Ravulizumab

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution, Intravenous [preservative free]:

Ultomiris: ravulizumab-cwvz 300 mg/30 mL (30 mL) [contains polysorbate 80]

Pharmacology

Mechanism of Action

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).

Pharmacokinetics/Pharmacodynamics

Distribution

V_d: 5.22 L (atypical hemolytic uremic syndrome patients); 5.34 L (paroxysmal nocturnal hemoglobinuria patients).

Excretion

Clearance: 0.08 L/day.

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).

Half-Life Elimination

Terminal: 51.8 days (atypical hemolytic uremic syndrome patients); 49.7 days (paroxysmal nocturnal hemoglobinuria patients).

Use: Labeled Indications

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.

Paroxysmal nocturnal hemoglobinuria: Treatment of paroxysmal nocturnal hemoglobinuria in adults.

Contraindications

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.

Dosage and Administration

Dosing: Adult

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 7 days 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:

≥20 kg to <30 kg:

Loading dose: 900 mg.

Maintenance dose: 2,100 mg once every 8 weeks starting 2 weeks after the loading dose.

≥30 kg to <40 kg:

Loading dose: 1,200 mg.

Maintenance dose: 2,700 mg once every 8 weeks starting 2 weeks after the loading dose.

≥40 kg to <60 kg:

Loading dose: 2,400 mg.

Maintenance dose: 3,000 mg once every 8 weeks starting 2 weeks after the loading dose.

≥60 kg to <100 kg:

Loading dose: 2,700 mg.

Maintenance dose: 3,300 mg once every 8 weeks starting 2 weeks after the loading dose.

≥100 kg:

Loading dose: 3,000 mg.

Maintenance dose: 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:

≥40 kg to <60 kg:

Loading dose: 2,400 mg

Maintenance dose: 3,000 mg once every 8 weeks starting 2 weeks after the loading dose

≥60 kg to <100 kg:

Loading dose: 2,700 mg

Maintenance dose: 3,300 mg once every 8 weeks starting 2 weeks after the loading dose

≥100 kg:

Loading dose: 3,000 mg

Maintenance dose: 3,600 mg once every 8 weeks starting 2 weeks after the loading dose

Conversion from eculizumab: When converting from eculizumab to ravulizumab, administer the ravulizumab loading dose 2 weeks after the last eculizumab dose and then administer ravulizumab maintenance doses once every 8 weeks (beginning 2 weeks after the ravulizumab loading dose).

Dosing: Geriatric

Refer to adult dosing.

Dosing: Adjustment for Toxicity

Adverse reaction during infusion: May slow or stop infusion (at discretion of health care provider).

Reconstitution

Withdraw the calculated volume of ravulizumab solution from vial(s) and dilute in an infusion bag using sodium chloride 0.9% (NS) only to a final concentration of 5 mg/mL. Mix gently; do not shake.

≥20 kg to <30 kg: Dilute loading dose (900 mg) with NS 90 mL to a total volume of 180 mL. Dilute maintenance dose (2,100 mg) with NS 210 mL to a total volume of 420 mL.

≥30 kg to <40 kg: Dilute loading dose (1,200 mg) with NS 120 mL to a total volume of 240 mL. Dilute maintenance dose (2,700 mg) with NS 270 mL to a total volume of 540 mL.

≥40 kg to <60 kg: Dilute loading dose (2,400 mg) with NS 240 mL to a total volume of 480 mL. Dilute maintenance dose (3,000 mg) with NS 300 mL to a total volume of 600 mL.

≥60 kg to <100 kg: Dilute loading dose (2,700 mg) with NS 270 mL to a total volume of 540 mL. Dilute maintenance dose (3,300 mg) with NS 330 mL to a total volume of 660 mL.

≥100 kg: Dilute loading dose (3,000 mg) with NS 300 mL to a total volume of 600 mL. Dilute maintenance dose (3,600 mg) with NS 360 mL to a total volume of 720 mL.

Administration

IV: Infuse through a 0.2 or 0.22 micron filter. 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 based on patient weight.

≥20 kg to <30 kg: Infuse loading dose (900 mg in a total volume of 180 mL) at 120 mL/hour (minimum infusion time: 1.5 hours). Infuse maintenance dose (2,100 mg in a total volume of 420 mL) at 127 mL/hour (minimum infusion time: 3.3 hours).

≥30 kg to <40 kg: Infuse loading dose (1,200 mg in a total volume of 240 mL) at 184 mL/hour (minimum infusion time: 1.3 hours). Infuse maintenance dose (2,700 mg in a total volume of 540 mL) at 192 mL/hour (minimum infusion time: 2.8 hours).

