Coding System: Applying the Ratings Code to Antihypertensive Agents

Every drug listed in the Orange Book has a 2-letter code. The first letter -- A or B -- indicates whether the drug is therapeutically equivalent to other pharmaceutically equivalent products. An "A" designation means that the FDA considers the drug to be the therapeutic equivalent of another pharmaceutically equivalent drug. By contrast, the "B" designation means that some actual or potential bioequivalence differences have been identified and therefore a drug cannot be considered therapeutically equivalent with the reference drug.

• A rated - the FDA considers the drug to be the therapeutic equivalent of another product  
• B rated - actual or potential bioequivalence differences have been identified; therefore, the drug cannot be considered therapeutically equivalent

In practical terms, the A or B code indicates whether a drug will produce the same clinical effects and carries the same risk of adverse events when given to patients under the conditions specified in the labeling. Thus, the first letter provides essential information about the potential substitutability of a drug.

The second letter (A, B, C, D, E, N, O, P, R, S, T, or X) of the therapeutic equivalence code provides information about the dosage form and, in some cases, about the results of the FDA's evaluation of actual or potential bioequivalence problems. The second letter enables pharmacists to rapidly assess whether a proposed substitute has the same route of administration in the same dosage as the originally prescribed drug. It may also convey information about whether pharmacokinetic and pharmacodynamic studies have been done to address bioequivalence issues.

A-Rated Drug Subcategories

Drug products that are A rated have clear in vivo and/or in vitro evidence of their equivalence. Some products are suspected of having actual or potential bioequivalence issues. When in vivo or in vitro testing resolves those issues, the second letter of the code is "B." Thus, the drug is labeled AB.

AA: Products in conventional dosage forms not presenting bioequivalence problems.

AB: Drugs that have been proven to meet the necessary bioequivalence requirements through in vivo and/or in vitro testing compared to a reference standard that is currently approved. AB is the most common designation. Drugs coded as AB under a specific product heading are considered therapeutically equivalent only to other drugs coded as AB under that heading. Thus, products in this category are considered to be generic drugs. However, an AB-rated product may carry an individual brand name. Under no circumstances may an AB-rated generic product use the patented brand name of the reference standard.

Table 1 shows the ratings as applied to AB-rated formulations of lisinopril and verapamil as 2 familiar examples of branded equivalents. You will notice that among the lisinopril group, there is no AB-rated equivalent to lisinopril 30 mg. Zestril 30 mg is the only product available. In the case of the immediate-release verapamil products, there are 2 branded products but also 9 generic products that are AB rated. There are extended-release verapamil formulations that do not have an AB-rated equivalent. These will be discussed in the following section. The drugs within each table are therapeutic equivalents at the same dosage level.

Table 1. Examples of AB-Rated Products

Generic name	Strength (mg)	AB-rated Products Proprietary Name
Lisinopril	2.5	Zestril / Prinivil
Lisinopril	5	Zestril / Prinivil
Lisinopril	10	Zestril / Prinivil
Lisinopril	20	Zestril / Prinivil
Lisinopril	30	Zestril
Lisinopril	40	Zestril / Prinivil
Verapamil	40	Isoptin / Calan / 9 generic formulations
Verapamil	80	Isoptin / Calan / 9 generic formulations
Verapamil	120	Isoptin / Calan / 9 generic formulations

In other coding subcategories associated with A-rated drugs, the second letter provides information about the dosage form. These subcategories include:

AN: Solutions and powders for aerosolization

AO: Injectable oil solutions; these are considered to be pharmaceutically and therapeutically equivalent only when the active ingredient, its concentration, and the type of oil used as a vehicle are all identical.

AP: Injectable aqueous solutions

AT: Topical products, including those for dermatologic, ophthalmic, otic, rectal, and vaginal administration formulated as solutions, creams, ointments, gels, lotions, pastes, sprays, and suppositories

For some AB-rated products, a number is added to the end of the code (eg, AB1, AB2, etc). This indicates that more than 1 reference drug of the same strength has been designated under the same heading. Two or more reference drugs are generally identified only when there are at least 2 potential reference drug products that are not bioequivalent to each other.

