substance. In healthy subjects, the average total body clearance estimated from whole blood concentrations was 2.25 L/h. In adult liver, kidney, and heart transplant patients, values of 4.1 L/h, 6.7 L/h, and 3.9 L/h, respectively, have been observed. Factors such as low haematocrit and protein levels, which result in an increase in the unbound fraction of tacrolimus, or corticosteroid-induced increased metabolism, are considered to be 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 is approximately 30 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 count and motility was observed in rats.
6. Pharmaceutical particulars
6.1 List of excipients
Hypromellose
Lactose monohydrate
Macrogol 6000
Poloxamer 188
Magnesium stearate
Tartaric acid (E334)
Butylated hydroxytoluene (E321)
Dimethicone 350
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
30 months.
After opening the aluminium foil wrapper: 45 days.
6.4 Special precautions for storage
Do not store above 25°C.
Store in the original aluminium foil wrapper in order to protect from light.
6.5 Nature and contents of container
PVC blisters containing 10 prolonged-release tablets. 3 blisters are packed together in an aluminium foil wrapper containing a desiccant.
Pack sizes: 30, 60 and 90 prolonged-release tablets.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal and other handling
No special requirements.
7. Marketing authorisation holder
Chiesi Farmaceutici S.p.A.
Via Palermo, 26/A
43122 Parma
Italy
8. Marketing authorisation number(s)
0,75mg
EU/1/14/935/001 1mg
EU/1/14/935/004 4mg
EU/1/14/935/007
9. Date of first authorisation/renewal of the authorisation
Date of first authorisation: June 2014
10. Date of revision of the text
April 2016
Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu.
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