10.1331 JAPhA.2007.07502

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Prescription drug product substitution decision support

Patti Gasdek Manolakis
Abstract
Objective: To generate patient-centered, evidence-based decision support tools and compile resources that will assist pharmacists in prescription drug product substitution activities and related communication, and to present the resulting tools and resources. Data Sources: Food and Drug Administration (FDA) publications, data, and communication; peer-reviewed literature; interviews with pharmacists; structured discussions with members of the project Advisory Board; and authors own knowledge and records of events. Summary: A decision whether to substitute an alternative product for a prescribed medication is a clinically based process that must be grounded in appropriate medical evidence, therapeutic equivalence information, nancial factors, and consideration of how the substitution will impact the patient. Product substitution decisions are inuenced by therapeutic issues, legal matters, patient-centered concerns, and pharmacy practice factors, including work ow, supply issues, access to current resources, and misperceptions about database information. While generic substitution is clearly dened in many cases, some medication categories require special consideration, i.e., critical dose and narrow therapeutic index drugs, products with special release mechanisms, bioengineered protein products, many hormonal products, older drugs marketed before 1938 that were not subject to FDA approval, and others with limited bioequivalence data. In response to reports of the challenges pharmacists face when determining the appropriateness of product substitution and in support of their interdisciplinary efforts to improve medication use, the American Pharmacists Association (APhA) convened an advisory board to create the decision support tool featured in this article. Conclusion: The U.S. health care system and patients rely on pharmacists as medication use experts to ensure that prescription drug product substitutions are appropriate. Pharmacists must be able to efciently determine therapeutic equivalence, identify situations where further research is required, have access to timely resources for gathering information, and effectively communicate with patients and physicians about substitution issues. The prescription drug product substitution tool and related resources presented are intended to assist pharmacists in making and communicating clinically sound product substitution decisions that are patient centered, evidence based, consistent with state and federal laws and regulations, and reective of the realities of health care today. Keywords: Bioequivalence, substitution (generic), substitution (therapeutic), Food and Drug Administration, co-payments, managed care, technology, narrow therapeutic index drugs, communication, patients, physicians, prescribers. J Am Pharm Assoc. 2007;47:328347. doi: 10.1331/JAPhA.2007.07502
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Received January 29, 2007. Accepted for publication January 31, 2007. Patti Gasdek Manolakis, PharmD, is President of PMM Consulting, Charlotte, N.C. Correspondence: Patti Gasdek Manolakis, PharmD, 16726 Hammock Creek Place, Charlotte, NC 28273. E-mail: pmanolakis@ gmail.com Disclosure: Dr. Manolakis is under contract with the American Pharmacists Association to develop educational programming and publications and received payment for preparing this article. The author declares no other potential conicts of interest or nancial interests in any product or service mentioned in this article, including grants, employment, gifts, stock holdings, or honoraria. Funding support: An educational grant from Ortho-McNeil Pharmaceutical, Inc.
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PRODUCT SUBSTITUTION DECISION SUPPORT
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harmacists face product substitution questions with patients, other health care professionals, and third-party payers on a daily basis. Often, substituting brand-name prescription drugs with equivalent generic products decreases costs to patients, employers, health plans, and the health care system through reduced prescription drug costs and lower copayments. As such, many third-party payers, state Medicaid programs, and Medicare Part D plans require the use of generic products when available and promote adherence to formularies. Increasingly, patients are incentivized to comply through tiered co-payment systems and strict coverage guidelines that prohibit payment for brand-name products when generics are available. Fifty-six percent of all prescriptions are lled with generic medications.1 The question of substitution often arises when a rejection message is received from a third-party payer in
Product Substitution Advisory Board

APhA and the author acknowledge the signicant contributions of the following individuals who served as members of the Advisory Board that guided the development of this decision support tool and related resources included in this report. n Ross Brickley, BPharm, MBA, CGP Neil Medical Group n Jay Campbell IV, BPharm, JD North Carolina Board of Pharmacy n Lynn E. Connelly, BPharm Medicine Mart Pharmacy n Winnie A. Landis, BPharm Albertsons/Osco Drug n Elliott M. Sogol, PhD, BPharm, FAPhA Target Pharmacy n Julie Suko, PharmD First DataBank, Inc. n Hal Wand, BPharm, MBA Arizona State Board of Pharmacy APhA and the author recognize the following individuals for contributing to project research, eld testing, and/or serving as reviewers of the decision support tool. n Michael Hardin, PharmD Chase Drugs n Scott Leslie, BPharm Walgreens Pharmacy n Elliott M. Sogol, PhD, BPharm, FAPhA Target Pharmacy n Sheila Hunter, DPh City Drug Company n Timothy Tucker, PharmD City Drug Company
the course of dispensing prescription medications, or when a patient requests a generic alternative. Some states have plans that mandate generic products. In many cases, equivalent generic products are available and substituted routinely in the course of caring for patients. Many pharmacy operating systems are programmed to automatically substitute generic or alternative preferred products when the brand-name or alternative product is entered. A decision whether to substitute is a clinically based process that is grounded in appropriate research, clinical information, nancial factors, and consideration of how the substitution will impact the patient. However, substitution decisions are not always clear-cut. Computer programsno matter how well designedserve as an efcient means to process and store information and supplement professional judgment only, but they cannot generate clinical decisions. Pharmacists must be able to efciently identify situations where further research is required; pharmacy technicians, including student pharmacists, who are entering orders into computer systems must learn when to question the appropriateness of substitutionparticularly when automatic substitution systems are in place. Furthermore, pharmacists must clearly understand the source of drug equivalency information entered into their drug and wholesaler databases to avoid basing decisions on inaccurate assumptions. Examples of products requiring special consideration and research include critical dose and narrow therapeutic index drugs, products with special release mechanisms (e.g., extended release, delayed release), bioengineered protein products including insulin, older drugs marketed before 1938 which are not FDA approved drugs, and others with limited bioequivalence data; these products and related issues are discussed in detail in the following pages. Issues inuencing product substitution decisions fall into four broad, interrelated categories: therapeutic concerns, legal matters, pharmacy practice factors, and patient-centered issues. n Therapeutic concerns relate to bioequivalence data, drug delivery, onset of action, and patients clinical condition and response. n Legal matters are driven by state and federal pharmacy laws and regulations. n Pharmacy practice factors encompass formularies, real-time electronic communication from third-party payers, computer management systems, drug databases, and both work-ow and workload pressures that compress the time available for pharmacists to investigate product substitution issues in the course of delivering patient care. Related problems include misperceptions about information in databases and operating systems and limited access to information available via the Internet (e.g., the Electronic Orange Book [EOB] searchable database, PubMed). n Patient-centered issues range from patients expectations of the medication and its effects to nancial pressures and frusw w w.p h a r m a c i s t . c o m 4 7: 3
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trations in dealing with changing formularies, cost containment strategies, and changes in drug appearance from one rell to the next. As more patients are becoming empowered partners in their health care, they also may initiate requests for product substitutions based on factors such as cost, advertising, and research into what they believe will yield a positive clinical response. The U.S. health care system relies on pharmacists as medication use experts; this responsibility includes ensuring that product substitutions are appropriate. In support of pharmacists interdisciplinary efforts to improve medication use and advance patient care, and in response to reports of the many challenges pharmacists face when determining the appropriateness of product substitution, the American Pharmacists Association (APhA) spearheaded an initiative to dene and address key substitution issues. During the fall of 2006, APhA convened a Product Substitution Decision Support Advisory Board to create the decision support tool featured in this article. The tool is intended to assist pharmacists in making clinically sound product substitution decisions that are patient centered, evidence based, consistent with state laws, and reective of the realities of health care today.
A live meeting of the Advisory Board was conducted on October 26, 2006, in Washington, D.C., during which the draft decision support tool and related issues were further discussed. A revised draft was generated and reviewed by the Advisory Board. The resulting draft was reviewed and informally eldtested by pharmacists in chain and independent community pharmacy settings. The tool was further rened and subsequently reviewed by the Advisory Board, along with the table of the select commonly prescribed medications, talking points, and the application examples.
Sources of therapeutic equivalence information

The primary source of therapeutic equivalence information among brand-name drug products, generics, and products containing the same active ingredient manufactured by different companies is the Orange Book, formally titled Approved Drug Products With Therapeutic Equivalence Evaluations, published by the Food and Drug Administration (FDA). The Orange Book is widely accepted as the authoritative source for therapeutic equivalence information based on data submitted to the FDA by manufacturers as part of the drug approval process. Information from the Orange Book is repackaged into other print and software publications, including the USP DI Volume III: Approved Drug Products and Legal Requirements from Thomson Micromedex, Facts and Comparisons Approved Bioequivalency Codes, and Thomson PDRs Red Book. Other sources of product substitution information include pharmacy operating systems, pharmacy databases, wholesaler databases and Web sites, manufacturers, the medical and pharmacy literature, and related databases (e.g., PubMed). The challenge is to help pharmacists evaluate and assimilate the information to determine when substitution is appropriate and safe, when it is not, and how to communicate that information to the patient, health care provider, and third-party payer.
The Orange Book
A new tool for the medication use toolbox

