Simulekt - instructions for use, doses, side effects, contraindications

Active substanceBasiliximabBasiliximab

Similar drugsTo uncover

lyophilizate in / in

Dosage form: & nbspLyophilizate for the preparation of a solution for intravenous administration

Composition:

1 bottle contains: active substance: basiliximab - 20 mg; auxiliary substances: sodium hydrophosphate anhydrous - 0.992 mg, sodium chloride - 1.608 mg, potassium dihydrogen phosphate - 7.212 mg, sucrose - 20.0 mg, glycine - 40.0 mg, mannitol - 80.0 mg.

It comes with a solvent: water for injection - 5 ml.

Description:

Lyophilizate white or almost white.
Solvent: clear, colorless liquid.
Reconstituted solution: colorless, clear or slightly opalescent solution.

Pharmacotherapeutic group:Immunosuppressive means - antibodies monoclonal

ATX: & nbsp

L.04.A.C.02 Basiliximab

Pharmacodynamics:

The preparation is a chimeric monoclonal antibody having the properties of mouse and human antibodies (IgG1k), the action of which is directed against the alpha chain of the interleukin-2 receptor (CD25 antigen) expressed on the surface of T lymphocytes in response to antigen challenge.

Simulect® specifically and with high affinity (K_R 0.1 nm) binds to the CD25 antigen on activated T lymphocytes expressing the high affinity interleukin-2 receptor and thus prevents the binding of interleukin-2, which serves as a signal for the proliferation of T cells.Complete and continuous interleukin-2 receptor blockade is maintained until the serum basiliximab concentration exceeds 0.2 μg / ml. At a concentration below this value, the CD25 antigen expression level returns to the baseline values within 1-2 weeks. Simulect® does not cause myelosuppression.

Results of clinical trials

The effectiveness of Simulect® in the prevention of graft rejection in patients with kidney transplantation for the first time was demonstrated in double-blind, placebo-controlled studies. The results of two 12-month multi-center studies comparing Simulect® and placebo showed that the use of Simulect® in combination with basic immunosuppressive therapy with cyclosporine (in the form of a microemulsion) and glucocorticoids significantly reduces the number of reactions of acute graft rejection as 6 months after transplantation (31% vs. 45%, p <0.001), and after 12 months (33% vs. 48%, p <0.001). For such an indicator as survival of the transplant at 6 and 12 months after transplantation there were significant differences between Simulect® and placebo (the number of cases of graft loss after 12 months was 32 (9%) in the group receiving Simulect® and 37 (10%) in the placebo group).The incidence of acute rejection of the graft was significantly lower in patients who received Simulect® against a background of three-component basic immunosuppressive therapy.
The results of two multicenter double "blind" studies comparing Simulect® and placebo with the three-component regimen of immunosuppressive therapyciclosporin + glucocorticoids + azathioprine or mycophenolate mofetil) suggest that Simulect® significantly reduces the incidence of acute rejection at 6 months after transplantation (21% vs. 35%, p = 0.005, Fisher's exact method, for a subgroup of azathioprine; or 15% vs. 27%, p = 0.046, Kaplan-Mayer method, for the subgroup of mycophenolate mofetil). The number of cases of graft loss after 6 months was 6% in the Simulect® group, and 10% in the placebo group. Both groups had comparable profiles of undesirable phenomena.
In a randomized, open, actively controlled study of 12 months, Simulect® was compared with the preparation of polyclonal antilymphocyte immunoglobulin (ATG / ALG). Patients in both groups also received basic immunosuppressive therapyglucocorticoids, mycophenolate mofetil and cyclosporin in the form of a microemulsion (in the group Simulect® ciclosporin appointed in the early period, and in the ATG / ALG group his appointment was delayed). Twelve months after transplantation, the incidence of rejection confirmed by biopsy was 19% in the Simulect® group and 20% in the ATG / ALG group.
As a result of a combined analysis of two five-year, open, actively controlled extension trials involving 586 patients, it was shown that there was no significant difference between Simulect® and placebo in the combined indicator that included graft survival and patient survival. These studies also showed that patients who had acute graft rejection reactions within the first year after transplantation lost graft loss and deaths over the next five years more often than those who did not have acute rejection reactions. The described phenomena were not associated with the use of Simulec®.
In a study in children with a newly transplanted kidney, Simulect® was administered against a background of a two-component regimen (ciclosporin + glucocorticoids). The incidence of acute rejection was 14.6% at 6 months after transplantation and 24.3% at 12 months after transplantation. The nature of adverse events in this study was practically the same as that of children who underwent kidney transplantation, as well as phenomena recorded in controlled clinical trials in adult patients who underwent kidney transplantation.
Of the 339 patients with a renal transplant who received Simulect® and were examined for anti-idiotypic antibodies, the latter were detected in 4 patients (1.2%). Of the 172 patients who received Simulect® in a clinical trial, the HAMA response (that is, the immune response to basiliximab) was noted in 2 of 138 patients who did not receive muromonab-CD3, and in 4 of 34 patients who received concomitantly muromonab-CD3, which had no prognostic value for assessing the tolerability of Simulect®. Currently available clinical data do not exclude the possibility of using mouromonab-CD3, as well as other drugs of murine antilymphocytic antibodies, in patients who received Simulect®.

