Due to challenges with completion of required laboratory testing or imaging studies for REMS drugs because of self-isolation or quarantine during the COVID-19 public health emergency, the FDA is recommending health care providers prescribing and/or dispensing REMS drugs consider whether there are compelling reasons or not to complete these requirements during this public health emergency and weigh with the patient the benefits and risks of continuing treatment in the absence of the laboratory testing and imaging studies. The FDA will not take action against sponsors and others during the public health emergency for failing to adhere to REMS requirements.
Further information may be found at https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-provides-update-patient-access-certain-rems-drugs-during-covid-19.
Life-threatening meningococcal infections/sepsis have occurred in patients treated with ravulizumab. Meningococcal infection may become rapidly life-threatening or fatal if not recognized and treated early.
Comply with the most current Advisory Committee on Immunization Practices (ACIP) recommendations for meningococcal vaccination in patients with complement deficiencies.
Immunize patients with meningococcal vaccines at least 2 weeks prior to administering the first dose of ravulizumab, unless the risks of delaying ravulizumab therapy outweigh the risk of developing a meningococcal infection.
Vaccination reduces, but does not eliminate, the risk of meningococcal infections. Monitor patients for early signs of meningococcal infections and evaluate immediately if infection is suspected.
Because of the risk of meningococcal infections, ravulizumab is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called Ultomiris REMS.
Note: Vaccinate with meningococcal vaccine at least 2 weeks prior to treatment initiation; revaccinate according to current guidelines. If urgent ravulizumab initiation is necessary and less than 2 weeks after vaccination, provide 2 weeks of antibacterial prophylaxis. In unvaccinated patients, administer meningococcal vaccine as soon as possible and provide 2 weeks of antibacterial prophylaxis. To reduce the risk for meningococcal disease, consider antimicrobial prophylaxis with oral antibiotics (penicillin, or macrolides if penicillin-allergic) for the duration of ravulizumab therapy (McNamara 2017). Following the first maintenance dose, the ravulizumab dosing schedule is allowed to occasionally vary within 1 day (SUBQ) or 7 days (IV) of the scheduled infusion day, although the subsequent dose should be administered according to the original schedule.
Atypical hemolytic uremic syndrome:
Note: A minimum treatment duration of 6 months is recommended. Dose is based on weight at time of treatment.
IV:
Weight 20 kg to <30 kg:
Loading dose: IV: 900 mg as a single dose.
Maintenance dose: IV: 2,100 mg once every 8 weeks starting 2 weeks after the loading dose.
Weight 30 kg to <40 kg:
Loading dose: IV: 1,200 mg as a single dose.
Maintenance dose: IV: 2,700 mg once every 8 weeks starting 2 weeks after the loading dose.
Weight 40 kg to <60 kg:
Loading dose: IV: 2,400 mg as a single dose.
Maintenance dose: IV: 3,000 mg once every 8 weeks starting 2 weeks after the loading dose.
Weight 60 kg to <100 kg:
Loading dose: IV: 2,700 mg as a single dose.
Maintenance dose: IV: 3,300 mg once every 8 weeks starting 2 weeks after the loading dose.
Weight ≥100 kg:
Loading dose: IV: 3,000 mg as a single dose.
Maintenance dose: IV: 3,600 mg once every 8 weeks starting 2 weeks after the loading dose.
SUBQ: Weight ≥40 kg: Maintenance dose: 490 mg once weekly starting 2 weeks after weight-based IV loading dose.
Myasthenia gravis, generalized, chronic immunosuppression:
Note: Dose is based on weight at time of treatment. Use in patients with anti-acetylcholine receptor antibody-positive (AChR+) myasthenia gravis.
Weight 40 kg to <60 kg:
Loading dose: IV: 2,400 mg as a single dose.
Maintenance dose: IV: 3,000 mg once every 8 weeks starting 2 weeks after the loading dose.
Weight 60 kg to <100 kg:
Loading dose: IV: 2,700 mg as a single dose.
Maintenance dose: IV: 3,300 mg once every 8 weeks starting 2 weeks after the loading dose.
Weight ≥100 kg:
Loading dose: IV: 3,000 mg as a single dose.
Maintenance dose: IV: 3,600 mg once every 8 weeks starting 2 weeks after the loading dose.
Paroxysmal nocturnal hemoglobinuria: Dose is based on weight at time of treatment:
IV:
Weight 20 kg to <30 kg:
Loading dose: IV: 900 mg as a single dose.
Maintenance dose: IV: 2,100 mg once every 8 weeks starting 2 weeks after the loading dose.
Weight 30 kg to <40 kg:
Loading dose: IV: 1,200 mg as a single dose.
Maintenance dose: IV: 2,700 mg once every 8 weeks starting 2 weeks after the loading dose.
