ravulizumab (Rx)

Brand and Other Names:Ultomiris, ravulizumab-cwvz
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Dosing & Uses

AdultPediatric

Dosage Forms & Strengths

injectable solution

  • 300mg/30mL (10mg/mL) single-dose vial

Paroxysmal Nocturnal Hemoglobinuria

Indicated for paroxysmal nocturnal hemoglobinuria (PNH)

Weight-based dosing is initiated with a single loading dose, and then maintenance doses q8Week starting 2 weeks after the loading dose

Also see Administration for dilution and infusion rate instructions

Loading dose

  • 40 to <60 kg: 2400 mg IV
  • ≥60 to <100 kg: 2700 mg IV
  • ≥100 kg: 3000 mg IV

Maintenance dose

  • Initiate maintenance doses 2 weeks after loading dose
  • Dosing schedule allows for occasionally variation within 7 days of the scheduled infusion day (except for the first maintenance dose), but administer subsequent doses according to original schedule
  • 40 to <60 kg: 3000 mg IV q8Week
  • ≥60 to <100 kg: 3300 mg IV q8Week
  • ≥100 kg: 3600 mg IV q8Week

Atypical Hemolytic Uremic Syndrome

Indicated for treatment of adults with atypical hemolytic uremic syndrome (aHUS) to inhibit complement-mediated thrombotic microangiopathy (TMA)

Loading dose

  • 40 to <60 kg: 2400 mg IV
  • ≥60 to <100 kg: 2700 mg IV
  • ≥100 kg: 3000 mg IV

Maintenance dose

  • Initiate maintenance doses 2 weeks after loading dose
  • Dosing schedule allows for occasionally variation within 7 days of the scheduled infusion day (except for the first maintenance dose), but administer subsequent doses according to original schedule
  • 40 to <60 kg: 3000 mg IV q8Week
  • ≥60 to <100 kg: 3300 mg IV q8Week
  • ≥100 kg: 3600 mg IV q8Week

Dosage Modifications

Renal impairment

  • Mild-to-moderate (CrCl 30-89 mL/min): No dosage adjustment required
  • Severe (CrCl <30 mL/min): Not studied

Dosing Considerations

Switching from eculizumab to ravulizumab: Administer loading dose 2 weeks after the last eculizumab infusion, and then administer maintenance doses once q8Weeks, starting 2 weeks after loading dose administration

Limitation of use

  • Not indicated for treatment of patients with Shiga toxin E coli related hemolytic uremic syndrome (STEC-HUS)

Vaccination and antibiotic prophylaxis

  • Vaccinate for meningococcal disease according to current Advirsory Committee on Immunization Practices (ACIP) guidelines to reduce the risk of serious infection
  • Provide antibacterial drug prophylaxis for 2 weeks if ravulizumab must be initiated immediately and vaccines are administered <2 weeks before initiating ravulizumab

Plasmapheresis or FFP

  • Administration of PE/PI (plasmapheresis or plasma exchange, or fresh frozen plasma infusion) may reduce ravulizumab serum levels
  • There is no experience with administration of supplemental doses of ravulizumab

Dosage Forms & Strengths

injectable solution

  • 300mg/30mL (10mg/mL) single-dose vial

Atypical Hemolytic Uremic Syndrome

<1 month: Safety and efficacy not established

≥1 month

  • Indicated for treatment of adults and pediatric patients aged ≥1 month with atypical hemolytic uremic syndrome (aHUS) to inhibit complement-mediated thrombotic microangiopathy (TMA)
  • Loading dose
    • 5 to <10 kg: 600 mg IV
    • ≥10 to <20 kg: 600 mg IV
    • ≥20 to <30 kg: 900 mg IV
    • ≥30 to <40 kg: 1200 mg IV
    • ≥40 to <60 kg: 2400 mg IV
    • ≥60 to <100 kg: 2700 mg IV
    • ≥100 kg: 3000 mg IV
  • Maintenance dose
    • Initiate maintenance doses 2 weeks after loading dose
    • Dosing schedule allows for occasionally variation within 7 days of the scheduled infusion day (except for the first maintenance dose), but administer subsequent doses according to original schedule
    • 5 to <10 kg: 300 mg IV q4Week
    • ≥10 to <20 kg: 600 mg IV q4Week
    • ≥20 to <30 kg: 2100 mg IV q8Week
    • ≥30 to <40 kg: 2700 mg IV q8Week
    • ≥40 to <60 kg: 3000 mg IV q8Week
    • ≥60 to <100 kg: 3300 mg IV q8Week
    • ≥100 kg: 3600 mg IV q8Week

