Source: European Medicines Agency (EU) Revision Year: 2023 Publisher: Immedica Pharma AB, 113 63 Stockholm, Sweden
Severe hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.
Hypersensitivity reactions (such as facial swelling, rash, flushing) have occurred in Loargys treated subjects. The reactions generally occurred with the first few doses, see section 4.8 for additional details.
The initial administrations of Loargys should be performed under medical observation where proper medical care for hypersensitivity reactions could be provided.
If a hypersensitivity reaction occurs, appropriate medical treatment should be provided and the patient monitored until signs and symptoms are resolved. The management of hypersensitivity reactions may include temporarily interrupting the infusion, lowering the infusion rate, and/or treatment with antihistamines and/or corticosteroids. Pre-medication with an antihistamine and/or corticosteroid should be considered in patients who previously have developed a hypersensitivity reaction in connection with pegzilarginase treatment.
In case of home administration by a non-healthcare professional, the patient should be informed of the early signs of severe hypersensitivity reactions e.g., hives, generalised urticaria, tightness of the chest, wheezing and hypotension. If symptoms of severe hypersensitivity occur, patient should be advised to stop administration immediately and contact their health-care provider or emergency department. Prescription of medication for treatment of a potential severe hypersensitivity reaction should be considered.
Pegzilarginase will interfere with routine arginine laboratory analysis, resulting in erroneous low measurements due to post-collection degradation of arginine. The testing laboratory should be informed that the patient is treated with a medicinal product that metabolises and reduces arginine levels. Alternative validated sampling procedures to measure arginine must be used in patients treated with Loargys. This includes CE-marked blood collection tubes containing the enzyme-blocker nor-NOHA.
No data from clinical trials are available in middle-age and elderly patients with long-existing motoric impairment, or in patients with arginine levels near 200 µM on dietary protein restriction alone. Extrapolation of the treatment effects as shown in the clinical trial population is unclear (see section 5.1). The benefit-risk need to be determined on an individual basis in these patients.
This medicinal product contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially ‘sodium-free’.
This medicinal product contains less than 1 mmol potassium (39 mg) per dose, that is to say essentially ‘potassium-free’.
No interaction studies have been performed. Pegzilarginase is a recombinant human enzyme and therefore no cytochrome P450 mediated drug-drug interactions are expected.
There are no or limited data from the use of pegzilarginase in pregnant women.
Studies in animals have shown reproductive toxicity (see section 5.3).
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 Loargys therapy taking into account the benefit of breast feeding for the child and the benefit of therapy for the woman.
No human data are available. In animal studies, pegzilarginase produced effects on spermatogenesis and reduced female fertility (see section 5.3).
Loargys has no or negligible influence on the ability to drive and use machines.
The most commonly reported adverse reaction in patients in clinical trials was hypersensitivity (12.5%).
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 (see section 5.1).
Adverse reactions are listed by MedDRA system organ class and by frequency in Table 1 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.
Table 1. Adverse reactions:
| System organ class | Very common | Common |
|---|---|---|
| Immune system disorders | Hypersensitivity | |
| General disorders and administration site conditions | Injection site reaction |
Hypersensitivity reactions with symptoms including facial swelling, rash and flushing have been reported. In clinical trials, when administered intravenously, 6 of 48 (12.5%) Loargys-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 (see section 4.4).
Injection site reactions were reported in 8.8% (3/34) of Loargys-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.
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 Loargys in patients with ARG1-D.
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.
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.
This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.
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