orptions, decreased numbers of live births, and decreased pup weight and viability. Tacrolimus, given orally at 1.0 and 3.2 mg/kg (equivalent to 0.7 to 1.4X and 2.3 to 4.6X the recommended clinical dose range based on body surface area corrections) to pregnant rats after organogenesis and during lactation, was associated with reduced pup weights.
No reduction in male or female fertility was evident.
There are no adequate and well-controlled studies in pregnant women. Tacrolimus is transferred across the placenta. The use of tacrolimus during pregnancy has been associated with neonatal hyperkalemia and renal dysfunction. Tacrolimus should be used during pregnancy only if the potential benefit to the mother justifies potential risk to the fetus.
Nursing Mothers
Since tacrolimus is excreted in human milk, nursing should be avoided.
Pediatric Patients
Experience with tacrolimus in pediatric kidney transplant patients is limited. Successful liver transplants have been performed in pediatric patients (ages up to 16 years) using tacrolimus. Two randomized active-controlled trials of tacrolimus in primary liver transplantation included 56 pediatric patients. Thirty-one patients were randomized to tacrolimus-based and 25 to cyclosporine-based therapies. Additionally, a minimum of 122 pediatric patients were studied in an uncontrolled trial of tacrolimus in living related donor liver transplantation. Pediatric patients generally required higher doses of tacrolimus to maintain blood trough concentrations of tacrolimus similar to adult patients (see DOSAGE AND ADMINISTRATION ).
ADVERSE REACTIONS
Liver Transplantation
The principal adverse reactions of tacrolimus are tremor, headache, diarrhea, hypertension, nausea, and abnormal renal function. These occur with oral and IV administration of tacrolimus and may respond to a reduction in dosing. Diarrhea was sometimes associated with other gastrointestinal complaints such as nausea and vomiting.
Hyperkalemia and hypomagnesemia have occurred in patients receiving tacrolimus therapy. Hyperglycemia has been noted in many patients; some may require insulin therapy (see WARNINGS ).
The incidence of adverse events was determined in two randomized comparative liver transplant trials among 514 patients receiving tacrolimus and steroids and 515 patients receiving a cyclosporine-based regimen (CBIR). The proportion of patients reporting more than one adverse event was 99.8% in the tacrolimus group and 99.6% in the CBIR group. Precautions must be taken when comparing the incidence of adverse events in the U.S. study to that in the European study. The 12-month posttransplant information from the U.S. study and from the European study is presented below. The two studies also included different patient populations and patients were treated with immunosuppressive regimens of differing intensities. Adverse events reported in ≥ 15% in tacrolimus patients (combined study results) are presented below for the two controlled trials in liver transplantation:
LIVER TRANSPLANTATION: ADVERSE EVENTS OCCURRING IN ≥ 15% OF TACROLIMUS-TREATED PATIENTS
LIVER TRANSPLANTATION: ADVERSE EVENTS OCCURRING IN ≥ 15% OF TACROLIMUS-TREATED PATIENTS
U.S. STUDY EUROPEAN STUDY
Tacrolimus (N=250) CBIR (N=250) Tacrolimus (N=264) CBIR (N=265)
Nervous System
Headache (see WARNINGS ) 64% 60% 37% 26
