Shire Human Genetic Therapies

Replagal 1 mg/ml concentrate for solution for infusion.

1 ml of concentrate for solution for infusion contains 1 mg of agalsidase alfa.

Each vial of 1 ml of concentrate contains 1 mg of agalsidase alfa.

Each vial of 3.5 ml of concentrate contains 3.5 mg of agalsidase alfa.

Agalsidase alfa is the human protein α-galactosidase A produced in a human cell line by genetic engineering technology.

For a full list of excipients, see section 6.1.

Concentrate for solution for infusion.

A clear and colourless solution.

Replagal is indicated for long-term enzyme replacement therapy in patients with a confirmed diagnosis of Fabry Disease (α-galactosidase A deficiency).

Replagal treatment should be supervised by a physician experienced in the management of patients with Fabry Disease or other inherited metabolic diseases.

Posology

Replagal is administered at a dose of 0.2 mg/kg body weight every other week by intravenous infusion over 40 minutes.

Patients aged over 65 years

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 post-kidney transplantation, no dose adjustment is recommended.

Paediatric Population

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.

Method of administration

For instructions on reconstitution of the medicinal product before administration, see section 6.6.

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.

Hypersensitivity to the active substance or 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.

Allergic-type hypersensitivity reactions

As with any intravenous protein product, allergic-type hypersensitivity reactions are possible. If severe allergic or anaphylactic-type 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.

IgG antibodies to the protein

As with all protein pharmaceutical products, patients may develop IgG 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% 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. No IgE antibodies have been detected in any patient receiving Replagal.

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.

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

Very limited clinical data on pregnancies exposed to Replagal (n=4) have shown no adverse effects on the mother and newborn child. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy or embryonal/foetal development when exposed during organogenesis (see Section 5.3).

Breastfeeding

It is not known whether Replagal is excreted in human milk. Caution should be exercised when prescribing to pregnant or breast-feeding women.

Replagal has no or negligible influence on the ability to drive and use machines.

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, and from post-marketing spontaneous reports. Information is presented by system organ class and frequency (very common >1/10; common >1/100, <1/10; uncommon >1/1000, <1/100). The ADRs categorized as incidence “not known” are derived from post-marketing spontaneous reports and are shown in italics. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. The occurrence of an event in a single patient is defined as uncommon in view of the number of patients treated. A single patient could be affected by several ADRs.

The following ADRs have been identified for agalsidase alfa:

Table 1

See also section 4.4.

Infusion related reactions reported in the postmarketing setting (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, hyperhidrosis, and hypotension. The most frequent were mild infusion-related reactions that mainly included rigors, pyrexia, flushing, headache, nausea, and dyspnoea.

Patients with renal disease

Adverse drug reactions reported in patients with history of end stage renal disease were similar to those reported in the general patient population.

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.

No case of overdose has been reported.

Pharmacotherapeutic group: Other alimentary tract and metabolism products - Enzymes.

ATC code: A16AB03 agalsidase alfa.

Mechanism of action

Fabry Disease is a glycosphingolipid storage disorder that is caused by deficient activity of the lysosomal enzyme α-galactosidase A, resulting in accumulation of globotriaosylceramide (also referred to as Gb3 or CTH), the glycosphingolipid substrate for this enzyme. Agalsidase alfa catalyses the hydrolysis of Gb3, cleaving a terminal galactose residue from the molecule. Treatment with the enzyme has been shown to reduce accumulation of Gb3 in many cell types including endothelial and parenchymal cells. Agalsidase alfa has been produced in a human cell line to provide for a human glycosylation profile that can influence uptake by mannose-6-phosphate receptors on the surface of target cells.

Clinical efficacy and safety

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.

