WATCH (VPRIV)

Composition Pharmacodynamics Indications Carefully Contraindications Dosing and Administration Side effects Form release / dosage
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Active substanceVelagglutzerase alfaVelagglutzerase alfa
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  • WATCH
    lyophilizate d / infusion 
    Shayer AG     Switzerland
    • Dosage form: & nbsp

    lyophilizate for solution for infusion

    Composition:

    Active substance: velagglucerase alpha 200 ED (5 mg) and 400 ED (10 mg)

    Excipients:

    sucrose 100.00 mg or 200.00 mg, sodium citrate dihydrate 25.88 mg or 51.76 mg, citric acid monohydrate 2.52 mg or 5.04 mg, polysorbate-20 0.22 mg or 0.44 mg.

    * Unit of enzyme - the amount of enzyme that is needed to convert 1 μm p-nitrophenyl β-D-glucopyranoside at p-nitrophenol for 1 minute at 37 ° C.

    Description:

    White or almost white lyophilized powder or porous mass.

    Description of reconstituted solution

    Colorless transparent or slightly opalescent liquid.

    Pharmacotherapeutic group:Enzyme agent
    ATX: & nbsp

    A.16.A.B.10   Velagglutzerase alfa

    A.16.A.B   Enzyme preparations

    Pharmacodynamics:

    Velagglucerase alpha is produced on the HT-1080 line of human fibroblasts using recombinant DNA technology.

    Pharmacodynamics:

    Gaucher's disease is an autosomal recessive disease caused by a mutation of the glucocerebrosidase gene (GBA), which leads to a deficiency of the lysosomal enzyme beta-glucocerebrosidase. Deficiency of the lysosomal enzyme causes the accumulation of glucocerebroside, primarily in macrophages, leading to their overflow and growth of foam cells or "Gaucher cells".

    The disease belongs to the group of lysosomal storage diseases (LBN), the clinical manifestations are caused by the distribution of Gaucher cells in organs and tissues, and include hepatomegaly, splenomegaly, bone marrow, skeletal and lung bones. The accumulation of glucocerebroside in the liver and spleen leads to organomegaly. The defeat of bone tissue is accompanied by deformation and abnormalities of the bones of the skeleton, as well as bone crises. The accumulation of cells in the bone marrow and spleen leads to clinically pronounced anemia and thrombocytopenia.

    Velagglucerase alpha is produced by the method of gene activation on the human cell line. Velagglutzerase alfa is a glycoprotein. The monomer has a molecular weight of 63 kDa, includes 497 amino acids, the sequence of which is similar to the natural glucocerebrosidase enzyme. Contains 5 potential sites for binding to Nglycosaminoglycans, 4 of them are not free. Velagglutzerase alfa contains mainly glycosaminoglycans with a high content of mannose, which promote internalization of the enzyme by phagocytic target cells with the participation of receptors to mannose.

    Velaglucerase alpha replaces or enhances the action of the enzyme beta-glucocerebrosidase, which accelerates the hydrolysis of glucocerebroside with the formation of glucose and ceramide in lysosomes, reducing the concentration of accumulated glucocerebroside and, thereby, has a beneficial effect on the pathogenetic mechanisms of Gaucher disease. The use of velagglutzerase alpha is accompanied by an increase in the concentration of hemoglobin and the total number of platelets in the blood in patients with Gaucher type I disease.

    Pharmacokinetics:

    When intravenously, the concentration of velagglucerase alpha in blood plasma increases significantly during the first 20 minutes, the maximum concentration in the blood plasma (CmOh) is reached, as a rule, in 40-60 minutes. After completion of the administration of alpha-valglucerase at doses of 15, 30, 45 and 60 U / kg, the enzyme concentration rapidly decreases in a monophasic or biphasic curve, the half-life T1/2 an average of 5 to 12 minutes.

    The parameters of the pharmacokinetics of velagglucerase alpha are linear or close to the linear profile, CmOh and the area under the "concentration-time" curve (AUC) increase with increasing dose from 15 to 60 U / kg.The equilibrium state is achieved with a volume distribution, which is about 10% of body weight. The high clearance of velagglucerase alpha (6.7-7.6 ml / min / kg) is maintained and is accompanied by rapid absorption of the enzyme by macrophages with the participation of receptors to mannose.

    The clearance of velagglutzerase alpha in children (aged 4 to 17 years) does not differ from the corresponding parameters in adults (age 19 to 62 years). There were no significant differences in pharmacokinetics in patients with Gaucher's disease of type I of both sexes.

    During the study of pharmacokinetics, no cases of antibodies to velagglucose were observed. Thus, it is not possible to evaluate the effect of antibodies on the pharmacokinetic profile of the velagglucerase alpha.

    Preclinical safety data

    In the course of preclinical studies, the adverse effect of the drug on pharmacological safety was not established, including the absence of toxic effects in single or multiple dosing, as well as in the study of reproductive and embryotoxicity.

    Indications:

    VPRIV is indicated for long-term treatment of patients with Gaucher type I disease.

    Contraindications:

    Severe allergic reactions to the active substance or to any of the auxiliary substances.

