General Information

Prograf (tacrolimus) is a calcineurin-inhibitor immunosuppressant.

Prograf is specifically indicated indicated for the prophylaxis of organ rejection in adult and pediatric patients receiving allogeneic liver, kidney, heart, or lung transplants, in combination with other immunosuppressants.

Prograf is supplied as capsules, for oral use, an injection for intravenous use or as granules for oral suspension. See the tables below for the recommended dosing/administration schedules.

Mechanism of Action

Prograf (tacrolimus) binds to an intracellular protein, FKBP-12. A complex of tacrolimus-FKBP-12, calcium, calmodulin, and calcineurin (a ubiquitous mammalian intracellular enzyme) is then formed, after which the phosphatase activity of calcineurin is inhibited. Such inhibition prevents the dephosphorylation and translocation of various factors such as the nuclear factor of activated T-cells (NF-AT), and nuclear factor kappa-light-chain enhancer of activated B-cells (NF-κB). Tacrolimus inhibits the expression and/or production of several cytokines that include interleukin (IL)-1 beta, IL-2, IL-3, IL-4, IL-5, IL-6, IL-8, IL-10, gamma interferon, tumor necrosis factor-alpha, and granulocyte macrophage colonystimulating factor. Tacrolimus also inhibits IL-2 receptor expression and nitric oxide release, induces apoptosis and production of transforming growth factor beta that can lead to immunosuppressive activity. The net result is the inhibition of T-lymphocyte activation and proliferation, as well as T-helper-cell-dependent B-cell response (i.e., immunosuppression).

Side Effects

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

• abnormal renal function
• hypertension
• diabetes mellitus
• fever
• CMV infection
• tremor
• hyperglycemia
• leukopenia
• infection
• anemia
• bronchitis
• pericardial effusion
• urinary tract infection
• constipation
• diarrhea
• headache
• abdominal pain
• insomnia
• paresthesia
• peripheral edema
• nausea
• hyperkalemia
• hypomagnesemia
• hyperlipemia

The Prograf drug label comes with the following Black Box Warning: Increased risk for developing serious infections and malignancies with Prograf or other immunosuppressants that may lead to hospitalization or death.

Clinical Trial Results

The FDA approval of Prograf was based on the following trials:

Kidney Transplant: The approval of Prograf + MMF for use in kidney transplant recipients was based on two clinical studies in approximately 2,000 kidney transplant recipients.

• In a phase III, multi-center, open-label clinical trial 424 kidney transplant recipients received Prograf or cyclosporine in combination with MMF, basiliximab induction and corticosteroids. The rate for the combined endpoint of biopsy proven acute rejection, graft failure, death and/or lost to follow-up at 12 months in the Prograf/MMF group was similar to the rate in the cyclosporine (CyA)/MMF group. Mortality at 12 months was higher in those patients receiving Prograf/MMF (4.2%) compared to those receiving CyA/MMF (2.4%), including cases attributed to overimmunosuppression.  
• ELITE-Symphony was a prospective, randomized, open-label, multicenter study in four parallel groups of kidney transplant recipients. The trial randomized 1,589 kidney transplant recipients to receive standard dose CyA, MMF and corticosteroids (CS); or daclizumab induction, MMF and corticosteroids in combination with low-dose CyA, Prograf or sirolimus (Siro). The primary endpoint of the study was renal function, measured by estimated glomerular filtration rates (GFR), at 12 months after transplantation. Acute rejection, graft survival and overall mortality were also assessed as secondary endpoints. Mortality at 12 months in patients receiving Prograf/MMF (2.7%) was similar compared to patients receiving cyclosporine/MMF (3.3% and 1.8%) or sirolimus/MMF (3.0%). Patients in the Prograf group exhibited higher estimated creatinine clearance rates (eCLcr) using the Cockcroft-Gault formula and experienced fewer efficacy failures, defined as biopsy proven acute rejection (BPAR), graft loss, death and/or lost to follow-up in comparison to each of the other three groups: Prograf/MMF (20.4%), CyA/MMF (36.2% and 31.6%) and Siro/MMF (46.4%).

Liver Transplant: The FDA approval was based on two prospective, randomized, non-blinded multicenter trials. The active control groups were treated with a cyclosporine-based immunosuppressive regimen (CsA/AZA). Both trials used concomitant adrenal corticosteroids as part of the immunosuppressive regimens. These trials compared patient and graft survival rates at 12 months following transplantation. In one trial, 529 patients were enrolled at 12 clinical sites in the United States. In the second trial, 545 patients were enrolled at 8 clinical sites in Europe. One-year patient survival and graft survival in the Prograf-based treatment groups were similar to those in the CsA/AZA treatment groups in both trials. The overall 1-year patient survival (CsA/AZA and Prograf-based treatment groups combined) was 88% in the U.S. trial and 78% in the European trial. The overall 1-year graft survival (CsA/AZA and Prograf-based treatment groups combined) was 81% in the U.S. trial and 73% in the European trial. In both trials, the median time to convert from IV to oral Prograf dosing was 2 days.

Heart Transplant: The FDA approval of Prograf was based on two open-label, randomized, comparative trials which evaluated the safety and efficacy of Prograf-based and cyclosporine-based immunosuppression in primary orthotopic heart transplantation. In a trial conducted in Europe, 314 patients received a regimen of antibody induction, corticosteroids, and azathioprine in combination with Prograf or cyclosporine modified for 18 months. In a 3-arm trial conducted in the U.S., 331 patients received corticosteroids and Prograf plus sirolimus, Prograf plus mycophenolate mofetil (MMF) or cyclosporine modified plus MMF for 1 year. In the European trial, patient/graft survival at 18 months post-transplant was similar between treatment arms, 92% in the tacrolimus group and 90% in the cyclosporine group. In the U.S. trial, patient and graft survival at 12 months was similar with 93% survival in the Prograf plus MMF group and 86% survival in the cyclosporine modified plus MMF group.

Lung Transplant: FDA approval was based on an observational study that provided real-world evidence of the effectiveness of tacrolimus to prevent organ rejection in adults and children undergoing lung transplantation. The study analyzed outcomes based on discharge immunosuppression treatment regimen in recipients of a primary lung transplant between 1999 and 2017 who were alive at the time of discharge. In adult patients receiving tacrolimus immediate-release products in combination with MMF (n=15,478) or tacrolimus immediate-release products in combination with AZA (n=4,263), the one-year graft survival estimates from time of discharge were 90.9% and 90.8%, respectively. In pediatric patients receiving tacrolimus immediate-release products in combination with MMF (n= 450) or tacrolimus immediate-release products in combination with AZA (n=72), the one-year graft survival estimates from time of discharge were 91.7% and 84.7%, respectively.