Fabrazyme

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT FABRAZYME® (FABRAZYME®)

Composition:

Active substance: agalsidase beta (r-haGAL) (agalsidase beta (r-haGAL));

1 vial contains a nominal amount of 5 mg or 35 mg of agalsidase beta;

after reconstitution, each vial contains 5 mg/mL (or 35 mg/7 mL) of agalsidase beta;

Excipients: mannitol (E 421); sodium dihydrogen phosphate monohydrate; disodium hydrogen phosphate heptahydrate.

Pharmaceutical form. Powder for concentrate for solution for infusion (5 mg/mL).

Main physicochemical properties: powder or mass of white or almost white color.

Pharmacotherapeutic group. Agents affecting the digestive system and metabolism. Enzymes. ATC code A16AB04.

Pharmacological Properties

Pharmacodynamics

Agalsidase beta is a recombinant form of human alpha-galactosidase A produced by recombinant DNA technology using mammalian cell cultures, specifically Chinese Hamster Ovary (CHO) cells. The amino acid sequence of the recombinant form, as well as the nucleotide sequence encoding it, is identical to that of the natural alpha-galactosidase.

Fabry Disease

Fabry disease is an inherited, heterogeneous, and multisystem progressive disorder affecting both sexes. The disease is characterized by a deficiency of the enzyme alpha-galactosidase. Reduced or absent enzyme activity leads to elevated concentrations of GL-3 and its related soluble form, lyso-GL-3, in plasma, as well as accumulation of GL-3 (globotriaosylceramide 3) in lysosomes of many cell types, including endothelial and parenchymal cells, ultimately resulting in life-threatening clinical manifestations due to renal, cardiac, and cerebrovascular complications.

Mechanism of Action

The fundamental principle of enzyme replacement therapy is restoration of enzymatic activity to a level sufficient for degradation of accumulated substrate in organ tissues. Thus, enzyme replacement therapy prevents, stabilizes, or slows progressive organ dysfunction before irreversible consequences occur.

Following intravenous injection, agalsidase beta is rapidly cleared from circulation and transported across vascular endothelial and parenchymal cells into lysosomes, possibly via mannose-6-phosphate, mannose, and asialoglycoprotein receptors.

Clinical Efficacy and Safety

The efficacy and safety of the medicinal product Fabrazyme® were evaluated in two studies involving children, one dose-finding study, two double-blind placebo-controlled trials, one open-label extension study involving both men and women, and scientific publications.

In the dose-finding study, the drug was administered at doses of 0.3, 1.0, and 3.0 mg/kg every two weeks, and 1.0 and 3.0 mg/kg every two days. Reduction in GL-3 concentration in kidneys, heart, skin, and plasma was observed with all dosing regimens. Plasma GL-3 concentration decreased in a dose-dependent manner, but the least reduction occurred with the 0.3 mg/kg dose. In addition, the incidence of infusion reactions was dose-dependent.

In the first placebo-controlled trial involving 58 patients with classic phenotype Fabry disease (56 males and 2 females), Fabrazyme® demonstrated efficacy in reducing GL-3 concentration in renal vascular endothelium after 20 weeks of treatment. Such changes were observed in 69% (20/29) of patients receiving the drug, and no such effect was observed in any patient receiving placebo (p < 0.001). This finding was supported by statistically significant reductions in GL-3 deposits in kidney, heart, and skin tissues, as well as in individual organs of patients treated with agalsidase beta compared to those receiving placebo (p < 0.001). Sustained reduction in GL-3 concentration in renal vascular endothelium during treatment with agalsidase beta was also observed in the open-label extension study of this drug. This result was achieved in 47 of 49 patients (96%) at month 6 of treatment and in all 8 patients (100%) at the end of the study (up to 5 years of treatment). Reduction in GL-3 concentration was also observed in several other types of kidney cells. During treatment, plasma GL-3 levels normalized rapidly and remained within normal limits for 5 years.

