ravulizumab (Rx)

>10%

PNH (adults)

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

PNH (pediatric patients)

• Treatment naïve

  • Anemia (20%)
  • Pyrexia (20%)
  • Upper respiratory tract infection (20%)

• Eculizumab experienced

  • Upper respiratory tract infection (75%)
  • Abdominal pain (38%)
  • Anemia (25%)
  • Constipation (25%)
  • Pain in extremity (25%)
  • Headache (25%)
  • Pyrexia (13%)

aHUS (adults)

• Headache, all grades (40%)
• Diarrhea, all grades (31%)
• Nausea, all grades (26%)
• Vomiting, all grades (26%)
• Upper respiratory tract infection, all grades (26%)
• Hypertension, all grades (24%)
• Arthralgia, all grades (22%)
• Pyrexia, all grades (19%)
• Peripheral edema, all grades (17%)
• Urinary tract infection (17%)
• Cough, all grades (17%)
• Dyspnea, all grades (17%)
• Gastrointestinal infection, all grades (14%)
• Anemia, all grades (14%)
• Constipation, all grades (14%)
• Fatigue, all grades (14%)
• Anxiety, all grades (14%)
• Back pain, all grades (12%)
• Abdominal pain, all grades (12%)
• Hypertension, Grade ≥3 (12%)

aHUS (pediatric patients)

• Age <2

  • Diarrhea (50%)
  • Upper respiratory tract infection (50%)
  • Tonsilitis (50%)
  • Decreased appetite (50%)
  • Myalgia (50%)
  • Dyspnea (50%)
  • Hypertension (50%)

• Age 2 to <12

  • Upper respiratory tract infection (50%)
  • Pyrexia (42%)
  • Constipation (33%)
  • Headache (33%)
  • Diarrhea (25%)
  • Vomiting (25%)
  • Cough (25%)
  • Hypertension (17%)
  • Lymphadenopathy (17%)
  • Abdominal pain (17%)
  • Gastroenteritis viral (17%)
  • Contusion (17%)
  • Vitamin D decreased (17%)
  • Iron deficiency (17%)
  • Pain in extremity (17%)
  • Rash (17%)
  • Hypotension (17%)

• Age 12-16

  • Constipation (100%)
  • Pyrexia (100%)
  • Vitamin D decreased (100%)

1-10%

PNH (adults)

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

aHUS (adults)

• Hypokalemia, all grades (10%)
• Muscle spasms, all grades (10%)
• Pain in extremity, all grades (10%)
• Urinary tract infection, Grade ≥3 (9%)
• Gastrointestinal infection, Grade ≥3 (3%)
• Diarrhea, Grade ≥3 (3%)
• Nausea, Grade ≥3 (3%)
• Vomiting, Grade ≥3 (3%)
• Constipation, Grade ≥3 (2%)
• Abdominal pain, Grade ≥3 (2%)
• Hypokalemia, Grade ≥3 (2%)
• Back pain, Grade ≥3 (2%)
• Headache, Grade ≥3 (2%)
• Anxiety, Grade ≥3 (2%)
• Dyspnea, Grade ≥3 (2%)
• Pyrexia, Grade ≥3 (2%)

aHUS (pediatric patients)

• Age 2 to <12

  • Tonsilitis (8%)
  • Decreased appetite (8%)
  • Myalgia (8%)
  • Dyspnea (8%)

<1%

• PNH (adults)

  • Infusion-related reactions

Postmarketing Reports

Anaphylaxis

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

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

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

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

Infusion reactions reported; reactions included lower back pain, drop in blood pressure, elevation in blood pressure, limb discomfort, drug hypersensitivity (allergic reaction), dysgeusia (bad taste), and drowsiness, but did not require discontinuation; interrupt infusion and institute appropriate supportive measures if signs of cardiovascular instability or respiratory compromise occur

On-body SC injector uses acrylic adhesive; may result in allergic reaction for patients with known allergy to acrylic adhesive; consider premedication and supportive measures if signs of allergy emerge

Serious meningococcal infections

• Life-threatening meningococcal infections have occurred
• Use increases patients’ susceptibility to serious meningococcal infections (septicemia and/or meningitis)
• Vaccinate for meningococcal disease according to most current Advisory Committee on Immunization Practices (ACIP) recommendations for patients with complement deficiencies; revaccinate patients according to ACIP recommendations considering duration of therapy
• Immunize patients without a history of meningococcal vaccination at least 2 weeks before initiating
• If urgent therapy is indicated in an unvaccinated patient, administer meningococcal vaccine(s) as soon as possible and provide patients with 2 weeks of antibacterial drug prophylaxis; must receive appropriate prophylactic antibiotics until 2 weeks after vaccination
• Closely monitor for signs and symptoms of meningococcal infection and evaluate if infection is suspected
• Consider discontinuation in patients who are undergoing treatment for serious meningococcal infection

