To Substitute or Not to Substitute: That Is the Question

Tina Zerilli, PharmD; Andy He, PharmD Candidate 2011; Joseph P. Nathan, MS, PharmD; and Sara Grossman, PharmD
Published Online: Monday, March 14, 2011
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With generic prescriptions on the rise, every pharmacist needs a through understanding of therapeutic equivalence and the generic approval process.

With the rising cost of health care, it is not surprising that sales of generic prescription medications have markedly increased. In fact, in 2009 the total number of generic prescriptions dispensed rose by 5.9%, representing 75% of all dispensed prescriptions in the United States, compared with a decline of 7.6% for branded prescriptions.1 The market share for generic products will no doubt continue to increase in 2011 when the patents of several popular prescription products (eg, Lipitor, Xalatan) are scheduled to expire.2-4

Pharmacists often encounter questions from their patients concerning differences between branded and generic products. Furthermore, the availability of multiple generic products for a given branded medication may potentially lead to inappropriate generic substitution. For example, upon receipt of a prescription for Cardizem CD 240 mg, which does not indicate that the branded product must be dispensed, a pharmacist may face a dilemma as to which generic diltiazem products, if any, are suitable for substitution. In order to address these issues, an understanding of generic substitution and its intricacies is warranted.

To understand the concepts relating to generic substitution, common terminology must first be defined. Two drug products are deemed to be pharmaceutical equivalents if they have the same active ingredient(s), strength or concentration, dosage form, and route of administration. They may differ in shape, scoring design, release mechanisms, packaging, excipients, expiration time, and to some extent, labeling.4 Pharmaceutical alternatives are defined as drug products that have the same therapeutic moiety, but are different salts, esters, or complexes of that moiety, or are different dosage forms (eg, immediate release vs extended release) or strengths.4

Bioequivalent products are either pharmaceutical equivalents or pharmaceutical alternatives that exhibit comparable bioavailability, that is, similar rate and extent to which the active ingredient/moiety is absorbed from a drug product and becomes available at the site of action.4 Finally, 2 products are considered to be therapeutic equivalents only if they are pharmaceutically equivalent and bioequivalent. Thus, they are expected to have the same clinical effect and safety profiles when administered to patients under the conditions specified in the labeling.4

Legal Issues
The FDA’s role in generic substitution is through its evaluation of the therapeutic equivalency of drug products.4 Drugs evaluated by the FDA are identified in the FDA’s publication entitled Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book). Notably, the FDA does not dictate which drug products may be substituted and/or dispensed for one another. Rather, the FDA’s rating of therapeutic equivalence is meant to provide advice to the public, practitioners, and the states concerning drug product selection. Most states have adopted the FDA’s guidance as the legal basis for substitution of generic products, that is, the substituted generic must be therapeutically equivalent to the brand product.5 However, state-specific generic substitution laws vary. Ultimately, one should consult individual state-specific laws to ensure compliance.

The Generic Approval Process
Once patent and exclusivity rights of a branded product expire, manufacturers may seek FDA approval for a generic product. Due to the complexity of issues related to patent and exclusivity laws, a thorough discussion is beyond the scope of this article. In brief, a US-issued patent is defined as a grant of property rights that excludes others from making, using, or selling the invention in the United States.6 The patent term is 20 years from the date the patent was first filed.6 Manufacturers may also seek additional exclusive marketing rights for a branded product from the FDA. These exclusivity rights may delay the time for generic products to become available on the market. Additionally, 180-day market exclusivity is granted to the first generic manufacturer that submits a complete abbreviated new drug application (ANDA) to the FDA.7,8

Unlike the approval of branded products, the approval process for generic products requires submission of an ANDA to the FDA. The application is abbreviated partly because generic drug manufacturers are not required to conduct preclinical and clinical studies to establish safety and effectiveness. However, evidence of bioequivalence to the branded product must be provided.9 For most oral tablet or capsule dosage forms, bioequivalence is demonstrated in vivo by comparing the concentrations of the branded and generic products in blood, plasma, serum, or other biologic fluid over time.9 Bioequivalence studies are typically conducted in 24 to 36 healthy volunteers.4,10

The 2 pharmacokinetic parameters of interest are maximum drug concentration (Cmax), an indirect measure of the rate of absorption, and the area under the plasma concentration time curve (AUC), which displays the extent of drug absorption.4,9,10 Bioequivalence between 2 products is established when the 90% confidence intervals for the generic/brand Cmax and AUC ratios lie within the boundaries of 80% to 125%.4,9,10 This should not be interpreted to mean that the Cmax and AUC may vary by -20% to 25% between products, as the statistical criteria utilized by the FDA to ascertain bioequivalence is complex.10 The Orange Book should be consulted for a more comprehensive description.

