Composition, form of production and packaging
Solution for infusions in the form of a colorless or light yellow transparent or slightly opalescent liquid.
proteins of human plasma, of which immunoglobulin G is not less than 98% of 100 mg
Excipients: L-proline 28.8 mg, water q / and qs up to 1 ml.
25 ml - bottles of glass (1) - packs of cardboard.
50 ml - bottles of glass (1) - packs of cardboard.
100 ml - bottles of glass (1) - packs of cardboard.
INSTRUCTION FOR THE SPECIALIST.
Description of the drug approved by the manufacturer for the printed edition of 2014.
The ghost is mainly composed of immunoglobulin G (IgG) with a wide range of functionally intact antibodies to infectious agents. Both functions of Fc and Fab of IgG molecules are preserved. The ability of Fab sites to bind to antigens has been demonstrated by biochemical and biological methods. The Fc function was tested by complement activation and Fc receptor-mediated activation of leukocytes. In the preparation Prividzhen, inhibition of the immune complex-induced complement activation ("purification", anti-inflammatory effect of immunoglobulin for intravenous administration) is retained. Spiny does not lead to nonspecific activation of the complement system or prekallikrein.
Distribution of subclasses of IgG approximately corresponds to their distribution in normal human plasma. Optimal doses of PrivГ©gen can restore a low concentration of IgG to normal values.
The mechanism of action when applied according to the indications, with the exception of substitution therapy, is not fully explained, but includes the immunopotentiation effect. The drug increases the nonspecific resistance of the body.
After intravenous injection Prividzhen becomes immediately and completely bioavailable in the patient's blood circulation.
The drug PrivГ©dzhen is distributed relatively quickly between plasma and viscous fluid. The balance between the intravascular and extravascular parts is achieved in about 3-5 days.
The pharmacokinetic parameters for the Privigene preparation were determined in both clinical trials of primary immunodeficiency therapy. Pharmacokinetic parameters were determined in 25 patients aged 13 to 69 years in the main study and in 13 patients aged 9 to 59 years in the extended study (see table below).
Pharmacokinetic parameters of the drug Privyzhen in patients with primary immunodeficiencies
Parameter Main study (n = 25) Mean concentration (range) Extended study (n = 13) Average concentration (range)
C max in g / l 23.4 (10.4-34.6) 26.3 (20.9-32.9)
C min in g / l 10.2 (5.8-14.7) 9.75 (5.72-18.01)
T 1/2 in days 36.6 (20.6-96.6) 31.1 (14.6 ^ 13.6)
In the main study, the median half-life of Prividgen in patients with primary immunodeficiency was 36.6 days and 31.1 days in the extended study. The half-life may vary from patient to patient. IgG and IgG complexes are destroyed in the cells of the reticuloendothelial system.
Substitution therapy with:
- Primary immunodeficiencies (FID), such as: congenital agammaglobulinemia and hypogammaglobulinemia; general variable immune deficiency; severe combined immune deficiency; Wiskott-Aldrich syndrome;
- Multiple myeloma with severe form of secondary hypogammaglobulinemia and recurrent bacterial infections with ineffective vaccination with pneumococcal vaccine;
- chronic lymphoid leukemia with severe form of secondary hypogammaglobulinemia and recurrent bacterial infections with ineffective prophylactic antibacterial therapy;
- congenital syndrome of acquired human immunodeficiency (AIDS) in children with recurrent infections;
- hypogammaglobulinemia in patients with allogeneic transplantation of hematopoietic stem cells.
As an immunomodulating agent with:
- idiopathic thrombocytopenic purpura (ITP) in children or adults with a high risk of bleeding or before surgery to correct the number of platelets;
- Guillain-Barre syndrome;
- Kawasaki's disease;
- chronic inflammatory demyelinating polyneuropathies.
The dose and dosage regimen depend on the indication for use. In the case of substitution therapy, the dose of the drug can be selected individually for each patient, depending on the pharmacokinetic parameters and the clinical response. The following doses are recommended as guidelines.
