Fabagal^® (Lyophilisate) Instructions for Use

Marketing Authorization Holder

Petrovax Pharm NPO, LLC (Russia)

Manufactured By

Korea Vaccine, Co. Ltd. (Republic of Korea)

Quality Control Release

ISU ABXIS, Co. Ltd. (Republic of Korea)

Contact Information

NPO Petrovax Pharm LLC (Russia)

ATC Code

A16AB04 (Agalsidase beta)

Active Substance

Agalsidase beta (Rec.INN registered by WHO)

Dosage Form

Fabagal®

Lyophilizate for preparation of concentrate for preparation of solution for infusion 35 mg: vial 1 pc.

Dosage Form, Packaging, and Composition

Lyophilizate for preparation of concentrate for preparation of solution for infusion in the form of a lyophilized tablet or powder from white to almost white color; the reconstituted solution is a clear colorless liquid.

Excipients: D-mannitol, sodium dihydrogen phosphate dihydrate, disodium hydrogen phosphate dihydrate.

Vials (type I glass) with a capacity of 20 ml (1) – cardboard packs with first opening control.

Clinical-Pharmacological Group

Drug for the treatment of hereditary enzymatic deficiency

Pharmacotherapeutic Group

Other agents for the treatment of gastrointestinal diseases and metabolic disorders; enzymes

Pharmacological Action

Agalsidase beta is a recombinant form of human α-galactosidase A. Agalsidase beta is produced by recombinant DNA method using Chinese hamster ovary (CHO) cell culture. The amino acid sequence of the recombinant form, as well as the nucleotide sequence encoding it, are identical to those of the natural form of β-galactosidase.

Fabagal^® is a biosimilar (biologics-like drug).

Fabry Disease

Fabry disease is a hereditary heterogeneous and progressive multi-system disease that occurs in both men and women. The disease is characterized by a deficiency of α-galactosidase. Reduced or absent activity of α-galactosidase leads to the accumulation of globotriaosylceramide (GL-3) in the lysosomes of many cell types, including endothelial and parenchymal cells, which ultimately leads to life-threatening clinical consequences and complications from the kidneys, heart, and cerebrovascular complications.

Mechanism of action

Enzyme replacement therapy is used to restore the level of enzyme activity sufficient for the hydrolysis and removal of substrate deposits from organ tissues, thereby preventing, stabilizing, or reversing the progressive deterioration of the function of these organs, which without therapy can lead to their irreversible damage.

After intravenous infusion, Agalsidase beta rapidly leaves the systemic circulation and is taken up by the lysosomes of vascular endothelial and parenchymal cells, most likely via mannose-6-phosphate, mannose, and asialoglycoprotein receptors.

Clinical efficacy and safety

The efficacy and safety of the drug were evaluated in 9 clinical studies with a total number of participants – 215 patients. In a dose-range finding study conducted in 15 patients, the effects of 5 dosing regimens were evaluated: 0.3, 1.0 and 3.0 mg/kg once every 2 weeks and 1.0, and 3.0 mg/kg once every 2 days. With all dosing regimens, a decrease in GL-3 content in plasma, kidneys, heart and skin was observed, confirmed biochemically and histologically using light and electron microscopy. There was a reduction in pain, improvement in the ability to sweat and improvement in quality of life. At the end of this study, the most favorable safety and efficacy ratio was observed with a dose of 1.0 mg/kg every two weeks. A dose-dependent clearance of GL-3 from plasma was observed. Infusion-related reactions were also dose-dependent. 14 patients who participated in the dose-range finding study were included in an open-label extension clinical study of the drug at a dose of 1.0 mg/kg every 2 weeks.