After 6 months of therapy Replagal stabilised renal function compared with a decline in placebo treated patients. Kidney biopsy specimens revealed a significant increase in the fraction of normal glomeruli and a significant decrease in the fraction of glomeruli with mesangial widening in patients reated with Replagal in contrast to the patients treated with placebo. After 12 to 18 months of maintenance therapy, Replagal improved renal function as measured by inulin based glomerular filtration rate by 8.7 ± 3.7 ml/min. (p=0.030). Longer term therapy (48-54 months) resulted in stabilisation of GFR in male patients with normal baseline GFR ( 90 mL/min/1.73 m²) and with mild to moderate renal dysfunction (GFR 60 to < 90 mL/min/1.73 m²), and in slowing of the rate of decline in renal function and progression to end-stage renal disease in male Fabry patients with more severe renal dysfunction (GFR 30 to < 60 mL/min/1.73 m²).

In a second study, fifteen patients with left ventricular hypertrophy completed a 6 month placebo-controlled study and entered an extension study. Treatment with Replagal resulted in an 11.5 g decrease in left ventricular mass as measured by magnetic resonance imaging (MRI) in the controlled study, while patients receiving placebo exhibited an increase in left ventricular mass of 21.8 g. In addition, in the first study involving 25 patients, Replagal effected a significant reduction in cardiac mass after 12 to 18 months of maintenance therapy (p<0.001). Replagal was also associated with improved myocardial contractility, a decrease in mean QRS duration and a concomitant decrease in septal thickness on echocardiography. Two patients with right bundle branch block in the studies conducted reverted to normal following therapy with Replagal. Subsequent open label studies demonstrated significant reduction from baseline in left ventricular mass by echocardiography in both male and female Fabry patients over 24 to 36 months of Replagal treatment. The reductions in LV mass observed by echocardiography in both male and female Fabry patients over 24 to 36 months of Replagal treatment were associated with meaningful symptom improvement as measured using the NYHA and CCS in Fabry patients with severe heart failure or anginal symptoms at baseline.

Compared with placebo, treatment with Replagal also reduced accumulation of Gb3. After the first 6 months of therapy mean decreases of approximately 20 - 50 % were observed in plasma, urine sediment and liver, kidney and heart biopsy samples. After 12 to 18 months treatment a reduction of 50 – 80% was observed in plasma and urine sediment. The metabolic effects were also associated with clinically significant weight gain, increased sweating and increased energy. Consistent with the clinical effects of Replagal, treatment with the enzyme reduced accumulation of Gb3 in many cell types, including renal glomerular and tubular epithelial cells, renal capillary endothelial cells (cardiac and dermal capillary endothelial cells were not examined) and cardiac myocytes. 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.

Infusion of Replagal at home may be considered for patients who are tolerating their infusions well.

Paediatric population

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.

For patients between 0 and 7 years of age, limited data indicate no specific safety issues.

Immunogenicity

Antibodies to agalsidase alfa have not been shown to be associated with any clinically significant effects on safety (e.g. infusion reactions) or efficacy.

This medicinal product has been authorised under “Exceptional Circumstances”. This means that due to the rarity of the disease it has not been possible to obtain complete information on this medicinal product.

The European Medicines Agency will review any new information which may become available every year and this SPC will be updated as necessary.

Single doses ranging from 0.007 - 0.2 mg enzyme per kg body weight were administered to adult male patients as 20 - 40 minute intravenous infusions while female patients received 0.2 mg enzyme per kg body weight as 40 minute infusions. The pharmacokinetic properties were essentially unaffected by the dose of the enzyme. Following a single intravenous dose of 0.2 mg/kg, agalsidase alfa had a biphasic distribution and elimination profile from the circulation. Pharmacokinetic parameters were not significantly different between male and female patients. Elimination half-lives were 108 ± 17 minutes in males compared to 89 ± 28 minutes in females and volume of distribution was approximately 17% body weight in both sexes. Clearance normalised for body weight was 2.66 and 2.10 ml/min/kg for males and females, respectively. Based on the similarity of pharmacokinetic properties of agalsidase alfa in both males and females, tissue distribution in major tissues and organs is also expected to be comparable in male and female patients.