The Patient-Centered Product Substitution Decision Support Tool for Pharmacists (Figure 1) is composed of two parts: (1) a decision algorithm, which guides the pharmacist through a series of considerations and questions that should be addressed, and (2) companion text, which explains the issues inuencing product substitution in greater detail, including recommended actions, a glossary, reference citations, and other sources of information. Additional tools and resources, including a product substitution table (Appendix 1), talking points for communicating with patients and prescribers (Appendices 2 and 3), and patient application examples (Appendix 4), are included in this report. Ultimately, pharmacists must determine the appropriateness of product substitution in consideration of patients needs (clinical and nancial), condition, characteristics, and circumstances. Pharmacists should understand the relevant upstream factors that inuence substitution and be able to skillfully communicate with patients, prescribers, and payers about important issues. The key to making sound substitution decisions in a busy pharmacy practice setting is being vigilant knowing when to pause and gather additional information.
Decision support toolDevelopment process
After preliminary research of substitution issues, pharmacist survey data, and the literature, an issues document was generated that outlined key factors inuencing prescription drug product substitution decisions. The Advisory Board (see sidebar on page E3) was convened by teleconference to discuss and expand on the dened issues. Following the teleconference, the author drafted a decision algorithm and companion text suggesting a process for making product substitution decisions.
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The Orange Book is intended to provide public information and advice to health professionals and state health agencies in order to promote public education in drug product selection and to foster containment of health care costs. Originally published as a printed publication with monthly supplements (bearing an orange coverhence the popular name), the Orange Book is now in its 27th edition and is available online (the EOB) through the FDA Center for Drug Evaluation and Research at www.fda. gov/cder/orange. The EOB is fully searchable, and the query database is updated daily with new product approvals, making this the most up-to-date therapeutic equivalence resource available. Changes are summarized monthly in a cumulative supplement, also available on the Web site. Full access to this site is ideal in supporting pharmacists decision making. The Orange Book is no longer available as a printed publication, therefore if on-demand Internet access in the pharmacy is limJour nal of the A mer ican Phar macists A ssociation
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ited, the annual edition and monthly cumulative supplements can be downloaded for reference purposes. The EOB home page (www.fda.gov/cder/ob) is self-explanatory and includes: n The date through which information is current. n Frequently asked questions. n A link to access and browse the complete edition and cumulative supplement. n Links to search for specic products online. Pharmacists may search for therapeutic equivalence codes in multiple ways, including entering the active ingredient, proprietary name, or other information related to the applicant holder and patents. By entering a drug name, the user is directed to the EOB list with the product and its therapeutic equivalence code; if the active ingredient query is used, the reference drug and other multisource products codes are also listed. Orange Book denitions and therapeutic equivalence information.8 The Orange Book denes a series of terms regarding pharmaceutical and therapeutic equivalents and explains the therapeutic equivalence coding system in detail: n Pharmaceutical equivalents refer to products with the same active ingredient, in the same dosage form, with identical strength or concentration and route of administration. Differences may exist with respect to shape, color, etc. n Therapeutic equivalents are drug products that are (1) pharmaceutically equivalent and (2) can be expected to have the same clinical effect and safety prole when administered to patients as specied in the labeling. For the FDA to classify drugs as therapeutically equivalent, the products must be bioequivalent, safe, and effective; have the same active drug ingredient(s) in the same dosage form and with the same route of administration; meet dened standards of strength, quality, purity, and identity; and be manufactured in compliance with current good manufacturing practice regulations. The nature of bioequivalence is explored in detail in the EOB introduction. The FDA considers that drug products classied as therapeutically equivalent may be substituted for one another with the full expectation that the alternative product will produce the same clinical effect and safety prole as the prescribed product. Conversely, products classied as not therapeutically equivalent should not be expected to produce the same effects. It should be noted that Orange Book therapeutic equivalence evaluations encompass a comparison only of products with the same active ingredient(s) within a therapeutic category. Brand-name products are usually identied as the reference listed drug product within a category, with which multisource drugs are compared. Some categories have more than one reference drug (e.g., when different release mechanisms produce different clinical effects). In the case of extended-release nifedipine, Bayers Adalat CC and Pzers Procardia XL are each reference drugs, but they are not considered therapeutically equivalent. Therapeutic equivalence ratingsA codes. Therapeutic
equivalence codes are designated by a short series of letters and in some cases numbers (e.g., AA, AB, AN, AB2, BX). Acodes designate therapeutic equivalence. AA refers to products in conventional dosage forms without potential bioequivalence problems, and AB refers to products for which actual or potential bioequivalence problems have been resolved with adequate evidence.8 In other A codes, the second letter in the code corresponds to the dosage form; thus, therapeutic equivalence for nonconventional dosage forms is designated as A_ (e.g., AN for solutions and powders for inhalation, AT for topical products). Occasionally, when there is more than one reference listed drug, a third component (a number) is added to the code. When this third component is designated, only products with the corresponding letters and numbers are interchangeable.8 In the previously mentioned example of extended-release nifedipine, Adalat CC and Procardia XL each have therapeutically equivalent alternatives, coded AB1 and AB2, respectively. Therapeutic equivalence ratingsB codes. B codes are assigned to drug products that the FDA currently considers not to be therapeutically equivalent to other pharmaceutically equivalent products, namely, those for which actual or potential bioequivalence problems have not been resolved.8 These products should not be substituted without careful consideration. The second letter in the code indicates the dosage form or other reason behind the bioequivalence problem (i.e., BC for extendedrelease products, BP for potential bioequivalence problems, BX for insufcient data, and BD for documented bioequivalence problems). Different products with extended-release dosage forms containing the same active ingredient in equal strengths often are not considered by the FDA to be therapeutically equivalent; the same is true for delayed-release products and other dosage forms (e.g., transdermal, otic) for which equivalence has not been demonstrated. The B* rating signies that the FDA has received new information that raises a signicant question about therapeutic equivalence, requiring investigation and review. B-coded products may become AB-coded products if adequate in vivo bioequivalence data are submitted to the FDA. Therapeutic equivalence ratings do not affect the legal status (i.e., approval status) of products. In the context of generic drug approval, B ratings among pharmaceutical equivalents are either: (1) generic products approved prior to the passage of the Drug Price Competition and Patent Term Restoration Act of 1984 (Waxman-Hatch Act) or (2) products approved through new drug applications (NDAs), not abbreviated new drug applications (ANDAs) (Don Hare, FDA Ofce of Generic Drugs, oral communication, January 2007). Prior to 1984, submission of bioequivalence data could be deferred; the Waxman-Hatch Act requires ANDA applicants to submit data demonstrating bioequivalence to the innovator product prior to approval. Thus, under the current system, ANDAs with insufcient bioequivalence data would not be approved. Continued on page 336
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Figure 1. Patient-centered product substitution decision support tool for pharmacists Product substitution decision support tool companion text
Box 1Product substitution inquiry Pharmacist is faced with a decision to determine the appropriateness of a potential substitution. This inquiry is often triggered by third-party rejection messages, patient request for lower cost therapy, or legal mandates requiring generic substitution. Box 2Information gathering Gather necessary information from the patient to factor into product substitution decision: n Is this a prescription for new therapy or continuation of ongoing therapy? n Does the patient desire substitution? n Identify cost/coverage factors (e.g., difference in co-payment amount or prescription cost). n Determine whether there are medication administration factors that may inuence the patients use of substituted medication (e.g., avor of liquid or chewable tablet, size of tablet). n Does the patient have allergies to potential excipients (e.g., red dye)? Review state laws and regulations regarding substitution. Box 3 branchCritical dose drugs and bioengineered products (includes boxes 3, 8, 9, and 14) Critical dose and narrow therapeutic index drugs. Critical dose drugs: n Have a narrow therapeutic range. n Are dosed based on body weight or other highly individualized dosing requirements. n Are associated with serious clinical consequences of toxicity or underdosing. n Have a steep dose-response relationship for efcacy and/or toxicity. n Usually have some requirements for blood level monitoring. Many of these drugs are also called narrow therapeutic index (NTI) drugs in state laws and in the literature. Small changes in dose, absorption, bioavailability, or drug delivery may yield signicant therapeutic differencesincluding efcacy and/or toxicityeven among equivalent products; caution should be exercised with substitution of any of these products. Therapeutic equivalence (TE) information located in the Food and Drug Administrations (FDA) Approved Drug Products With Therapeutic Equivalence Evaluations (the Orange Book), available
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at www.fda.gov/cder/orange, provides important guidance to health professionals related to this category of drugs. If a product is A-coded and substitution is required, all parties (i.e., prescriber, patient, case manager, and caregivers) should be notied in advance. A plan for monitoring patient response and follow-up should be dened and implemented; the patient should be monitored as necessary based on clinical response. Products that are not rated therapeutically equivalent should not be substituted.2 Examples: Lithium, cyclosporine, warfarin, phenytoin, levothyroxine, carbamazepine, digoxin, quinidine, theophylline. Levothyroxine products. The Orange Book provides a separate section in the introduction detailing which products are bioequivalent, because the TE coding of these products is complicated (e.g, AB1, AB2, AB3, AB4, BX) and bioequivalence data for these products have become available through new drug applications (NDAs) and abbreviated new drug applications (ANDAs) in recent years. In general, only AB products with corresponding numbers are equivalent (i.e., a product with an AB1 code is equivalent to other AB1-rated products, but not to AB3-rated products.) Some levothyroxine products have multiple three-letter codes indicating they have demonstrated bioequivalence to more than one reference listed drug (e.g., Levo-T is rated AB2 and AB3, therefore it would be considered therapeutically equivalent to any of the other products rated AB2 or AB3, but not to products rated AB4). To be considered therapeutically equivalent, two products must share at least one common TE code. Although some overlap among categories exists, there is no transitive property of bioequivalence that transfers bioequivalence across categories without the actual designation. For example, referring to the list of TE ratings of multisource levothyroxine products, note that both Mylans generic levothyroxine and Abbotts Synthroid brand of levothyroxine have AB1 ratings and are considered equivalent.3 Synthroid is not equivalent to Levothroid (Lloyds AB4-rated product), even though Mylans levothyroxine product is equivalent; this could be a result of the additive bioavailability differences extending beyond acceptable limits between the rst and third products. While an Electronic Orange Book search would reveal the list of TE codes for each manufacturers product, sorted by manufacturer, the FDA provides a reference table, sorted by TE code to aid in interpreting therapeutic equivalence among products. Biotechnology products. Bioengineered, large protein products, also referred to as therapeutic biological proteins, have the potential to generate wide variability in response; therefore switching among products may result in serious consequences for patients (e.g., severe immunological response).4,5 This variability stems from the complex structure of these products, which are usually not as fully characterized as chemically synthesized, small molecular weight drugs. As such, the FDA considers each product distinct and not interchangeable.5 In fact, manufacturers that adjust manufacturing processes for a product must demonstrate equivalence to their original product.4,6 In recent years, oversight of many of these products has moved from the FDA Center for Biologics Evaluation and Research to the FDA Center for Drug Evaluation and Research; as a result of this change, some of these products are included in the Orange Book. While some researchers7 have explored the outcomes of midtherapy interchange among different manufacturers products, the FDAs strong position on this issuebacked by the potential for serious patient consequencesobliges health professionals not to substitute biological proteins without compelling data supporting their therapeutic equivalence and without very close monitoring.5 Examples: Recombinant human insulin, recombinant somatropin, urokinase, alteplase, lgrastim, iniximab.
Therapeutic equivalence ratings of multisource levothyroxine products3

