INSTRUCTION for medical use of the medicinal product SIMULECT® (Simulect®)

Composition:

Active substance: basiliximab;

1 vial contains 20 mg of basiliximab;

Excipients: apyrogenic mannitol, apyrogenic glycine, apyrogenic sucrose, potassium dihydrogen phosphate, sodium chloride, anhydrous disodium phosphate, nitrogen.

Solvent: water for injections; 1 ampoule of solvent contains 5 ml of water for injections.

Pharmaceutical form. Lyophilisate for solution for injection/infusion.

Main physicochemical properties: white lyophilisate; particles may form after transportation.

Pharmacotherapeutic group. Immunosuppressants. Interleukin inhibitors. Basiliximab.

ATC code: L04A C02.

Immunological and biological properties.

Pharmacodynamics.

SIMULECT® is a mouse/human chimeric monoclonal antibody (IgG1k) that acts against the α-chain of the interleukin-2 receptor (CD25 antigens) expressed on the surface of T-lymphocytes in response to antigenic stimulation. SIMULECT® specifically binds (KD value 0.1 nmol) to the CD25 antigen on activated T-lymphocytes expressing the high-affinity interleukin-2 receptor, thereby preventing interleukin-2 binding. Interleukin-2 is a signal for T-cell proliferation involved in transplant rejection. Complete and sustained blockade of the interleukin-2 receptor is maintained while serum basiliximab levels exceed 0.2 µg/mL (typically up to 4–6 weeks after administration). When concentration falls below this level, CD25 antigen expression returns to pre-treatment baseline values within 1–2 weeks. SIMULECT® does not cause myelosuppression.

Clinical efficacy and safety

The efficacy of basiliximab as a prophylactic agent against organ rejection in de novo kidney transplantation has been demonstrated in double-blind, placebo-controlled studies. Results from two main 12-month multicenter trials (total 722 patients), comparing basiliximab with placebo, show that basiliximab, when used concomitantly with microemulsion cyclosporine and corticosteroids, significantly reduces the incidence of acute rejection both at 6 months (31% vs. 45%, p < 0.001) and at 12 months (33% vs. 48%, p < 0.001) post-transplantation. No significant difference was observed between basiliximab and placebo groups in graft survival at 6 and 12 months (at 12 months, graft loss was 32 in the basiliximab group (9%) and 37 graft losses in the placebo group (10%)). The incidence of acute rejection was significantly lower in patients receiving basiliximab in combination with a three-drug immunosuppressive regimen.

Results from two multicenter, double-blind studies comparing basiliximab with placebo (total 463 patients) show that basiliximab significantly reduces the incidence of acute rejection within 6 months after transplantation when used concomitantly with microemulsion cyclosporine, corticosteroids, and either azathioprine (21% vs. 35%) or mycophenolate mofetil (15% vs. 27%). Graft loss within 6 months occurred in 6% of patients receiving basiliximab and in 10% of patients receiving placebo. The adverse event profile in these treatment groups remained comparable.

In a pooled analysis of two five-year open-label extension studies (total 586 patients), overall graft and patient survival rates did not differ statistically between the basiliximab and placebo groups. The extension studies also showed that patients who experienced an episode of acute rejection during the first year after transplantation had higher rates of graft loss and death during the subsequent five-year follow-up period compared to patients without rejection. Basiliximab did not influence these outcomes.

Pediatric patient population

The efficacy and safety of basiliximab in children were evaluated in two studies.

Basiliximab was administered concomitantly with microemulsion cyclosporine and steroids in an uncontrolled study involving 41 pediatric recipients of de novo kidney transplantation. Acute rejection was observed in 14.6% of patients at 6 months and in 24.3% at 12 months post-transplantation. Overall, the adverse event profile was consistent with the general clinical experience of kidney transplantation in the pediatric population and with the profile observed in controlled adult transplantation studies.