Weight 40 kg to <60 kg:
Loading dose: IV: 2,400 mg as a single dose.
Maintenance dose: IV: 3,000 mg once every 8 weeks starting 2 weeks after the loading dose.
Weight 60 kg to <100 kg:
Loading dose: IV: 2,700 mg as a single dose.
Maintenance dose: IV: 3,300 mg once every 8 weeks starting 2 weeks after the loading dose.
Weight ≥100 kg:
Loading dose: IV: 3,000 mg as a single dose.
Maintenance dose: IV: 3,600 mg once every 8 weeks starting 2 weeks after the loading dose.
SUBQ: Weight ≥40 kg: Maintenance dose: 490 mg once weekly starting 2 weeks after weight-based IV loading dose.
Conversion from eculizumab to IV ravulizumab: When converting from eculizumab to IV ravulizumab, administer the ravulizumab loading dose at the time of the next scheduled eculizumab dose and then administer ravulizumab maintenance doses once every 4 or 8 weeks (depending on body weight) beginning 2 weeks after the ravulizumab loading dose.
Conversion from eculizumab to SUBQ ravulizumab: When converting from eculizumab to SUBQ ravulizumab, administer IV ravulizumab as the loading dose at the time of the next scheduled eculizumab dose and then administer SUBQ ravulizumab maintenance doses weekly beginning 2 weeks after the ravulizumab IV loading dose.
Conversion from ravulizumab IV to SUBQ: When converting from IV ravulizumab to SUBQ ravulizumab, begin SUBQ maintenance dose 8 weeks after last IV maintenance dose.
Conversion from ravulizumab SUBQ to IV: When converting from SUBQ ravulizumab to IV ravulizumab, begin IV maintenance dose 1 week after last SUBQ maintenance dose.
Supplemental dose following plasma exchange, plasmapheresis, or IV immune globulin (IVIG):
|
Weight (kg)b |
Most recent ravulizumab dose (mg) |
Supplemental ravulizumab dose (mg) following each PE or PP intervention |
Supplemental ravulizumab dose (mg) following completion of an IVIG cycle |
|---|---|---|---|
|
a PE = plasma exchange; PP = plasmapheresis; IVIG = IV immune globulin. | |||
|
b Weight at time of treatment. | |||
|
40 to <60 kg |
2,400 mg |
1,200 mg |
600 mg |
|
3,000 mg |
1,500 mg | ||
|
60 to <100 kg |
2,700 mg |
1,500 mg |
600 mg |
|
3,300 mg |
1,800 mg | ||
|
≥100 kg |
3,000 mg |
1,500 mg |
600 mg |
|
3,600 mg |
1,800 mg | ||
|
Timing of ravulizumab supplemental dose |
Within 4 hours following each PE or PP intervention |
Within 4 hours following completion of an IVIG cycle | |
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
There are no dosage adjustments provided in the manufacturer's labeling; however, renal impairment had no clinically important effect on ravulizumab pharmacokinetics.
There are no dosage adjustments provided in the manufacturer's labeling; however, hepatic impairment had no clinically important effect on ravulizumab pharmacokinetics.
(For additional information see "Ravulizumab: Pediatric drug information")
Note: Vaccinate with meningococcal vaccine at least 2 weeks prior to treatment initiation; revaccinate according to current guidelines. If urgent ravulizumab initiation is necessary and it has been <2 weeks after vaccination, provide 2 weeks of antibacterial prophylaxis. To reduce the risk for meningococcal disease, consider antimicrobial prophylaxis with oral antibiotics (penicillin, or macrolides if penicillin-allergic) for the duration of therapy (McNamara 2017). Multiple concentrations of solutions are available (10 mg/mL and 100 mg/mL); only a single concentration should be used to prepare a dose for infusion (see "Preparation for Administration").
Atypical hemolytic uremic syndrome (aHUS) or paroxysmal nocturnal hemoglobinuria (PNH):
Infants, Children, and Adolescents: IV infusion: Administer the first maintenance dose 2 weeks after loading dose; for subsequent maintenance doses, the interval varies with weight; use precaution to ensure appropriate interval. Dose is based on weight at time of treatment for that dose. Following the first maintenance dose, the ravulizumab dosing schedule is allowed to occasionally vary within 7 days of the scheduled infusion day; subsequent dose should be administered according to the original schedule. For aHUS, treatment should continue for a minimum of 6 months.
|
Weight (at time of treatment) |
Loading Dose (fixed, mg/dose) |
Maintenance Dose (fixed, mg/dose) |
Maintenance Interval |
|---|---|---|---|
|
5 to <10 kg |
600 mg |
300 mg |
Every 4 weeks |
|
10 to <20 kg |
600 mg |
600 mg | |
|
20 to <30 kg |
900 mg |
2,100 mg |
Every 8 weeks |
|
30 to <40 kg |
1,200 mg |
2,700 mg | |
|
40 to <60 kg |
2,400 mg |
3,000 mg | |
|
60 to <100 kg |
2,700 mg |
3,300 mg | |
|
≥100 kg |
3,000 mg |
3,600 mg |
Dosing adjustment for toxicity: May slow or stop infusion at the discretion of the health care provider if adverse reaction occurs.
