NeoCytotect, 100 U/ml, solution for infusion, 50 ml, 1 pc.

NEOCYTOTEKT solution for infusion 10ml bottle No. 1

When using drugs from human blood or plasma due to the transmission of infectious disease agents, infection by the latter cannot be completely excluded. This also applies to pathogens of a still unknown nature. To reduce the risk of pathogen transmission, donors are screened using strict criteria, donated plasma is tested and selected, and the plasma pool is monitored. The manufacturing process includes steps to remove and/or inactivate pathogens. To produce NeoCytotect, only plasma from healthy donors is used, in which antibodies to HIV type 1 and 2, to the hepatitis C virus and the surface antigen of the hepatitis B virus were not detected, and the activity of liver enzymes (transaminase) does not exceed the normal limit value. In addition to testing the plasma of individual donors, first minipools are subject to control (PCR testing for HIV, hepatitis A, B and C viruses, parvovirus 19), and then the production pool of plasma processed at NeoCytotect (repeated testing for antibodies to HIV -1,2, hepatitis B and C, as well as PCR for HIV, hepatitis B and C viruses). A pool of plasma is used in production only if the test results are negative. NeoCytotect is prepared by cold ethanol fractionation. To inactivate and remove possible viruses, treatment is carried out with tri-n-butyl phosphate/Tween 80 and octanoic acid. Precautions for Use Certain severe side effects may be dependent on the rate of administration. Since its increase is associated with a tendency towards an increase in side effects, the rate of administration recommended in the section “Method of administration and dosage” should be strictly observed. Certain side effects may occur most often: at high rates of administration in patients with complete or partial immunodeficiency, both with and without IgA deficiency; in patients receiving human immunoglobulin for the first time or in rare cases when switching to another immunoglobulin preparation, or if treatment with immunoglobulins was carried out for a very long time. True hypersensitivity reactions are extremely rare, in cases in which there is no immunoglobulin A (IgA) in the blood and antibodies to IgA are formed. In rare cases, after the administration of immunoglobulin, a decrease in blood pressure and, in isolated cases, anaphylactic shock are possible, even if the patient did not show excessive sensitivity during the previous administration of the drug. In most cases, possible complications can be avoided if: - make sure that the patient does not have allergic reactions to a very slow injection of immunoglobulin (0.08 ml/kg/min); - carefully monitor the patient during the entire administration of the drug and monitor for signs of undesirable effects. Patients who have never previously received human immunoglobulins, or who have received other immunoglobulins, or who have been administered immunoglobulins for a very long time should be observed especially carefully throughout the infusion and for at least 1 hour after its completion. All other patients should be observed for at least 20 minutes after completion of administration. There is a suspected relationship between the administration of intravenous immunoglobulins and thromboembolic events such as myocardial infarction, stroke, pulmonary embolism and deep vein thrombosis. It is assumed that in patients at risk, the administration of a high dose of immunoglobulin leads to a relative increase in blood viscosity. It is recommended to prescribe and administer immunoglobulins with caution to the following patients: old age, with high blood pressure, diabetes mellitus, vascular disease or history of thrombosis, hereditary or acquired thrombophilic disorders, patients who have been immobile for a long time, with severe hypovolemia, and patients with chronic diseases in which blood viscosity increases. With the administration of intravenous immunoglobulins, isolated cases of acute renal failure have been described, which occurred in patients with additional risk factors: impaired renal function, diabetes mellitus, reduced circulating blood volume, excess body weight, taking medications that have a nephrotoxic effect, age over 65 years. Most often, impaired renal function and acute renal failure are associated with the use of drugs containing sucrose as a stabilizer. Therefore, patients with any risk factor are recommended to use immunoglobulins that do not contain sucrose, for example, NeoCytotect. In patients at risk of developing acute renal failure or thromboembolism, the immunoglobulin drug should be administered at the lowest possible rate and dose. When treating with NeoCytotect for all groups of patients it is necessary: ​​sufficient fluid intake before starting the drug infusion; diuresis control; serum creatinine control; Avoid simultaneous use of diuretics. Effect on the ability to drive vehicles and operate machinery There is no indication that immunoglobulins can affect the ability to drive a car or operate machinery. When using drugs from human blood or plasma due to the transmission of infectious disease agents, infection by the latter cannot be completely excluded. This also applies to pathogens of a still unknown nature. To reduce the risk of pathogen transmission, donors are screened using strict criteria, donated plasma is tested and selected, and the plasma pool is monitored. The manufacturing process includes steps to remove and/or inactivate pathogens. To produce NeoCytotect, only plasma from healthy donors is used, in which antibodies to HIV type 1 and 2, to the hepatitis C virus and the surface antigen of the hepatitis B virus were not detected, and the activity of liver enzymes (transaminase) does not exceed the normal limit value. In addition to testing the plasma of individual donors, first minipools are subject to control (PCR testing for HIV, hepatitis A, B and C viruses, parvovirus 19), and then the production pool of plasma processed at NeoCytotect (repeated testing for antibodies to HIV -1,2, hepatitis B and C, as well as PCR for HIV, hepatitis B and C viruses). A pool of plasma is used in production only if the test results are negative. NeoCytotect is prepared by cold ethanol fractionation. To inactivate and remove possible viruses, treatment is carried out with tri-n-butyl phosphate/Tween 80 and octanoic acid. Precautions for Use Certain severe side effects may be dependent on the rate of administration. Since its increase is associated with a tendency to increase side effects, the rate of administration recommended in the section “Method of administration and dosage” should be strictly observed. Certain side effects may occur most often: at high rates of administration in patients with complete or partial immunodeficiency, both with and without IgA deficiency; in patients receiving human immunoglobulin for the first time or in rare cases when switching to another immunoglobulin preparation, or if treatment with immunoglobulins was carried out for a very long time. True hypersensitivity reactions are extremely rare, in cases in which there is no immunoglobulin A (IgA) in the blood and antibodies to IgA are formed. In rare cases, after the administration of immunoglobulin, a decrease in blood pressure and, in isolated cases, anaphylactic shock are possible, even if the patient did not show excessive sensitivity during the previous administration of the drug. In most cases, possible complications can be avoided if: - make sure that the patient does not have allergic reactions to a very slow injection of immunoglobulin (0.08 ml/kg/min); - carefully monitor the patient during the entire administration of the drug and monitor for signs of undesirable effects. Patients who have never previously received human immunoglobulins, or who have received other immunoglobulins, or who have been administered immunoglobulins for a very long time should be observed especially carefully throughout the infusion and for at least 1 hour after its completion. All other patients should be observed for at least 20 minutes after completion of administration. There is a suspected relationship between the administration of intravenous immunoglobulins and thromboembolic events such as myocardial infarction, stroke, pulmonary embolism and deep vein thrombosis. It is assumed that in patients at risk, the administration of a high dose of immunoglobulin leads to a relative increase in blood viscosity. It is recommended to prescribe and administer immunoglobulins with caution to the following patients: old age, with high blood pressure, diabetes mellitus, vascular disease or history of thrombosis, hereditary or acquired thrombophilic disorders, patients who have been immobile for a long time, with severe hypovolemia, and patients with chronic diseases in which blood viscosity increases. With the administration of intravenous immunoglobulins, isolated cases of acute renal failure have been described, which occurred in patients with additional risk factors: impaired renal function, diabetes mellitus, reduced circulating blood volume, excess body weight, taking medications that have a nephrotoxic effect, age over 65 years. Most often, impaired renal function and acute renal failure are associated with the use of drugs containing sucrose as a stabilizer. Therefore, patients with any risk factor are recommended to use immunoglobulins that do not contain sucrose, for example, NeoCytotect. In patients at risk of developing acute renal failure or thromboembolism, the immunoglobulin drug should be administered at the lowest possible rate and dose. When treating with NeoCytotect for all groups of patients it is necessary: ​​sufficient fluid intake before starting the drug infusion; diuresis control; monitoring serum creatinine levels; Avoid simultaneous use of diuretics. Effect on the ability to drive vehicles and operate machinery There is no indication that immunoglobulins can affect the ability to drive a car or operate machinery.