Brand name Applicant Unithroid Stevens J Levothyroxine sodium Mylan Levoxyl Jones Pharma Synthroid Abbott Synthroid Abbott Levothyroxine sodium Mylan Levo-T Alara Pharm Unithroid Stevens J Levothyroxine sodium Genpharm Levoxyl Jones Pharma Levo-T Alara Pharm Unithroid Stevens J Levothyroxine sodium Mylan Levothyroxine sodium Genpharm Levothroid Lloyd Levothyroxine sodium Mylan Novothyrox Genpharm Levolet Vintage Orange Book TE code AB1 AB1 AB1 AB1 AB2 AB2 AB2 AB2 AB2 AB3 AB3 AB3 AB3 AB3 AB4 AB4 BX BX
Box 4 branchControlled-release, delayed-release, extended-release, topical absorption, or hormonal products (includes boxes 4, 10, 11, and 1518) Various manufacturers employ different approaches to achieve delayed, extended, or sustained release. Accordingly, the rate and extent of absorption of productseven with the same active ingredient in the same dosemay vary signicantly. With these bioavailability differences, substitution would be expected to generate a different response. The FDA rates these products as not therapeutically equivalent unless manufacturers submit bioequivalence data, in which case the FDA would grant an AB rating.8 If the product is designated AB or other equivalent A code, then substitution is appropriate. Review the patient prole for allergies to excipients (e.g., red dye). Educate the patient, and communicate as necessary with the prescriber. For products designated with a B code, substitution is not recommended. If a strongly compelling patient or supply issue exists, review the bioequivalence information and conduct a risk/benet analysis. Clinical practice situations that might compel pharmacists to consider substituting include when the wholesalers supply is depleted as a result of a manufacturers product being temporarily unavailable or when refusal to substitute would create a nancial hardship for the patient (e.g., $120 co-pay or no coverage for highcost prescription drug vs $0$10 co-pay). In the latter situation, patients sometimes choose no treatment over a treatment they cannot afford. When deciding whether substitution is appropriate, pharmacists should evaluate the clinical signicance of the potential variability. For example, if the patient has been maintained and stabilized on a particular product, then the clinical pitfalls of substitution may be more pronouncedas in uctuations in blood pressure levels (e.g., for antihypertensive agent) or pain control (e.g., for chronic pain management)compared with initiation of new therapy. In such situations, substitution may compromise control of the patients condition or result in actual harm to the patient. In any case, weighing the potential risks against the potential benets will help achieve the best outcome for the patient. Communicating with the prescriber and the patient is important; they need to understand substitution options and consequences, compelling issues, what to expect, and recommended monitoring parameters if substitution is made.
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Examples: Diltiazem, nifedipine, testosterone gel, estrogen patches, hydrouoroalkane (HFA)-propellant albuterol products, extended-release theophylline capsules and some tablets. Controlled-release, delayed-release, and extended-release products not found in the Orange Book. For products not listed in the Orange Book, consult data from known sources to determine the clinical signicance of potential or actual variable response. Sources to consult include clinical pharmacotherapeutic databases and Medline searches at www.pubmed.com. Although wholesaler databases, pharmacy operating systems, and chain pharmacy databases may list and link drugs with the same active ingredient in the same dosage form and strength, such links do not always reect TE. Pharmacists should be aware of how the links are dened before assuming that products listed as alternatives are interchangeable particularly with many of the sustained-release formulations. Some operating systems include Orange Book TE codes, but this varies among systems. Pharmacists should base their decisions on available evidence, their clinical expertise, and accepted resources. When the possible risks outweigh the potential benets of substituting, do not substitute. In this case, particularly if nancial disincentives are in place, the pharmacist may be able to work with the physician to obtain medical necessity prior authorization with the patients third-party payer. If, in the pharmacists professional judgment after evaluating the evidence, substitution is unlikely to compromise control or cause harm to the patient, and the patient desires to substitute, the pharmacist may determine that substitution is appropriate. In this case, the pharmacist should communicate with both the prescriber and the patient to develop a plan for adjusting and monitoring therapy. Ensure compliance with state laws and obtain a new prescription if necessary. Hormonal products. Evidence of bioequivalence is lacking with many hormonal endocrine products. The Orange Book lists some therapeutic equivalents; many others are B rated. For products not listed in the Orange Book, consult the available literature to ascertain bioequivalence. If a patient is stabilized on a particular product and there are no data demonstrating bioequivalence of the alternative product, it may be in the patients best interest to continue current therapy without substitution. For B-rated products, substitution is not recommended. Examples: Oral or topical estrogen and testosterone products. Box 5 branchOlder, pre-1938, pre-DESI, unapproved drug products (includes boxes 5, 12, and 1618) Products marketed in the United States prior to 1938 were not subject to FDA approval; the FDA refers to these as unapproved drug products.9,10 Since 1962, federal law has required pharmaceutical manufacturers to provide safety and efcacy data for drug approval. Between 1938 and 1962, federal law required manufacturers to provide only safety data for the Drug Efcacy Study Implementation (DESI) review; drugs approved during this time are referred to as DESI drugs, noting efforts initiated by the FDA to demonstrate efcacy of these products in the 1960s.10 Some drug products released prior to 1938 remain on the market today; these are not FDA approved, and thus neither safety nor efcacy data have been submitted to the FDA. Although some assume these products have been grandfathered, the FDAs interpretation of grandfathering is very narrow, and to date no product has been formally recognized as grandfathered by the FDA.10 Historically, data regarding safety, efcacy, and bioequivalence of these products have been sparse; however, the FDA is requiring manufacturers to submit data if they intend to continue marketing these drugs. In the meantime, health professionals need guidance to determine when substitution of these products is or is not appropriate. Sources of data include clinical drug information databases, PubMed searches, pharmaceutical sciences journals, and manufacturers. Pancreatic enzyme products (e.g., Creon, Pancrease, Viokase)
used to treat pancreatic insufciency in conditions such as cystic brosis and pancreatitis serve as an example of products without FDA approval. The literature documents wide variations in bioavailability among different manufacturers products, resulting in signicant changes in patients clinical status when products are interchanged. Most pancreatic enzyme products are not yet FDA approved and are awaiting NDAs by 2008. However, the FDA, prompted by reports of adverse reactions, has issued a guidance on this topic, including a statement that substitution of pancreatic enzyme products made by different manufacturers is not recommended.11-13 Digoxin and levothyroxine products have historically been included in this category, however many of these products have received FDA approval through NDAs and ANDAs in recent years (see the Orange Book and Appendix 1 for available TE codes). Eventually, all unapproved products will either become approved through NDA or ANDA processes or will be withdrawn or removed from the market.9 If the evidence shows that benets outweigh potential risks, substitution may be acceptable. Communicate with the prescriber to develop a plan for patient education, initiating or adjusting therapy, monitoring, and follow-up as needed. If the risk of harm exceeds potential benets, do not substitute. Examples: Phenobarbital, pancreatic enzyme products. Box 6 branchProduct substitution in other categories (includes boxes 6, 7, 13, and 1618) Because the Orange Book is accepted as the authoritative source of therapeutic equivalency information, health professionals should rst look to this source for product substitution guidance. If a product is not immediately found in an Electronic Orange Book search (www.fda.gov/cder/ob), refer to the product package to make certain that the original source manufacturer is referenced for the search. Also check that the appropriate search category is being used (e.g., active ingredient, proprietary name). In determining therapeutic equivalence (TE), the FDA requires the products to be pharmaceutical equivalents (PE) and to be bioequivalent (B); thus, TE = PE + B. If products have equivalent A ratings (indicating they are equivalent), the pharmacist can substitute with an expectation that the alternative medication will produce a similar response.14 [Note: The pharmacist should ensure that the patient has no history of allergies to excipients in the alternative product.] Based on the products Orange Book TE code, see the following paragraph and the related discussion of therapeutically equivalent products (i.e., A or AB rated) in text for the box 4 branch. B-rated products have known or potential bioequivalence problems and would not be expected to produce the same response in patients. Either do not substitute, or conduct additional research to ensure that substitution would be unlikely to reduce control of the condition being treated or cause harm to the patient. Products not found in the Orange Book. For products not listed in the Orange Book, consult data from known sources to determine the clinical signicance of potential or actual variable response. Sources include Medline searches of the pharmacy and medical literature at www.pubmed.gov, the Journal of Pharmaceutical Sciences (a common source of published bioequivalence studies), clinical pharmacotherapeutic databases, FDA guidance documents, and clinical drug information publications such as APhA DrugInfoLine, Pharmacists Letter, and The Medical Letter. For a quick Medline search, enter the keywords, bioequivalence and the chemical name of the drug under consideration. Although wholesaler databases, pharmacy operating systems, and chain pharmacy databases may list or group drugs with the same active ingredient in the same dosage form and strength (i.e., pharmaceutical equivalents), the groupings do not always reect drugs that have been shown to be therapeutically equivalent. Pharmacists should be aware of how the groups are dened before assuming that items listed as alternatives are interchangeable. Orange Book TE codes are included in some operating systems, but this varies among systems. Pharmacists should rely on the evidence, their clinical expertise, and accepted
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resources. If necessary resources are limited within the practice setting, pharmacists are encouraged to advocate for changes to pharmacy policies that would provide them access to information and resources required to make professional judgment regarding patients therapy. When the possible risks outweigh the potential benets of substituting, do not substitute. For medically necessary products denied by a third-party payer, inform the patient, and contact both the payer and prescriber for medical necessity prior authorization of the prescribed product. This collaborative effort may be particularly helpful to the patient if nancial disincentives are in place. If, in the pharmacists professional judgment based on the evidence, substitution is unlikely to compromise control or to cause potential harm to the patient, and the patient desires to substitute, the pharmacist may determine that substitution is appropriate. Communicate with both the prescriber and the patient to develop a plan for adjusting and monitoring therapy. Ensure compliance with state laws and obtain a new prescription if necessary.
Boxes 16 through 18Results of risk/benet analysis. When the possible risks of substitution outweigh the potential benets, do not substitute. In these circumstances, particularly if nancial disincentives are in place, the pharmacist may be able to work with the physician to obtain medical necessity prior authorization for the prescribed product with the patients third-party payer. If, in the pharmacists professional judgment after evaluating the available evidence, substitution is unlikely to compromise control or to cause potential harm to the patient, and the patient wishes to substitute, the pharmacist may determine that substitution is appropriate. Communicate with both the prescriber and the patient to develop and implement a clear plan for adjusting therapy, monitoring, and follow-up evaluation. Ensure compliance with state laws and obtain a new prescription if necessary.
Glossary
Bioengineered products or biological products: Biological products, also referred to as therapeutic proteins, are a subset of drugs used for the treatment, prevention, or cure of disease in humans. These large protein products are often produced through biotechnology and are generally derived from living materialhuman, animal, or microorganism. They are complex in structure and usually are not fully characterized (in contrast to chemically synthesized, small molecular weight drugs, which have a well-dened structure and can be thoroughly characterized). 4 Bioengineered products are regulated not only under provisions of section 505 of the Food, Drug, and Cosmetic Act as other drugs are, but many also are licensed under section 351 of the Public Health System Act. Examples: Epoetin, lgrastim, human growth hormone, streptokinase, urokinase, recombinant human insulin. Bioequivalence: Drugs are determined to be bioequivalent if the rate and extent of absorption are not signicantly different from the reference-listed drug when administered in the same dose under similar conditions. 8 Critical dose drugs: Drugs with a narrow therapeutic range are dosed based on body weight or other highly individualized dosing requirements; are associated with serious clinical consequences of overdosing/toxicity or underdosing; have a steep dose-response relationship for efcacy and/or toxicity; and usually have some requirements for blood level monitoring. Small changes in dose, absorption, or bioavailability may lead to signicant changes in efcacy and/or toxicity. 2 Many critical dose drugs are referred to as narrow therapeutic index drugs. Examples: Lithium, cyclosporine, warfarin, phenytoin, levothyroxine, carbamazepine, digoxin, quinidine, theophylline. Narrow therapeutic index (NTI) drugs: When small differences in drug dose or bioavailability result in signicant changes in effectiveness and toxicity they are commonly referred to as having a narrow therapeutic index. 2 Safe and effective use of these drug products requires careful titration and patient monitoring. Many state regulations include a list of narrow therapeutic index drugs for which substitution is often limited. See critical dose drugs for examples. Pharmaceutical equivalents: Products with the same active ingredient, in the same dosage form, with identical strength or concentration and route of administration are pharmaceutically equivalent. 8 Differences may exist with respect to shape, color, and other factors that do not inuence bioavailability. Therapeutic equivalents: Drug products that are pharmaceutically equivalent can be expected to have the same clinical effect and safety prole when administered to patients as specied in the labeling are therapeutic equivalents. Products classied by the FDA as therapeutically equivalent are bioequivalent, safe, and effective; have the same active drug ingredient(s) in the same dosage form and route of administration; meet dened standards of strength, quality, purity, and identity; and are manufactured in compliance with current good manufacturing practice regulations. Bioequivalence is often the variable upon which therapeutic equivalence is determined (TE = PE + B). The FDA states that products classied as therapeutically equivalent may be substituted with the full expectation that the substituted product will produce the same clinical effect and safety prole as the prescribed product. 8 Conversely, products not classied as therapeutically equivalent would not be expected to produce the same effects. Pharmaceutical equivalents that are A or AB rated, sharing at least one common A code, are therapeutic equivalents; others, including those designated with B codes or without a common three-character A code (e.g., AB1, AB3), are not. 8 The Orange Book evaluations do not address therapeutic interchange among products with different active ingredients within a therapeutic category. Therapeutic proteins or therapeutic biological products: See entry for bioengineered products/biological products. Unapproved drug products: Drugs marketed in the United States that do not have FDA approval; many of these were released prior to 1938 when FDA approval was not required.10 Examples: Phenobarbital, pancreatic enzyme products.
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Other sources of bioequivalence information
A variety of other print and electronic publications contain therapeutic equivalence ratings dened by the Orange Book. USP DI Volume III: Approved Drug Products and Legal Requirements is available as a companion to USP DI Volume I: Drug Information for the Health Care Professional and USP DI Volume II: Advice for the Patient, or for purchase separately. Published annually as a single-volume print publication, its current format includes the annual edition of the Orange Book, without monthly supplements. Red Book, widely recognized as a pricing resource, includes Orange Book therapeutic equivalence codes for all approved products, including those that are repackaged and distributed by multiple sources. It is available as a single-volume, soft-cover, annual publication (with or without updates), as a CD-ROM for Windows, and in database format. Approved Bioequivalency Codes (ABC) is a loose-leaf printed reference with Orange Book therapeutic equivalence coding information provided in an alternative tabular format; it is sold as an annual subscription with monthly updates. The most signicant limitations of these resources are that they do not provide signicant bioequivalence information beyond therapeutic equivalence coding and they do not provide guidance on products for which therapeutic equivalence codes are unavailable. Other sources of information available to support product substitution decisionseach with its own set of advantages and limitationsinclude pharmacy operating systems, drug databases, wholesaler databases and Web sites, manufacturers, and the medical and pharmacy literature and databases (e.g., Medline available at www.pubmed.gov). Many bioequivalence studies are published in the Journal of Pharmaceutical Sciences, accessible through Medline. The APhA DrugInfoLine newsletter, Pharmacists Letter, and The Medical Letter are additional resources.
when displaying alternative products. The fact is that some do and some do not. Most of these systems display alternatives with the same active ingredient in the same dosage form and strength (i.e., pharmaceutical equivalents) without regard to Orange Book therapeutic equivalence codes or other bioequivalence data. Thus, while many may be therapeutically equivalent generic products, many wholesaler databases, pharmacy operating systems, and chain pharmacy databases lists of alternative products also include products with the same active ingredient that are not therapeutically equivalent to each other. Pharmacists should be aware of how the groups or links are dened and not assume that items listed as alternatives are interchangeable, recognizing that sometimes those in the position of entering the data or contracting for preferred products may not have a clinical education background. Some pharmacy operating systems include Orange Book therapeutic equivalence codes, but this varies among systems. Pharmacists should rely on the evidence, their clinical expertise, and accepted resources. If access to necessary resources is limited within the practice setting, pharmacists are encouraged to advocate for changes to pharmacy policies that would provide them access to information and resources necessary to make professional judgment regarding patients therapy.
Limited (or lack of) Internet access
Challenges and upstream problems inuencing product substitution

