Ravulizumab is an intravenously or subcutaneously administered complement inhibitor indicated for the treatment of paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic uremic syndrome (aHUS), anti-acetylcholine receptor (AChR) antibody-positive generalized myasthenia gravis (gMG), and anti-aquaporin-4 antibody-positive neuromyelitis optica spectrum disorder (NMOSD). Ravulizumab increases the risk of serious, life-threatening, or fatal infections caused by meningococcal bacteria in any serogroup. Life-threatening and fatal meningococcal infections have occurred in both vaccinated and unvaccinated persons treated with complement inhibitors; vaccination for meningococcal disease is recommended to be completed at least 2 weeks before starting ravulizumab to reduce the risk of 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 parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
--Ravulizumab 10 mg/mL is a clear to translucent, slight whitish color solution.
-Ravulizumab 100 mg/mL is a translucent, clear to yellowish color solution.
Intravenous Administration
-Do not mix together the 100 mg/mL vials and the 10 mg/mL vials.
Dilution of the 10 mg/mL (30 mL) vials
-Withdraw the calculated volume of ravulizumab from the appropriate number of vials.
-Dilute in an infusion bag containing 0.9% Sodium Chloride Injection to a final concentration of 5 mg/mL.
-Mix gently; do not shake.
-Administer immediately after preparation.
-Storage: Protect from light. If not used immediately, store refrigerated at 2 to 8 degrees C (36 to 46 degrees F) for up to 24 hours taking into account the expected infusion time. Once removed from refrigeration, administer within 6 hours. Do not freeze. Vials are single-dose.
Dilution of the 100 mg/mL (3 mL and 11 mL) vials
-Withdraw the calculated volume of ravulizumab from the appropriate number of vials.
-Dilute in an infusion bag containing 0.9% Sodium Chloride Injection to a final concentration of 50 mg/mL.
-Mix gently; do not shake.
-Administer immediately after preparation.
-Storage: Protect from light. If not used immediately, store refrigerated at 2 to 8 degrees C (36 to 46 degrees F) for up to 24 hours taking into account the expected infusion time. Once removed from refrigeration, administer within 4 hours. Do not freeze. Vials are single-dose.
Intravenous Infusion
-Allow admixture to adjust to room temperature before administration. Do not heat admixture with any heat source other than ambient air temperature.
-Infuse through a 0.2 or 0.22-micron filter.
-Slow or stop the infusion if an adverse reaction occurs.
-Monitor the patient for at least 1 hour after completion of the infusion for signs and symptoms of an infusion-related reaction.
-Flush the entire line with 0.9% Sodium Chloride Injection after ravulizumab administration.
Administration of ravulizumab 5 mg/mL dilution (final concentration) based on patient weight and corresponding dose:
-Loading dose:
--Weighing 100 kg or more = 3,000 mg load
--Minimum infusion time: 1.8 hours
-Maximum infusion rate: 334 mL/hour
-Weighing 60 to 99 kg = 2,700 mg load
--Minimum infusion time: 1.7 hours
-Maximum infusion rate: 318 mL/hour
-Weighing 40 to 59 kg = 2,400 mg load
--Minimum infusion time: 1.9 hours
-Maximum infusion rate: 253 mL/hour
-Weighing 30 to 39 kg = 1,200 mg load
--Minimum infusion time: 1.3 hours
-Maximum infusion rate: 185 mL/hour
-Weighing 20 to 29 kg = 900 mg load
--Minimum infusion time: 1.5 hours
-Maximum infusion rate: 120 mL/hour
-Weighing 10 to 19 kg = 600 mg load
--Minimum infusion time: 1.9 hours
-Maximum infusion rate: 64 mL/hour
-Weighing 5 to 9 kg = 600 mg load
--Minimum infusion time: 3.8 hours
-Maximum infusion rate: 32 mL/hour
-Maintenance dose:
--Weighing 100 kg or more = 3,600 mg dose
--Minimum infusion time: 2.2 hours
-Maximum infusion rate: 328 mL/hour
-Weighing 60 to 99 kg = 3,300 mg dose
--Minimum infusion time: 2 hours
-Maximum infusion rate: 330 mL/hour
-Weighing 40 to 59 kg = 3,000 mg dose
--Minimum infusion time: 2.3 hours
-Maximum infusion rate: 261 mL/hour
-Weighing 30 to 39 kg = 2,700 mg dose
--Minimum infusion time: 2.8 hours
-Maximum infusion rate: 193 mL/hour
-Weighing 20 to 29 kg = 2,100 mg dose
--Minimum infusion time: 3.3 hours
-Maximum infusion rate: 128 mL/hour
-Weighing 10 to 19 kg = 600 mg dose
