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  • CLASSES

    C5 Complement Inhibitors

    BOXED WARNING

    Fungal infection, immunosuppression, infection, meningococcal infection, neutropenia, streptococcal infection

    The use of eculizumab increases a patient's susceptibility to serious meningococcal infection (septicemia and/or meningitis). Life-threatening and fatal meningococcal infections have occurred in patients treated with eculizumab. Meningococcal infection may become rapidly life-threatening or fatal if not recognized and treated early. Monitor patients for signs of meningococcal infections during therapy. Eculizumab is contraindicated in patients with unresolved serious Neisseria meningitidis infection and in patients who are not currently vaccinated against Neisseria meningitidis, unless the risks of delaying treatment outweigh the risks of developing a meningococcal infection. Vaccinate for meningococcal disease according to the most current Advisory Committee on Immunization Practices (ACIP) recommendations for patients with complement deficiencies. Revaccinate patients in accordance with ACIP recommendations, considering the duration of therapy. Immunize patients without a history of meningococcal vaccination at least 2 weeks prior to receiving the first dose of eculizumab. If urgent therapy is indicated in an unvaccinated patient, administer the meningococcal vaccine as soon as possible and provide patients with 2 weeks of antibacterial drug prophylaxis. Vaccination reduces, but does not eliminate, the risk of meningococcal infections. Serious meningococcal infections have been reported in vaccinated patients receiving eculizumab treatment. Eculizumab blocks terminal complement activation and results in a complement deficiency similar to that of patients with complement deficiency; therefore patients may have increased susceptibility to other types of infections, especially with encapsulated bacteria. Additionally, fungal infection with Aspergillus sp. have occurred in patients with immunosuppression and those with neutropenia. Pediatric patients treated with eculizumab may be at increased risk of developing serious infections, such as streptococcal infection due to Streptococcus pneumoniae or infection due to Haemophilus influenzae type b (Hib). Administer vaccinations for the prevention of streptococcal and Hib infections according to ACIP guidelines. Use caution when administering eculizumab to patients with any systemic infection. If an infection is suspected, the patients should be evaluated immediately and treated with antibiotics, if necessary. Strongly consider discontinuing eculizumab during the treatment of such infections.

    DEA CLASS

    Rx

    DESCRIPTION

    Monoclonal antibody that inhibits terminal complement activation
    Used for paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic uremic syndrome (aHUS), anti-acetylcholine receptor antibody positive generalized myasthenia gravis, and anti-aquaporin-4 antibody positive neuromyelitis optica spectrum disorder (NMOSD)
    Associated with an increased risk of meningococcal infection

    COMMON BRAND NAMES

    Soliris

    HOW SUPPLIED

    Soliris Intravenous Inj Sol: 1mL, 10mg

    DOSAGE & INDICATIONS

    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 .
    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.

    MAXIMUM DOSAGE

    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.

    DOSING CONSIDERATIONS

    Hepatic Impairment

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

    Renal Impairment

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

    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.

    STORAGE

    Soliris:
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Discard unused portion. Do not store for later use.
    - Do not freeze
    - Protect from light
    - Refrigerate (between 36 and 46 degrees F)
    - Store in carton until time of use

    CONTRAINDICATIONS / PRECAUTIONS

    Fungal infection, immunosuppression, infection, meningococcal infection, neutropenia, streptococcal infection

    The use of eculizumab increases a patient's susceptibility to serious meningococcal infection (septicemia and/or meningitis). Life-threatening and fatal meningococcal infections have occurred in patients treated with eculizumab. Meningococcal infection may become rapidly life-threatening or fatal if not recognized and treated early. Monitor patients for signs of meningococcal infections during therapy. Eculizumab is contraindicated in patients with unresolved serious Neisseria meningitidis infection and in patients who are not currently vaccinated against Neisseria meningitidis, unless the risks of delaying treatment outweigh the risks of developing a meningococcal infection. Vaccinate for meningococcal disease according to the most current Advisory Committee on Immunization Practices (ACIP) recommendations for patients with complement deficiencies. Revaccinate patients in accordance with ACIP recommendations, considering the duration of therapy. Immunize patients without a history of meningococcal vaccination at least 2 weeks prior to receiving the first dose of eculizumab. If urgent therapy is indicated in an unvaccinated patient, administer the meningococcal vaccine as soon as possible and provide patients with 2 weeks of antibacterial drug prophylaxis. Vaccination reduces, but does not eliminate, the risk of meningococcal infections. Serious meningococcal infections have been reported in vaccinated patients receiving eculizumab treatment. Eculizumab blocks terminal complement activation and results in a complement deficiency similar to that of patients with complement deficiency; therefore patients may have increased susceptibility to other types of infections, especially with encapsulated bacteria. Additionally, fungal infection with Aspergillus sp. have occurred in patients with immunosuppression and those with neutropenia. Pediatric patients treated with eculizumab may be at increased risk of developing serious infections, such as streptococcal infection due to Streptococcus pneumoniae or infection due to Haemophilus influenzae type b (Hib). Administer vaccinations for the prevention of streptococcal and Hib infections according to ACIP guidelines. Use caution when administering eculizumab to patients with any systemic infection. If an infection is suspected, the patients should be evaluated immediately and treated with antibiotics, if necessary. Strongly consider discontinuing eculizumab during the treatment of such infections.

