating the safety and efficacy of eculizumab for aHUS included a total of 25 pediatric patients (ages 2 months to 17 years). LIMITS OF USE: Not indicated for patients with Shiga toxin E. coli related hemolytic uremic syndrome (STEC-HUS). DURATION OF TREATMENT: A duration of therapy is not defined; following discontinuation, monitor patients for at least 12 weeks to detect signs and symptoms of TMA complications. If TMA complications are detected after discontinuation, consider initiating plasma exchange or plasmapheresis, infusing fresh frozen plasma, restarting eculizumab therapy, or beginning appropriate organ-specific supportive care.

For the treatment of anti-acetylcholine antibody positive generalized myasthenia gravis:
NOTE: The FDA has designated eculizumab as an orphan drug for this indication.
Intravenous dosage:
Adults: 900 mg IV infusion every 7 days for the first 4 weeks, followed by a single dose of 1,200 mg IV infusion given 7 days after the fourth dose, and then 1,200 mg IV infusion every 14 days. Clinical response is usually achieved by 12 weeks.

For the treatment of anti-aquaporin-4 (AQP4) antibody positive neuromyelitis optica spectrum disorder (NMOSD):
Intravenous dosage:
Adults: 900 mg IV infusion every 7 days for the first 4 weeks, followed by a single dose of 1,200 mg IV infusion given 7 days after the fourth dose, and then 1,200 mg IV infusion every 14 days.

Therapeutic Drug Monitoring:
Dosage adjustment after plasmapheresis or plasma exchange:
Most recent eculizumab dose of 300 mg: Administer a supplemental dose of 300 mg within 60 minutes after each plasmapheresis or plasma exchange session.
Most recent eculizumab dose of 600 mg or more: Administer a supplemental dose of 600 mg within 60 minutes after each plasmapheresis or plasma exchange session.

Dosage adjustment after fresh frozen plasma infusion:
Most recent eculizumab dose of 300 mg or more: Administer a supplemental dose of 300 mg per unit of fresh frozen plasma 60 minutes before each 1 unit of fresh frozen plasma is infused.

Maximum Dosage Limits:
-Adults
1,200 mg IV infusion/dose for aHUS, myasthenia gravis, and NMOSD; 900 mg IV infusion/dose for PNH.
-Geriatric
1,200 mg IV infusion/dose for aHUS, myasthenia gravis, and NMOSD; 900 mg IV infusion/dose for PNH.
-Adolescents
40 kg or more: 1,200 mg IV infusion/dose for aHUS; safety and efficacy have not been established for PNH, myasthenia gravis, or NMOSD.
30 to 39 kg: 900 mg IV infusion/dose for aHUS; safety and efficacy have not been established for PNH, myasthenia gravis, or NMOSD.
10 to 29 kg: 600 mg IV infusion/dose for aHUS; safety and efficacy have not been established for PNH, myasthenia gravis, or NMOSD.
-Children
40 kg or more: 1,200 mg IV infusion/dose for aHUS; safety and efficacy have not been established for PNH, myasthenia gravis, or NMOSD.
30 to 39 kg: 900 mg IV infusion/dose for aHUS; safety and efficacy have not been established for PNH, myasthenia gravis, or NMOSD.
10 to 29 kg: 600 mg IV infusion/dose for aHUS; safety and efficacy have not been established for PNH, myasthenia gravis, or NMOSD.
5 to 9 kg: 300 mg IV infusion/dose for aHUS; safety and efficacy have not been established for PNH, myasthenia gravis, or NMOSD.
-Infants
2 to 11 months and 5 to 9 kg: 300 mg IV infusion/dose for aHUS; safety and efficacy have not been established for PNH, myasthenia gravis, or NMOSD.
Younger than 2 months or less than 5 kg: Safety and efficacy have not been established.
-Neonates
Safety and efficacy have not been established.

Patients with Hepatic Impairment Dosing
Specific guidelines for dosage adjustments in hepatic impairment are not available. Pharmacokinetic studies in patients with hepatic impairment have not been conducted.

Patients with Renal Impairment Dosing
Specific guidelines for dosage adjustments in renal impairment are not available. Pharmacokinetic studies in patients with renal impairment have not been conducted.

*non-FDA-approved indication

Cholera Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the live cholera vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to cholera bacteria after receiving the vaccine.

Dengue Tetravalent Vaccine, Live: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the dengue virus vaccine. When feasible, administer indicated vaccines at least 2 weeks prior to initiating immunosuppressant medications. If vaccine administration is necessary, consider revaccination following restoration of immune competence. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure after receiving the vaccine.

Efgartigimod Alfa: (Major) Avoid coadministration of efgartigimod and eculizumab. Both medications provide targeted treatment in patients with generalized myasthenia gravis who are anti-acetylcholine receptor antibody positive. Duplicate treatment may increase the risks of immunosuppression and infection.

