Fabrazyme

Fabrazyme treatment should be supervised by a physician experienced in the management of patients with Fabry disease or other inherited metabolic diseases. Posology The recommended dose of Fabrazyme is 1 mg/kg body weight administered once every 2 weeks as an intravenous infusion.

Infusion of Fabrazyme at home may be considered for patients who are tolerating their infusions well. The decision to have a patient move to home infusion should be made after evaluation and recommendation by the treating physician.

Patients experiencing adverse events during the home infusion need to immediately stop the infusion process and seek the attention of a healthcare professional. Subsequent infusions may need to occur in a clinical setting. Dose and infusion rate 3 should remain constant while at home, and not be changed without supervision of a healthcare professional.

Special populations Renal impairment No dose adjustment is necessary for patients with renal insufficiency. Hepatic impairment Studies in patients with hepatic insufficiency have not been performed. Elderly The safety and efficacy of Fabrazyme in patients older than 65 years have not been established and no dosage regimen can presently be recommended in these patients.

Paediatric population The safety and efficacy of Fabrazyme in children aged 0 to 7 years have not yet been established. 2 but no recommendation on posology can be made in children aged 5 to 7 years. No data are available in children 0 to 4 years.

No dose adjustment is necessary for children 8-16 years. 25 mg/min (15 mg/hr). Method of administration Fabrazyme should be administered as an intravenous (IV) infusion. 25 mg/min (15 mg/hour). The infusion rate may be slowed in the event of infusion-associated reactions.

083 mg/min (increments of 3 to 5 mg/hr) with each subsequent infusion. In clinical trials with classic patients, the infusion rate was increased incrementally to reach a minimum duration of 2 hours. 25 mg/min (15 mg/hr), without any IARs, change in infusion rate, or infusion interruption.

5 hours was allowed for patients without new IARs during the last 10 infusions or reported serious adverse events within the last 5 infusions. 083 mg/min (~5 mg/hr) was maintained for 3 consecutive infusions, without any new IARs, change in infusion rate, or infusion interruption, before subsequent rate increases.

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).

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: 6 Incidence of adverse reactions with Fabrazyme treatment System organ class Very common Common Uncommon Not known Infections and infestations --- nasopharyngitis rhinitis Immune system disorders --- --- --- anaphylactoid reaction Nervous system disorders headache, paraesthesia dizziness, somnolence, hypoaesthesia, burning sensation, lethargy, syncope hyperaesthesia, tremor --- Eye disorders --- lacrimation increased eye pruritus, ocular hyperaemia --- Ear and labyrinth disorders --- tinnitus, vertigo auricular swelling, ear pain --- Cardiac Disorders --- tachycardia, palpitations, bradycardia sinus bradycardia --- Vascular disorders --- flushing, hypertension, pallor, hypotension, hot flush peripheral coldness --- Respiratory, thoracic and mediastinal disorders --- dyspnoea, nasal congestion, throat tightness, wheezing, cough, dyspnoea exacerbated bronchospasm, pharyngolaryngeal pain, rhinorrhoea, tachypnoea, upper respiratory tract congestion hypoxia Gastrointestinal Disorders nausea, vomiting abdominal pain, abdominal pain upper, abdominal discomfort, stomach discomfort, hypoaesthesia oral, diarrhoea dyspepsia, dysphagia --- Skin and subcutaneous tissue disorders --- pruritus, urticaria, rash, erythema, pruritus generalised, angioneurotic oedema, swelling face, rash maculo-papular livedo reticularis, rash erythematous, rash pruritic, skin discolouration, skin discomfort leukocytoclastic vasculitis Musculoskeletal and connective tissue disorders --- pain in extremity, myalgia, back pain, muscle spasms, arthralgia, muscle tightness, musculoskeletal stiffness musculoskeletal pain --- General disorders and administration site conditions chills, pyrexia, feeling cold fatigue, chest discomfort, feeling hot, oedema peripheral, pain, asthenia, chest pain, face oedema, hyperthermia feeling hot and cold, influenza-like illness, infusion site pain, infusion site reaction, injection site thrombosis, malaise, oedema --- Investigations oxygen saturation decreased For the purpose of this table, ≥1% is defined as reactions occurring in 2 or more patients.

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 4 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. 8). Antibody status should be regularly monitored.

8). The frequency of IARs decreased over time. 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 be increased to reach the therapeutic dose of 1 mg/kg and the infusion rate may be increased by slowly titrating upwards, as tolerated.

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