lite of thiotepa, exceed the concentrations of the parent compound.
Biotransformation
Thiotepa undergoes rapid and extensive hepatic metabolism and metabolites could be detected in urine within 1 hour after infusion. The metabolites are active alkylating agents but the role they play in the antitumor activity of thiotepa remains to be elucidated. Thiotepa undergoes oxidative desulphuration via the cytochrome P450 CYP2B and CYP3A isoenzyme families to the major and active metabolite TEPA (triethylenephosphoramide). The total excreted amount of thiotepa and its identified metabolites accounts for 54-100% of the total alkylating activity, indicating the presence of other alkylating metabolites. During conversion of GSH conjugates to N-acetylcysteine conjugates, GSH, cysteinylglycine, and cysteine conjugates are formed. These metabolites are not found in urine, and, if formed, are probably excreted in bile or as intermediate metabolites rapidly converted into thiotepa-mercapturate.
Elimination
The total clearance of thiotepa ranged from 11.4 to 23.2 l/h/m2. The elimination half-life varied from 1.5 to 4.1 hours. The identified metabolites TEPA, monochlorotepa and thiotepa-mercapturate are all excreted in the urine. Urinary excretion of thiotepa and TEPA is nearly complete after 6 and 8 hours respectively. The mean urinary recovery of thiotepa and its metabolites is 0.5% for the unchanged medicinal product and monochlorotepa, and 11% for TEPA and thiotepa-mercapturate.
Linearity/non-linearity
There is no clear evidence of saturation of metabolic clearance mechanisms at high doses of thiotepa.
Special populations
Paediatric population
The pharmacokinetics of high dose thiotepa in children between 2 and 12 years of age do not appear to vary from those reported in children receiving 75 mg/m2 or adults receiving similar doses.
Renal impairment
The effects of renal impairment on thiotepa elimination have not been assessed.
Hepatic impairment
The effects of hepatic impairment on thiotepa metabolism and elimination have not been assessed.
5.3 Preclinical safety data
No conventional acute and repeat dose toxicity studies were performed.
Thiotepa was shown to be genotoxic in vitro and in vivo, and carcinogenic in mice and rats.
Thiotepa was shown to impair fertility and interfere with spermatogenesis in male mice, and to impair ovarian function in female mice. It was teratogenic in mice and in rats, and foeto-lethal in rabbits. These effects were seen at doses lower than those used in humans.
6. Pharmaceutical particulars
6.1 List of excipients
None.
6.2 Incompatibilities
TEPADINA is unstable in acid medium.
This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.
6.3 Shelf life
Unopened vial
18 months.
After reconstitution
Chemical and physical in-use stability after reconstitution has been demonstrated for 8 hours when stored at 2°C-8°C.
After dilution
Chemical and physical in-use stability after dilution has been demonstrated for 24 hours when stored at 2°C-8°C and for 4 hours when stored at 25°C.
From a microbiological point of view, the product should be used immediately after dilution. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than the above mentioned conditions when dilution has taken place in controlled and validated |
