AZT LOWER DOSE APPROVED

During the last several months there has been a strong movement among physicians to prescribe lower doses of AZT for most patients -- not the 1200 mg per day which has been officially recommended. While there is still difference of opinion in the medical community, the standard of care seems to be moving toward 500 mg per day -- a dose which appears to be just as effective as 1200, and less toxic. Physicians could legally prescribe the lower dose all along; but because many will follow the official recommendation, there was much pressure on Burroughs Wellcome to apply to the FDA for a change in the official "labeling" of the drug, and to provide the data to support the change. The FDA could not make the change on its own, without an application and data from the company.

Recently this work has been accomplished, and the labeling now includes an optional dose reduction, to 600 mg per day, after one month of 1200. (There is still some question of whether the lower dose will work as well as the 1200 mg dose for treating patients with neurological complications, and this uncertainty is reflected in the official language.)

One major benefit of the labeling change is that some of the new clinical trials anticipated the movement to the lower dose; their protocols allowed the AZT dose to be reduced as soon as the FDA changed the labeling. Since those protocols had already been approved by the Institutional Review Boards (IRBs) of the different institutions which will run the trials, the change to low dose can be made quickly, without waiting for all the IRBs to meet again to approve the new dose. The high AZT dose has seriously slowed recruitment for some of the trials, because patients have been unwilling to risk receiving that much AZT.

Why does the official labeling specify 600 mg, instead of 500 which was becoming medical practice? The 600 mg dose implies that patients will wake up in the middle of the night to take a pill; the 500 dose does not. Also, why does the official labeling specify at least one month at 1200 mg? This month of high dose may cause some patients to discontinue the drug, due to side effects such as headache and nausea.

We have heard repeatedly from AIDS experts that there is no medical reason for the choice of 600 mg per day, or for the recommendation of 1200 for at least the first month the patient is on the drug. The official recommendation came out as it did because the data Burroughs Wellcome submitted to support the change came from one study (ACTG 002). About three years ago, when this study was being designed, there was much less experience with AZT The regimen for the low-dose arm of the trial was selected as a compromise among the study designers. The FDA had
to decide the new labeling based on the data submitted. Therefore the new labeling, while a great improvement over the old, may have been outdated on the day it was issued.