≥40 kg to <60 kg: Infuse loading dose (2,400 mg in a total volume of 480 mL) at 252 mL/hour (minimum infusion time: 1.9 hours). Infuse maintenance dose (3,000 mg in a total volume of 600 mL) at 257 mL/hour (minimum infusion time: 2.3 hours).

≥60 kg to <100 kg: Infuse loading dose (2,700 mg in a total volume of 540 mL) at 317 mL/hour (minimum infusion time: 1.7 hours). Infuse maintenance dose (3,300 mg in a total volume of 660 mL) at 330 mL/hour (minimum infusion time: 2 hours).

≥100 kg: Infuse loading dose (3,000 mg in a total volume of 600 mL) at 333 mL/hour (minimum infusion time: 1.8 hours). Infuse maintenance dose (3,600 mg in a total volume of 720 mL) at 327 mL/hour (minimum infusion time: 2.2 hours).

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.

Storage

Store intact vials at 2°C to 8°C (36°F to 46°F); do not freeze. Do not shake. Store in original carton to protect from light. Solutions diluted for infusion should be administered immediately following preparation; if the diluted solution is not used immediately, may store refrigerated at 2°C to 8°C (36°F to 46°F) for a maximum of 24 hours (accounting for infusion time); do not freeze. Once removed from refrigeration, allow solution to adjust to room temperature at ambient air temperature (do not use a heat source) prior to infusion and administer within 6 hours. Do not shake diluted solution. Protect diluted solution from light.

Drug Interactions

Baricitinib: Immunosuppressants may enhance the immunosuppressive effect of Baricitinib. Management: Use of baricitinib in combination with potent immunosuppressants such as azathioprine or cyclosporine is not recommended. Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted. Consider therapy modification

BCG (Intravesical): Immunosuppressants may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

Cladribine: May enhance the immunosuppressive effect of Immunosuppressants. Avoid combination

Coccidioides immitis Skin Test: Immunosuppressants may diminish the diagnostic effect of Coccidioides immitis Skin Test. Monitor therapy

Denosumab: May enhance the adverse/toxic effect of Immunosuppressants. Specifically, the risk for serious infections may be increased. Monitor therapy

Echinacea: May diminish the therapeutic effect of Immunosuppressants. Consider therapy modification

Fingolimod: Immunosuppressants may enhance the immunosuppressive effect of Fingolimod. Management: Avoid the concomitant use of fingolimod and other immunosuppressants when possible. If combined, monitor patients closely for additive immunosuppressant effects (eg, infections). Consider therapy modification

Leflunomide: Immunosuppressants may enhance the adverse/toxic effect of Leflunomide. Specifically, the risk for hematologic toxicity such as pancytopenia, agranulocytosis, and/or thrombocytopenia may be increased. Management: Consider not using a leflunomide loading dose in patients receiving other immunosuppressants. Patients receiving both leflunomide and another immunosuppressant should be monitored for bone marrow suppression at least monthly. Consider therapy modification

Natalizumab: Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased. Avoid combination

Nivolumab: Immunosuppressants may diminish the therapeutic effect of Nivolumab. Consider therapy modification

Ocrelizumab: May enhance the immunosuppressive effect of Immunosuppressants. Monitor therapy

Pidotimod: Immunosuppressants may diminish the therapeutic effect of Pidotimod. Monitor therapy

Pimecrolimus: May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Roflumilast: May enhance the immunosuppressive effect of Immunosuppressants. Consider therapy modification

Siponimod: Immunosuppressants may enhance the immunosuppressive effect of Siponimod. Monitor therapy

Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Management: Evaluate patients to see if it is medically appropriate to reduce or discontinue therapy with immunosuppressants prior to initiating sipuleucel-T therapy. Consider therapy modification

Smallpox and Monkeypox Vaccine (Live): Immunosuppressants may diminish the therapeutic effect of Smallpox and Monkeypox Vaccine (Live). Monitor therapy

Tacrolimus (Topical): May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Tertomotide: Immunosuppressants may diminish the therapeutic effect of Tertomotide. Monitor therapy

Tofacitinib: Immunosuppressants may enhance the immunosuppressive effect of Tofacitinib. Management: Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted, and this warning seems particularly focused on more potent immunosuppressants. Consider therapy modification

Trastuzumab: May enhance the neutropenic effect of Immunosuppressants. Monitor therapy

Upadacitinib: Immunosuppressants may enhance the immunosuppressive effect of Upadacitinib. Avoid combination

Vaccines (Inactivated): Immunosuppressants may diminish the therapeutic effect of Vaccines (Inactivated). Management: Vaccine efficacy may be reduced. Complete all age-appropriate vaccinations at least 2 weeks prior to starting an immunosuppressant. If vaccinated during immunosuppressant therapy, revaccinate at least 3 months after immunosuppressant discontinuation. Consider therapy modification