Substitution therapy for primary immunodeficiencies
It is recommended to choose a dosing regimen in which the concentration of IgG increases to a minimum of 5-6 g / l (the IgG content is determined before the subsequent infusion). Equilibrium concentrations are achieved 3-6 months after the start of treatment. The recommended starting vine is from 0.4 to 0.8 g / kg of body weight, subsequent doses - not less than 0.2 g / kg of body weight every 3-4 weeks. Doses of the drug necessary to achieve a concentration of IgG 5-6 g / l, are from 0.2 to 0.8 g / kg body weight per month. The interval between doses, when equilibrium concentrations are reached, varies from 3 to 4 weeks. The concentrations of IgG for dose adjustment and the interval of administration should be measured.
Replacement therapy for multiple myeloma with severe form of secondary hypogammaglobulinemia and recurrent bacterial infections with ineffective vaccination with pneumococcal vaccine: chronic lymphoid leukemia with severe form of secondary hypogammaglobulinemia and recurrent bacterial infections or inefficiency of preventive antibacterial therapy; congenital AIDS in children in the presence of recurrent infections
A dosage regimen of 0.2 to 0.4 g / kg body weight is recommended every 3-4 weeks.
Hypogammaglobulinemia in patients with allogeneic transplantation of hematopoietic stem cells
Doses of the drug, necessary to maintain IgG concentration at the level of more than 5 g / l, range from 0.2 to 0.4 g / kg of body weight every 3-4 weeks.
Idiopathic thrombocytopenic purpura
In case of an exacerbation, appoint 0.8 to 1 g / kg of body weight on the first day (it is possible to repeat this dose once more for the next 3 days) or 0.4 g / kg of body weight daily for 2-5 days. In case of relapse, treatment can be repeated.
0.4 g / kg body weight for 5 days. There is limited experience in children.
From 1.6 to 2 g / kg body weight in separate equal doses for 2-5 days or a single dose of 2 g / kg body weight once. Patients should be assigned acetylsalicylic acid as concomitant therapy.
Chronic inflammatory demyelinating polyneuropathies *
The starting dose is 2 g / kg body weight in separate equal doses for 2-5 days in a row; subsequent doses in the calculation of 1 g / kg of body weight every 3 weeks for 1-2 consecutive days.
Recommendations for dosage regimens are given in the following table.
Indications Dose Interval between injections
Primary immunodeficiency Starting dose: 0,4-0,8 g / kg body weight further: 0,2-0,8 g / kg body weight Once, every 3-4 weeks until the concentration of IgG is not less than 5-6 g / l .
Secondary immunodeficiency 0.2-0.4 g / kg body weight Once, every 3-4 weeks until the concentration of IgG is not less than 5-6 g / l.
Children with congenital AIDS in the presence of recurrent infections 0.2-0.4 g / kg body weight Once, every 3-4 weeks.
Hypogammaglobulinemia (<4 g / l) in patients with allogeneic transplantation of hematopoietic stem cells 0.2-0.4 g / kg body weight Once, every 3-4 weeks, to maintain IgG concentration more than 5 g / l.
Application as an immunomodulator
Idiopathic thrombocytopenic purpura 0.8-1 g / kg body weight On the first day; it is possible to repeat a single administration in the next 3 days from the date of the first administration.
or 0.4 g / kg body weight daily for 2-5 days.
Guillain-Barre Syndrome 0.4 g / kg body weight Daily for 5 days.
Kawasaki disease 1.6-2 g / kg body weight Assign in equal doses for 2-5 days in combination with the appointment of acetylsalicylic acid.
or 2 g / kg body weight Once in combination with the appointment of acetylsalicylic acid.
Chronic inflammatory demyelinating polyneuropathies * Starting dose: 2 g / kg body weight; Assign in equal doses for 2-5 days.
Maintenance dose: 1 g / kg body weight Every 3 weeks for 1-2 consecutive days.
* Treatment duration of more than 24 weeks should be considered by a doctor and be based on observable !! response to the use of the drug and evaluation of the expected efficacy in long-term treatment. The dosage regimen should be selected in accordance with the observed clinical picture of the course of the disease.