For example, the Orange Book lists Cardizem SR, Cardizem CD, Dilacor XR, and Tiazac under the heading for diltiazem. These extended-release products are not bioequivalent to each other; however, some have generic equivalents available (Table 2). When generic products became available for Cardizem SR, Cardizem SR and the generic formulations received an AB rating. However, when a second extended-release diltiazem formulation that was not bioequivalent to Cardizem SR became available on a multisource basis, Cardizem SR was designated "AB1," and the second product (Dilacor XR) was designated "AB2." When Cardizem CD became a generic --- the third extended-release product containing diltiazem -- it became "AB3." Drugs with a 3-character code under a heading are considered therapeutically equivalent only to other drugs with the same 3-character code under that heading.

Table 2. Ratings for Different Extended-Release Diltiazem Products

Proprietary Name	Therapeutic Equivalence Rating	Strengths (mg)
Cardizem SR	AB1	60, 90, 120
Dilacor XR	AB2	120, 180, 240
Cardizem CD	AB3	120, 180, 240, 300
Cardizem CD	BC	360
Tiazac	BC	120, 180, 240, 300, 360, 420

B-Rated Drug Subcategories

Table 2 lists Tiazac as a BC-rated brand of diltiazem. This section will review the meaning of B ratings. The "B" designation indicates that a drug is not bioequivalent to other commercially available formulations of the same drug. B-rated drugs, while similar to another compound, should not be considered interchangeable with any other product. This designation is often attributable to pharmacokinetic differences linked to the specific delivery forms rather than to any question about safety or efficacy. Thus, one of the subcategories of B-rated drugs is BC, which represents extended-release dosage forms (capsules, injectables, tablets).

An extended-release dosage form is defined as one that allows at least a 2-fold reduction in dosing frequency as compared with that drug presented as a conventional dosage form.

For example, the calcium-channel blocker verapamil (previously discussed in terms of its AB-rated products) is also available as Covera-HS, which is an extended-release tablet available in 180- and 240-mg strengths. Covera-HS is rated BC to Isoptin SR and Calan SR. BC-rated products are not therapeutically equivalent and therefore are not readily substitutable in most states. Examples of common BC-rated formulations are shown in Table 3.

Table 3. Some Examples of Nonequivalent BC-Rated Products*

Generic Name	Strengths (mg)	Proprietary Names of BC-Rated Products
Diltiazem	120, 180, 240, 300, 360, 420	Tiazac is not equal to Cardizem CD is not equal to Dilacor XR
Nifedipine	30, 60, 90	Procardia XL is not equal to Adalat CC
Verapamil	180, 240	Covera HS is not equal to Calan SR is not equal to Isoptin SR

*	Although these products contain the same drug, they are not equivalent.

Although the BC rating is of immediate interest in light of the various extended-release formulations that have recently been developed, pharmacists should be familiar with other subcategories of B-rated drugs, as defined by route of administration. These include:

BD: Active ingredients and dosage forms with documented bioequivalence problems; studies not submitted to FDA

BE: Delayed-release oral dosage forms, eg, enteric-coated formulations

BN: Products in aerosol-nebulizer drug delivery systems

BP: Active ingredients and dosage forms with potential bioequivalence problems

BR: Suppositories or enemas that deliver drugs for systemic absorption

BS: Products having drug standard deficiencies

BT: Topical products with bioequivalence issues

BX: Drug products for which the data are insufficient to determine therapeutic equivalence

B*: Drugs that may have been assigned an A or B code before new information raising significant questions about therapeutic equivalence was received by the FDA. The therapeutic equivalence of these drugs may be redetermined after further FDA investigation and review.^[4]

Placement of Drug Ratings

Because drug substitution is so prevalent, these ratings are now being considered for inclusion on the container labels and drug product labeling.^[4] Federal legislation that may make it mandatory to include the therapeutic equivalence code on the container label, first proposed in 1998, is pending. The code may be formatted as "AB to Brand X" or "BC to Brand Y." The codes are designed to help healthcare professionals rapidly assess the suitability of switching a drug and to assist state health agencies in the administration of the drug product selection laws. This code does not supersede any state determination of substitutability.