Conversion from eculizumab: When converting from eculizumab to ravulizumab, administer the ravulizumab loading dose 2 weeks after the last eculizumab dose and then administer subsequent ravulizumab maintenance doses according to weight-based schedule, beginning 2 weeks after the ravulizumab loading dose.
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
There are no dosage adjustments provided in the manufacturer's labeling; however, renal impairment had no clinically important effect on ravulizumab pharmacokinetics.
There are no dosage adjustments provided in the manufacturer's labeling; however, hepatic impairment had no clinically important effect on ravulizumab pharmacokinetics.
Refer to adult dosing.
Adverse reaction during infusion: May slow or stop infusion (at discretion of health care provider). Interrupt infusion and begin appropriate supportive measures if signs of cardiovascular instability or respiratory compromise occur.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product
Solution, Intravenous [preservative free]:
Ultomiris: Ravulizumab-cwvz 300 mg/3 mL (3 mL); Ravulizumab-cwvz 300 mg/30 mL (30 mL [DSC]); Ravulizumab-cwvz 1100 mg/11 mL (11 mL) [contains polysorbate 80]
No
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Solution, Intravenous:
Ultomiris: 300 mg/30 mL (30 mL) [contains polysorbate 80]
Ultomiris 245 mg/3.5 mL single-dose prefilled cartridge: FDA approved July 2022; anticipated availability currently unknown.
An FDA-approved patient medication guide, which is available with the product information and as follows, must be dispensed with this medication:
Ultomiris: https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/761108s023lbl.pdf#page=41
IV: Infuse through a 0.2- or 0.22-micron filter. Allow solution to adjust to room temperature (do not use a heat source) prior to infusion. Infusion rate for loading, maintenance, and supplemental doses is based on patient weight.
3 mL or 11 mL vial (100 mg/mL):
Loading dose:
|
Weight (kg)a |
Loading dose (mg) |
Total volume to be administered (mL) |
Minimum infusion time (hours) |
Maximum infusion rate (mL/hour) |
|---|---|---|---|---|
|
a Weight at time of treatment. | ||||
|
20 to <30 kg |
900 mg |
18 mL |
0.6 hours |
30 mL/hour |
|
30 to <40 kg |
1,200 mg |
24 mL |
0.5 hours |
48 mL/hour |
|
40 to <60 kg |
2,400 mg |
48 mL |
0.8 hours |
60 mL/hour |
|
60 to <100 kg |
2,700 mg |
54 mL |
0.6 hours |
90 mL/hour |
|
≥100 kg |
3,000 mg |
60 mL |
0.4 hours |
150 mL/hour |
Maintenance dose:
|
Weight (kg)a |
Maintenance dose (mg) |
Total volume to be administered (mL) |
Minimum infusion time (hours) |
Maximum infusion rate (mL/hour) |
|---|---|---|---|---|
|
a Weight at time of treatment. | ||||
|
20 to <30 kg |
2,100 mg |
42 mL |
1.3 hours |
33 mL/hour |
|
30 to <40 kg |
2,700 mg |
54 mL |
1.1 hours |
50 mL/hour |
|
40 to <60 kg |
3,000 mg |
60 mL |
0.9 hours |
67 mL/hour |
|
60 to <100 kg |
3,300 mg |
66 mL |
0.7 hours |
95 mL/hour |
|
≥100 kg |
3,600 mg |
72 mL |
0.5 hours |
144 mL/hour |
Supplemental dose:
|
Weight (kg)b |
Supplemental dose (mg) |
Total volume to be administered (mL) |
Minimum infusion time (hours) |
Maximum infusion rate (mL/hour) |
|---|---|---|---|---|
|
a Supplemental doses are only indicated following plasma exchange, plasmapheresis, or IV immune globulin (IVIG) therapy. | ||||
|
b Weight at time of treatment. | ||||
|
40 to <60 kg |
600 mg |
12 mL |
0.25 hours |
48 mL/hour |
|
1,200 mg |
24 mL |
0.42 hours |
57 mL/hour | |
|
1,500 mg |
30 mL |
0.5 hours |
60 mL/hour | |
|
60 to <100 kg |
600 mg |
12 mL |
0.2 hours |
60 mL/hour |
|
1,500 mg |
30 mL |
0.36 hours |
83 mL/hour | |
|
1,800 mg |
36 mL |