A 12-month, randomized, placebo-controlled, double-blind, multicenter study evaluated the effect of basiliximab in combination with microemulsion cyclosporine, mycophenolate mofetil, and steroids in pediatric kidney transplant recipients. The primary objective of this study was to demonstrate the superiority of this combination compared to treatment with microemulsion cyclosporine, mycophenolate mofetil, and steroids alone in preventing acute rejection episodes. Of 202 patients, 104 were randomized to the basiliximab treatment group and 98 to placebo. The primary efficacy endpoint—time to first biopsy-proven acute rejection (BPAR) or treatment failure defined as graft loss, death, or probable rejection within the first 6 months after transplantation—was reached in 16.7% of patients receiving basiliximab and 21.7% of patients receiving placebo. When borderline rejection cases were included in the primary efficacy endpoint, the rates were 26.0% and 23.9%, respectively, with no statistically significant difference between the basiliximab and placebo groups (relative risk (RR): 1.04, 90% CI: [0.64; 1.68]). The incidence of BPAR was 9.4% in the basiliximab group and 17.4% in the placebo group (RR: 0.50, 90% CI: [0.25; 0.99]). When borderline cases were included, the rates were 20.8% and 19.6%, respectively (RR: 1.01, 90% CI: [0.59; 1.72]). The overall safety profiles in both groups were similar. The frequency and nature of adverse events in these two treatment groups were comparable and consistent with expectations for the proposed treatment regimens and underlying disease.

Immunogenicity

Among 339 kidney transplant patients who received basiliximab and were tested for anti-idiotypic antibodies, 4 (1.2%) developed an anti-idiotypic response to the antibody. In a clinical study of basiliximab use involving 172 kidney transplant recipients, human anti-mouse antibodies (HAMA) were detected in 2 of 138 patients who had not been exposed to muromonab-CD3, and in 4 of 34 patients who received muromonab-CD3 concomitantly. Available data on the use of muromonab-CD3 in patients previously treated with basiliximab suggest that subsequent administration of muromonab-CD3 or another murine antilymphocyte antibody is not precluded.

Pharmacokinetics

Adults

Pharmacokinetic studies were conducted after single and multiple doses in patients who underwent kidney transplantation. Total doses ranged from 20 mg to 60 mg.

Maximum serum concentration of the drug 30 minutes after intravenous infusion of 20 mg was 7.1 ± 5.1 mg/L. A dose-proportional increase in Cmax and AUC was observed up to the highest tested single dose of 60 mg.

The volume of distribution at steady state is 8.6 ± 4.1 L. The extent and distribution in various body compartments have not been fully investigated. In vitro studies using human tissues showed that SIMULECT® binds only to lymphocytes and macrophages/monocytes. The terminal half-life is 7.2 ± 3.2 days. Total clearance is 41 ± 19 mL/h. In adult patients, no clinically significant effect of body weight or sex on volume of distribution and clearance was observed. Age, sex, and race did not influence the half-life.

Children

Pharmacokinetics of basiliximab were evaluated in 39 pediatric patients who underwent de novo kidney transplantation. In neonates and children (age 1–11 years, n=25), the steady-state volume of distribution was 4.8±2.1 L, the half-life was 9.5±4.5 days, and clearance was 17±6 mL/h. Volume of distribution and clearance were approximately 50% lower compared to adult kidney transplant recipients. In this age group, distribution parameters were not clinically significantly affected by age (1–11 years), body weight (9–37 kg), or body surface area (0.44–1.20 m²). In adolescents (age 12–16 years, n=14), the steady-state volume of distribution was 7.8±5.1 L, the half-life was 9.1±3.9 days, and clearance was 31±19 mL/h. Distribution in adolescents was similar to that in adult kidney transplant recipients. The relationship between serum concentration and receptor saturation was assessed in 13 patients and was similar to that observed in adult kidney transplant recipients.

Clinical characteristics.

Indications.

Prophylaxis of acute organ rejection in adult and pediatric (aged 1 to 17 years) patients following de novo allogeneic kidney transplantation. The drug is used as part of immunosuppressive therapy with cyclosporine (microemulsion) and corticosteroids in patients with panel-reactive antibody levels below 80%, or as part of triple maintenance immunosuppressive therapy with cyclosporine (microemulsion), corticosteroids, and either azathioprine or mycophenolate mofetil.

Contraindications.

Known hypersensitivity to basiliximab or to any other component of the drug; pregnancy and lactation.

Interaction with other medicinal products and other forms of interaction.

Since SIMULECT® is an immunoglobulin, metabolic drug-drug interaction reactions are not expected. Additionally, the concomitant use of cyclosporine (microemulsion), corticosteroids, azathioprine, and mycophenolate mofetil, as well as other medicinal products commonly used in organ transplantation, does not increase the incidence of adverse reactions. These concomitant therapies include systemic antiviral, antibacterial, and antifungal agents, analgesics, and antihypertensive drugs such as beta-blockers, calcium channel blockers, and diuretics.