Mode of application
Spiny should be administered only in the form of intravenous infusions.
The ghost is a solution ready for use. In the case of storing the drug in the refrigerator before the introduction of the temperature of the solution should be brought to room temperature. For the introduction should use an infusion system with an air valve and built-in filter. The vial plug should always be pierced in the center in the marked area.
If dilution is necessary, use a 5% dextrose solution. To prepare the solution of immunoglobulin 50 mg / ml (5%) preparation Prividzen solution for infusions of 100 mg / ml (10%) should be spread in the bulk volume of 5% dextrose solution. The technique of working in aseptic conditions should be strictly observed during the breeding of Prividzhen. Pristavgen can not be mixed with a 0.9% solution of sodium chloride. The solution should be clear or slightly opalescent.
In case of turbidity of the solution or the presence of mechanical inclusions in the solution, the preparation is not to be used.
Unused product and consumables should be disposed of in a suitable way.
The rate of administration
The drug should be administered initially at a rate of 0.3 ml / kg body weight / hour (0.5 mg / kg body weight / minute for approximately 30 minutes). If the drug is well tolerated, the infusion rate can be gradually increased to 4.8 ml / kg body weight / h (8 mg / kg body weight / min). In patients with primary immunodefence. who were well tolerated with PrivГ©gen's replacement therapy, the infusion rate can be gradually increased to a maximum of 7.2 mL / kg body weight / h (12 mg / kg body weight / minute).
Special patient groups
In the baseline Phase III trial, 19 patients aged 3 to 11 years and 15 patients aged 12 to 18 years were enrolled in patients with primary immunodeficiency (n = 80).
In an expanded clinical trial, 13 patients aged 3 to 11 years and 11 patients aged 12 to 18 years took part in patients with primary immunodefineimmun (n = 50).
In a clinical study involving 57 patients with chronic idiopathic thrombocytopenic purpura, 2 patients aged 15 and 16 took part. None of the three studies required a dosage adjustment for children.
The undesirable reactions presented below are listed in accordance with the defeat of organs and organ systems (McdDRA classification) and frequency of occurrence. Frequency of occurrence is defined as follows: very often (? 1/10), often (? 1/100 and <1/10), infrequently (? 1/1 000 and <1/100), rarely (? 1/10000 and < 1/1 000), very rarely (<1/10 000, including individual cases). Frequency categories were formed on the basis of data obtained during clinical trials of the drug.
In connection with the intravenous route of administration of the drug, such undesirable reactions as chills, headache, fever, vomiting, allergic reactions, nausea, joint pain, lowering of blood pressure and moderate back pains occurred infrequently.
Rarely, hypersensitivity reactions with a sharp decrease in blood pressure and, in some cases, anaphylactic shock, even when the patient has not previously revealed hypersensitivity reactions with the use of the drug. Cases of reversible aseptic meningitis and, in rare cases, temporary skin reactions were observed in patients after using human immunoglobulin. Hemolytic reactions were observed in patients with blood groups A (II), B (III) and AB (IV). Hemolytic anemia requiring blood transfusion may rarely occur after treatment with high doses of human immunoglobulin preparations for intravenous administration (see section "Special instructions").
There have been cases of increased serum creatinine and or acute renal failure.
Very rarely there were thromboembolic complications, such as myocardial infarction, stroke, pulmonary embolism and deep vein thrombosis.
Four clinical studies were conducted with Privigene, two in patients with primary immunodeficiency (FID), one involving patients with idiopathic thrombocytopenic purpura (ITPl) and one involving patients with chronic inflammatory demyelinating polyneuropathies. In the main clinical study of the HDPE, 80 patients were treated with Prividgen. Of these, 72 patients received treatment within 12 months. 55 patients were enrolled in the expanded clinical study of Priwidgen PID therapy. A clinical study of ITP was performed with the participation of 57 patients. A clinical study of chronic inflammatory demyelinating polyneuropathies was performed with the participation of 28 patients. Most of the adverse reactions observed in four clinical trials were mild or moderate.