In the first placebo-controlled clinical trial conducted in 58 patients (56 male patients and 2 female patients) with the classic phenotype of Fabry disease, the use of the drug led to effective elimination of GL-3 from the renal vascular endothelium after 20 weeks of treatment. Clearance was observed in 69% (20/29) of patients receiving the drug and was not observed in any patient receiving placebo (p< 0.001). These data were further confirmed by a statistically significant decrease in GL-3 inclusions in kidney, heart and skin tissues, as well as in individual organs in patients receiving agalsidase beta compared with patients receiving placebo (p< 0.001). Sustained clearance of GL-3 from the renal vascular endothelium with agalsidase beta was also observed in the open-label extension of this study, during which all 58 patients received treatment with algasidase beta. This result was achieved in 47 out of 49 patients (96%) for whom information was available at 6 months, and in 8 out of 8 patients (100%) for whom information was available at the end of the study (up to 5 years of treatment in total). Clearance of GL-3 was also observed from several other types of kidney cells. Rapid normalization of plasma GL-3 levels was observed during treatment, and they remained normal for 5 years (see table below).

* Results were reported where biopsy was performed.

** In the AGAL-005-99 clinical trial, biopsy at week 54 was optional.

In most patients, renal function remained stable according to glomerular filtration rate, serum creatinine concentration and proteinuria. However, in some patients with late-stage kidney disease, the effect of drug treatment on renal function was limited.

The efficacy of the drug was also evaluated in an open-label phase 2 clinical trial conducted in 13 Japanese patients who received the drug at a dose of 1 mg/kg body weight per day every 2 weeks for 20 weeks. The results of the Japanese phase 2 clinical trial were similar to the results of the double-blind phase 3 clinical trial.

Although specific studies to evaluate the effect on neurological signs and symptoms were not conducted, the results of the conducted studies also show that patients may achieve pain reduction and improved quality of life with enzyme replacement therapy with the drug.

In another randomized (2:1) double-blind placebo-controlled phase 4 study conducted in 82 patients (72 men and 10 women) with the classic phenotype of Fabry disease, the ability of the drug at a dose of 1 mg/kg every 2 weeks to slow the rate of clinical progression of Fabry disease and reduce the incidence of kidney, heart or cerebrovascular diseases, as well as fatal outcome, was evaluated. The frequency of clinical events was significantly lower in patients receiving the drug compared with patients receiving placebo (53% risk reduction in the population of all included patients (p=0.0577), 61% risk reduction in the population of patients without protocol violations (p=0.0341). This result was robust for cardiac, renal and cerebrovascular complications of Fabry disease.

The results of these studies show that therapy with the drug at a dose of 1 mg/kg every two weeks provides clinical efficacy according to key clinical outcomes, both in patients with newly diagnosed disease and in advanced Fabry disease. Since this condition progresses slowly, early detection and treatment is critical to achieving the best outcomes.

The efficacy of the drug was evaluated based on the results of an international, multicenter, uncontrolled open-label phase 2 clinical trial involving 16 patients with Fabry disease (14 male patients and 2 female patients) aged 8 to 16 years. All patients received the drug at a dose of 1 mg/kg every 2 weeks for a total duration of 48 weeks. By the end of treatment, all male patients (14 people) had an elevated concentration of GL-3 in the blood (>7.03 µg/ml), in women (2 people) this indicator corresponded to normal values. The results of skin biopsy after treatment showed moderate or severe GL-3 inclusions in the capillary endothelium in 12 men. The concentration of GL-3 in the blood at 24 and 48 weeks of treatment in 14 male patients was within the normal range. GL-3 inclusions in the capillary endothelium at 24 and 48 weeks of treatment in 12 men reached an inclusion index of 0. In women (2 patients), the plasma GL-3 concentration remained normal throughout the study.

An additional study included 21 male patients to track the clearance of GL-3 from kidney and skin tissues with an alternative dosing regimen. After treatment with a dose of 1 mg/kg every two weeks for 24 weeks, a dosing regimen of 0.3 mg/kg every 2 weeks for 18 months in most patients allowed maintaining the clearance of GL-3 from renal capillary endothelial cells, other types of kidney cells and skin (superficial skin capillary endothelium). However, when used at a lower dose, IgG class antibodies in some patients may affect GL-3 clearance. Due to the limitations associated with the study design (small number of patients), final conclusions regarding the maintenance treatment regimen cannot be made, but these results show that in some patients after using the initial dose of 1.0 mg/kg once every 2 weeks, a dose of 0.3 mg/kg once every 2 weeks may be sufficient to maintain GL-3 clearance.

