Reductions in immunosuppression should be considered for patients who develop evidence of PVAN or PML. Physicians should also consider the risk that reduced immunosuppression represents to the functioning allograft.

5.5 Cytomegalovirus (CMV) Infections
Patients receiving immunosuppressants, including Tacrolimus, are at increased risk of developing CMV viremia and CMV disease. The risk of CMV disease is highest among transplant recipients seronegative for CMV at time of transplant who receive a graft from a CMV seropositive donor. Therapeutic approaches to limiting CMV disease exist and should be routinely provided. Patient monitoring may help detect patients at risk for CMV disease. Consideration should be given to reducing the amount of immunosuppression in patients who develop CMV viremia and/or CMV disease.

5.6 New Onset Diabetes After Transplant
Tacrolimus was shown to cause new onset diabetes mellitus in clinical trials of kidney and liver transplantation. New onset diabetes after transplantation may be reversible in some patients. Black and Hispanic kidney transplant patients are at an increased risk. Blood glucose concentrations should be monitored closely in patients using Tacrolimus [see Adverse Reactions (6.1)].

5.7 Nephrotoxicity
Tacrolimus, like other calcineurin-inhibitors, can cause acute or chronic nephrotoxicity, particularly when used in high doses. Acute nephrotoxicity is most often related to vasoconstriction of the afferent renal arteriole, is characterized by increasing serum creatinine, hyperkalemia, and/or a decrease in urine output, and is typically reversible. Chronic calcineurininhibitor nephrotoxicity is associated with increased serum creatinine, decreased kidney graft life, and characteristic histologic changes observed on renal biopsy; the changes associated with chronic calcineurin-inhibitor nephrotoxicity are typically progressive. Patients with impaired renal function should be monitored closely as the dosage of Tacrolimus may need to be reduced. In patients with persistent elevations of serum creatinine who are unresponsive to dosage adjustments, consideration should be given to changing to another immunosuppressive therapy.

Based on reported adverse reactions terms related to decreased renal function, nephrotoxicity was reported in approximately 52% of kidney transplantation patients and in 40% and 36% of liver transplantation patients receiving Tacrolimus in the U.S. and European randomized trials, respectively, and in 59% of heart transplantation patients in a European randomized trial  [see Adverse Reactions (6.1)].

Due to the potential for additive or synergistic impairment of renal function, care should be taken when administering Tacrolimus with drugs that may be associated with renal dysfunction. These include, but are not limited to, aminoglycosides, ganciclovir, amphotericin B, cisplatin, nucleotide reverse transcriptase inhibitors (e.g., tenofovir) and protease inhibitors (e.g., ritonavir, indinavir). Similarly, care should be exercised when administering with CYP3A4 inhibitors such as antifungal drugs (e.g., ketoconazole), calcium channel blockers (e.g., diltiazem, verapamil), and macrolide antibiotics (e.g., clarithromycin, erythromycin, troleandomycin) which will result in increased Tacrolimus w