responsible for the higher clearance rates observed following transplantation.
The half-life of tacrolimus is long and variable. In healthy subjects, the mean half-life in whole blood was approximately 43 hours. In adult and paediatric liver transplant patients, it averaged 11.7 hours and 12.4 hours, respectively, compared with 15.6 hours in adult kidney transplant recipients. Increased clearance rates contribute to the shorter half-life observed in transplant recipients.
Following intravenous and oral administration of 14C-labelled tacrolimus, most of the radioactivity was eliminated in the faeces. Approximately 2% of the radioactivity was eliminated in the urine. Less than 1% of unchanged tacrolimus was detected in the urine and faeces, indicating that tacrolimus is almost completely metabolised prior to elimination: bile being the principal route of elimination.
Paediatric data
In paediatric liver transplant patients the mean oral bioavailability of tacrolimus (investigated with the Modigraf granules) is 26%± 23% (individual range in paediatric liver transplant patients 4 - 80%). Data on oral bioavailability of Modigraf in other indications is not available.
After oral administration (0.30 mg/kg/day) to paediatric liver transplant patients, steady-state concentrations of tacrolimus were achieved within 3 days in the majority of patients.
In paediatric liver and kidney transplant patients, values for total body clearance of 2.3 ± 1.2 ml/min/kg and 2.1 ± 0.6 ml/min/kg, respectively, have been observed. Highly variable age dependent total body clearance and half life were observed in limited paediatric clinical investigations, especially in early childhood.
The half-life in paediatric transplant patients averages approximately 12 hours.
5.3 Preclinical safety data
The kidneys and the pancreas were the primary organs affected in toxicity studies performed in rats and baboons. In rats, tacrolimus caused toxic effects to the nervous system and the eyes. Reversible cardiotoxic effects were observed in rabbits following intravenous administration of tacrolimus.
When tacrolimus is administered intravenously as rapid infusion/bolus injection at a dose of 0.1 to 1.0 mg/kg, QTc prolongation has been observed in some animal species. Peak blood concentrations achieved with these doses were above 150 nanogram/mL which is more than 6-fold higher than mean peak concentrations observed with Modigraf in clinical transplantation.
Embryofoetal toxicity was observed in rats and rabbits and was limited to doses that caused significant toxicity in maternal animals. In rats, female reproductive function including birth was impaired at toxic doses and the offspring showed reduced birth weights, viability and growth.
A negative effect of tacrolimus on male fertility in the form of reduced sperm counts and motility was observed in rats.
6. Pharmaceutical particulars
6.1 List of excipients
Lactose monohydrate
Hypromellose (E464)
Croscarmellose sodium (E468)
6.2 Incompatibilities
Tacrolimus is not compatible with PVC (polyvinylchloride) plastics. Materials used to prepare and administer the suspension, e.g. drinking vessels, cups, or tubing, must not contain PVC.
6.3 Shelf life
3 years.
After preparation, the suspension should be administered immediately.
6.4 Special precautions for storage
This medicinal product does not require any special storage c |
