The half-life of tacrolimus is long and variable. In healthy subjects, the mean half-life in whole blood is approximately 43 hours.

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.

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.

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

 Capsule content:

Hypromellose

Ethylcellulose

Lactose monohydrate

Magnesium stearate.

Capsule shell:

Titanium dioxide (E 171)

Yellow iron oxide (E 172)

Red iron oxide (E 172)

Sodium laurilsulfate

Gelatin.

Printing ink (Opacode S-1-15083):

Shellac

Lecithin (soya)

Simeticone

Red iron oxide (E 172)

Hydroxypropylcellulose.

6.2 Incompatibilities

 Tacrolimus is not compatible with PVC (polyvinylchloride). Tubing, syringes and other equipment used to prepare a suspension of Advagraf capsule contents must not contain PVC.

6.3 Shelf life

 3 years

After opening the aluminium wrapper: 1 year

6.4 Special precautions for storage

 Store in the original package in order to protect from moisture.

6.5 Nature and contents of container

 Transparent PVC/PVDC aluminium blister or unit-dose perforated blister wrapped in an aluminium pouch with a desiccant containing 10 capsules per blister.

Pack sizes: 30, 50 and 100 prolonged-release hard capsules in blisters or 30x1, 50x1 and 100x1 prolonged-release hard capsule in unit-dose perforated blisters.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

 No special requirements.

7. MARKETING AUTHORISATION HOLDER

 Astellas Pharma Europe B.V.

Elisabethhof 19

2353 EW Leiderdorp

Netherlands

8. MARKETING AUTHORISATION NUMBER(S)

 EU/1/07/387/001

EU/1/07/387/002

EU/1/07/387/009

EU/1/07/387/014

EU/1/07/387/015

EU/1/07/387/016

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

 23/04/2007

10. DATE OF REVISION OF THE TEXT

 09/2011