Fabrazyme · 4.4 Special warnings and precautions for use · 1

HOS-093118 · has-adverse-reaction-information · PDF-Seite 5

Summary of the safety profile Since agalsidase beta (r-hαGAL) is a recombinant protein, the development of IgG antibodies is expected in patients with little or no residual enzyme activity. Patients with antibodies to r-hαGAL have a greater potential to experience infusion-associated reactions (IARs). Reactions suggestive of immediate (Type I) hypersensitivity have been reported in a small number of patients (see section 4.4). Very common adverse reactions included chills, pyrexia, feeling cold, nausea, vomiting, headache and paraesthesia. Sixty seven percent (67%) of the patients experienced at least one infusion-associated reaction. Anaphylactoid reactions have been reported in the postmarketing setting. Tabulated list of adverse reactions Adverse reactions reported from clinical trials with a total of 168 patients (154 males and 14 females) treated with Fabrazyme administered at a dose of 1 mg/kg every 2 weeks for a minimum of one infusion up to a maximum of 5 years are listed by System Organ Class and frequency (very common ≥ 1/10; common ≥ 1/100 to < 1/10 and uncommon ≥ 1/1,000 to < 1/100) in the table below. The occurrence of an adverse reaction in a single patient is defined as uncommon in light of the relatively small number of patients treated. Adverse reactions only reported during the Post Marketing period are also included in the table below at a frequency category of “not known” (cannot be estimated from the available data). Adverse reactions were mostly mild to moderate in severity: 5 Incidence of adverse reactions with Fabrazyme treatment System organ Very common Common Uncommon Not known class Infections and --- nasopharyngitis rhinitis infestations Immune system --- --- --- anaphylactoid disorders reaction Nervous system headache, dizziness, somnolence, hyperaesthesia, --- disorders paraesthesia hypoaesthesia, burning tremor sensation, lethargy, syncope Eye disorders --- lacrimation increased eye pruritus, ocular --- hyperaemia Ear and --- tinn

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HOS-093114 · has-contraindication-information · PDF-Seite 3

Life threatening hypersensitivity (anaphylactic reaction) to the active substance or any of the excipients listed in section 6.1.

HOS-093113 · has-indication-information · PDF-Seite 2

Fabrazyme is indicated for long-term enzyme replacement therapy in patients with a confirmed diagnosis of Fabry disease (α-galactosidase A deficiency). Fabrazyme is indicated in adults, children and adolescents aged 8 years and older.

HOS-093116 · has-interaction-information · PDF-Seite 4

No interaction studies and no in vitro metabolism studies have been performed. Based on its metabolism, agalsidase beta is an unlikely candidate for cytochrome P450 mediated drug-drug interactions. Fabrazyme should not be administered with chloroquine, amiodarone, benoquin or gentamycin due to a theoretical risk of inhibition of intra-cellular -galactosidase A activity. 4

HOS-093117 · has-pregnancy-information · PDF-Seite 5

Pregnancy There are limited data from the use of agalsidase beta 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 Fabrazyme during pregnancy. Breast-feeding Agalsidase beta is excreted in human milk. The effect of agalsidase beta on newborns/infants is unknown. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from Fabrazyme therapy taking into account the benefit of breast feeding for the child and the benefit of therapy for the woman. Fertility Studies have not been conducted to assess the potential effects of Fabrazyme on impairment of fertility.

HOS-093115 · has-warning-information · PDF-Seite 3

Immunogenicity Since agalsidase beta (r-hαGAL) is a recombinant protein, the development of IgG antibodies is expected in patients with little or no residual enzyme activity. The majority of patients developed IgG antibodies to r-hαGAL, typically within 3 months of the first infusion with Fabrazyme. Over time, the majority of seropositive patients in clinical trials demonstrated either a downward trend in titres (based on a ≥ 4-fold reduction in titre from the peak measurement to the last measurement) (40% of 3 the patients), tolerised (no detectable antibodies confirmed by 2 consecutive radioimmuno- precipitation (RIP) assays) (14% of the patients) or demonstrated a plateau (35% of the patients). Infusion associated reactions Patients with antibodies to r-hαGAL have a greater potential to experience infusion-associated reactions (IARs), which are defined as any related adverse event occurring on the infusion day. These patients should be treated with caution when re-administering agalsidase beta (see section 4.8). Antibody status should be regularly monitored. In clinical trials, sixty seven percent (67 %) of the patients experienced at least one infusion- associated reaction (see section 4.8). The frequency of IARs decreased over time. Patients experiencing mild or moderate infusion-associated reactions when treated with agalsidase beta during clinical trials have continued therapy after a reduction in the infusion rate (~0.15 mg/min; 10 mg/hr) and/or pre-treatment with antihistamines, paracetamol, ibuprofen and/or corticosteroids. Hypersensitivity As with any intravenous protein medicinal product, allergic-type hypersensitivity reactions are possible. A small number of patients have experienced reactions suggestive of immediate (Type I) hypersensitivity. If severe allergic or anaphylactic-type reactions occur, immediate discontinuation of the administration of Fabrazyme should be considered and appropriate treatment initiated. The current medical standards for emergency treatment are to be observed. With careful rechallenge Fabrazyme has been re-administered to all 6 patients who tested positive for IgE antibodies or had a positive skin test to Fabrazyme in a clinical trial. In this trial, the initial rechallenge administration was at a low dose and a lower infusion rate (1/2 the therapeutic dose at 1/25 the initial standard recommended rate). Once a patient tolerates the infusion, the dose may

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