--Minimum infusion time: 1.9 hours
-Maximum infusion rate: 64 mL/hour
-Weighing 5 to 9 kg = 300 mg dose
--Minimum infusion time: 1.9 hours
-Maximum infusion rate: 32 mL/hour
-Supplemental dose after each of plasmapheresis or plasma exchange intervention, or IVIG treatment cycle:
--Weighing 100 kg or more = 600 mg dose
--Minimum infusion time: 0.4 hours
-Maximum infusion rate: 300 mL/hour
-Weighing 100 kg or more = 1,500 mg dose
--Minimum infusion time: 1 hour
-Maximum infusion rate: 300 mL/hour
-Weighing 100 kg or more = 1,800 mg dose
--Minium infusion time: 1.1 hours
-Maximum infusion rate: 327 mL/hour
-Weighing 60 to 99 kg = 600 mg dose
--Minimum infusion time: 0.4 hours
-Maximum infusion rate: 300 mL/hour
-Weighing 60 to 99 kg = 1,500 mg dose
--Minimum infusion time: 1 hour
-Maximum infusion rate: 300 mL/hour
-Weighing 60 to 99 kg = 1,800 mg dose
--Minimum infusion time: 1.1 hours
-Maximum infusion rate: 327 mL/hour
-Weighing 40 to 59 kg = 600 mg dose
--Minimum infusion time: 0.5 hours
-Maximum infusion rate: 240 mL/hour
-Weighing 40 to 59 kg = 1,200 mg dose
--Minimum infusion time: 1 hour
-Maximum infusion rate: 240 mL/hour
-Weighing 40 to 59 kg = 1,500 mg dose
--Minimum infusion time: 1.2 hours
-Maximum infusion rate: 250 mL/hour
Administration of ravulizumab 50 mg/mL dilution (final concentration) based on patient weight and corresponding dose:
-Loading dose:
--Weighing 100 kg or more = 3,000 mg load
--Minimum infusion time: 0.4 hours
-Maximum infusion rate: 150 mL/hour
-Weighing 60 to 99 kg = 2,700 mg load
--Minimum infusion time: 0.6 hours
-Maximum infusion rate: 90 mL/hour
-Weighing 40 to 59 kg = 2,400 mg load
--Minimum infusion time: 0.8 hours
-Maximum infusion rate: 60 mL/hour
-Weighing 30 to 39 kg = 1,200 mg load
--Minimum infusion time: 0.5 hours
-Maximum infusion rate: 48 mL/hour
-Weighing 20 to 29 kg = 900 mg load
--Minimum infusion time: 0.6 hours
-Maximum infusion rate: 30 mL/hour
-Weighing 10 to 19 kg = 600 mg load
--Minimum infusion time: 0.8 hours
-Maximum infusion rate: 15 mL/hour
-Weighing 5 to 9 kg = 600 mg load
--Minimum infusion time: 1.4 hours
-Maximum infusion rate: 9 mL/hour
-Maintenance dose:
--Weighing 100 kg or more = 3,600 mg dose
--Minimum infusion time: 0.5 hours
-Maximum infusion rate: 144 mL/hour
-Weighing 60 to 99 kg = 3,300 mg dose
--Minimum infusion time: 0.7 hours
-Maximum infusion rate: 95 mL/hour
-Weighing 40 to 59 kg = 3,000 mg dose
--Minimum infusion time: 0.9 hours
-Maximum infusion rate: 67 mL/hour
-Weighing 30 to 39 kg = 2,700 mg dose
--Minimum infusion time: 1.1 hours
-Maximum infusion rate: 50 mL/hour
-Weighing 20 to 29 kg = 2,100 mg dose
--Minimum infusion time: 1.3 hours
-Maximum infusion rate: 33 mL/hour
-Weighing 10 to 19 kg = 600 mg dose
--Minimum infusion time: 0.8 hours
-Maximum infusion rate: 15 mL/hour
-Weighing 5 to 9 kg = 300 mg dose
--Minimum infusion time: 0.8 hours
-Maximum infusion rate: 8 mL/hour
-Supplemental dose after each of plasmapheresis or plasma exchange intervention, or IVIG treatment cycle:
--Weighing 100 kg or more = 600 mg dose
--Minimum infusion time: 0.17 hours
-Maximum infusion rate: 71 mL/hour
-Weighing 100 kg or more = 1,500 mg dose
--Minimum infusion time: 0.25 hours
-Maximum infusion rate: 120 mL/hour
-Weighing 100 kg or more = 1,800 mg dose
--Minimum infusion time: 0.28 hours
-Maximum infusion rate: 129 mL/hour
-Weighing 60 to 99 kg = 600 mg dose
--Minimum infusion time: 0.2 hours
-Maximum infusion rate: 60 mL/hour
-Weighing 60 to 99 kg = 1,500 mg dose
--Minimum infusion time: 0.36 hours
-Maximum infusion rate: 83 mL/hour
-Weighing 60 to 99 kg = 1,800 mg dose
--Minimum infusion time: 0.42 hours
-Maximum infusion rate: 86 mL/hour
-Weighing 40 to 59 kg = 600 mg dose
--Minimum infusion time: 0.25 hours
-Maximum infusion rate: 48 mL/hour
-Weighing 40 to 59 kg = 1,200 mg dose
--Minimum infusion time: 0.42 hours
-Maximum infusion rate: 57 mL/hour
-Weighing 40 to 59 kg = 1,500 mg dose
--Minimum infusion time: 0.5 hours
-Maximum infusion rate: 60 mL/hour
Subcutaneous Administration
-Patients and caregivers may administer ravulizumab via on-body delivery system after training from a health care provider.
Preparation:
-Wait at least 45 minutes for the on-body injectors and prefilled cartridges to naturally reach room temperature prior to administration.
