Elfabrio · 4.6 Fertility, pregnancy and lactation · 1

HOS-099849 · has-adverse-reaction-information · PDF-Seite 7

Summary of the safety profile The most common adverse reactions were infusion-related reactions reported in 7.8% of patients, followed by nausea and asthenia, both reported in 5.6% of patients and headache, reported in 4.2% of patients. In clinical studies, 5 patients (3.5%) experienced a serious reaction that was considered related to pegunigalsidase alfa. Four of these reactions were confirmed IgE-mediated hypersensitivity (bronchospasm, hypersensitivity) that occurred at the first infusion of pegunigalsidase alfa and resolved within the day after occurrence. Tabulated summary of adverse reactions The data described below reflects data from 141 patients with Fabry disease who received pegunigalsidase alfa in 8 clinical studies, following the posology of 1 mg/kg every two weeks or 2 mg/kg every four weeks for a minimum of 1 infusion up to 7 years. Adverse reactions are listed in Table 3. Information is presented by system organ class. 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); frequency not known (cannot be estimated from available data). Table 3: Adverse reactions reported during treatment with pegunigalsidase alfa Frequency System organ class Common Uncommon Immune system disorders hypersensitivity* type I hypersensitivity* Psychiatric disorders agitation* insomnia Nervous system disorders paraesthesia* restless legs syndrome dizziness* peripheral neuropathy headache* neuralgia burning sensation tremor* syncope* Ear and labyrinth disorders vertigo Vascular disorders flushing hypotension* hypertension* lymphoedema

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HOS-099845 · has-contraindication-information · PDF-Seite 5

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

HOS-099844 · has-indication-information · PDF-Seite 2

Elfabrio is indicated for long-term enzyme replacement therapy in adult patients with a confirmed diagnosis of Fabry disease (deficiency of alpha-galactosidase).

HOS-099847 · has-interaction-information · PDF-Seite 6

No interaction studies and no in vitro metabolism studies have been performed. Based on its metabolism, pegunigalsidase alfa is an unlikely candidate for cytochrome P450 mediated drug-drug interactions. Pegunigalsidase alfa is a protein and is expected to be metabolically degraded through peptide hydrolysis.

HOS-099848 · has-pregnancy-information · PDF-Seite 6

Pregnancy There are no or limited amount of data from the use of pegunigalsidase alfa in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3). As a precautionary measure, it is preferable to avoid the use of pegunigalsidase alfa during pregnancy unless clearly necessary. Breast-feeding It is unknown whether pegunigalsidase alfa/metabolites are excreted in human milk. Available pharmacodynamic/toxicological data in animals have shown excretion of pegunigalsidase alfa in milk (for details see section 5.3). A risk to the newborns/infants cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from pegunigalsidase alfa therapy taking into account the benefit of breast feeding for the child and the benefit of therapy for the woman. 6  Fertility There are no studies assessing the potential effect of pegunigalsidase alfa on fertility in humans. Animal studies show no evidence of impaired fertility (see section 5.3).

HOS-099846 · has-warning-information · PDF-Seite 5

Traceability In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded. Treatment monitoring For patients switched to pegunigalsidase alfa 2 mg/kg body weight once every 4 weeks, regular monitoring (e.g.: after 3, 6, 12, 18 and 24 months) should be performed. Monitoring should include at least the evaluation of lyso-Gb3, renal (eGFR, proteinuria), cardiac (LVMi, NT-proBNP, troponin or ECG), and biochemical parameters. A change in any individual parameter should be interpreted in the context of the patient's overall clinical status, and clinically relevant deterioration should prompt re- evaluation of the treatment regimen. Infusion related reactions Infusion-related reactions (IRRs), defined as any related adverse events with onset after start of infusion and up to 2 hours after end of infusion have been reported (see section 4.8). The most commonly observed symptoms of IRRs were hypersensitivity, itching, nausea, dizziness, chills and muscular pain. The management of IRRs must be based on the severity of the reaction, and include slowing the infusion rate and treatment with medicinal products such as antihistamines, antipyretics and/or corticosteroids, for mild to moderate reactions. Pre-treatment with antihistamines and/or corticosteroids may prevent subsequent reactions in those cases where symptomatic treatment was required, although IRRs occurred in some patients after receiving pre-treatment (see section 4.2). Hypersensitivity Hypersensitivity reactions have been reported in patients in clinical studies (see section 4.8). As with any intravenous protein product, allergic-type hypersensitivity reactions may manifest and can include localised angioedema (including swelling of the face, mouth, and throat), bronchospasm, hypotension, generalised urticaria, dysphagia, rash, dyspnoea, flushing, chest discomfort, pruritus, nausea, chills and nasal congestion. If a severe allergic or anaphylactic-type reactions occur, immediate discontinuation of pegunigalsidase alfa is recommended and current medical standards for emergency treatment are to be followed. In patients who have experienced severe hypersensitivity reactions during pegunigalsidase alfa infusion, caution should be exercised upon re-challenge and appropriate medical support should be readily available. Moreover, for patients who experienced severe hypersensitivity reactions with ERT infusion in

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