Replagal: detailed information

INSTRUCTION for medical use of the medicinal product Replagal (Replagal)

Composition:

Active substance: agalsidase alfa;

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

1 vial with 3.5 ml of concentrate contains 3.5 mg of agalsidase alfa;

Excipients: sodium dihydrogen phosphate monohydrate; polysorbate 20; sodium chloride; sodium hydroxide; water for injections.

Pharmaceutical form. Concentrate for solution for infusion.

Main physicochemical properties: clear, colorless solution.

Pharmacotherapeutic group. Drugs for the treatment of gastrointestinal disorders and metabolic disturbances. Enzymes.

ATC code A16A B03.

Pharmacological Properties

Pharmacodynamics

Mechanism of action

Fabry disease is a glycosphingolipid storage disorder caused by deficient activity of the lysosomal enzyme α-galactosidase A, resulting in the accumulation of globotriaosylceramide (Gb3, also known as GL-3 or globotriaosylceramide, GbO3), the glycosphingolipid substrate of the enzyme. Agalsidase alfa catalyzes the hydrolysis of Gb3 by cleaving the terminal galactose residue from the molecule. Enzyme replacement therapy has been shown to reduce Gb3 accumulation in multiple cell types, including endothelial and parenchymal cells. Agalsidase alfa is produced in a human cell line to ensure a human glycosylation profile, which may influence uptake via the mannose-6-phosphate receptors on the surface of target cells. The selected dose of 0.2 mg/kg (administered as a 40-minute infusion) for registration clinical trials was justified by the potential for transient saturation of mannose-6-phosphate receptors in the liver, allowing distribution of the enzyme to tissues of other organs. Data indicate that a dose of at least 0.1 mg/kg is required to achieve a pharmacodynamic response.

Clinical efficacy and safety

The safety and efficacy of Replagal were evaluated in two randomized, double-blind, placebo-controlled studies and open-label extension studies involving a total of 40 patients with Fabry disease confirmed by clinical and biochemical criteria. Patients received the recommended dose of 0.2 mg/kg. Twenty-five patients completed the first study and entered the extension studies. After 6 months of therapy, patients treated with Replagal showed a significant reduction in pain compared to the placebo group (p = 0.021) as assessed by a validated pain scoring scale. This was accompanied by a significant reduction in the dosage and duration of medications used for chronic neuropathic pain. In subsequent studies in male pediatric patients aged 7 years and older, pain reduction was observed at 9 and 12 months of Replagal therapy compared to baseline. This pain reduction was sustained over 4 years of Replagal therapy in 9 patients (aged 7–18 years).

Treatment with Replagal for 12–18 months resulted in improvement in quality of life (QoL), as assessed by validated methods.

After 6 months of Replagal therapy, kidney function stabilized compared to a decline in patients receiving placebo. Kidney biopsies revealed a significant increase in the proportion of normal glomeruli and a significant reduction in the proportion of glomeruli with mesangial expansion in Replagal-treated patients compared to those receiving placebo. Replagal improved kidney function, as measured by inulin clearance, by 8.7 ± 3.7 mL/min (p = 0.030).

Longer-term therapy leads to stabilization of GFR in male patients with baseline values within the normal range (≥ 90 mL/min/1.73 m²) and with mild to moderate kidney dysfunction (GFR from 60 to < 90 mL/min/1.73 m²), as well as slowing the rate of decline in kidney function and progression to end-stage renal disease in male patients with more severe kidney dysfunction (GFR from 30 to < 60 mL/min/1.73 m²).

In the second study, 15 patients with left ventricular hypertrophy completed a 6-month placebo-controlled study and were included in extension studies. In the controlled study, Replagal treatment resulted in a reduction of left ventricular mass by 11.5 g as measured by magnetic resonance imaging, while patients receiving placebo showed an increase in left ventricular mass by 21.8 g. Additionally, in the first study involving 25 patients, Replagal administration led to a significant reduction in heart mass over 12–18 months of established therapy (p < 0.001). Replagal also improved myocardial contractility, reduced mean QRS duration, and simultaneously decreased septal thickness as assessed by ECG. In the conducted studies, two patients with right bundle branch block returned to normal ECG findings after Replagal therapy. In subsequent open-label studies, ECG data showed a significant reduction in left ventricular mass compared to baseline values in patients with Fabry disease of both sexes over 24–36 months of Replagal treatment, accompanied by significant symptom improvement compared to baseline as measured by NYHA and CCS classifications in patients with severe heart failure or angina symptoms.

Compared to placebo, Replagal treatment also reduced Gb3 accumulation. Within the first 6 months of therapy, Gb3 levels decreased by approximately 20–50% in plasma, urinary sediment, and biopsy samples of liver, kidney, and heart. After 12–18 months of treatment, reductions of 50–80% were observed in plasma and urinary sediment. Metabolic effects were also accompanied by clinically significant increases in body weight, sweating, and energy levels. Consistent with the clinical effects of Replagal, enzyme replacement therapy reduced Gb3 accumulation in multiple tissue types, including glomerular and tubular epithelial cells of the kidney, endothelial cells of renal capillaries (cardiac and skin capillary endothelial cells were not studied), and cardiac myocytes. In male pediatric patients with Fabry disease, after 6 months of therapy with 0.2 mg/kg Replagal, plasma Gb3 levels decreased by 40–50%, and this reduction was maintained over 4 years of treatment in 11 patients.

