ravulizumab

Binds to the complement protein C5 and inhibits its cleavage to C5a and C5b, preventing the production of the terminal complement complex, C5b-9, which is a necessary step in the initiation of hemolysis in paroxysmal noctural hemoglobinuria and development of thrombotic microangiopathy in atypical hemolytic uremic syndrome. Mechanism in generalized myasthenia gravis may be due to decreased deposition of C5b-9 complex at neuromuscular junction. Mechanism in neuromyelitis optica spectrum disorder may be due to inhibition of aquaporin-4 antibody-induced terminal complement C5b-9 deposition.

Therapeutic effects:

Decreased hemolysis associated with paroxysmal noctural hemoglobinuria.
Decreased complement-mediated thrombotic microangiopathy in atypical hemolytic uremic syndrome.
Reduction in muscle weakness and improvement in ability to perform activities of daily living in generalized myasthenia gravis.
Reduction in risk of relapse in neuromyelitis optica spectrum disorder.

Pharmacokinetics ⬆ ⬇

Absorption: IV administration results in complete bioavailability.

Distribution: Distributed to tissues.

Metabolism/Excretion: Unknown.

Half-Life: 50 days.

Time/Action Profile ⬆ ⬇

(inhibition of serum free C5)

ROUTE	ONSET	PEAK	DURATION
IV	Rapid	End of infusion	8 wk

Contraind./Precautions ⬆ ⬇

Contraindicated in:

Unresolved Neisseria meninigitidis infection;
Patients not vaccinated against Neisseria meninigitidis (unless risk of delaying treatment outweighs risks of developing a meningococcal infection);
Lactation: Lactation.

Use Cautiously in:

OB: Use during pregnancy only if potential maternal benefit justifies potential fetal risk;
Pedi: Children <1 mo (safety and effectiveness not established).

Adv. Reactions/Side Effects ⬆ ⬇

GI: abdominal pain, diarrhea, nausea

Neuro: headache, dizziness

Resp: upper respiratory tract infection

MS: arthralgia

Misc: fever, HYPERSENSITIVITY REACTIONS (INCLUDING ANAPHYLAXIS), INFECTIONS (INCLUDING HAEMOPHILUS INFLUENZAE, NEISSERIA GONORRHOEAE, AND STREPTOCOCCUS PNEUMONIAE)., Haemophilus influenzae, Neisseria gonorrhoeae, and Streptococcus pneumoniae)., MENINGOCOCCAL INFECTIONS, infusion reactions

Interactions ⬆ ⬇

Drug-drug:

None reported.

Route/Dosage ⬆ ⬇

Paroxysmal Nocturnal Hemoglobinuria or Atypical Hemolytic Uremic Syndrome

IV (Adults and Children ≥1 mo and ≥100 kg): Loading dose: 3000 mg single dose (if switching from eculizumab, give loading dose 2 wk after last eculizumab dose); Maintenance dose (initiated 2 wk after loading dose): 3600 mg every 8 wk. Treatment should continue for ≥6 mo for atypical hemolytic uremic syndrome.
IV (Adults and Children ≥1 mo and 60–<100 kg): Loading dose: 2700 mg single dose (if switching from eculizumab, give loading dose 2 wk after last eculizumab dose); Maintenance dose (initiated 2 wk after loading dose): 3300 mg every 8 wk. Treatment should continue for ≥6 mo for atypical hemolytic uremic syndrome.
IV (Adults and Children ≥1 mo and 40–<60 kg): Loading dose: 2400 mg single dose (if switching from eculizumab, give loading dose 2 wk after last eculizumab dose); Maintenance dose (initiated 2 wk after loading dose): 3000 mg every 8 wk. Treatment should continue for ≥6 mo for atypical hemolytic syndrome.
IV (Adults and Children ≥1 mo and 30–<40 kg): Loading dose: 1200 mg single dose (if switching from eculizumab, give loading dose 2 wk after last eculizumab dose); Maintenance dose (initiated 2 wk after loading dose): 2700 mg every 8 wk. Treatment should continue for ≥6 mo for atypical hemolytic uremic syndrome.
IV (Adults and Children ≥1 mo and 20–<30 kg): Loading dose: 900 mg single dose (if switching from eculizumab, give loading dose 2 wk after last eculizumab dose); Maintenance dose (initiated 2 wk after loading dose): 2100 mg every 8 wk. Treatment should continue for ≥6 mo for atypical hemolytic uremic syndrome.
IV (Adults and Children ≥1 mo and 10–<20 kg): Loading dose: 600 mg single dose (if switching from eculizumab, give loading dose 2 wk after last eculizumab dose); Maintenance dose (initiated 2 wk after loading dose): 600 mg every 4 wk. Treatment should continue for ≥6 mo for atypical hemolytic uremic syndrome.
IV (Adults and Children ≥1 mo and 5–<10 kg): Loading dose: 600 mg single dose (if switching from eculizumab, give loading dose 2 wk after last eculizumab dose); Maintenance dose (initiated 2 wk after loading dose): 300 mg every 4 wk. Treatment should continue for ≥6 mo for atypical hemolytic uremic syndrome.