In the post-registration period, experience was gained with the use of the drug in patients who started therapy at a dose of 1 mg/kg every 2 weeks and then received a reduced dose for a long period. In some of these patients, a spontaneous increase in the severity of some of the following symptoms was noted: pain, paresthesia and diarrhea, and disorders of the heart, central nervous system and kidneys were also recorded. The noted symptoms correspond to the natural course of Fabry disease.

In a study of 10 patients over 16 years of age, the drug Fabagal^® was administered at a dose of 1 mg/kg every 2 weeks, 12 times in total. One hour before the administration of the study drug, acetaminophen (1000 mg or less) or ibuprofen (400 mg or less) and hydroxyzine (50 mg or less) were administered. The infusion rate of Fabagal^® was up to 0.25 mg/min, and the plasma GL-3 level reached a normal level and remained so during the entire observation period of 22 weeks). The use of Fabagal^® led to a significant decrease in Gb3 levels in plasma and urine in patients with Fabry disease. Thus, this study showed the efficacy and safety of Fabagal^®.

In a study involving 8 patients, the drug Fabagal^® was administered a total of 48 times over 118 weeks with the same dose and administration regimen, the long-term effect was evaluated. At week 70, the plasma GL-3 level remained below the normal level.

Use in children

In an open-label study in children with Fabry disease, 16 patients aged 8 to 16 years (14 male patients and 2 female patients) participated and received treatment for one year. Clearance of GL-3 from the superficial vascular endothelium of the skin was achieved in all patients who had GL-3 accumulation at baseline. In 2 female patients, there was practically no GL-3 accumulation in the superficial vascular endothelium of the skin at baseline, which makes this conclusion applicable only to male patients.

In a conducted 5-year open-label phase 3b clinical trial in children, 31 male patients aged 5 to 18 years were randomized before the development of clinical symptoms involving major organs. All patients received the drug at doses of 0.5 mg/kg every 2 weeks or 1.0 mg/kg every 4 weeks (both doses were lower than the recommended dose of 1 mg/kg every 2 weeks). The efficacy of treatment in both groups was comparable. During treatment, in 19 out of 27 patients who completed the study without a dose increase, the GL-3 inclusion index in superficial skin capillaries decreased or remained at zero. The results of kidney biopsy after treatment and after 5 years showed a decrease to 0 in the GL-3 index in the renal capillary endothelium in 6 patients. 10 patients met the protocol-defined criteria for dose increase, and two patients had their dose increased to the recommended dose of 1 mg/kg every 2 weeks.

Pharmacokinetics

After intravenous administration of agalsidase beta to adult patients at doses of 0.3 mg, 1 mg and 3 mg/kg body weight, the AUC_0-∞ values of agalsidase beta and its clearance did not increase proportionally with the dose increase due to decreased clearance, indicating that the enzyme has nonlinear pharmacokinetics and saturable clearance. T_1/2 was dose-dependent and ranged from 45 to 102 min.

The pharmacokinetics of agalsidase beta were studied in Europe in 11 adult patients with Fabry disease. After intravenous infusion of the drug at a dose of 1 mg/kg body weight, administered over 280-300 min, the mean values of the parameters were: C_max in plasma – 2.09-3.49 µg/ml; AUC_0-∞ – 372-784 µg/ml·min; V_ss – 0.12-0.57 l/kg; plasma clearance – 1.75-4.87 ml/min/kg; elimination T_1/2 – 82.3-119 min. Comparative pharmacokinetic studies in patients in Europe and Japan have shown comparable results in patients with Fabry disease.

Agalsidase beta, being a protein, is expected to be metabolized by peptide hydrolysis. Therefore, no clinically significant effect of impaired liver function on the pharmacokinetics of agalsidase beta is expected. Renal excretion of agalsidase beta is considered a secondary clearance mechanism.

Use in children

The pharmacokinetics of agalsidase beta were also evaluated in 15 children (age from 8.5 to 16 years, body weight from 27.1 to 64.9 kg). In this population, the clearance of agalsidase beta was independent of body weight. At baseline, clearance was 77 ml/min with V_ss 2.6 l; T_1/2 was 55 min. After IgG seroconversion, clearance decreased to 35 ml/min, V_ss increased to 5.4 l, and T_1/2 increased to 240 min. The final effect of these changes after seroconversion was a 2-3-fold increase in exposure based on AUC and C_max indicators. No unforeseen safety problems related to increased systemic exposure of agalsidase beta after seroconversion were identified in patients.

