Replagal 1 mg/ml concentrate for solution for infusion

Other= manufacturer

Section 4.4

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
Deleted text : No IgE antibodies have been detected in any patient receiving Replagal
Replacement text : Borderline IgE antibody positivity not associated with anaphylaxis has been reported in clinical trials in a very limited number of patients.

Section 4.8
New ADR added : Immune system disorders - Anaphylactic reaction, hypersensitivity

Revised wording

Description of selected adverse reactions

Infusion related reactions reported in the postmarketing setting (also see section 4.4) 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.

Section 5.1
Revised wording

Study in patients switching from agalsidase beta to Replagal (agalsidase alfa)

100 patients [(naïve (n=29); or previously treated with agalsidase beta who switched to Replagal (n=71)) were treated for up to 30 months in an open label, uncontrolled study. An analysis showed that serious adverse events were reported in 39.4% of those patients who switched from agalsidase beta compared to 31.0% in those who were naïve to therapy prior to study entry.  Patients switched from agalsidase beta to Replagal had a safety profile consistent with that observed in other clinical experience. Infusion related reactions have been  experienced by 9 patients of the naïve population (31.0%) compared to 27 patients of the switched population (38.0%).

4.2       Posology and method of administration

Paediatric population. Statement for children 7-18 years updated.

5.1     Pharmacodynamic properties

Paediatric population data updated.

Some rewording, addtional detail and reformatting in section 4.8    Undesirable effects.   

Additional information included in sections 4.6, 4.9, 5.1 :

4.6         Fertility, pregnancy and lactation

Fertility

No effects on male fertility were seen in reproductive studies in male rats.

4.9         Overdose

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.

5.1 Pharmacodynamic properties

Study with various dosing regimen.

In an open-label randomised study, there were no statistically significant differences between adult patients treated for 52 weeks with 0.2 mg/kg intravenously every other week (n=20) and those treated with 0.2 mg/kg weekly (n=19) in mean change from baseline LVMI or other endpoints (cardiac functional status, renal function, and pharmacodynamic activity). In each treatment group, LVMI remained stable over the treatment period of the study. The overall incidence of SAEs by treatment group did not show any obvious effect of treatment regimen on the SAE profile of the different treatment groups.

5.1              Pharmacodynamic properties

New study data added from patients switching from agalsidase beta to agalsidase alfa

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 height^2.7 was within normal range for children (<39 g/m^2.7 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/m^2.7 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.