Tacromax Special Precautions

Hypertension is a common adverse effect of Tacrolimus (Tacromax) therapy. Mild or moderate hypertension is more frequently reported than severe hypertension. Antihypertensive therapy may be required; the control of blood pressure can be accomplished with any of the common antihypertensive agents. Since tacrolimus may cause hyperkalemia, potassium sparing diuretics should be avoided. While calcium channel blocking agents can be effective in treating Tacrolimus (Tacromax) associated hypertension, care should be taken since interference with tacrolimus metabolism may require a dosage reduction.
Carcinogenicity/Mutagenicity: 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 (Tacromax) 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 immunosuppressant 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 0.8-2.5 times (mice) and 3.5-7.1 times (rats) the recommended clinical dose range of 0.1-0.2 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 (0.7-1.4X the recommended clinical dose range of 0.1-0.2 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 embryo lethality and with adverse effects on female reproduction. Effects on female reproductive function and embryo lethal 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 (2.3-4.6X 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.
Use in 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. 5-1X and 1.6-3.3X the recommended clinical dose range (0.1-0.2 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 0.7-1.4X and 2.3-4.6X 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 (Tacromax) should be used during pregnancy only if the potential benefit to the mother justifies potential risk to the fetus.
Use in Lactation: Since tacrolimus is excreted in human milk, nursing should be avoided.
Use in Children: Experience with Tacrolimus (Tacromax) in pediatric kidney and heart transplant patients is limited. Successful liver transplants have been performed in pediatric patients (ages up to 16 years) using Tacrolimus (Tacromax) Two randomized active controlled trials of Tacrolimus (Tacromax) in primary liver transplantation included 56 pediatric patients. Thirty-one patients were randomized to Tacrolimus (Tacromax) 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 (Tacromax) to maintain blood trough concentrations of tacrolimus similar to adult patients.