Ravulizumab

Indications

Ravulizumab is used for: Paroxysmal Nocturnal Hemoglobinuria

Adult Dose

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

Child Dose

<18 years: Safety and efficacy not established

Renal Dose

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

Administration

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 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

Contra Indications

Unresolved Neisseria meningitidis infection

Precautions

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

Pregnancy-Lactation

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 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

Interactions

Adverse Effects

Side effects of Ravulizumab : >10% Upper respiratory tract infection (39%) Headache (32%) 1-10% Diarrhea (9%) Nausea (9%) Pyrexia (7%) Abdominal pain (6%) Pain in extremity (6%) Arthralgia (5%) Dizziness (5%)

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