Active substanceAgalsidase betaAgalsidase beta
Similar drugsTo uncover
  • Fabrazym®
    lyophilizate d / infusion 
    Genzyme Europe BV     Netherlands
  • Dosage form: & nbsplyophilizate for the preparation of concentrate for the preparation of a solution for infusions
    Composition:

    Each vial contains:

    Active substance: agalsidaz beta - 35 mg (+ excess of filling 2 mg);

    Excipients: mannitol, sodium dihydrogen phosphate monohydrate, sodium hydrogen phosphate heptahydrate.

    After reconstitution with 7.2 ml of water for injection, each vial of Fabrazyme ® contains 5 mg / ml (35 mg / 7 ml) of agalicidase beta. The reconstituted solution should be further diluted (see section "Instructions for use, handling and destruction of drug residues").

    Agalsidase beta is a recombinant form α-galactosidase A, which is identical to the natural form of α-galactosidase.

    Description:

    Compact weight (lyophilizate) or powder from white to almost white.

    Pharmacotherapeutic group:Enzyme agent
    ATX: & nbsp

    M.09.A.B   Enzyme preparations

    Pharmacodynamics:

    Fabry disease is a heterogeneous and polysystemic disease characterized by a deficiency of α-galactosidase, lysosomal hydralase, which catalyzes the hydrolysis of glycosphingolipids, in particular globotriaosylceramide (globotriaosylceramide-GL-3).

    The decrease or absence of α-galactosidase activity causes the accumulation of GL-3 in lysosomes of many cell types, including endothelial and parenchymal cells, which ultimately leads to life-threatening clinical manifestations as a result of damage to the kidneys, heart and brain vessels.

    Enzyme replacement therapy is aimed at restoring the level of enzymatic activity sufficient to remove the substrate accumulating in the tissues of the organs, thereby preventing, stabilizing or completely restoring the progressive decrease in the function of these organs before irreversible changes develop.

    After intravenous administration agalsidase beta is quickly removed from the systemic blood flow and is captured by the vascular endothelium and parenchymal cells, including in the lysosomes, probably through mannose-6-phosphate, mannose, and asialoglycoprotein receptors. The effects of doses 0.3, 1.0 and 3.0 mg / kg once every 2 weeks and doses of 1.0 and 3.0 mg / kg once every 2 days were evaluated. Reduction of the GL-3 content was observed in the kidneys, heart, skin and plasma under all dosage regimes.The decrease in GL-3 content in plasma was dose-dependent, but was less constant with a dose of 0.3 mg / kg. In addition, it was found that the reactions related to infusion (RI) also had a dose-dependent character. Fabrazyme was effective in removing GL-3 from the renal vascular endothelium after 20 weeks of treatment.

    Renal function, determined by glomerular filtration rate, serum creatinine and proteinuria, remained stable in most patients. However, the effect on renal function, with the use of Fabrazyme® in some patients with developed renal pathology, was limited.

    Although no specific studies have been conducted to evaluate the effect on neurologic symptoms, the results also indicate that patients with ferment replacement therapy may experience pain reduction and improve quality of life.

    The incidence of clinical complications was significantly lower among patients treated with Fabrazim®, compared with patients receiving placebo. This result was equally related to complications from the kidneys, heart and vessels of the brain.

    Treatment with Fabrazym® at a dose of 1 mg / kg once every two weeks provides an improvement in the main clinical results (reduces the incidence of renal, cardiac, cerebral infarction) in patients with Fabry's disease in the early and advanced stages. In view of the slow progression of the disease, its early detection and treatment are the determining factors for achieving better results.

    For 24 weeks of treatment with a dose of 1 mg / kg once every two weeks, the 0.3 mg / kg dosing regimen every 2 weeks for 18 months maintained the clearance of cellular GL-3 in the capillary endothelium of the kidneys, other types of kidney and skin cells (superficial endothelium of the skin capillaries) in most patients. However, with a lower dose, IgG antibodies can play a role in the clearance of GL-3 in some patients. Due to the small number of patients, an accurate conclusion regarding the maintenance regimen can not be made, but the results suggest that, after applying an initial dose of 1.0 mg / kg every 2 weeks, reducing the bulk of GL-3, a dose of 0.3 mg / kg every 2 weeks may be sufficient to maintain the clearance of GL-3 in some patients.

    Pharmacokinetics:

    After of intravenous agalysidase beta to adults at a dose of 0.3 mg, 1 mg, and 3 mg / kg of body weight, the AUC values ​​(area under the concentration-time curve) increased more than proportionally to the dose due to decreased clearance, indicating saturation clearance. The half-life was dose-dependent and ranged from 45 to 100 minutes.

