What is Fabrazyme used for?

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.

What is the active ingredient in Fabrazyme?

Agalsidasum beta (Agalsidasum beta)

What pharmaceutical form is Fabrazyme available in?

Fabrazyme: Proszek do przygotowania koncentratu do sporządzania roztworu do infuzji 35 mg (dożylna)

Is Fabrazyme OTC or prescription only?

Fabrazyme requires a doctor's prescription.

What are the side effects of Fabrazyme?

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,

Who should NOT take Fabrazyme?

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

Does Fabrazyme interact with other medications?

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 α-galactosidase A activity.

Can Fabrazyme be used during pregnancy?

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. 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 Fabra

What ATC class does Fabrazyme belong to?

Fabrazyme: ATC A16AB04. ATC is the WHO Anatomical Therapeutic Chemical classification — it groups drugs by organ system and pharmacological mechanism.

Fabrazyme

This information is for educational purposes only. It is not intended as medical advice. Always consult a qualified healthcare professional.

Pharmacotherapeutic group: Other alimentary tract and metabolism products, enzymes. ATC code: A16AB04. Fabry disease Fabry disease is an inherited heterogeneous and multisystemic progressive disease, that affects both males and females. It is characterised by the deficiency of α-galactosidase. Reduced or absent α-galactosidase activity results in the presence of elevated concentrations of GL-3 and its associated soluble form lyso-GL-3 in plasma and in accumulation of GL-3 in the lysosomes of many cell types including the endothelial and parenchymal cells, ultimately leading to life-threatening clinical deteriorations as a result of renal, cardiac and cerebrovascular complications. Mechanism of action The rationale for enzyme replacement therapy is to restore a level of enzymatic activity sufficient to clear the accumulating substrate in the organ tissues; thereby, preventing, stabilizing or reversing the progressive decline in function of these organs before irreversible damage has occurred. After intravenous infusion, agalsidase beta is rapidly removed from the circulation and taken up by vascular endothelial and parenchymal cells into lysosomes, likely through the mannose-6 phosphate, mannose and asialoglycoprotein receptors. Clinical efficacy and safety Efficacy and safety of Fabrazyme was evaluated in two studies with children, one dose-finding study, two double-blind placebo-controlled studies, one open-label extension study in both male and female patients and published scientific literature. In the dose finding study, the effects of 0.3, 1.0 and 3.0 mg/kg once every 2 weeks and 1.0 and 3.0 mg/kg once every 2 days were evaluated. A reduction in GL-3 was observed in kidney, heart, skin and plasma at all doses. Plasma GL-3 was cleared in a dose dependent manner but was less consistent at the dose of 0.3 mg/kg. In addition, infusion-associated reactions were dose dependent. In the first placebo-controlled clinical trial of 58 Fabry patients with classic phenotype (56 males and 2 females), Fabrazyme was effective in clearing GL-3 from the vascular endothelium of the kidney after 20 weeks of treatment. This clearance was achieved in 69% (20/29) of the Fabrazyme treated patients, but in none of the placebo patients (p<0.001). This finding was further supported by a statistically significant decrease in GL-3 inclusions in kidney, heart and skin combined and in the individual organs in patients treated with agalsidase beta compared to placebo patients (p<0.001). Sustained clearance of GL-3 from kidney vascular endothelium upon agalsidase beta treatment was demonstrated further in the open label extension of this trial. This was achieved in 47 of the 49 patients (96%) with available information at month 6, and in 8 of the 8 patients (100%) with available information at the end of the study (up to a total of 5 years of treatment). Clearance of GL-3 was also achieved in several other cell types from the kidney. Plasma GL-3 levels rapidly normalised with treatment and remained normal through 5 years. Renal function, as measured by glomerular filtration rate and serum creatinine, as well as proteinuria, remained stable in the majority of the patients. However, the effect of Fabrazyme treatment on the kidney function was limited in some patients with advanced renal disease. Although no specific study has been conducted to assess the effect on the neurological signs and symptoms, the results also indicate that patients may achieve reduced pain and enhanced quality of life upon enzyme replacement therapy. Another double-blind, placebo-controlled study of 82 Fabry patients with classic phenotype (72 males and 10 females) was performed to determine whether Fabrazyme would reduce the rate of occurrence of renal, cardiac, or cerebrovascular disease or death. The rate of clinical events was substantially lower among Fabrazyme-treated patients compared to placebo-treated patients (risk reduction = 53% intent-to-treat population (p=0.0577); risk reduction = 61 % per-protocol population (p=0.0341)). This result was consistent across renal, cardiac and cerebrovascular events. Two large observational studies followed a group of patients (n=89 to 105) who were maintained on standard-dose Fabrazyme (1.0 mg/kg every 2 weeks) or assigned to a reduced dose of Fabrazyme (0.3-0.5 mg/kg every 2 weeks) followed by a switch to agalsidase alfa (0.2 mg/kg every 2 weeks) or directly switched to agalsidase alfa (0.2 mg/kg every 2 weeks). Due to the observational, multi-centre design of these studies based in a real-world clinical setting, there are confounding factors affecting the interpretation of the results, including the selection of patients and assignment of treatment groups and available parameters between centres over time. Due to the rarity of Fabry disease, the study populations of the observational studies overlapped and the treatment groups in respective studies were small. Moreover, most patients with more severe disease, especially men, remained on standard dose Fabrazyme, whereas a treatment switch occurred more frequently in patients with less severe disease and women. Comparisons between the groups should therefore be cautiously interpreted. The Fabrazyme standard-dose group demonstrated no significant changes in cardiac, renal, or neurologic organ function or in symptoms related to Fabry disease. Similarly, no significant changes in cardiac or neurologic function were observed in patients in the Fabrazyme dose-reduction group. However, deterioration in renal parameters, as measured by estimated glomerular filtration rate (eGFR), was observed in patients treated with a lower dose (p<0.05). The annual decreases in eGFR were attenuated in patients who re-switched back to standard dose Fabrazyme. These results are consistent with 10-year follow-up evidence from the Canadian Fabry Disease Initiative Registry. In the observational studies an increase in symptoms related to Fabry disease (e.g., gastrointestinal pain, diarrhoea) was observed in patients who had received a dose reduction of agalsidase beta. Also, in the postmarketing setting, experience was gained in patients who initiated Fabrazyme treatment at a dose of 1 mg/kg every 2 weeks and subsequently received a reduced dose for an extended period. In some of these patients, an increase of some of the following symptoms was spontaneously reported: pain, paraesthesia and diarrhoea, as well as cardiac, central nervous system and renal manifestations. These reported symptoms resemble the natural course of Fabry disease. In an analysis conducted in the Fabry Registry, the incidence rates (95% confidence interval) of the first severe clinical event in Classic male Fabrazyme-treated patients with sustained anti-agalsidase beta IgG antibodies were 43.98 (18.99, 86.66), 48.60 (32.03, 70.70), and 56.07 (30.65, 94.07) per 1000 person-years in the low, medium, and high peak titer groups, respectively. These observed differences were not statistically significant. Paediatric population In one open-label paediatric study, sixteen patients with Fabry disease (8-16 years old; 14 males, 2 females) had been treated for one year at 1.0 mg/kg every 2 weeks. Clearance of GL-3 in the superficial skin vascular endothelium was achieved in all patients who had accumulated GL-3 at baseline. The 2 female patients had little or no GL-3 accumulation in the superficial skin vascular endothelium at baseline, making this conclusion applicable in male patients only. In an additional 5-year open-label paediatric study, 31 male patients aged 5 to 18 years were randomised prior to the onset of clinical symptoms involving major organs and treated with two lower dose regimens of agalsidase beta, 0.5 mg/kg every 2 weeks or 1.0 mg/kg every 4 weeks. Results were similar between the two treatment groups. Superficial skin capillary endothelium GL-3 scores were reduced to zero or maintained at zero at all time points post-baseline upon treatment in 19/27 patients completing the study without a dose increase. Both baseline and 5-year kidney biopsies were obtained in a subset of 6 patients: in all, kidney capillary endothelium GL-3 scores were reduced to zero, but highly variable effects were observed in podocyte GL-3, with a reduction in 3 patients. Ten (10) patients met per protocol dose increase criteria, two (2) had a dose increase to the recommended dose of 1.0 mg/kg every 2 weeks.

