INFO - On Arava (leflunomide) persistence/clearance from the body

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Letter to Public Citizen

from Dr. Galson at the FDA

regarding Public Citizen's petition to have Arava withdrawn from the market

March 23, 2004

http://www.fda.gov/ohrms/dockets/dailys/04/mar04/033104/02p-0139-pdn00001-vol1.p\

df

Excerpt:

" As your petition notes, Arava is quickly metabolized to M1 after oral

administration. As explained in Arava's labeling, M1 has a long half-life

(in general, approximately 2 weeks). You maintain that this long half-life

contributes to Arava's toxicity (Petition at 14).18 Specifically, you assert

that labeling suggesting that women should wait two years after Arava

treatment before attempting to conceive " impl[ies] that there are body

depots where [M1] remains for many months. " (Petition at 14) This contention

is wrong. The two-year time period was calculated to reflect an extreme,

worst-case scenario for drug elimination and does not represent a typical

time period that M1 is likely to be retained. In fact, the two-year period

exceeds the retention period that would be expected based on the longest

half-life observed in Arava's population pharmacokinetics database; we

lengthened the retention period expected based on the longest half-life

observed to create an added margin of safety. Moreover, the two-year time

period does not account for use of the enhanced drug elimination procedures

recommended in Arava's labeling. As the labeling indicates, if these

procedures are followed, M1 plasma levels can be sharply diminished below

detectable levels within two weeks of Arava's discontinuation. This rapid

diminishment belies your claim that M1 remains in body depots for many

months. The elimination agents recommended in Arava's labeling (discussed

below) interrupt the recycling (i.e., continued elimination and

re-absorption) of M1 that occurs in the gastrointestinal tract. It is this

recycling that accounts for M1's long half-life. If M1's half-life were

attributable to its retention in body depots, the recommended elimination

agents would not be expected to have much, if any, effect.

You also claim that, because of its longer half-life, the average length of

time required to attain steady-state plasma levels for M1 (10 to 12 weeks)

is much longer than for methotrexate (1 to 2.5 days) (Petition at 14). You

further contend that the time required to attain steady-state plasma levels

reflects the time expected for a drug to disappear from the body once it is

discontinued (Petition at 14). These contentions are misleading. The 10 to

12 week period you cite represents the average time expected to achieve

steady-state M1 plasma levels in the absence of a loading dose. Because of

M1's half-life, the Dosage and Administration section of Arava's labeling

advises that therapy with this drug be initiated using a loading dose (one

100 mg tablet per day for three days) to expedite the attainment of

steady-state concentrations.20 Similarly, as earlier noted, Arava's

labeling recommends the use of enhanced elimination (i.e., washout)

procedures to hasten the depletion of M1 plasma levels upon Arava's

discontinuation. These procedures are further discussed below. "

Not an MD

I'll tell you where to go!

Mayo Clinic in Rochester

http://www.mayoclinic.org/rochester

s Hopkins Medicine

http://www.hopkinsmedicine.org