FDA published a conversation piece on narrow therapeutic index drugs entitled, “Setting and Implementing Standards for Narrow Therapeutic Index Drugs” (here ) to better inform health care professionals (HCP), patients, and other consumers regarding the use of and how the FDA treats narrow therapeutic index (NTI) drugs.  Let’s look at what an NTI drug is and some of the issues surrounding the public’s and HCP’s perception of NTI drugs and substitution. 

All drugs have what is known as a therapeutic window, that is, a dosage above which there may be serious drug adverse events (too much drug) and below which the drug will likely not be effective. For most drugs, the therapeutic window is rather large, like a picture window.  However, for some drugs, the window is like that little bathroom window above the shower that barely lets any light in. The little window in this case represents the NTI drugs, where a very small change in dosage or potency can get a patient into trouble.  For most NTI drugs, patients must be periodically monitored as slight changes can cause safety or efficacy issues.  Some of the factors that could impact the performance of NTI drugs include weight gain or loss, an infection or newly developed underlying condition, changes in diet, among other factors like the product’s stability over time.  This is especially true if the drug is given in very low doses, like levothyroxine which has 13 different strengths with small, microgram differences between the various approved strengths.  For example, while the levothyroxine strengths stretch from 0.025 mg to 0.3 mg (or 25 mcg to 300 mcg) the 13 individual strengths change in increments of between 12 to 25 mcg.  Thus, small differences in dosage may have a significant and dramatic impact on a patient’s well-being.  Slight changes could result in toxic effects or diminished efficacy.  

Drug products typically decrease in strength over the life of the expiration date of the product.  Most drug products with a wide window are permitted to have a stability specification of 90-110% of the active drugs over the approved expiration date, but those with a narrow therapeutic window may be given a narrower specification of 95-105%. 

In addition, complaints from HCPs and patients about problems when switching from one NTI product to another has caused the Agency to reevaluate the bioequivalence testing requirements of NTI products and, as a result, they have adopted a more stringent testing scheme to better assure that products could be substituted without concern.  FDA now requires that the study design for NTI products should be a single-dose, four-way, fully replicated crossover in vivo approach in order to: 

  • Scale bioequivalence limits to the variability of the referenced product; and  
  • Compare test and referenced product within-subject variability.

These changes have made a significant difference in assuring that AB-rated products in the Orange Book for NTI drugs can be substituted with the expectation that the products will perform the same as that of the reference listed product. However, old views are difficult to change, and a bias persists to this day among HCPs and patients.  FDA has provided HCPs and patients access to various educational material to assist then in making the best choices regarding substitution of NTI drugs.