Renal function, assessed by glomerular filtration rate and serum creatinine, as well as proteinuria, remained stable in many patients. However, the effect of Fabrazyme® on renal function was limited in patients with severe renal insufficiency.

Although no specific study was conducted to evaluate the effect of the drug on neurological symptoms, results confirm that enzyme replacement therapy may reduce pain and improve patients' quality of life.

Another double-blind, placebo-controlled trial involved 82 patients with classic phenotype Fabry disease (72 males and 10 females) to assess the effect of Fabrazyme® on reducing the incidence of renal, cardiac, or cerebrovascular events and death. The number of clinical events was significantly lower in patients receiving Fabrazyme® compared to those receiving placebo [risk reduction of 53% in all patients enrolled in the study (p = 0.0577), and 61% in the per-protocol population who completed the study (p = 0.0341)]. This result remained consistent for renal, cardiac, and cerebrovascular events.

In two large observational studies, groups of patients (n = 89–105) receiving standard-dose Fabrazyme® (1.0 mg/kg every 2 weeks), reduced-dose Fabrazyme® (0.3–0.5 mg/kg every 2 weeks) followed by transition to agalsidase alfa (0.2 mg/kg every 2 weeks), or immediate transition to agalsidase alfa (0.2 mg/kg every 2 weeks) were monitored. Due to the observational, multicenter design of these studies conducted under real-world clinical conditions, there are confounding factors affecting interpretation of results, including patient selection, treatment group allocation, and variability in center-specific monitoring parameters. Because of the rarity of Fabry disease, the studied populations in observational studies overlapped, and treatment groups in respective studies were small. Furthermore, most patients with more severe disease, particularly males, remained on standard-dose Fabrazyme®, whereas patients with milder disease and females were more likely to transition to agalsidase alfa. Therefore, comparisons between groups should be interpreted with caution.

The standard-dose Fabrazyme® treatment group showed no significant changes in cardiac, renal, or neurological function or in Fabry disease-related symptoms. Similarly, in patients receiving reduced-dose Fabrazyme®, no significant changes in cardiac or neurological function were observed. However, worsening of renal parameters, assessed by estimated glomerular filtration rate (eGFR), was observed in patients receiving the lower dose (p < 0.05). Annual decline in eGFR slowed in patients who returned to standard-dose Fabrazyme®. These results are consistent with data from a 10-year follow-up in the Canadian Fabry Disease Initiative Registry.

In observational studies, patients who had their agalsidase beta dose reduced experienced worsening of Fabry disease-related symptoms (e.g., gastrointestinal pain, diarrhea).

Also, post-marketing experience has been obtained in patients who initially received Fabrazyme® at a dose of 1 mg/kg every 2 weeks and subsequently received reduced doses over a prolonged period. Spontaneous reports from some of these patients described worsening of symptoms such as pain, paresthesia, and diarrhea, as well as clinical manifestations affecting the heart, central nervous system, and kidneys. These reported symptoms resembled the natural course of Fabry disease.

According to data from the Fabry Disease Patient Registry, the rate (95% confidence interval) of first severe clinical event in male patients receiving standard-dose Fabrazyme® with stable IgG antibodies to agalsidase beta was 43.98 (18.99, 86.66), 48.60 (32.03, 70.70), and 56.07 (30.65, 94.07) per 1000 patient-years in low, medium, and high peak titer groups, respectively. These observed differences were not statistically significant.

Children

In an open-label pediatric study, 16 patients with Fabry disease (aged 8–16 years; 14 boys, 2 girls) were treated for one year with the drug at a dose of 1.0 mg/kg every 2 weeks. Clearance of GL-3 from endothelial cells of superficial skin vessels was observed in all patients who had GL-3 accumulation at baseline. This conclusion was based only on observations in boys, as the two female patients had either no or minimal GL-3 accumulation in skin vascular endothelium, at borderline normal levels.