The following summary table provides information on the side effects of Privigene, identified in four clinical trials. Within the frequency of occurrence in each group, adverse reactions are listed in descending order of severity.
Classification of adverse reactions in accordance with organ and organ damage (MedDRA) Clinical manifestations Frequency category
Infectious and parasitic diseases Infections of ENT organs (otitis media, nasopharyngitis), influenza Infrequently
Violations from the blood and lymphatic system Anemia, anisocytosis, leukopenia, hemolysis Infrequent
Nervous system disorders Headache Very often
Dizziness, discomfort in the head, drowsiness, tremor, sinus headache, migraine, dysesthesia Infrequent
Heart palpitations Rapid palpitation (palpitation) Infrequently
Vascular disorders Arterial hypertension Often
Arterial hypotension, hot flashes, peripheral vascular disorders
Disturbances from the respiratory system, chest and mediastinal organs Difficulty breathing, the formation of bubble cells on the mucous membrane of the mouth and throat, pain in breathing, a feeling of restraint in the throat Not often
Disorders from the gastrointestinal tract Vomiting, nausea Often
Diarrhea, epigastric pain
Disturbances from the liver and bile duct Hyperbilirubinemia Infrequent
Disorders from the skin and subcutaneous tissues Hives, rashes Frequently
Itching, skin lesions, night sweats
Disturbances from musculoskeletal and connective tissue Back pain Frequently
Pain in the neck, pain in the limbs, stiff muscles, muscle spasms, muscle and bone pain, myalgia, muscle weakness
Kidney and urinary tract disorders Proteinuria Infrequent
General disorders and disorders at the site of injection Chills, fatigue, fever, asthenia, flu-like condition Often
Chest pain, general malaise, fever, pain, pain at the injection site Infrequently
Laboratory and instrumental data Increased concentration of bound and unbound bilirubin in blood, Positive direct Coombs test, Positive indirect Coombs test, increased lactate dehydrogenase activity in the blood, decreased hematocrit, increased activity of alanine aminotransferase, increased activity of aspartate amylotransferase, increased blood creatinine concentration, decreased blood pressure, increased arterial pressure, increased body temperature, decreased hemoglobin
- hypersensitivity to the active substance or any other component included in the preparation;
- hypersensitivity to homologous immunoglobulins, especially in very rare cases of immunoglobulin A (IgA) deficiency, when the patient has antibodies to IgA;
- Hyperprolinaemia (a very rare disease that affects only a few families in the world).
PREGNANCY AND LACTATION
The safety of Prividzhen during pregnancy and the period of breastfeeding in controlled clinical trials has not been established. Immunoglobulins penetrate the placenta, especially in the third trimester of pregnancy. Immunoglobulins are excreted in breast milk, while antibodies can have a protective effect in a newborn. In this way. Prisyzhen during pregnancy and the period of breastfeeding should be used with caution.
However, large clinical experience with immunoglobulins suggests that the occurrence of a negative impact on the course of pregnancy, the fetus or newborn is unlikely.
Research excipient L-proline, carried out on animals have revealed no direct or indirect toxic effect on the course of pregnancy, the developing embryo or fetus.
APPLICATION FOR CHILDREN
The basic phase III study in patients with primary immunodeficiency (n = 80) of 19 patients participated in age from 3 to 11 years and 15 patients aged 12 to 18 years.
The extended clinical study 13 patients were involved in patients with primary immunodefniitamn (n = 50) aged 3 to 11 years and 11 patients aged 12 to 18 years.
In a clinical trial involving 57 patients with chronic idiopathic thrombocytopenic purpura, 2 patients attended at the age of 15 and 16 years. None of these three studies did not require correction dosing regimen for children.
Prividzhen not be mixed with other drugs and with 0.9% sodium chloride solution. However, dilution is permitted a 5% dextrose solution. Installed severe adverse reactions may be associated with the rate of administration. It should be carefully observed injection rate specified in the "Method of use and dosage." It is necessary to carry out careful monitoring of patients and monitoring for the occurrence of any symptoms throughout the infusion period.