Efgartigimod Alfa; Hyaluronidase: (Major) Avoid coadministration of efgartigimod and eculizumab. Both medications provide targeted treatment in patients with generalized myasthenia gravis who are anti-acetylcholine receptor antibody positive. Duplicate treatment may increase the risks of immunosuppression and infection.

Ravulizumab: (Major) Avoid coadministration of ravulizumab and eculizumab. For patients switching from eculizumab, administer the loading dose of ravulizumab 2 weeks after the last eculizumab infusion or 1 week after the last eculizumab induction infusion. Both medications provide targeted treatment and duplicate treatment may increase the risks of immunosuppression and infection.

SARS-CoV-2 (COVID-19) vaccines: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.

SARS-CoV-2 Virus (COVID-19) Adenovirus Vector Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.

SARS-CoV-2 Virus (COVID-19) mRNA Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.

SARS-CoV-2 Virus (COVID-19) Recombinant Spike Protein Nanoparticle Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.

Eculizumab is a monoclonal antibody designed to selectively block terminal complement activation. Eculizumab binds to the terminal complement protein C5 with high affinity, which inhibits its cleavage into C5a and C5b and prevents the generation of the terminal complement complex C5b-9. A genetic mutation in patients with paroxysmal nocturnal hemoglobinuria (PNH) causes the formation of abnormal red blood cells, which are deficient in terminal complement inhibitors. The deficiency in terminal complement inhibitors causes the abnormal cells to be sensitive to lysis by terminal complements leading to intravascular hemolysis. In patients with PNH, eculizumab inhibits intravascular hemolysis mediated by terminal complements. Eculizumab inhibits complement-mediated thrombotic microangiopathy in patients with atypical hemolytic uremic syndrome. The presumed mechanism of action of eculizumab in generalized myasthenia gravis is the reduction of the terminal complement complex C5b-9 deposition at the neuromuscular junction. Eculizumab may inhibit aquaporin-4-antibody induced terminal complement C5b-9 deposition in neuromyelitis optica spectrum disorder.

Eculizumab is administered via intravenous infusion. The volume of distribution for a typical 70 kg patient is 5 to 8 L. Steady state is achieved at 4 weeks with an accumulation ratio of approximately 2-fold for all indications. Pharmacokinetics are dose-linear and time-independent over the 600 to 1,200 mg dose range with inter-individual variability of 21% to 38%. The half-life of eculizumab is approximately 270 to 414 hours.


-Route-Specific Pharmacokinetics
Intravenous Route
The mean +/- SD Cmax and Ctrough of eculizumab were 194 +/- 76 mcg/mL and 97 +/- 60 mcg/mL, respectively, after IV maintenance doses of 900 mg every 2 weeks for 26 weeks in patients with paroxysmal nocturnal hemoglobinuria (PNH). The mean Ctrough of eculizumab was 242 +/- 101 mcg/mL after IV maintenance doses of 1,200 mg every 2 weeks for 26 weeks in patients with atypical hemolytic uremic syndrome (aHUS). The mean +/- SD Cmax and Ctrough of eculizumab were 783 +/- 288 mcg/mL and 341 +/- 172 mcg/mL, respectively, after IV maintenance doses of 1,200 mg every 2 weeks for 26 weeks in patients with generalized myasthenia gravis (gMG). The mean +/- SD Cmax and Ctrough of eculizumab were 877 +/- 331 mcg/mL and 429 +/- 188 mcg/mL, respectively, after IV maintenance doses of 1,200 mg every 2 weeks for 24 weeks in patients with neuromyelitis optica spectrum disorder (NMOSD). In PNH, eculizumab reduced serum LDH concentrations from 2,200 +/- 1,034 units/L (mean +/- SD) at baseline to 700 +/- 388 units/L in 1 week during a placebo-controlled study; the effect was maintained through week 26 (327 +/- 433 units/L). The lowering effect on LDH was maintained through week 52 in a single-arm study. Free C5 concentrations of less than 0.5 mcg/mL were correlated with the complete blockade of terminal complement activity in patients with PNH, aHUS, gMG, and NMOSD.


-Special Populations
Hepatic Impairment
Pharmacokinetics have not been evaluated in patients with hepatic impairment.

Renal Impairment
Renal function did not affect the pharmacokinetics of eculizumab in patients with paroxysmal nocturnal hemoglobinuria (CrCl 8 to 396 mL/minute), atypical hemolytic uremic syndrome (eGFR 5 to 105 mL/minute/1.73 m2), or generalized myasthenia gravis (eGFR 44 to 168 mL/minute/1.73 m2).

Pediatrics
The pharmacokinetics of eculizumab were not affected by age in patients 2 months or older.

Geriatric
The pharmacokinetics of eculizumab were not affected by age in patients up to 85 years.

Gender Differences
The pharmacokinetics of eculizumab were not affected by gender.

Ethnic Differences
The pharmacokinetics of eculizumab were not affected by race.

Other
Plasma exchange or infusion
The clearance of eculizumab increased by approximately 250-fold during plasma exchange or infusion. The half-life decreased to 1.26 hours.