Dosage Modifications

Hepatic impairment: No dosage adjustment required

Renal impairment

  • Mild-to-moderate (CrCl 30-89 mL/min): No dosage adjustment required
  • Severe (CrCl <30 mL/min): Not studied

Dosing Considerations

Limitation of use

  • Switching from eculizumab to ravulizumab: Administer loading dose 2 weeks after the last eculizumab infusion, and then administer maintenance doses once q8Week or q4Week (depending on body weight), starting 2 weeks after loading dose administration
  • Not indicated for treatment of patients with Shiga toxin E. coli related hemolytic uremic syndrome (STEC-HUS)

Vaccination and antibiotic prophylaxis

  • Vaccinate for meningococcal disease according to current Advisory Committee on Immunization Practices (ACIP) guidelines to reduce the risk of serious infection
  • Provide antibacterial drug prophylaxis for 2 weeks if ravulizumab must be initiated immediately and vaccines are administered <2 weeks before initiating ravulizumab

Plasmapheresis or FFP

  • Administration of PE/PI (plasmapheresis or plasma exchange, or fresh frozen plasma infusion) may reduce ravulizumab serum levels
  • There is no experience with administration of supplemental doses of ravulizumab
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Adverse Effects

>10%

PNH

  • Upper respiratory tract infection (39%)
  • Headache (32%)

aHUS

  • Upper respiratory tract infection (26-44%)
  • Headache (40%)
  • Diarrhea (31-38%)
  • Nausea (26%)
  • Vomiting (26%)
  • Constipation, all grades (25%)
  • Vomiting, all grades (25%)
  • Hypertension, all grades (25%)
  • Hypertension (24%)
  • Arthralgia (22%)
  • Pyrexia (19%)
  • Contusion, all grades (19%)
  • Abdominal pain, all grades (19%)
  • Cough, all grades (19%)
  • Rash, all grades (19%)
  • Peripheral edema (17%)
  • Urinary tract infection (17%)
  • Cough (17%)
  • Dyspnea (17%)
  • Gastrointestinal infection (14%)
  • Constipation (14%)
  • Fatigue (14%)
  • Anemia (14%)
  • Anxiety (14%)
  • Hypotension, all grades (13%)
  • Nausea, all grades (13%)
  • Anemia, all grades (13%)
  • Lymphadenopathy, all grades (13%)
  • Gastroenteritis viral, all grades (13%)
  • Pneumonia, all grades (13%)
  • Decreased appetite, all grades (13%)
  • Iron deficiency, all grades (13%)
  • Tonsillitis, all grades (13%)
  • Pain in extremity, all grades (13%)
  • Dyspnea, all grades (13%)
  • Gastroenteritis viral, Grade ≥3 (6%)
  • Back pain (12%)

1-10%

PNH

  • Diarrhea (9%)
  • Nausea (9%)
  • Pyrexia (7%)
  • Abdominal pain (6%)
  • Pain in extremity (6%)
  • Arthralgia (5%)
  • Dizziness (5%)

aHUS

  • Hypokalemia (10%)
  • Muscle spasms (10%)
  • Pain in extremity (10%)
  • Alopecia (10%)
  • Dry skin (10%)
  • Hypertension, Grade ≥3 (6%)
  • Upper respiratory tract infection, Grade ≥3 (6%)
  • Pneumonia, Grade ≥3 (6%)
  • Anemia, Grade ≥3 (6%)
  • Vomiting, Grade ≥3 (6%)
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Warnings

Black Box Warnings

Meningococcal infections/sepsis

  • Life-threatening meningococcal infections/sepsis reported
  • Meningococcal infection may become rapidly life-threatening or fatal if not recognized and treated early
  • Comply with the most current ACIP recommendations for meningococcal vaccination in patients with complement deficiencies
  • Immunize patients with meningococcal vaccines at least 2 weeks prior to administering the first ravulizumab dose, unless the risks of delaying ravulizumab outweigh the risk of developing a meningococcal infection
  • Vaccination reduces, but does not eliminate, meningococcal infection risk
  • Monitor for early signs of meningococcal infections and evaluate immediately if infection is suspected

Risk evaluation and mitigation strategy (REMS)

  • Available only through REMS program
  • Prescribers must enroll in the program
  • Enrollment and additional information available: 1-844-259-6783 or www.ultomirisrems.com

Contraindications

Unresolved Neisseria meningitidis infection

Patients who are not currently vaccinated against Neisseria meningitidis, unless the risks of delaying treatment outweigh the risks of developing a meningococcal infection

Cautions

Life-threatening meningococcal infections reported; vaccinate according to ACIP guidelines ideally at least 2 weeks before initiating ravulizumab