Risk Evaluation and Mitigation Strategy (REMS)

• Owing to risk of meningococcal infections, drug is only available only through a restricted REMS program
• Prescribers must enroll in the program, counsel patients about the risk of meningococcal infection/sepsis, provide patients with the REMS educational materials, and ensure patients are vaccinated with meningococcal vaccines; patient must carry the Patient Safety Card with them at all times during and for 8 months following treatment with this drug
• Enrollment in the ULTOMIRIS REMS and additional information are available by telephone: 1-888-765-4747 or at www.ultomirisrems.com

Drug interaction overview

• Concomitant use with plasma exchange (PE), plasmapheresis (PP), or intravenous immunoglobulin (IVIg) treatment can reduce serum ravulizumab concentrations and requires a supplemental dose of ravulizumab

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.

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)

IV Compatibilities

0.9% NaCl

IV Preparation

Dilute before use

Each vial intended for single-dose only

Do not mix 100 mg/mL (3-mL and 11-mL vials) and 10 mg/mL (30-mL vials) together

Determine number of vials needed based on prescribed dose

Visually inspect vials; discard if any particulate matter or precipitation is present

Withdraw calculated volume and dilute in 0.9% NaCl infusion bag to final concentration of 50 mg/mL for the 3-mL and 11-mL vials OR 5 mg/mL for 30-mL vial

Mix gently; do not shake

100 mg/mL vials

• Loading dose

  • 600 mg: Dilute 6 mL of drug with 6 mL 0.9% NaCl; total volume 12 mL
  • 900 mg: Dilute 9 mL of drug with 9 mL 0.9% NaCl; total volume 18 mL
  • 1200 mg: Dilute 12 mL of drug with 12 mL 0.9% NaCl; total volume 24 mL
  • 2400 mg: Dilute 24 mL of drug with 24 mL 0.9% NaCl; total volume 48 mL
  • 2700 mg: Dilute 27 mL of drug with 27 mL 0.9% NaCl; total volume 54 mL
  • 3000 mg: Dilute 30 mL of drug with 30 mL 0.9% NaCl; total volume 60 mL

• Maintenance dose

  • 300 mg: Dilute 3 mL of drug with 3 mL 0.9% NaCl; total volume 6 mL
  • 600 mg: Dilute 6 mL of drug with 6 mL 0.9% NaCl; total volume 12 mL
  • 2100 mg: Dilute 21 mL of drug with 21 mL 0.9% NaCl; total volume 42 mL
  • 2700 mg: Dilute 27 mL of drug with 27 mL 0.9% NaCl; total volume 54 mL
  • 3000 mg: Dilute 30 mL of drug with 30 mL 0.9% NaCl; total volume 60 mL
  • 3300 mg: Dilute 33 mL of drug with 33 mL 0.9% NaCl; total volume 66 mL
  • 3600 mg: Dilute 36 mL of drug with 36 mL 0.9% NaCl; total volume 72 mL

• Supplemental dose

  • 600 mg: Dilute 6 mL of drug with 6 mL 0.9% NaCl; total volume 12 mL
  • 1200 mg: Dilute 12 mL of drug with 12 mL 0.9% NaCl; total volume 24 mL
  • 1500 mg: Dilute 15 mL of drug with 15 mL 0.9% NaCl; total volume 30 mL
  • 1800 mg: Dilute 18 mL of drug with 18 mL 0.9% NaCl; total volume 36 mL

10 mg/mL vials

• Loading dose

  • 600 mg: Dilute 60 mL of drug with 60 mL 0.9% NaCl; total volume 120 mL
  • 900 mg: Dilute 90 mL of drug with 90 mL 0.9% NaCl; total volume 180 mL
  • 1200 mg: Dilute 120 mL of drug with 120 mL 0.9% NaCl; total volume 240 mL
  • 2400 mg: Dilute 240 mL of drug with 240 mL 0.9% NaCl; total volume 480 mL
  • 2700 mg: Dilute 270 mL of drug with 270 mL 0.9% NaCl; total volume 540 mL
  • 3000 mg: Dilute 300 mL of drug with 300 mL 0.9% NaCl; total volume 600 mL

• Maintenance dose

  • 300 mg: Dilute 30 mL of drug with 30 mL 0.9% NaCl; total volume 60 mL
  • 600 mg: Dilute 60 mL of drug with 60 mL 0.9% NaCl; total volume 120 mL
  • 1200 mg: Dilute 120 mL of drug with 120 mL 0.9% NaCl; total volume 240 mL
  • 2700 mg: Dilute 270 mL of drug with 270 mL 0.9% NaCl; total volume 540 mL
  • 3000 mg: Dilute 300 mL of drug with 300 mL 0.9% NaCl; total volume 600 mL
  • 3300 mg: Dilute 330 mL of drug with 330 mL 0.9% NaCl; total volume 660 mL
  • 3600 mg: Dilute 360 mL of drug with 360 mL 0.9% NaCl; total volume 720 mL

