Basiliximab is a chimeric (murine/human) monoclonal antibody (IgG1к), produced by recombinant DNA technology, that functions as an immunosuppressive agent, specifically binding to and blocking the interleukin-2 receptor α-chain (IL-2Rα, also known as CD25 antigen) on the surface of activated T-lymphocytes. Based on the amino acid sequence, the calculated molecular weight of the protein is 144 kilodaltons. It is a glycoprotein obtained from fermentation of an established mouse myeloma cell line genetically engineered to express plasmids containing the human heavy and light chain constant region genes and mouse heavy and light chain variable region genes encoding the RFT5 antibody that binds selectively to the IL-2Rα.

Simulect® (basiliximab) for injection is a sterile, preservative-free lyophilisate, which is available in single-dose vials and is available in 10 mg and 20 mg strengths for intravenous administration after reconstitution.

Each 10-mg vial contains 10 mg of basiliximab, and dibasic sodium phosphate (anhydrous) (0.50 mg), glycine (20.3 mg), mannitol (40.6 mg), monobasic potassium phosphate (3.66 mg), sodium chloride (0.82 mg), and sucrose (10.1 mg) to be reconstituted in 2.5 mL of Sterile Water for Injection, USP.

Each 20-mg vial contains 20 mg of basiliximab, and dibasic sodium phosphate (anhydrous) (0.99 mg), glycine (40.1 mg), mannitol (80.1 mg), monobasic potassium phosphate (7.22 mg), sodium chloride (1.61 mg), and sucrose (20 mg) to be reconstituted in 5 mL of Sterile Water for Injection, USP.

The safety and efficacy of Simulect® (basiliximab) for the prophylaxis of acute organ rejection in adults following cadaveric- or living-donor renal transplantation were assessed in four randomized, double-blind, placebo-controlled clinical studies (1,184 patients). Of these four, two studies (Study 1 [EU/CAN] and Study 2 [US Study]) compared two 20-mg doses of Simulect with placebo, each administered intravenously as an infusion, as part of a standard immunosuppressive regimen comprised of cyclosporine, USP (MODIFIED) and corticosteroids. The other two controlled studies compared two 20-mg doses of Simulect with placebo, each administered intravenously as a bolus injection, as part of a standard triple-immunosuppressive regimen comprised of cyclosporine, USP (MODIFIED), corticosteroids and either azathioprine or mycophenolate mofetil (Study 3 and Study 4, respectively). The first dose of Simulect or placebo was administered within 2 hours prior to transplantation surgery (Day 0) and the second dose administered on Day 4 post-transplantation. The regimen of Simulect was chosen to provide 30-45 days of IL-2Rα saturation.

Seven hundred twenty-nine patients were enrolled in the two studies using a dual maintenance immunosuppressive regimen comprised of cyclosporine, USP (MODIFIED) and corticosteroids, of which 363 patients were treated with Simulect and 358 patients were placebo-treated. Study 1 was conducted at 21 sites in Europe and Canada (EU/CAN Study); Study 2 was conducted at 21 sites in the USA (US Study). Patients 18-75 years of age undergoing first cadaveric- (Study 1 and Study 2) or living-donor (Study 2 only) renal transplantation, with ≥ 1 HLA mismatch, were enrolled.1,2

The primary efficacy endpoint in both studies was the incidence of death, graft loss or an episode of acute rejection during the first 6 months post-transplantation. Secondary efficacy endpoints included the primary efficacy variable measured during the first 12 months post-transplantation, the incidence of biopsy-confirmed acute rejection during the first 6 and 12 months post-transplantation and patient survival and graft survival, each measured at 12 months post-transplantation. Table 1 summarizes the results of these studies. Figure 1 displays the Kaplan-Meier estimates of the percentage of patients by treatment group experiencing the primary efficacy endpoint during the first 12 months post-transplantation for Study 2. Patients in both studies receiving Simulect experienced a significantly lower incidence of biopsy-confirmed rejection episodes at both 6 and 12 months post-transplantation. There was no difference in the rate of delayed graft function, patient survival, or graft survival between Simulect-treated patients and placebo-treated patients in either study.

There was no evidence that the clinical benefit of Simulect was limited to specific subpopulations based on age, gender, race, donor type (cadaveric or living donor allograft), or history of diabetes mellitus.

Two double-blind, randomized, placebo-controlled studies (Study 3 and Study 4) assessed the safety and efficacy of Simulect for the prophylaxis of acute renal transplant rejection in adults when used in combination with a triple immunosuppressive regimen. In Study 3, 340 patients were concomitantly treated with cyclosporine, USP (MODIFIED), corticosteroids and azathioprine (AZA), of which 168 patients were treated with Simulect and 172 patients were treated with placebo. In Study 4, 123 patients were concomitantly treated with cyclosporine, USP (MODIFIED), corticosteroids and mycophenolate mofetil (MMF), of which 59 patients were treated with Simulect and 64 patients were treated with placebo. Patients 18-70 years of age undergoing first or second cadaveric or living donor (related or unrelated) renal transplantation were enrolled in both studies.