0.42 hours |
86 mL/hour | |
|
≥100 kg |
600 mg |
12 mL |
0.17 hours |
71 mL/hour |
|
1,500 mg |
30 mL |
0.25 hours |
120 mL/hour | |
|
1,800 mg |
36 mL |
0.28 hours |
129 mL/hour | |
30 mL vial (10 mg/mL):
Loading dose:
|
Weight (kg)a |
Loading dose (mg) |
Total volume to be administered (mL) |
Minimum infusion time (hours) |
Maximum infusion rate (mL/hour) |
|---|---|---|---|---|
|
a Weight at time of treatment. | ||||
|
20 to <30 kg |
900 mg |
180 mL |
1.5 hours |
120 mL/hour |
|
30 to <40 kg |
1,200 mg |
240 mL |
1.3 hours |
185 mL/hour |
|
40 to <60 kg |
2,400 mg |
480 mL |
1.9 hours |
253 mL/hour |
|
60 to <100 kg |
2,700 mg |
540 mL |
1.7 hours |
318 mL/hour |
|
≥100 kg |
3,000 mg |
600 mL |
1.8 hours |
334 mL/hour |
Maintenance dose:
|
Weight (kg)a |
Maintenance dose (mg) |
Total volume to be administered (mL) |
Minimum infusion time (hours) |
Maximum infusion rate (mL/hour) |
|---|---|---|---|---|
|
a Weight at time of treatment. | ||||
|
20 to <30 kg |
2,100 mg |
420 mL |
3.3 hours |
128 mL/hour |
|
30 to <40 kg |
2,700 mg |
540 mL |
2.8 hours |
193 mL/hour |
|
40 to <60 kg |
3,000 mg |
600 mL |
2.3 hours |
261 mL/hour |
|
60 to <100 kg |
3,300 mg |
660 mL |
2 hours |
330 mL/hour |
|
≥100 kg |
3,600 mg |
720 mL |
2.2 hours |
328 mL/hour |
Supplemental dose:
|
Weight (kg)b |
Supplemental dose (mg) |
Total volume to be administered (mL) |
Minimum infusion time (hours) |
Maximum infusion rate (mL/hour) |
|---|---|---|---|---|
|
a Supplemental doses are only indicated following plasma exchange, plasmapheresis, or IV immune globulin (IVIG) therapy. | ||||
|
b Weight at time of treatment. | ||||
|
40 to <60 kg |
600 mg |
120 mL |
0.5 hours |
240 mL/hour |
|
1,200 mg |
240 mL |
1 hour |
240 mL/hour | |
|
1,500 mg |
300 mL |
1.2 hours |
250 mL/hour | |
|
60 to <100 kg |
600 mg |
120 mL |
0.4 hours |
300 mL/hour |
|
1,500 mg |
300 mL |
1 hour |
300 mL/hour | |
|
1,800 mg |
360 mL |
1.1 hours |
327 mL/hour | |
|
≥100 kg |
600 mg |
120 mL |
0.4 hours |
300 mL/hour |
|
1,500 mg |
300 mL |
1 hour |
300 mL/hour | |
|
1,800 mg |
360 mL |
1.1 hours |
327 mL/hour | |
Assess immunization status prior to initiation; patients should receive meningococcal vaccine at least 2 weeks prior to treatment initiation. If ravulizumab must be initiated urgently and less than 2 weeks after vaccination, provide 2 weeks of antibacterial prophylaxis; in unvaccinated patients, administer meningococcal vaccine as soon as possible and provide 2 weeks of antibacterial prophylaxis. Revaccinate according to current guidelines.
SUBQ: For use with the on-body delivery system; see manufacturer's labeling for detailed administration instructions. Self-administration may occur after proper training from a health care provider. Administer SUBQ into abdomen, thigh, or upper arm; do not administer into tender, bruised, red, or hard skin; avoid injecting into areas with scars, stretch marks, wrinkles, skin folds, tattoos, moles, or excessive hair. Rotate injection sites. The 2 on-body delivery systems may be administered concurrently or sequentially; each injection is administered over ~10 minutes.
Note: Assess immunization status prior to initiation (see "Dosing: Pediatric" for specific information).
Parenteral:
IV: Infuse through a 0.2 or 0.22 micron filter. If previous refrigeration, allow solution to adjust to room temperature at ambient air temperature (do not use a heat source) prior to infusion. Infusion rate for loading and maintenance dose is highly variable as it is based on concentration of ravulizumab used to prepare the infusion and patient weight; use extra precaution. Decrease infusion rate or discontinue for infusion reactions.