Generalized Myasthenia Gravis or Neuromyelitis Optica Spectrum Disorder

IV (Adults ≥100 kg): Loading dose: 3000 mg single dose (if switching from eculizumab, give loading dose 2 wk after last eculizumab dose); Maintenance dose (initiated 2 wk after loading dose): 3600 mg every 8 wk.
IV (Adults 60–<100 kg): Loading dose: 2700 mg single dose (if switching from eculizumab, give loading dose 2 wk after last eculizumab dose); Maintenance dose (initiated 2 wk after loading dose): 3300 mg every 8 wk.
IV (Adults 40–<60 kg): Loading dose: 2400 mg single dose (if switching from eculizumab, give loading dose 2 wk after last eculizumab dose); Maintenance dose (initiated 2 wk after loading dose): 3000 mg every 8 wk.

Availability ⬆ ⬇

Solution for injection: 10 mg/mL; 100 mg/mL

Assessment ⬆ ⬇

Monitor for signs or symptoms of infusion reaction (lower back pain, drop in BP, infusion-related muscle pain or spasm, ↑ BP, limb discomfort, rigors, dysgeusia) or drug hypersensitivity (allergic reaction) for ≥1 hr following completion of infusion. If signs of cardiovascular instability or respiratory compromise occur, interrupt infusion and institute supportive measures.
Monitor for early signs and symptoms of meningococcal infections (headache with nausea or vomiting, headache and fever, headache with nuchal rigidity, stiff neck, stiff back, fever, fever and a rash, confusion, muscle aches with flu-like symptoms, eyes sensitive to light) during therapy. Evaluate immediately if infection is suspected. Consider discontinuation of therapy during treatment of serious meningococcal infections.
Paroxysmal Nocturnal Hemoglobinuria: On discontinuation of therapy, monitor for signs and symptoms of hemolysis (↑ LDH, reappearance of fatigue, hemoglobinuria, abdominal pain, shortness of breath, major adverse vascular event, dysphagia, erectile dysfunction) for ≥16 wk. If signs and symptoms of hemolysis occur after discontinuation, including ↑ LDH, may require restarting ravulizumab.
Atypical Hemolytic Uremic Syndrome: On discontinuation, monitor for signs and symptoms of complement-mediated thrombotic microangiopathy (changes in mental status, seizures, angina, dyspnea, thrombosis, ↑ BP) for ≥12 mo. In addition to clinical symptoms, monitor for ≥two concurrent lab values (↓ in platelet count ≥25% of baseline or peak platelet count during ravulizumab therapy; ↑ in serum creatinine ≥25% of baseline or to nadir during ravulizumab therapy; ↑ in serum LDH ≥25% of baseline or of nadir during ravulizumab therapy). If thrombotic microangiopathy complications occur on discontinuation, consider restarting ravulizumab.
Myasthenia Gravis: Monitor for steady improvement in affected areas of muscle weakness. Signs of worsening or continued weakness include skeletal muscle weakness, eye and facial muscle weakness, drooping eyelids, blurred or double vision, difficulty swallowing, slurred speech, dyspnea, and easily fatigued after periods of activity.
Neuromyelitis Optica Spectrum Disorder: Monitor for symptoms in the eyes (pain, blurred vision, loss of vision in one or both eyes), muscles (weakness, spasms, pain, paresthesia, paralysis), bladder and bowel (incontinence), uncontrollable vomiting and hiccups, or confusion. In children, monitor for confusion, seizures, or coma.
Pedi: Monitor children for signs of serious infections due to Streptococcus pneumoniae and Haemophilus influenzae type b such as pneumonia or bronchitis (tachypnea, cough, wheezing, fever), meningitis (severe headache, nausea and vomiting, fever, nuchal rigidity or stiff neck, Brudzinski or Kernig sign), ear infections, sinusitis, and conjunctivitis (inflammation, redness, drainage of the eye).

