tebral arch, vertebral and rib malformations, omphalocele, and gallbladder agenesis) and developmental variations. In pregnant rats, Tacrolimus at oral doses of 3.2 mg/kg, 2.6 to 6.9 times the clinical dose range was associated with maternal toxicity, an increase in late resorptions, decreased numbers of live births, and decreased pup weight and viability. Tacrolimus, given orally to pregnant rats after organogenesis and during lactation at 1.0 and 3.2 mg/kg, 0.8 to 6.9 times the recommended clinical dose range was associated with reduced pup weights and pup viability (3.2 mg/kg only); among the high dose pups that died early, an increased incidence of kidney hydronephrosis was observed.
Nursing Mothers
Tacrolimus is excreted in human milk. As the effect of chronic exposure to Tacrolimus in healthy infants is not established, patients maintained on Tacrolimus should discontinue nursing taking into consideration importance of drug to the mother.
Pediatric Use
The safety and efficacy of Tacrolimus in pediatric kidney and heart transplant patients have not been established. 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 (2.2)].
Geriatric Use
Clinical trials of Tacrolimus did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
8.6 Use in Renal Impairment
The pharmacokinetics of Tacrolimus in patients with renal impairment was similar to that in healthy volunteers with normal renal function. However, consideration should be given to dosing Tacrolimus at the lower end of the therapeutic dosing range in patients who have received a liver or heart transplant and have pre-existing renal impairment. Further reductions in dose below the targeted range may be required [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3)].
8.7 Use in Hepatic Impairment
The mean clearance of Tacrolimus was substantially lower in patients with severe hepatic impairment (mean Child-Pugh score: >10) compared to healthy volunteers with normal hepatic function. Close monitoring of Tacrolimus trough concentrations is warranted in patients with hepatic impairment [see Clinical Pharmacology (12.3)].
The use of Tacrolimus in liver transplant recipients experiencing post-transplant hepatic impairment may be associated with increased risk of developing renal insufficiency related to high whole-blood trough concentrations of Tacrolimus. These patients should be monito