The results of Study 3 are shown in Table 2. These results are consistent with the findings from Study 1 and Study 2.

In Study 4, the percentage of patients experiencing biopsy-proven acute rejection by 6 months was 15% (9 of 59 patients) in the Simulect group and 27% (17 of 64 patients) in the placebo group. Although numerically lower, the difference in acute rejection was not significant.

In a multicenter, randomized, double-blind, placebo-controlled trial of Simulect for the prevention of allograft rejection in liver transplant recipients (n = 381) receiving concomitant cyclosporine, USP (MODIFIED) and steroids, the incidence of the combined endpoint of death, graft loss, or first biopsy-confirmed rejection episode at either 6 or 12 months was similar between patients randomized to receive Simulect and those randomized to receive placebo.

The efficacy of Simulect for the prophylaxis of acute rejection in recipients of a second renal allograft has not been demonstrated.

Simulect® (basiliximab) is indicated for the prophylaxis of acute organ rejection in patients receiving renal transplantation when used as part of an immunosuppressive regimen that includes cyclosporine, USP (MODIFIED), and corticosteroids.

The efficacy of Simulect for the prophylaxis of acute rejection in recipients of other solid organ allografts has not been demonstrated.

Simulect® (basiliximab) is contraindicated in patients with known hypersensitivity to basiliximab or any other component of the formulation. See composition of Simulect under DESCRIPTION.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The adverse reaction information from clinical trials does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates.

The incidence of adverse events for Simulect® (basiliximab) was determined in four randomized, double-blind, placebo-controlled clinical trials for the prevention of renal allograft rejection. Two of the studies (Study 1 and Study 2), used a dual maintenance immunosuppressive regimen comprised of cyclosporine, USP (MODIFIED) and corticosteroids, whereas the other two studies (Study 3 and Study 4) used a triple-immunosuppressive regimen comprised of cyclosporine, USP (MODIFIED), corticosteroids, and either azathioprine or mycophenolate mofetil.

Simulect did not appear to add to the background of adverse events seen in organ transplantation patients as a consequence of their underlying disease and the concurrent administration of immunosuppressants and other medications. Adverse events were reported by 96% of the patients in the placebo-treated group and 96% of the patients in the Simulect-treated group. In the four placebo-controlled studies, the pattern of adverse events in 590 patients treated with the recommended dose of Simulect was similar to that in 594 patients treated with placebo. Simulect did not increase the incidence of serious adverse events observed compared with placebo.

The most frequently reported adverse events were gastrointestinal disorders, reported in 69% of Simulect-treated patients and 67% of placebo-treated patients.

The incidence and types of adverse events were similar in Simulect-treated and placebo-treated patients. The following adverse events occurred in ≥ 10% of Simulect-treated patients: Gastrointestinal System: constipation, nausea, abdominal pain, vomiting, diarrhea, dyspepsia; Body as a Whole-General: pain, peripheral edema, fever, viral infection; Metabolic and Nutritional: hyperkalemia, hypokalemia, hyperglycemia, hypercholesterolemia, hypophosphatemia, hyperuricemia; Urinary System: urinary tract infection; Respiratory System: dyspnea, upper respiratory tract infection; Skin and Appendages: surgical wound complications, acne; Cardiovascular Disorders-General: hypertension; Central and Peripheral Nervous System: headache, tremor; Psychiatric: insomnia; Red Blood Cell: anemia.