Drug databases and dispensing/information systems
Pharmacists should be aware that the data entered into drug databases, dispensing systems, and wholesaler databases for alternative products may be broadly dened and may not reect Orange Book therapeutic equivalence codes. Consistent with critical thinking in caring for patients, pharmacists also must question the information furnished through these databases and dispensing systems. It is easy to assume that the information provided on the screen accurately reects the information sought, but pharmacists must evaluate the source to ensure their ultimate decisions are based in evidence and datanot misinformation. A common misperception is that all systemsdrug databases, wholesalers systems, and dispensing systemsgroup therapeutically equivalent alternatives
Many employers limit Internet access through pharmacy computers. This practice, while understandable from a business standpoint, hinders pharmacists access to important information and data required for making decisions on behalf of patients. As previously noted, the most timely therapeutic equivalence information is available on the EOB Web site. Furthermore, if additional research regarding bioequivalence and safety is required, access to online clinical data will expedite research efforts. Pharmacists are encouraged to nd creative solutions in collaboration with their employers to meet the information access needs to care for patients while respecting the companys need to minimize and control Internet usage. Suggestions include limiting access to a few select links (e.g., EOB Web site, PubMed, APhA DrugInfoLine ) or having one stand-alone computer in the pharmacy with Internet access. Pharmacists should join with work colleagues to draft a proposal to management; the proposal should address anticipated pitfalls and incorporate possible solutions.
Manufacturer and wholesaler supply issues
Sometimes when a wholesaler is out of stock on a particular manufacturers generic product, another manufacturers product is used to fulll the orders. In many cases, the products are therapeutic equivalents, and the only difference may be in the color or shape of the tablet. However, with critical dose or narrow therapeutic index drugs (e.g., levothyroxine, warfarin) and other products with bioequivalency problems (e.g., pancreatic enzyme
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products, testosterone gel), this difference may be signicant. As noted in the decision support tool, patients maintained on a particular manufacturers product may not be switched readily among other available products and some wholesaler decision makers are unaware of this nuance.
Orange Book limitation
other approved generics. Although made available by the FDA in approval announcements and on its Web site, this information is often overlooked as seemingly insignicant. Furthermore, imprecise understanding of the distinction is a likely source of misperceptions among information systems programmers, database links among alternative products, and wholesalers.
The Orange Book lists approved products only from companies that have led applications with the FDA, including NDAs and ANDAs. This limitation is signicant for products that are manufactured by one company and repackaged for distribution by another company. For example, Product X, produced by Company X, is listed in the Orange Book as having an AB rating. Company X also manufactures the drug product for Company Y, which distributes it as Product Y. A pharmacist seeking to nd the therapeutic equivalence rating of Product Y will not nd Company Y (nor Product Y) listed in the Orange Book; the pharmacist must identify the original source (i.e., Company X) and look up the rating for the product manufactured by that company. Source information usually can be found on the product label and/or packaging.
Work-ow issues
ConclusionMaking sound product substitution decisions