Pharmacokinetic data of agalsidase beta were evaluated in a phase 3b clinical trial involving 30 patients aged 5 to 18 years. Patients received agalsidase beta at a dose of 0.5 mg/kg every 2 weeks and 1.0 mg/kg every 4 weeks (both doses were lower than the recommended dose of 1 mg/kg every 2 weeks) and the mean values of the parameters were: clearance – 4.6 and 2.3 ml/min/kg; V_ss – 0.27 and 0.22 l/kg; elimination T_1/2 – 88 and 107 min, respectively. After IgG seroconversion, clearance did not change, V_ss increased by 1.8-2.2 times. The final effect of these changes after seroconversion was a slight decrease in C_max (up to 34%) and no effect on AUC.

Preclinical safety data

Preclinical data obtained in pharmacology, safety, single-dose toxicity, repeated-dose toxicity and embryonic/fetal toxicity studies did not show any specific hazard of the drug to humans. No studies on the effects on other stages of human development have been conducted.

No genotoxic or carcinogenic effects are expected.

Indications

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

The drug Fabagal^® is indicated for use in adults, children and adolescents aged 8 years and older.

ICD codes

Dosage Regimen

Treatment of Fabry disease should be carried out under the supervision of a physician with experience in managing patients with Fabry disease or other hereditary metabolic disorders.

The recommended dose of Fabagal^® is 1 mg/kg body weight every 2 weeks as an intravenous infusion.

Alternative treatment regimens were used in clinical studies. In one of these studies, after using an initial dose of 1.0 mg/kg every 2 weeks for 6 months, using a dose of 0.3 mg/kg every 2 weeks could maintain GL-3 clearance from certain cell types in some patients; however, the clinical significance of these data in long-term treatment has not been established.

The initial infusion rate should not exceed 0.25 mg/min (15 mg/h) in order to minimize the risk of infusion-related reactions. After the patient’s tolerance to the drug is established, the infusion rate can be gradually increased during subsequent infusions if well tolerated.

For patients with body weight ≥30 kg with normal drug tolerance, the infusion rate can be gradually increased by 0.05-0.08 mg/min (increase step 3-5 mg/h) with each subsequent infusion. In clinical studies, the infusion duration was reduced to 1.5 h in patients with body weight ≥30 kg based on individual drug tolerance.

For patients with a body weight <30 kg the maximum infusion rate is 0.25 mg/min (15 mg/h).

Conducting infusions at home can be considered in patients who tolerate them well. The decision to transfer a patient to home infusions should be made after assessment and appropriate recommendation from the attending physician. Patients who experience adverse events during home infusion must immediately stop the infusion and seek medical attention. Subsequent infusions may need to be conducted in a clinical setting. The administered dose and infusion rate should remain constant during home administration and should not be changed without appropriate medical supervision.

In patients with renal impairment dose adjustment is not required.

In patients with hepatic impairment dose adjustment is not required. Studies in patients with hepatic impairment have not been conducted.

The safety and efficacy of the drug in patients over 65 years of age have not been established, therefore dosing recommendations for such patients are currently unavailable.

Dose adjustment in children is not required. Overall, the safety and efficacy of the drug administered at a dose of 1 mg/kg body weight every 2 weeks in children aged 8 to 16 years in clinical studies were comparable to those in adults. Patients under 8 years of age were not included in clinical studies. Within an observational study, 24 patients aged 2 to 7 years and 36 patients aged 8 to 16 years were evaluated. During post-registration use, the overall safety profile of the drug in children corresponded to the safety profile in adults.

Instructions for preparation, dilution, administration of the solution for infusion and disposal of the medicinal product

The lyophilisate for the preparation of a concentrate for solution for infusion should be reconstituted with Water for Injections, diluted with 0.9% Sodium Chloride solution for intravenous administration and then administered by intravenous infusion.

Aseptic technique must be observed.

