Cerezyme - instructions for use, dose, side effects, contraindications

Active substanceImigluceraseImiglucerase

Similar drugsTo uncover

lyophilizate in / in

Dosage form: & nbsplyophilizate for solution for infusion

Composition:

Each vial contains:

Active Ingredient: imiglucerase ** 200 ED or 400 U *. Excipients: mannitol, sodium citrate dihydrate, citric acid monohydrate, polysorbate 80.

* ED denotes the amount of enzyme that catalyzes the hydrolysis of 1 micromole of the synthetic substrate of para-nitrophenyl P-D-pocypyranoside (pNP-Glc) per minute at 37 ° C.

** Imiglucerase is a modified form of acidic human beta-glucosidase produced by Chinese hamster ovary cells using recombinant DNA technology, with mannose modification for directed interaction with macrophages.

Description:Lyophilized powder or lyophilisate of white or almost white color.

Pharmacotherapeutic group:Enzyme agent

ATX: & nbsp

A.16.A.B.02 Imiglucerase

Pharmacodynamics:

Gaucher's disease is a rare autosomal-recessive metabolic disease caused by deficiency of lysosomal enzyme - acidic p-glucosidase. This enzyme catalyzes the hydrolysis of glucosylceramide, a key component of the lipid structure of cell membranes, to glucose and ceramide.In patients with Gaucher's disease there is an insufficient decomposition of glucosylceramide, which leads to the accumulation of a large amount of this substrate in the lysosomes of macrophages (they are called "Gaucher cells"), resulting in widespread secondary pathological changes. Gaucher cells are usually found in the liver, spleen and bone marrow, sometimes in the lungs, kidneys and intestines. From a clinical point of view, Gaucher's disease is characterized heterogeneous

phenotypic spectrum. The most frequent manifestations of the disease are hepatosplenomegaly, thrombocytopenia, anemia and pathological changes in bone tissue. These changes often are the most disabling manifestations of Gaucher disease. These include: bone marrow infiltration, osteonecrosis, bone pain and bone crises, osteopenia and osteoporosis, pathological fractures and bone growth disorders. Gaucher's disease is associated with increased glucose production and increased energy expenditure at rest, which can contribute to the emergence of increased fatigue and the development of cachexia. In patients with Gaucher's disease, there may also be mild inflammatory changes.In addition, Gaucher disease is associated with an increased risk of developing disproteinemia in the form of hypergammaglobulinemia, polyclonal gammopathy, monoclonal gammopathy of unknown etiology and myeloma. As a rule, the course of Gaucher's disease is characterized by progression with the risk of developing irreversible complications that appear from the side of various organs over time. Clinical manifestations of Gaucher disease can adversely affect the quality of life. The disease is characterized by a problem of increased morbidity and early death. When signs and symptoms appear in childhood, as a rule, the disease is more severe. In children, Gaucher's disease can lead to a delay in growth and sexual development.

Imiglucerase (recombinant macrophage-targeted (5-glucosidase) replaces the deficiency of the enzyme by hydrolyzing glucosylceramide, thereby stopping the initial pathophysiological changes and preventing the development of secondary pathological manifestations of the disease.Cerezyme leads to a decrease in the size of the spleen and liver, improves or normalizes the level of platelets and erythrocytes in the blood ,improves or normalizes bone mineral density and reduces bone marrow infiltration, and also weakens or alleviates bone pain and bone crises. Tserezim reduces the degree of energy expenditure at rest. It has been shown that it improves both the mental and physical characteristics of the quality of life of patients with Gauchers disease. Tserezim reduces the level of chitotriosidase, a biomarker for the accumulation of glucosylceramide in macrophages and the response to ongoing therapy. When used in children, Cerezim leads to normal sexual development and catching up growth, which in adulthood is manifested by normal growth and normal bone mineral density. The speed and severity of the reaction to treatment with Ceresime depends on the dose. As a rule, improvements on the part of organ systems appear more quickly in systems with a higher rate of metabolism, for example, on the part of the blood system, compared with those where this process is slower, such as bone tissue.

