Data Sheet

Replagal

Agalsidase alfa 1 mg/ml concentrate for solution for infusion.

Qualitative and Qualitative Composition

Qualitative Composition

Each vial contains 3.5mg agalsidase alfa.

The concentrate must be diluted further; see "Instructions for use and handling".

See "Pharmacuetical Particulars" for the list of excipients. This contains no preservative.

Pharmaceutical Form

Concentrate for solution for infusion.

Clinical Particulars

Therapeutic indications

Replagal is indicated for long-term enzyme replacement therapy adult patients (>18years) with a confirmed diagnosis of Fabry Disease (α-galactosidase A deficiency).

Posology and method of administration

Posology

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

Method of Administration

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

For preparation and administration instructions see " Instructions for use, handling and administration"

Contraindications

Life-threatening hypersensitivity (anaphylactic reaction) to the active substance or any of the excipients.

Special Warnings and Special Precautions for Use

In approximately 10% of patients, Replagal has been associated with mild, acute idiosyncratic infusion effects, during or within one hour following infusion. The most common symptoms have been chills and facial flushing. Onset of symptoms has generally occurred 2-4 months after initiation of treatment with Replagal. These effects are most likely related to the rate of infusion of Replagal, since the incidence of infusion reactions was markedly higher when a shorter infusion time of 20 minutes was used. 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 reactions are possible. If severe allergic or anaphylactic-type reactions occur, immediate discontinuation of Replagal should be considered and an appropriate treatment has to be 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 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.

No studies have been performed in patients with hepatic impairment.

Interaction with Other Medicinal Products and Other Forms of Interaction

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

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 (see Section 5.3). It is not known whether Replagal is excreted in human milk. Caution should be exercised when prescribing to pregnant or nursing women.

Children adolescents and elderly

Studies in children and adolescents (0-17 years) or 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.

Effects on ability to drive and use machines

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

Undesirable Effects

The most commonly reported undesirable effects were associated with infusion reactions which occurred in approximately 10% of patients treated in clinical trials. Most undesirable effects were mild to moderate in severity and the majority were consistent with the natural course of Fabry Disease.

Table 1 lists those adverse drug reactions (ADRs) reported for the 40 patients treated with agalsidase alfa in clinical trials where causality is at least suspected in one or more cases (see 5.1). Information is presented by system organ class and frequency (very common >1/10; common >1/100, <1/10). The occurrence of an event in a single patient is defined as common in view of the number of patients treated. A single patient could be affected by several ADRs.

Table 1

In pre-approval clinical trials approximately 10% agalsidase alfa treated patients have experienced an idiosyncratic infusion-related effect (see 4.4). These effects have decreased with time. Symptoms have included predominantly rigors (chills) and facial flushing with a few patients experiencing headache, dyspnoea, abdominal pain, nausea or chest pain. No changes in vital signs or urticaria have accompanied these reactions. All symptoms resolved with appropriate intervention, such as, stopping the infusion prior to restarting or medical therapy with antihistamines and corticosteroids.

Considering the rarity of Fabry Disease and the relatively limited number of patients exposed to agalsidase alfa to date, health-care professionals should be aware of the occurrence of the following adverse events observed in this patient population that were considered unrelated to agalsidase alfa: anxiety, bronchospasm, constipation, decreased hearing, dyspepsia, ear ache, flatulence, hypoaesthesia, impaired concentration, involuntary muscle contractions, leg pain, malaise, melaena, palpitation, purpura, sinusitis, unspecified infection, upper respiratory tract infection, urinary retention, and vertigo.

An increase in the frequency of some events considered unrelated to treatment was reported following 6 to 12 months of therapy, none were considered serious. Most events were associated with Fabry Disease such as gastrointestinal disorders, changed temperature sensation / heat intolerance and dyspnoea. Events that were not reported in placebo controlled trials but were observed after longer term treatment include asthenia.

Overdose

No case of overdose has been reported.

Pharmacological Properties

Pharmacodynamic properties

Pharmacotherapeutic group: Other alimentary tract and metabolism products - Enzymes

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.

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. No women or children were included in clinical trials.

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.

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 treated 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).

In a second study, fifteen patients with left ventricular enlargement 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.

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.

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

Pharmacokinetic properties

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. 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. The elimination half-life of the protein from the blood was approximately 108 ± 17 minutes. Plasma clearance was approximately 193 ± 97 ml/minute and the volume of distribution was approximately body weight. Following six months of Replagal treatment 12 of 28 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 were observed in the patients studied.

Based on the analysis of pre- and post-dose liver biopsies in adults 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, ie peptide hydrolysis, 3) unlikely to be a candidate for drug-drug interactions.

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

Preclinical safety data

Preclinical 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.

Pharmaceutical Particulars

List of excipients

Sodium phosphate monobasic, monohydrate
Polysorbate 20
Sodium chloride
Sodium hydroxide
Water for injections

Incompatibilities

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

Shelf life

1 year

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.

Special precautions for storage

Store at 2°C - 8°C (in a refrigerator).

Nature and contents of container

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

Carton containing 1 vial.

Instructions for use, handling and disposal.

1. Calculate the dose and number of Replagal vials needed. Each Replagal vial contains 3.5 mg agalsidase alfa.
2. Dilute the total volume of Replagal concentrate required in 100 ml of 9mg/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.
3. The solution should be inspected visually for particulate matter and discolouration prior to administration.
4. Administer the infusion solution over a period of 40 minutes using an intravenous line with an integral filter (0.2 micron). Since no preservative is present, it is recommended that administration is started as soon as possible and within 3 hours of dilution.
5. Do not infuse Replagal concomitantly in the same intravenous line with other agents.
6. For single use only. Any unused product or waste material should be disposed of in accordance with local requirements.
7. No dose adjustment is necessary in patients with renal impairment.

Medicine Classification

Prescription Medicine

Name and Address

New Zealand sponsor

Pharmacy Retailing Limited trading as Healthcare Logistics
(on behalf of Orphan Australia Pty Ltd)
58 Richard Pearse DRive
Airport Oaks
Auckland
New Zealand

Marketing Authorisation Holder

Orphan Australia Pty. Ltd.
12 Langmore Lane
Berwick
Victoria 3806
AUSTRALIA

Date of Preparation

4 September 2007

Original SmPC Version 5.1 January 2001