Determine the required number of vials for reconstitution according to the patient’s individual body weight, remove them from the refrigerator and leave for approximately 30 minutes to reach room temperature (from 23°C (73.4°F) to 27°C (80.6°F)). Each vial of the drug is intended for single use only.

Reconstitution of the lyophilisate (preparation of the concentrate)

Each vial of the drug is reconstituted with 7.2 ml of Water for Injections.

Foaming and rapid addition of water to the lyophilisate should be avoided. Water for Injections should be added slowly dropwise onto the inner wall of the drug vial, avoiding direct addition onto the lyophilisate, carefully tilting and rotating the vial. The vial should not be inverted, swirled, or shaken.

The reconstituted solution is a clear, colorless liquid.

Dilution of the concentrate

1. Before adding the reconstituted solution (concentrate) of Fabagal^® to provide the patient’s dose, it is recommended to remove an equal volume of 0.9% Sodium Chloride solution from the infusion container.
2. Remove air from the infusion container to minimize air-solution interaction.
3. From each vial, slowly withdraw 7.0 ml of concentrate (equivalent to 35 mg) until the total volume required to provide the patient’s dose is reached. Do not use filter needles and avoid foaming.
4. Slowly inject the concentrate directly into the 0.9% Sodium Chloride solution (the needle tip must be in the solution) until the concentration of the final solution is 0.05-0.7 mg/ml. Based on the patient’s individual dose, determine the total volume of 0.9% Sodium Chloride infusion solution (50-500 ml). For doses below 35 mg use a minimum of 50 ml, for doses of 35-70 mg use a minimum of 100 ml, for doses of 70-100 mg use a minimum of 250 ml and for doses over 100 mg use no more than 500 ml of 0.9% Sodium Chloride infusion solution. Gently invert or lightly press the surface of the infusion container to mix the diluted solution. Do not shake or vigorously agitate the contents of the infusion container.

Administration of the solution for infusion

It is recommended to administer the diluted solution through a 0.2 µm low protein-binding filter to remove any protein particles and avoid any loss of agalsidase beta activity. The initial infusion rate should not exceed 0.25 mg/min (15 mg/h) to minimize the potential development of reactions to intravenous infusion. After determining the patient’s tolerance to the drug, the infusion rate can be gradually increased in subsequent infusions, if the increase is tolerated.

Disposal

All remaining medicinal product and waste should be destroyed in accordance with established national legal requirements.

Adverse Reactions

Since Agalsidase beta (r-hαGAL) is a recombinant protein, the formation of IgG antibodies can be expected in patients with little or no residual α-galactosidase A enzyme activity. Patients who developed antibodies to agalsidase beta have a higher probability of experiencing infusion-related reactions. In a small number of patients, reactions indicative of immediate hypersensitivity (type I) were reported.

Very common adverse reactions included chills, hyperthermia, feeling cold, nausea, vomiting, headache, and paresthesia. In 67% of patients, at least one infusion-related reaction was observed. Anaphylactoid reactions were observed in the post-registration period.

The table below presents adverse reactions (with specification of system-organ classes and frequency) observed in clinical studies in a total of 168 patients (154 men and 14 women) receiving the drug at a dose of 1 mg/kg every 2 weeks (from one infusion up to a maximum 5-year treatment period). The following frequency grading was used for adverse reactions: very common (≥1/10), common (≥1/100 and <1/10), uncommon (≥1/1000 and <1/100).

The frequency of adverse reactions in one patient is defined as “uncommon” considering the relatively small number of treated patients. Adverse reactions observed only in the post-registration period are also included in the table below with the frequency category “frequency unknown” (frequency cannot be estimated from the available data). Most adverse reactions were mild to moderate in severity.

In this table, the rate of ≥1% is defined for reactions noted in two or more patients.

Adverse reaction terms are based on MedDRA terminology.

Description of selected adverse reactions

Infusion-related reactions (IRR)

Infusion-related reactions (defined as adverse reactions associated with drug administration occurring on the day of infusion) were the most frequently reported treatment-related adverse reactions observed in clinical studies. These IRRs included chills, fever (pyrexia/increased body temperature/hyperthermia), sensation of temperature change (feeling cold/feeling hot), nausea, vomiting, abdominal pain, hypertension (increased blood pressure), skin flushing (“hot flushes”), paresthesia (burning sensation), feeling of tiredness (lethargy/feeling of general discomfort/asthenia), pain (pain in extremity), myalgia, headache, pruritus (generalized pruritus), chest pain (chest discomfort), urticaria, dyspnea (increased dyspnea), dizziness, pallor, somnolence, tachycardia, and palpitations.

