Pegzilarginase

There are no or limited data from the use of pegzilarginase in pregnant women.

Studies in animals have shown reproductive toxicity.

Pegzilarginase is not recommended during pregnancy and in women of childbearing potential not using contraception.

It is unknown whether pegzilarginase is excreted in human or animal milk.

A risk to the breastfed new-born/infant cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from pegzilarginase therapy taking into account the benefit of breast feeding for the child and the benefit of therapy for the woman.

Fertility

No human data are available. In animal studies, pegzilarginase produced effects on spermatogenesis and reduced female fertility.

Pegzilarginase has no or negligible influence on the ability to drive and use machines.

Summary of the safety profile

The most commonly reported adverse reaction in patients in clinical trials was hypersensitivity (12.5%).

Tabulated list of adverse reactions

Assessment of adverse reactions was based on exposure in 48 ARG1-D patients (8 adults and 40 children between the ages of 2 and 31 years) with treatment duration of up to approximately 4 years across 3 clinical trials.

Adverse reactions are listed by MedDRA system organ class and by frequency in the table below. Frequencies are defined as: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1 000 to <1/100); rare (≥1/10 000 to <1/1 000); very rare (<1/10 000); not known (cannot be estimated from available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Due to the small size of the medicinal product safety ARG1-D population database (N=48), the adverse reaction frequency for uncommon, rare and very rare could not be reliably estimated.

Adverse reactions:

Description of selected adverse reactions

Hypersensitivity

Hypersensitivity reactions with symptoms including facial swelling, rash and flushing have been reported. In clinical trials, when administered intravenously, 6 of 48 (12.5%) pegzilarginase-treated patients, experienced signs and symptoms either consistent with, or that may be related to a hypersensitivity reaction. The reactions generally occurred with the first few doses. The reactions were mild or moderate and resolved spontaneously, or rapidly after treatment with standard medical care. None of the reactions led to discontinuation of treatment. In the clinical trials, pre-medication with nonsedating antihistamines was considered on an individual basis prior to administration.

Injection site reactions

Injection site reactions were reported in 8.8% (3/34) of pegzilarginase-treated patients after subcutaneous administration. Signs and symptoms included erythema, swelling, and rash at the injection site. The injection site reactions were mild in severity and resolved spontaneously or with standard medical care without dose interruption.

Immunogenicity

There is potential for immunogenicity to pegylated therapeutic proteins. The observed incidence of anti-drug antibodies (ADAs) is highly dependent on the sensitivity and specificity of the assay. Across all clinical trials in the pegzilarginase ARG1-D development program, 12 of 48 subjects (25%) tested positive for ADAs against PEG and/or the protein moiety of pegzilarginase, with the majority detected early after the first dose. There was no assay available for detecting neutralising antibodies during the clinical development programme. The ADAs were transient in nature and resolved during continued treatment. The presence of ADAs was associated with transient changes in the pharmacokinetics (PK) and pharmacodynamics (PD) of pegzilarginase in patients with ARG1-D.

Paediatric population

The majority of patients treated with pegzilarginase in the ARG1-D development programme were paediatric patients with 88% (40/48) being children (2-18 years old). The safety profile of pegzilarginase presented in the safety section is therefore considered representative for the paediatric population above 2 years.