4.1. Therapeutic indications

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

4.2. Posology and method of administration

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.

Special populations

Elderly patients

Studies in patients over the age of 65 years 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 safety and efficacy of Replagal in children aged 0-6 years has not yet been established. Currently available data are described in section 5.1 but no recommendation on posology can be made.

In clinical studies of children (7-18 years) who received Replagal 0.2 mg/kg every other week, no unexpected safety issues were encountered (see section 5.1).

Method of administration

For instructions on dilution 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.

Replagal home infusion, and administration by the patient in presence of a responsible adult or administration by the patient's caregiver (self-administration), may be considered for patients who are tolerating their infusions well. The decision to have a patient move to home infusion and/or self‑administration should be made after evaluation and recommendation by the treating physician.

Appropriate training should be given by the treating physician and/or nurse to the patient and/or caregiver prior to initiation of self-administration. Dose and infusion rate should remain constant while at home, and not be changed without supervision of a healthcare professional. Self‑administration should be closely followed by the treating physician.

Any patients experiencing adverse events during the home infusion/self-administration need to immediately stop the infusion process and seek the attention of a healthcare professional. Subsequent infusions may need to occur in a clinical setting.

4.3. Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

4.4. Special warnings and precautions for use

Traceability

In order to improve the traceability of biological medicinal products, the name and batch number of the administered product should be clearly recorded.

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 years 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 years of age, 0/7 male patients tested positive for IgG anti-agalsidase alfa antibodies. 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.

Sodium

This medicinal product contains 14.2 mg sodium per vial, equivalent to 0.7 % of the WHO recommended maximum daily intake of 2 g sodium for an adult.

Polysorbate 20

This medicinal product contains 0.836 mg of polysorbate 20 in each vial which is equivalent to 0.22 mg/ml. Polysorbates may cause allergic reactions.

4.5. 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.

4.6. Fertility, pregnancy and lactation

Pregnancy

There is very limited data on pregnancies exposed to Replagal. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy or embryonic/fetal development when exposed during organogenesis (see Section 5.3). Caution should be exercised when prescribing to pregnant women.

Breast-feeding

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

Fertility

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

4.7. Effects on ability to drive and use machines

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

4.8. Undesirable effects

Summary of safety profile

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.

Tabulated list of adverse reactions

Table 1 lists adverse reactions reported for the 344 patients treated with Replagal in clinical trials, including 21 patients with history of end stage renal disease, 30 paediatric patients (≤18 years of age) and 98 female patients, and from post-marketing spontaneous reports. Information is presented by system organ class and frequency (very common ≥1/10; common ≥1/100 to <1/10; uncommon ≥1/1 000 to <1/100). The adverse reactions categorized as incidence “not known (cannot be estimated from the available data)” are derived from post-marketing spontaneous reports. 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 adverse reactions.

The following adverse reactions have been identified for agalsidase alfa:

Table 1

System organ class

Adverse reaction

Very common

Common

Uncommon

Not known

Metabolism and nutrition disorders

peripheral oedema

Nervous system disorders

headache, dizziness, neuralgia, tremor, hypoesthesia, paraesthesia

dysgeusia, hypersomnia

parosmia

Eye disorders

lacrimation increased

corneal reflex decreased

Ear and labyrinth disorders

tinnitus

tinnitus aggravated

Cardiac disorders

palpitations

tachycardia, atrial fibrillation

tachyarrhythmia

myocardial ischaemia, cardiac failure, ventricular extrasystoles

Vascular disorders

hypertension, hypotension, flushing

Respiratory, thoracic and mediastinal disorders

dyspnoea, cough, nasopharyngitis, pharyngitis

dysphonia, throat tightness, rhinorrhoea

oxygen saturation decreased, increased upper airway secretion

Gastrointestinal disorders

vomiting, nausea, abdominal pain, diarrhoea

abdominal discomfort

Skin and subcutaneous tissue disorders

rash

urticaria, erythema, pruritus, acne, hyperhidrosis

angioedema, livedo reticularis

Musculoskeletal, connective tissue and bone disorders

arthralgia, pain in extremity, myalgia, back pain

musculoskeletal discomfort, peripheral swelling, joint swelling

sensation of heaviness

Immune system disorders

hypersensitivity

anaphylactic reaction

General disorders and administration site conditions

chest pain, chills, pyrexia, pain, asthenia, fatigue

chest discomfort, fatigue, feeling hot, feeling cold, influenza like illness, discomfort, malaise

injection site rash

See also section 4.4.

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, dyspnoea, 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.

Other special populations

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.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme, Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

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.