    Infants, neonates

    The safe and effective use of eculizumab to treat paroxysmal nocturnal hemoglobinuria (PNH) has not been established in infants, children, or adolescents less than 18 years of age. However, eculizumab is FDA-approved to treat atypical hemolytic uremic syndrome (aHUS) in pediatric patients at least 2 months of age and weighing at least 5 kg; the approval is based on the results of 3 studies that included a total of 25 pediatric patients. The safety and effectiveness of eculizumab for the treatment of aHUS appear similar in pediatric and adult patients. Safety and efficacy of eculizumab have not been established in neonates and infants less than 2 months of age.

    Pregnancy

    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.

    Breast-feeding

    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.

    ADVERSE REACTIONS

    Severe

    anaphylactoid reactions / Rapid / Incidence not known
    meningococcal infection / Delayed / Incidence not known
    thrombotic microangiopathy / Delayed / Incidence not known
    hemolytic-uremic syndrome / Delayed / Incidence not known

    Moderate

    hypertension / Early / 18.0-33.0
    anemia / Delayed / 2.0-26.0
    peripheral edema / Delayed / 8.0-23.0
    cystitis / Delayed / 8.0-22.0
    sinus tachycardia / Rapid / 21.0-21.0
    hypotension / Rapid / 17.0-17.0
    leukopenia / Delayed / 5.0-15.0
    hypokalemia / Delayed / 12.0-12.0
    proteinuria / Delayed / 10.0-10.0
    constipation / Delayed / 7.0-9.0
    conjunctivitis / Delayed / 9.0-9.0
    cataracts / Delayed / 6.0-6.0
    lymphopenia / Delayed / 5.0-5.0
    antibody formation / Delayed / 0-3.0
    meningitis / Delayed / Incidence not known

    Mild

    fever / Early / 2.0-50.0
    headache / Early / 18.0-44.0
    diarrhea / Early / 15.0-37.0
    cough / Delayed / 12.0-36.0
    abdominal pain / Early / 8.0-32.0
    infection / Delayed / 5.0-32.0
    pharyngitis / Delayed / 10.0-32.0
    vomiting / Early / 16.0-30.0
    nausea / Early / 10.0-23.0
    nasal congestion / Early / 21.0-21.0
    back pain / Delayed / 10.0-19.0
    rash / Early / 14.0-18.0
    rhinitis / Early / 18.0-18.0
    asthenia / Delayed / 5.0-17.0
    dizziness / Early / 15.0-15.0
    musculoskeletal pain / Early / 6.0-15.0
    dyspepsia / Early / 14.0-14.0
    muscle cramps / Delayed / 5.0-14.0
    insomnia / Early / 14.0-14.0
    fatigue / Early / 12.0-13.0
    arthralgia / Delayed / 11.0-13.0
    influenza / Delayed / 5.0-11.0
    pruritus / Rapid / 10.0-10.0
    paresthesias / Delayed / 8.0-8.0
    sinusitis / Delayed / 6.0-7.0
    myalgia / Early / 7.0-7.0
    alopecia / Delayed / 5.0-5.0
    shivering / Rapid / Incidence not known

    DRUG INTERACTIONS

    There are no drug interactions associated with Eculizumab products.

    PREGNANCY AND LACTATION

    Pregnancy

    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.

    MECHANISM OF ACTION

    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.[45742]

    PHARMACOKINETICS

    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.[45742]

    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.[45742]