Drug Interactions between crovalimab and eculizumab

ADJUST DOSING INTERVAL: Transitioning patients from one C5 inhibitor to another (e.g., eculizumab or ravulizumab to crovalimab, or vice versa) can lead to type III hypersensitivity reactions. Additionally, switching from eculizumab or ravulizumab to crovalimab may cause a transient reduction in serum crovalimab concentrations. The proposed mechanism involves crovalimab binding to different epitopes on C5 compared to eculizumab and ravulizumab, which can result in the formation of drug-target-drug complexes (DTDCs) that are bound to both crovalimab and the other C5 inhibitor. These DTDCs are anticipated to be cleared within approximately 8 weeks if eculizumab is involved, or longer with ravulizumab, potentially leading to type III hypersensitivity reactions. In the COMMODORE 1 and 2 clinical studies, 19.4% (39 out of 201) of patients who switched from eculizumab or ravulizumab to crovalimab experienced type III hypersensitivity reactions, specifically immune complex-mediated reactions. Among these, 6 patients had switched treatments twice, and 2 of them experienced a second type III hypersensitivity reaction after discontinuing crovalimab and starting ravulizumab, with one developing Grade 3 axonal neuropathy and the other Grade 2 arthralgia and myalgia. Similarly, type III hypersensitivity reactions were reported in 2 of 8 patients (25%) who switched from crovalimab to eculizumab or ravulizumab, including one patient who developed Grade 3 axonal neuropathy. According to product labeling, initiating crovalimab less than 5.5 half-lives after the last dose of a C5 inhibitor (e.g., eculizumab or ravulizumab) or starting a C5 inhibitor less than 5.5 half-lives after the last dose of crovalimab increases the risk of type III hypersensitivity reactions. Therefore, patients are expected to be at reduced risk of type III hypersensitivity reactions if the previous C5 inhibitor is cleared from the body before starting crovalimab, or if crovalimab is cleared before starting another C5 inhibitor.

MANAGEMENT: When transitioning from eculizumab or ravulizumab to crovalimab, product labeling recommends administering the first intravenous loading dose of crovalimab no sooner than the time of the next scheduled dose of the previous C5 inhibitor. Additionally, patients should be monitored for symptoms of type III hypersensitivity reactions (e.g., rash, pruritus, fever, arthralgia, myalgia, fatigue, renal abnormalities) during the first 30 days of therapy with the new C5 inhibitor. Individual product labeling for the specific C5 inhibitor should be consulted for more guidance.