For patients who tolerate infusions well, treatment at home may be considered.

Children

In male pediatric patients with Fabry disease aged ≥ 7 years, the earliest sign of kidney involvement may be hyperfiltration. Elevated eGFR values above normal range decreased within 6 months after initiation of Replagal therapy. In this subgroup, after one year of treatment with 0.2 mg/kg agalsidase alfa weekly, abnormally high eGFR values decreased from 143.4 ± 6.8 to 121.3 ± 5.6 mL/min/1.73 m². These eGFR values remained stably within the normal range over 4 years of therapy with 0.2 mg/kg Replagal, indicating absence of hyperfiltration.

In male pediatric patients aged ≥ 7 years, heart rate was abnormal at baseline and improved after 6 months of Replagal therapy in 15 boys. In an open-label long-term extension study in 9 boys, improvement was maintained over 6.5 years of Replagal therapy at 0.2 mg/kg. Among 9 boys with height-corrected left ventricular mass index (LVMI) within the normal range for children at baseline (< 39 g/m in boys), LVMI remained stable at levels below the threshold for left ventricular hypertrophy (LVH) over 6.5 years of treatment. In the second study involving 14 patients aged ≥ 7 years, heart rate findings were consistent with previous data. In this study, only one patient had LVH at baseline, which remained stable throughout the observation period.

In patients aged 0 to 7 years, based on limited data, no specific safety-related findings were observed.

Studies in patients switched from agalsidase beta to Replagal (agalsidase alfa)

In an open-label, uncontrolled study over a period of up to 30 months, 100 patients were treated (previously untreated (n=29) or previously treated with agalsidase beta and switched to Replagal (n=71)). Analysis showed serious adverse events occurred in 39.4% of patients switched from agalsidase beta therapy, compared to 31.0% of patients who had not received prior treatment.

The safety profile for patients switched from agalsidase beta to Replagal was consistent with that established in other clinical observations. Infusion-related reactions occurred in 9 patients in the previously untreated group (31.0%) compared to 27 patients in the group switched from another enzyme (38.0%).

Studies with different dosing regimens

In an open-label, randomized study, no statistically significant differences were observed between groups in changes from baseline in mean LVMI or other endpoints (cardiac function status, kidney function, and pharmacological activity) in adult patients who received 0.2 mg/kg intravenously every other week (n=20) versus those receiving 0.2 mg/kg weekly (n=19) over 52 weeks. In each treated group, LVMI remained stable throughout the study period. Overall assessment of serious adverse reactions showed no obvious impact of dosing regimen on the serious adverse reaction profile across groups.

Immunogenicity

The development of antibodies to agalsidase alfa has not been associated with clinically significant effects on safety (e.g., infusion reactions) or efficacy.

Pharmacokinetics

Single doses of 0.007–0.2 mg/kg of enzyme were administered to male adult patients as 20–40-minute intravenous infusions, while female patients received 0.2 mg/kg enzyme over 40-minute infusions. Enzyme dose did not significantly affect pharmacokinetic properties. After a single intravenous dose of 0.2 mg/kg, agalsidase alfa exhibited a biphasic distribution and elimination profile from the bloodstream. Pharmacokinetic parameters differed only slightly between male and female patients. Elimination half-life was 108 ± 17 minutes in males compared to 89 ± 28 minutes in females, and volume of distribution was approximately 17% of body weight in patients of both sexes. Body weight-normalized clearance was 2.66 and 2.10 mL/min/kg in males and females, respectively. Given the similarity in pharmacokinetic properties of agalsidase alfa in males and females, similar tissue and organ distribution can be expected in both male and female patients.

After six months of Replagal treatment, changes in pharmacokinetics, including a significant increase in clearance, were observed in 12 of 28 male patients. These changes were associated with the development of low-titer antibodies to agalsidase alfa, but no clinically significant impact on efficacy or safety was observed in these patients.

Based on liver biopsy analyses in men with Fabry disease before and after treatment, the tissue half-life exceeds 24 hours, and hepatic uptake of the enzyme is estimated at 10% of the administered dose.

Agalsidase alfa is a protein. Protein binding is not expected. Its metabolic degradation is believed to occur via pathways typical for other proteins, i.e., peptide hydrolysis. Agalsidase alfa is unlikely to be involved in drug interactions.

Renal impairment

Renal elimination of agalsidase alfa is considered to occur with negligible clearance, as pharmacokinetic parameters do not change in patients with impaired kidney function.

Hepatic impairment

Since metabolism is believed to occur via peptide hydrolysis, it is unlikely that hepatic impairment would have a clinically significant effect on the pharmacokinetics of agalsidase alfa.

Children

In children aged 7–18 years, Replagal administered at 0.2 mg/kg was cleared from the bloodstream faster than in adults. Mean clearance of Replagal in children aged 7–11 years, 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 confirm that at a dose of 0.2 mg/kg, Gb3 reduction in adolescents and younger children is broadly comparable (see section "Pharmacodynamics").

Clinical characteristics.

Indications.

Long-term enzyme replacement therapy in patients with a confirmed diagnosis of Fabry disease (α-galactosidase deficiency).

Contraindications.

Hypersensitivity to the active substance or to any of the excipients.

Interaction with other medicinal products and other forms of interaction.