-Storage: Do not return to the refrigerator. Discard after 3 days if unused.
Administration:
-Load the first cartridge into the first on-body injector and secure in place before closing the cartridge door on the injector. Do not insert the cartridge more than 5 minutes before the injection to prevent from drying out the solution.
-Remove adhesive backing of the first on-body injector and apply onto a clean, dry, injection site on the abdomen, thigh or, upper arm. Do not apply to areas where the skin is tender, bruised, red, or hard. Avoid injecting into areas with scars or stretch marks. Rotate injection sites.
-Start the injection by firmly pressing and releasing the blue start button.
-Do not remove until the injection is complete. Each injection is delivered over approximately 10 minutes. Completion is signaled by the solid green status light, 3 beeping sounds, and the white plunger filling the medication window.
-Repeat the above steps for the second on-body injector. The 2 on-body delivery systems can be administered concurrently or sequentially.
-Monitor for signs and symptoms of infusion-related reaction for at least 1 hour after the injection. If an allergic reaction occurs, stop the injection, remove the on-body injector, and seek immediate medical attention.
Upper respiratory tract infection (8% to 39%), which included nasopharyngitis, rhinitis, rhinorrhea, oropharyngeal pain, pharyngitis, and upper respiratory tract inflammation, was among the most commonly reported adverse reactions reported in adults during clinical trials for paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic syndrome (aHUS). Urinary tract infection (17%), gastrointestinal infection (13% to 14%) including gastroenteritis, enterocolitis, and infectious colitis, pneumonia (13%), tonsillitis (13% or less), and viral infection (less than 10%) were reported during adult aHUS trials. In pediatric trials, upper respiratory tract infection (47% to 54%) was also common; viral gastroenteritis (13%), tonsillitis (13%), and viral infection (less than 10%) occurred less frequently. Death due to sepsis was reported in 3 subjects overall during clinical trials. In clinical trials for PNH, 3 of 261 subjects (1.1%) developed serious meningococcal infection/sepsis while receiving ravulizumab treatment; all 3 subjects had been vaccinated and recovered while continuing treatment. Upper respiratory tract infection (14%) and urinary tract infection (6%) were reported in adults who received ravulizumab during a randomized, double-blind, placebo-controlled trial for myasthenia gravis. Infections were the most serious adverse reaction reported from the trial, reported in at least 9% of subjects who received ravulizumab. A single case of fatal COVID-19 pneumonia occurred in subject treated with ravulizumab. In clinical trials for the treatment of neuromyelitis optica spectrum disorder (NMOSD) in adults, COVID-19 (24%) and urinary tract infection (10%) were among the most commonly reported adverse reactions. Cystitis (9%), upper respiratory tract infection (9%), nasopharyngitis (5%), and sinusitis (5%) were also reported. The use of ravulizumab increases a person's susceptibility to encapsulated bacterial infections, especially those caused by N. meningitidis but also S. pneumoniae, H. influenzae, and to a lesser extent, N. gonorrhoeae. Serious infections with Neisseria species, other than N. meningitidis, including disseminated gonococcal 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 ravulizumab in persons who are being treated for a serious meningococcal infection, depending on the risks of interrupting treatment in the disease being treated.
Hypertension (24%) and hypotension (13%) were reported in subjects treated with ravulizumab during adult trials for atypical hemolytic uremic syndrome (aHUS). Incidence rates in pediatric trials were similar (25% and 13%, respectively). Infusion-related reactions may lead to cardiovascular instability or respiratory compromise; interrupt the infusion, and institute appropriate supportive measures if such symptoms occur. In clinical trials, approximately 1% to 7% of subjects experienced infusion-related reactions, including lower back pain, abdominal pain, muscle spasms, drop in blood pressure, elevation in blood pressure, rigors, limb discomfort, drug hypersensitivity, dysgeusia, and drowsiness; these reactions did not require drug discontinuation. Subcutaneous ravulizumab administration resulted in injection site reaction in 27% of subjects during clinical trials; injection site reactions included application site rash and device allergy as well as bruising, erythema, hematoma, induration, inflammation, pain, pruritus, rash, swelling, urticaria at the injection site. Anaphylaxis/anaphylactoid reactions have been reported with postmarketing use of ravulizumab.
Fever (7% to 19% adults; 15% to 50% pediatrics) was reported with ravulizumab during clinical trials. In paroxysmal nocturnal hemoglobinuria trials in adults, serious adverse reactions, including fever and hyperthermia, were reported in 15 (6.8%) subjects treated with ravulizumab. General disorders including peripheral edema (17%) and fatigue (14%) were reported in adult clinical trials for atypical hemolytic uremic syndrome (aHUS). In clinical trials for the treatment of neuromyelitis optica spectrum disorder (NMOSD) in adults, fever (9%), chills (5%), fatigue (5%), malaise (5%), non-cardiac chest pain (unspecified) (5%), and vaccination site pain (5%) were reported.