In an additional 5-year open-label pediatric study, 31 male patients aged 5 to 18 years were randomized prior to onset of clinical manifestations, including major organ involvement, and treated with lower doses of agalsidase beta: 0.5 mg/kg every 2 weeks or 1.0 mg/kg every 4 weeks. Results were similar between the two treatment groups. GL-3 accumulation in skin vascular endothelium decreased to zero or remained at zero at all post-baseline time points in 19 of 27 patients who completed the study without dose escalation. In a subgroup of 6 patients, kidney biopsies were performed before the study and after 5 years: overall, GL-3 accumulation in renal vascular endothelium decreased to zero, but variable effects were observed in podocyte GL-3 levels, with reductions in 3 patients. Ten patients met criteria for dose escalation per protocol, and 2 patients had their dose increased to the recommended 1.0 mg/kg every 2 weeks.

Pharmacokinetics

Prolonged intravenous infusion of agalsidase beta in adults at doses of 0.3 mg/kg, 1 mg/kg, and 3 mg/kg according to body weight increases AUC (area under the concentration-time curve) more than proportionally to dose due to decreased clearance, indicating saturable clearance of the drug. Elimination half-life was dose-dependent and ranged from 45 to 100 minutes.

Following intravenous administration of agalsidase beta to adults as infusions lasting approximately 300 minutes at a dose of 1 mg/kg body weight every two weeks, plasma concentration (Cmax) ranged from 2000 to 3500 ng/mL, and AUCinf ranged from 370 to 780 µg·min/mL. The steady-state volume of distribution (Vss) was 8.3–40.81 mL/kg, plasma clearance was 119–345 mL/min, and mean elimination half-life was 80–120 minutes.

Agalsidase beta is a protein subject to metabolic degradation via peptide hydrolysis. Therefore, hepatic impairment is not expected to significantly affect the pharmacokinetic properties of agalsidase beta. Renal elimination of agalsidase beta is considered the shortest elimination pathway of the drug.

Children

The pharmacokinetics of the medicinal product Fabrazyme® were also evaluated in two pediatric studies. Fifteen pediatric patients with known pharmacokinetic data (aged 8.5 to 16 years, body weight 27.1 to 64.9 kg) received treatment at a dose of 1.0 mg/kg every 2 weeks. In this patient group, body weight did not influence agalsidase beta clearance. Saturable clearance was 77 mL/min, with a steady-state volume of distribution (Vss) of 2.6 L; elimination half-life was 55 minutes. After immunoglobulin seroconversion, clearance decreased to 35 mL/min and Vss increased to 5.4 L; elimination half-life extended to 240 minutes. The combined effect of these changes after seroconversion resulted in a 2- to 3-fold increase in drug exposure based on AUC and Cmax values. No unexpected safety issues were observed in patients despite increased drug exposure after seroconversion.

In another study, 30 pediatric patients with known pharmacokinetic data (aged 5 to 18 years) received reduced-dose treatment: 0.5 mg/kg every 2 weeks and 1.0 mg/kg every 4 weeks. Mean clearance was 4.6 and 2.3 mL/min/kg, respectively; Vss was 0.27 and 0.22 L/kg; and mean elimination half-life was 88 and 107 minutes, respectively. After IgG seroconversion, no significant changes in clearance were observed (+24% and +6%, respectively), while Vss increased by 1.8 and 2.2 times, ultimately resulting in a modest decrease in Cmax (to -34% and -11%, respectively) and no change in AUC (-19% and -6%, respectively).

Non-clinical Safety Data

Non-clinical studies revealed no hazard to human health following safety pharmacology, single-dose toxicity, repeated-dose toxicity, and embryotoxicity/fetotoxicity studies. Studies on the effect of the drug on other developmental stages were not conducted. Genotoxic and carcinogenic potential are considered unlikely.

Clinical characteristics.

Indications.