Note: Multiple final concentrations for infusion exist (5 mg/mL and 50 mg/mL) and each concentration has different infusion rates; use extra precaution verifying concentration of infusion solution.
|
5 mg/mL Solution Administration Rates and Infusion Times Final Concentration of Infusion 5 mg/mLa | ||||
|---|---|---|---|---|
|
Weight |
Dose type |
Total dose/Total volume (5 mg/mL) |
Maximum infusion rate (mL/hour) |
Minimum infusion time (hours) |
|
aSolutions prepared from the 10 mg/mL (30 mL) vial and further diluted in NS. | ||||
|
5 to <10 kg |
Loading |
600 mg/120 mL |
31 mL/hour |
3.8 hours |
|
Maintenance |
300 mg/60 mL |
31 mL/hour |
1.9 hours | |
|
10 to <20 kg |
Loading |
600 mg/120 mL |
63 mL/hour |
1.9 hours |
|
Maintenance |
600 mg/120 mL |
63 mL/hour |
1.9 hours | |
|
20 to <30 kg |
Loading |
900 mg/180 mL |
120 mL/hour |
1.5 hours |
|
Maintenance |
2,100 mg/420 mL |
127 mL/hour |
3.3 hours | |
|
30 to <40 kg |
Loading |
1,200 mg/240 mL |
184 mL/hour |
1.3 hours |
|
Maintenance |
2,700 mg/540 mL |
192 mL/hour |
2.8 hours | |
|
40 to <60 kg |
Loading |
2,400 mg/480 mL |
252 mL/hour |
1.9 hours |
|
Maintenance |
3,000 mg/600 mL |
257 mL/hour |
2.3 hours | |
|
60 to <100 kg |
Loading |
2,700 mg/540 mL |
317 mL/hour |
1.7 hours |
|
Maintenance |
3,300 mg/660 mL |
330 mL/hour |
2 hours | |
|
≥100 kg |
Loading |
3,000 mg/600 mL |
333 mL/hour |
1.8 hours |
|
Maintenance |
3,600 mg/720 mL |
327 mL/hour |
2.2 hours | |
|
50 mg/mL Solution Administration Rates and Infusion Times Final Concentration of Infusion 50 mg/mLa | ||||
|---|---|---|---|---|
|
Weight |
Dose type |
Total dose/Total volume (50 mg/mL) |
Maximum infusion rate (mL/hour) |
Minimum infusion time (hours) |
|
aSolutions prepared from the 100 mg/mL (3 mL or 11 mL) vial and further diluted in NS. | ||||
|
5 to <10 kg |
Loading |
600 mg/12 mL |
8 mL/hour |
1.4 hours |
|
Maintenance |
300 mg/6 mL |
8 mL/hour |
0.8 hours | |
|
10 to <20 kg |
Loading |
600 mg/12 mL |
16 mL/hour |
0.8 hours |
|
Maintenance |
600 mg/12 mL |
16 mL/hour |
0.8 hours | |
|
20 to <30 kg |
Loading |
900 mg/18 mL |
30 mL/hour |
0.6 hours |
|
Maintenance |
2,100 mg/42 mL |
33 mL/hour |
1.3 hours | |
|
30 to <40 kg |
Loading |
1,200 mg/24 mL |
46 mL/hour |
0.5 hours |
|
Maintenance |
2,700 mg/54 mL |
49 mL/hour |
1.1 hours | |
|
40 to <60 kg |
Loading |
2,400 mg/48 mL |
64 mL/hour |
0.8 hours |
|
Maintenance |
3,000 mg/60 mL |
65 mL/hour |
0.9 hours | |
|
60 to <100 kg |
Loading |
2,700 mg/54 mL |
92 mL/hour |
0.6 hours |
|
Maintenance |
3,300 mg/66 mL |
99 mL/hour |
0.7 hours | |
|
≥100 kg |
Loading |
3,000 mg/60 mL |
144 mL/hour |
0.4 hours |
|
Maintenance |
3,600 mg/72 mL |
144 mL/hour |
0.5 hours | |
Atypical hemolytic uremic syndrome: Treatment of atypical hemolytic uremic syndrome to inhibit complement-mediated thrombotic microangiopathy in adult and pediatric patients ≥1 month of age.
Limitations of use: Not indicated for the treatment of Shiga toxin Escherichia coli-related hemolytic uremic syndrome.
Myasthenia gravis, generalized, chronic immunosuppression (IV only): Treatment of generalized myasthenia gravis in adults who are anti-acetylcholine receptor antibody-positive (AChR+).
Paroxysmal nocturnal hemoglobinuria: Treatment of paroxysmal nocturnal hemoglobinuria in adults and pediatric patients ≥1 month of age.