Replagal should not be used concomitantly with chloroquine, amiodarone, benoxine, or gentamicin, as these substances have the ability to inhibit intracellular α-galactosidase activity.

Since α-galactosidase A is an enzyme itself, it is unlikely to be involved in drug interactions mediated by cytochrome P450. Clinical trials have shown that in most patients, concomitant administration of neuropathic agents (such as carbamazepine, phenytoin, and gabapentin) is not associated with any manifestations of interaction.

Special Warnings and Precautions for Use

Traceability

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

Infusion-Related Reactions

Infusion-related reactions occurred in 13.7% of adult patients receiving Replagal in clinical trials. Four out of 17 (23.5%) pediatric patients aged ≥ 7 years included in clinical studies experienced at least one infusion reaction during 4.5 years of treatment (mean duration approximately 4 years). Three out of 8 (37.5%) pediatric patients aged ˂ 7 years experienced at least one infusion reaction over a mean observation period of 4.2 years. The most commonly reported symptoms were fever, headache, nausea, hyperthermia, flushing, and fatigue. Serious infusion-related reactions have been reported rarely and included hyperthermia, fever, tachycardia, urticaria, nausea/vomiting, angioedema with throat tightness, stridor, and tongue swelling. Other infusion-related symptoms may include dizziness and hyperhidrosis. Analysis of cardiac manifestations has shown that infusion reactions may be associated with hemodynamic stress, which may trigger cardiac events in patients with pre-existing cardiac manifestations of Fabry disease.

Infusion-related reactions generally occurred within the first 2–4 months after initiation of Replagal treatment, although later occurrences (after 1 year) have also been reported. These effects tend to diminish over time. If mild or moderate acute infusion reactions occur, immediate medical attention and appropriate interventions are required. Infusion should be temporarily interrupted (for 5–10 minutes) until symptoms subside, after which it may be resumed. Mild and transient effects may not require medical intervention or interruption of the infusion. Additionally, if necessary, symptomatic treatment with oral or intravenous premedication with antihistamines and/or corticosteroids administered 1–24 hours prior to infusion may prevent the occurrence of such reactions.

Hypersensitivity Reactions

Hypersensitivity reactions have been reported. In the case of severe hypersensitivity or anaphylactic reactions, Replagal administration should be discontinued immediately and appropriate treatment initiated. Current medical standards for emergency care should be followed.

Antibodies to Protein

As with all protein pharmaceuticals, patients may develop antibodies to the protein. IgG antibodies were observed in 24% of male patients receiving Replagal. Based on limited data, this proportion appears lower (7%) in the male pediatric population. IgG antibodies are thought to develop after approximately 3–12 months of treatment. After 12–54 months of therapy, 17% of patients receiving Replagal remained antibody-positive, while 7% developed immunological tolerance, manifested by the disappearance of IgG antibodies over time.

The remaining 76% of patients were antibody-negative during this period. Among pediatric patients aged > 7 years, one out of 16 male patients tested positive for IgG anti-agalsidase alpha antibodies during the study. No increased incidence of adverse events was observed in this age group (> 7 years). Among pediatric patients aged < 7 years, all 7 male patients tested negative for IgG anti-agalsidase alpha antibodies. The presence of specific IgE antibodies observed in clinical trials involving a very small number of patients has not been associated with anaphylaxis.

Patients with Renal Impairment

Severe renal dysfunction may limit the kidney's response to enzyme replacement therapy due to existing irreversible pathological changes. In such cases, loss of kidney function remains within the expected range of the natural progression of the disease.

Sodium

This medicinal product contains 14.2 mg of sodium per vial, equivalent to 0.7% of the WHO recommended maximum daily intake of sodium for adults (2 g). Caution should be exercised when prescribing to patients on a sodium-controlled diet.

Use during Pregnancy or Breastfeeding

Pregnancy

Data on the use of Replagal in pregnant women are very limited. Animal studies have not shown any direct or indirect harmful effects on pregnancy or embryonic/fetal development when the drug was administered during organogenesis. Caution should be exercised when prescribing Replagal to pregnant women.

Breastfeeding

It is unknown whether Replagal is excreted in human breast milk. Caution should be exercised when administering the product to breastfeeding women.

Effects on Fertility

Reproductive studies in male rats showed no effect on fertility.

Ability to Affect Reaction Speed While Driving or Operating Machinery

Replagal has no effect or has a negligible effect on the ability to drive or operate machinery.

Administration and Dosage

Dosage

Replagal is administered at a dose of 0.2 mg/kg body weight once every week via intravenous infusion lasting 40 minutes using an intravenous administration set with an in-line filter. Do not administer Replagal infusion simultaneously in the same intravenous line with other medicinal products.

Administration method

Reconstitution procedure:

Calculate the required dose and number of Replagal vials needed.
Any dose adjustment must only be made under the direction of a physician.
Dilute the required volume of Replagal concentrate in 100 mL of 9 mg/mL (0.9%) sodium chloride solution for infusion. Care must be taken during preparation to maintain sterility of the solution, as Replagal does not contain preservatives or bacteriostatic agents; aseptic equipment must be used. After dilution, gently mix the solution, but do not shake.
Because no preservative is present, administration should be started as soon as possible after reconstitution (see section "Storage conditions").
Prior to administration, inspect the solution for the presence of particulate matter and discoloration.
For single use only. Unused materials or waste must be disposed of in accordance with local requirements.