Fabrazyme® is indicated for long-term enzyme replacement therapy in adults and children aged 8 years and older with confirmed Fabry disease (alpha-galactosidase A deficiency).

Contraindications.

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

Interaction with other medicinal products and other forms of interaction.

Studies on interactions with other drugs and the effect on metabolism in vitro have not been conducted. Based on available information, it is unlikely that agalsidase beta interacts via the cytochrome P450 system in a "drug-drug" manner.

Fabrazyme® must not be administered simultaneously with chloroquine, amiodarone, benoxinate, or gentamicin due to the theoretical risk of inhibition of intracellular alpha-galactosidase A activity.

Special precautions for use.

Immunogenicity

Since agalsidase beta (r-hαGAL) is a recombinant protein, the development of immunoglobulin G antibodies may occur in patients with low or residual enzyme activity. Most patients developed immunoglobulin G antibodies to r-hαGAL, usually within 3 months after the first infusion of Fabrazyme®. Subsequently, in most seropositive patients, a decrease in antibody titers (defined as a reduction of ≥ 4-fold from peak to last measurement) was observed (40% of patients), tolerance was noted (antibodies not detected during two consecutive radioimmunoprecipitation assays) (14% of patients), or titers stabilized (35% of patients).

Infusion-related reactions

Patients with antibodies to agalsidase beta have a higher likelihood of experiencing an infusion-related reaction, manifested by any adverse reaction on the day of drug administration. These patients require closer monitoring upon subsequent infusions of agalsidase beta (see section "Adverse reactions") and continuous monitoring of antibody levels.

During clinical trials, 67% of patients experienced at least one infusion-related reaction (see section "Adverse reactions"). The frequency of such events decreased over time. Patients who experienced mild to moderate reactions during agalsidase beta infusions in clinical trials continued treatment after reducing the infusion rate (~0.15 mg/min; 10 mg/h) and/or after premedication with antihistamines, paracetamol, ibuprofen, and/or corticosteroids.

Hypersensitivity reactions

Allergic reactions due to hypersensitivity to components of the drug may occur, as it is a protein product administered intravenously.

Immediate-type (Type I) allergic reactions have been observed in a small number of patients. In case of severe allergic or anaphylactic reactions, administration of Fabrazyme® must be stopped immediately and appropriate treatment initiated. Established medical standards for emergency care should be followed.

Extreme caution is required when re-administering Fabrazyme® to patients who have developed immunoglobulin E antibodies or had a positive skin test during clinical trials. In such cases, the initial re-challenge should be performed with a low dose administered at a reduced infusion rate (1/2 of the therapeutic dose at 1/25 of the standard recommended initial infusion rate). If the patient tolerates the first infusion well, the dose may be increased to the therapeutic dose of 1 mg/kg and the infusion rate gradually titrated upwards.

Patients with severe renal disease

The therapeutic effect of Fabrazyme® may be reduced in patients with advanced renal impairment.

Sodium

This medicinal product contains less than 1 mmol of sodium (23 mg) per vial, i.e., essentially "sodium-free".

Traceability

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

Use during pregnancy or breastfeeding.

Pregnancy

Data on the use of agalsidase beta in pregnant women are limited.

Animal studies did not show any direct or indirect harmful effects related to reproductive toxicity (see section "Pharmacological properties").

As a precautionary measure, it is advisable to avoid using Fabrazyme® during pregnancy.

Breastfeeding

Agalsidase beta is excreted in human breast milk. The effect of agalsidase beta on newborns/infants is unknown. A decision should be made whether to discontinue breastfeeding or to discontinue/abstain from treatment with Fabrazyme®, taking into account the benefits of breastfeeding for the child and the benefits of therapy for the woman.

Fertility

No studies have been conducted on potential effects of Fabrazyme® on fertility or reproductive function.

Ability to influence the speed of reactions when driving vehicles or operating machinery.