NeoCytotect

NeoCytotect is an immunoglobulin preparation that is made from donor plasma with a high titer of antibodies against cytomegalovirus (CMV). NeoCytotect has an established and high titer of antibodies against CMV with high avidity. NeoCytotect also contains IgG antibodies against other pathogens present in a large number of healthy people who were donors to form the plasma pools from which the drug was obtained. The distribution of immunoglobulin G (IgG) subclasses in the NeoCytotect preparation corresponds to the distribution in the plasma of healthy donors.

Mechanism of action

NeoCytotect is a CMV-specific polyclonal immunoglobulin preparation that binds to CMV surface antigens, thereby preventing CMV from entering host cells and presenting CMV particles for phagocytosis. NeoCytotect antibodies also modulate and interact with immune cells (dendritic cells, monocytes, B and T cells), creating a positive immunological balance in addition to virostatic inhibition of CMV replication.

Pharmacodynamic effects

The main mechanism of action of the drug NeoCytotect is binding to the circulating virus. These CMV-specific antibodies block infection by various cell types, including all CMV genotypes, and virus strains that are resistant to viral agents. In addition, NeoCytotect can activate CMV-reactive immune cells to form long-lasting CMV-specific immune responses. It also has additional immunomodulatory properties, independent of CMV, that are associated with reduced rates of organ rejection.