⚠️ Warnings

The powder for concentrate for solution for infusion has to be reconstituted with water for injections, diluted with 0.9% sodium chloride solution for injection and then administered by intravenous infusion. Aseptic technique should be used The number of vials should be determined to be reconstituted based on the individual patient's weight and the required vials should be removed from the refrigerator in order to allow them to reach room temperature (in approximately 30 minutes). Each vial of Fabrazyme is intended for single use only. Reconstitution Each vial of Fabrazyme 35 mg has to be reconstituted with 7.2 ml water for injections. Forceful impact of the water for injections on the powder and foaming should be avoided. This is done by slow drop-wise addition of the water for injection down the inside of the vial and not directly onto the lyophilisate. Each vial should be rolled and tilted gently. The vial should not be inverted, swirled or shaken. The reconstituted solution contains 5 mg agalsidase beta per ml and appears as a clear colourless solution. The pH of the reconstituted solution is approximately 7.0. Before further dilution, the reconstituted solution in each vial should be visually inspected for particulate matter and discolouration. The solution should not be used if foreign particles are observed or if the solution is discoloured. After reconstitution it is recommended to promptly dilute the vials, to minimise protein particle formation over time. Dilution Prior to adding the reconstituted volume of Fabrazyme required for the patient dose, it is recommended to remove an equal volume of 0.9% sodium chloride solution for injection, from the infusion bag. The airspace within the infusion bag should be removed to minimise the air/liquid interface. 7.0 ml (equal to 35 mg) of the reconstituted solution from each vial up to the total volume required should be slowly withdrawn for the patient dose. Filter needles should not be used and foaming should be avoided. The reconstituted solution should slowly be injected directly into the 0.9% sodium chloride solution for injection (not in any remaining airspace) to a final concentration between 0.05 mg/ml and 0.7 mg/ml. The total volume of sodium chloride 0.9% solution for infusion (between 50 and 500 ml) should be determined based on the individual dose. For doses lower than 35 mg a minimum of 50 ml should be used, for doses 35 to 70 mg a minimum of 100 ml should be used, for doses 70 to 100 mg a minimum of 250 ml should be used and for doses greater than 100 mg only 500 ml should be used. The infusion bag should be gently inverted or lightly massaged to mix the diluted solution. The infusion bag should not be shaken or excessively agitated. Administration It is recommended to administer the diluted solution through an in-line low protein-binding 0.2 µm filter to remove any protein particles which will not lead to any loss of agalsidase beta activity. The initial (IV) infusion rate should be no more than 0.25 mg/min (15 mg/hour) The infusion rate may be slowed in the event of infusion-associated reactions. After patient tolerance is well established, the infusion rate may be increased in increments of 0.05 to 0.083 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. This was achieved after 8 initial infusions at 0.25 mg/min (15 mg/hr), without any IARs, change in infusion rate, or infusion interruption. A further decrease of infusion time to 1.5 hours was allowed for patients without new IARs during the last 10 infusions or reported serious adverse events within the last 5 infusions. Each rate increment of 0.083 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. For patients weighing < 30 kg, the maximum infusion rate should remain at 0.25 mg/min (15 mg/hr). Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

Fabrazyme

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