Substituting therapeutically equivalent generic medications often results in quality care at lower prescription costs or co-payments. Some drug productseven generics or other brand-name products with the same active ingredientsshould not be substituted because of differences in bioavailability and the impact on patients. Determining whether substitution is appropriate in a given situation is a decision that needs to be grounded in research, clinical information, nancial factors, and consideration of how the substitution will impact the patient. Often this process occurs rapidly in the course of dispensing prescription medications. Pharmacists must be prepared to identify situations where the process should be paused because further research is indicated. They also must ensure that pharmacy technicians and student pharmacists know when to seek guidance during order entry. The sources of drug equivalency information found in drug and wholesaler databases and pharmacy operating systems should be conrmed to ensure accuracy of the information and to prevent erroneous assumptions from negatively inuencing patient care. To effectively evaluate therapeutic equivalence, pharmacists must have access to the necessary sources of information, including online resources such as the EOB and PubMed. Pharmacists are encouraged to use tools such as the algorithm, talking points, table of commonly prescribed products requiring special consideration, and application examples in this article to enhance their interdisciplinary efforts to provide evidence-based, patient-centered care aimed at improving medication use and advancing patient care.
References
1. Generic Pharmaceutical Association. Statistics. Available at: www.gphaonline.org/Content/NavigationMenu/AboutGenerics/Statistics/default.htm. Accessed January 16, 2007. 2. American Pharmaceutical Association. Substitution of Critical Dose Drugs: Issues, Analysis, and Decision Making. 2000. Available at: www.pharmacist.com/pdf/critical_dose.pdf. Accessed October 12, 2006. 3. Food and Drug Administration. Approved Drug Products With Therapeutic Equivalence Evaluations. 26th ed. Cumulative Supplement 12. December 2006;viiiix. Available at: www.fda. gov/cder/orange/obcs.pdf. Accessed January 16, 2007. 4. Food and Drug Administration. Frequently Asked Questions About Therapeutic Biological Products. Available at: www.fda. gov/cder/biologics/qa.htm. Accessed November 2, 2006. 5. Food and Drug Administration. U.S. FDA Considerations: Discussion by National Regulatory Authorities With World Health Organization (WHO) on Possible International Non-proprietary Name (INN) Policies for Biosimilars. September 1, 2006.
In many practices, prescriptions are entered into the pharmacy computer system by pharmacy technicians (in some cases student pharmacists). Although pharmacists check these orders, the decision whether to substitute often occurs at the beginning of the process instead of the point of pharmacist verication. This underscores the need for communication, training, and decision support among the pharmacy staff. Alerting pharmacy technicians to the special product substitution situations where pharmacist guidance is necessary will help to ensure that substitutions are appropriate and that unwitting, inappropriate substitutions are avoided. The decision points in the algorithm portion of the decision support tool can be useful in educating pharmacy staff about the situations that require additional research and consideration.
Generic misperceptions
The FDA communicates to consumers and health professionals that approved generic products are safe, effective, equal alternatives to brand-name products and other approved generics.15,16 These products are usually available at a lower cost and with the expectation of equal efcacy.1517 However, pharmaceutical equivalents marketed without a brand name are sometimes mistaken by health professionals and patients to be therapeutically equivalent generics, translating into signicant, yet easily explainable, misperceptions in practice.18 Confusion commonly results from products approved through the NDA process and marketed under the chemical or generic name; their approval is for a new drug product, not an ANDA approval as therapeutically equivalent generic alternatives to innovator products and
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12. Exocrine Pancreatic Insufciency Drug Products: Draft Guidance for Submitting NDAs, Notices, 69 Federal Register 23410 4 (2004). 13. Food and Drug Administration. Questions and Answers on Pancreatic Insufciency Drug Products. April 27, 2004. Available at: www.fda.gov/cder/drug/infopage/pancreatic_drugs/ pancreatic_QA.htm. Accessed October 17, 2006. 14. Food and Drug Administration. Approved Drug Products With Therapeutic Equivalence Evaluations. Electronic Orange Book. Available at: www.fda.gov/cder/ob. Accessed November 17, 2006, to January 16, 2007, to conduct active ingredient queries. 15. Food and Drug Administration. FDA Ensures Equivalence of Generic Drugs. 2003. Available at: www.fda.gov/cder/consumerinfo/generic_equivalence.htm. Accessed January 16, 2007. 16. Food and Drug Administration. Facts About Generic Drugs. 2006. Available at: www.fda.gov/cder/consumerinfo/generic_ FactsAbout_text.htm. Accessed January 16, 2007. 17. Food and Drug Administration. Generic Drugs: What Everyone Should Know. 2005. Available at: www.fda.gov/cder/consumerinfo/generic-what_everyone_should_know.htm. Accessed January 16, 2007. 18. Wisniewski L, Holquist C. The absence of a trade name does not equal a generic drug. Drug Topics. October 10, 2005;52.Available at: www.fda.gov/cder/drug/MedErrors/no_tradename. pdf. Accessed January 5, 2007.
6. Food and Drug Administration. FDA Guidance Concerning Demonstration of Comparability of Human Biological Products Including Therapeutic Biotechnology-Derived Products. Available at: www.fda.gov/cder/guidance/compare.htm. Accessed November 2, 2006. 7. Thames WA, Smith SL, Scheifele AC, et al. Evaluation of the U.S. Oncology Networks recommended guidelines for therapeutic substitution with darbepoetin alfa 200 mg every 2 weeks in both naive patients and patients switched from epoetin alfa. Pharmacotherapy. 2004;24:31323. 8. Food and Drug Administration. Approved Drug Products With Therapeutic Equivalence Evaluations. 26th ed. 2006;iiixxii, 2-1. Available at: www.fda.gov/cder/orange/obannual.pdf. Accessed August 14, 2006, to January 16, 2007. 9. Food and Drug Administration. Guidance for FDA Staff and Industry: Marketing Unapproved DrugsCompliance Policy Guide. June 2006. Available at: www.fda.gov/cder/guidance/ 6911fnl.pdf. Accessed October 22, 2006. 10. Food and Drug Administration. Questions and Answers on the Unapproved Drug Compliance Policy Guide. 2003. Available at: www.fda.gov/cder/compliance/CPG_QandA.htm. Accessed October 23, 2006. 11. Food and Drug Administration. Guidance for Industry: Exocrine Pancreatic Insufciency Drug ProductsSubmitting NDAs. April 28, 2004. Available at: www.fda.gov/cder/guidance/ 6275fnl.pdf. Accessed December 2, 2006.
Appendix 1. Therapeutic equivalence codes of select commonly prescribed medications14