    After intravenous agalsidase beta-beta for adults for approximately 300 minutes at a dose of 1 mg / kg body weight 1 every 2 weeks the mean maximum plasma concentration (CmOh) were 2000 to 3500 ng / ml, while the AUC valuesinf were from 370 to 780 μg.min / ml. The volume of the distribution in the equilibrium state (Vss) was 8.3 - 40.8 l, plasma clearance - 119 - 345 ml / min, and the average half-life is 80 -120 min.

    For children, the patient's body weight did not affect the clearance of agalsidase. The initial clearance was 77 ml / min, Vss - 2.6 liters, and the half-life is 55 minutes. After seroconversion of IgG, the clearance was reduced to 35 ml / min, Vss increased to 5.4 liters, and the half-life increased to 240 minutes. The overall effect of these changes after seroconversion consisted in a 2 to 3 fold increase in action, which was confirmed by the values ​​of AUC and CmOh. In the case of patients who reported increased potency after seroconversion, no additional safety measures were taken. Agalsidase beta is a protein, therefore it is believed that its metabolism is carried out by peptide hydrolysis. Accordingly, the effect of liver function abnormalities on the pharmacokinetics of agalsidase beta in a clinically significant degree is unlikely. It is believed that excretion through the kidneys is an insignificant part of the clearance of agalsidase beta.

    Indications:Fabrazym® is intended for prolonged enzyme replacement therapy in patients with a confirmed diagnosis of Fabry disease (α-galactosidase A deficiency).
    Contraindications:

    Hypersensitivity (anaphylactic reaction) to the active substance or to any ingredient in the preparation.

    Pregnancy and lactation:

    There are no reliable data on the use of agalsidase beta during pregnancy and lactation. Fabrazym® should not be used during pregnancy, except in cases of obvious need.

    Agal oxidase beta can be excreted into breast milk. Since data on the effect of agalsidase beta on newborns who are breastfed are absent,It is recommended that breastfeeding be discontinued during the use of Fabrazyme®.

    Dosing and Administration:

    The treatment of Fabry's disease should be performed under the supervision of a physician with experience in managing patients with Fabry's disease or other congenital metabolic diseases.

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

    In clinical trials, alternative dosing regimens were used. One study found that after an initial dose of 1 mg / kg every two weeks for 6 months, a dose of 0.3 mg / kg every two weeks could maintain GL-3 clearance in certain cell types in some patients; however, the significance of these data in the long-term period is not established (see the section "Pharmacodynamics").

    In order to reduce the potential for the development of reactions associated with infusion, the initial infusion rate should not exceed 0.25 mg / min (15 mg / hour). After establishing tolerance, with subsequent infusions, the infusion rate can be gradually increased.

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

    Studies in patients with hepatic insufficiency have not been conducted.

    The safety and efficacy of Fabrazyme in patients older than 65 years have not been established, and there are currently no recommendations on the dosing regimen for this category of patients.

    Application in pediatrics Studies in children from birth to 7 years have not been conducted.

    At the moment there are no recommendations on the dosing regimen in this age group of pediatric patients, data on the safety and efficacy of the drug are not available.

    In children aged 8-16 years, dose adjustment is not required.

    Side effects:

    Adverse reactions (PR) detected during the course of clinical trials related to the use of Fabrazyme, which were administered to a total of 168 patients (154 men and 14 women) at a dose of 1 mg / kg in an amount from one infusion to a maximum of 5 years of use, are listed lower in the table and classified according to organ systems and frequency (very often more than 1/10, often more than 1/100 and less than 1/10 and rarely more than 1/1000 and less than 1/100). The development of PR in one patient is defined as rare in light of the relatively small number of patients receiving treatment.OL identified in the postmarketing period are also included in the table below with an unknown frequency category. PRs were mainly from mild to moderate severity.

    Body System

    Often

    Often

    Rarely

    Unknown frequency

    Infections and invasions

    Nasopharyngitis

    Rhinitis

    The immune system

    Anaphylactoid reaction

    Nervous system

    Headache, paresthesia

    Dizziness, drowsiness, hypoesthesia, burning sensation, apathy, fainting

    Hyperesthesia, tremor

    Body of sight

    Increased lacrimation

    Itching of the eyes, hyperemia of the eyes

    The organ of hearing and balance

    Noises in the ears, dizziness

    Puffiness of the external ear, pain in the ears

    Cardiac system

    Tachycardia, palpitation, bradycardia

    Sinus bradycardia

    Vascular system

    "Tides", increased blood pressure, pallor, hypotension, "hot flashes" of heat

    Coldness of the extremities

    Respiratory system, thorax and mediastinum

    Shortness of breath, nasal congestion, a feeling of tightness in the throat, stridor, cough, increased dyspnoea

