CLINICAL AND SAFETY CONSIDERATIONS OF NAMING DRUG MOIETIES AND COMPLEXES

To encourage regulatory agencies to incorporate pharmacists when considering clinical, operational, access, and safety factors when approving and classifying medications with different moieties or complexes that are used to deliver the active drug; further,

To oppose the consolidation of existing drug classes that include drugs that have distinct pharmacologic effects and pharmacokinetic/pharmacodynamic profiles; further,

To foster increased public notification when changes in approved drug products with therapeutic equivalence occur.

Rationale

The Food and Drug Administration (FDA) publication Approved Drug Products with Therapeutic Equivalence Evaluations, commonly known as the Orange Book, identifies drug products approved by the Food and Drug Administration (FDA) under the Federal Food, Drug, and Cosmetic Act (the FD&C Act) and contains therapeutic equivalence evaluations for approved multisource prescription drug products.

In May of 2021, the FDA changed four iron-carbohydrate drugs with distinct, established, names with different dosing and administration practices and consolidated them under a singular active ingredient, ferric oxyhydroxide. The intravenous formulations of ferric oxyhydroxide, iron sucrose, sodium ferric gluconate, and iron dextran all have different dosing and administration requirements including test infusions, different infusion rates, doses spread out over multiple days and at different concentrations and different monitoring parameters and safety considerations (Iron dextran has a black box warning due to an increased rate of anaphylaxis than other IV iron therapies), Furthermore, the oral formulation is not used for the treatment of iron deficiency anemia, further complicating the clinical and operational picture.

Additionally, this consolidation introduces several areas of concern including risk for incorrect usage of these medications, formulary considerations, administration of the iron-carbohydrate drug, patient safety, and adverse drug event reporting.

This also creates the potential for the FDA to change labeling of drugs with the same active ingredient but different molecular delivery attributes, such as metoprolol tartrate and succinate which have different frequencies, or liposomal amphotericin B and amphotericin deoxycholate, which have different doses.

In general, the FDA considers an active ingredient to be the active moiety as “the molecule or ion, excluding those appended portions of the molecule that cause the drug to be an ester, salt (including a salt with hydrogen or coordination bonds), or other noncovalent derivative (such as a complex, chelate, or clathrate) of the molecule, responsible for the physiological or pharmacological action of the drug substance.” However, because the dosing, administration and monitoring are distinct for different drugs-complexes, even if the active moiety is the same – they should be distinguished by name.

Further, this change was performed under the auspices of a response to a regulatory request in a citizen petition, and therefore did not follow the statue requirement delineated in the FD&C Act that includes an opportunity for comment on this change.  While the goal of this consolidation appears to mitigate potential abuse of new chemical entity exclusivity, the negative safety and clinical implications necessitate an examination of this approach, particularly when it is retroactive in nature.