Pharmacokinetics:

Pharmacokinetic studies with a single and multiplethe administration of the drug was carried out in patients who underwent renal transplantation. Total doses ranged from 15 mg to 150 mg.

Suction
After an intravenous 30-minute infusion of 20 mg of Simulect®, the maximum serum concentration is 7.1 ± 5.1 mg / L. The maximum concentration (Cmax) and the area under the concentration-time curve (AUC) increase in proportion to the increase in the single dose (up to a value of 60 mg, which was the maximum value studied).

Distribution
The volume of distribution when an equilibrium state is reached is 8.6 ± 4.1 liters. The distribution of basiliximab to various organs and tissues has not yet been fully explored. Experiments in vitro using human tissues have shown that Simulect® binds only to lymphocytes and macrophages / monocytes.

Excretion
The final half-life is 7.2 ± 3.2 days. The total ground clearance is 41 ± 19ml / h.

Pharmacokinetics in selected groups of patients
In adult patients, there was no clinically significant effect of body weight or sex on such pharmacokinetic parameters as volume distribution and clearance. It was also shown that the half-life does not depend on age (in the range of 20-69 years), sex and race.
Have adult patients who underwent liver transplantation, the equilibrium volume of distribution was 7.5 ± 2.5 l, the half-life was 4.1 ± 2.1 days, the clearance was 75 ± 24 ml / h. The value of clearance was affected by the loss of the drug with ascitic fluid during drainage of the abdominal cavity and postoperative bleeding. In this category of patients, higher clearance values were counterbalanced by a lower threshold concentration of the drug in the serum (0.1 μg / ml), at which the receptors saturated. Therefore, the duration of the blockade IL-2Ra At a given dosage, Simulect® was the same as in adult patients after kidney transplantation.

Pharmacokinetics in children.
The pharmacokinetics of Simulect ® in children were studied in 39 children with a newly transplanted kidney. In children aged 1 to 11 years (n = 25) who had a body weight of 9 to 37 kg and body surface area from 0.44 to 1.2 m², the equilibrium volume of distribution was 4.8 ± 2.1 L, the half-life period was 9.5 ± 4.5 days, the total clearance was 17 ± 6 ml / h. Values of distribution and clearance in children are approximately 50% lower than in adults. In this age group, there is no clinically significant effect of age, body weight and body surface area on pharmacokinetic parameters.In adolescents (age 12-16 years, n = 14), the parameters of pharmacokinetics were similar to those in adult patients and were: the equilibrium volume of distribution of 7.8 ± 5.1 liters, the period elimination half-life 9.1 ± 3.9 days, clearance 31 ± 19 ml / h. The relationship between serum concentration and receptor saturation was evaluated in 13 children and was similar to that in adult patients.

Indications:Prevention of acute graft rejection in adults and children with transplantation for the first time. The drug is used against a background of basic immunosuppressive therapy with cyclosporine (in the form of a microemulsion) and glucocorticoids or in addition to a three-component regimen of immunosuppression - ciclosporin in the form of a microemulsion, glucocorticoids and azathioprine (or preparations of mycophenolic acid).

Contraindications:

Hypersensitivity to basiliximab or other components of the drug.

Carefully:

Therapy with Simullect® can be performed only by physicians with experience of application immunosuppressive therapy after organ transplantation and only in a medical institution equipped with appropriate equipment prepared staff and medicinal drugs for therapeutic and resuscitative measures (including in the case of development of hypersensitivity reactions).

Care should be taken when re-applying the drug to the same patient.

Pregnancy and lactation:

There is no data on the use of the drug during pregnancy. Use the drug during pregnancy should be only in cases where the expected benefit for the mother exceeds the possible risk to the fetus.
Patients should use reliable contraceptives during therapy with the drug, and also within 4 months after its termination.

