Tacrolimus (Page 3 of 9)

INDICATIONS AND USAGE

Tacrolimus Capsule is indicated for the prophylaxis of organ rejection in patients receiving allogeneic liver, or kidney transplants. It is recommended that tacrolimus be used concomitantly with adrenal corticosteroids. In kidney transplant recipients, it is recommended that tacrolimus capsules be used in conjunction with azathioprine or mycophenolate mofetil (MMF).

CONTRAINDICATIONS

Tacrolimus Capsule is contraindicated in patients with a hypersensitivity to tacrolimus. Tacrolimus injection is contraindicated in patients with a hypersensitivity to HCO-60 (polyoxyl 60 hydrogenated castor oil).

WARNINGS

(See boxed WARNING.)

Post-Transplant Diabetes Mellitus

Insulin-dependent post-transplant diabetes mellitus (PTDM) was reported in 20% of tacrolimus-treated kidney transplant patients without pretransplant history of diabetes mellitus in the Phase III study (See Tables Below). The median time to onset of PTDM was 68 days. Insulin dependence was reversible in 15% of these PTDM patients at one year and in 50% at 2 years post transplant. Black and Hispanic kidney transplant patients were at an increased risk of development of PTDM.

Incidence of Post Transplant Diabetes Mellitus and Insulin Use at 2 Years in Kidney Transplant Recipients in the Phase III study

Status of PTDMa Tacrolimus CBIR
Patients without pretransplant history of diabetes mellitus. 151 151
New onset PTDMa , 1st Year 30/151 (20%) 6/151 (4%)
Still insulin dependent at one year in those without prior history of diabetes. 25/151 (17%) 5/151 (3%)
New onset PTDMa post 1 year 1 0
Patients with PTDMa at 2 years 16/151 (11%) 5/151 (3%)

a) use of insulin for 30 or more consecutive days, with < 5 day gap, without a prior history of insulin dependent diabetes mellitus or non insulin dependent diabetes mellitus.

Development of Post Transplant Diabetes Mellitus by Race and by Treatment Group during First Year Post Kidney Transplantation in the Phase III study

Patient Race Tacrolimus CBIR
No. of Patients at Risk Patients Who Developed PTDMa No. of Patients At Risk Patients Who Developed PTDMa
Black 41 15 (37%) 36 3 (8%)
Hispanic 17 5 (29%) 18 1 (6%)
Caucasian 82 10 (12%) 87 1 (1%)
Other 11 0 (0%) 10 1 (10%)
Total 151 30 (20%) 151 6 (4%)

a use of insulin for 30 or more consecutive days, with < 5 day gap, without a prior history of insulin dependent diabetes mellitus or non insulin dependent diabetes mellitus.

Insulin-dependent post-transplant diabetes mellitus was reported in 18% and 11% of tacrolimus-treated liver transplant patients and was reversible in 45% and 31% of these patients at 1 year post transplant, in the U.S. and European randomized studies, respectively (See Table below). Hyperglycemia was associated with the use of tacrolimus in 47% and 33% of liver transplant recipients in the U.S. and European randomized studies, respectively, and may require treatment (see ADVERSE REACTIONS).

Incidence of Post Transplant Diabetes Mellitus and Insulin Use at 1 Year in Liver Transplant Recipients

Status of PTDMa US Study European Study
Tacrolimus CBIR Tacrolimus CBIR
Patients at riskb 239 236 239 249
New Onset PTDMa 42 (18%) 30 (13%) 26 (11%) 12 (5%)
Patients still on insulin at 1 year 23 (10%) 19 (8%) 18 (8%) 6 (2%)

a) use of insulin for 30 or more consecutive days, with < 5 day gap, without a prior history of insulin dependent diabetes mellitus or non insulin dependent diabetes mellitus.

b) Patients without pretransplant history of diabetes mellitus.

Nephrotoxicity

Tacrolimus can cause nephrotoxicity, particularly when used in high doses. 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 (see ADVERSE REACTIONS). More overt nephrotoxicity is seen early after transplantation, characterized by increasing serum creatinine and a decrease in urine output. 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. Care should be taken in using tacrolimus with other nephrotoxic drugs. In particular, to avoid excess nephrotoxicity, tacrolimus should not be used simultaneously with cyclosporine. Tacrolimus or cyclosporine should be discontinued at least 24 hours prior to initiating the other. In the presence of elevated tacrolimus or cyclosporine concentrations, dosing with the other drug usually should be further delayed.

Hyperkalemia

Mild to severe hyperkalemia was reported in 31% of kidney transplant recipients and in 45% and 13% of liver transplant recipients treated with tacrolimus in the U.S. and European randomized trials, respectively (see ADVERSE REACTIONS). Serum potassium levels should be monitored and potassium-sparing diuretics should not be used during tacrolimus therapy ( see PRECAUTIONS).

Neurotoxicity

Tacrolimus can cause neurotoxicity, particularly when used in high doses. Neurotoxicity, including tremor, headache, and other changes in motor function, mental status, and sensory function were reported in approximately 55% of liver transplant recipients in the two randomized studies. Tremor occurred more often in tacrolimus-treated kidney transplant patients (54%) compared to cyclosporine-treated patients. The incidence of other neurological events in kidney transplant patients was similar in the two treatment groups (see ADVERSE REACTIONS). Tremor and headache have been associated with high whole-blood concentrations of tacrolimus and may respond to dosage adjustment. Seizures have occurred in adult and pediatric patients receiving tacrolimus (see ADVERSE REACTIONS). Coma and delirium also have been associated with high plasma concentrations of tacrolimus.

Patients treated with tacrolimus have been reported to develop posterior reversible encephalopathy syndrome (PRES). Symptoms indicating PRES include headache, altered mental status, seizures, visual disturbances and hypertension. Diagnosis may be confirmed by radiological procedure. If PRES is suspected or diagnosed, blood pressure control should be maintained and immediate reduction of immunosuppression is advised. This syndrome is characterized by reversal of symptoms upon reduction or discontinuation of immunosuppression.

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