Tacrolimus (Page 5 of 9)

Other Drug Interactions

Immunosuppressants may affect vaccination. Therefore, during treatment with tacrolimus, vaccination may be less effective. The use of live vaccines should be avoided; live vaccines may include, but are not limited to measles, mumps, rubella, oral polio, BCG, yellow fever, and TY 21a typhoid.1

At a given MMF dose, mycophenolic acid (MPA) exposure is higher with tacrolimus co-administration than with cyclosporine co-administration due to the differences in the interruption of the enterohepatic recirculation of MPA. Clinicians should be aware that there is also a potential for increased MPA exposure after crossover from cyclosporine to tacrolimus in patients concomitantly receiving MMF or MPA.

Carcinogenesis, Mutagenesis and Impairment of Fertility

An increased incidence of malignancy is a recognized complication of immunosuppression in recipients of organ transplants. The most common forms of neoplasms are non-Hodgkin’s lymphomas and carcinomas of the skin. As with other immunosuppressive therapies, the risk of malignancies in tacrolimus recipients may be higher than in the normal, healthy population. Lymphoproliferative disorders associated with Epstein-Barr Virus infection have been seen. It has been reported that reduction or discontinuation of immunosuppression may cause the lesions to regress.

No evidence of genotoxicity was seen in bacterial (Salmonella and E. coli) or mammalian (Chinese hamster lung-derived cells) in vitro assays of mutagenicity, the in vitro CHO/HGPRT assay of mutagenicity, or in vivo clastogenicity assays performed in mice; tacrolimus did not cause unscheduled DNA synthesis in rodent hepatocytes.

Carcinogenicity studies were carried out in male and female rats and mice. In the 80-week mouse study and in the 104-week rat study no relationship of tumor incidence to tacrolimus dosage was found. The highest doses used in the mouse and rat studies were 0.8 to 2.5 times (mice) and 3.5 to 7.1 times (rats) the recommended clinical dose range of 0.1 to 0.2 mg/kg/day when corrected for body surface area.

No impairment of fertility was demonstrated in studies of male and female rats. Tacrolimus, given orally at 1.0 mg/kg (0.7 to 1.4X the recommended clinical dose range of 0.1 to 0.2 mg/kg/day based on body surface area corrections) to male and female rats, prior to and during mating, as well as to dams during gestation and lactation, was associated with embryolethality and with adverse effects on female reproduction. Effects on female reproductive function (parturition) and embryolethal effects were indicated by a higher rate of pre-implantation loss and increased numbers of undelivered and nonviable pups. When given at 3.2 mg/kg (2.3 to 4.6X the recommended clinical dose range based on body surface area correction), tacrolimus was associated with maternal and paternal toxicity as well as reproductive toxicity including marked adverse effects on estrus cycles, parturition, pup viability, and pup malformations.

Pregnancy:

Category C

In reproduction studies in rats and rabbits, adverse effects on the fetus were observed mainly at dose levels that were toxic to dams. Tacrolimus at oral doses of 0.32 and 1.0 mg/kg during organogenesis in rabbits was associated with maternal toxicity as well as an increase in incidence of abortions; these doses are equivalent to 0.5 to 1X and 1.6 to 3.3X the recommended clinical dose range (0.1 to 0.2 mg/kg) based on body surface area corrections. At the higher dose only, an increased incidence of malformations and developmental variations was also seen. Tacrolimus, at oral doses of 3.2 mg/kg during organogenesis in rats, was associated with maternal toxicity and caused an increase in late resorptions, 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%
Tremor (see WARNINGS ) 56% 46% 48% 32%
Insomnia 64% 68% 32% 23%
Paresthesia 40% 30% 17% 17%
Gastrointestinal
Diarrhea 72% 47% 37% 27%
Nausea 46% 37% 32% 27%
Constipation 24% 27% 23% 21%
LFT Abnormal 36% 30% 6% 5%
Anorexia 34% 24% 7% 5%
Vomiting 27% 15% 14% 11%
Cardiovascula r
Hypertension (see PRECAUTIONS) 47% 56% 38% 43%
Urogenital
Kidney Function Abnormal (see WARNINGS) 40% 27% 36% 23%
Creatinine Increased (see WARNINGS) 39% 25% 24% 19%
BUN Increased (see WARNINGS) 30% 22% 12% 9%
Urinary Tract Infection 16% 18% 21% 19%
Oliguria 18% 15% 19% 12%
Metabolic and Nutritional
Hyperkalemia (see WARNINGS) 45% 26% 13% 9%
Hypokalemia 29% 34% 13% 16%
Hyperglycemia (see WARNINGS) 47% 38% 33% 22%
Hypomagnesemia 48% 45% 16% 9%
Hemic and Lymphatic
Anemia 47% 38% 5% 1%
Leukocytosis 32% 26% 8% 8%
Thrombocytopenia 24% 20% 14% 19%
Miscellaneous
Abdominal Pain 59% 54% 29% 22%
Pain 63% 57% 24% 22%
Fever 48% 56% 19% 22%
Asthenia 52% 48% 11% 7%
Back Pain 30% 29% 17% 17%
Ascites 27% 22% 7% 8%
Peripheral Edema 26% 26% 12% 14%
Respiratory System
Pleural Effusion 30% 32% 36% 35%
Atelectasis 28% 30% 5% 4%
Dyspnea 29% 23% 5% 4%
Skin and Appendages
Pruritus 36% 20% 15% 7%
Rash 24% 19% 10% 4%

Less frequently observed adverse reactions in both liver transplantation and kidney transplantation patients are described
under the subsection Less Frequently Reported Adverse Reactions below.

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