There is no evidence that basiliximab can penetrate difficult milk. However, since the drug belongs to antibodies of the immunoglobulin group G (IgG1k), the penetration of basiliximab through the placenta in humans, as well as penetration into breast milk. In view of the above, patients who are currently receiving therapy with the drug, and also within 4 months after the end, should stop breastfeeding.

Dosing and Administration:

For of adults the recommended dose is 40 mg divided into 2 injections.

For children and adolescents (aged 1 to 17 years) with body weight less than 35 kg the recommended total dose is 20 mg divided into two 10 mg administrations; if the body weight ist 35 kg or more, Simulect® is administered in a total dose of 40 mg divided into two 20 mg injections.

There is limited information on the use of Simulect® elderly patients (65 years and older). There are no data that would indicate the need for a change in the dosing regimen compared to the recommendations for younger adult patients.

The first administration is performed 2 hours before the transplantation operation. Introduction Simulect ® is possible only in the case of absolute certainty that the transplant will be performed and the patient will be prescribed basic immunosuppressive therapy. The second administration of 20 mg of Simulec® is carried out 4 days after the operation. From the introduction of the second dose should be refrained in case of loss (rejection) of the transplant or in the case of development of reactions of hypersensitivity to the introduction of the first dose of Simulect ®.

Recommendations for the preparation of solution for injection or infusion.

A solution for injections or infusions is prepared under aseptic conditions.

In a vial containing 20 mg of lyophilisate to prepare an injection solution, add 5 ml of water for injection from the enclosed ampoule. Gently shake the vial until the powder is dissolved. The prepared solution should be transparent or slightly opalescent, colorless, should not contain visible inclusions. It is desirable to use the solution immediately after preparation, but it is possible to store not more than 4 hours at room temperature (20-22 ° C) or for no more than 24 hours at a temperature of 2-8 ° C. If during the specified time, under the appropriate storage conditions, the solution has not been used, it should be destroyed.

The resulting Simulets® solution is isotonic and can be administered as a bolus injection. To prepare a solution for infusion, the resulting solution is adjusted to a volume of at least 50 ml with a 0.9% solution of sodium, chloride or 5% glucose solution. Duration of infusion - 20 - 30 min.

Simulect® should always be administered with a separate system and not mixed with other drugs for intravenous administration.

The compatibility of the solution with the following infusion systems was checked and established: an infusion bag Baxter minibag NaCl 0.9%; infusion systems Luer Lock™, N.N.oolens; Sterile vented i.v. set, Abbott; Infusion set, Codan; Infusomat™, Braun; Infusiongerat R 87 plus, Ohmeda; Lifecare 5000™ Plumset Microdrip, Abbott; Vented basic set, Baxter; Flashball device, Baxter; Vented primary administration set, Imed. Compatibility c other commercial systems have not been tested.

Side effects:

The following information on adverse events is based on data from four randomized, double-blind, placebo-controlled studies in patients with a transplanted kidney. In assessing the possible association of an undesirable phenomenon with the use of Simulept®, concomitant immunosuppressive therapy should also be considered, which was prescribed to patients as part of standard schemes: in two studies, ciclosporin in the form of a microemulsion and glucocorticoids (346 and 380 patients); in one study - ciclosporin in the form of a microemulsion, azathioprine and glucocorticoids (340 patients) and in one study - ciclosporin in the form of a microemulsion, mycophenolate mofetil and glucocorticoids (123 patients). In addition, in one controlled trial in patients with a transplanted kidney (135 patients), Simulect® was studied in comparison with the preparation of polyclonal antilymphocytic immunoglobulin (ATG/ALG) on the background of basic immunosuppressive therapy (ciclosporin + mycophenolate mofetil + glucocorticoids). Data on the safety of the use of Simulect ® in children were obtained in an open pharmacokinetic and pharmacodynamic study in patients with a transplanted kidney (41 patients).

Frequency of adverse events. The purpose of Simulec® does not lead to an increase in the incidence of adverse events that are commonly observed in patients who underwent organ transplantation and are due to the condition of the patient and the simultaneous use of immunosuppressive and other drugs. In four placebo-controlled studies, the nature and severity of adverse events did not differ in the two groups: in 590 patients treated with the recommended dose of Simulect®; in 595 patients who received a placebo. The incidence of serious adverse events in the appointment of Simulect® also did not change (when compared with the placebo group). The overall incidence of adverse events that the researchers estimated to be associated with the use of Simulect® did not differ significantly between the groups receiving Simulect® (7.1% -40%) and those receiving placebo (7.6% -39%). According to a comparative study with a preparation of polyclonal antilymphocyte immunoglobulin (ATG/ALG), undesirable phenomena associated with the use of the drug were significantly less common in the Simulect® group (11.4%) than in the group ATG/ALG (41.5%).

