Therapeutic Margins Are Too Small

The variances between generic and innovator preparations that are used by regulatory agencies to make decisions about relative bioavailability (20-25% difference in the outer boundaries of 95% confidence intervals) are perfectly fine for most drugs that have a broad therapeutic window and a wide toxic-therapeutic ratio. For a minority of drugs, this is not adequate, and this includes antiarrhythmic drugs, anticoagulants, and anti-convulsants. Here, small differences in concentration can have disastrous consequences, and frequently do.  In the cited article, electrophysiologists were able to identify clear cases in which a change in formulation was associated with deterioration in patients’ otherwise stable cardiac condition.