Diarrhea (4% to 13%), nausea (9%), and abdominal pain (6%) were reported in ravulizumab-treated adults during paroxysmal nocturnal hemoglobinuria (PNH) clinical trials. Similar gastrointestinal adverse events were reported during adult trials for atypical hemolytic uremic syndrome (aHUS) at a greater frequency and include diarrhea (31% to 38%), nausea (13% to 26%), vomiting (25% to 26%), abdominal pain (12% to 19%), and constipation (14% to 25%). During pediatric trials, diarrhea (33%), vomiting (20%), abdominal pain (13% to 23%), and constipation (15% to 27%) also occurred. Diarrhea (15%) and abdominal pain (6%) were reported in adults who received ravulizumab during a randomized, double-blind, placebo-controlled trial for myasthenia gravis. Gastrointestinal adverse reactions were also reported during clinical trials of adults for neuromyelitis optica spectrum disorder (NMOSD) and include constipation (7%), vomiting (7%), diarrhea (5%) and gastroesophageal reflux (5%).
Arthralgia (5%) and extremity pain (6%) were reported in ravulizumab-treated subjects during paroxysmal nocturnal hemoglobinuria (PNH) clinical trials. Musculoskeletal effects were also reported during atypical hemolytic uremic syndrome (aHUS) trials in adults and include arthralgia (22%), myalgia (19%), back pain (12%), muscle spasms or muscle cramps (10%), and extremity pain (10% to 13%). Myalgia (13%), extremity pain (13% to 15%), and contusion (19%) were reported in pediatric subjects. Back pain was reported in 8% of adults who received ravulizumab during a randomized, double-blind, placebo-controlled trial for myasthenia gravis. In clinical trials for the treatment of neuromyelitis optica spectrum disorder (NMOSD) in adults, back pain (12%), arthralgia (10%), and myalgia (5%) were all reported.
Headache was reported in 9% to 40% of adults and 23% to 27% of pediatric subjects receiving ravulizumab during clinical trials. Additionally, dizziness (5%) and anxiety (14%) were reported in ravulizumab-treated adults during clinical trials for paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic syndrome (aHUS), respectively. Dizziness was reported in 9% of adults who received ravulizumab during a randomized, double-blind, placebo-controlled trial for myasthenia gravis. In clinical trials for the treatment of neuromyelitis optica spectrum disorder (NMOSD) in adults, headache (24%), dizziness (7%), and migraine (5%) were reported.
As with all therapeutic proteins, there is a potential for immunogenicity with ravulizumab. During clinical trials with intravenous ravulizumab, treatment-emergent antibody formation was detected in 1 of 219 subjects (0.5%) with paroxysmal nocturnal hemoglobinuria (PNH) and 1 of 71 subjects (1.4%) with atypical hemolytic uremic syndrome (aHUS). No treatment-emergent antibodies to ravulizumab were detected in subjects receiving subcutaneous ravulizumab or subjects with generalized myasthenia gravis or neuromyelitis optica spectrum disorder (NMOSD). There was no apparent correlation of antibody development to altered pharmacokinetic profile, clinical response, or adverse events. However, the assay used to measure anti-drug antibodies is subject to interference by serum ravulizumab, which may result in an underestimation of incidence.
Anemia (14% adults; 13% to 23% pediatrics) and lymphadenopathy (5% to 13%) were reported in ravulizumab-treated subjects during clinical trials. A subject died from intracranial bleeding during clinical trials for atypical hemolytic uremic syndrome (aHUS).
Anorexia (13%), iron deficiency (13%), hypokalemia (10%), and vitamin D deficiency (19%) were reported in ravulizumab-treated subjects during adult clinical trials for atypical hemolytic uremic syndrome (aHUS). Anorexia (13%), iron deficiency (13%), and decreased vitamin D (19%) were also reported during pediatric trials.
Cough (17%) and dyspnea (13% to 17%) were reported in ravulizumab-treated subjects during adult clinical trials for atypical hemolytic uremic syndrome (aHUS). Both cough (19%) and dyspnea (13%) were also reported during pediatric trials for aHUS. In clinical trials for the treatment of neuromyelitis optica spectrum disorder (NMOSD) in adults, cough was reported in 5% of subjects. Respiratory compromise may be related to an infusion-related reaction; interrupt the infusion, and institute appropriate supportive measures if such symptoms occur.
Alopecia (10%), xerosis (10%), and rash (19%) were reported in ravulizumab-treated subjects during adult clinical trials for atypical hemolytic uremic syndrome (aHUS). Rash (20%) was also reported during pediatric trials.
Consider premedication before use of the on-body injector for subcutaneous ravulizumab in persons with a known allergy to acrylic adhesive as use may result in an allergic reaction. If signs of allergy occur, initiate supportive measures. The on-body injector for subcutaneous ravulizumab uses acrylic adhesive.
Ravulizumab is contraindicated in persons with unresolved meningococcal infection. Ravulizumab 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 ravulizumab, according to current Advisory Committee on Immunization Practices (ACIP) recommendations for persons receiving a complement inhibitor. Revaccinate considering the duration of ravulizumab 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 ravulizumab 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 ravulizumab. Consider the benefits and risks of treatment with ravulizumab 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 ravulizumab 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 ravulizumab 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. Infants and children treated with ravulizumab may be at increased risk of developing serious S. pneumoniae and H. influenzae type b (Hib) infections; administer vaccinations for the prevention of streptococcal 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.