Adverse events in adult patients. Most often (> 20%) in both compared groups (Simulect® vs. Placebo or Simulation® vs. ATG/ALG, against a background of two- or three-component immunosuppressive therapies) there were constipations, infections of the urinary tract; pain caused mainly by surgical intervention; nausea, peripheral edema, increased blood pressure, anemia, headache, hyperkalemia, hypercholesterolemia, wound infections, weight gain, increased serum creatinine concentration, hypophosphatemia, diarrhea, upper respiratory infections.

Adverse events in children. In both weight groups of patients (with a body weight of less than 35 kg and a body weight of 35 kg and above), urinary tract infections, hypertrichosis, rhinitis, pyrexia, increased arterial pressure, infectious diseases of the upper divisions were most often (> 20%) respiratory tract infections, viral infections, sepsis, constipation.

Frequency of malignant neoplasms. According to all the studies conducted, the total incidence of malignant neoplasms was similar in the groups of patients who received Simulect® and the groups receiving any of the reference drugs. For example, lymphoma / lymphoproliferative diseases were found in the Simulect® group at a frequency of 0.1% (1/701); in the placebo group - 0.3% (2/595) and 0% -group ATG/ALG. The frequency of occurrence of other malignant neoplasms was 1% (7/701) in the Simulect® group; 1.2% (7/595) in the placebo group and 4.6% (3/65) in the group ATG/ALG.

According to the combined analysis of two five-year studies, Simulect® did not increase the incidence of malignant neoplasms and lymphoproliferative diseases compared with placebo (7% in the Simulect® group and 7% in the placebo group).

Frequency of infectious diseases. The overall frequency and range of infectious diseases in patients receiving baseline immunosuppressive therapy (two- or three-component) were similar in the groups receiving Simulect® (75.9%) and those receiving placebo (75.6%) or ATG/ALG (75.6%). Severe infectious diseases occurred with approximately the same frequency in the group of patients receiving Simulect®, and in the group of patients who received the reference drug (26.1% and 24.8%respectively). The incidence of cytomegalovirus infection was similar in both groups (14.6% and 17.3%).

The incidence of deaths and causes of death in the Simulect® group and in placebo or ATG/ALG were also the same (2.9% and 2.6%, respectively). The most common cause of death was infection (the Simulect ® group - 1.3%, placebo group or ATG/ALG - 1.4%).

A combined analysis of two five-year studies showed that the rate of deaths and their causes were the same in both groups (the Simulect® group was 15%, the placebo group was 11%). The main cause of death was cardiac dysfunction (Simulect® group - 5%, placebo group - 4%).

Postmarketing data indicate the following violations from the immune system: rarely - hypersensitivity reactions / allergic reactions, such as skin rash, urticaria, sneezing, wheezing, bronchospasm, pulmonary edema, heart failure, respiratory failure, capillary permeability syndrome; very rarely - a syndrome of cytokine release.

Overdose:

In clinical trials, Simulect® was administered to patients in a single dose up to 60 mg or in fractional doses up to a total dose of 150 mg for 24 days, without any acute adverse events noted.

In a four-week study of Rh-monkeys, when the drug was administered at a dose of 5 mg / kg 2 times a week with C_max basiliximab, 170 μg / ml, there were no signs of an overdose. Basiliximab concentrations in humans are usually less than 10 μg / ml when using the recommended dosing regimen.

Interaction:

Since Simulect® is an immunoglobulin, no metabolic interactions are expected with concomitantly administered other drugs.

Along with cyclosporine in the form of a microemulsion, steroids, azathioprine and mycophenolate mofetil, the following drugs were used concomitantly with Simulekt® as a concomitant therapy: systemic antiviral, antibacterial, antifungal agents, analgesics, antihypertensives such as beta-blockers, calcium antagonists and diuretics. There was no increase in the incidence of adverse events.

In the first 3 months after transplantation, there were cases of acute graft rejection (in 14% of patients in the Simulect® group and in 27% of patients in the placebo group) for which antibody preparations were used (for example, OCT 3 or ATG / ALG).However, in the group receiving Simulect®, when compared with the group receiving the placebo, there was no increase in the incidence of infectious diseases or other adverse events.