Ravulizumab may be confused with eculizumab, ramucirumab, ranibizumab, raxibacumab, reslizumab.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Adverse reactions reported in adults with paroxysmal nocturnal hemoglobinuria (PNH) unless otherwise indicated for generalized myasthenia gravis (gMG).
>10%:
Gastrointestinal: Diarrhea (gMG: 15%; PNH: 4% to 13%)
Local: Injection-site reaction (SUBQ: 27%)
Nervous system: Headache (9% to 32%)
Respiratory: Upper respiratory tract infection (gMG, PNH: 8% to 39%)
1% to 10%:
Gastrointestinal: Abdominal pain (gMG, PNH: 6%), nausea (9%)
Genitourinary: Urinary tract infection (gMG: 6%)
Hypersensitivity: Infusion-related reaction (1%; including hypersensitivity reaction)
Nervous system: Dizziness (gMG: 9%; PNH: 5%)
Neuromuscular & skeletal: Arthralgia (5%), back pain (gMG: 8%), limb pain (6%)
Miscellaneous: Fever (7%)
<1%:
Immunologic: Antibody development
Infection: Meningococcal infection, sepsis
Frequency not defined: Nervous system: Hyperthermia
Postmarketing: Hypersensitivity: Anaphylaxis
Unresolved Neisseria meningitidis infection; patients not currently vaccinated against N. meningitidis, unless the risks of delaying ravulizumab treatment outweigh the risks of developing a meningococcal infection.
Canadian labeling: Additional contraindications (not in the US labeling): Hypersensitivity to ravulizumab or any component of the formulation.
Concerns related to adverse effects:
• Infection: Ravulizumab blocks terminal complement activation and therefore may increase the risk for susceptibility to bacterial infections, especially encapsulated bacteria, such as infections caused by Neisseria meningitidis but also Streptococcus pneumoniae, Haemophilus influenzae, and, to a lesser extent, Neisseria gonorrhoeae. Pediatric patients receiving ravulizumab may be at increased risk for serious S. pneumoniae and H. influenzae type b (Hib) infections; vaccinate for S. pneumoniae and Hib according to the Advisory Committee on Immunization Practices (ACIP) recommendations.
• Infusion reactions: Administration of ravulizumab may result in infusion reactions, including anaphylaxis and hypersensitivity. In clinical trials, a small number of patients experienced infusion reactions (lower back pain, BP changes, and limb discomfort) during administration. Infusion reactions did not require ravulizumab discontinuation. If signs of cardiovascular instability or respiratory compromise occur, interrupt infusion and manage supportively.
• Meningococcal infection: The use of ravulizumab increases susceptibility to serious meningococcal infections (septicemia and/or meningitis). Meningococcal disease due to any serogroup may occur. If urgent ravulizumab therapy is indicated in an unvaccinated patient, administer meningococcal vaccine(s) as soon as possible and provide at least 2 weeks of antibacterial prophylaxis. To reduce the risk for meningococcal disease, consider antimicrobial prophylaxis with oral antibiotics (penicillin, or macrolides if penicillin-allergic) for the duration of ravulizumab therapy (McNamara 2017). A small number of vaccinated patients developed serious meningococcal infections/sepsis while receiving ravulizumab treatment in studies; the patients recovered while continuing ravulizumab treatment. Educate patients on signs/symptoms of meningitis and steps necessary to seek immediate medical care. Consider ravulizumab discontinuation in patients who are undergoing treatment for serious meningococcal infection. Revaccinate for meningococcal disease according to ACIP recommendations, taking the duration of ravulizumab therapy into consideration.
Concurrent drug therapy issues:
• Anticoagulation: Treatment with ravulizumab should not alter anticoagulation management; the effect of anticoagulant therapy withdrawal is unknown.
Dosage form specific issues:
• Acrylic adhesive: On-body injector uses acrylic adhesive; allergic reactions may occur in patients with an allergy to acrylic adhesive. Consider premedication and supportive therapy if allergic reaction occurs.
• Polysorbate 80: Some dosage forms may contain polysorbate 80 (also known as Tweens). Hypersensitivity reactions, usually a delayed reaction, have been reported following exposure to pharmaceutical products containing polysorbate 80 in certain individuals (Isaksson 2002; Lucente 2000; Shelley 1995). Thrombocytopenia, ascites, pulmonary deterioration, and renal and hepatic failure have been reported in premature neonates after receiving parenteral products containing polysorbate 80 (Alade 1986; CDC 1984). See manufacturer's labeling.
Other warnings/precautions:
• Appropriate use: Vials are intended for IV use only. Prefilled cartridge and on-body injector are intended for SUBQ maintenance use only.