In the Gaucher patients' register of the Joint International Gaucher Disease Group (ICGG), analysis of a large group of patients (n = 528) with Gaucher's Type 1 disease showed a time and dose-dependent effect of Cerezyme on hematologic and

visceral manifestations (number of platelets, hemoglobin concentration, liver and spleen size) at doses of 15, 30 and 60 U / kg once every 2 weeks. Patients who received 60 U / kg every 2 weeks showed a faster improvement and the greatest maximum treatment effect compared to patients receiving lower doses.

Similarly, in the register of patients with Gaucher's disease (ICGG), bone mineral density analysis using dual-energy X-ray absorptiometry (DEPA) showed that in 342 patients after 8 years of therapy, a normal bone mineral density was achieved with a dose of Cerezyme equal to 60 ED / kg once every 2 weeks, but this was not observed at lower doses - 15 and 30 U / kg once every 2 weeks (Wenstrup et al., 2007). In a study evaluating 2 groups of patients who received an average dose of 80 U / kg and 30 U / kg every 4 weeks, among patients, the degree of bone marrow infiltration> 6, in a larger number in the group with a higher dose (33%; n = 22) a reduction in infiltration was achieved by 2 points after 24 months of Ceresim therapy compared to the group receiving a lower dose (10%, n = 13) (de Fost et al., 2006).

Therapy with Cerezyme at a dose of 60 U / kg once every 2 weeks resulted in a decrease in back pain after 3 months, within 12 months, the severity of bone crises decreased, and bone mineral density improved within 24 months of therapy (Sims et al. , 2008). Physicians and healthcare providers are advised to register patients with Gaucher disease, including those who have had chronic neuropathic manifestations of the disease, in the register of patients with Gaucher disease

The Joint International Group for the Study of Gaucher Disease (ICGG). In this register, anonymous patient data are collected. The goal of creating the register of patients with Gaucher's disease (ICGG) was to improve the understanding of Gaucher's disease and evaluate the effectiveness of enzyme replacement therapy, ultimately being a prerequisite for improving the safety and effectiveness of Cerezima.

Pharmacokinetics:As a result of intravenous infusions, 4 doses of imiglucerase (7.5, 15, 30, 60 U / kg body weight) for 1 hour, stable enzyme activity was achieved by 30 minutes. After the infusion, the enzyme activity in the plasma rapidly decreased with a half-life of 3.6 to 10.4 minutes.The plasma clearance varied from 9.8 to 20.3 ml / min / kg (mean ± standard deviation, 14.5 ± 4.0 ml / min / kg). The volume of distribution in terms of the weight of the patient ranged from 0.09 to 0.15 l / kg (mean ± standard deviation, 0.12 ± 0.02 l / kg). Probably, these indices do not depend on the dose or duration of infusion, however, only one or two patients studied each dose and infusion rate.

Indications:For prolonged enzyme replacement therapy in patients with a confirmed diagnosis of Gaucher disease of the first type (without neuronopathic manifestations) or a third type (with chronic neuronopathic manifestations) who have clinically significant non-neurological manifestations of the disease.

Non-neurological manifestations of Gaucher's disease include one or more of the following symptoms:

- anemia (after exclusion of other causes, such as iron deficiency)

- thrombocytopenia

- bone disease (after exclusion of other causes, such as vitamin D deficiency)

- hepatomegaly or splenomegaly

Contraindications:Hypersensitivity to the active ingredient or other components of the drug.

Carefully:Caution should be exercised when administering the drug to patients who develop antibodies or symptoms of hypersensitivity to Ceredase (alglucerase).

Pregnancy and lactation:

A limited number of available data on the outcomes of 150 pregnancies (mainly based on spontaneous reports and literature data) indicate that the use of Cerezyme helps control Gaucher's disease during pregnancy. In addition, these data did not confirm the presence of the toxic effect of Cerezyme on the fetus that causes malformation, although there was little statistical data. Reports of fetal death have been rare and it is not known exactly whether these cases were associated with the use of Cerezyme, or due to the presence of Gaucher disease.

Preclinical studies on animals regarding the evaluation of the effect of Cerezyme on pregnancy, development of the embryo / fetus, delivery and postnatal development have not been carried out. There is no information as to whether Cerezim penetrates the placenta to the developing fetus.