In clinical studies involving 172 patients who received basiliximab without prior assessment of clinical tolerability, human antimurine antibodies (HAMA) were reported in 2 out of 138 patients who had not been exposed to muromonab-CD3 (OKT3), and in 4 out of 34 patients who received muromonab-CD3 concurrently. The use of basiliximab did not preclude subsequent administration of murine antilymphocyte antibody preparations.

In the original phase III studies, during the first 3 months after transplantation, episodes of acute rejection requiring treatment with antibodies (OKT3 or antithymocyte/antilymphocyte globulin (ATG/ALG)) occurred in 14% of patients in the basiliximab group and in 27% of patients in the placebo group. No increase in the frequency of adverse events or infections was observed in the basiliximab group compared to placebo.

In three clinical studies, the use of basiliximab in combination with triple-drug regimens including either azathioprine or mycophenolate mofetil was evaluated. The total clearance of basiliximab decreased by an average of 22% when azathioprine was added to cyclosporine (microemulsion) and corticosteroid therapy. The total clearance of basiliximab decreased by an average of 51% when mycophenolate mofetil was added to cyclosporine (microemulsion) and corticosteroid therapy. The use of basiliximab in combination with triple-drug regimens including azathioprine or mycophenolate mofetil did not increase the frequency of adverse events compared to placebo in the basiliximab group.

Special precautions.

Traceability

In order to improve the traceability of biological medicinal products, the name and batch number of the administered medicinal product should be clearly documented.

Patients receiving SIMULECT® must be treated in healthcare facilities equipped with laboratories having appropriate equipment and supported by trained personnel and auxiliary medical resources, including means for the management of severe hypersensitivity reactions.

Immunosuppressive regimens involving combination therapy increase susceptibility to infections, including opportunistic infections, fatal infections, and sepsis; the risk increases with increasing total immunosuppressive burden.

SIMULECT® should not be administered unless there is absolute certainty that the patient is receiving a transplant and concomitant immunosuppression.

Hypersensitivity reactions

Severe acute (within less than 24 hours) allergic reactions have been observed both after initial exposure to SIMULECT® and after re-exposure in subsequent treatment courses. These included anaphylactoid-type reactions such as rash, urticaria, pruritus, sneezing, dyspnea, hypotension, tachycardia, respiratory distress, bronchospasm, pulmonary edema, cardiac failure, respiratory failure, and capillary leak syndrome. In the event of a severe allergic reaction, administration of SIMULECT® must be permanently discontinued and no further doses should be administered. Caution is advised when patients previously treated with SIMULECT® are re-exposed to this medicinal product in a subsequent treatment course. Increasing reports indicate that this subgroup of patients has an increased risk of developing allergic reactions. These are patients in whom concomitant immunosuppression was discontinued prematurely after initial administration of SIMULECT®, for example due to transplant cancellation or early graft rejection. Acute allergic reactions have been observed in some of these patients upon re-administration of SIMULECT® for a subsequent transplantation.

Neoplasms and infections

Transplant recipients receiving immunosuppressive therapy, including regimens with or without basiliximab, have an increased risk of developing lymphoproliferative disorders (LPDs) (such as lymphoma) and opportunistic infections (such as cytomegalovirus (CMV), BK virus). In clinical trials, the incidence of opportunistic infections was similar among patients receiving immunosuppressive therapy with or without SIMULECT®. In a pooled analysis of two five-year extension studies, no differences were observed in the frequency of malignant neoplasms and LPDs between immunosuppressive regimens with or without basiliximab.

Vaccination

There are no data on the effects of live or inactivated vaccines or on transmission of infection from live vaccines in patients receiving SIMULECT®. Despite this, live vaccines are not recommended for immunosuppressed patients. Inactivated vaccines may be administered to immunosuppressed patients; however, the immune response to vaccination may depend on the degree of immunosuppression, so vaccination during treatment with SIMULECT® may be less effective.

Use in heart transplantation

The efficacy and safety of SIMULECT® for the prevention of acute rejection in solid organ transplant recipients other than kidney have not been established. In several small clinical studies involving heart transplant recipients, serious cardiac adverse reactions such as cardiac arrest (2.2%), atrial fibrillation (1.9%), and tachycardia (1.4%) occurred more frequently with SIMULECT® than with other induction agents.