Treatment with Replagal must be supervised by a physician experienced in managing patients with Fabry disease or other inherited metabolic disorders.

For patients who tolerate infusions well, administration at home and self-administration by the patient in the presence of a responsible adult or caregiver may be considered. The decision to transition a patient to home infusions and/or self-administration should be made following evaluation and recommendation by a physician.

Prior to transitioning to self-administration, the physician and/or nurse must provide appropriate training to the patient and/or caregiver. The dosage and infusion rate must remain unchanged at home and must not be modified without medical supervision. Self-administration must be performed under close medical supervision.

Patients who experience adverse reactions during infusion/self-administration at home must immediately stop the infusion and contact a healthcare professional. Subsequent infusions may need to be administered in a healthcare setting.

Elderly patients (≥ 65 years of age)

Clinical studies involving patients aged over 65 years have not been conducted, and therefore a dosing regimen cannot currently be recommended for this population, as safety and efficacy have not been established.

Hepatic impairment

Clinical studies in patients with hepatic impairment have not been conducted.

Renal impairment

No dose adjustment is required for patients with renal impairment.

Severe renal impairment (eGFR < 60 mL/min) may limit the kidney's response to enzyme replacement therapy. Limited data are available for patients on dialysis or after kidney transplantation; dose adjustment is not recommended.

Children

The use of this medicinal product in pediatric practice is permitted. The safety and efficacy of Replagal in children aged 0–6 years have not been established.

In clinical studies involving children (7–18 years of age) receiving Replagal at a dose of 0.2 mg/kg every two weeks, no unexpected safety events were observed.

Overdose

There have been no reports of overdose. In clinical trials, doses up to 0.4 mg/kg weekly were used, and the safety profile was not different from that observed with the recommended dose of 0.2 mg/kg weekly.

Side effects.

Short description of safety profile

The most commonly reported adverse reactions were infusion-related reactions occurring in 13.7% of adult patients in clinical trials. The majority of adverse events were mild to moderate in severity.

List of adverse reactions

Below is a list of adverse reactions reported in 344 patients who received Replagal in clinical trials, including 21 patients with a history of end-stage renal disease, 30 pediatric patients (under 18 years of age), and 17 female patients. The list also includes adverse reactions identified from post-marketing spontaneous reports. The information is presented by system organ class and frequency (very common ≥ 1/10; common ≥ 1/100 to < 1/10; uncommon ≥ 1/1000 to < 1/100). Adverse reactions with unknown frequency (cannot be estimated from available data) are derived from post-marketing spontaneous reports. Within each frequency grouping, adverse reactions are presented in order of decreasing severity. An event occurring in only one patient is classified as uncommon, considering the number of treated patients. Multiple adverse reactions could occur in a single patient.

Immune system disorders: common – hypersensitivity reactions; uncommon – anaphylactic reaction.

Nervous system disorders: very common – headache, dizziness, neuropathic pain, tremor, hypoesthesia, paraesthesia; common – dysgeusia, hypersomnia; uncommon – parosmia.

Cardiac disorders: very common – palpitations; common – tachycardia, atrial fibrillation; uncommon – tachyarrhythmia; unknown – myocardial ischemia, heart failure, ventricular extrasystoles.

Vascular disorders: common – flushing, hypertension, hypotension.

Gastrointestinal disorders: very common – nausea, vomiting, abdominal pain, diarrhea; common – abdominal discomfort.

Skin and subcutaneous tissue disorders: very common – rash; common – urticaria, acne, erythema, pruritus, hyperhidrosis; uncommon – livedo reticularis, angioneurotic edema.

Musculoskeletal and connective tissue disorders: very common – arthralgia, limb pain, myalgia, back pain; common – musculoskeletal discomfort, peripheral edema, joint swelling; uncommon – feeling of heaviness.

General disorders and administration site conditions: very common – chest pain, chills, hyperthermia, pain, asthenia, fatigue; common – chest tightness, increased fatigue, hot flush, cold sensation, influenza-like illness, malaise, discomfort; uncommon – injection site rash.

Respiratory, thoracic and mediastinal disorders: very common – dyspnea, cough, nasopharyngitis, pharyngitis; common – hoarseness, throat tightness, rhinorrhea; uncommon – decreased oxygen saturation, excessive mucus production in throat.

Ear and labyrinth disorders: very common – tinnitus; common – severe tinnitus.

Eye disorders: common – increased lacrimation; uncommon – decreased corneal reflex.

Metabolism and nutrition disorders: very common – peripheral edema.

Description of selected adverse reactions

Infusion-related reactions reported during post-marketing surveillance may include cardiac events such as cardiac arrhythmia (atrial fibrillation, ventricular extrasystoles, tachyarrhythmia), myocardial ischemia, and heart failure in patients with Fabry disease and cardiac involvement. The most common infusion-related reactions were mild and included chills, hyperthermia, flushing, headache, nausea, dyspnea, tremor, and pruritus. Other symptoms associated with infusion may include dizziness, hyperhidrosis, hypotension, cough, vomiting, and fatigue. Hypersensitivity reactions, including anaphylaxis, have been reported.

Patients with renal disease

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

Pediatric population

Adverse reactions reported in pediatric patients (children and adolescents) were generally similar to those in adults. However, infusion-related reactions (hyperthermia, dyspnea, chest pain) and exacerbation of pain occurred more frequently.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after marketing authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, patients, and their legal representatives should report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.