Controversies Regarding the Therapeutic Equivalence of Generic Drugs
Despite the rigorous standards imposed by the FDA for generic drug approval, the therapeutic equivalence of certain generic products has been questioned. For instance, in 2007, the FDA received numerous postmarketing reports noting loss of antidepressant effect, and in some cases, worsening of adverse effects, following a switch from Wellbutrin XL 300 mg to Teva Pharmaceuticals’ therapeutically equivalent generic formulation Budeprion XL.11 After reexamining the bioequivalency data, the FDA confirmed the products’ therapeutic equivalence, despite small variations in their pharmacokinetic profiles.

The changes in efficacy were attributed to the recurrent nature of major depressive disorder and the side effects were noted to be few and typical of those seen in clinical trials.11 More recently, the approval of Sandoz’s generic enoxaparin in July 2010 was challenged by sanofiaventis, the manufacturer of Lovenox. Sanofi-aventis claimed that the FDA failed to ensure that the generic product contained the same complex semisynthetic biologically derived active ingredient found in the branded product.12 The FDA contended that Sandoz’s product met all requirements for generic approval and was determined to contain the same active ingredient as the brand, based on newly created specific criteria, and therefore was deemed to be therapeutically equivalent to the branded product.13

Particular concerns have also been raised with narrow therapeutic index (NTI) drugs, including warfarin, certain antiepileptics, levothyroxine, and certain immunosuppressants. The interchangeability between Coumadin and generic warfarin has been questioned in reports of subtherapeutic international normalized ratio values in patients switched to generic formulations, despite their therapeutic equivalence ratings.14,15 With respect to certain antiepileptics, the American Academy of Neurology published a position statement opposing “generic substitution of anticonvulsant drugs for the treatment of epilepsy without the attending physician’s approval,” noting that minor differences between generic and branded products may result in breakthrough seizures and/or toxicity.16

Similarly, the American Association of Clinical Endocrinologists, the American Thyroid Association, and The Endocrine Society have expressed concerns regarding the interchangeability between branded and generic levothyroxine preparations, 17 as has the American Society of Transplantation regarding certain branded and generic immunosuppressants.18 Nonetheless, the FDA maintains its position that therapeutically equivalent, less expensive generic products can be safely substituted for branded products irrespective of the indication.10 Despite this, certain states maintain specific requirements for substitution of NTI drugs.5 Furthermore, when there are reasons to be concerned, the appropriateness of generic substitution for a given patient should be evaluated on a case-by-case basis.

FDA Resources for Identifying Therapeutically Equivalent Drug Products
As mentioned, the Orange Book serves as a guide for identifying suitable generic alternatives for branded products. The Orange Book is available on the FDA’s Web site ( under the Drugs link in the Spotlight section. A simple method of using the Orange Book for identifying therapeutically equivalent prescription medications involves searching by active ingredient. To conduct such a search, the user enters the active ingredient in the space provided and submits the query. This search yields a list of prescription medications containing the active ingredient, noting the different dosage forms, strengths, and manufacturers of the products. Additionally, the list indicates whether a particular product is the reference listed drug (RLD).

RLDs are the medications with which generic products are compared in bioequivalency studies. Furthermore, the therapeutic equivalence (TE) codes for the drug products on the list are provided. TE codes consist of 2 letters, which at times are followed by a number. The first of the 2 letters indicates whether the drug product is therapeutically equivalent to the RLD. According to the Orange Book, “A” codes denote “[d]rug products that are considered to be therapeutically equivalent to other pharmaceutically equivalent products.”4 On the other hand, a “B” designation signifies “[d]rug products that FDA, at this time, considers not to be therapeutically equivalent to other pharmaceutically equivalent products.”4 The second letter provides additional information about whether a bioequivalence problem was suspected and/or resolved, or the dosage form of the drug product.4

When more than 1 RLD is available, a number designation follows the 2-letter code. For example, when 2 branded drug products are available with the same active ingredient and each serves as an RLD and several generics are available, the FDA determines whether each generic is therapeutically equivalent to 1 or both RLDs. Thus, if a branded product is rated “AB1” only generics that are rated “AB1” are deemed therapeutically equivalent to that branded product. Similarly, if the other branded product is rated “AB2”, therapeutically equivalent generics will be rated “AB2”. Notably, an RLD may be rated both “AB1” and “AB2”, thus allowing for substitution with generics that bear either designation.

Another perhaps more user-friendly method of identifying therapeutically equivalent drug products is via the Drugs@FDA feature on the FDA’s Web site. This feature is also available through the Drugs link in the Spotlight section. Drugs@FDA allows the user to enter brand or generic drug names, select the product to be evaluated, and view all therapeutic equivalents to the selected drug product. It is important to note that when using the Orange Book or Drugs@FDA, one must be careful to consider the dosage form and strength of the specific product in question when selecting therapeutic equivalent drug products. With respect to the dilemma concerning Cardizem CD noted earlier, a search of the Orange Book revealed that Cardizem CD 240 mg is rated “AB3”; thus, generic products rated “AB3”, such as Apotex’s generic, are suitable for substitution.