The study of Simulect®, applied against a background of a three-component regimen of immunosuppressive therapy (ciclosporin in the form of a microemulsion, glucocorticoids and azathioprine or mycophenolate mofetil), was conducted in three clinical studies. When azathioprine is added to a two-component therapy (ciclosporin + glucocorticoids) there was a decrease in the total clearance of Simulect® on average by 22%. When added to the two-component therapy of mycophenolate mofetil, the decrease in Simulect® clearance was on average 51%. When using Simulect® against a three-component therapy regimen that included azathioprine or mycophenolate mofetil, there was no evidence of any increase in infectious diseases or other adverse events (when compared with the placebo group).

NAMA cases were reported in a clinical trial involving 172 patients in 2 of 138 patients who did not receive muromonab-Cd3, and in 4 of 34 patients who received concomitant muro-Cd3, which has no prognostic value for evaluating the tolerability of Simulect ®. Therapy Simulect® does not exclude the possibility of simultaneous application of muromonab-Cd3, as well as other preparations of murine antilymphocytic antibodies.

Special instructions:

The cases of the development of severe hypersensitivity reactions during the first 24 hours as after the first and repeated administration preparation of Simulect®. These anaphylactoid reactions included such manifestations, as a rash, urticaria, itching, sneezing, wheezing, arterial hypotension, tachycardia, dyspnea, bronchospasm, pulmonary edema, acute cardiac and acute respiratory failure, syndrome of increased permeability of capillaries. If the hypersensitivity reaction develops, the drug should be immediately discontinued; repeated use of the drug is contraindicated.

There is evidence that a certain group of patients has an increased risk of developing hypersensitivity reactions. This group includes patients who previously received the drug simultaneously with immunosuppressants, Therapy was prematurely canceled, for example, in connection with the rejection of transplantation or in the event of early rejection of the graft. In some patients with repeated application of Simulect® before acute transplantation there were acute reactions hypersensitivity.

Patients after transplantation, receiving combined immunosuppressive therapy with / without the preparation of Simulect®, increased risk of lymphoproliferative diseases, such as lymphomas, and opportunistic infections, such as cytomegalovirus infection. Before There has been no increase in the incidence of any lymphoproliferative diseases or opportunistic infections in patients treated with Simulect®, despite the fact that the drug is immunosuppressive. According to the combined analysis of two five-year studies, no differences were found the incidence of malignant and lymphoproliferative diseases in patients receiving combined immunosuppressive therapy with or without preparation of Simulect®.
There is no evidence of possible effects or the possible development of infections associated with the use of live attenuated vaccines during treatment with the Simulect® preparation.However, despite this, vaccination with live attenuated vaccines should be avoided during immunosuppressive therapy. Have This category of patients may use inactivated vaccines, but the effect depends on the degree of immunosuppression.

Effect on the ability to drive transp. cf. and fur:Studies of the effect of the Simulect® on the ability drive vehicles and they did not work with mechanisms. The possibility of a negative effect of the drug on the ability to perform these activities is unlikely.

Form release / dosage:

Lyophilizate for the preparation of a solution for intravenous administration of 20 mg.

Packaging:Lyophilizate for the preparation of a solution for intravenous administration of 20 mg in 1 bottle of colorless glass with 1 ampoule of solvent (5 ml of water for injection) together with instructions for use, packed in a cardboard box.

Storage conditions:

Lyophilizate: At a temperature of 2-8 ° C.
Prepared solution: no more than 24 hours at a temperature of 2-8 ° C or no more than 4 hours at a temperature of 15-25°C.
The drug should be stored out of the reach of children.

Shelf life:

Lyophilizate - 3 years;

Solvent - 5 years.

The expiration date of the kit is determined by the earlier expiry date of the component included in the kit.

The drug should not be used after the expiry date indicated on the package.

Terms of leave from pharmacies:On prescription

Registration number:П N011528 / 01

Date of registration:09.11.2011

The owner of the registration certificate:Novartis Pharma AGNovartis Pharma AG Switzerland

Manufacturer: & nbsp

NOVARTIS PHARMA, AG Switzerland

Representation: & nbspNOVARTIS CONSUMER HELS S.A. (part of Novartis groups) NOVARTIS CONSUMER HELS S.A. (part of Novartis groups) Switzerland

Information update date: & nbsp31.03.2015

Illustrated instructions

Instructions

Simulect® (Simulect®)