Shelf life. 2 years.

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

Storage conditions.

Store in the original packaging in a refrigerator (at 2–8 °C).

Keep out of the reach of children.

From a microbiological standpoint, the diluted preparation should be used immediately. If not used immediately, the storage period and conditions prior to use are the responsibility of the user and must not exceed 24 hours at a temperature of 2 to 8 °C.

Packaging.

5 ml vial (Type I glass) with a stopper (butyl rubber with fluorinated coating), aluminum seal, and removable cap. One vial per cardboard box.

Prescription category. Prescription only.

Manufacturer.

Takeda Pharmaceuticals International AG Ireland Branch.

Manufacturer's address and place of business.

Block 2 Mezzanine Plaza, 50-58 Baggot Street Lower, Dublin 2, D02 HW68, Ireland.

INSTRUCTIONS

for medical use of the medicinal product

Replagal

(Replagal)

Composition:

Active substance: agalsidase alfa;

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

1 vial containing 3.5 ml of concentrate contains 3.5 mg of agalsidase alfa;

Excipients: monosodium phosphate monohydrate; polysorbate 20; sodium chloride; sodium hydroxide; water for injections.

Pharmaceutical form. Concentrate for solution for infusion.

Main physicochemical properties: clear, colorless solution.

Pharmacotherapeutic group. Medicinal products for the treatment of gastrointestinal disorders and metabolic disturbances. Enzymes.

ATC code A16AB03.

Pharmacological Properties.

Pharmacodynamics.

Mechanism of action.

Fabry disease is a glycosphingolipid storage disorder caused by deficient activity of the lysosomal enzyme α-galactosidase A, resulting in the accumulation of globotriaosylceramide (Gb3, or GL-3, also known as ceramide trihexoside (CTH)). Agalsidase alfa catalyzes the hydrolysis of Gb3 by cleaving the terminal galactose residue from the molecule. Enzyme replacement therapy has been shown to reduce Gb3 accumulation in multiple cell types, including endothelial and parenchymal cells. Agalsidase alfa is produced in a human cell line to ensure a human glycosylation profile, which may influence uptake via the mannose-6-phosphate receptors on the surface of target cells. The dose of 0.2 mg/kg (administered as a 40-minute infusion) used in registration clinical trials was selected based on the capacity to temporarily saturate mannose-6-phosphate receptor uptake in the liver, allowing distribution of the enzyme to tissues of other organs. Available data indicate that a dose of at least 0.1 mg/kg is required to achieve a pharmacodynamic response.

Clinical efficacy and safety

The safety and efficacy of Replagal were evaluated in two randomized, double-blind, placebo-controlled trials and open-label extension studies involving a total of 40 patients with Fabry disease diagnosed based on clinical and biochemical criteria. Patients received the recommended dose of 0.2 mg/kg. Twenty-five patients completed the first study and entered the extension studies. After 6 months of therapy, patients treated with Replagal showed a significant reduction in pain compared to the placebo group (p = 0.021) as assessed by a validated pain scoring scale. This was accompanied by a significant reduction in the dosage and duration of medications used for chronic neuropathic pain. In subsequent studies in male pediatric patients aged 7 years and older, pain reduction was observed at 9 and 12 months of Replagal therapy compared to baseline values before treatment. This pain reduction was sustained over 4 years of Replagal therapy in 9 patients (aged 7–18 years).

Treatment with Replagal for 12–18 months led to improvement in quality of life (QoL), assessed using validated methods.

After 6 months of Replagal therapy, renal function stabilized compared to a decline observed in patients receiving placebo. Kidney biopsies revealed a significant increase in the proportion of normal glomeruli and a significant reduction in the proportion of glomeruli with mesangial expansion in Replagal-treated patients compared to those receiving placebo. Replagal improved renal function, as measured by inulin clearance, by 8.7 ± 3.7 mL/min (p = 0.030).

Longer-term therapy led to stabilization of GFR in male patients with baseline values within the normal range (≥ 90 mL/min/1.73 m²) and those with mild to moderate renal impairment (GFR from 60 to < 90 mL/min/1.73 m²), as well as to a slowing of the rate of decline in renal function and progression to end-stage renal disease in male patients with more severe renal impairment (GFR from 30 to < 60 mL/min/1.73 m²).

In the second study, 15 patients with left ventricular hypertrophy completed a 6-month placebo-controlled trial and were included in extension studies. In the controlled trial, Replagal treatment led to a reduction in left ventricular mass by 11.5 g as measured by magnetic resonance imaging, whereas patients receiving placebo showed an increase in left ventricular mass by 21.8 g. Furthermore, in the first study involving 25 patients, Replagal administration resulted in a significant reduction in cardiac mass over 12–18 months of established therapy (p < 0.001). Replagal also improved myocardial contractility, reduced mean QRS duration, and simultaneously decreased septal thickness on ECG. In the conducted studies, two patients with right bundle branch block reverted to normal ECG after Replagal therapy. In subsequent open-label studies, ECG data showed a significant reduction in left ventricular mass compared to baseline values in patients with Fabry disease of both sexes over 24–36 months of Replagal treatment, accompanied by significant symptomatic improvement compared to baseline as measured by NYHA and CCS classifications in patients with severe heart failure or angina symptoms.

