Velagglutzerase alfa (Velaglucerase alfa *)

Pharmacodynamics Pharmacokinetics Indications Carefully Contraindications Dosing and Administration Side effects
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Clinical and pharmacological group: & nbsp

Enzymes and antiferments

Included in the formulation
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    lyophilizate d / infusion 
    Shayer AG     Switzerland
    • Included in the list (Order of the Government of the Russian Federation No. 2782-r of 30.12.2014):

    7 nosologies

    VED

    АТХ:

    A.16.A.B.10   Velagglutzerase alfa

    A.16.A.B   Enzyme preparations

    Pharmacodynamics:

    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 N-glycosaminoglycans, 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.

    Gaucher's disease is an autosomal recessive disease caused by a mutation of the glucocerebrosidase gene, 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 accumulation diseases, 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.

    Pharmacokinetics:

    With intravenous administration, the concentration of velagglucerase alpha in plasma increases significantly during the first 20 minutes, Cmax is achieved, as a rule, in 40-60 minutes. After completion of the administration of velagglutzerase alpha at doses of 15, 30, 45 and 60 U / kg, the enzyme concentration rapidly decreases in a monophasic or two-phase curve, half-life an average of 5 to 12 minutes.

    The parameters of the pharmacokinetics of velagglucerase alpha have a linear or near-linear profile, Cmax and the area under the "concentration-time" curve increases 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:

    Long-term treatment of patients with Gaucher's disease type I.

    ICD-10

    IV.E70-E90.E75   Disorders of sphingolipids exchange and other diseases of lipid accumulation

    Contraindications:

    Severe allergic reactions to the active substance or to any of the excipients.

    Carefully:

    Care should be taken when prescribing pregnant women.

    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.

    Pregnancy and lactation:

    Pregnancy

    Currently, there is no data on the use of the drug 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 tests of reproductive toxicity and evaluation of fetal development,studies in animals have not confirmed an adverse effect on the ability to reproduce.

    Dosing and Administration:

    For intravenous infusion.

    The drug should be administered under the supervision of a doctor who has experience in treating patients with Gaucher 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 the drug 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. The drug 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 0.22 μm filter.

    Follow the rules of asepsis.

    Instructions for reconstitution and dilution of the drug:

    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 dilution, 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; 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 100 ml of 0.9% sodium chloride solution. Stir gently. Do not shake.

    The drug should be started within 24 hours after dilution.

    Side effects:

    Data on adverse reactions include information on 5 clinical trials of the use of the drug in 94 patients aged 4-71 years (46 men and 48 women) with Gaucher type I disease who were using velagglutzerase alpha at doses of 15 to 60 U / kg 1 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,lowering blood pressure, increasing 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. The information is presented in accordance with the MedDRA Convention on 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 - reactions of hypersensitivity.

    Impaired nervous system: very often - headache, dizziness.

    Disorders from the cardiovascular system: often - tachycardia, increased blood pressure, decrease blood pressure, "tides" of blood to the skin of the face.

    Disorders from the digestive tract: often - pain in the abdomen, pain in the upper abdomen, nausea.

    Disturbances from the skin and subcutaneous tissues: often - a rash, hives.

    Disturbances from the musculoskeletal and connective tissue: very often - pain in the bones, joints, back pain

    General disorders and disorders at the site of administration: very often - reactions associated with infusion, fatigue / asthenia, fever / fever.

    Laboratory and instrumental data: often - an increase in the duration of activated partial thromboplastin time, 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 physicians of any symptoms that occur with the simultaneous use of this drug with other drugs. Strictly forbidden to mix and inject the drug with other drugs in one bottle.

    Special instructions:

    Hypersensitivity

    With the infusion of a drug containing a protein, the development of hypersensitivity reactions is possible.In the period of drug treatment, 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 reduction in the rate of administration of the drug, the use of such drugs as antihistamines and antipyretics, 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.

    Immunogenicity

    In clinical studies, one in 94 patients (1% of patients) had antibodies of IgG class 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. Antibodies of IgE class to velagglucerase were not detected.

    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 ED, this fact should be taken into account in patients who need a diet with sodium 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 infusion solution

    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, subject to the above conditionsStorage should not exceed 24 hours, the responsibility for non-compliance with storage requirements rests with the consumer.

    Impact on the ability to drive vehicles and mechanisms:

    The drug does not adversely affect the ability to drive a car or other mechanisms.

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