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In section 4.2 (Posology and method of administration), has been amended for paediatric patients.
Paediatric Patients
The experience in children is limited. No dosage regimen in children (0-6 years) can presently be recommended as safety and efficacy have not yet been sufficiently established. Limited clinical data in children (7-18 years) do not permit to recommend an optimal dosage regimen presently (see sections 5.1 and 5.2). Because no unexpected safety issues were encountered in the 6 month study with Replagal administered at 0.2 mg/kg in this population, this dose regimen is suggested for children between 7– 18 years of age. In section 4.4 (Special warnings and precautions for use). Idiosyncratic infusion related reactions 13.7% of adult patients treated with Replagal in clinical trials have experienced idiosyncratic infusion related reactions. Four of 17 (23.5%) paediatric patients >7 years of age enrolled in clinical trials experienced at least one infusion reaction over a period of 4.5 years of treatment (mean duration of approx. 4 years). Three of 8 (37.5%) paediatric patients <7 years of age experienced at least one infusion related reaction over a mean observation time of 4.2 years… A review of cardiac events showed that infusion reactions may be associated with hemodynamic stress triggering cardiac events in patients with pre-existing cardiac manifestations of Fabry disease. IgG antibodies to the protein The remaining 76% remained antibody negative throughout. In paediatric patients >7 yrs of age, 1/16 male patients tested positive for IgG anti-agalsidase alfa antibodies during the study. No increase in the incidence of adverse events was apparent for this patient. In paediatric patients <7 yrs of age, 0/7 male patients tested positive for IgG anti-agalsidase alfa antibodies. In section 4.8 (Undesirable effects), has been updated to specify paediatric sub-populations and includes cardiac events. The most commonly reported undesirable effects were infusion associated reactions, which occurred in 13.7% of adult patients treated with Replagal in clinical trials. Most undesirable effects were mild to moderate in severity. Table 1 lists adverse drug reactions (ADRs) reported for the 177 patients treated with Replagal in clinical trials, including 21 patients with history of endstage renal disease, 24 paediatric patients (7 to 17 years of age) and 17 female patients. Infusion related reactions (also see section 4.4 Special warnings and precautions for use) may also include cardiac events such as cardiac arrhythmias (atrial fibrillation, ventricular extrasystoles, tachyarrhythmia), myocardial ischemia, and heart failure in patients with Fabry disease involving the heart structures. Infusion-related symptoms may include dizziness and hyperhidrosis. The most frequent were mild infusion-related reactions that mainly included rigors, pyrexia, flushing, headache, nausea, and dyspnoea. Adverse drug reactions reported in the paediatric population (children and adolescents) were, in general, similar to those reported in adults. However, infusion related reactions (pyrexia, dyspnoea, chest pain) and pain exacerbation occurred more frequently. In section 5.1 (Pharmacodynamic properties), has been updated to specify paediatric sub-populations. The safety and efficacy of Replagal was assessed in two randomised, double blind, placebo controlled studies and open label extension studies, in a total of forty patients with a diagnosis of Fabry Disease based on clinical and biochemical evidence. Patients received the recommended dosage of 0.2 mg/kg of Replagal. Twenty-five patients completed the first study and entered an extension study. After 6 months of therapy there was a significant reduction in pain in the Replagal treated patients compared with placebo (p=0.021), as measured by the Brief Pain Inventory (a validated pain measurement scale). This was associated with a significant reduction in chronic neuropathic pain medication use and number of days on pain medication. In subsequent studies, in male paediatric patients above the age of 7, a reduction in pain was observed after 9 and 12 months of Replagal therapy compared to pre-treatment baseline. This pain reduction persisted through 4 years of Replagal therapy in 9 patients (in patients 7 – 18 years of age). Twelve to 18 months of treatment with Replagal resulted in improvement in quality of life (QoL), as measured by validated instruments. For patients between 0 and 7 years of age, limited data indicate no specific safety issues. In male paediatric Fabry patients > 7 years of age, hyperfiltration can be the earliest manifestation of renal involvement in the disease. Reduction in their hypernormal eGFRs was observed within 6 months of initiating Replagal therapy. After one year of treatment with agalsidase alfa 0.2mg/kg every other week, the abnormally high eGFR decreased from 143.4 ± 6.8 to 121.3 ± 5.6 mL/min/1.73 m2 in this subgroup and these eGFRs stabilized in the normal range during 4 years of Replagal 0.2mg/kg therapy, as did the eGFRs of the non-hyperfiltrators. In male paediatric patients > 7 years of age, heart rate variability was abnormal at baseline and improved after 6 months of Replagal therapy in 15 boys and the improvement was sustained through 4.0 years of Replagal 0.2mg/kg therapy in an open-label long-term extension study in 9 boys. Individual left ventricular mass indexed to height2.7 was within normal range for children (<39 g/m2.7 in boys) at baseline. A relative reduction in mean LVM of 11% was observed during the 4.5 years of treatment. In 5/6 children < 7 years old, individual left ventricular mass indexed to height 2.7 was borderline elevated or elevated (>95%) for (<39 g/m2.7 in boys) at baseline. LVMI values for all 5 children fell within normal range after starting therapy. In male paediatric Fabry patients plasma Gb3 decreased 40-50% after 6 months of Replagal therapy 0.2mg/kg and this reduction persisted after a total 4 years of treatment in 11 patients. In section 10 (Date of revision of the text), has been updated to 12/2009.