Some undesirable reactions may occur more frequently:
- in case of high injection speed:
- in patients with hypogammaglobulinemia and agammaglobulinemia IgA deficiency with or without IgA deficiency;
- in patients who receive treatment with human normal immunoglobulin for the first time, or in rare cases, when the human normal immunoglobulin preparation is replaced by Prividzhen, or a long interval since the previous infusion.
Possible complications can be avoided to ensure that:
- the patient is not shown giperchuvstvitslnost Human normal immunoglobulin with slow administration of the drug (0.3 ml / kg body / weight parts):
- during and after the infusion period all the symptoms that occur in patients carefully monitored. In particular, patients who have not received prior therapy of human immunoglobulins normal, and transferred to the treatment of other immunoglobulin preparation for intravenous administration, or at long interval since the previous infusion should be monitored during the first infusion and during the first hour after the first infusion to identify potential adverse events. All other patients should be monitored for at least 20 minutes after drug application.
In the case of undesired phenomena should decrease the rate of introduction of fire stop administering the drug. The required treatment depends on the nature and severity of the undesirable phenomena.
In the case of shock, you must use the standard treatment of states of shock.
All patients before the introduction of human immunoglobulin for intravenous administration requires adequate hydration.
True hypersensitivity reactions are rare. They can occur in very rare cases with a deficit IgAs antibodies to IgA.
Occasionally normal human immunoglobulin can be a cause of lowering of blood pressure with the development anafilaktoidioy reaction, even in patients who previously burying transferred to normal human immunoglobulin therapy.
Chronic inflammatory polyneuropathy demielinziruyuschie
There is limited experience with the use of intravenous immunoglobulins in children with chronic inflammatory demyelinating polyneuropathy.
human immunoglobulin preparations for intravenous administration can contain antibodies against blood group antigens that may act as hemolysins in vivo and bind to red blood cells that may cause a positive direct antiglobulin test (Coombs' test) and, rarely, hemolysis. Hemolytic anemia can develop after treatment of the human immunoglobulin preparations for intravenous administration as a result of the increased sequestration of erythrocytes. Occasional cases of renal impairment and / or renal disease or syndrome diessminirovannogo intravascular coagulation associated with hemolysis.
Development of hemolysis associated with the following risk factors: high doses, regardless of the administration as a single dose or in divided doses for a few days; and a blood group A (II), In (III) and AB (IV) in combination with the concomitant presence of an inflammatory process. In the treatment of patients with blood group A (II), In (III) or AB (IV) with high doses of the drug for indications other than PID, extreme caution is recommended.
There are some reports of hemolysis in patients with PID, substitution therapy. It is necessary to monitor clinical signs and symptoms of hemolysis in patients receiving therapy of human immunoglobulin preparations for intravenous administration. If you have any signs and / or symptoms of hemolysis during or after infusions of immunoglobulin for intravenous administration, the physician should consider the abolition of further treatment (see. Also "Side effects" section).
Aseptic meningitis syndrome (NAS)
In the treatment of immunoglobulin preparations for intravenous administration of cases of aseptic meningitis syndrome have been reported. After the abolition of immunoglobulin for intravenous injection within a few days into remission CAM without any consequences. Typically, this period begins on the syndrome from several hours to 2 days after treatment immunoglobulin for intravenous administration. When analyzing CSF pleocytosis often observed to several thousand cells per mm 3 , usually due to a number of granulocyte cells, and the increased concentration of protein, up to several hundreds of mg / dl.
CAM may occur more frequently on a background application immunoglobulin for intravenous administration in the high dose (2 g / kg).
There is clinical evidence of an association between the use of human immunoglobulin for intravenous administration and cases of thromboembolic complications, such as myocardial infarction, acute cerebrovascular disease (including stroke), pulmonary embolism and deep vein thrombosis, which presumably are associated with a relative increase in blood viscosity the introduction of a large number of immunoglobulins. Caution should be exercised in the appointment and conduct of infusions of immunoglobulin for intravenous administration to patients with obesity and patients with previously established risk factors for thrombotic events such as advanced age, hypertension, diabetes mellitus, thromboembolism or cardiovascular disease history, cases of hereditary or acquired thrombophilia,prolonged period of disturbance of mobility, in patients with severe gilovolemiey and patients with diseases which increase blood viscosity is observed.