    Carefully:
    Pregnancy and lactation:

    Pregnancy

    Currently, there is no data on the use of the drug WEDD by pregnant women. Preclinical studies do not indicate a direct or indirect adverse effect on pregnancy, embryonic / fetoplacental and postnatal fetal development and the process of delivery. Care should be taken when prescribing pregnant women.

    Breast-feeding

    Data on the use of the drug by women during breastfeeding are absent. It is not established whether the velagglucose alpha in breast milk. Due to the fact that it is possible to penetrate many drugs into breast milk, during the period of breastfeeding the use of the drug is recommended with caution.

    The use in women of childbearing age

    In women of childbearing age, suffering from Gaucher's disease, the deterioration of the course of the disease during pregnancy is possible. The benefit / risk ratio should be evaluated in each case of pregnancy.An individual approach to the management of pregnancy and control of the patient's condition is needed, as well as to assess the effectiveness of the treatment.

    Influence on reproductive capacity

    Experimental studies have not revealed signs of impaired ability to reproduce. There was no adverse effect of the drug in studies on the study of pharmacology, toxicity in single and repeated use of doses, in reproductive toxicity tests and evaluation of fetal development, studies in animals did not confirm an adverse effect on reproductive ability.

    Dosing and Administration:

    For intravenous infusion.

    WFI should be administered under the supervision of a physician experienced in treating patients with Gaucher's disease. In patients who received the drug 3 times or more, under the condition of good tolerability of treatment, under the supervision of a medical officer, it is possible to continue using the drug at home.

    Doses

    The recommended dose is 60 units / kg once every 2 weeks.

    The dose can be adjusted individually, based on the achievement of the expected effect and its conservation. In clinical studies, doses of the drug were administered from 15 to 60 U / kg once every 2 weeks.Doses above 60 U / kg were not studied.

    Conducted enzyme replacement therapy

    Patients who receive imiglucetase for the purpose of enzyme replacement therapy for Gaucher type I disease can start therapy with a WHIT immediately after the abolition of previous therapy, the drug is administered at the same dose and with the same frequency of use.

    Impaired liver and kidney function

    Dose adjustments are not required in patients with hepatic and renal impairment, taking into account the pharmacokinetics and pharmacodynamics of velagglucerase alpha.

    Use in children

    In clinical trials, 20 out of 94 patients (21%) were children (4 to 17 years). Profiles of efficiency and safety in adults and children were close.

    In the elderly (over 65)

    Correction of the dose is not required.

    Method of administration

    Only for intravenous infusions!

    The duration of the infusion is 60 minutes. VPRIV should be diluted, the drug is intended only for intravenous infusion. The contents of the vial are for single use only. The drug should be administered only through a filter with a diameter 0,22 microns.

    Follow the rules of asepsis.

    Instructions for reconstitution and dilution of the preparation WEL:

    1. It is necessary to determine the number of vials, the contents of which must be diluted, taking into account the patient's body weight and the recommended dose.

    2. The required number of vials is extracted from the refrigerator.

    - Dilution of vials 400 U / ml. In each vial, place 4.3 ml of sterile water for injection.
    - Dilution of vials 200 U / ml. In each vial, place 2.2 ml of sterile water for injection.

    3. After breeding, gently flip the vials. Do not shake. A bottle with 400 units will contain an extractable volume of 4.0 ml (100 U / ml) or 200 ED - 2.0 ml (100 U / ml).

    4. Before the next dilution, evaluate the contents of the vial - the solution should be slightly transparent and colorless (see "Description"); Do not use the drug if the solution has changed color or foreign substances have been detected,

    5. It is necessary to extract the calculated volume of the preparation from the appropriate number of bottles and dilute in 0.9 ml of 0.9% sodium chloride solution. Stir gently. Do not shake.

    The drug should be started within 24 hours after dilution.

    Application in case of impaired renal and hepatic function

    Taking into account the peculiarities of pharmacokinetics and pharmacodynamics of velagglucerase alpha, in patients with impaired renal and hepatic function, dose adjustment is not required.

    Application in elderly patients (≥65 years old)

    Older patients do not require dose adjustment.

    Side effects:

    Data on adverse reactions include information on 5 clinical trials for the use of the drug in 94 patients aged 4-71 years (46 men and 48 women) with Gaucher's disease of type I, who used velagglucerase alpha at doses of 15 to 60 U / kg every 2 weeks. In 54 patients, treatment was performed for the first time, and in 40 patients, imiglucetraz was previously used.

    The most serious adverse reactions in patients in clinical trials were hypersensitivity reactions.

    The most frequent undesirable reactions were the reactions associated with infusion. The most common symptoms are associated with infusion administration of the drug: headache, dizziness, decreased blood pressure, increased blood pressure, nausea, fatigue / asthenia, and fever / fever. The drug was canceled only because of undesirable reactions associated with infusion.

    Undesirable reactions noted in more than 1 patient with Gaucher's disease type I are listed below. Information is provided in accordance with the Convention MedDRA according to the organ class system and depending on the frequency of occurrence: very often (≥ 1/10) and often (≥ 1/100 to <1/10). In each group, adverse reactions are presented in order of decreasing severity.

