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Teratogen Update: Reproductive Risks of Leflunomide (Arava™); a Pyrimidine Synthesis - page 10 / 21





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risk, i.e., below 0.03 g/ml.  This is an extremely conservative approach.   This approach was suggested by the FDA; namely to get the blood level down to undetectable levels.  HPLC cannot determine leflunomide levels below 0.02 g/ml and eleven days of cholestyramine therapy will accomplish this goal.  Cholestyramine, 8 g,  three times daily, reduces the half-life of the active metabolite to approximately one day. Therefore, an eleven day regimen of cholestyramine,  8 g, three times daily is recommended.

Without cholestyramine, half lives of up to 96 days have been found (population kinetics analysis). Thus, it may take up to two years to reach plasma active metabolite levels less than 0.02 g/ml due to individual variations in drug clearance.

In the absence of specific  data on safe blood levels for developing sperm and ova, the assumption is made that levels below 0.03 g/ml represent  no measurable risk.

D. Carcinogenesis, Mutagenesis and Impairment  of Fertility  from Leflunomide Exposure:

Two year carcinogenicity studies in mice and rats were conducted including exposures in mice that were above those used clinically.  Results in the mouse carcinogenicity study showed increased incidences of malignant lymphomas (males, high dose 15 mg/kg/day) and lung adenoma/carcinoma (females). The incidence for the latter, however, was within the spontaneous range known for the mouse strain (CD-l). Results from the rat carcinogenicity study did not indicate a carcinogenic potential of leflunomide  (6 mg/kg/day).  These results are very difficult to interpret because the rat enzyme, dihydroorotate dehydrogenase (DHODH), is 40 times more sensitive to leflunomide and the mouse is also more sensitive.

Leflunomide did not show mutagenic/genotoxic effects in vitro (Ames test, HGPRT test, UDS test) or in vivo (mouse micronucleus test, Chinese hamster chromosome aberration

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