13.7% of adult patients treated with Replagal in clinical trials have experienced idiosyncratic infusion related reactions. Four of 17 (23.5%) paediatric patients >7 years of age enrolled in clinical trials experienced at least one infusion reaction over a period of 4.5 years of treatment (mean duration of approx. 4 years). Three of 8 (37.5%) paediatric patients <7 years of age experienced at least one infusion related reaction over a mean observation time of 4.2 years… A review of cardiac events showed that infusion reactions may be associated with hemodynamic stress triggering cardiac events in patients with pre-existing cardiac manifestations of Fabry disease.
IgG antibodies to the protein
The remaining 76% remained antibody negative throughout. In paediatric patients >7 yrs of age, 1/16 male patients tested positive for IgG anti-agalsidase alfa antibodies during the study. No increase in the incidence of adverse events was apparent for this patient. In paediatric patients <7 yrs of age, 0/7 male patients tested positive for IgG anti-agalsidase alfa antibodies.
In section 4.8 (Undesirable effects), has been updated to specify paediatric sub-populations and includes cardiac events.
The most commonly reported undesirable effects were infusion associated reactions, which occurred in 13.7% of adult patients treated with Replagal in clinical trials. Most undesirable effects were mild to moderate in severity. Table 1 lists adverse drug reactions (ADRs) reported for the 177 patients treated with Replagal in clinical trials, including 21 patients with history of endstage renal disease, 24 paediatric patients (7 to 17 years of age) and 17 female patients.
Infusion related reactions (also see section 4.4 Special warnings and precautions for use) may also include cardiac events such as cardiac arrhythmias (atrial fibrillation, ventricular extrasystoles, tachyarrhythmia), myocardial ischemia, and heart failure in patients with Fabry disease involving the heart structures. Infusion-related symptoms may include dizziness and hyperhidrosis. The most frequent were mild infusion-related reactions that mainly included rigors, pyrexia, flushing, headache, nausea, and dyspnoea.
Adverse drug reactions reported in the paediatric population (children and adolescents) were, in general, similar to those reported in adults. However, infusion related reactions (pyrexia, dyspnoea, chest pain) and pain exacerbation occurred more frequently.
In section 5.1 (Pharmacodynamic properties), has been updated to specify paediatric sub-populations.
The safety and efficacy of Replagal was assessed in two randomised, double blind, placebo controlled studies and open label extension studies, in a total of forty patients with a diagnosis of Fabry Disease based on clinical and biochemical evidence. Patients received the recommended dosage of 0.2 mg/kg of Replagal. Twenty-five patients completed the first study and entered an extension study. After 6 months of therapy there was a significant reduction in pain in the Replagal treated patients compared with placebo (p=0.021), as measured by the Brief Pain Inventory (a validated pain measurement scale). This was associated with a significant reduction in chronic neuropathic pain medication use and number of days on pain medication. In subsequent studies, in male paediatric patients above the age of 7, a reduction in pain was observed after 9 and 12 months of Replagal therapy compared to pre-treatment baseline. This pain reduction persisted through 4 years of Replagal therapy in 9 patients (in patients 7 – 18 years of age).