Generic and brand names Dosage form and strengths (if TE varies) Applicant/manufacturer (grouped by TE code, listed alphabetically) Bupropion HCl: Wellbutrin SR 100 mg, 150 mg, 200 mg extended-release tablets GlaxoSmithKline (Wellbutrin SR) Impax Sandoz Bupropion HCl: Zyban 150 mg extended-release tablets GlaxoSmithKline (Zyban) Impax Sandoz Bupropion HCl: Wellbutrin XL 150 mg, 300 mg extended-release tablets Anchen Impax (300 mg only) SmithKline Beecham (Wellbutrin XL) Bupropion HCl: Wellbutrin SR 50 mg extended-release tablet (GlaxoSmithKline) Digoxin 0.125 mg and 0.25 mg oral tablets Actavis Totowa Caraco SmithKline Beecham (Lanoxin) Stevens J
TE code
Special consideration category and notes Extended release
AB1 AB1 AB1 Extended release AB2 AB2 AB2 Extended release AB3 AB3 AB3 [Not rated] Extended release No therapeutic equivalents Critical dose/NTI AB AB AB AB
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Appendix 1. Therapeutic equivalence codes of select commonly prescribed medications14 (continued)

Generic and brand names Dosage form and strengths (if TE varies) Applicant/manufacturer (grouped by TE code, listed alphabetically) Diltiazem HCl extended-release capsules all strengths except 360 mg Andrx (diltiazem) Mylan Torpharm (diltiazem) Watson Labs (Dilacor XR) Actavis Elizabeth Andrx Pharms (Cartia XT) Biovail (diltiazem) Biovail (Cardizem CD) Torpharm (Dilt-CD) Andrx Pharms (Taztia XT) Apotex (Diltzac) Biovail (Tiazac) KV Pharm Diltiazem HCl: Cardizem CD 360 mg extended-release capsules (Bioavail) Diltiazem HCl: Cardizem LA extended-release capsules (Biovail) Estradiol lm extended release; transdermal Berlex (Climara) Mylan Technologies (estradiol) Novartis (Vivelle 0.05 mg/24 h) Novartis (Vivelle-Dot 0.05 mg/24 h) Novartis (Vivelle 0.1 mg/24 h) Novartis (Vivelle-Dot 0.1 mg/24 h) Berlex (Climara) Mylan Technologies (estradiol) Novartis (Vivelle-Dot 0.025 mg/24 h) Novartis (Vivelle-Dot 0.0375 mg/24 h) Novartis (Vivelle-Dot 0.075 mg/24 h) Novartis (Estraderm 0.05 mg/24 h) Novartis (Estraderm 0.1 mg/24 h) Watson Labs (Alora; all strengths) Fentanyl transdermal patch: Duragesic Alza (Duragesic) Multisource Glipizide: Glucotrol and Glucotrol XL tablets and extended-release tablets Pzer (Glucotrol) Multisource generics TE code Special consideration category and notes
Extended release AB2 AB2 AB2 AB2 AB3 AB3 AB3 AB3 AB3 AB4 AB4 AB4 AB4 BC [Not rated] No equivalents yet Transdermal, hormonal, extended release AB AB AB1 AB1 AB1 AB1 AB2 AB2 BX BX BX BX BX BX AB AB Transdermal, hormonal, extended release Extended release
Extended release
Extended release
Transdermal, hormonal, extended release Transdermal, hormonal, extended release
Transdermal All approved products AB rated All approved products in like dosage forms are AB rated
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Generic and brand names Dosage form and strengths (if TE varies) Applicant/manufacturer (grouped by TE code, listed alphabetically) Glyburide: Micronase Pharmacia and Upjohn (Micronase) Sano Aventis (DiaBeta) Multisource generics Levothyroxine sodium: Various brand names tablets, all strengths Abbott (Synthroid) Jones Pharma (Levoxyl) Mylan Stevens J (Unithroid) Abbott (Synthroid) Alara Pharm (Levo-T) Genpharm (levothyroxine sodium) Mylan Stevens J (Unithroid) Alara Pharm (Levo-T) Genpharm (levothyroxine sodium) Jones Pharma (Levoxyl) Mylan Stevens J (Unithroid) Lloyd (Levothroid) Mylan Genpharm (Novothyrox) Vintage (Levolet) Metformin: Glucophage XR extended-release tablets Bristol Myers Squibb (Glucophage XR) Actavis Elizabeth Andrx Labs (generic) Apotex Barr Cobalt Impax Labs Ivax Pharms Mutual Pharm Mylan Nostrum Ranbaxy Sandoz Sun Pharm Inds Teva Zydus Pharms USA Andrx Labs (Fortamet) Depomed (Glumetza) Special consideration category and notes All current generics rated AB, equivalent to Micronase brand No generic equivalents to DiaBeta brand Critical dose/NTI drug AB1 AB1 AB1 AB1 AB2 AB2 AB2 AB2 AB2 AB3 AB3 AB3 AB3 AB3 AB4 AB4 BX BX Critical dose/NTI
TE code AB BX AB
Critical dose/NTI
Critical dose/NTI Critical dose/NTI Extended release
AB AB AB AB AB AB AB AB AB AB AB AB AB AB AB AB BX BX
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Generic and brand names Dosage form and strengths (if TE varies) Applicant/manufacturer (grouped by TE code, listed alphabetically) Nifedipine: Adalat CC, Procardia XL oral; extended-release tablets Bayer Pharms (Adalat CC) Biovail Watson Labs (Afeditab CR) Pzer (Procardia XL) Biovail Martec USA Osmotica Pharm Pancreatic enzyme products, pancrelipase McNeil (Pancrease, Pancrease MT) Organon (Cotazym, Cotazym-S) Solvay (Creon) Various (all distinct products) Phenobarbital Multisource Theophylline extended-release capsules Inwood Labs UCB, Inc. (Theo-24) Theophylline extended-release tablets Inwood Labs (Theochron) Nostrum Pliva Purdue Frederick (Uniphyl) Monarch Pharms (Quibron-T/SR) Tizanidine: Zanaex capsules Acorda (Zanaex) Tizanidine: Zanaex tablets Acorda (Zanaex) Acatavis Elizabeth Actavis Totowa Alphapharm Barr Caraco Corepharma Dr. Reddys Labs Inc. Ivax Pharms Mylan Sandoz Teva Torpharm Special consideration category and notes Extended release AB1 AB1 AB1 AB2 AB2 AB2 AB2 [Not rated] Pre-DESI; high variability among products with profound clinical differences possible; none are bioequivalent; do not interchange products Pre-DESI; some older studies show bioequivalence among multisource products Extended release BC BC Extended release AB AB AB AB BC [Not rated] Extended release Different dosage forms are not interchangeable; reports of confusion concerning interchangeability of generic tablets for brand-name capsules All generic and brand-name tablets are AB rated; may not substitute for capsules
TE code
[Not rated]
AB AB AB AB AB AB AB AB AB AB AB AB AB
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Generic and brand names Dosage form and strengths (if TE varies) Applicant/manufacturer (grouped by TE code, listed alphabetically) Warfarin sodium: Coumadin oral tablets Barr Bristol-Myers Squibb (Coumadin) Genpharm Pliva Sandoz Taro USL Pharma Zydus Pharms USA Special consideration category and notes Critical dose/NTI AB AB AB AB AB AB AB AB
TE code
Abbreviations used: DESI = Drug Efcacy Study Implementation; NTI = narrow therapeutic index; TE = therapeutic equivalence. Source: Reference 14.
Appendix 2. Communicating with patients about product substitution issues

Talking points and outline Comments/suggested language Begin with an advocacy statement. Use the dialogue as an opportunity to reinforce the pharmacists role as a member of the health care team to help patients use medications appropriately. Explain to patient the importance of staying with one pharmacy. Use patient language. Be aware of the patients literacy, health literacy, and cultural inuences. Target language in the 4th8th grade range, avoid technical terms, and be sensitive to patients needs and concerns. Diffuse the patients frustration and demonstrate Diffuse the patients frustration and anxiety concerning the potential that you recognize nancial implications. cost differences and additional waiting time. Use empathy and reection. Sample phrasing: That amount is higher than you expected to pay, and this is a medication you/your physician believe is right for you. This medication has been working so well for you these past few months. It is frustrating when our choices are limited. Inform the patient of the reason for difference in co-pay and offer a few alternatives you will explore on his or her behalf. Sample phrasing: The pharmacy benets manager is enforcing the benet [your employer] created. Oftentimes formularies are used to reduce costs to keep premium increases and out-of-pocket expenses to a minimum. They encourage patients to use generics when available by offering a lower co-pay. There are a couple of generic alternatives that will reduce your co-pay to $X. Explain why additional research is necessary before substituting. If a formulary agent cannot be used, let the patient know what else can be done. [Offer to help facilitate medical necessity prior approval with the patients prescriber and payer as noted in box 18 of the decision support tool.] Continued on next page
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Appendix 2. Communicating with patients about product substitution issues (continued)