Closely monitor for signs and symptoms of hemolysis after discontinuing ravulizumab treatment for paroxysmal nocturnal hemoglobinuria. Signs and symptoms may include elevated LDH along with a sudden decrease in paroxysmal nocturnal hemoglobinuria clone size or hemoglobin, or the reappearance of symptoms such as fatigue, hemoglobinuria, abdominal pain, shortness of breath, dysphagia, erectile dysfunction, or major vascular adverse events such as thrombosis. Monitor patients for at least 16 weeks after therapy discontinuation. Consider treatment reinitiation if signs and symptoms of hemolysis occur.
Monitor patients for clinical symptoms and laboratory signs of thrombotic microangiopathy (TMA) for at least 12 months after discontinuing ravulizumab treatment for atypical hemolytic uremic syndrome. Consider reinitiation of ravulizumab treatment or appropriate organ-specific supportive measures if TMA complications occur after treatment discontinuation. Clinical symptoms of TMA include changes in mental status, seizures, angina, dyspnea, thrombosis, or increasing blood pressure. In addition, at least 2 of the following laboratory signs observed concurrently and confirmed by a second measurement 28 days apart with no interruption may identify TMA complications after therapy discontinuation: 1) decrease in platelet count of 25% or more a compared to either baseline or peak platelet count during treatment, 2) an increase in serum creatinine of 25% or more as compared to baseline or to nadir during treatment, or 3) an increase in serum LDH of 25% of more as compared to baseline or to nadir during treatment.
There are no available data with ravulizumab use during human pregnancy to inform a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. There are risks to the mother and fetus associated with untreated paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic syndrome (aHUS). PNH in pregnancy is associated with worsening cytopenias, thrombotic events, infections, bleeding, miscarriage, increased maternal mortality, premature delivery, and fetal death. In pregnancy, aHUS is associated with preeclampsia, preterm delivery, intrauterine growth restriction, low birth weight, and fetal death. Animal studies using a mouse analog of ravulizumab showed increased rates of developmental abnormalities and an increased rate of dead and moribund offspring at doses 0.8- to 2.2-times the human dose. Among 230 mice offspring born to mothers exposed to the higher antibody dose during organogenesis, 2 cases of retinal dysplasia and 1 case of umbilical hernia were observed. When maternal exposure occurred during implantation through weaning, a higher number of male offspring became moribund or died (1/25 controls, 2/25 low-dose group, 5/25 high-dose group). Human IgG are known to cross the placenta; thus, ravulizumab may potentially cause terminal complement inhibition in the fetal circulation.
Discontinue breast-feeding during ravulizumab treatment and for 8 months after the final dose. There are no data on the presence of ravulizumab in human milk, the effect on the breast-fed child, or the effect on milk production. However, many medicinal products and immunoglobulins are secreted into human milk.
General Dosing Information
-Vaccinate persons against meningococcal infection (serogroups A, C, W, Y, and B) at least 2 weeks prior to initiation of ravulizumab according to the most current Advisory Committee on Immunization Practices (ACIP) recommendations for persons receiving a complement inhibitor.
--If urgent ravulizumab 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 intravenous dosing schedule is allowed to occasionally vary within the 7 days of the scheduled administration day (except for the first maintenance dose); administer the subsequent dose according to the original schedule.
-The subcutaneous dosing schedule is allowed to occasionally vary by 1 day of the scheduled administration day; administer the subsequent dose according to the original schedule.
-Switching from eculizumab or between ravulizumab administration routes:
--Conversion from eculizumab to IV or subcutaneous ravulizumab: Administer ravulizumab IV loading dose at the time of the next scheduled eculizumab dose. Begin ravulizumab IV or subcutaneous maintenance dosing 2 weeks after the IV loading dose.
-Conversion from IV ravulizumab to subcutaneous ravulizumab: Begin ravulizumab subcutaneous maintenance dosing 2 weeks after IV loading dose or 8 weeks after the last IV maintenance dose.
-Conversion from subcutaneous ravulizumab to IV ravulizumab: Begin ravulizumab IV maintenance dosing 1 week after the last subcutaneous maintenance dose.
-A supplemental dose of ravulizumab is required in the setting of plasmapheresis, plasma exchange, or during use of intravenous immunoglobulin as ravulizumab concentrations may be reduced.
For the treatment of paroxysmal nocturnal hemoglobinuria (PNH):
Intravenous dosage:
Adults weighing 100 kg or more: 3,000 mg IV loading dose, then 3,600 mg IV every 8 weeks starting 2 weeks after the loading dose.
Adults weighing 60 to 99 kg: 2,700 mg IV loading dose, then 3,300 mg IV every 8 weeks starting 2 weeks after the loading dose.
Adults weighing 40 to 59 kg: 2,400 mg IV loading dose, then 3,000 mg IV every 8 weeks starting 2 weeks after the loading dose.
Adolescents weighing 100 kg or more: 3,000 mg IV loading dose, then 3,600 mg IV every 8 weeks starting 2 weeks after the loading dose.
Children and Adolescents weighing 60 to 99 kg: 2,700 mg IV loading dose, then 3,300 mg IV every 8 weeks starting 2 weeks after the loading dose.