In each case, in pregnant patients with Gaucher disease and those who plan pregnancy, an evaluation of the risk-expected benefit ratio is necessary.Pregnant women with Gaucher disease may experience a period of increased

during pregnancy and in the postpartum period, which is manifested by an increased risk of changes in the bones, exacerbation of cytopenia, bleeding and increased need for blood transfusion. As you know, pregnancy and breastfeeding have a stressful effect on calcium metabolism in the mother and accelerate the process of bone tissue remodeling. This can contribute to the

severity of bone changes in Gaucher disease.

Women who have not received treatment should be advised to consider starting therapy before conception in order to achieve an optimal level of general condition. Women receiving Cerezyme should consider the continuation of therapy throughout pregnancy. For individual selection of a dose in accordance with the needs of the patient and its response to treatment, careful monitoring of the course of pregnancy and clinical manifestations of Gauchers disease is necessary. There is no evidence as to whether the active substance of the drug penetrates into breast milk or not, however,most likely this enzyme still enters the child's gastrointestinal tract.

Dosing and Administration:For intravenous infusion. Each Cerezyme vial is intended for single use only. After reconstitution and dilution, the drug is administered by intravenous infusion. With the first infusions, Cerezyme should be administered at a rate not exceeding 0.5 U / kg / min. Subsequently, the infusion rate can be increased, but not more than 1 unit / kg / min. Increase the speed of infusion should be carried out under the supervision of a medical professional. Cerezyme infusion can be performed at home in patients who have had a good reaction to the drug for several months. The decision on the possibility of administering the drug at home is taken after receiving the appropriate assessment and recommendations of the treating doctor. Cerezyme infusion by the patient or caregiver requires training by a medical professional in a clinic setting. The patient or the person who cares for him explains the technique of infusion and the need to keep a diary. Patients who developed undesirable effects during the infusion should immediately stop the infusion and seek medical help.For subsequent infusions, the conditions of the clinic may be required. The dose and frequency of infusions should not be changed when carrying out their home, nor should they be changed without the supervision of a medical professional. Due to heterogeneity and the multisystem nature of Gaucher disease, the dosage regimen must be individual for each patient and be based on a comprehensive assessment of the clinical manifestations of the disease. Only after a clear definition of the patient's individual response to treatment (for all relevant clinical manifestations of the disease) can the dose and frequency of drug administration be adjusted, either to maintain the optimal clinical state already achieved, or to subsequently improve those clinical indicators that have not yet been normalized .

Various dosing regimens have shown efficacy against some or all of the non-neurological manifestations of the disease. The use of initial doses of 60 U / kg once every 2 weeks demonstrated improvement of hematologic and visceral parameters during 6 months of therapy, and continued treatment resulted in the suspension of progression or reduced the severity of bone lesions.Doses of 15 U / kg once every 2 weeks showed an improvement

hematologic indices and a decrease in organomegaly, but did not affect the parameters of the osseous system. The usual frequency of infusion is once every 2 weeks; this is the frequency with which most of the data is presented. Typically, the infusion rate is once every 2 weeks. A study of maintenance therapy every 4 weeks (Q4) at the same total dose as with the therapy every 2 weeks (Q2) was performed in adult patients with stable residual manifestations of Gaucher's disease. Changes in hemoglobin level, platelet count, spleen and liver size, bone crista index and changes in bone tissue, compared with baseline values, constituted a pre-determined combined endpoint of the study; achievement and maintenance of the established positive therapeutic effect on hematologic and visceral

manifestations of Gaucher's disease constituted an additional endpoint. 63% of patients receiving Q4 treatment and 81% of those receiving Q2 corresponded to the combined endpoint when assessed at 24 months; differences were not statistically significant when

a confidence interval of 95% (-0.357, 0.058).89% of patients receiving Q4 therapy and 100% of those receiving Q2 treatment were at an endpoint based on a positive therapeutic effect; differences were not statistically significant when

a confidence interval of 95% (-0.231, 0.060). Q4 regimen can be therapeutically justified for some adult patients with persistent residual manifestations of Gaucher's disease type 1, but at the moment there is little clinical evidence.

