What therapeutic equivalence codes like AB, AA and BX mean

To explain its rating codes, FDA reaches for a familiar thyroid drug. The preface to the Orange Book¹ walks through levothyroxine sodium tablets, which have several reference drugs at the same strength. FDA sorts the products into four groups, AB1 through AB4, and treats two of them as therapeutically equivalent when they share a code. Some products carry more than one.

Most of the time the codes are simpler than that. Next to each generic in the Orange Book sits a short code, usually AB, sometimes AP or BX. These therapeutic equivalence (TE) codes are FDA's judgment on whether one product can be swapped for another, and pharmacists check them when they fill a prescription written for a brand.

They matter because the federal government only rates. Each state writes its own rules for when a pharmacist may, or must, substitute, and a 2021 study found those rules vary widely.

Two tests a generic has to pass

Federal regulations define the term. Under 21 CFR 314.3², therapeutic equivalents are "approved drug products that are pharmaceutical equivalents for which bioequivalence has been demonstrated, and that can be expected to have the same clinical effect and safety profile when administered to patients under the conditions specified in the labeling."

Pharmaceutical equivalence means the same active ingredient, dosage form, route and strength as the reference product. Shape, scoring, release mechanism and inactive ingredients may differ, which is why one generic can look nothing like another. Bioequivalence means no significant difference in how fast and how much of the active ingredient reaches the bloodstream, a standard explained in our piece on the 80-125 rule. FDA's Drugs@FDA glossary³ puts it plainly: products rated therapeutically equivalent "can be expected to have equal effect and no difference when substituted for the brand name product."

A product that clears both bars gets a code starting with A. One that FDA does not currently consider equivalent gets a code starting with B.

The 16 codes

FDA defines six A codes and ten B codes in the Orange Book preface¹:

AB is the one most people meet. It covers products whose equivalence rests on bioequivalence evidence, which describes most generic tablets and capsules. The other A codes are groupings by dosage form, such as injectable solutions (AP) or topical products (AT).

Reading an entry

Take a hypothetical extended-release tablet at one strength in the Orange Book⁶. The brand is flagged as the reference listed drug. Three generics sit beneath it. Two carry AB, one carries BX.

A pharmacist reading that entry knows FDA rates the two AB products as substitutable for the brand and for each other. The BX product is approved and can be dispensed when it is the product prescribed. FDA has not found it interchangeable, though, so it would not normally be swapped in under a state substitution law.

Numbered codes and multiple references

Levothyroxine is the textbook case because sometimes two brand products contain the same ingredient at the same strength but were never shown to be bioequivalent to each other. Both can be reference drugs. FDA then adds a digit, generally only when more than one reference of the same strength has been designated, the preface explains¹. A generic gets the same three-character code as the reference it matched.

An AB1 generic can stand in for the AB1 reference but not for the AB2 reference, unless it carries both codes. FDA says the number does not signal any preference between the groups. For patients on levothyroxine, this is one reason a pharmacy may keep dispensing a product from the same group, and a question about switching between groups belongs with the pharmacist or prescriber.

What a B code does and does not say

A B rating is not a finding that a product is unsafe or ineffective. It means FDA has not determined that the product can be swapped for another one. A BX product may work well for the patients it is prescribed for; it simply lacks the data FDA needs to call it interchangeable. Several B codes, such as BC for extended-release forms and BE for delayed-release forms, describe exactly the kinds of complex products where proving equivalence is harder.

Two groups carry no code at all. Of the book's four product lists, only the prescription list comes "with therapeutic equivalence evaluations," the preface says¹, so over-the-counter and discontinued products go unrated. New generic approvals, by contrast, are added to the electronic edition with their codes daily, a practice FDA has followed since February 2005, its Orange Book FAQ says⁵.

State law decides what happens at the counter

FDA's role stops at the rating. The preface states¹ that its evaluations do not mandate which products are purchased, prescribed, dispensed or substituted, and that generic substitution "may involve social and economic policy administered by the states."

Every state has a drug product selection law, surveyed in our guide to state generic substitution laws, and many tie a pharmacist's authority to substitute to FDA's ratings. A prescriber can generally block substitution with a dispense-as-written instruction, though the method differs by state. A team at Brigham and Women's Hospital and Harvard Medical School surveyed every state's law as of Sept. 1, 2019, and reported the results in JAMA Internal Medicine in 2021⁴:

Researchers scored each jurisdiction from zero to four, with higher scores meaning more requirements that limit substitution, and argued⁴ that states should revisit their laws to encourage generic use. Some states also add rules for particular drug classes, such as narrow therapeutic index drugs, where small differences in blood levels matter more. Pharmacists follow the law where they practice, which is one reason two pharmacies in different states can handle the same prescription differently.

Biologics follow a separate system

TE codes cover drugs in the Orange Book, which are approved through the abbreviated new drug application⁷ pathway described in how a generic drug gets approved. Biologics are different. FDA can designate a biosimilar as interchangeable with its reference product, and those designations appear in the Purple Book⁸. The 2019 survey found that 45 states had stricter requirements for substituting an interchangeable biologic than for a generic, most often a requirement to notify the prescriber, according to the study's abstract⁴. Our explainer on biosimilars and generics covers the differences.