Ravulizumab blocks terminal complement activation; therefore, an increased susceptibility to encapsulated bacterial infections is possible, especially infections caused by N meningitidis but also Streptococcus pneumoniae, Haemophilus influenzae, and to a lesser extent, Neisseria gonorrhoeae

Monitor for hemolysis signs and symptoms after discontinuing ravulizumab, including elevated LDH with sudden decrease in PNH clone size or hemoglobin, or reappearance of symptoms (eg, fatigue, hemoglobinuria, abdominal pain, dyspnea, thrombosis, dysphagia, erectile dysfunction); monitor any patient who discontinues treatment for at least 16 weeks to detect hemolysis and other reactions

Effect of discontinuing anticoagulants during ravulizumab therapy is not established; therefore, do not alter anticoagulant management

Infusion reactions occurred clinical trials, but did not require discontinuation; interrupt infusion and institute appropriate supportive measures if signs of cardiovascular instability or respiratory compromise occur

Minimum duration of treatment of aHUS should be 6 months; treatment duration beyond initial 6 months should be individualized; after discontinuing treatment, monitor for clinical symptoms and laboratory signs of TMA complications for at least 12 months; if TMA complications occur after discontinuation, consider reinitiating ravulizumab treatment or appropriate organ-specific supportive measures

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Pregnancy

Pregnancy

No data are available for use in pregnant women 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 PNH or aHUS, including preeclampsia and preterm delivery, and adverse fetal/neonatal outcomes, including intrauterine growth restriction (IUGR), fetal death and low birth weight

Animal studies

  • Mouse analogue of the ravulizumab-cwvz molecule (murine anti-C5 antibody) showed increased rates of developmental abnormalities and an increased rate of dead and moribund offspring at doses 0.8-2.2 times the human dose

Clinical considerations

  • PNH in pregnancy is associated with adverse maternal outcomes, including worsening cytopenias, thrombotic events, infections, bleeding, miscarriages, and increased maternal mortality, and adverse fetal outcomes, including fetal death and premature delivery

Lactation

There are no data on the presence of ravulizumab in human milk, the effects on the breastfed child, or the effects on milk production

Because many drugs are excreted in human milk and because of the potential for adverse reactions in a breastfed child, advise lactating women not to breastfeed while receiving ravulizumab and for 8 months after the last dose

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

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Pharmacology

Mechanism of Action

Monoclonal antibody that is a terminal complement inhibitor

It specifically binds to complement protein C5 with high affinity, thereby inhibiting cleavage to C5a (proinflammatory anaphylatoxin) and C5b (initiating subunit of the terminal complement complex [C5b-9]) and preventing the generation of the terminal complement complex C5b9

Inhibits terminal complement-mediated intravascular hemolysis in patients with PNH

Absorption

Peak plasma concentration

  • Loading dose (PNH): 771 mcg/mL (complement inhibitor-naïve); 843 mcg/mL (previously-treated eculizumab)
  • Maintenance dose (PNH): 1379 mcg/mL (complement inhibitor-naïve); 1386 mcg/mL (previously-treated eculizumab)
  • Loading dose (aHUS): 656 mcg/mL (<20 kg); 600 mcg/mL (≥20 to <40 kg); 754 mcg/mL (≥40 kg)
  • Maintenance dose (aHUS): 1467 mcg/mL (<20 kg); 1863 mcg/mL (≥20 to <40 kg); 1458 mcg/mL (≥40 kg)

Minimum plasma concentration

  • Loading dose (PNH): 391 mcg/mL (complement inhibitor-naïve); 405 mcg/mL (previously-treated eculizumab)
  • Maintenance dose (PNH): 473 mcg/mL (complement inhibitor-naïve); 501 mcg/mL (previously-treated eculizumab)
  • Loading dose (aHUS): 241 mcg/mL (<20 kg); 186 mcg/mL (≥20 to <40 kg); 313 mcg/mL (≥40 kg)
  • Maintenance dose (aHUS): 683 mcg/mL (<20 kg); 549 mcg/mL (≥20 to <40 kg); 507 mcg/mL (≥40 kg)

Distribution

Vd (steady-state): 5.34 L (PNH); 5.22 L (aHUS)

Elimination

Half-life: 49.7 days (PNH); 51.8 days (aHUS)

Clearance: 0.08 L/day (PNH); 0.08 L/day (aHUS)

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Administration

IV Compatibilities

0.9% NaCl

IV Preparation

Injectable solution requires dilution to final concentration of 5 mg/mL

Determine number of vials required for calculated dose

Visually inspect solution; do not use if particulate matter or precipitation observed

Withdraw calculated dose and dilute in infusion bag using 0.9% NaCl to final concentration of 5 mg/mL

