What is ravulizumab?
Ravulizumab is a complement 5 (C5) inhibitor that produces quick, complete, and sustained inhibition of C5 allowing for extended interval dosing as compared to eculizumab.
How does ravulizumab work?
Ravulizumab is a humanized monoclonal antibody which inhibits the complement process by binding to the terminal complement C5. This inhibits C5 from cleaving to C5a and C5b which is responsible for complement-mediated hemolysis associated with paroxysmal nocturnal hemoglobinuria.
What is this approved for?
Ravulizumab is approved for the treatment of adult patients with paroxysmal nocturnal hemoglobinuria (PNH).
What is the basis for this approval?
Ravulizumab was approved based on the results of two phase III clinical trials (study 301 and 302) comparing ravulizumab to eculizumab for the treatment of PNH (Blood 2019;133:530-539; Blood 2019;133:540-549).
Study 302 randomized 195 patients receiving > 6 months of therapy with eculizumab to either continue eculizumab every 2 weeks or switch to ravulizumab every 8 weeks. The non-inferiority primary endpoint was change in LDH from baseline to day 183. Ravulizumab was deemed to be non-inferior to ecuzilumab for the percentage change in LDH (-0.82% for ravulizumab vs. 8.39% for eculizumab; 95% CI: -0.42 to 18.84). All secondary endpoints demonstrated non-inferiority as well including breakthrough hemoloysis (Blood 2019;133:540-549).
Study 301 randomized 246 treatment-naive PNH patients to either eculizumab every 2 weeks or ravulizumab every 8 weeks in a non-inferiority study. The coprimary endpoints were percentage of patients transfusion-free and LDH normalization. Both endpoints met the non-inferiority criteria with 73.6 percent of ravulizumab and 66.1 percent of eculizumab patients transfusion-free (95% CI, -4.66 to 18.14; p < 0.0001) and LDH normalization of 53.6 percent of ravulizumab and 49.4 percent of eculizumab patients (95% CI, 0.80-1.77, p < 0.0001). Non-inferiority was maintained for all secondary endpoints (Blood 2019;133:530-539).
How do you administer this drug?
Ravulizumab is given IV as a loading dose, followed in 2 weeks by a maintenance dose every 8 weeks. Dose selection is based on the patient's weight as indicated below.
Are there any premedications needed for ravulizumab?
No premedications are needed for ravulizumab, but patients must receive meningococcal vaccination, which is recommended at least 2 weeks prior to treatment initiation. If vaccination is not able to occur 2 weeks prior to treatment, the vaccine should be administered as soon as possible and 2 weeks of antimicrobial prophylaxis should be used.
What are the common side effects associated with ravulizumab (> or =10%)?
* Headache (32%)
* Upper respiratory tract infection (39%)
What are the uncommon side effects associated with ravulizumab (less than 10%)?
Additional side effects include dizziness (5%), diarrhea (9%), nausea (9%), abdominal pain (6%), limb pain (6%), arthralgia (5%), and fever (7%).
Are there any important drug interactions I should be aware of?
There are no known drug-drug interactions, but caution should be used in patients with a systemic infection.
How do I adjust the dose in the setting of renal or hepatic insufficiency?
There are no known renal or hepatic dose adjustments for ravulizumab.
Practical tips
* Ravulizumab is only available through a restricted Risk Evaluation and Mitigation Strategy (REMS) program. Prescribers must be enrolled in the REMS program prior to prescribing ravulizumab.
* Despite meningococcal vaccination, patients are still at risk for meningococcal infections or other encapsulated bacterial infections.
* A low number of patients experienced an infusion reaction with ravulizumab, but did not lead to discontinuation of drug.
What should my patients know about ravulizumab?
Patients should contact their health care provider if they experience fever, headache, or stiff neck.
What else should I know about ravulizumab?
If a patient is switching from eculizumab therapy to ravulizuamb therapy, the loading dose of ravulizuamb should be given 2 weeks after the last eculizumab infusion. The maintenance dosing should start 2 weeks after the loading dose.
What useful links are available regarding ravulizumab?
* FDA Approval Announcement: https://bit.ly/2jXEUGy
* Drug Trials Snapshots for Ravulizumab-Cwvz: https://bit.ly/2lAcEtU
Any ongoing clinical trials related to ravulizumab?
Clinical trials with ravulizumab are ongoing in pediatric and adult treatment of atypical hemolytic uremic syndrome and generalized myasthenia gravis. More information is available about the clinical trials at https://clinicaltrials.gov.
SARA BUTLER, PHARMD, BCOP, BCPS, is Manager of Clinical Pharmacy and Investigational Drug Services at Barnes-Jewish Hospital in St. Louis, Mo. JANELLE E. MANN, PHARMD, BCOP, is an Ambulatory Clinical Oncology Pharmacist, Washington University School of Medicine, Alvin J. Siteman Cancer Center, St. Louis, Mo., and serves as the Pharmacy Forum column editor. RAMASWAMY GOVINDAN, MD, Professor of Medicine; Anheuser Busch Chair in Medical Oncology; Director, Section of Medical Oncology, Division of Oncology, Washington University School of Medicine, serves as the Pharmacy Forum column physician advisor.