Talking points and outline Comments/suggested language Help the patient understand the clinical implications Patients need to understand how their condition may be inuenced by a of substituting (or not substituting). decision to substitute. This is particularly important for products that have bioequivalence problems and should not or cannot be substituted. Discuss benetsWhy substitute? For a patient reluctant to try generics when substitution is appropriate: Inform patient of the FDAs rigor in approving generic products to ensure that they are equal to the brand-name product. [Many patient education resources on safety, efcacy, and bioequivalence of generics are available on the FDA Ofce of Generic Drugs Web site www.fda.gov/ogd.] Mention co-pay difference. Discuss risksExplain why substituting is For a patient desiring generic substitution when the product cannot be not recommended. substituted: Use appropriate language to help the patient understand how the medication change could affect him or her clinically. Inform the patient that the same generic name does not always equate to therapeutically equivalent generic (or brand) alternatives; explain how this situation differs from typical substitution scenarios and why you are not recommending substitution. What other options are there? Outline other options available to the patient, including medical necessity prior authorization and getting a new prescription with careful monitoring. Involve the patient in nding a solution; outline logistics and what the patient may expect, including timing for each option. Explore prior authorization options. Explain medical necessity prior authorization. Briey outline logistics and what the patient may expect, including timing. Sample phrasing: It seems that substituting a generic might not be safe for you at this point. Lets see if we can get a medical necessity prior approval for you. Supply issues; different generics appearance. If relevant, explain supply issues to help patient understand why the appearance of the medication has changed, or why special monitoring may be required (if substituting with a product that may have bioequivalence differences). Patient counseling: Medication-specic parameters Educate the patient about medication-specic information, including and monitoring requirementsincluding additional alarm symptoms and any changes in monitoring parameters (e.g., labs (and associated costs) and what symptoms additional labs when changing from among brands of warfarin). might indicate problems.
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Appendix 3. Communicating with prescribers about product substitution issuesa

Talking points and outline Plan for efcient, organized, professional, patient-centered, and solution-oriented interdisciplinary interchange. Avoid unintentionally putting the prescriber on the defensive. Emphasize data as they relate directly to the patient. Explain upstream issues that may be driving the request. Suggested outline: Provide a brief introduction of yourself. Indicate you are calling on behalf of the patient. Provide a succinct description of the problem (including upstream issues) and how it impacts the patient. Make a recommendation to remedy the problem. Explain how this potential solution impacts the patient.
a
Comments/suggested language Create a communication plan with concrete recommendations. Call the ofce. Build rapport by being organized and emphasizing the patient, not the prescription or product. Flow of information: (1) Quickly introduce the substitution problem, (2) follow up immediately with your recommendation; (3) back up the recommendation with how it will impact the patient clinically, using data as necessary. Be prepared to fax a written recommendation to follow up the phone call. Format the fax communication with bullets, including necessary clinical background as outlined below. When presenting a problem with the prescribed medication, keep language in third person (e.g., A problem with the medication the patient was prescribed) instead of second person, which confronts the physician personally (e.g., A problem with the medication you prescribed). Instead of hearing about numbers, data, and statistics, physicians want to know how the patient will be affected. Help the physician understand the reason for the recommendation to change therapy. For example: Wholesaler product disruption scenario: Wholesalers may experience drug shortages from different manufacturers. Most physicians are unaware of issues related to the drug supply chain. If this situation applies, share it (briey) with the physician to put your request to change therapy into context; then formulate a plan for switching and any necessary monitoring. Patient nancial constraint scenario: A tiered co-pay system may be preventing a patient from affording the medication, thereby forcing him or her to make a decision to either forgo any treatment or switch to an alternative treatment. Sample phrasing: [Greeting and introduce yourself.] I am calling in regard to [patient name]. (Instead of: ...calling about a prescription you wrote for [patient name] .) There seems to be a problem [briey describe formulary conict/supply issue/ substitution problem] with the medication the patient was prescribed. I recommend we [succinct recommendation] . It will help [patient] by [add specics related to justify change and link your recommendation to its impact on the patient]. Offer to take verbal order and follow up with fax.
Many product substitutions occur without the need to communicate directly with prescribers. Situations do arise, however, when a call to the prescribing physicians ofce is necessary. Some examples include: substitution of AB-rated critical dose/narrow therapeutic index drugs; signicant nancial disincentives drive a substitution requiring authorization; or wholesaler supply shortages require substitution with another manufacturers producteven when substitution is not idealto avoid interruption in therapy for certain chronic conditions. In these and similar situations, the following approach for communication with prescribers is suggested. (Often, initial communication occurs with a nurse or other staff member who relays information to the prescriber; it is important to ensure that this middle person understands the reason for your recommendation.)
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Appendix 4. Patient-centered product substitution decision support tool for pharmacistsApplication examples
Thousands of times every day in the United States, generic and alternative brand-name products are safely and appropriately substituted for the prescribed medication. The following application examples are intended to illustrate how this decision support tool, as a complement to pharmacists professional judgment, may be applied to identify special situations that warrant the acquisition of additional patient and bioequivalence information to determine the potential impact of substitution on the patients clinical condition. The examples also raise nancial, legal, and supply-chain issues, as well as educational and communication considerations that are factored into substitution decisions.
Application example 1. Chronic hypertension and extended-release product options