Generic substitution is governed by state laws; however, most states refer to the FDA’s therapeutic equivalence ratings to guide product selection. Although controversies have been raised concerning the substitution of certain products, in general, the therapeutic equivalence system appears to function well. The FDA’s Orange Book is a useful and easily accessible resource that all pharmacists should be familiar with and should be consulted when questions regarding substitution arise. PT

Dr. Zerilli is assistant professor of pharmacy practice and a drug information specialist at the International Drug Information Center, Arnold & Marie Schwartz College of Pharmacy and Health Sciences at Long Island University in Brooklyn, New York. Mr. He is a PharmD candidate, Arnold & Marie Schwartz College of Pharmacy and Health Sciences at Long Island University. Dr. Nathan is an associate professor of pharmacy practice and director of the International Drug Information Center, Arnold & Marie Schwartz College of Pharmacy and Health Sciences at Long Island University. Dr. Grossman is a drug information specialist, International Drug Information Center, and adjunct assistant professor of pharmacy practice at Arnold & Marie Schwartz College of Pharmacy and Health Sciences at Long Island University.

1. IMS Health reports U.S. prescription sales grew 5.1 percent in 2009, to $300.3 billion. IMS Health Web site. Published April 1, 2010. Accessed November 13, 2010.
2. Goldstein J. Countdown to expiry: Lipitor goes generic on 11/30/11. The Wall Street Journal Web site. Published June 18, 2008. Accessed November 19, 2010.
3. FDAnews Drug Daily Bulletin. Xalatan patent affirmed by appeals court. FDAnews Web site. Published August 23, 2005. Accessed November 22, 2010.
4. Food and Drug Administration. Orange Book: Approved Drug Products with Therapeutic Equivalence Evaluations. 30th ed. Silver Spring, MD; Food and Drug Administration, 2010. Accessed November 22, 2010.
5. State regulations on generic substitution. Pharmacist’s Letter/Prescriber’s Letter. 2006; 22(9):220901.
6. USPTO general questions page. United States Patent and Trademark Office Web site.  Published on August 14, 2003. Accessed November 28, 2010.
7. Code of Federal Regulations. New drug product exclusivity. 21CFR 314.108. Published October 3, 1994. Accessed November 28, 2010.

8. Code of Federal Regulations. Effective date of approval of a 505(b)(2) application or abbreviated new drug application under section 505(j) of the act. (21CFR 314.107) . Published October 3, 1994. Accessed November 28, 2010.

9. Welage LS, Kirking DM, Ascione FJ, Gaither CA. Understanding the scientific issues embedded in the generic drug approval process. J Am Pharm Assoc. 2001;41:856-867.
10. Davit BM, Nwakama PE, Buehler GJ, et al. Comparing generic and innovator drugs: A review of 12 years of bioequivalence data from the United States Food and Drug Administration. Ann Pharmacother. 2009;43:1583-1597.
11. Review of therapeutic equivalence generic bupropion XL 300 mg and Wellbutrin XL 300 mg. Food and Drug Administration Web site. Published September 18, 2009. Accessed November 28, 2010.
12. Waknine Y. Sanofi-aventis sues FDA over generic Lovenox approval. Web site. Published July 29, 2010. Accessed November 28, 2010.
13. Establishing active ingredient sameness for a generic enoxaparin sodium, a low molecular weight heparin. Food and Drug Administration Web site. Published July 23, 2010. Accessed November 28, 2010.
14. Halkin H, Shapiro J, Kurnik D, Loebstein R, Shalev V, Kokia E. Increased warfarin doses and decreased international normalized ratio response after nationwide generic switching. Clin Pharmacol Ther. 2003;74:215-221.
15. Witt DM, Tillman DJ, Evans CM, Plotkin TV, Sadler MA. Evaluation of the clinical and economic impact of a brand name-to-generic warfarin sodium conversion program. Pharmacotherapy. 2003;23:360-368.
16. Liow K, Barkley GL, Pollard JR, Harden CL, Bazil CW. Position statement on the coverage of anticonvulsant drugs for the treatment of epilepsy. Neurology. 2007;68:1249-1250.
17. AACE/ATA/TES Joint Statement RE: FDA approval of generic levothyroxine preparations as equivalent to branded preparations. American Association of Clinical Endocrinologists Web site. Published June 24, 2004. Accessed November 28, 2010.
18. Alloway RR, Isaacs R, Lake K, et al. Report of the American Society of Transplantation conference on immunosuppressive drugs and the use of generic immunosuppressants. Am J Transplant. 2003;3:1211-1215.

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