Twelve to 18 months of treatment with Replagal resulted in improvement in quality of life (QoL), as measured by validated instruments. For patients between 0 and 7 years of age, limited data indicate no specific safety issues. In male paediatric Fabry patients > 7 years of age, hyperfiltration can be the earliest manifestation of renal involvement in the disease. Reduction in their hypernormal eGFRs was observed within 6 months of initiating Replagal therapy. After one year of treatment with agalsidase alfa 0.2mg/kg every other week, the abnormally high eGFR decreased from 143.4 ± 6.8 to 121.3 ± 5.6 mL/min/1.73 m2 in this subgroup and these eGFRs stabilized in the normal range during 4 years of Replagal 0.2mg/kg therapy, as did the eGFRs of the non-hyperfiltrators. In male paediatric patients > 7 years of age, heart rate variability was abnormal at baseline and improved after 6 months of Replagal therapy in 15 boys and the improvement was sustained through 4.0 years of Replagal 0.2mg/kg therapy in an open-label long-term extension study in 9 boys. Individual left ventricular mass indexed to height2.7 was within normal range for children (<39 g/m2.7 in boys) at baseline. A relative reduction in mean LVM of 11% was observed during the 4.5 years of treatment. In 5/6 children < 7 years old, individual left ventricular mass indexed to height 2.7 was borderline elevated or elevated (>95%) for (<39 g/m2.7 in boys) at baseline. LVMI values for all 5 children fell within normal range after starting therapy. In male paediatric Fabry patients plasma Gb3 decreased 40-50% after 6 months of Replagal therapy 0.2mg/kg and this reduction persisted after a total 4 years of treatment in 11 patients. In section 10 (Date of revision of the text), has been updated to 12/2009.
In male paediatric Fabry patients > 7 years of age, hyperfiltration can be the earliest manifestation of renal involvement in the disease. Reduction in their hypernormal eGFRs was observed within 6 months of initiating Replagal therapy. After one year of treatment with agalsidase alfa 0.2mg/kg every other week, the abnormally high eGFR decreased from 143.4 ± 6.8 to 121.3 ± 5.6 mL/min/1.73 m2 in this subgroup and these eGFRs stabilized in the normal range during 4 years of Replagal 0.2mg/kg therapy, as did the eGFRs of the non-hyperfiltrators. In male paediatric patients > 7 years of age, heart rate variability was abnormal at baseline and improved after 6 months of Replagal therapy in 15 boys and the improvement was sustained through 4.0 years of Replagal 0.2mg/kg therapy in an open-label long-term extension study in 9 boys. Individual left ventricular mass indexed to height2.7 was within normal range for children (<39 g/m2.7 in boys) at baseline. A relative reduction in mean LVM of 11% was observed during the 4.5 years of treatment. In 5/6 children < 7 years old, individual left ventricular mass indexed to height 2.7 was borderline elevated or elevated (>95%) for (<39 g/m2.7 in boys) at baseline. LVMI values for all 5 children fell within normal range after starting therapy. In male paediatric Fabry patients plasma Gb3 decreased 40-50% after 6 months of Replagal therapy 0.2mg/kg and this reduction persisted after a total 4 years of treatment in 11 patients. In section 10 (Date of revision of the text), has been updated to 12/2009.
In male paediatric patients > 7 years of age, heart rate variability was abnormal at baseline and improved after 6 months of Replagal therapy in 15 boys and the improvement was sustained through 4.0 years of Replagal 0.2mg/kg therapy in an open-label long-term extension study in 9 boys. Individual left ventricular mass indexed to height2.7 was within normal range for children (<39 g/m2.7 in boys) at baseline. A relative reduction in mean LVM of 11% was observed during the 4.5 years of treatment. In 5/6 children < 7 years old, individual left ventricular mass indexed to height 2.7 was borderline elevated or elevated (>95%) for (<39 g/m2.7 in boys) at baseline. LVMI values for all 5 children fell within normal range after starting therapy.
In male paediatric Fabry patients plasma Gb3 decreased 40-50% after 6 months of Replagal therapy 0.2mg/kg and this reduction persisted after a total 4 years of treatment in 11 patients.
In section 10 (Date of revision of the text), has been updated to 12/2009.