Presentation and Status in Health Basket
1 X 1 mg/ml
Posology: Replagal is administered at a dose of 0.2 mg/kg body weight every other week by intravenous infusion over 40 minutes.
Elderly patients: Studies in patients over the age of 65 have not been performed and no dosage regimen can presently be recommended in these patients as safety and efficacy have not yet been established.
Patients with hepatic impairment: No studies have been performed in patients with hepatic impairment.
Patients with renal impairment: No dose adjustment is necessary in patients with renal impairment. The presence of extensive renal damage (eGFR <60mL/min) may limit the renal response to enzyme replacement therapy. Limited data are available in patients on dialysis or postkidney transplantation, no dose adjustment is recommended.
Paediatric Population: The safety and efficacy of Replagal in children aged 0-6 years has not yet been established.
In clinical studies of children (7-18 years) who received Replagal 0.2 mg/kg every other week, no unexpected safety issues were encountered.
Method of administration: For instructions on dilution of the medicinal product before administration, see prescribing information.
Administer the infusion solution over a period of 40 minutes using an intravenous line with an integral filter.
Do not infuse Replagal concomitantly in the same intravenous line with other agents.
Long-term enzyme replacement therapy in patients with a confirmed diagnosis of Fabry disease (alfa-galactosidase A deficiency).
Hypersensitivity to the active substance or to any of the excipients.
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. The most common symptoms have been rigors, headache, nausea, pyrexia, flushing and fatigue. Serious infusion reactions have been reported uncommonly; symptoms reported include pyrexia, rigors, tachycardia, urticaria, nausea/vomiting, angioneurotic oedema with throat tightness, stridor and swollen tongue. Other infusion-related symptoms may include dizziness and hyperhidrosis. 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.
The onset of infusion related reactions has generally occurred within the first 2-4 months after initiation of treatment with Replagal although later onset (after 1 year) has been reported as well. These effects have decreased with time. If mild or moderate acute infusion reactions occur, medical attention must be sought immediately and appropriate actions instituted. The infusion can be temporarily interrupted (5 to 10 minutes) until symptoms subside and the infusion may then be restarted. Mild and transient effects may not require medical treatment or discontinuation of the infusion. In addition, oral or intravenous pre-treatment with antihistamines and/or corticosteroids, from 1 to 24 hours prior to infusion may prevent subsequent reactions in those cases where symptomatic treatment was required.
Hypersensitivity reactions: Hypersensitivity reactions have been reported. If severe hypersensitivity or anaphylactic reactions occur, the administration of Replagal should be discontinued immediately and appropriate treatment initiated. The current medical standards for emergency treatment are to be observed.
Antibodies to the protein: As with all protein pharmaceutical products, patients may develop antibodies to the protein. A low titre IgG antibody response has been observed in approximately 24% of the male patients treated with Replagal. Based on limited data this percentage has been found to be lower (7%) in the male paediatric population. These IgG antibodies appeared to develop following approximately 3-12 months of treatment. After 12 to 54 months of therapy, 17% of Replagal treated patients were still antibody positive whereas 7% showed evidence for the development of immunologic tolerance, based on the disappearance of IgG antibodies over time. The remaining 76% were 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 detected for this patient. In paediatric patients <7 yrs of age, 0/7 male patients tested positive for IgG anti-agalsidase alfa antibodies. Borderline IgE antibody positivity not associated with anaphylaxis has been reported in clinical trials in a very limited number of patients.
Patients with renal impairment: The presence of extensive renal damage may limit the renal response to enzyme replacement therapy, possibly due to underlying irreversible pathological changes. In such cases, the loss of renal function remains within the expected range of the natural progression of disease.
Adults: The most commonly reported adverse reactions 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.
Description of selected adverse reactions: Infusion related reactions reported in the postmarketing setting may 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. The most common infusion related reactions were mild and include rigors, pyrexia, flushing, headache, nausea, dyspnea, tremor and pruritus.
Infusion-related symptoms may also include dizziness, hyperhidrosis, hypotension, cough, vomiting and fatigue. Hypersensitivity, including anaphylaxis, has been reported.
Paediatric population: 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.
See prescribing information for full details.
Replagal should not be co-administered with chloroquine, amiodarone, benoquin or gentamicin since these substances have the potential to inhibit intra-cellular α-galactosidase activity.
As α-galactosidase A is itself an enzyme, it would be an unlikely candidate for cytochrome P450 mediated drug-drug interactions. In clinical studies, neuropathic pain medicinal products (such as carbamazepine, phenytoin and gabapentin) were administered concurrently to most patients without any evidence of interaction.
Pregnancy and Lactation
Pregnancy: There is very limited data on pregnancies exposed to Replagal. Caution should be exercised when prescribing to pregnant women.
Lactation: It is not known whether Replagal is excreted in human milk. Caution should be exercised when prescribing to breast-feeding women.
See prescribing information for full details.
In clinical trials doses up to 0.4 mg/kg weekly were used, and their safety profile was not different from the recommended dose of 0.2 mg/kg biweekly.
Storage: Store in a refrigerator (2°C – 8°C).