Acute renal failure
Cases of acute renal failure have been identified in patients treated with human immunoglobulin therapy for intravenous administration. In most cases, risk factors have been identified, such as the prior existence of renal insufficiency, diabetes mellitus, hypovolemia, overweight, concomitant treatment with nephrotoxic drugs or age greater than 65 years. In the case of renal insufficiency should be interrupted therapy human immunoglobulin for intravenous administration. It should be noted that among the reported cases of renal dysfunction or renal failure, developing on the background of preparations for the human immunoglobulin fraction of preparations containing sucrose as a stabilizer, was disproportionately high. Thus, for patientswho are at risk, it is recommended the use of immunoglobulin for intravenous administration, which does not contain sucrose, contains Prividzhen not contain sucrose or other sugars.
Patients at risk for acute renal failure or thromboembolic complications preparations of immunoglobulins for intravenous administration must be entered at a minimum rate of infusion and at the lowest possible dose.
Effect on diagnostic tests
After administration of immunoglobulins in the blood temporarily increases the number of different passively transferred antibodies, which may lead to false positives in serologic tests.
Passive transfer of antibodies to red cell antigens, such as A, B and D, can lead to incorrect results, in some tests for serological detection of antibodies to erythrocytes (e.g., Coombs test), in determining the amount of reticulocytes and gaptoglobinovom test.
Information on safety with respect to infectious agents Prividzhen made from human plasma.
Standard measures to prevent transmission resulting from the application of medicines, produced from human blood or plasma include selection of donors, by individual donations and plasma pools for the presence of specific markers of infection and the inclusion of effective manufacturing steps directed to the inactivation and / or removal of viruses . Despite this, the application of products prepared from human blood or plasma, we can not completely exclude the possibility of transmitting infectious agents. This provision is also applicable in relation to unknown or emerging viruses and other infectious agents. Measures taken to ensure the safety of antiviral, are considered effective for enveloped viruses such as HIV, hepatitis viruses B and C, as well as non-enveloped viruses,such as hepatitis A virus and parvovirus B19. Encouraging clinical experience indicating no transmission of hepatitis A virus and parvovirus B19 human immunoglobulin preparations, and it is also assumed that the presence of antibodies is making a significant contribution to the viral safety. It recommended for each application Prividzhen preparation register name and serial number of the drug, which is administered to a patient to maintain communication between the patient and a series of drug.which is administered to a patient to maintain communication between the patient and a series of drug.which is administered to a patient to maintain communication between the patient and a series of drug.
Prividzhen can not be used after the expiration date printed on the carton box and vial label.
Prividzhen intended for single use only. After opening the bottle the consumer is responsible for the storage time and storage conditions. The solution contains no preservatives. Thus, after opening the contents of the vial must be used within 24 hours.
Impact on the ability to drive vehicles and manage mechanisms
Some adverse reactions associated with the action Prividzhen drug, may affect the ability to drive a vehicle or moving machinery. For patients who experienced adverse reactions at the injection of the drug Prividzhen, driving a vehicle or moving machinery is possible only after the disappearance of symptoms of unwanted hazardous reactions.
Overdose may lead to fluid overload and increased blood viscosity, particularly in patients who are at risk, including elderly patients and patients with impaired function nochek.
Live virus vaccines atgenuirovannye
After therapy immunoglobulins efficacy of live vaccines against root, mumps, rubella, varicella n may be reduced for at least 6 weeks and 3 months. Caution must be interval of 3 months between the appointment Prividzhen medication and vaccination with live attenuated vaccines. In the case of measles vaccination decrease the effectiveness of the vaccine can last up to 1 year. Thus, in patients vaccinated against measles, it is necessary to control the level of antibodies.
TERMS OF RELEASE FROM PHARMACY
TERMS AND CONDITIONS OF STORAGE
At a temperature of no higher than 25 В° C in a dark place. Do not freeze. Keep out of the reach of children. Shelf life - 3 years.