    Bronchospasm, pharyngolaryngeal pain, rhinorrhea, tachypnea, upper respiratory tract obstruction

    Digestive system

    Nausea, vomiting

    Pain in the abdomen, incl. In the epigastric region, discomfort in the abdomen, incl.in the stomach, decreased sensitivity of the oral mucosa, diarrhea

    Dyspepsia, dysphagia

    Skin and subcutaneous tissue

    Itching, hives, rashes, erythema, generalized itching, angioedema, facial edema, maculopapular rash

    Reticulum, erythematous rash, rash with itching, discoloration, skin discomfort

    Leukocytoclastic vasculitis

    Musculoskeletal and connective tissue system

    Pain in the extremities, muscle pain, back pain, muscle spasms, arthralgia, muscle stiffness, musculoskeletal stiffness

    Musculoskeletal pain

    Place of injection and general health

    Chills, fever, cold sensation

    Fatigue, chest discomfort, fever, peripheral edema, pain, asthenia, chest pain, facial swelling, hyperthermia

    Feeling of heat and cold, flu-like condition, pain at the injection site, reaction at the injection site, thrombosis at the injection site, malaise, swelling

    PR with a frequency of> 1% is defined as PR occurring in two or more patients. The above terminology corresponds to the international medical terminology MedDRA

    Reactions associated with infusion (RSI), manifested itself more often in the form of fever and chills. Additional symptoms included dyspnea of ​​mild or moderate severity, a feeling of tightness in the throat, chest discomfort, hot flashes, itching, urticaria, face swelling, angioedema, rhinitis, bronchospasm, tachypnea, stridor, increased blood pressure, lowering blood pressure, tachycardia, palpitations , abdominal pain, nausea, vomiting, pain associated with infusion, incl. pain in the extremities, myalgia, and headache.

    With the development of RCI reduced the rate of infusion and prescribed non-steroidal anti-inflammatory drugs, antihistamines and / or glucocorticosteroids. At 67% of patients, at least one RCI was noted. Most of these reactions can be related to the formation of IgG antibodies to beta-agalyzidase and / or complement activation. IgE antibodies were detected in a limited number of patients (see section "Special instructions").

    Pediatric Use

    Based on the limited information available, it can be assumed that the Fabrazyme® safety profile in children older than 7 years and in adults does not differ.

    Overdose:

    No cases of drug overdose have been reported.In clinical studies, doses up to 3 mg / kg body weight were used.

    Interaction:

    There were no laboratory studies on the metabolism of the drug. Based on the metabolism of agalsidase beta, its effect on cytochrome P450, which mediates the interaction of drugs among themselves, is unlikely.

    Fabrazym® should not be used concomitantly with chloroquine, amiodarone, benochin, or gentamicin because of the theoretical risk of decreasing the activity of α-aglysidase. Due to the lack of compatibility studies, Fabrazym® should not be mixed with other medical products in one infusion.
    Special instructions:

    As agalsidase beta (r-hαGAL) is a recombinant protein, the formation of IgG antibodies is expected in patients with little or no enzymatic activity. Most patients developed IgG antibodies to r-hαGAL usually within 3 months after the first infusion of Fabrazyme. Over time, the majority of seropositive patients in clinical trials demonstrated either a decrease in titres (> 4-fold decrease in titer from the peak to the last measurement) (40% of patients),or no response (antibodies were not detected, as confirmed by 2 consecutive radioimmunoprecipitation (RIP) reactions) (14% of patients) or demonstrated a continuous antibody titer (35% of patients).

    Patients with antibodies to r-hαGAL are more likely to develop RSI, which is any side effect that developed on the day of the infusion. In these patients, repeated administration of agalsidase beta should be carried out with caution (see section "Side effect"). It is necessary to regularly monitor antibody titers.

    In clinical trials, 67% of patients experienced at least one RCI (see the "Side effect" section). The incidence of RSI decreased with time. Patients with developed lung or moderate RSI with agalsidase beta during clinical trials continued therapy after reducing infusion rate (-0.15 mg / min; 10 mg / h) and / or after premedication with antihistamines, paracetamol, ibuprofen and / or glucocorticosteroids.

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

    In a small number of patients, reactions resembling immediate type hypersensitivity reactions (type I) were noted. In the case of a severe allergic reaction or anaphylactic-type reaction, the immediate administration of Fabrazyme® and take appropriate action. It is necessary to monitor the current medical standards of emergency therapy. In clinical studies, after conducting provocative samples, repeated administration of Fabrazyme® to patients with a positive IgE titer and a positive skin test to Fabrazyme®. In this study, repeated administration of the drug was first performed at a lower dose and at a lower rate (1/2 therapeutic dose and 1/25 of the initial standard recommended rate). With normal infusion tolerance, the dose can be increased to a therapeutic dose of 1 mg / kg, and the infusion rate can be gradually increased as the patient is tolerated.