Following six months of Replagal treatment 12 of 28 male patients showed altered pharmacokinetics including an apparent increase in clearance. These changes were associated with the development of low titre antibodies to agalsidase alfa but no clinically significant effects on safety or efficacy were observed in the patients studied.

Based on the analysis of pre- and post-dose liver biopsies in males with Fabry Disease, the tissue half-life has been estimated to be in excess of 24 hours and hepatic uptake of the enzyme estimated to be 10% of administered dose.

Agalsidase alfa is a protein and is therefore: 1) not expected to bind to proteins, 2) expected that metabolic degradation will follow the pathways of other proteins, i.e. peptide hydrolysis, 3) unlikely to be a candidate for drug-drug interactions.

Renal impairment

Renal elimination of agalsidase alfa is considered to be a minor clearance pathway since pharmacokinetic parameters are not altered by impaired renal function.

Hepatic impairment

As metabolism is expected to occur by peptide hydrolysis, impaired liver function is not expected to affect the pharmacokinetics of agalsidase alfa in a clinically significant manner.

Paediatric population

In children (aged 7-18 years), Replagal administered at 0.2 mg/kg was cleared faster from the circulation than in adults. Mean clearance of Replagal in children aged (7-11 years), in adolescents (aged 12-18 years), and adults was 4.2 ml/min/kg, 3.1 ml/min/kg, and 2.3 ml/min/kg, respectively. Pharmacodynamic data suggest that at a dose of 0.2 mg/kg Replagal, the reductions in plasma Gb₃ are more or less comparable between adolescents and young children (see section 5.1).

Non-clinical data reveal no special hazard for humans based on studies of repeated dose toxicity. Genotoxic and carcinogenic potential are not expected. Reproduction toxicity studies in female rats and rabbits have shown no effect on pregnancy or the developing foetus. No studies have been conducted with respect to parturition or peri/post-natal development. It is not known whether Replagal crosses the placenta.

Sodium phosphate monobasic, monohydrate

Polysorbate 20

Sodium chloride

Sodium hydroxide

Water for injections

In the absence of compatibility studies this medicinal product must not be mixed with other medicinal products.

2 years

Chemical and physical in use stability has been demonstrated for 24 hours at 25°C.

From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2 to 8°C, unless dilution has taken place in controlled and validated aseptic conditions.

Store in a refrigerator (2°C – 8°C).

1 ml of concentrate for solution for infusion in a 3 ml vial (Type I glass) with a stopper (fluoro-resin coated butyl rubber), a one piece seal (aluminium) and flip-off cap. Pack sizes of 1, 4 or 10 vials.

3.5 ml of concentrate for solution for infusion in a 5 ml vial (Type I glass) with a stopper (fluoro-resin coated butyl rubber), a one piece seal (aluminium) and flip-off cap. Pack sizes of 1, 4 or 10 vials.

Not all pack sizes may be marketed.

• Calculate the dose and number of Replagal vials needed.

• Dilute the total volume of Replagal concentrate required in 100 ml of 9 mg/ml (0.9%) sodium chloride solution for infusion. Care must be taken to ensure the sterility of the prepared solutions since Replagal does not contain any preservative or bacteriostatic agent; aseptic technique must be observed. Once diluted, the solution should be mixed gently but not shaken.

• Since no preservative is present, it is recommended that administration is started as soon as possible after dilution.

• The solution should be inspected visually for particulate matter and discolouration prior to administration.

• For single use only. Any unused product or waste material should be disposed of in accordance with local requirements.

Shire Human Genetic Therapies AB, Svärdvägen 11 D, 182 33 Danderyd, Sweden

Tel: +46 8 5449 6400

Fax: +46 8 5449 6429

EU/1/01/189/001-006

Date of first authorisation: 03/08/2001

Date of last renewal: 03/08/2006

Detailed information on this medicinal product is available on the website of the European Medicines Agency (EMA) http://www.ema.europa.eu/.