General Information

Simulect (basiliximab) 

Simulect is specifically indicated for the prophylaxis of acute organ rejection in patients receiving renal transplantation when used as part of an immunosuppressive regimen that includes cyclosporine and corticosteroids.

Simulect is for central or peripheral intravenous administration only. 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.

Adults

• In adult patients, the recommended regimen is two doses of 20 mg each. The first 20-mg dose should be given within 2 hours prior to transplantation surgery. The recommended second 20-mg dose should be given 4 days after transplantation. The second dose should be withheld if complications, such as severe hypersensitivity reactions to Simulect or graft loss occur.

Pediatrics

• In pediatric patients weighing less than 35 kg, the recommended regimen is two doses of 10 mg each. In pediatric patients weighing 35 kg or more, the recommended regimen is two doses of 20 mg each. The first dose should be given within 2 hours prior to transplantation surgery. The recommended second dose should be given 4 days after transplantation. The second dose should be withheld if complications, such as severe hypersensitivity reactions to Simulect or graft loss occur.

Mechanism of Action

Basiliximab functions as an IL-2 receptor antagonist by binding with high affinity (Ka = 1 x 1010 M-1 ) to the alpha chain of the high affinity IL-2 receptor complex and inhibiting IL-2 binding. Basiliximab is specifically targeted against IL-2Rα, which is selectively expressed on the surface of activated T-lymphocytes. This specific high affinity binding of Simulect (basiliximab) to IL-2Rα competitively inhibits IL-2-mediated activation of lymphocytes, a critical pathway in the cellular immune response involved in allograft rejection. While in the circulation, Simulect impairs the response of the immune system to antigenic challenges. Whether the ability to respond to repeated or ongoing challenges with those antigens returns to normal after Simulect is cleared is unknown.

Side Effects

Adverse effects associated with the use of Simulect may include, but are not limited to, the following:

gastrointestinal disorders, including constipation, nausea, abdominal pain, vomiting, diarrhea, dyspepsia

The Simulect drug label comes with the following Warning: Only physicians experienced in immunosuppression therapy and management of organ transplantation patients should prescribe Simulect (basiliximab). The physician responsible for Simulect administration should have complete information requisite for the follow-up of the patient. Patients receiving the drug should be managed in facilities equipped and staffed with adequate laboratory and supportive medical resources,

Clinical Trial Results

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.

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. For the primary endpoint: 

• Study 1: placebo 57% and Simulect 42%
• Study 2: placebo 55% and Simulect 38% 

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. 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 Primary endpoint of Acute rejection episode (0-6 months) was 35% for placebo and 21% for Simulect.

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. 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..