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35 mg / 7.5 ml
The recommended dose of Fabrazyme is 1 mg/kg body weight administered once every 2 weeks as an intravenous infusion. For further instructions see section 6.6. Alternative dosing regimens have been used in clinical studies. In one of these studies, after an initial dose of 1.0 mg/kg every 2 weeks for 6 months, 0.3 mg/kg every 2 weeks may maintain clearance of GL-3 in certain cell types in some patients; however, the long term clinical relevance of these findings has not been established (see section 5.1). The initial infusion rate should be no more than 0.25 mg/min (15 mg/hour) to minimise the potential occurrence of infusion-associated reactions. After patient tolerance is well established, the infusion rate may be increased gradually with subsequent infusions. 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 should remain constant while at home, and not be changed without supervision of a healthcare professional.
Patients with renal impairment: No dose adjustment is necessary for patients with renal insufficiency.
Patients with hepatic impairment: Studies in patients with hepatic insufficiency have not been performed.
Elderly patients: The safety and efficacy of Fabrazyme patients older than 65 years have not been established and no dosage regimen can presently be recommended in these patients.
Paediatric population: Studies in children 0-7 years have not been performed and no dosage regimen can presently be recommended in patients in this paediatric age group as safety and efficacy have not yet been established. No dose adjustment is necessary for children 8-16 years.
Long-term enzyme replacement therapy in patients with a confirmed diagnosis of Fabry disease (alfa-galactosidase A deficiency).
Life threatening hypersensitivity (anaphylactic reaction) to the active substance or any of the excipients listed.
Immunogenicity: Since agalsidase beta (rhαGAL) 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 titers (based on a ≥ 4-fold reduction in titer from the peak measurement to the last measurement) (40% of the patients), tolerised (no detectable antibodies confirmed by 2 consecutive radioimmunoprecipitation (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. Antibody status should be regularly monitored. In clinical trials, sixty seven percent (67 %) of the patients experienced at least one infusion-associated reaction. 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 pretreatment 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.
Patients with advanced renal disease: The effect of Fabrazyme treatment on the kidneys may be limited in patients with advanced renal disease.
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. 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 infusionassociated reaction. Anaphylactoid reactions have been reported in the postmarketing setting.
For full details see prescribing information.
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 gentamicin due to a theoretical risk of inhibited intra-cellular α-galactosidase activity.
Pregnancy and Lactation
Pregnancy: There are no adequate data from the use of agalsidase beta in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to embryonal foetal development. Fabrazyme should not be used during pregnancy unless clearly necessary.
Breast-feeding: Agalsidase beta may be excreted in milk. Because there are no data available on effects in neonates exposed to agalsidase beta via breast milk, it is recommended to stop nursing when Fabrazyme is used.
Fertility: Studies have not been conducted to assess the potential effects of Fabrazyme on impairment of fertility.
In clinical trials, doses up to 3 mg/kg body weight were used.