Ultomiris: Package Insert and Label Information (Page 3 of 7)

6.2 Immunogenicity

As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibodies) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications and underlying disease. For these reasons, comparison of the incidence of antibodies in the studies described below with the incidence of antibodies in other studies or to other ravulizumab-cwvz products may be misleading.

The immunogenicity of ravulizumab-cwvz has been evaluated using an enzyme-linked immunosorbent assay (ELISA) for the detection of binding anti-ravulizumab-cwvz antibodies. For patients whose sera tested positive in the screening immunoassay, an in vitro biological assay was performed to detect neutralizing antibodies.

In clinical studies, treatment-emergent antibodies to ravulizumab-cwvz were detected in 1 of 219 (0.5%) patients with PNH and 1 of 71 (1.4%) patients with aHUS. In these 2 patient populations, no apparent correlation of antibody development to altered pharmacokinetic profile, clinical response, or adverse events was observed.

No treatment-emergent antibodies to ravulizumab-cwvz were detected in patients with gMG treated with ULTOMIRIS.

However, the assay used to measure anti-drug antibodies (ADA) is subject to interference by serum ravulizumab-cwvz, possibly resulting in an underestimation of the incidence of antibody formation. Due to the limitation of the assay conditions, the potential clinical impact of antibodies to ravulizumab-cwvz is not known.

6.3 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of ULTOMIRIS. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to ULTOMIRIS exposure.

Serious Adverse Reaction: Anaphylaxis [see Warnings and Precautions (5.5)]

7 DRUG INTERACTIONS

7.1 Plasma Exchange, Plasmapheresis, and Intravenous Immunoglobulins

Concomitant use of ULTOMIRIS with plasma exchange (PE), plasmapheresis (PP), or intravenous immunoglobulin (IVIg) treatment can reduce serum ravulizumab concentrations and requires a supplemental dose of ULTOMIRIS [see Dosage and Administration (2.3)].

7.2 Neonatal Fc Receptor Blockers

Concomitant use of ULTOMIRIS with neonatal Fc receptor (FcRn) blockers (e.g., efgartigimod) may lower systemic exposures and reduce effectiveness of ULTOMIRIS. Closely monitor for reduced effectiveness of ULTOMIRIS.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

There are no available data on ULTOMIRIS use in pregnant women to inform a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. There are risks to the mother and fetus associated with untreated PNH and aHUS in pregnancy (see Clinical Considerations). Animal studies using a mouse analogue of the ravulizumab-cwvz molecule (murine anti-C5 antibody) showed increased rates of developmental abnormalities and an increased rate of dead and moribund offspring at doses 0.8-2.2 times the human dose (see Data).

The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Clinical Considerations

Disease-associated maternal and/or fetal/neonatal risk

PNH in pregnancy is associated with adverse maternal outcomes, including worsening cytopenias, thrombotic events, infections, bleeding, miscarriages, and increased maternal mortality, and adverse fetal outcomes, including fetal death and premature delivery.

In pregnancy, aHUS is associated with adverse maternal outcomes, including preeclampsia and preterm delivery, and adverse fetal/neonatal outcomes, including intrauterine growth restriction (IUGR), fetal death and low birth weight.

Data

Animal Data

Animal reproduction studies were conducted in mice using doses of a murine anti-C5 antibody that approximated 1-2.2 times (loading dose) and 0.8-1.8 times (maintenance dose) the recommended human ULTOMIRIS dose, based on a body weight comparison. When animal exposure to the antibody occurred in the time period from before mating until early gestation, no decrease in fertility or reproductive performance was observed. When maternal exposure to the antibody occurred during organogenesis, two cases of retinal dysplasia and one case of umbilical hernia were observed among 230 offspring born to mothers exposed to the higher antibody dose; however, the exposure did not increase fetal loss or neonatal death. When maternal exposure to the antibody occurred in the time period from implantation through weaning, a higher number of male offspring became moribund or died (1/25 controls, 2/25 low dose group, 5/25 high dose group). Surviving offspring had normal development and reproductive function. Human IgG are known to cross the human placental barrier, and thus ULTOMIRIS may potentially cause terminal complement inhibition in fetal circulation.

8.2 Lactation

Risk summary

There are no data on the presence of ravulizumab-cwvz in human milk, the effect on the breastfed child, or the effect on milk production. Since many medicinal products and immunoglobulins are secreted into human milk, and because of the potential for serious adverse reactions in a nursing child, breastfeeding should be discontinued during treatment and for 8 months after the final dose.