• Discontinuation in atypical hemolytic uremic syndrome: If thrombotic microangiopathy complications occur after discontinuation, consider restarting ravulizumab treatment or appropriate organ-specific supportive measures.
• Discontinuation in paroxysmal nocturnal hemoglobinuria: If hemolysis signs/symptoms (including elevated lactate dehydrogenase) occur after discontinuation, consider restarting ravulizumab treatment.
• Plasmapheresis/plasma exchange: Plasmapheresis and plasma exchange may reduce ravulizumab levels; supplemental ravulizumab doses are recommended.
• REMS program:Counsel patients about the risk of meningococcal infection/sepsis; provide REMS educational materials to patients, and ensure patients are vaccinated with meningococcal vaccines. Additional information is available at www.ultomirisrems.com or 1-888-765-4747.
None known.
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
Abrocitinib: May enhance the immunosuppressive effect of Immunosuppressants (Therapeutic Immunosuppressant Agents). Risk X: Avoid combination
Baricitinib: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Baricitinib. Risk X: Avoid combination
Brincidofovir: Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Brincidofovir. Risk C: Monitor therapy
Cladribine: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Cladribine. Risk X: Avoid combination
Coccidioides immitis Skin Test: Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the diagnostic effect of Coccidioides immitis Skin Test. Management: Consider discontinuing therapeutic immunosuppressants several weeks prior to coccidioides immitis skin antigen testing to increase the likelihood of accurate diagnostic results. Risk D: Consider therapy modification
COVID-19 Vaccine (Virus-like Particles): Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of COVID-19 Vaccine (Virus-like Particles). Risk C: Monitor therapy
Denosumab: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Denosumab. Management: Consider the risk of serious infections versus the potential benefits of coadministration of denosumab and immunosuppressants. If combined, monitor for signs/symptoms of serious infections. Risk D: Consider therapy modification
Deucravacitinib: May enhance the immunosuppressive effect of Immunosuppressants (Therapeutic Immunosuppressant Agents). Risk X: Avoid combination
Efgartigimod Alfa: May diminish the therapeutic effect of Fc Receptor-Binding Agents. Risk C: Monitor therapy
Filgotinib: May enhance the immunosuppressive effect of Immunosuppressants (Therapeutic Immunosuppressant Agents). Risk X: Avoid combination
Immune Globulin: May decrease the serum concentration of Ravulizumab. Management: Administer a supplemental dose of ravulizumab (600 mg) within 4 hours of completion of the immune globulin cycle. Risk D: Consider therapy modification
Inebilizumab: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Inebilizumab. Risk C: Monitor therapy
Leflunomide: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Leflunomide. Management: Increase the frequency of chronic monitoring of platelet, white blood cell count, and hemoglobin or hematocrit to monthly, instead of every 6 to 8 weeks, if leflunomide is coadministered with immunosuppressive agents. Risk D: Consider therapy modification
Natalizumab: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Natalizumab. Risk X: Avoid combination
Ocrelizumab: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Ocrelizumab. Risk C: Monitor therapy
Ofatumumab: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Ofatumumab. Risk C: Monitor therapy
Pidotimod: Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Pidotimod. Risk C: Monitor therapy
Pimecrolimus: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Pimecrolimus. Risk X: Avoid combination
Polymethylmethacrylate: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the potential for allergic or hypersensitivity reactions to Polymethylmethacrylate. Management: Use caution when considering use of bovine collagen-containing implants such as the polymethylmethacrylate-based Bellafill brand implant in patients who are receiving immunosuppressants. Consider use of additional skin tests prior to administration. Risk D: Consider therapy modification
Ruxolitinib (Topical): Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Ruxolitinib (Topical). Risk X: Avoid combination
Sipuleucel-T: Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Sipuleucel-T. Management: Consider reducing the dose or discontinuing the use of immunosuppressants prior to initiating sipuleucel-T therapy. Risk D: Consider therapy modification
Sphingosine 1-Phosphate (S1P) Receptor Modulator: May enhance the immunosuppressive effect of Immunosuppressants (Therapeutic Immunosuppressant Agents). Risk C: Monitor therapy
Tacrolimus (Topical): Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Tacrolimus (Topical). Risk X: Avoid combination
Talimogene Laherparepvec: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the adverse/toxic effect of Talimogene Laherparepvec. Specifically, the risk of infection from the live, attenuated herpes simplex virus contained in talimogene laherparepvec may be increased. Risk X: Avoid combination
Tertomotide: Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Tertomotide. Risk X: Avoid combination
Tofacitinib: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Tofacitinib. Management: Coadministration of tofacitinib with potent immunosuppressants is not recommended. Use with non-biologic disease-modifying antirheumatic drugs (DMARDs) was permitted in psoriatic arthritis clinical trials. Risk X: Avoid combination
Upadacitinib: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Upadacitinib. Risk X: Avoid combination
Ravulizumab is a humanized monoclonal antibody (IgG2). Placental transfer of human IgG is dependent upon the IgG subclass, maternal serum concentrations, birth weight, and gestational age, generally increasing as pregnancy progresses. The lowest exposure would be expected during the period of organogenesis (Palmeira 2012; Pentsuk 2009).