Vaccines (Live): Immunosuppressants may enhance the adverse/toxic effect of Vaccines (Live). Immunosuppressants may diminish the therapeutic effect of Vaccines (Live). Management: Avoid use of live organism vaccines with immunosuppressants; live-attenuated vaccines should not be given for at least 3 months after immunosuppressants. Exceptions: Smallpox and Monkeypox Vaccine (Live). Avoid combination

Adverse Reactions

>10%:

Central nervous system: Headache (32%)

Respiratory: Upper respiratory tract infection (39%)

1% to 10%:

Central nervous system: Dizziness (5%)

Gastrointestinal: Diarrhea (9%), nausea (9%), abdominal pain (6%)

Neuromuscular & skeletal: Limb pain (6%), arthralgia (5%)

Miscellaneous: Fever (7%), infusion related reaction (2%)

<1%, postmarketing, and/or case reports: Antibody development, hyperthermia, meningococcal infection, sepsis

Warnings/Precautions

Concerns related to adverse effects:

• Infection: Ravulizumab blocks terminal complement activation and therefore may increase the risk for susceptibility to encapsulated bacterial infections, especially 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. Monitor closely for signs/symptoms of worsening infection if administering ravulizumab to patients with active systemic infections.
• Infusion reactions: Administration of ravulizumab may result in infusion reactions. In clinical trials, a small number of patients experienced infusion reactions (lower back pain, blood pressure changes, limb discomfort, and infusion-related pain) 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: [US Boxed Warning]: Life-threatening meningococcal infections/sepsis have occurred with ravulizumab. If not recognized and treated early, meningococcal infection may become rapidly life-threatening or fatal. Comply with the most current ACIP recommendations for meningococcal vaccination in patients with complement deficiencies. Immunize with meningococcal vaccines at least 2 weeks prior to administering the first ravulizumab dose, 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 for early signs of meningococcal infections and evaluate immediately if infection is suspected. 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.
• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Dosage form specific issues:

• 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:

• Discontinuation in 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 lactic dehydrogenase (LDH) increased ≥25% compared to baseline or to nadir during ravulizumab treatment. If TMA complications occur after discontinuation, consider restarting ravulizumab treatment or appropriate organ-specific supportive measures.
• Discontinuation in paroxysmal nocturnal hemoglobinuria: Monitor closely for at least 16 weeks (after discontinuation) to detect hemolysis and other reactions; monitor for signs/symptoms of hemolysis (eg, elevated LDH along with sudden decrease in PNH 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. If hemolysis signs/symptoms (including elevated LDH) occur after discontinuation, consider restarting ravulizumab treatment.
• Plasmapheresis/plasma exchange: Plasmapheresis, plasma exchange, or fresh frozen plasma may reduce ravulizumab levels; the effect of supplemental ravulizumab doses has not been established.
• REMS program: [US Boxed Warning]: Ravulizumab is available only through a restricted Risk Evaluation and Mitigation Strategy (REMS) program. Prescribers must enroll in the Ultomiris REMS program; enrollment and additional information are available at 1-888-765-4747 or at http://www.ultomirisrems.com. Counsel patients about the risk of meningococcal infection/sepsis; provide REMS educational materials to patients, and ensure patients are vaccinated with meningococcal vaccines.

Monitoring Parameters

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.

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.

Pregnancy

Pregnancy Considerations

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). Females who were pregnant or planning to become pregnant were excluded from initial clinical studies (Kulasekararaj 2019; Lee 2019).

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. Women with aHUS may have an increased risk of preeclampsia and preterm delivery; intrauterine growth restriction/low birth weight and fetal death may also occur.

Patient Education

What is this drug used for?

• It is used to treat a blood disease called paroxysmal nocturnal hemoglobinuria (PNH).
• It is used to treat a blood and kidney disease called atypical hemolytic uremic syndrome (aHUS).

Frequently reported side effects of this drug

• Common cold symptoms
• Constipation
• Vomiting
• Lack of appetite
• Fatigue
• Loss of strength and energy
• Diarrhea
• Nausea
• Abdominal pain
• Painful extremities
• Joint pain
• Muscle pain
• Muscle spasm
• Anxiety
• Hair loss
• Dry skin

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• Infection
• Meningococcal infection like severe headache with or without nausea, vomiting, fever, or stiff neck or back; confusion; high fever; fever with a rash; sensitivity to light; or severe muscle aches or pain with or without flu-like signs
• Low potassium like muscle pain or weakness, muscle cramps, or an abnormal heartbeat
• Severe headache
• Vision changes
• Swollen glands
• Swelling of arms or legs
• Chest pain
• Severe dizziness
• Passing out
• Shortness of breath
• Back pain
• Injection site pain or irritation
• Signs of a significant reaction like wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.