    The effect of treatment with Fabrazyme® on the kidneys can be reduced in patients with severe kidney disease. There were no studies of the effect of Fabrazyme on reproductive function.

    Instructions on the use, handling and destruction of drug residues

    Lyophilizate for the preparation of concentrate for the preparation of solution for infusions should be restored with water for injection, diluted with 0.9% sodium chloride solution for intravenous administration and then administered by intravenous infusion.

    Follow the rules of asepsis. Determine the number of reconstituted vials according to the individual body weight of the patient, remove them from the refrigerator and leave them to warm to room temperature, for about 30 minutes. Each vial of Fabrazyme® is intended for single use only.

    Recovery (preparation of concentrate)

    Each vial of Fabrazyme® is reconstituted with 7.2 ml of water for injection. Avoid foaming and rapid addition of water to the lyophilizate. Water for injection should be added by slowly digging to the wall of the vial with the drug, avoiding its addition directly to the lyophilizate. Carefully tilt and turn each bottle. The bottle should not be turned, rotated or shaken.

    The reconstituted solution (concentrate) contains 5 mg / ml agalicidase beta, and is a clear and colorless solution. The pH of the concentrate is about 7.Before further dilution, visually inspect the vial for particles and discoloration. In the presence of particles or when changing colors, concentrate should not be used.

    After reconstitution (preparation of the concentrate), it is recommended that the contents of the vials be quickly diluted to prevent the formation of protein lumps that occur over time.

    Any unused product or waste should be disposed of in accordance with local requirements.

    Dilution of concentrate

    Before diluting the concentrate from the infusion container, it is recommended to remove the volume of 0.9% sodium chloride solution equal to the volume of the concentrate.

    Remove air from the infusion container to minimize the interaction of air and solution.

    From each vial, 7.0 ml of concentrate (equivalent to 35 mg) are slowly withdrawn to the total volume required to provide the patient's dose. Do not use a needle with a filter and avoid foaming.

    Slowly inject the concentrate directly into a 0.9% solution of sodium chloride (the tip of the needle should be in solution) until the concentration of the finished solution is 0.05 -0.7 mg / ml.Based on the individual dose of the patient, the total volume of 0.9% of the infusion solution of sodium chloride (50 - 500 ml) is determined. For doses below 35 mg, a minimum of 50 ml is used, a minimum of 100 ml is used for doses of 35 to 70 mg, a minimum of 250 ml is used for doses of 70-100 mg, and 500 ml of 0.9% sodium chloride infusion solution is used for doses greater than 100 mg. Carefully turn over or lightly press on the surface of the infusion container to mix the diluted solution. Do not shake or vigorously shake the contents of the infusion container.

    Introduction

    A diluted solution is recommended to be injected through a 0.2 μm filter with a low level of protein binding to remove any protein particles and to avoid any loss of agsidase beta activity. The initial infusion rate should be no more than 0.25 mg / min (15 mg / hour) to minimize the possible development of RSI. After determining the tolerability of the drug by the patient, the infusion rate can be gradually increased with subsequent infusions.

    Effect on the ability to drive transp. cf. and fur:

    Studies have not been conducted.

    Form release / dosage:Lyophilizate for the preparation of a concentrate for the preparation of a solution for infusions of 35 mg in an amount equivalent to 35 mg r-hαGAL.
    Packaging:

    Lyophilizate for the preparation of a concentrate for the preparation of a solution for infusions of 35 mg in an amount equivalent to 35 mg r-hαGAL, in a glass of Type I glass with a capacity of 20 ml, sealed with a siliconized rubber stopper with aluminum rolling and crimped with a plastic cap.

    For 1, 5 or 10 vials with instructions for use in a cardboard pack.

    Storage conditions:

    At a temperature of 2 to 8 ° C (in the refrigerator).

    Keep out of the reach of children!

    Storage of reconstituted and diluted solution:

    In terms of microbiological safety, the product should be used immediately. If the solution has not been used immediately, the responsibility for its storage and storage conditions lies entirely with the person using it, however this solution should not be stored for more than 24 hours at a temperature of 2 ° C to 8 ° C in a dark place.

    Shelf life:

    3 years.

    Do not use after the expiration date stated on the package.
    Terms of leave from pharmacies:On prescription
    Registration number:LSR-003334/09
    Date of registration:30.04.2009
    The owner of the registration certificate:Genzyme Europe BVGenzyme Europe BV Netherlands
    Manufacturer: & nbsp
    GENZYME, Ltd. United Kingdom
    Representation: & nbspJENZAIM RUS LLCJENZAIM RUS LLCRussia
    Information update date: & nbsp27.01.2014
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