C.H. is a 71-year-old man who presents with a prescription written for Cardizem CD 180 mg capsules, following his annual physical examination. During the initial discussion with the patient and review of his prole, the following information is revealed: C.H. was diagnosed with hypertension 18 months ago. After attempting therapy with various antihypertensives, his physician initiated Cardizem CD 3 months ago, and he is nally stable. He is relieved that his blood pressure is under control. Today, his physician wrote a prescription to continue taking the medication, with rells for 1 year. C.H. is glad he has a new pharmacy benet to pay for his medication. He is reluctant to consider substituting because he has tried many other medications and this one nally works. C.H.s new Medicare Part D prescription plan mandates substitution with generic products when available. No coverage is provided for brand-name products when a generic exists. Initiating the process. When the pharmacist begins to process the prescription, she sees that the patient has a new prescription drug card and suspects that generics may be mandated. During order entry for the brand name, the pharmacist receives the following rejection message: Not covered; generic substitution required. Referring to the Product Substitution Decision Support Tool, the pharmacist scans the algorithm and sees that she has most of the information (from the initial intake of the prescription by the technician and the patients prole) sought in box 2 to proceed. Specically, she sees that the physician signed on the may substitute product selection line, and substitution is legal in her state. The technician had written, however, that the patient said he wanted the brand-name product. From the prole, she determines that this is a product the patient has been taking for the past few months, after rst trying three other antihypertensives during the preceding year. Scanning for special considerations. Proceeding past box 3 (the prescription is not for a critical dose drug), the pharmacist stops at box 4 noting that this is an extended-release product and follows the Yes arrow to box 10: Ascertaining therapeutic equivalence. To nd the therapeutic equivalence rating, the pharmacist consults the Electronic Orange Book at www.fda.gov/cder/ob and nds that Cardizem CD is rated AB3, therefore only AB3-rated generics are equivalent to the prescribed product. Note: If the pharmacist did not have Internet access in the pharmacy, she could nd this information in Table 1 of this article; diltiazem products are among the listings of therapeutic equivalence codes for commonly prescribed prescription medications. On the pharmacy shelf, she nds the following diltiazem extended-release products: n Cardizem CD, a Biovail brand n Cardizem LA, a Biovail brand n Diltiazem hydrochloride, a Mylan generic n Tiazac, a Biovail generic diltiazem hydrochloride n Cartia XT, an Andrx generic diltiazem hydrochloride Reaching a decision. According to the Orange Book, Cartia XT has a TE code of AB3; by following the Yes arrow, the pharmacist conrms that substitution is appropriate from a bioequivalence/clinical stance. There are no allergies to consider, but she must talk with the patient because he indicated a desire to continue using the brand-name product. Communicating with the patient. The pharmacist must be prepared to offer choices with pricing (self-pay vs generic co-pay) and to educate the patient about therapeutic equivalence with generic products. Appendix 2 lists tips for communicating with patients about product substitution issues. A sample dialogue is outlined below:
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The pharmacist invites the patient to the counseling area and begins, Hi, Mr. H., Im [name], the pharmacist, and its nice seeing you again. I have a question about your Cardizem prescription. It seems this product has worked well for you. C.H.: It has. Im so glad we nally found something that works. Its been a long road getting here. Is there a problem with my prescription? Pharmacist: Well, this particular brand is not covered by your new insurance. I understand that you would prefer staying with Cardizem, but I want to let you know there is a generic available that has been shown to be equal to Cardizem. Your insurance covers this product, so your cost would be the $10 co-pay. C.H.: [Visibly angry.] Those blasted insurance companies! I know the generic wont be as good. Do they want me to end up in the hospital?! Pharmacist: It is frustrating to have our choices limited. [Pause.] Did you know that generics go through an FDA approval process? To get a rating to be equal to a brand-name product, the generic company has to prove that their medicine is just as strong and works the same way. [Pause.] C.H.: [Says nothing, but is listening and seems less angry.] Pharmacist: While some other generic brands might work differently, I have conrmed that this is one has proven it is equal to Cardizem CD. I could still dispense the Cardizem; your cost would be $67. C.H.: Thats a lot more than my co-pay; I cant afford that every month. How do you know this generic is any good? Pharmacist: The FDA publishes a list of drugs that shows which ones are equal, and the company that makes this generic proved to the FDA that it will work the same as the brand name. [Pause.] Which product would you like me to dispense for you? C.H.: I guess Ill try the generic if its supposed to be equal. It had better be. Pharmacist: Okay. Please rest assured that if it werent expected to be safe to substitute, I wouldnt recommend it. If youd like to check your blood pressure periodically, just stop in and well check it. Discussion. None of the other diltiazem products on the pharmacy shelves would be equivalent, because they are rated AB2 (Mylan) and AB4 (Biovails Tiazac). Although Biovail manufactures both Tiazac and Cardizem, their extended-release mechanisms vary and the products are not therapeutically equivalent. Andrx markets three different diltiazem products, each with different TE codes. Cardizem CD and Cardizem LA also are not equivalent to each other. Because of the variability of coding among products, the pharmacist also may choose to document with the prescriber that the patient is taking Cartia XT and complete the continuity of care loop.
Application example 2. Thyroid replacement and critical dose/narrow therapeutic index drug selection
A.J. is an otherwise healthy 42-year-old woman who calls in a rell request for her levothyroxine 0.025 mg tablets. Shes been taking Levoxyl (Jones Pharma) for the past 6 months. The pharmacist attempts to dispense the medication only to discover that there is none on the pharmacy shelf. When he goes to pull the supply from the order that just arrived from the wholesaler, he sees that Levoxyl is on backorder and that Levothroid (Lloyd) was substituted by the wholesaler in fullling their stock order. The pharmacist knows that substitution of levothyroxine products may cause problems, so he consults the Product Substitution Decision Support Tool. Box 2 says: He already has the initial patient information needed to proceed, scans the algorithm, and stops right away at box 3levothyroxine is a critical dose drug, also referred to as a narrow therapeutic index (NTI) product. Following the Yes arrow to box 8: The pharmacist consults the Electronic Orange Book at www.fda.gov/cder/ob and discovers that Levoxyl is AB1 and AB3, and Levothroid is AB4; therefore, they are not rated equivalent to each other. Both products are required to share at least one common three-character code to be equivalent. Following the No arrow to box 9 (because the products are not equivalent), the recommended action is not to substitute. By following the Yes arrow to box 14, the pharmacist sees that if he nds another therapeutically equivalent alternative, he could at least work with the patient and prescriber to devise a plan to temporarily substitute the product and monitor the patient. He conrms with the wholesaler that their supply of Levoxyl is still depleted. He conrms with the patient that she is completely out of Levoxyl; she took her last one this morning. In the pharmacy, Synthroid brand is the only other levothyroxine product on the shelves in the 0.025 mg tablets; according to the Orange Book, it is designated AB1 and AB2. With this information (i.e., both products share the AB1 code), he decides to pursue substitution with Synthroid and contacts the physician to determine a plan for product substitution and monitoring. Note: In some states, the law would require that the pharmacist contact the physician when substituting an NTI drug; other states permit substitution as part of the pharmacists professional judgment.
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The pharmacist refers to the companion text for the decision algorithm. It indicates that when a critical dose drug must be substituted with another therapeutically equivalent product, the pharmacist, physician, and caregivers (if applicable) should collaborate to ensure appropriate monitoring occurs and records are noted. From a clinical standpoint, the pharmacist would contact the physician even if his state did not require it. Physician communication. The pharmacist calls the physicians ofce and asks for authorization to substitute Synthroid for Levoxyl. The physician calls back and the following dialogue takes place: MD: Dont you know that levothyroxine products cannot be interchanged? These are narrow therapeutic index drugs and theyre also older drugs that didnt have bioequivalence data reviewed by the FDA. Pharmacist: Hi, Dr. X. I do understand and your concern is well founded. Let me explain why Im asking. [Pause.] Mrs. A.J. called this morning because she has completely run out of Levoxyl. Our wholesaler is also out of supply and cannot predict when they will be able to send more. Unfortunately, the generic they sent is not therapeutically equivalent to Levoxyl and therefore it isnt an option for us. MD: Thats outrageous. Pharmacist: Since we cannot use the other product and going without treatment for a couple of days could be dangerous for Mrs. A.J., heres what I recommend. Synthroid and Levoxyl are bioequivalent by FDA standards with an AB1 rating in the Orange Book. According to available guidelines, these have the greatest likelihood of producing the same effect, but because they are NTI drugs, Mrs. A.J. could experience some variability in response. This is why I wanted to talk with you to be sure you were aware of the issues and to come up with a plan to help Mrs. A.J. substitute products and monitor for signs and symptoms of any problems. MD: Okay, lets go with the Synthroid for this month. Please have Mrs. A.J. call our ofce to talk with the nurse about special monitoring. Pharmacist: Thank you. Ill mention that she should be aware of any changes in heart rate, gastrointestinal symptoms, or chest pain, and I will tell her to call your nurse for additional instructions for monitoring and follow-up. By the way, the FDA is requiring all levothyroxine manufacturers to submit NDAs with bioequivalence data by 2008 to continue marketing their products. Soon well have more information about these products. Patient communication. When A.J. comes to pick up her rell, the technician sees a note on the bag that a consultation with the pharmacist is required. The pharmacist explains to A.J. that the wholesaler was out of stock, and that a different product has been dispensed. He explains that although the products are equal by FDA standards for all drugs, this type of drug is one where slight changes could change the response. The pharmacist tells her that he spoke with Dr. X, and he is aware of the change. The doctor has requested that she call his nurse to discuss special monitoring and follow-up instructions. The pharmacist tells her to take the Synthroid as she did the Levoxyl for this month. She should be alert to changes in how she feels, including gastrointestinal symptoms (pain, diarrhea, vomiting), heart rate (beating too fast), or chest pain. Any changes should be reported immediately to her physician. If she has questions or concerns, she should call anytime. Discussion. With critical dose drugs, like levothyroxine, digoxin, warfarin, and cyclosporine, it is ideal to stay with a singlesource product on a chronic basis. Sometimes, however, situations dictate the need to nd an alternative (e.g., supply issues from manufacturers or wholesalers, travel to different areas where different generic products may be more common). Levothyroxine ratings are complicated, ranging from A1 through A4 and BX, and many products have multiple codes. As noted, only products with equivalent ratings should be substitutedand then only under careful monitoring with collaboration among health professionals and the patient. Note that the pharmacist made two calls to conrm information before deciding to pursue a switch. The rst was to the patient; she may have had additional tablets remaining from her previous prescription to last through the Levoxyl shortage, making the substitution and additional efforts unnecessary. The call to the wholesaler conrmed that a different product would be required; if the wholesaler had just received a shipment, it may have been possible to wait until the next morning to rell A.J.s prescription because she had already taken her dose for the current day. Another option for dealing with supply shortages would have been to help A.J. nd another pharmacy with Levoxyl in stock. At press time, Mylans generic levothyroxine is the only product rated AB1, AB2, AB3, and AB4, making it equivalent to most available products, except those rated BX (i.e., Levolet manufactured by Vintage and Novothyrox manufactured by Genpharm). There is a difference when dispensing a critical dose drug that is a new prescription compared with a rell of a chronic medication. In the latter scenario, control has likely been established and any change may alter the control. Note: The above information from the Electronic Orange Book also may be found in the levothyroxine table in the decision support tool and in Appendix 1 of this article, which lists therapeutic equivalence codes for commonly prescribed medications.
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SPECIaL FEaTURE

Prescription drug product substitution decision support

Jour nal of the A mer ican Phar macists A ssociation

PRODUCT SUBSTITUTION DECISION SUPPORT

Product Substitution Advisory Board

Jour nal of the A mer ican Phar macists A ssociation

PRODUCT SUBSTITUTION DECISION SUPPORT

Sources of therapeutic equivalence information

A new tool for the medication use toolbox

PRODUCT SUBSTITUTION DECISION SUPPORT

PRODUCT SUBSTITUTION DECISION SUPPORT

Jour nal of the A mer ican Phar macists A ssociation

PRODUCT SUBSTITUTION DECISION SUPPORT

Therapeutic equivalence ratings of multisource levothyroxine products3

Jour nal of the A mer ican Phar macists A ssociation

PRODUCT SUBSTITUTION DECISION SUPPORT

PRODUCT SUBSTITUTION DECISION SUPPORT

Jour nal of the A mer ican Phar macists A ssociation

PRODUCT SUBSTITUTION DECISION SUPPORT

Other sources of bioequivalence information

Challenges and upstream problems inuencing product substitution

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PRODUCT SUBSTITUTION DECISION SUPPORT

ConclusionMaking sound product substitution decisions

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Appendix 1. Therapeutic equivalence codes of select commonly prescribed medications14

Special consideration category and notes Extended release

Continued on next page

PRODUCT SUBSTITUTION DECISION SUPPORT

Appendix 1. Therapeutic equivalence codes of select commonly prescribed medications14 (continued)

Transdermal, hormonal, extended release Transdermal, hormonal, extended release

AB AB Continued on page 340

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Appendix 1. Therapeutic equivalence codes of select commonly prescribed medications14 (continued)

Critical dose/NTI Critical dose/NTI Extended release

Continued on next page

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Appendix 1. Therapeutic equivalence codes of select commonly prescribed medications14 (continued)

Continued on page 342

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Appendix 1. Therapeutic equivalence codes of select commonly prescribed medications14 (continued)

Appendix 2. Communicating with patients about product substitution issues

PRODUCT SUBSTITUTION DECISION SUPPORT

Appendix 2. Communicating with patients about product substitution issues (continued)

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Appendix 3. Communicating with prescribers about product substitution issuesa

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PRODUCT SUBSTITUTION DECISION SUPPORT

Application example 1. Chronic hypertension and extended-release product options

PRODUCT SUBSTITUTION DECISION SUPPORT

PRODUCT SUBSTITUTION DECISION SUPPORT

Jour nal of the A mer ican Phar macists A ssociation

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