Compared to placebo, Replagal treatment also reduced Gb3 accumulation. Within the first 6 months of therapy, Gb3 levels decreased by approximately 20–50% in plasma, urinary sediment, and liver, kidney, and heart biopsy samples. After 12–18 months of treatment, reductions of 50–80% were observed in plasma and urinary sediment. Metabolic effects were also accompanied by clinically meaningful increases in body weight, sweating, and energy levels. Consistent with the clinical effects of Replagal, enzyme replacement therapy reduced Gb3 accumulation in multiple tissue types, including glomerular and tubular epithelial cells of the kidneys, endothelial cells of renal capillaries (cardiac and skin capillary endothelial cells were not studied), and cardiac myocytes. In male pediatric patients with Fabry disease, after 6 months of therapy with 0.2 mg/kg Replagal, plasma Gb3 levels decreased by 40–50%, and this reduction was maintained over 4 years of treatment in 11 patients.

For patients who tolerate infusions well, treatment at home may be considered.

Children

In male pediatric patients with Fabry disease aged ≥ 7 years, the earliest sign of renal involvement may be hyperfiltration. Elevated eGFR values above normal decreased within 6 months after initiation of Replagal therapy. In this subgroup, abnormally high eGFR values decreased from 143.4 ± 6.8 to 121.3 ± 5.6 mL/min/1.73 m² after one year of treatment with 0.2 mg/kg agalsidase alfa weekly. These eGFR values remained stably within the normal range over 4 years of therapy with 0.2 mg/kg Replagal, indicating absence of hyperfiltration.

In male pediatric patients aged ≥ 7 years, heart rate was abnormal at baseline and improved after 6 months of Replagal therapy in 15 boys. In an open-label long-term extension study of 9 boys, improvement was sustained over 6.5 years of Replagal therapy at a dose of 0.2 mg/kg. Among 9 boys with height-corrected left ventricular mass index (LVMI) within the normal pediatric range at baseline (< 39 g/m in boys), LVMI remained stable at levels below the threshold for left ventricular hypertrophy (LVH) over 6.5 years of treatment. In the second study of 14 patients aged ≥ 7 years, heart rate findings were consistent with previous data. In this study, LVH remained at baseline levels and was stable throughout the observation period in only one patient.

In patients aged 0 to 7 years, based on limited data, no specific safety-related findings were identified.

Studies in patients switched from agalsidase beta to Replagal (agalsidase alfa)

The safety profile for patients switched from agalsidase beta to Replagal was consistent with that established in other clinical observations. Infusion-related reactions occurred in 9 patients in the untreated group (31.0%) compared to 27 patients in the group switched from another drug (38.0%).

Studies with different dosing regimens

In an open-label, randomized study, no statistically significant differences were observed in changes from baseline in mean LVMI or other endpoints (cardiac function status, renal function, and pharmacological activity) between adult patients who received 0.2 mg/kg intravenously every other week for 52 weeks (n=20) and those who received 0.2 mg/kg weekly (n=19). In each treated group, LVMI remained stable throughout the study period. Overall assessment of serious adverse reactions showed no obvious impact of treatment regimen on the profile of serious adverse reactions across groups.

Immunogenicity

The development of antibodies to agalsidase alfa has not been associated with clinically significant effects on safety (e.g., infusion reactions) or efficacy.

Pharmacokinetics.

Single doses of 0.007–0.2 mg/kg of the enzyme were administered to male adult patients as 20–40-minute intravenous infusions, while female patients received 0.2 mg/kg of the enzyme via 40-minute infusions. Enzyme dose did not significantly affect pharmacokinetic properties. After a single intravenous dose of 0.2 mg/kg, agalsidase alfa exhibited a biphasic distribution and elimination profile from the bloodstream. Pharmacokinetic parameters differed only slightly between male and female patients. Elimination half-life was 108 ± 17 minutes in males compared to 89 ± 28 minutes in females, and volume of distribution was approximately 17% of body weight in patients of both sexes. Body weight-normalized clearance was 2.66 and 2.10 mL/min/kg for males and females, respectively. Given the similarity in pharmacokinetic properties of agalsidase alfa in males and females, similar tissue and organ distribution can be expected in male and female patients.

Based on liver biopsy analyses in males with Fabry disease before and after treatment, the tissue elimination half-life exceeds 24 hours, and hepatic uptake of the enzyme is estimated at 10% of the administered dose.

Renal impairment

Renal elimination of agalsidase alfa is considered to occur with negligible clearance, as pharmacokinetic parameters do not change in the presence of renal dysfunction.

Hepatic impairment

Since metabolism is believed to occur via peptide hydrolysis, it is unlikely that hepatic dysfunction would affect the pharmacokinetics of agalsidase alfa at a clinically significant level.

Children

In children aged 7–18 years, Replagal administered at a dose of 0.2 mg/kg was cleared from the bloodstream faster than in adults. Mean clearance of Replagal in children aged 7–11 years, 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 confirm that at a dose of 0.2 mg/kg, Gb3 reduction in adolescents and younger children is broadly comparable (see section "Pharmacodynamics").

Clinical characteristics.

Indications.

Long-term enzyme replacement therapy in patients with a confirmed diagnosis of Fabry disease (α-galactosidase deficiency).

Contraindications.

Hypersensitivity to the active substance or to any of the excipients.

Interaction with other medicinal products and other forms of interaction.