The following adverse events, not mentioned above, were reported with an incidence of ≥ 3% and < 10% in pooled analysis of patients treated with Simulect in the four controlled clinical trials, or in an analysis of the two dual-therapy trials: Body as a Whole-General: accidental trauma, asthenia, chest pain, increased drug level, infection, face edema, fatigue, dependent edema, generalized edema, leg edema, malaise, rigors, sepsis; Cardiovascular: abnormal heart sounds, aggravated hypertension, angina pectoris, cardiac failure, chest pain, hypotension; Endocrine: increased glucocorticoids; Gastrointestinal: enlarged abdomen, esophagitis, flatulence, gastrointestinal disorder, gastroenteritis, GI hemorrhage, gum hyperplasia, melena, moniliasis, ulcerative stomatitis; Heart Rate and Rhythm: arrhythmia, atrial fibrillation, tachycardia; Metabolic and Nutritional: acidosis, dehydration, diabetes mellitus, fluid overload, hypercalcemia, hyperlipemia, hypertriglyceridemia, hypocalcemia, hypoglycemia, hypomagnesemia, hypoproteinemia, weight increase; Musculoskeletal: arthralgia, arthropathy, back pain, bone fracture, cramps, hernia, myalgia, leg pain; Nervous System: dizziness, neuropathy, paraesthesia, hypoesthesia; Platelet and Bleeding: hematoma, hemorrhage, purpura, thrombocytopenia, thrombosis; Psychiatric: agitation, anxiety, depression; Red Blood Cell: polycythemia; Reproductive Disorders, Male: genital edema, impotence; Respiratory: bronchitis, bronchospasm, abnormal chest sounds, coughing, pharyngitis, pneumonia, pulmonary disorder, pulmonary edema, rhinitis, sinusitis; Skin and Appendages: cyst, herpes simplex, herpes zoster, hypertrichosis, pruritus, rash, skin disorder, skin ulceration; Urinary: albuminuria, bladder disorder, dysuria, frequent micturition, hematuria, increased non-protein nitrogen, oliguria, abnormal renal function, renal tubular necrosis, surgery, ureteral disorder, urinary retention; Vascular Disorders: vascular disorder; Vision Disorders: cataract, conjunctivitis, abnormal vision; White Blood Cell: leucopenia. Among these events, leucopenia and hypertriglyceridemia occurred more frequently in the two triple-therapy studies using azathioprine and mycophenolate mofetil than in the dual-therapy studies.

A maximum tolerated dose of Simulect® (basiliximab) has not been determined in patients. During the course of clinical studies, Simulect has been administered to adult renal transplantation patients in single doses of up to 60 mg, or in divided doses over 3-5 days of up to 120 mg, without any associated serious adverse events. There has been one spontaneous report of a pediatric renal transplantation patient who received a single 20-mg dose (2.3 mg/kg) without adverse events.

Simulect® (basiliximab) is used as part of an immunosuppressive regimen that includes cyclosporine, USP (MODIFIED) and corticosteroids. Simulect is for central or peripheral intravenous administration only. Reconstituted Simulect should be given either as a bolus injection or diluted to a volume of 25 mL (10-mg vial) or 50 mL (20-mg vial) with 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP and administered as an intravenous infusion over 20 to 30 minutes. Bolus administration may be associated with nausea, vomiting and local reactions, including pain.

Simulect should only be administered once it has been determined that the patient will receive the graft and concomitant immunosuppression. Patients previously administered Simulect should only be re-exposed to a subsequent course of therapy with extreme caution due to the potential risk of hypersensitivity (see WARNINGS).

Parenteral drug products should be inspected visually for particulate matter and discoloration before administration. After reconstitution, Simulect should be a clear-to-opalescent, colorless solution. If particulate matter is present or the solution is colored, do not use.

Care must be taken to assure sterility of the prepared solution because the drug product does not contain any antimicrobial preservatives or bacteriostatic agents.

It is recommended that after reconstitution, the solution should be used immediately. If not used immediately, it can be stored at 2ºC to 8ºC (36ºF to 46ºF) for 24 hours or at room temperature for 4 hours. Discard the reconstituted solution if not used within 24 hours.

No incompatibility between Simulect and polyvinyl chloride bags or infusion sets has been observed. No data are available on the compatibility of Simulect with other intravenous substances. Other drug substances should not be added or infused simultaneously through the same intravenous line.

Simulect® (basiliximab) is supplied in a single-dose glass vial.

Each carton contains one of the following

1 Simulect 10 mg vial…………………………………………………….NDC 0078-0393-61

1 Simulect 20 mg vial…………………………………………………….NDC 0078-0331-84

Store lyophilized Simulect under refrigerated conditions at 2ºC to 8ºC (36ºF to 46ºF).

Do not use beyond the expiration date stamped on the vial.

1. Kahan, B.D., Rajagopalan P.R. and Hall M., Transplantation, 67, 276-284 (1999).
   
2. Nashan, B., Moore R., Amlot P., Schmidt A.-G., Abeywickrama K. and Soulillou J.-P., Lancet 350, 1193-1198 (1997).

Manufactured by:
Novartis Pharmaceuticals Corporation
East Hanover, New Jersey 07936

US License No. 1244

© Novartis

T2020-125

Revised: August 2020

NOVARTIS            NDC 0078-0393-61

Simulect®
(basiliximab)
for injection

10 mg (single-dose vial)

FOR INTRAVENOUS ADMINISTRATION AFTER RECONSTITUTION.
Discard unused portion.

Rx only

NOVARTIS            NDC 0078-0331-84

Simulect®
(basiliximab)
for injection

20 mg (single-dose vial)

FOR INTRAVENOUS ADMINISTRATION AFTER RECONSTITUTION.
Discard unused portion.

Rx only