Use in children

There is no need for a special dose for children. Studies of the effectiveness of the drug against neurological symptoms in patients with chronic neuronopathic manifestations of Gaucher disease have not been carried out, therefore, a special dosing regimen for the treatment of these manifestations is not established. It is necessary to regularly evaluate the response of patients to treatment and adjust the applied doses (increase or decrease) based on a comprehensive assessment of the patient's response to all clinical manifestations of the disease. Only after a clear definition and stabilization of the patient's individual response to treatment (for all relevant clinical manifestations of the disease),a dose adjustment may be performed to continue effective treatment, provided that the patient's response to treatment and the general state of his health continue to be carefully monitored. Usually, the intervals between the control examinations of the patient are from 6 to 12 months.

Instructions for reconstitution and dilution of the drug

The lyophilizate for the preparation of the solution for infusions is reconstituted with water for injection, followed by dilution with 0.9% sodium chloride solution for IV injections and then administered by IV infusion.

On the basis of a patient-specific dosing regimen, it is necessary to determine the number of vials the contents of which must be restored, and to get them out of the refrigerator. In some cases, a small dose change is allowed to avoid incomplete use of the contents of the vials. Doses may be rounded to the nearest value corresponding to the number of complete vials, but so that the monthly dose administered is not significantly altered. Restoration and dilution of the drug should be carried out under aseptic conditions.

Recovery

The contents of each vial are reconstituted by adding 5.1 ml (for a dosage of 200 units) or 10.2 ml (for a dosage of 400 units) of water for injection, avoiding the injection of water for injection with a strong stream, and gently stir the solution, preventing the formation of foam. The volume of the reconstituted solution is 5.3 ml (for a dosage of 200 U) or 10.6 ml (for a dosage of 400 U), and the pH of the reconstituted solution is approximately 6.1. The reconstituted solution should be clear, colorless and should not contain foreign particles. After reconstitution, the contents of the vials must be immediately diluted. Before breeding, it is necessary to visually inspect the reconstituted solution for the presence of foreign particles and discoloration. Do not use vials if there are foreign particles in the resulting solution or when the color of the solution changes. After reconstitution, the contents of the vials are immediately diluted, the preparation is not stored for later use.

Breeding

The reconstituted solution contains 40 units of IM imiglucerase in 1 ml. The recovered volume of the reconstituted solution from each vial is 5.0 ml (for a dosage of 200 units).A 5.0 ml (for a dosage of 200 units) or 10.0 ml (for a dosage of 400 units) of the reconstituted solution is withdrawn from each vial, the resulting volume is combined, then it is diluted with 0.9% sodium chloride solution for IV injections to the total volume 100-200 ml. The resulting solution is gently mixed.

Side effects:Below are the undesirable reactions classified by organ systems and frequency of occurrence (often from> 1/100 to <1/10, infrequently (from> 1 / 1,000 to <1/100) and rarely (from> 1/10000 to <1 / 1000)). In each group, unwanted reactions are listed in order of decreasing severity.

Disturbances from the nervous system Infrequently Dizziness, headache, paresthesia *

Heart Disease Infrequently Tachycardia *, cyanosis *

Disorders from the vascular system Infrequently Tides *, hypotension *

Disturbances from the respiratory system,

organs of the chest and mediastinum Often Shortness of breath *, cough *

Disorders from the gastrointestinal tract

tract Infrequently Vomiting, nausea, abdominal cramps, diarrhea

Immune system disorders Often Hypersensitivity reactions

Rarely Anaphylactic reactions

Disturbances from the skin and

subcutaneous tissue Often Urticaria / angioedema *, itching *, rash *

Disorders from the side of the skeletal- Infrequently Arthralgia, back pain *

muscular and connective

fabrics

General disorders and undesirable Infrequently Feeling of discomfort, burning and swelling at the injection site,

reactions at the injection site a sterile abscess at the injection site, discomfort in the area

chest, * fever, chills, fatigue

Only about 3% of patients had hypersensitivity symptoms (indicated * in the table above). They were recorded during or immediately after the infusion. Typically, such symptoms are eliminated application of

antihistamines and / or glucocorticoids. Patients should be advised to stop the infusion of the drug and contact the doctor if these symptoms appear.