Children and Adolescents weighing 40 to 59 kg: 2,400 mg IV loading dose, then 3,000 mg IV every 8 weeks starting 2 weeks after the loading dose.
Children and Adolescents weighing 30 to 39 kg: 1,200 mg IV loading dose, then 2,700 mg IV every 8 weeks starting 2 weeks after the loading dose.
Children weighing 20 to 29 kg: 900 mg IV loading dose, then 2,100 mg IV every 8 weeks starting 2 weeks after the loading dose.
Infants and Children weighing 10 to 19 kg: 600 mg IV loading dose, then 600 mg IV every 4 weeks starting 2 weeks after the loading dose.
Infants and Children weighing 5 to 9 kg: 600 mg IV loading dose, then 300 mg IV every 4 weeks starting 2 weeks after the loading dose.
Subcutaneous dosage:
Adults weighing 40 kg or more: 490 mg subcutaneously once weekly starting 2 weeks after IV loading dose or 8 weeks after IV maintenance dose.
For the treatment of atypical hemolytic-uremic syndrome (aHUS):
NOTE: Ravulizumab is not indicated for the treatment of patients with Shiga toxin E. coli-related hemolytic-uremic syndrome (STEC-HUS).
Intravenous dosage:
Adults weighing 100 kg or more: 3,000 mg IV loading dose, then 3,600 mg IV every 8 weeks starting 2 weeks after the loading dose. Treat for at least 6 months.
Adults weighing 60 to 99 kg: 2,700 mg IV loading dose, then 3,300 mg IV every 8 weeks starting 2 weeks after the loading dose. Treat for at least 6 months.
Adults weighing 40 to 59 kg: 2,400 mg IV loading dose, then 3,000 mg IV every 8 weeks starting 2 weeks after the loading dose. Treat for at least 6 months.
Adolescents weighing 100 kg or more: 3,000 mg IV loading dose, then 3,600 mg IV every 8 weeks starting 2 weeks after the loading dose. Treat for at least 6 months.
Children and Adolescents weighing 60 to 99 kg: 2,700 mg IV loading dose, then 3,300 mg IV every 8 weeks starting 2 weeks after the loading dose. Treat for at least 6 months.
Children and Adolescents weighing 40 to 59 kg: 2,400 mg IV loading dose, then 3,000 mg IV every 8 weeks starting 2 weeks after the loading dose. Treat for at least 6 months.
Children and Adolescents weighing 30 to 39 kg: 1,200 mg IV loading dose, then 2,700 mg IV every 8 weeks starting 2 weeks after the loading dose. Treat for at least 6 months.
Children weighing 20 to 29 kg: 900 mg IV loading dose, then 2,100 mg IV every 8 weeks starting 2 weeks after the loading dose. Treat for at least 6 months.
Infants and Children weighing 10 to 19 kg: 600 mg IV loading dose, then 600 mg IV every 4 weeks starting 2 weeks after the loading dose. Treat for at least 6 months.
Infants and Children weighing 5 to 9 kg: 600 mg IV loading dose, then 300 mg IV every 4 weeks starting 2 weeks after the loading dose. Treat for at least 6 months.
Subcutaneous dosage:
Adults weighing 40 kg or more: 490 mg subcutaneously once weekly starting 2 weeks after IV loading dose or 8 weeks after IV maintenance dose.
For the treatment of generalized myasthenia gravis (gMG) in adult patients who are anti-acetylcholine receptor (AChR) antibody-positive:
Intravenous dosage:
Adults weighing 100 kg or more: 3,000 mg IV loading dose infusion, then 3,600 mg IV infusion every 8 weeks starting 2 weeks after the loading dose.
Adults weighing 60 to 99 kg: 2,700 mg IV infusion loading dose, then 3,300 mg IV infusion every 8 weeks starting 2 weeks after the loading dose.
Adults weighing 40 to 59 kg: 2,400 mg IV infusion loading dose, then 3,000 mg IV infusion every 8 weeks starting 2 weeks after the loading dose.
For the treatment of anti-aquaporin-4 (AQP4) antibody positive neuromyelitis optica spectrum disorder (NMOSD):
NOTE: Ravulizumab is designated as an orphan drug by the FDA for this indication.
Intravenous dosage:
Adults weighing 100 kg or more: 3,000 mg IV loading dose, then 3,600 mg IV every 8 weeks starting 2 weeks after the loading dose.
Adults weighing 60 to 99 kg: 2,700 mg IV loading dose, then 3,300 mg IV every 8 weeks starting 2 weeks after the loading dose.
Adults weighing 40 to 59 kg: 2,400 mg IV loading dose, then 3,000 mg IV every 8 weeks starting 2 weeks after the loading dose.
Maximum Dosage Limits:
-Adults
Weighing 100 kg or more: 3,000 mg IV load; 3,600 mg/dose IV every 8 weeks or 490 mg subcutaneously every week maintenance dose.
Weighing 60 to 99 kg: 2,700 mg IV load; 3,300 mg/dose IV every 8 weeks or 490 mg subcutaneously every week maintenance dose.
Weighing 40 to 59 kg: 2,400 mg IV load; 3,000 mg/dose IV every 8 weeks or 490 mg subcutaneously every week maintenance dose.
