YARTEMLEA Solution for injection Ref.[116145] Active ingredients: Narsoplimab

5.1 Serious Infections

Serious and life-threatening infections have occurred in patients treated with YARTEMLEA.

Serious infections, independent of causality, were reported in 36% (10/28) of patients with TA-TMA receiving YARTEMLEA in clinical trials. These infections included sepsis, viral infections, pneumonia, bacteremia, fungal infection, gastroenteritis, respiratory tract infection and urosepsis.

If YARTEMLEA is administered to patients with active infections, monitor closely for signs and symptoms of worsening infection and treat promptly.

The following clinically significant adverse reactions are described elsewhere in the labeling:

• Serious Infections [see Warnings and Precautions (5.1)]

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The safety data described in this section reflect exposure to YARTEMLEA in the TA-TMA Study in which 28 adult patients received YARTEMLEA. In total, 24 patients received YARTEMLEA at a dose of 4 mg/kg intravenously once weekly for 4 or 8 weeks and 4 patients received 370 mg intravenously weekly for 8 weeks [see Clinical Studies (14)]. The median duration of treatment with YARTEMLEA was 8 weeks (range: 2 to 16.4 weeks).

Serious adverse reactions were reported in 61% of patients receiving YARTEMLEA. Serious adverse reactions in >5% of patients who received YARTEMLEA included acute kidney injury, confusional state, acute respiratory failure, neutropenic sepsis, septic shock, pulmonary edema, and vomiting. Fatal adverse reactions occurred in 7% of patients, including neutropenic sepsis and septic shock.

Adverse reactions leading to dosage interruptions occurred in 7% of patients who received YARTEMLEA and included Escherichia sepsis, pyrexia, pulmonary alveolar hemorrhage, and acute myocardial infarction.

The most common adverse reactions (≥20%) were viral infections, sepsis, hemorrhage, diarrhea, vomiting, nausea, neutropenia, pyrexia, fatigue, and hypokalemia.

Table 2 summarizes the adverse reactions, without regard to causality or relatedness to YARTEMLEA, in the TA-TMA Study.

Table 2. Adverse Reactions (≥15%) in Patients Receiving YARTEMLEA in the TA-TMA Study:

^* Grouped terms

An additional 221 adult and pediatric patients with TA-TMA were treated with YARTEMLEA in a global expanded access program (EAP) that included patients for whom YARTEMLEA was their initial treatment following diagnosis of TA-TMA as well as patients who had previously failed or stopped other treatments. The median number of YARTEMLEA doses received by the 221 patients in the EAP was 8 and the median duration of therapy was 5.5 weeks. No new clinically significant safety signals were identified in patients treated in the EAP.

The observed incidence of anti-drug antibodies (ADA) is highly dependent on the sensitivity and the specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of ADA in the narsoplimab-wuug studies described below with the incidence of ADA in other studies.

Anti-Drug Antibody Effects on Pharmacokinetics and Pharmacodynamics

In the 8-week treatment period in the TA-TMA Study, treatment-emergent antibodies to narsoplimab-wuug were detected in 3 of 28 patients (11%) with TA-TMA. One of the 3 patients (33%) developed neutralizing antibodies. There is no apparent correlation of antibody development to PK or PD response, and no alteration in clinical response or adverse events was observed.

Risk Summary

The available data on the use of YARTEMLEA during pregnancy are insufficient to evaluate for a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. In animal reproduction studies, narsoplimab-wuug was administered subcutaneously and intravenously twice weekly to pregnant mice and rabbits during organogenesis at dose exposures up to 22 and 91-fold, respectively, the human exposure at the maximum recommended human dose (MRHD) based on area under the concentration-time curve (AUC). There were no adverse effects observed in the absence of maternal toxicity (see Data).

The background risk of major birth defects and miscarriage for the indicated population 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 to 4% and 15 to 20%, respectively.

Clinical Considerations

Fetal/Neonatal Adverse Reactions

Transport of endogenous IgG antibodies across the placenta increases as pregnancy progresses and peaks during the third trimester. Therefore, it is expected that YARTEMLEA, following administration, will be present in infants exposed in utero during the third trimester. The potential clinical impact of narsoplimab-wuug exposure on infants exposed in utero should be considered.

Data

Animal Data

Narsoplimab-wuug was administered to pregnant mice at doses of 50, 150, or 300 mg/kg by subcutaneous injection and 300 mg/kg by intravenous injection approximately twice weekly during the major period of organogenesis. Intravenous administration caused reduced body weight gain in dams, reduced fetal body weight up to 4.8%, and an increase of approximately 33% in post-implantation loss at 22-fold the exposure expected at the MRHD (based on AUC) of 4 mg/kg intravenously once weekly in humans. Narsoplimab-wuug was administered to pregnant rabbits at doses of 50 or 150 mg/kg by subcutaneous injection and 150 mg/kg by intravenous injection approximately twice weekly during the major period of organogenesis. Intravenous administration increased post-implantation loss during early gestation days and reduced fetal body weights up to 8.5% below controls at 91-fold the exposure expected at the MRHD (based on AUC) of 4 mg/kg intravenously once weekly in humans.

In an enhanced pre- and postnatal development study, pregnant mice were dosed with narsoplimab-wuug at doses up to 300 mg/kg intravenously twice weekly from day 6 of gestation through lactation. There was a transiently reduced maternal body weight gain but no adverse effects of narsoplimab-wuug on pregnancy nor on the viability, growth, or development of the infants up to 22-fold the exposure expected at the MRHD (based on AUC).

Risk Summary

There are no data on the presence of narsoplimab-wuug in human milk, the effects on the breastfed child, or the effects on milk production. Narsoplimab-wuug is present in the milk of lactating mice (see Data). When a drug is present in animal milk, it is likely that the drug will be present in human milk. Endogenous maternal IgG and monoclonal antibodies are transferred into human milk. The effects of local gastrointestinal exposure and the extent of systemic exposure in the breastfed child to narsoplimab-wuug are unknown. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for YARTEMLEA and any potential adverse effects on the breastfed child from YARTEMLEA or from the underlying maternal condition.

Data

In a pre- and postnatal development study, after subcutaneous and intravenous administration of narsoplimab-wuug to maternal mice, narsoplimab-wuug was detected in the blood of preweaning pups when measured on lactation day 21.

The safety and effectiveness of YARTEMLEA for treatment of TA-TMA have been established in pediatric patients aged 2 years and older. Use of YARTEMLEA for this indication is supported by evidence from studies in adults and in 6 pediatric patients, and additional safety data from 83 more pediatric patients aged 2 years and older [see Adverse Reactions (6.1) and Clinical Studies (14.1)].

The safety and effectiveness of YARTEMLEA have not been established in pediatric patients younger than 2 years old.

Of the total number of YARTEMLEA-treated patients in the clinical trial and EAP for TA-TMA, 21 (8.4%) were 65 years of age and older, while 1 (0.4%) was at least 75 years of age [see Clinical Studies (14)]. Clinical studies of YARTEMLEA did not include sufficient numbers of subjects at least 65 years of age to determine whether they respond differently than younger subjects. Other reported clinical experience has not identified differences in responses between elderly and younger patients.