Fabrazyme® may have a minor influence on the ability to drive vehicles or operate machinery, occurring on the day of administration and related to possible dizziness, somnolence, vertigo, and syncope (see section "Adverse reactions").

Administration and Dosage

Treatment with Fabrazyme® should be conducted under the supervision of a physician experienced in the management of Fabry disease or other inherited metabolic disorders.

Dosage

The recommended dose of Fabrazyme® is 1 mg/kg body weight, administered via intravenous infusion every two weeks.

The initial infusion rate should not exceed 0.25 mg/min (15 mg/hour) to minimize the risk of possible infusion-related reactions. After confirming a normal patient response to the drug, the infusion rate may be gradually increased with each subsequent infusion.

Patients who tolerate infusions well may be allowed to receive them at home. The decision to transition a patient to home infusion therapy must be made following evaluation of clinical data and physician recommendations. Patients who experience adverse events during home infusions must immediately stop the infusion and seek medical assistance. Subsequently, such patients may require infusions to be administered in a clinical setting. When administering the drug at home, the dose and infusion rate must remain unchanged; patients must not alter them independently without medical supervision.

Special Patient Groups

Renal Impairment

Patients with renal impairment do not require dose adjustment.

Hepatic Impairment

Studies on the use of Fabrazyme® in patients with hepatic impairment have not been conducted.

Elderly Patients

The safety and efficacy of Fabrazyme® in patients aged 65 years and older have not been established. There are currently no dosage recommendations for these patients.

Method of Administration

The powder for concentrate must be reconstituted with Water for Injections, then diluted with 0.9% Sodium Chloride Solution for intravenous infusion and administered intravenously. Aseptic technique must be used.

The number of vials to reconstitute is determined based on the patient's body weight. The required number of vials should be removed from the refrigerator and allowed to reach room temperature (approximately 30 minutes prior to reconstitution). Each vial of Fabrazyme® is for single use only.

Reconstitution

Fabrazyme®, 35 mg, powder for concentrate

Reconstitute the contents of each 35 mg Fabrazyme® vial with 7.2 mL of Water for Injections. Avoid direct forceful impact of Water for Injections on the powder and foaming. To achieve this, add the water slowly, drop by drop, and do not pour it directly onto the lyophilized material. Gently rock the vial and swirl its contents carefully. Do not invert or shake the vial.

Fabrazyme®, 5 mg, powder for concentrate

Reconstitute the contents of each 5 mg Fabrazyme® vial with 1.1 mL of Water for Injections. Avoid direct forceful impact of Water for Injections on the powder and foaming. To achieve this, add the water slowly, drop by drop, and do not pour it directly onto the lyophilized material. Gently rock the vial and swirl its contents carefully. Do not invert or shake the vial.

The resulting solution contains 5 mg of agalsidase beta per 1 mL of solution, is clear and colorless, and has a pH of approximately 7.0. Before further dilution, inspect the solution in each vial for color and clarity. Do not use the solution if it contains particulate matter or if discoloration is observed.

After reconstitution, it is recommended to dilute the solution in the vial promptly to prevent the formation of protein particles over time.

Unused vials or leftover medication must be disposed of according to local regulations.

Dilution

Fabrazyme®, 35 mg, powder for concentrate

Prior to diluting the reconstituted Fabrazyme® dose (as determined for the patient), withdraw the appropriate volume of 0.9% Sodium Chloride Solution for intravenous use from the infusion bag.

Vent the infusion bag to avoid air-liquid interaction.

Slowly withdraw 1.0 mL (corresponding to 5 mg) or 7.0 mL (corresponding to 35 mg) of reconstituted solution from each vial to achieve the required patient dose. Do not use filter needles and avoid foaming.