Lab Test Considerations:

Monitor LDH, serum creatinine, and platelet levels at baseline and for ≥12 mo after last dose; normalization or improvement in LDH and platelets, and ≥25% improvement in serum creatinine from baseline indicates efficacy.

Implementation ⬆ ⬇

Vaccinate patients for meningococcal infection according to current Advisory Committee on Immunization Practices guidelines ≥2 wk before starting ravulizumab to ↓ risk of serious infection. May revaccinate patients considering duration of ravulizumab therapy. If ravulizumab is started immediately due to urgent need or vaccines are administered <2 wk before starting ravulizumab therapy, administer 2 wk of antibacterial prophylaxis. Administer vaccines as soon as possible if not prior to therapy initiation.
Pedi: In children, may ↑ risk of developing serious infections due to Streptococcus pneumoniae and Haemophilus influenzae type b. Vaccinate for prevention of Streptococcus pneumoniae and Haemophilus influenzae type b infections according to Advisory Committee on Immunization Practices guidelines.
REMS: Available only through Ultomiris and Soliris REMS program. Prescribers must enroll in program by accessing UltSolREMS.com, or 1-888-765-4747 for more information.
Intermittent Infusion: Solution is clear to translucent, slightly whitish; do not use solutions that are cloudy, discolored, or contain particulate matter. Diluent: Withdraw volume required and dilute with 0.9% NaCl.Concentration: Dilute to a final concentration of 5 mg/mL (for 10 mg/mL vials) or 50 mg/mL (for 100 mg/mL vials).Vials are single use only. Mix gently; do not shake. Do not mix 100 mg/mL and 10 mg/mL vials together. Protect from light; do not freeze. If not used immediately after preparation, store refrigerated for no longer than 24 hr, taking into account the expected infusion time. Once removed from refrigeration, administer within 6 hr if prepared with 10 mg/mL vials or within 4 hr if prepared with 100 mg/mL vials. Allow to warm to room temperature before infusing; do not heat in a microwave or with any heat source other than ambient air temperature. After administration, flush the entire line with 0.9% NaCl.
Rate: Infuse through a 0.2- or 0.22-micron filter. Rate is based on body weight. See manufacturer's instructions for rate of loading dose and maintenance doses.

Patient/Family Teaching ⬆ ⬇

Explain the purpose and side effects of ravulizumab to patient. Do not stop receiving drug without consulting health care professional. If an appointment is missed, contact health care professional as soon as possible to reschedule. Advise patient to read Medication Guide before starting and periodically during therapy in case of changes.
Explain need for continued medical follow-up to assess effectiveness and possible side effects of medication. Periodic lab tests or exams may be needed.
Caution patients about risk of meningococcal infection/sepsis. Advise patient to notify health care professional immediately if symptoms of meningitis or other infections occur. Inform patient of need for vaccination before starting therapy. May ↑ risk of infections caused by Streptococcus pneumoniae, Haemophilus influenzae type b, and gonorrhea. Advise patient to consult health care professional if at risk for gonorrhea infection about gonorrhea prevention and regular testing.
REMS: Inform patient of REMS program. Provide REMS educational materials and ensure patients are vaccinated with meningococcal vaccines. Enrollment in the Ultomiris and Soliris REMS and additional information are available by telephone: 1-888-765-4747 or at UltSolREMS.com.
Instruct patient to carry Ultomiris Patient Safety Card that describes symptoms with them at all times and to immediately seek medical evaluation if symptoms occur during and for at least 8 mo after therapy.
Advise patient to notify health care professional of all Rx or OTC medications, vitamins, or herbal products being taken and consult health care professional before taking any new medications.
Rep: Advise females of reproductive potential to notify health care professional if pregnancy is planned or suspected and to avoid breastfeeding during therapy and for≥8 mo after last dose of ravulizumab. Patients or health care providers may call 1-833-793-0563 or go to UltomirisPregnancyStudy.comto enroll in or to obtain information about the pregnancy exposure registry that monitors pregnancy outcomes in women exposed to ravulizumab-cwvz.

section name header

Pronunciation ⬇

Classifications ⬆ ⬇

Indications ⬆ ⬇

Action ⬆ ⬇