controls, 2/25 low dose group, 5/25 high dose group).
Surviving offspring had normal development and reproductive function. Human IgG areknown to cross the human placental barrier, and thus ULTOMIRIS may potentially cause
terminal complement inhibition in the fetal circulation.
8.2 Lactation
Risk summary
There are no data on the presence of ravulizumab-cwvz in human milk, the effect on thebreastfed child, or the effect on milk production. Since many medicinal products andimmunoglobulins are secreted into human milk, and because of the potential for seriousadverse reactions in a nursing child, breastfeeding should be discontinued duringtreatment and for 8 months after the final dose.
8.4 Pediatric Use
The safety and efficacy of ULTOMIRIS in pediatric patients have not been established.
8.5 Geriatric Use
Clinical studies of ULTOMIRIS did not include sufficient numbers of subjects aged 65and over to determine whether they respond differently from younger subjects. Other
reported clinical experience has not identified differences in responses between theelderly and younger patients.
11 DESCRIPTION
Ravulizumab-cwvz, a complement inhibitor, is a humanized monoclonal antibody (mAb)produced in Chinese hamster ovary (CHO) cells. Ravulizumab-cwvz consists of 2
identical 448 amino acid heavy chains and 2 identical 214 amino acid light chains andhas a molecular weight of approximately 148 kDa. The constant regions of ravulizumabcwvzinclude the human kappa light chain constant region, and the protein engineered"IgG2/4" heavy chain constant region.
The heavy chain CH1 domain, hinge region, and the first 5 amino acids of the CH2domain match the human IgG2 amino acid sequence, residues 6 to 36 in the CH2 region(common to both human IgG2 and IgG4 amino acid sequences), while the remainder ofthe CH2 domain and the CH3 domain match the human IgG4 amino acid sequence. The
heavy and light chain variable regions that form the human C5 binding site consist ofhuman framework regions grafted to murine complementarity-determining regions.
ULTOMIRIS (ravulizumab-cwvz) injection is a sterile, clear to translucent, slight whitishcolor, preservative-free solution for intravenous use. Each single-dose vial contains 300mg ravulizumab-cwvz at a concentration of 10 mg/mL with a pH of 7.0. Each mL alsocontains polysorbate 80 (0.2 mg) (vegetable origin), sodium chloride (8.77 mg), sodiumphosphate dibasic (1.78 mg), sodium phosphate monobasic (0.46 mg), and Water forInjection, USP.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Ravulizumab-cwvz is a terminal complement inhibitor that specifically binds to thecomplement protein C5 with high affinity, thereby inhibiting its cleavage to C5a (the
proinflammatory anaphylatoxin) and C5b (the initiating subunit of the terminalcomplement complex [C5b-9]) and preventing the generation of the terminal complement
complex C5b9. ULTOMIRIS inhibits terminal complement-mediated intravascularhemolysis in patients with PNH.
12.2 Pharmacodynamics
Immediate and complete inhibition of serum free C5 (concentration of less than 0.5mcg/mL) was observed by the end of the first ULTOMIRIS infusion and sustained
throughout the entire 26-week treatment period in all patients, both complement-inhibitornaïve and previously treated with eculizumab.The extent and duration of the pharmacodynamic response in patients with PNH wereexposure depend |