Data related to maternal use of ravulizumab during pregnancy (Tomazos 2020) or immediately postpartum (Gäckler 2021) are limited.
Adverse pregnancy outcomes are associated with untreated paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic syndrome (aHUS). Adverse maternal outcomes associated with PNH may include worsening cytopenias, thrombotic events, infections, bleeding, fetal loss, and increased maternal mortality; increased fetal death and premature delivery is also reported. Patients with aHUS may have an increased risk of preeclampsia and preterm delivery; intrauterine growth restriction/low birth weight and fetal death may also occur.
It is not known if ravulizumab is present in breast milk.
Due to the potential for serious adverse reactions in the breastfed infant, breastfeeding is not recommended by the manufacturer during therapy and for 8 months after the last ravulizumab dose.
Assess immunization status (prior to treatment). Monitor for early signs of meningococcal infection; evaluate immediately if infection is suspected. Monitor closely for signs/symptoms of worsening infection (if administering ravulizumab to patients with active systemic infections). Monitor for signs/symptoms of an infusion reaction; monitor patients receiving SUBQ injection for at least 1 hour after completion of injection.
After ravulizumab discontinuation for paroxysmal nocturnal hemoglobinuria: Monitor closely for ≥16 weeks (after discontinuation) to detect hemolysis and other reactions; monitor for signs/symptoms of hemolysis (eg, elevated lactate dehydrogenase [LDH] along with sudden decrease in paroxysmal nocturnal hemoglobinuria clone size or hemoglobin, or re-appearance of symptoms such as fatigue, hemoglobinuria, abdominal pain, shortness of breath [dyspnea], major adverse vascular event [including thrombosis], dysphagia, or erectile dysfunction) after discontinuation of ravulizumab treatment.
After ravulizumab discontinuation for atypical hemolytic uremic syndrome: Monitor closely for ≥12 months (after discontinuation) for signs/symptoms of thrombotic microangiopathy (TMA) complications. TMA complications may be identified by clinical symptoms (changes in mental status, seizures, angina, dyspnea, thrombosis, or increasing blood pressure) in addition to ≥2 of the following laboratory values observed concurrently (and confirmed by a second measurement 28 days apart with no interruption): platelet count decreased ≥25% compared to baseline or peak count during ravulizumab treatment; serum creatinine increased ≥25% compared to baseline or to nadir during ravulizumab treatment; or LDH increased ≥25% compared to baseline or to nadir during ravulizumab treatment.
Ravulizumab is a humanized monoclonal antibody which is a terminal complement inhibitor that specifically binds to the complement protein C5 (with high affinity), inhibiting its cleavage to C5a (the proinflammatory anaphylatoxin) and C5b (the initiating subunit of the terminal complement complex [C5b-9]) and preventing generation of the terminal complement complex C5b9. Ravulizumab inhibits terminal complement-mediated intravascular hemolysis in paroxysmal nocturnal hemoglobinuria (PNH) and complement-mediated thrombotic microangiopathy in atypical hemolytic uremic syndrome. The C5 inhibition of complement-mediated hemolysis achieved by ravulizumab in patients with PNH is immediate, thorough, and sustained (Lee 2019). The mechanism in generalized myasthenia gravis has not been fully elucidated but is presumed to involve reduction of terminal complement complex C5b-9 at the neuromuscular junction.
Onset of action: Lactate dehydrogenase (LDH) reduction: Rapid and sustained, beginning as early as day 8 (Roth 2018). LDH normalization: By week 4 (in complement-inhibitor naive patients with paroxysmal nocturnal hemoglobinuria [PNH]).
Bioavailability: SUBQ: ~79%.
Distribution: Vd: IV: 5.22 L (atypical hemolytic uremic syndrome [aHUS] patients); 5.3 L (PNH patients); 5.74 L (generalized myasthenia gravis patients [gMG]); SUBQ: 5.3 L (PNH patients).
Half-life elimination: Terminal: IV: 51.8 days (aHUS patients); 49.6 days (PNH patients); 56.6 days (gMG patients); SUBQ: 52.4 days (PNH patients).
Excretion: Clearance: IV: 0.08 L/day; SUBQ: 0.07 L/day.
Solution (Ultomiris Intravenous)
300 mg/3 mL (per mL): $2,561.60
1100MG/11ML (per mL): $2,561.60
Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.