The development of somnolence may be associated with premedication with antihistamines.

IRRs were managed by reducing the infusion rate along with the use of non-steroidal anti-inflammatory drugs, antipyretics, antihistamines, and/or corticosteroids. In 67% of patients, at least one infusion-related reaction was observed. The frequency of these reactions decreased over time.

Cases of IRR development may be associated with the formation of IgG antibodies. Most patients with classic Fabry disease developed IgG antibodies to r-hαGAL, which was expected. In most patients, antibodies appeared within the first 3 months of treatment. Antibody titers decreased over time, and in some patients, the antibody test result became negative. Some patients developed neutralizing antibodies (NAb) that in vitro inhibited the catalytic activity of agalsidase beta and which also decreased over time; a small number of patients developed NAb inhibiting cellular uptake.

Typically, women develop antibodies less frequently and have lower titers than men, with most female patients testing negative for antibodies.

Patients with truncated GLA gene mutations or with plasma α-galactosidase A activity ≤1.5 nmol/h/ml had a higher risk of antibody formation and higher titers compared to patients with non-truncated GLA gene mutations or higher enzyme activity.

Overall, in more than 90% of adult patients and children treated with agalsidase beta, normal plasma globotriaosylceramide (GL-3) levels were achieved and maintained, regardless of the formation of antibodies to agalsidase beta. Antibody formation did not have a significant impact on the clinical efficacy of the drug.

Use in children

In a phase 2 clinical study, the safety profile of treatment with the drug in children aged 8 years and older was comparable to that in adult patients.

Limited information from a phase 3b clinical study confirms that the safety profile of treatment with the drug in children aged 5-7 years at a dose of 0.5 mg/kg every 2 weeks or 1.0 mg/kg every 4 weeks is similar to the safety profile in children aged 8 years and older receiving 1.0 mg/kg every 2 weeks.

Postmarketing experience

The adverse reaction profiles during postmarketing use and clinical studies are comparable.

Adverse reactions observed in the postmarketing period included: sensations of heat or cold, malaise, musculoskeletal pain, edema, rhinitis, rhinorrhea, and decreased blood oxygen saturation, administration site reactions. One patient experienced leukocytoclastic vasculitis. One case of membranous glomerulonephritis was reported.

A small number of patients experienced anaphylactoid reactions, which in some cases were assessed as life-threatening. Signs and symptoms of possible anaphylactoid reactions included localized angioedema, generalized urticaria, bronchospasm, and arterial hypotension.

Contraindications

• Hypersensitivity to agalsidase beta or to any of the excipients of the drug.

Use in Pregnancy and Lactation

Pregnancy

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

In studies conducted in animals, no direct or indirect adverse effects regarding reproductive toxicity were found.

The drug Fabagal^® can be used during pregnancy only if the expected benefit to the mother outweighs the potential risk to the fetus.

Studies on perinatal toxicity have not been conducted.

Breast-feeding period

It is unknown whether Agalsidase beta is excreted in human breast milk. Since many drugs are excreted in breast milk, a decision should be made, taking into account the benefit of breastfeeding for the child and the advantage of continued use of the drug for the mother, to discontinue breastfeeding or discontinue the drug Fabagal^® during the breastfeeding period.

Fertility

Studies evaluating the potential adverse effects of the drug Fabagal^® on fertility have not been conducted.

Use in Hepatic Impairment

In patients with hepatic impairment, dose adjustment is not required. Studies in patients with hepatic impairment have not been conducted.

Use in Renal Impairment

In patients with renal impairment, dose adjustment is not required.

Pediatric Use

Dose adjustment in children is not required. Patients under 8 years of age were not included in clinical studies.

Geriatric Use

The safety and efficacy of the drug in patients over 65 years of age have not been established, therefore dosing recommendations for such patients are currently unavailable.