-Geriatric
Weighing 100 kg or more: 3,000 mg IV load; 3,600 mg/dose IV every 8 weeks or 490 mg subcutaneously every week maintenance dose.
Weighing 60 to 99 kg: 2,700 mg IV load; 3,300 mg/dose IV every 8 weeks or 490 mg subcutaneously every week maintenance dose.
Weighing 40 to 59 kg: 2,400 mg IV load; 3,000 mg/dose IV every 8 weeks or 490 mg subcutaneously every week maintenance dose.
-Adolescents
Weighing 100 kg or more: 3,000 mg IV load; 3,600 mg/dose IV every 8 weeks maintenance dose.
Weighing 60 to 99 kg: 2,700 mg IV load; 3,300 mg/dose IV every 8 weeks maintenance dose.
Weighing 40 to 59 kg: 2,400 mg IV load; 3,000 mg/dose IV every 8 weeks maintenance dose.
Weighing 30 to 39 kg: 1,200 mg IV load; 2,700 mg/dose IV every 8 weeks maintenance dose.
-Children
Weighing 60 to 99 kg: 2,700 mg IV load; 3,300 mg/dose IV every 8 weeks maintenance dose.
Weighing 40 to 59 kg: 2,400 mg IV load; 3,000 mg/dose IV every 8 weeks maintenance dose.
Weighing 30 to 39 kg: 1,200 mg IV load; 2,700 mg/dose IV every 8 weeks maintenance dose.
Weighing 20 to 29 kg: 900 mg IV load; 2,100 mg/dose IV every 8 weeks maintenance dose.
Weighing 10 to 19 kg: 600 mg IV load; 600 mg/dose IV every 4 weeks maintenance dose.
Weighing 5 to 9 kg: 600 mg IV load; 300 mg/dose IV every 4 weeks maintenance dose.
-Infants
Weighing 10 to 19 kg: 600 mg IV load; 600 mg/dose IV every 4 weeks maintenance dose.
Weighing 5 to 9 kg: 600 mg IV load; 300 mg/dose IV every 4 weeks maintenance dose.
-Neonates
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
No dosage adjustments are recommended for hepatic impairment.
Patients with Renal Impairment Dosing
No dosage adjustments are recommended for renal impairment.
Other Dosage Adjustments
A supplemental dose of ravulizumab is required in the setting of plasmapheresis, plasma exchange, or during use of intravenous immunoglobulin (IVIG) as ravulizumab concentrations may be reduced.
Give supplemental dose within 4 hours following each plasmapheresis (PP) or plasma exchange (PE) intervention or IVIG cycle completion as follows:
Body Weight 100 kg or more
-Most recent ravulizumab dose = 3,600 mg-PP or PE supplemental dose = 1,800 mg
-IVIG supplemental dose = 600 mg
-Most recent ravulizumab dose = 3,000 mg-PP or PE supplemental dose = 1,500 mg
-IVIG supplemental dose = 600 mg
Weight 60 to 99 kg
-Most recent ravulizumab dose = 3,300 mg-PP or PE supplemental dose = 1,800 mg
-IVIG supplemental dose = 600 mg
-Most recent ravulizumab dose = 2,700 mg-PP or PE supplemental dose = 1,500 mg
-IVIG supplemental dose = 600 mg
Weight 40 to 59 kg
-Most recent ravulizumab dose = 3,000 mg-PP or PE supplemental dose = 1,500 mg
-IVIG supplemental dose = 600 mg
-Most recent ravulizumab dose = 2,400 mg-PP or PE supplemental dose = 1,200 mg
-IVIG supplemental dose = 600 mg
*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.
Eculizumab: (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.
Efgartigimod Alfa: (Moderate) Monitor for reduced efficacy of ravulizumab during coadministration with efgartigimod. Concomitant use of ravulizumab with human neonatal Fc receptor (FcRn) blockers, such as efgartigimod, may reduce ravulizumab exposure and efficacy.
Efgartigimod Alfa; Hyaluronidase: (Moderate) Monitor for reduced efficacy of ravulizumab during coadministration with efgartigimod. Concomitant use of ravulizumab with human neonatal Fc receptor (FcRn) blockers, such as efgartigimod, may reduce ravulizumab exposure and efficacy.
Hyaluronidase, Recombinant; Immune Globulin: (Major) Administer a supplemental dose of ravulizumab and monitor for reduced efficacy of ravulizumab during concurrent use with immune globulin. Consult the manufacturer's recommendations for the supplemental dosage. Concomitant use of immune gloublin with ravulizumab may reduce ravulizumab exposure and efficacy.
Immune Globulin IV, IVIG, IGIV: (Major) Administer a supplemental dose of ravulizumab and monitor for reduced efficacy of ravulizumab during concurrent use with immune globulin. Consult the manufacturer's recommendations for the supplemental dosage. Concomitant use of immune gloublin with ravulizumab may reduce ravulizumab exposure and efficacy.
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.