Replagal should not be used concomitantly with chloroquine, amiodarone, banoquine, or gentamicin, as these substances have the ability to inhibit the activity of intracellular α-galactosidase.

Since α-galactosidase A itself is an enzyme, it is unlikely to be involved in drug interactions mediated by cytochrome P450. Clinical trials have shown that concomitant administration of neuropathic agents (such as carbamazepine, phenytoin, and gabapentin) in most patients was not associated with any manifestations of interaction.

Special precautions for use.

Tracking

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

Infusion-related reactions

Infusion-related hypersensitivity reactions occurred in 13.7% of adult patients receiving Replagal in clinical trials. Four out of 17 (23.5%) pediatric patients aged ≥ 7 years included in clinical studies experienced at least one infusion reaction during 4.5 years of treatment (mean duration approximately 4 years). Three out of 8 (37.5%) pediatric patients aged ˂ 7 years experienced at least one infusion reaction over a mean observation period of 4.2 years. The most commonly reported symptoms were fever, headache, nausea, hyperthermia, flushing, and fatigue. Serious infusion-related reactions have been reported rarely and included hyperthermia, fever, tachycardia, urticaria, nausea/vomiting, angioedema with throat tightness, stridor, and tongue swelling. Other infusion-related symptoms may include dizziness and hyperhidrosis. Analysis of cardiac manifestations showed that infusion reactions may be associated with hemodynamic stress, leading to cardiac complications in patients with pre-existing cardiac manifestations of Fabry disease.

Infusion-related reactions generally occurred within the first 2–4 months after initiation of Replagal treatment, although later occurrences (after 1 year) have also been reported. These effects tend to decrease over time. If mild or moderate acute infusion reactions occur, immediate medical attention and appropriate interventions are required. Infusion should be temporarily interrupted (for 5–10 minutes) until symptoms subside, after which it may be resumed. Mild and transient effects may not require medical intervention or discontinuation of infusion. Additionally, if necessary, symptomatic treatment with oral or intravenous premedication with antihistamines and/or corticosteroids 1–24 hours prior to infusion may prevent the occurrence of such reactions.

Hypersensitivity reactions

Hypersensitivity reactions have been reported. In case of severe hypersensitivity or anaphylactic reactions, administration of Replagal must be discontinued immediately and appropriate treatment initiated. Current medical standards for emergency care should be followed.

Antibodies to the protein

As with all protein pharmaceuticals, patients may develop antibodies to the protein. Low titers of IgG antibodies were observed in 24% of male patients receiving Replagal. Based on limited data, this proportion appears lower (7%) in the male pediatric population. IgG antibodies are believed to develop after approximately 3–12 months of treatment. After 12–54 months of therapy, 17% of patients receiving Replagal remained antibody-positive, while 7% developed immunological tolerance, characterized by the disappearance of IgG antibodies over time.

The remaining 76% of patients were antibody-negative during this period. Among pediatric patients aged ˃ 7 years, 1 out of 16 male patients tested positive for IgG anti-agalsidase alfa antibodies during the study. No increased incidence of adverse events was established in this age group (˃ 7 years). Among pediatric patients aged ˂ 7 years, all 7 male patients tested negative for IgG anti-agalsidase alfa antibodies. The presence of IgE antibodies detected in clinical trials involving a very small number of patients has not been associated with anaphylaxis.

Patients with renal impairment

Severe renal dysfunction may limit the kidney's response to enzyme replacement therapy due to existing irreversible pathological changes. In such cases, renal function decline remains within the expected range of natural disease progression.

Sodium

This medicinal product contains 14.2 mg of sodium per vial, equivalent to 0.7% of the WHO recommended maximum daily intake of sodium for adults (2 g). Caution should be exercised when administering this product to patients on a sodium-controlled diet.

Use during pregnancy or breastfeeding.

Pregnancy

Data on the use of Replagal in pregnant women are very limited. Animal studies have not revealed direct or indirect harmful effects on pregnancy or embryonal/fetal development when the drug was administered during organogenesis. Caution should be exercised when prescribing this drug to pregnant women.

Breastfeeding

It is unknown whether Replagal is excreted in human breast milk. Caution should be exercised when administering this drug to breastfeeding women.

Effect on fertility

Reproductive studies in male rats did not show any effect on fertility.

Ability to affect reaction speed when driving or operating machinery.

Replagal has no effect or has a negligible effect on the ability to drive or operate machinery.

Administration and Dosage

Dosage

Replagal is administered at a dose of 0.2 mg/kg body weight every week via intravenous infusion over 40 minutes using an intravenous administration set with an in-line filter. Do not administer Replagal infusion simultaneously in the same intravenous line with other medicinal products.

Administration

Reconstitution procedure:

Calculate the required dose and number of Replagal vials needed.
Any dose adjustment must be made only under the guidance of a physician.
Dilute the required volume of Replagal concentrate in 100 mL of 9 mg/mL (0.9%) sodium chloride for infusion. Care must be taken during preparation to maintain sterility of the solution, as Replagal contains no preservatives or bacteriostatic agents; aseptic equipment must be used. After dilution, gently mix the solution, but do not shake.
Because no preservative is present, it is recommended to initiate infusion as soon as possible after reconstitution (see section "Storage conditions").
Prior to administration, inspect the solution for the presence of particulate matter and discoloration.
For single use only. Unused materials or waste must be disposed of according to local requirements.