Clinical efficacy and safety

The clinical efficacy of human anticytomegalovirus immunoglobulin has been studied in a variety of settings, including solid organ and stem cell transplant patients. In kidney transplantation, human anticytomegalovirus immunoglobulin reduced the incidence of CMV infection from 41.7% (control group) to 21.1% (NeoCytotect group). Other examples include lung transplantation, where the incidence of CMV disease was reduced from 43.3% (control group) to 13.2% (NeoCytotect group), and bone marrow transplantation, where the incidence of interstitial pneumonitis was reduced from 26.1% to 3. 8%.

Kidney transplant

A prospective randomized controlled trial examined the effectiveness of hyperimmunoglobulin prophylaxis for CMV infection in patients after kidney transplantation. The study included 74 patients who received a cadaveric kidney transplant for the first time. The average follow-up period was 45 months. Patients received immunosuppressive therapy according to a regimen consisting of methylprednisolone and cyclosporine A. In the treatment group, 38 patients received a dose of NeoCytotect 2 ml/kg intravenously immediately before transplantation, and then on 1.2, 4, 18, 32, 46, 60, 74 and 88 days after transplantation. The control group consisted of 36 patients who did not receive NeoCytotect. In the treatment group, only 8/38 patients (21.1%) had CMV infection, and 5/38 patients (13.2%) had CMV disease, while in the control group, only 15/36 patients (41.7%) had CMV infection and 6/36 patients (16.7%) had CMV disease.

Children

A retrospective study examined the effectiveness and safety of prophylaxis with a combination of acyclovir and NeoCytotect and early therapy with ganciclovir in pediatric patients at high risk of CMV infection undergoing kidney transplantation (79 patients with a mean age of 14.1 ± 4.9 years, range 2.5-20) . The minimum follow-up period was 12 months. Immunosuppressive therapy included cyclosporine A and steroids with the addition of azathioprine in 4 patients who received a living donor kidney transplant. For episodes of acute rejection, intravenous pulse therapy with methylprednisolone was used. 39 R- patients received 150 mg/kg NeoCytotect on the first day after surgery, 100 mg/kg on days 15 and 30 and 50 mg/kg on days 45, 60 and 120 after transplantation and oral acyclovir. 40 R+ patients received only oral acyclovir at the same dose as R- patients. In the presence of CMV infection, intravenous ganciclovir was administered at a dose of 10 mg/kg body weight for at least 2 weeks or until negative antigenemia results were obtained. In the R- group treated with NeoCytotect, out of 33 CMV-seronegative recipients (R-), who received a transplant from a CMV-seropositive donor (D+), 18 (54.5%) had CMV infection, and 6 CMV-seronegative In recipients (R-), who received a transplant from a CMV-negative donor, no infection was observed. In the R+ group receiving only acyclovir, out of 28 CMV R+ recipients who received a transplant from a CMV D+ donor, 11 (39.3%) suffered CMV infection, and out of 12 R+ recipients who received a transplant from a CMV D- donor, 1 recipient suffered CMV infection (8.3%).

Heart transplant

An open comparative retrospective study examined prophylaxis with the combination of NeoCytotect and ganciclovir versus NeoCytotect alone in 207 adult high-risk heart transplant recipients (mean age 52.2 years) who received an allograft from seropositive donors (D+/R-). All patients received polyclonal rabbit antithymocyte immunoglobulin as induction therapy. Cyclosporine A, azathioprine, and prednisone were used as maintenance immunosuppressive therapy. Episodes of acute allograft rejection were treated with a daily bolus of prednisone for 3 consecutive days. In group A, 96 patients received NeoCytotect alone, and in group BIII patients received NeoCytotect with ganciclovir. 100 mg/kg NeoCytotect was administered intravenously before transplantation and on days 1, 7, 14, 21 and 28 after surgery. Patients with CMV disease received ganciclovir for 21 days in combination with a reduction in immunosuppressive therapy. Additionally, NeoCytotect was administered at weekly intervals. In group A, 53.1% had CMV infection, and 32.3% (31/96 patients) had CMV disease. In group B, 65.8% had CMV infection, and 11.7% (13/111 patients) had CMV disease. Four CMV-related deaths occurred in group A; 3 patients died from severe CMV sepsis, and 1 patient died from CMV encephalitis. There were no CMV-related deaths in group B, which reflects a statistically significant advantage of prophylaxis with the combination of NeoCytotect and ganciclovir compared with NeoCytotect alone (p = 0.0326). An open-label, single-center study examined passive immunization against CMV in adult allograft recipients (146 heart transplant patients between 1984 and 1991 with a median age of 47 years). The follow-up period ranged from 13 to 73 months (median 43 months). Maintenance immunosuppression consisted of cyclosporine A and prednisone. In 11 patients, azathioprine was added to this regimen due to recurrent rejection during the first year. In the treatment group, 65 CMV (R-) patients received 150 mg/kg NeoCytotect during surgery and 100 mg/kg NeoCytotect on days 2, 7, 14, 28, 42, 56 and 72 after transplantation, while the control group consisted of 81 CMV (R+) patients who did not receive CMV prophylaxis. In the treatment group, 21/65 (R-) patients (32.3%) had CMV infection, and 11/65 (R-) patients (16.9%) had CMV disease. In the control group, 40/81 (R+) patients (49.4%) had CMV infection, and 10/81 (R+) patients (12.3%) had CMV disease.