Then, slowly transfer the solution directly into the 0.9% Sodium Chloride Solution (without introducing air) to achieve a final concentration between 0.05 mg/mL and 0.7 mg/mL. Determine the total volume of 0.9% Sodium Chloride Solution for infusion (between 50 and 500 mL) based on the patient's individual dose. For doses less than 35 mg, use a minimum of 50 mL of Sodium Chloride; for 35–70 mg, use at least 100 mL; for 70–100 mg, use a minimum of 250 mL; and for doses exceeding 100 mg, use only 500 mL of Sodium Chloride Solution. Gently invert or knead the infusion bag to mix the diluted solution. Do not shake the infusion bag or agitate its contents vigorously.

Fabrazyme®, 5 mg, powder for concentrate

Prior to diluting the reconstituted Fabrazyme® dose (as determined for the patient), withdraw the appropriate volume of 0.9% Sodium Chloride Solution for intravenous use from the infusion bag.

Vent the infusion bag to avoid air-liquid interaction.

Slowly withdraw 1.0 mL (corresponding to 5 mg) or 7.0 mL (corresponding to 35 mg) of reconstituted solution from each vial to achieve the required patient dose. Do not use filter needles and avoid foaming.

Then, slowly transfer the solution directly into the 0.9% Sodium Chloride Solution (without introducing air) to achieve a final concentration between 0.05 mg/mL and 0.7 mg/mL. Determine the total volume of 0.9% Sodium Chloride Solution for infusion (between 50 and 500 mL) based on the patient's individual dose. For doses less than 35 mg, use a minimum of 50 mL of Sodium Chloride; for 35–70 mg, use at least 100 mL; for 70–100 mg, use a minimum of 250 mL; and for doses exceeding 100 mg, use only 500 mL of Sodium Chloride Solution. Gently invert or knead the infusion bag to mix the diluted solution. Do not shake the infusion bag or agitate its contents vigorously.

Administration of the Drug

The diluted preparation should be administered through a 0.2 µm low-protein-binding in-line filter to minimize the formation of protein particles, although this does not reduce the activity of agalsidase beta. The initial infusion rate must not exceed 0.25 mg/min (15 mg/hour). The infusion rate may be reduced in the event of infusion-related reactions.

After confirming a normal patient response to the drug, the infusion rate may be increased in increments of 0.05 to 0.083 mg/min (3 to 5 mg/hour) with each subsequent infusion. In clinical trials involving patients with the classic phenotype, the infusion rate was gradually increased until the infusion duration reached a minimum of 2 hours. This was achieved after 8 initial infusions at a rate of 0.25 mg/min (15 mg/hour) without any infusion-related reactions, changes in infusion rate, or interruptions. Further reduction of the infusion time to 1.5 hours was permitted for patients who had no new infusion-related reactions during the last 10 infusions or no reports of serious adverse reactions during the last 5 infusions. Each increase in infusion rate of 0.083 mg/min (~5 mg/hour) was maintained for 3 consecutive infusions without any new infusion-related reactions, changes in rate, or interruptions before the next rate increase.

For patients with body weight < 30 kg, the maximum infusion rate should remain at 0.25 mg/min (15 mg/hour).

From a microbiological standpoint, the drug should be used immediately after reconstitution and dilution of the vial contents. If not used immediately, responsibility for storage conditions prior to use lies with the user. The reconstituted solution must not be stored and should be diluted promptly.

The diluted solution may be stored for up to 24 hours at 2–8 °C, protected from light and microbial contamination.

Children

Studies on the effect of the drug in children aged 0–7 years have not been conducted. Available data are presented in the section "Pharmacological Properties," but dosage recommendations for children aged 5–7 years are lacking. Data on the use of the drug in children aged 0–4 years are also unavailable.

No dose adjustment is required when administering the drug to children aged 8–16 years.

Overdose

Cases of overdose are unknown. During clinical trials, doses up to 3 mg/kg body weight were administered.