Overdose:No cases of drug overdose have been reported. Dosages up to 240 U / kg once every two weeks were used in patients.

Interaction:There were no studies of drug interaction.Therefore, the drug should not be mixed with other drugs.

Special instructions:

In managing patients with Gaucher's disease doctors should consult with doctors who have experience of therapy of this pathology. Physicians and medical professionals are encouraged to register patients with Gaucher disease, including those who have had neuropathic manifestations of the disease, in the Gaucher disease registry of the Joint International Gaucher Disease Group (ICGG). This drug contains sodium and is administered intravenously after dilution in a 0.9% solution of sodium chloride. After dilution, the solution contains 0.62 mmol sodium (200 U / 5 mL) or 1.24 mmol sodium (400 U / 10 mL).

This need to be taken into account by patients on a diet with salt restriction.

The dilute solution is recommended to be introduced through a pass filter having a low splicing activity with a pore diameter of 0.2 μm to remove protein particles, which will not lead to a decrease in the activity of imiglucerase. The diluted solution is recommended to be administered to the patient immediately or not later than 3 hours after its preparation.Dissolved 0.9% solution of sodium chloride solution of the drug retains its chemical stability for 24 hours when stored at 2-8 ° C in a dark place, however, microbiological safety depends on the observance of aseptic conditions during reconstitution and dilution of the drug. Hypersensitivity Data obtained using screening immunosorbent enzyme assay (ELISA) and confirmed by radioimmunoprecipitation analysis indicate that approximately 15% of patients receiving therapy receive IgG antibodies to imiglucerase during the first year of therapy. It is believed that the formation of IgG antibodies in such patients is most likely to occur during the first 6 months of therapy, and that after 12 months of therapy, antibodies to Cerezyme are rare. In this regard, if there is a suspicion of a decrease in response to therapy, it is recommended that the level of IgG antibodies to imiglucerase be periodically monitored. In patients who have antibodies to imiglucerase, there is a higher risk of developing hypersensitivity reactions. If the patient develops a suspected reaction sensitivity,

it is recommended to conduct a study for the presence of antibodies to imiglucerase. As with the use of other intravenous protein-containing preparations, it is possible to develop severe allergic-type hypersensitivity reactions, but they rarely occur. If such reactions occur, Cerezimus infusion should be stopped immediately and appropriate measures taken. It is necessary to comply with the current medical standards for emergency therapy.

If patients have been diagnosed with antibodies to Ceredase (alglucerase) or the appearance of a symptom (imiglucerase), caution should be exercised.

Pulmonary hypertension. Pulmonary hypertension is a known complication of Gaucher's disease. Patients with a history of splenectomy have an increased risk of developing pulmonary hypertension. Treatment with Cerezyme in most cases reduces the need for splenectomy, and the early onset of therapy with Cerezim reduced the risk of developing pulmonary hypertension. A regular examination for the detection of symptoms of pulmonary hypertension after diagnosis of Gaucher disease is recommended in the future.Patients who are diagnosed with pulmonary hypertension should in particular receive adequate doses of Cerezyme to control Gaucher disease, and they should be evaluated for the need for special therapy to treat pulmonary hypertension.

Effect on the ability to drive transp. cf. and fur:Ceresim® does not or does not significantly affect the ability to drive and use machinery.

Form release / dosage:Liofilizate for the preparation of a solution for infusions of 200 units and 400 units

Packaging:

In bottles of glass type I, a capacity of 20 ml, closed with a cork made of silicone butyl and an aluminum cover, on which a plastic cap is put on. Each vial with instructions for use is placed in a cardboard box.

Storage conditions:Store at 2 ° C - 8 ° C (in the refrigerator). Keep out of the reach of children.

Shelf life:

2 years.

Do not use after expiry date.

Terms of leave from pharmacies:On prescription

Registration number:П N013386 / 01

Date of registration:31.03.2008

The owner of the registration certificate: Genzyme Corporation Genzyme Corporation USA

Manufacturer: & nbsp

Representation: & nbspPHARMSTANDART-Ufa-VITA, JSCPHARMSTANDART-Ufa-VITA, JSC

Information update date: & nbsp12.08.2014

Illustrated instructions

Instructions

Ceresim® (Cerezyme® )