8.4 Pediatric Use

The safety and effectiveness of ULTOMIRIS for the treatment of PNH have been established in pediatric patients aged one month and older. Use of ULTOMIRIS for this indication is supported by evidence from adequate and well-controlled trials in adults with additional pharmacokinetic, efficacy and safety data in pediatric patients aged 9 to 17 years [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14.1)]. The safety and efficacy for the treatment of pediatric and adult patients with PNH appear similar. Use of ULTOMIRIS in pediatric patients with PNH aged less than 9 years and body weight <30 kg is based on extrapolation of pharmacokinetic / pharmacodynamic (PK/PD), and efficacy and safety data from aHUS and PNH clinical studies [see Clinical Pharmacology (12.3) and Clinical Studies (14)].

The safety and effectiveness of ULTOMIRIS for the treatment of aHUS have been established in pediatric patients aged one month and older. Use of ULTOMIRIS for this indication is supported by evidence from adequate and well-controlled studies in adults with additional pharmacokinetic, safety, and efficacy data in pediatric patients aged 10 months to <17 years. The safety and efficacy of ULTOMIRIS for the treatment of aHUS appear similar in pediatric and adult patients [see Adverse Reactions (6.1), and Clinical Studies (14.2)].

Safety and effectiveness of ULTOMIRIS for the treatment of gMG in pediatric patients have not been established.

8.5 Geriatric Use

Clinical studies of ULTOMIRIS did not include sufficient numbers of subjects aged 65 and over (58 patients with PNH, 9 with aHUS, and 54 with gMG) to determine whether they respond differently from younger subjects.

Other reported clinical experience has not identified differences in responses between elderly 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 and has a molecular weight of approximately 148 kDa. The constant regions of ravulizumab-cwvz include 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 CH2 domain 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 of the 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 of human framework regions grafted to murine complementarity-determining regions.

ULTOMIRIS 100 mg/mL (3 mL and 11 mL vials)

ULTOMIRIS (ravulizumab-cwvz) injection 100 mg/mL is a sterile, translucent, clear to yellowish color, preservative-free solution for intravenous use. Each single-dose vial contains 300 mg or 1,100 mg ravulizumab-cwvz at a concentration of 100 mg/mL with a pH of 7.4. Each mL also contains L-arginine (4.33 mg), polysorbate 80 (0.5 mg) (vegetable origin), sodium phosphate dibasic (4.42 mg), sodium phosphate monobasic (4.57 mg), sucrose (50 mg) and Water for Injection, USP.

ULTOMIRIS 10 mg/mL (30 mL vial)

ULTOMIRIS (ravulizumab-cwvz) injection 10 mg/mL is a sterile, clear to translucent, slight whitish color, preservative-free solution for intravenous use. Each single-dose vial contains 300 mg ravulizumab-cwvz at a concentration of 10 mg/mL with a pH of 7.0. Each mL also contains polysorbate 80 (0.2 mg) (vegetable origin), sodium chloride (8.77 mg), sodium phosphate dibasic (1.78 mg), sodium phosphate monobasic (0.46 mg), and Water for Injection, USP.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Ravulizumab-cwvz is a terminal complement inhibitor that specifically binds to the complement protein C5 with high affinity, thereby inhibiting its cleavage to C5a (the proinflammatory anaphylatoxin) and C5b (the initiating subunit of the membrane attack complex [MAC or C5b-9]) thus preventing MAC formation. ULTOMIRIS inhibits terminal complement-mediated intravascular hemolysis in patients with PNH and complement-mediated thrombotic microangiopathy (TMA) in patients with aHUS.

The precise mechanism by which ravulizumab-cwvz exerts its therapeutic effect in gMG patients is unknown, but is presumed to involve reduction of terminal complement complex C5b-9 deposition at the neuromuscular junction.

12.2 Pharmacodynamics

Complete inhibition of serum free C5 (concentration of less than 0.5 mcg/mL) was observed by the end of the first ULTOMIRIS infusion and sustained throughout the entire 26-week treatment period in both adult and pediatric patients with PNH, in the majority (93%) of adult and pediatric patients with aHUS, and all adult patients with gMG.

The extent and duration of the pharmacodynamic response in patients with PNH, aHUS, and gMG were exposure-dependent for ULTOMIRIS. Free C5 levels of <0.5 mcg/mL were correlated with maximal intravascular hemolysis control and complete terminal complement inhibition in patients with PNH.

