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Abstract

SPECIAL FEATURE

J o u r n a l o f t h e A m e r i c a n P h a r m a c i s t s A s s o c i a t i o n w w w. jap ha .o rg 328 47: 3

Received January 29, 2007. Accepted forpublication January 31, 2007.

Patti Gasdek Manolakis, PharmD, is Presi-dent of PMM Consulting, Charlotte, N.C.

Correspondence: Patti Gasdek Manolakis,PharmD, 16726 Hammock Creek Place,Charlotte, NC 28273. E-mail: pmanolakis@

gmail.comDisclosure: Dr. Manolakis is under contractwith the American Pharmacists Associa-tion to develop educational programmingand publications and received payment forpreparing this article. The author declaresno other potential conicts of interest or -nancial interests in any product or servicementioned in this article, including grants,employment, gifts, stock holdings, or hon-oraria.

Funding support: An educational grantfrom Ortho-McNeil Pharmaceutical, Inc.

Objective: To generate patient-centered, evidence-based decision support toolsand compile resources that will assist pharmacists in prescription drug product sub-stitution activities and related communication, and to present the resulting tools andresources.

Data Sources: Food and Drug Administration (FDA) publications, data, and com-munication; peer-reviewed literature; interviews with pharmacists; structured discus-sions with members of the project Advisory Board; and authors own knowledge andrecords of events.

Summary: A decision whether to substitute an alternative product for a prescribedmedication is a clinically based process that must be grounded in appropriate medicalevidence, therapeutic equivalence information, nancial factors, and consideration ofhow the substitution will impact the patient. Product substitution decisions are inu-enced by therapeutic issues, legal matters, patient-centered concerns, and pharmacypractice factors, including work ow, supply issues, access to current resources,

and misperceptions about database information. While generic substitution is clearlydened in many cases, some medication categories require special consideration,i.e., critical dose and narrow therapeutic index drugs, products with special releasemechanisms, bioengineered protein products, many hormonal products, older drugsmarketed before 1938 that were not subject to FDA approval, and others with limitedbioequivalence data.

In response to reports of the challenges pharmacists face when determining theappropriateness of product substitution and in support of their interdisciplinary effortsto improve medication use, the American Pharmacists Association (APhA) convenedan advisory board to create the decision support tool featured in this article.

Conclusion: The U.S. health care system and patients rely on pharmacists asmedication use experts to ensure that prescription drug product substitutions areappropriate. Pharmacists must be able to efciently determine therapeutic equiva-lence, identify situations where further research is required, have access to timelyresources for gathering information, and effectively communicate with patients andphysicians about substitution issues. The prescription drug product substitution tooland related resources presented are intended to assist pharmacists in making andcommunicating clinically sound product substitution decisions that are patient cen-tered, evidence based, consistent with state and federal laws and regulations, andreective of the realities of health care today.

Keywords: Bioequivalence, substitution (generic), substitution (therapeutic), Foodand Drug Administration, co-payments, managed care, technology, narrow therapeuticindex drugs, communication, patients, physicians, prescribers.

J Am Pharm Assoc. 2007;47:328347.doi: 10.1331/JAPhA.2007.07502

Prescription drug productsubstitution decision supportPatti Gasdek Manolakis

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PRODUCT SUBSTITUTION DECISION SUPPORT SPECIAL FEATURE

J o u r n a l o f t h e A m e r i c a n P h a r m a c i s t s A s s o c i a t i o n w w w.phar mac ist .c om 47:3 JAPhA 329

P harmacists face product substitution questions withpatients, other health care professionals, and third-partypayers on a daily basis. Often, substituting brand-nameprescription drugs with equivalent generic products decreasescosts to patients, employers, health plans, and the health care

system through reduced prescription drug costs and lower co-payments. As such, many third-party payers, state Medicaidprograms, and Medicare Part D plans require the use of genericproducts when available and promote adherence to formularies.Increasingly, patients are incentivized to comply through tieredco-payment systems and strict coverage guidelines that prohibitpayment for brand-name products when generics are available.

Fifty-six percent of all prescriptions are lled with genericmedications. 1 The question of substitution often arises whena rejection message is received from a third-party payer in

the course of dispensing prescription medications, or when apatient requests a generic alternative. Some states have plansthat mandate generic products. In many cases, equivalentgeneric products are available and substituted routinely in thecourse of caring for patients. Many pharmacy operating systems

are programmed to automatically substitute generic or alter-native preferred products when the brand-name or alternativeproduct is entered.

A decision whether to substitute is a clinically based pro-cess that is grounded in appropriate research, clinical informa-tion, nancial factors, and consideration of how the substitu-tion will impact the patient. However, substitution decisionsare not always clear-cut. Computer programsno matterhow well designedserve as an efcient means to processand store information and supplement professional judgmentonly, but they cannot generate clinical decisions. Pharmacistsmust be able to efciently identify situations where furtherresearch is required; pharmacy technicians, including studentpharmacists, who are entering orders into computer systemsmust learn when to question the appropriateness of substitu-tionparticularly when automatic substitution systems are inplace. Furthermore, pharmacists must clearly understand thesource of drug equivalency information entered into their drugand wholesaler databases to avoid basing decisions on inac-curate assumptions. Examples of products requiring specialconsideration and research include critical dose and narrowtherapeutic index drugs, products with special release mecha-nisms (e.g., extended release, delayed release), bioengineered

protein products including insulin, older drugs marketed before1938 which are not FDA approved drugs, and others with lim-ited bioequivalence data; these products and related issues arediscussed in detail in the following pages.