• Supplemental dose

  • 600 mg: Dilute 60 mL of drug with 60 mL 0.9% NaCl; total volume 120 mL
  • 1200 mg: Dilute 120 mL of drug with 120 mL 0.9% NaCl; total volume 240 mL
  • 1500 mg: Dilute 150 mL of drug with 150 mL 0.9% NaCl; total volume 300 mL
  • 1800 mg: Dilute 180 mL of drug with 180 mL 0.9% NaCl; total volume 360 mL

IV Administration

Infuse through 0.2- or 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, infusion may be slowed or stopped

Monitor for at least 1 hr after completing infusion for signs or symptoms for infusion-related reactions

Missed dose: Contact health care provider immediately

Maximum infusion rate (diluted 100-mg/mL vials)

• Loading dose

  • ≥5 to <10 kg: 8 mL/hr
  • 10 to <20 kg: 16 mL/hr
  • 20 to <30 kg: 30 mL/hr
  • 30 to <40 kg: 46 mL/hr
  • 40 to <60 kg: 64 mL/hr
  • 60 to <100 kg: 92 mL/hr
  • ≥100 kg: 144 mL/hr

• Maintenance dose

  • ≥5 to <10 kg: 8 mL/hr
  • 10 to <20 kg: 16 mL/hr
  • 20 to <30 kg: 33 mL/hr
  • 30 to <40 kg: 49 mL/hr
  • 40 to <60 kg: 65 mL/hr
  • 60 to <100 kg: 99 mL/hr
  • ≥100 kg: 144 mL/hr

• Supplemental dose (40 to <60 kg)

  • 600 mg-dose: 48 mL/hr
  • 1200 mg-dose: 57 mL/hr
  • 1500 mg-dose: 60 mL/hr

• Supplemental dose (60 to <100 kg)

  • 600 mg-dose: 60 mL/hr
  • 1500 mg-dose: 83 mL/hr
  • 1800 mg-dose: 86 mL/hr

• Supplemental dose (≥100 kg)

  • 600 mg-dose: 71 mL/hr
  • 1500 mg-dose: 120 mL/hr
  • 1800 mg-dose: 129 mL/hr

Maximum infusion rate (diluted 10-mg/mL vials)

• 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

• Supplemental dose (40 to <60 kg)

  • 600 or 1200 mg-dose: 240 mL/hr
  • 1500 mg-dose: 250 mL/hr

• Supplemental dose (≥60 kg)

  • 600 or 1500 mg-dose: 300 mL/hr
  • 1800 mg-dose: 327 mL/hr

SC Preparation

Remove 2 cartons of ravulizumab on-body delivery system for SC administration from refrigerator (2 on-body injectors and 2 prefilled cartridges required for full dose [490 mg])

Inspect packaging; discard if injectors or cartridges have been dropped or appear to be broken or damaged

Wait at least 45 minutes injectors and prefilled cartridges in cartons to naturally reach room temperature before administration

Do not return to refrigerator; discard after 3 days if unused

Before administration, visually inspect solution; discard if it contains flakes or particles, or is cloudy or discolored

SC Administration

SC injection for maintenance for adults only

For use only with on-body SC delivery system provided

Missed or partial dose: Contact health care provider immediately

Avoid areas where skin is tender, bruised, red, or hard; do not inject into scars or stretch marks

Rotate injection sites

May administer 2 on-body delivery systems concurrently or sequentially; each injection is delivered over ~10 minutes

See prescribing information for full instructions and diagrams

Allergic reactions

• If allergic reaction occurs during SC administration; stop treatment and remove on-body injector(s)
• Seek medical attention before further administration
• Monitor for signs or symptoms of infusion-related reaction for at least 1 hr following injection

Storage

Unopened IV vials

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

Diluted IV solution

• If not used immediately, refrigerate at 2-8°C (36-46°F) for up to 24 hr, including the expected infusion time
• Once removed from refrigerator, administer diluted infusion solution within 6 hr if prepared with 10 mg/mL vials or within 4 hr if prepared 100 mg/mL vials

SC

• Refrigerate prefilled cartridges and on-body injectors at 2-8ºC (36-46ºF) in original carton to protect from light and physical damage
• Do not freeze
• Do not shake or drop
• Do not allow on-body injector to get wet from water or other liquids
• If removed from refrigerator, store in original carton at 20-25ºC (68-77ºF) for up to 3 days
• If stored at room temperature, discard after 3 days
• Do not return to refrigerator
• Single-use on-body injector with prefilled cartridge are NOT made with natural rubber latex