Excipients with known effect

This medicinal product contains less than 1 mmol of sodium (23 mg) per vial, i.e., essentially "sodium-free".

This medicinal product contains less than 1 mmol of potassium (39 mg) per vial, i.e., essentially "potassium-free".

Use during pregnancy or breastfeeding

SIMULECT® is contraindicated during pregnancy and breastfeeding. Basiliximab has a potentially harmful immunosuppressive effect on pregnancy and on infants exposed to basiliximab via breastfeeding. Women of childbearing potential should use effective contraception during and for 16 weeks after receiving the drug.

Currently, there are no data on the excretion of basiliximab into human or animal breast milk. However, due to the IgG1 nature of basiliximab, excretion into breast milk can be expected. Therefore, breastfeeding should be avoided.

Ability to influence the speed of reactions while driving or operating machinery

SIMULECT® has no influence on the ability to drive or operate machinery.

Method of Administration and Dosage

SIMUMECT® must be prescribed only by a physician experienced in immunosuppressive therapy following organ transplantation. SIMULEKCT® should be administered under qualified medical supervision.

SIMUMECT® should not be administered unless there is absolute certainty that the patient will receive the transplant and concomitant immunosuppressive therapy.

SIMUMECT® is indicated for use in immunosuppressive regimens based on microemulsion formulation cyclosporine and corticosteroids. It may be used in triple immunosuppressive therapy regimens based on microemulsion formulation cyclosporine, corticosteroids, and either azathioprine or mycophenolate mofetil.

Dosage

Adults

The standard total dose is 40 mg, administered as two 20 mg doses.

The first 20 mg dose should be given within 2 hours before transplantation surgery. The second 20 mg dose should be administered 4 days after transplantation. The second dose should be omitted in case of a severe allergic reaction to SIMULECT® or postoperative complications such as graft rejection.

Instructions for Preparation of Solution

To prepare the injection or infusion solution, under aseptic conditions, add 5 mL of water for injection from the supplied vial to the vial containing SIMULECT® powder. Gently shake the vial to dissolve the powder, avoiding foaming. After reconstitution, the resulting colorless, clear, opalescent solution should be used immediately. The reconstituted solution should be visually inspected for particulate matter prior to administration. Do not use if foreign particles are present. After reconstitution, chemical and physical stability has been demonstrated for 24 hours at 2°C–8°C or for 4 hours at room temperature. From a microbiological standpoint, the product should be used immediately. If not used immediately, storage time and conditions prior to use are the responsibility of the user.

Any reconstituted solution not used within 24 hours should be discarded.

The reconstituted solution is isotonic and may be administered as an intravenous bolus injection or diluted to a volume of 50 mL or more with standard saline or 50 mg/mL (5%) glucose solution for infusion.

Because compatibility data with other intravenous medicinal products are lacking, SIMULECT® must not be mixed with other medicinal products and should always be administered through a separate infusion catheter.

Compatibility has been tested with a number of infusion sets.

Any unused medicinal product or waste material must be disposed of in accordance with local requirements.

Route of Administration

The prepared SIMULECT® solution may be administered either as an intravenous bolus injection or as an intravenous infusion over 20–30 minutes.

Elderly Patients (≥65 years of age)

Currently, data on the use of SIMULECT® in elderly patients are limited; however, there is no evidence that elderly patients require different dosing compared to younger adult patients.

Children

Dosage recommendations for pediatric patients and adolescents (1–17 years of age):

For pediatric patients with body weight less than 35 kg, the recommended total dose is 20 mg, administered as two 10 mg doses. For pediatric patients with body weight of 35 kg or more, the adult dose is recommended, i.e., a total dose of 40 mg administered as two 20 mg doses.

The first dose should be administered within 2 hours before transplantation surgery, and the second dose on day 4 after transplantation. The second dose should be withheld in case of a severe allergic reaction to SIMULECT® or postoperative complications such as graft rejection.

Overdose.

In clinical studies, SIMULECT® was administered to patients at single doses up to 60 mg and multiple doses up to 150 mg over 24 days without manifestation of adverse acute effects.

Side effects

SIMULECT® was studied in four randomized, double-blind, placebo-controlled trials involving kidney transplant patients as an induction agent in combination with the following immunosuppressive agents: microemulsion cyclosporine and corticosteroids in two studies (346 and 380 patients), microemulsion cyclosporine, azathioprine, and corticosteroids in one study (340 patients), and microemulsion cyclosporine, mycophenolate mofetil, and corticosteroids in another study (123 patients). Safety data in pediatric patients were obtained from one open-label pharmacokinetic and pharmacodynamic study in kidney transplant recipients (41 patients).