Do not shake; mix gently

Protect from light and do not freeze

Loading dose dilution instructions

  • ≥5 to <20 kg
    • Dilute 600 mg/60 mL-dose with 60 mL NS; total volume 120 mL
  • ≥20 to <30 kg
    • Dilute 900 mg/90 mL-dose with 90 mL NS; total volume 180 mL
  • 30 to <40 kg
    • Dilute 1200 mg/120 mL-dose with 120 mL NS; total volume 240 mL
  • 40 to <60 kg
    • Dilute 2400 mg/240 mL-dose with 240 mL NS; total volume 480 mL
  • ≥60 to <100 kg
    • Dilute 2700 mg/270 mL-dose with 270 mL NS; total volume 540 mL
  • ≥100 kg
    • Dilute 3000 mg/300 mL-dose with 300 mL NS; total volume 600 mL

Maintenance dose dilution instructions

  • ≥5 to <10 kg
    • Dilute 300 mg/30 mL-dose with 30 mL NS; total volume 60 mL
  • ≥10 to <20 kg
    • Dilute 600 mg/60 mL-dose with 60 mL NS; total volume 120 mL
  • ≥20 to <30 kg
    • Dilute 2100 mg/210 mL-dose with 210 mL NS; total volume 420 mL
  • 30 to <40 kg
    • Dilute 2700 mg/270 mL-dose with 270 mL NS; total volume 540 mL
  • 40 to <60 kg
    • Dilute 3000 mg/300 mL-dose with 300 mL NS; total volume 600 mL
  • ≥60 to <100 kg
    • Dilute 3300 mg/330 mL-dose with 330 mL NS; total volume 660 mL
  • ≥100 kg
    • Dilute 3600 mg/360 mL-dose with 360 mL NS; total volume 720 mL

IV Administration

Only administer diluted solution as IV infusion

Administer through 0.22-micron filter

Allow admixture to adjust to room temperature; do not heat in microwave or with any heat source other than ambient air temperature

If an adverse reaction occurs during administration, the infusion may be slowed or stopped

Monitor patient for at least 1 hr after completing infusion for infusion reaction signs or symptoms

Maximum infusion rate

  • Loading dose
    • ≥5 to <10 kg: 31 mL/hr
    • ≥10 to <20 kg: 63 mL/hr
    • ≥20 to <30 kg: 120 mL/hr
    • 30 to <40 kg: 184 mL/hr
    • 40 to <60 kg: 252 mL/hr
    • ≥60 to <100 kg: 317 mL/hr
    • ≥100 kg: 333 mL/hr
  • Maintenance dose
    • ≥5 to <10 kg: 31 mL/hr
    • ≥10 to <20 kg: 63 mL/hr
    • ≥20 to <30 kg: 127 mL/hr
    • 30 to <40 kg: 192 mL/hr
    • 40 to <60 kg: 257 mL/hr
    • ≥60 to <100 kg: 330 mL/hr
    • ≥100 kg: 327 mL/hr

Storage

Unopened vials

  • Refrigerate at 2-8°C (36-46°F) in original carton to protect from light
  • Do not freeze
  • Do not shake

Diluted solution

  • If diluted solution is not used immediately, refrigerate at 2-8°C (36-46°F) for up to 24 hr, taking into account the expected infusion time
  • Once removed from refrigeration, administer within 6 hr
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Formulary

FormularyPatient Discounts

Adding plans allows you to compare formulary status to other drugs in the same class.

To view formulary information first create a list of plans. Your list will be saved and can be edited at any time.

Adding plans allows you to:

  • View the formulary and any restrictions for each plan.
  • Manage and view all your plans together – even plans in different states.
  • Compare formulary status to other drugs in the same class.
  • Access your plan list on any device – mobile or desktop.

The above information is provided for general informational and educational purposes only. Individual plans may vary and formulary information changes. Contact the applicable plan provider for the most current information.

Tier Description
1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
2 This drug is available at a middle level co-pay. Most commonly, these are "preferred" (on formulary) brand drugs.
3 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs.
4 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
5 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
6 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
NC NOT COVERED – Drugs that are not covered by the plan.
Code Definition
PA Prior Authorization
Drugs that require prior authorization. This restriction requires that specific clinical criteria be met prior to the approval of the prescription.
QL Quantity Limits
Drugs that have quantity limits associated with each prescription. This restriction typically limits the quantity of the drug that will be covered.
ST Step Therapy
Drugs that have step therapy associated with each prescription. This restriction typically requires that certain criteria be met prior to approval for the prescription.
OR Other Restrictions
Drugs that have restrictions other than prior authorization, quantity limits, and step therapy associated with each prescription.
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Medscape prescription drug monographs are based on FDA-approved labeling information, unless otherwise noted, combined with additional data derived from primary medical literature.