Complete terminal complement inhibition following initiation of ULTOMIRIS treatment led to normalization of serum LDH by week 4 in complement-inhibitor naïve patients with PNH, and maintained LDH normalization in patients previously treated with eculizumab with PNH [see Clinical Studies (14)].

12.3 Pharmacokinetics

Ravulizumab-cwvz pharmacokinetics increase proportionally over a dose range of 200 to 5400 mg. Ravulizumab-cwvz Cmax and Ctrough parameters are presented in Table 15, Table 16, and Table 17.

Table 15: Mean (%CV) Pharmacokinetic Parameters of ULTOMIRIS in Patients with PNH who are Complement Inhibitor-Naïve and Patients Previously Treated with Eculizumab
Pediatric Patients Adult Patients
ALXN1210-PNH-304 ALXN1210-PNH-301 ALXN1210-PNH-302
N Complement Inhibitor-Naïve N Previously Treated with Eculizumab N Complement Inhibitor-Naïve N Previously Treated with Eculizumab
LD = Loading Dose; MD = Maintenance Dose
Cmax (mcg/mL) LD 4 733 (14.5) 8 885 (19.3) 125 771 (21.5) 95 843 (24.1)
MD 4 1490 (26.7) 8 1705 (9.7) 124 1,379 (20.0) 95 1,386 (19.4)
Ctrough (mcg/mL) LD 4 368 (14.7) 8 452 (15.1) 125 391 (35.0) 96 405 (29.9)
MD 4 495 (21.3) 8 566 (12.2) 124 473 (33.4) 95 501 (28.6)
Table 16: Mean (%CV) Pharmacokinetic Parameters of ULTOMIRIS in Patients with aHUS
Pediatric Patients (ALXN1210-aHUS-312) Adult Patients (ALXN1210-aHUS-311)
N < 20 kg MD Q4W N ≥ 20 to < 40 kg MD Q8W N ≥ 40 kg MD Q8W
LD = Loading Dose; MD = Maintenance Dose; Q4W = Every 4 Weeks; Q8W = Every 8 Weeks
Cmax (mcg/mL) LD 8 656 (38.1) 4 600 (17.3) 52 754 (35.2)
MD 7 1,467 (37.8) 6 1,863 (15.3) 46 1,458 (17.6)
Ctrough (mcg/mL) LD 9 241 (52.1) 5 186 (16.5) 55 313 (33.9)
MD 7 683 (46.1) 6 549 (34.1) 46 507 (42.5)
Table 17: Mean (%CV) Pharmacokinetic Parameters of ULTOMIRIS in Adult Patients with gMG
N Adult Patients (ALXN1210-MG-306)
LD = Loading Dose; MD=Maintenance Dose
Cmax (mcg/mL) LD 86 874 (21.1)
MD 76 1548 (23.2)
Ctrough (mcg/mL) LD 85 418 (27.6)
MD 70 587 (29.6)

Distribution

The mean (standard deviation [SD]) volume of distribution at steady state in patients with PNH, aHUS, and gMG are shown in Table 18.

Elimination

The mean (standard deviation [SD]) terminal elimination half-life and clearance of ravulizumab-cwvz are shown in Table 18.

Table 18: Distribution, Biotransformation, and Elimination parameters
Adult patients with PNH Adult and pediatric patients with aHUS Adult patients with gMG
Distribution
Volume of distribution at steady state (liters)Mean (SD) 5.35 (0.92) 5.22 (1.85) 5.74 (1.16)
Biotransformation and Elimination
Terminal elimination half-life (days)Mean (SD) 49.7 (8.9) 51.8 (16.2) 56.6 (8.36)
Clearance (liters/day)Mean (SD) 0.08 (0.022) 0.08 (0.04) 0.08 (0.02)

Specific Populations

No clinically significant differences in the pharmacokinetics of ravulizumab-cwvz were observed based on sex, age (10 months to 83 years), race, hepatic impairment, or any degree of renal impairment, including patients with proteinuria or receiving dialysis.

Body weight was a clinically significant covariate on the pharmacokinetics of ravulizumab-cwvz.

Drug Interactions

No drug-drug interaction studies have been performed.

Intravenous immunoglobulin (IVIg) and FcRn blocker treatment may interfere with the endosomal neonatal FcRn recycling mechanism of monoclonal antibodies such as ravulizumab and thereby decrease serum ravulizumab concentrations [see Drug Interactions (7.1, 7.2)].

Concomitant PE, PP, or IVIg treatment requires a supplemental dose of ULTOMIRIS [see Dosage and Administration (2.3)].

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