Adverse Reactions

Since agalsidase beta (r-hαGAL) is a recombinant protein, the formation of IgG antibodies is expected in patients who have low residual enzyme activity or no residual activity at all. Patients with antibodies to r-hαGAL have a higher probability of developing infusion-related reactions. Immediate-type hypersensitivity reactions (Type I) have been observed in a small number of patients (see section "Special Warnings and Precautions for Use").

Very common adverse reactions include chills, pyrexia, feeling cold, nausea, vomiting, headache, and paresthesia. At least one infusion-related adverse reaction occurred in 67% of patients. During the post-marketing surveillance period, cases of anaphylactoid reactions have been reported.

The table below presents results from clinical studies on adverse reactions associated with the administration of Fabrazyme® in 168 patients (154 males and 14 females), who received the drug at a dose of 1 mg/kg every two weeks at least once, with a maximum treatment duration of 5 years. The frequency of adverse reactions (very common ≥ 1/10, common ≥ 1/100 to < 1/10, and uncommon ≥ 1/1000 to < 1/100) is listed by system organ class. Occurrence of an adverse reaction in an individual patient is considered uncommon due to the relatively small number of treated patients.

Adverse reactions reported during the post-marketing period are also listed in the table under the category "Frequency unknown" (frequency cannot be estimated from available data). The severity of adverse reactions was mostly mild to moderate.

Frequency of adverse reactions following administration of Fabrazyme®

In this table, the frequency of adverse reactions ≥ 1% (≥ 1/100) refers to cases occurring in two or more patients. The terminology for adverse reactions is based on the MedDRA medical dictionary.

Infusion-related reactions

Post-infusion reactions occurred most frequently as fever and chills. Additional symptoms include hypoxia (reduced blood oxygen saturation), mild to moderate dyspnea, throat tightness, chest discomfort, flushing, pruritus, urticaria, facial swelling, angioneurotic edema, rhinitis, bronchospasm, tachypnea, wheezing, arterial hypertension, arterial hypotension, tachycardia, palpitations, abdominal pain, nausea, vomiting, post-infusion pain including limb pain, myalgia, and headache.

The impact of infusion-related reactions was reduced by slowing the infusion rate and/or by administering additional nonsteroidal anti-inflammatory drugs, antihistamines, and/or corticosteroids. 67% of patients experienced at least one reaction related to the administration of Fabrazyme®. The frequency of such reactions decreased over time. Most of these reactions may be associated with the formation of immunoglobulin G antibodies and/or complement activation. Immunoglobulin E antibodies were detected in a limited number of patients (see section "Special precautions for use").

Children

Limited data from clinical studies suggest that the safety profile of Fabrazyme® treatment in patients aged 5–7 years receiving the drug at a dose of 0.5 mg/kg every 2 weeks or 1.0 mg/kg every 4 weeks is similar to that in patients aged 7 years and older receiving treatment at a dose of 1.0 mg/kg every 2 weeks.

Reporting suspected adverse reactions

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

Shelf life. 3 years.

Storage conditions. Keep out of reach of children.

The medicinal product should be stored in a refrigerator (at +2 to +8 °C) in the original packaging to protect from light.

Incompatibilities. In the absence of compatibility studies, FabrazymeÒ must not be mixed with any other medicinal products.

Packaging. Each box of Fabrazyme® containing 5 mg includes 1 glass vial with a capacity of 5 mL; each box of Fabrazyme® containing 35 mg includes 1 glass vial with a capacity of 20 mL.

The vial is closed with a siliconized butyl stopper sealed with an aluminum crimp cap with a plastic flip-off cap.

Prescription status. Prescription only.

Manufacturer.

Genzyme Ireland Limited, Ireland / Genzyme Ireland Limited, Ireland.

Manufacturer's location and address of its place of business.

IDA Industrial Park, Old Kilmeaden Road, Waterford, Ireland / IDA Industrial Park, Old Kilmeaden Road, Waterford, Ireland.

Marketing authorization holder. Sanofi B.V., The Netherlands / Sanofi B.V., The Netherlands.