Lung transplantation

A retrospective single-center study examined the use of human anticytomegalovirus immunoglobulin for the prevention and treatment of CMV infection (156 adult lung transplant patients were analyzed between 2007 and 2011 with a mean age of 52 years (range 17-67 years)). The median follow-up duration was 19.2 months. All patients received induction with basiliximab and triple immunosuppression (tacrolimus, mycophenolate mofetil, methylprednisolone, then prednisolone). Intravenous ganciclovir was initiated in all at-risk patients (D+/R- or R+) within the first week after transplantation. In the treatment group, 23 D+/R- patients received 2 ml/kg NeoCytotect on days 1, 4, 8, 15 and 30 after transplantation, then monthly for the next year and valganciclovir for 6 months. In the control group, 133 R+ patients received valganciclovir for 3 months. In the treatment group, 14/23 (D+/R-) patients (61%) had CMV infection, and 4/23 (D+/R-) patients (17.4%) had CMV disease, while in the control group 46/133 (R+) patients (35%) had CMV infection and 6/133 (R+) patients (4%) had CMV disease. Mortality was 4/23 (D+/R-) patients (17.4%) in the treatment group and 40/133 (R+) patients (30%) in the control group.

A comparative retrospective study examined combined CMV prophylaxis after lung transplantation in 68 adult lung transplant patients (mean age 55.8 years in the treatment group and 49.2 years in the control group) with a CMV-seropositive donor allograft. The median follow-up period was 16.5 months in the control group (from 5.3 to 69.5 months) and 23.8 months in the study group (from 11.9 to 35 months). In the control group, 30 patients (who underwent transplantation from 1994 to 2000) received only ganciclovir during the first 3 months after surgery; in the treatment group, 38 patients (who underwent transplantation from 2000 to 2004) received additional treatment - 1 ml/kg of NeoCytotecta in number of 7 doses during the first month after transplantation.

Table 1: Study Results

Bone marrow transplantation (BMT)

A randomized comparative study examined the use of intravenous hyperimmunoglobulin for the prevention of CMV infection in 49 adult patients with leukemia who underwent allogeneic BMT from an HLA-matched sibling (mean age 22 years (NeoCytotect group) and 22.5 years (control group)).

The duration of observation was 110 days. All patients were subjected to cyclophosphamide conditioning and total body irradiation. In the treatment group, 26 patients received 1 ml/kg NeoCytotect, in the control group 23 patients received 2 ml/kg normal immunoglobulin on day 7 and on days 13, 33, 73 and 93 after BMT. During the first PO days after BMT, 1/26 patients (4%) developed interstitial pneumonitis associated with CMV in the treatment group and 6/23 patients (26%) in the control group. Two patients in the NeoCytotect group developed CMV-related interstitial pneumonitis after discontinuation of treatment (days 143 and 153).

An open-label, single-arm trial showed a reduction in the incidence of CMV infection with prophylaxis with CMV hyperimmune globulin and oral acyclovir in 93 adult BMT recipients (median age 22 years, range 1 to 49 years). Acute graft-versus-host disease (GVHD) was observed in 43 (48.3%) (grade

Results of meta-analyses

Meta-analyses of clinical efficacy data from the literature were conducted to analyze all published data on the use of NeoCytotect for its approved prophylactic indication, regardless of study design. The frequency of CMV infection was determined as the main evaluation criterion. One meta-analysis covered all studies regardless of transplantation type, and the other covered only solid organ transplantation (bone marrow transplantation/leukemia not included), the results are presented in Table 2.

Table 2: Results of meta-analyses

In both analyses, a significant reduction in the incidence of CMV infection was observed in patients receiving NeoCytotect. When all indications were included, the incidence of CMV infection was reduced from 44.9% of patients in the control group to 37.1% of patients in the NeoCytotect group (p = 0.001). When considering kidney, heart, and lung transplantation only, there was a decrease from 46.9% to 40.2% of all patients (p = 0.009).