Replagal - Letter to Health Professionals

2004-02-06

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Contact: Regulatory Affairs Division

January 2004

Re: Conditional approval of Replagal™ in Fabry Disease

Dear Health Care Professional:

Transkaryotic Therapies, Inc. is pleased to announce that Health Canada has granted a Notice of Compliance with Conditions (NOC/c) for Replagal (agalsidase alfa) for long-term enzyme replacement therapy in patients with a confirmed diagnosis of Fabry Disease (α-galactosidase A deficiency).

Fabry Disease is an X-linked 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 catalyzes 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.

Agalsidase alfa is the human protein a-galactosidase A produced by Gene Activation technology in a human cell line.

Replagal treatment should initially be supervised by a physician experienced in the management of patients with Fabry Disease or other inherited metabolic diseases. Replagal is intended for long term, chronic use under the guidance and supervision of a physician. Home infusion has been safely performed.

Replagal is administered at a dose of 0.2 mg/kg body weight every other week by intravenous infusion over 40 minutes. Replagal shows promising preliminary evidence of efficacy for treatment of patients with Fabry Disease; however, the optimal individual dose requires further investigation. Studies are underway to evaluate more frequent and/or higher doses of Replagal therapy.

Patients should be advised of the conditional nature of the market authorization for Replagal. Replagal is contraindicated in patients who develop a life-threatening hypersensitivity (anaphylactic reaction) to the active substance or any of the excipients.

The safety and efficacy of Replagal was assessed in two randomized, double-blind placebo controlled studies and open label extension studies. These studies indicated significant reductions in pain as measured by the Brief Pain Inventory, improvement of renal function, reduction in cardiac mass in patients with left ventricular hypertrophy, as well as clinically significant weight gain, increased sweating, and increased energy.

In approximately 10% of patients, Replagal has been associated with mild, acute idiosyncratic infusion reactions, during or within one hour following infusion. The most common symptoms have been chills and facial flushing. Severe infusion reactions have not been commonly reported. Symptoms reported include nausea, pyrexia, rigors, tachycardia, urticaria and vomiting. Such reactions have generally occurred within the first 2-4 months after initiation of treatment with Replagal. 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 pre-treatment, generally with oral antihistamines and corticosteroids, from 1 to 3 hours prior to infusion has prevented subsequent reactions in those cases where symptomatic treatment was required.

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.

As with all protein pharmaceutical products, patients may develop antibodies to the protein. A low titre IgG antibody response has been observed in approximately 55% of the patients treated with Replagal. The antibodies appear to develop following approximately 3 months of treatment. After 12 to 18 months of therapy, 60% of patients are antibody free and >80% of patients who were antibody positive showed evidence for the development of immunologic tolerance, based on the reduction of antibody titres over time.

Post-marketing safety experience with the use of commercial Replagal is similar to that which has been reported in clinical trials. The most commonly reported adverse drug reactions have been infusion related reactions or infusion associated symptoms and were mild to moderate in severity. Symptoms have predominantly included chills (rigors) and facial flushing with a small number of patients experiencing headache, dyspnoea, fever, urticaria and diarrhoea. All symptoms resolved either with or without intervention. Reported intervention has included temporarily stopping the infusion for a few minutes prior to restarting, restarting the infusion at a slower rate, medical treatment with analgesics, antipyretics, antihistamines and/or corticosteroids. In some cases subsequent infusions were premedicated, which after a limited period was successfully withdrawn.

No formal drug interaction studies have been conducted with Replagal, however interactions with other drugs, herbs or laboratory tests have not been established.

An open label study has been started to evaluate the safety and pharmacokinetics of Replagal over a 12 month duration in Fabry children between 7 to 17 years of age, at 0.2 mg/kg agalsidase alfa biweekly. To date six patients have completed the initial 6 month trial and all have received an additional 6 months of therapy in an extension trial. Pharmacokinetic parameters after the first dose were generally consistent with results for adult Fabry patients. In addition, pharmacokinetic parameters in all 6 children remained relatively unchanged after 6 months of therapy.

Studies in patients over the age of 65 have not been performed. For Replagal, no clinical data on exposed pregnancies are available. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy or embryonal/foetal development when exposed during organogenesis. It is not known whether Replagal is excreted in human milk.

The benefit versus risk balance should be considered carefully before prescribing Replagal to pregnant or nursing women, children or the elderly.

No special laboratory tests are required for patients receiving Replagal, other than the usual tests that are required for monitoring patients with Fabry Disease.

Replagal has a shelf life of 2 years and should be stored in a refrigerator (2 to 8 °C). After dilution, the product should be administered immediately, within 3 hours. However, the chemical and physical stability of the diluted solution has been demonstrated for 24 hours at 25 °C.

Please contact our Medical Information Department located at Paladin Labs Inc. at 1-888-550-6060 should you have any medical inquiries regarding Replagal.

John T. Flaherty, MD
Executive Director, Clinical Research

Product Monograph available to physicians, pharmacists and health care practitioners upon request.