Ravulizumab, a humanized monoclonal antibody, inhibits terminal complement-mediated intravascular hemolysis in persons with paroxysmal nocturnal hemoglobinuria (PNH) and complement-mediated thrombotic microangiopathy (TMA) in persons with atypical hemolytic uremic syndrome (aHUS). Ravulizumab binds to the complement protein C5 with high affinity, thereby inhibiting its cleavage to C5a (the proinflammatory anaphylatoxin) and C5b (the initiating subunit of the terminal complement complex [C5b-9]) and preventing the generation of the terminal complement complex C5b9. The presumed mechanism of action of ravulizumab in generalized myasthenia gravis (gMG) is the reduction of the terminal complement complex C5b-9 deposition at the neuromuscular junction. In the treatment of neuromyelitis optica spectrum disorder (NMOSD), ravulizumab is presumed to inhibit aquaporin-4 antibody-induced terminal complement C5b-9 deposition.
Ravulizumab is administered intravenously or subcutaneously. The mean Vd of ravulizumab at steady-state is 5.22 to 5.74 L and the mean clearance of ravulizumab is 0.05 to 0.08 L/day. The terminal elimination half-life of ravulizumab is 49.6 to 64.3 days.
Affected cytochrome P450 isoenzymes and drug transporters: none
-Route-Specific Pharmacokinetics
Intravenous Route
Ravulizumab pharmacokinetics increase proportionally over a dosage range of 200 to 5,400 mg. In adults with paroxysmal nocturnal hemoglobinuria (PNH) who are complement inhibitor-naive, mean Cmax was 771 mcg/mL and 1,379 mcg/mL after the loading and maintenance dose, respectively; mean Cmin was 391 mcg/mL and 473 mcg/mL. In subjects previously treated with eculizumab, mean Cmax was 843 mcg/mL and 1,386 mcg/mL after the loading and maintenance dose, respectively; mean Cmin was 405 mcg/mL and 501 mcg/mL. In adults with atypical hemolytic uremic syndrome (aHUS), mean Cmax was 754 mcg/mL and 1,458 mcg/mL after the loading and maintenance dose, respectively; mean Cmin was 313 mcg/mL and 507 mcg/mL. In adults with generalized myasthenia gravis (gMG), mean Cmax was 874 mcg/mL and 1,548 mcg/mL after the loading and maintenance dose, respectively; mean Cmin was 418 mcg/mL and 587 mcg/mL. In adults with neuromyelitis optica spectrum disorder (NMOSD), mean Cmax was 935 mcg/mL and 1,836 mcg/dL after the loading and maintenance dose, respectively; mean Cmin was 459 mcg/mL and 797 mcg/mL. Complete inhibition of serum-free C5 (concentration of less than 0.5 mcg/mL) was observed by the end of the first ravulizumab infusion and sustained through the entire 26-week treatment period in all adults with PNH and gMG, the majority (93%) of adult and pediatric subjects with aHUS, and in the majority (98.3%) of adults with NMOSD. The extent and duration of pharmacodynamic response were exposure-dependent. In subjects with PNH, free C5 concentrations of less than 0.5 mcg/mL correlated with maximal intravascular hemolysis control and complete terminal complement inhibition. Complete terminal complement inhibition led to normalization of serum LDH by week 4 in complement-inhibitor naive subjects and maintained LDH normalization in subjects previously treated with eculizumab.
Subcutaneous Route
The mean ravulizumab trough concentration at steady-state was 737.7 mcg/mL after subcutaneous administration. The estimated bioavailability of subcutaneous ravulizumab is approximately 79%. Complete inhibition of serum free C5 (concentration of less than 0.5 mcg/mL) occurs by the end of the first administration of subcutaneous ravulizumab and is sustained throughout the treatment period.
-Special Populations
Hepatic Impairment
No clinically significant differences in ravulizumab pharmacokinetics have been observed based on hepatic impairment.
Renal Impairment
No clinically significant differences in ravulizumab pharmacokinetics have been observed based on any degree of renal impairment, including subjects with proteinuria or those receiving dialysis.
Pediatrics
No clinically significant pharmacokinetic differences have been observed based on age; however, body weight is a clinically significant covariate of ravulizumab pharmacokinetics.
Atypical hemolytic uremic syndrome
Children and Adolescents weighing 21 to 39 kg
Mean Cmax was 600 mcg/mL and 1,863 mcg/mL after the loading and maintenance dose, respectively; mean Cmin was 186 mcg/mL and 549 mcg/mL.
Infants and Children 10 months and older weighing less than 20 kg
Mean Cmax was 656 mcg/mL and 1,467 mcg/mL after the loading and maintenance dose, respectively; mean Cmin was 241 mcg/mL and 683 mcg/mL.
Paroxysmal nocturnal hemoglobinuria
Children and Adolescents 9 to 17 years
Mean Cmax was 733 to 885 mcg/mL and 1,490 to 1,705 mcg/mL after the loading and maintenance dose, respectively; mean Cmin was 368 to 452 mcg/mL and 495 to 566 mcg/mL. Subjects previously treated with eculizumab had higher exposure than complement inhibitor naive subjects.
Geriatric
No clinically significant differences in ravulizumab pharmacokinetics have been observed based on age (10 months to 83 years).
Gender Differences
No clinically significant differences in ravulizumab pharmacokinetics have been observed based on sex.
Ethnic Differences
No clinically significant differences in ravulizumab pharmacokinetics have been observed based on race.
Obesity
Body weight is a clinically significant covariate on the pharmacokinetics of ravulizumab.