Incidence of adverse events: In the four placebo-controlled studies described above, the profile of adverse events in 590 patients receiving the recommended dose of basiliximab was similar to that observed in 595 patients receiving placebo. The overall incidence of drug-related adverse events in individual studies was not significantly different between the basiliximab (7.1–40%) and placebo (7.6–39%) groups.

Adult patients

The most commonly reported events (>20%) following dual or triple therapy in both experimental groups (basiliximab compared to placebo) were: constipation, urinary tract infection, pain, nausea, peripheral edema, hypertension, anemia, headache, hyperkalemia, hypercholesterolemia, postoperative wound complication, weight gain, increased blood creatinine, hypophosphatemia, diarrhea, and upper respiratory tract infection.

Pediatric population

The most commonly reported events (>20%) following dual-drug therapy in both cohorts (body weight <35 kg compared to ≥35 kg) were: urinary tract infection, hypertrichosis, rhinitis, fever, hypertension, upper respiratory tract infection, viral infection, sepsis, and constipation.

Incidence of malignancies. The overall number of malignancy cases in individual studies was similar in the basiliximab and comparator groups. Lymphoma/lymphoproliferative disorders (LPD) were observed in 0.1% (1 of 701) of patients in the basiliximab group compared to 0.3% (2 of 595) in the placebo group, in both cases with dual or triple immunosuppressive therapy. Other malignancies were reported in 1.0% (7 of 701) of patients receiving basiliximab compared to 1.2% (7 of 595) in the placebo group. In a combined analysis of two five-year extension studies, the incidence of LPD and cancer was identical with basiliximab (7%, 21 of 295) and placebo (7%, 21 of 291) (see section "Special precautions").

Incidence of infections. The overall incidence and profile of viral, bacterial, and fungal infections were similar in patients receiving basiliximab or placebo in combination with dual or triple immunosuppressive therapy across all groups. The overall incidence was 75.9% in the basiliximab group and 75.6% in the placebo group, with serious infection rates of 26.1% and 24.8%, respectively. The incidence of cytomegalovirus infections was similar in both groups (14.6% vs. 17.3%) following dual or triple therapy (see section "Special precautions").

The incidence of death following dual or triple therapy was similar in the basiliximab (2.9%) and placebo (2.6%) groups, with infections being the most common cause of death in both groups (basiliximab – 1.3%, placebo – 1.4%). In a combined analysis of two five-year extension studies, the incidence and causes of death remained similar in both treatment groups (basiliximab – 15%, placebo – 11%). The main causes of death were cardiovascular disorders, such as heart failure and myocardial infarction (basiliximab – 5%, placebo – 4%).

Adverse reactions from post-marketing spontaneous reports

The following adverse reactions have been identified from post-marketing spontaneous reports and are classified by system organ class. As these reactions were reported voluntarily from populations of unknown size, it is not possible to reliably estimate their frequency.

Immune system disorders

Allergic reactions/anaphylactoid reactions such as rash, urticaria, pruritus, sneezing, dyspnea, bronchospasm, respiratory distress, pulmonary edema, cardiac failure, hypotension, tachycardia, respiratory failure, capillary leak syndrome (see section "Special precautions"), and cytokine release syndrome.

Shelf life.

3 years.

Storage conditions.

Store in the original packaging at 2–8°C. Keep out of reach of children.

After reconstitution, the solution can be stored for 24 hours at 2–8°C and for no more than 4 hours at room temperature.

Incompatibilities.

There are no data on the compatibility of SIMULECT® with other intravenous substances. The product should not be mixed with other medicinal products/substances and should be administered through a separate infusion line.

Packaging.

One glass vial containing lyophilisate for solution for infusion/injection, supplied with solvent (5 mL of water for injections) in an ampoule, in a cardboard box.

Prescription category.

By prescription only.

Manufacturer.

1. Novartis Pharma GmbH (batch release).

Novartis Farma S.A. (batch release).

Manufacturer's address and location of operations.

Roonstrasse 25, Gostenhof, Nuremberg, Bavaria, 90429, Germany.
Gran Vía de les Corts Catalanes 764, Barcelona, 08013, Spain.