    Immune system disorders

    often: hypersensitivity reactions.

    Disturbances from the nervous system

    Often: headache, dizziness.

    Disorders from the cardiovascular system

    often: tachycardia, increased blood pressure, lower blood pressure, "tides" of blood to the skin of the face.

    Disorders from the gastrointestinal tract

    often: abdominal pain / pain in the upper abdomen, nausea.

    Disturbances from the skin and subcutaneous tissues:

    often: rash, hives.

    Disturbances from musculoskeletal and connective tissue

    Often: pain in the bones, joints, back pain

    General disorders and disorders at the site of administration

    highly often: reactions associated with infusion, fatigue / asthenia, fever / fever.

    Laboratory and instrumental data

    often: an increase in the duration of activated partial thromboplastin time (AF HB), a positive reaction to neutralizing antibodies.

    Children

    The profile of tolerability of the drug in children aged 4-17 did not differ from the corresponding observations in adults.

    Overdose:

    There are no known cases of drug overdose. The maximum dose is 60 units / kg.

    Interaction:

    Studies on the study of interactions were not conducted. Patients should be advised to inform clinicians of any symptoms when they are used concomitantly with other drugs.

    It is strictly forbidden to mix and inject the drug with another drug in one vial.

    Special instructions:

    Hypersensitivity

    With the infusion of a drug containing a protein, the development of hypersensitivity reactions is possible. In the period of treatment with the drug, WHIP, if necessary, the patient should provide adequate medical care. In the event of life-threatening anaphylactic reactions, emergency therapy is carried out.

    The use of the drug is recommended with caution in patients who have a history of hypersensitivity symptoms with the use of other enzyme replacement drugs.

    Reactions associated with infusion introduction

    In clinical trials, the most frequently reported reactions associated with infusion administration. The severity of the reactions was mainly assessed as a lung.In patients treated for the first time, a greater number of reactions were observed within 6 months.

    Treatment of reactions associated with infusion administration depends on the severity of the reactions, and includes, along with a decrease in the rate of drug administration, the use of drugs such as antihistamines and antipyretic agents, low doses of corticosteroids, it is also recommended that the drug be discontinued for a short time, followed by continued infusion.

    In some cases, when symptomatic therapy is shown to patients, antihistamines and / or corticosteroids are used. Preliminary premedication, as a rule, was not carried out in clinical studies.

    Immunogenicity

    In clinical studies, one in 94 patients (1% of patients) had antibodies of class IgG against velagglucerase alpha, in the analysis in vitro it is established that they are neutralizing. This patient has not identified any reactions associated with intravenous infusion. Antibody class IgE to velagglucerase was not revealed.

    Sodium

    Due to the fact that the medicinal product contains 12.15 mg of sodium in a vial containing 400 ED and 6.07 mg of sodium in a bottle containing 200 U,this fact should be taken into account in patients who need a diet with sodium content restriction.

    Special precautions when destroying an unused preparation

    Unused medication or its remnants must be disposed of in accordance with local requirements.

    Reconstituted and dissolved solution for infusions

    The chemical and physical stability of the preparation during storage for 24 hours at a temperature of 2 to 8 ° C in a dark place is confirmed.

    From a microbiological point of view, the drug should be used immediately after dilution. With a later application of the drug, the shelf-life of the diluted solution should not exceed 24 hours if the above storage conditions are observed, and the consumer is liable for non-compliance with storage requirements.

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

    VRVV does not adversely affect the ability to drive a car or other machinery.

    Form release / dosage:

    Lyophilizate for solution for infusion.

    Packaging:

    For 200 units of algla velagglucerase in bottles of borosilicate glass (type I) with a capacity of 5 ml, sealed with a butyl rubber stopper, coated with fluorine-containing resin and compacted from above aluminum cap, equipped with detachable plastic disc type "flip-off".

    By 400 units of algla dela velagglucerase in bottles of borosilicate glass (type I) with a capacity of 20 ml, sealed with a butyl rubber stopper, coated with fluorine-containing resin and compacted from above aluminum cap, equipped with detachable plastic disc type "flip-off".

    One bottle together with the instruction for use is placed in a cardboard box.

    Storage conditions:

    At a temperature of 2 to 8 ° C.

    Do not freeze.

    Keep the bottle in its original packaging, protected from light.

    KEEP OUT OF THE REACH OF CHILDREN.
    Shelf life:

    1,5 years (200 units), 3 years (400 units).

    Do not use after the expiry date printed on the package.

    Terms of leave from pharmacies:On prescription
    Registration number:LP-001975
    Date of registration:23.01.2013 / 15.07.2013
    Expiration Date:23.01.2018
    The owner of the registration certificate:Shayer AGShayer AG Switzerland
    Manufacturer: & nbsp
    Representation: & nbspSchayer Pharmaceutical Contracts LimitedSchayer Pharmaceutical Contracts LimitedRussia
    Information update date: & nbsp10.03.2017
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