Special Precautions

Since Agalsidase beta (r-hαGAL) is a recombinant protein, the formation of IgG antibodies is expected in patients with low or absent α-galactosidase A enzyme activity. Most patients developed IgG antibodies to r-hαGAL usually within 3 months after the first infusion of the drug. Over time, most seropositive patients in clinical studies demonstrated either a decrease in titers (≥4-fold decrease in titer from peak value to last measurement) (40% of patients), or no response (antibodies were not detected, confirmed by 2 consecutive negative radioimmunoprecipitation (RIP) assays) (14% of patients) or demonstrated a constant antibody titer (35% of patients).

Patients with antibodies to r-hαGAL have a higher probability of developing infusion-related reactions (IRR), which are any adverse reaction developing on the day of infusion. In these patients, re-administration of agalsidase beta should be performed with caution (see section “Adverse Reactions”).

IgG antibody titers should be regularly monitored.

Agalsidase beta has a negligible influence on the ability to drive and use machines on the day of drug administration, since dizziness, somnolence, and syncope may occur.

In clinical studies, 67% of patients experienced at least one IRR, most of which were mild or moderate in severity. The frequency of IRR occurrence decreased over time. Patients who developed mild or moderate IRRs during the use of agalsidase beta in clinical studies continued therapy after reducing the infusion rate (0.15 mg/min; 10 mg/h) and/or after premedication with antihistamines, paracetamol, ibuprofen, and/or corticosteroids.

As with the intravenous administration of any protein drug, hypersensitivity reactions, allergic reactions are possible.

In a small number of patients, reactions resembling immediate hypersensitivity (type I) reactions were noted. In case of a severe allergic or anaphylactoid reaction, the administration of Fabagal^® should be immediately stopped and intensive therapy should be initiated immediately in accordance with current clinical standards for emergency medical care. After the development of a severe hypersensitivity or anaphylactoid reaction, the risks and benefits of resuming the administration of Fabagal^® should be considered.

Successful resumption of treatment with Fabagal^® was conducted in patients who had a positive skin test or a positive test for the presence of IgE antibodies to r-hαGAL. Initial administration of the drug upon resumption of treatment should be at a low dose (half the therapeutic dose (0.5 mg/kg) and at a rate 25 times lower than the initial standard recommended administration rate (0.01 mg/min). With normal tolerance of such an infusion, the dose can be increased to the therapeutic dose of 1 mg/kg and the infusion rate can be gradually increased by slowly increasing it.

Sodium

This drug contains less than 1 mmol (23 mg) of sodium per vial, i.e., it is essentially sodium-free.

Effect on ability to drive and use machines

Agalsidase beta has an insignificant effect on the ability to drive vehicles and operate machinery on the day of drug administration, since dizziness, drowsiness, and fainting may occur.

Overdose

No cases of overdose of Fabagal^® have been reported. Doses up to 3 mg/kg of body weight were used in clinical studies.

Drug Interactions

No laboratory studies have been conducted regarding the metabolism of the drug. Based on the metabolism of agalsidase beta, its influence on cytochrome P450 isoenzymes and pharmacokinetic interaction at the metabolism level is unlikely. Fabagal^® should not be used concurrently with chloroquine, amiodarone, benoquin, or gentamicin due to the theoretical risk of reduced intracellular α-galactosidase (agalsidase alfa) activity.

Due to the lack of compatibility studies, Fabagal^® should not be mixed with other medicinal products in the same infusion.

Storage Conditions

The drug should be stored out of the reach of children at a temperature between 2°C (35.6°F) and 8°C (46.4°F). Do not freeze.

Shelf Life

The shelf life is 3 years.

Reconstituted and diluted solutions

The chemical and physical stability of the finished medicinal product has been confirmed for 24 hours at a temperature between 2°C (35.6°F) and 8°C (46.4°F).

From a microbiological point of view, the product should be used immediately. If the product is not used immediately, the storage of the finished product and the provision of conditions prior to administration are the responsibility of the user and should generally not exceed 24 hours at a temperature between 2°C (35.6°F) and 8°C (46.4°F), unless reconstitution (dilution) was carried out under verified and validated aseptic conditions.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.