Treatment with Replagal must be supervised by a physician experienced in managing patients with Fabry disease or other inherited metabolic disorders.

For patients who tolerate infusions well, administration at home and self-infusion by the patient in the presence of a responsible adult or caregiver may be considered. The decision to transition a patient to home infusions and/or self-administration must be made following evaluation and recommendation by a physician.

Prior to initiating self-administration, the physician and/or nurse must provide appropriate training to the patient and/or caregiver. The dose and infusion rate must remain unchanged at home and must not be modified without medical supervision. Self-administration must be performed under close medical supervision.

Elderly patients (≥ 65 years of age)

Studies in patients aged over 65 years have not been conducted, and at present, a dosing regimen cannot be recommended for such patients, as safety and efficacy have not been established.

Hepatic impairment

Studies in patients with hepatic impairment have not been conducted.

Renal impairment

Dose adjustment is not required for patients with renal impairment.

Severe renal dysfunction (eGFR < 60 mL/min) may limit the kidney's response to enzyme replacement therapy. Limited data are available for patients on dialysis or after kidney transplantation; dose adjustment is not recommended.

Children.

The product is used in pediatric practice. Safety and efficacy of Replagal in children aged 0–6 years have not been established.

In clinical studies involving children (7–18 years) receiving Replagal at a dose of 0.2 mg/kg every two weeks, no unexpected safety findings were observed.

Overdose.

Cases of overdose have not been reported. Doses up to 0.4 mg/kg weekly have been used in clinical trials, and the safety profile was comparable to that observed with the recommended dose of 0.2 mg/kg weekly.

Adverse reactions.

Summary of safety profile

The most common documented adverse reactions were infusion-related reactions occurring in 13.7% of adult patients in clinical trials. The majority of adverse effects were mild to moderate in severity.

List of adverse reactions

Below is a list of adverse reactions reported in 344 patients treated with Replagal in clinical trials, including 21 patients with a history of end-stage renal disease, 30 pediatric patients (under 18 years of age), and 17 female patients. The list also includes adverse reactions identified from post-marketing spontaneous reports. The information is presented by system organ class and frequency (very common ≥ 1/10; common ≥ 1/100 to < 1/10; uncommon ≥ 1/1000 to < 1/100). Adverse reactions with unknown frequency (cannot be estimated from available data) are derived from post-marketing spontaneous reports. Within each frequency grouping, adverse reactions are listed in order of decreasing severity. An event occurring in a single patient is classified as uncommon, considering the number of treated patients. Multiple adverse reactions could occur in a single patient.

Immune system disorders: common – hypersensitivity reactions; uncommon – anaphylactic reaction.

Nervous system disorders: very common – headache, dizziness, neuropathic pain, tremor, hypoesthesia, paraesthesia; common – dysgeusia, hypersomnia; uncommon – parosmia.

Vascular disorders: common – flushing, hypertension, hypotension.

Gastrointestinal disorders: very common – nausea, vomiting, abdominal pain, diarrhea; common – abdominal discomfort.

Skin and subcutaneous tissue disorders: very common – rash; common – urticaria, acne, erythema, pruritus, hyperhidrosis; uncommon – livedo reticularis, angioneurotic edema.

General disorders and administration site conditions: very common – chest pain, chills, hyperthermia, pain, asthenia, fatigue; common – chest tightness, increased fatigue, feeling of warmth, feeling of cold, influenza-like illness, malaise, discomfort; uncommon – injection site rash.

Aural disorders: very common – tinnitus; common – severe tinnitus.

Eye disorders: common – increased lacrimation; uncommon – decreased corneal reflex.

Metabolism and nutrition disorders: very common – peripheral edema.

Description of selected adverse reactions

Infusion-related reactions reported during post-marketing surveillance may include cardiac events such as cardiac arrhythmia (atrial fibrillation, ventricular extrasystoles, tachyarrhythmia), myocardial ischemia, and heart failure in patients with Fabry disease and cardiac involvement. The most frequent infusion-related reactions were mild and included chills, hyperthermia, flushing, headache, nausea, dyspnea, tremor, and pruritus. Other infusion-related symptoms may include dizziness, hyperhidrosis, hypotension, cough, vomiting, and fatigue. Hypersensitivity reactions, including anaphylaxis, have been reported.

Patients with renal disease

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

Pediatric patients

Adverse reactions reported in the pediatric population (children and adolescents) were generally similar to those observed in adults. However, infusion-related reactions (hyperthermia, dyspnea, chest pain) and exacerbation of pain occurred more frequently.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorization of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life. 2 years.

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

Storage conditions.

Store in the original packaging in a refrigerator (at 2–8 °C).

Keep out of the reach of children.

From a microbiological standpoint, the diluted preparation should be used immediately. If not used immediately, the responsibility for storage conditions and duration prior to use lies with the user and must not exceed 24 hours at a temperature of 2 to 8 °C.

Packaging.

A 5 ml vial (Type I glass) with a stopper (butyl rubber with fluorinated coating), aluminum seal, and removable cap. One vial per cardboard box.

Prescription status. Prescription only.

Manufacturer.

Shire Pharmaceuticals Ireland Limited.

Manufacturer's address and place of business.

Block 2/3 Mezzanine Plaza, 50-58 Baggot Street Lower, Dublin 2, D02 Y754, Ireland