Issues inuencing product substitution decisions fall intofour broad, interrelated categories: therapeutic concerns,legal matters, pharmacy practice factors, and patient-centeredissues.n Therapeutic concerns relate to bioequivalence data, drug

delivery, onset of action, and patients clinical condition andresponse.

n Legal matters are driven by state and federal pharmacy lawsand regulations.

n Pharmacy practice factors encompass formularies, real-timeelectronic communication from third-party payers, computermanagement systems, drug databases, and both work-owand workload pressures that compress the time available forpharmacists to investigate product substitution issues in thecourse of delivering patient care. Related problems includemisperceptions about information in databases and operatingsystems and limited access to information available via theInternet (e.g., the Electronic Orange Book [EOB] searchabledatabase, PubMed).

n Patient-centered issues range from patients expectations ofthe medication and its effects to nancial pressures and frus-

Product Substitution Advisory Board APhA and the author acknowledge the signicant

contributions of the following individuals who served asmembers of the Advisory Board that guided the develop-ment of this decision support tool and related resourcesincluded in this report.n Ross Brickley, BPharm, MBA, CGPNeil Medical Groupn Jay Campbell IV, BPharm, JDNorth Carolina Board of Pharmacy n Lynn E. Connelly, BPharm

Medicine Mart Pharmacy n Winnie A. Landis, BPharm

Albertsons/Osco Drugn Elliott M. Sogol, PhD, BPharm, FAPhATarget Pharmacy n Julie Suko, PharmDFirst DataBank, Inc.n Hal Wand, BPharm, MBA

Arizona State Board of Pharmacy APhA and the author recognize the following indi-

viduals for contributing to project research, eld test-ing, and/or serving as reviewers of the decision supporttool.n Michael Hardin, PharmDChase Drugsn Scott Leslie, BPharmWalgreens Pharmacy n Elliott M. Sogol, PhD, BPharm, FAPhATarget Pharmacy n Sheila Hunter, DPhCity Drug Company n Timothy Tucker, PharmDCity Drug Company

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J o u r n a l o f t h e A m e r i c a n P h a r m a c i s t s A s s o c i a t i o n w w w. ja pha .o rg 330 JAPhA 47:3

SPECIAL FEATURE PRODUCT SUBSTITUTION DECISION SUPPORT

trations in dealing with changing formularies, cost contain-ment strategies, and changes in drug appearance from onerell to the next. As more patients are becoming empoweredpartners in their health care, they also may initiate requestsfor product substitutions based on factors such as cost,

advertising, and research into what they believe will yield apositive clinical response.

The U.S. health care system relies on pharmacists as medica-tion use experts; this responsibility includes ensuring that prod-uct substitutions are appropriate. In support of pharmacistsinterdisciplinary efforts to improve medication use and advancepatient care, and in response to reports of the many challengespharmacists face when determining the appropriateness of prod-uct substitution, the American Pharmacists Association (APhA)spearheaded an initiative to dene and address key substitutionissues. During the fall of 2006, APhA convened a Product Sub-stitution Decision Support Advisory Board to create the decisionsupport tool featured in this article. The tool is intended to assistpharmacists in making clinically sound product substitution deci-sions that are patient centered, evidence based, consistent withstate laws, and reective of the realities of health care today.

A new tool for the medication use toolboxThe Patient-Centered Product Substitution Decision Sup-

port Tool for Pharmacists (Figure 1) is composed of two parts:(1) a decision algorithm, which guides the pharmacist through aseries of considerations and questions that should be addressed,and (2) companion text, which explains the issues inuencing

product substitution in greater detail, including recommendedactions, a glossary, reference citations, and other sources ofinformation. Additional tools and resources, including a prod-uct substitution table (Appendix 1), talking points for commu-nicating with patients and prescribers (Appendices 2 and 3),and patient application examples (Appendix 4), are included inthis report. Ultimately, pharmacists must determine the appro-priateness of product substitution in consideration of patientsneeds (clinical and nancial), condition, characteristics, andcircumstances. Pharmacists should understand the relevantupstream factors that inuence substitution and be able toskillfully communicate with patients, prescribers, and payersabout important issues. The key to making sound substitutiondecisions in a busy pharmacy practice setting is being vigilantknowing when to pause and gather additional information.

Decision support toolDevelopment process After preliminary research of substitution issues, pharma-

cist survey data, and the literature, an issues document wasgenerated that outlined key factors inuencing prescriptiondrug product substitution decisions. The Advisory Board (seesidebar on page E3) was convened by teleconference to discussand expand on the dened issues. Following the teleconference,

the author drafted a decision algorithm and companion text sug-gesting a process for making product substitution decisions.

A live meeting of the Advisory Board was conducted onOctober 26, 2006, in Washington, D.C., during which the draftdecision support tool and related issues were further discussed.

A revised draft was generated and reviewed by the AdvisoryBoard. The resulting draft was reviewed and informally eld-

tested by pharmacists in chain and independent communitypharmacy settings. The tool was further rened and subse-quently reviewed by the Advisory Board, along with the tableof the select commonly prescribed medications, talking points,and the application examples.

Sources of therapeutic equivalenceinformation

The primary source of therapeutic equivalence informationamong brand-name drug products, generics, and products con-taining the same active ingredient manufactured by differentcompanies is the Orange Book, formally titled Approved DrugProducts With Therapeutic Equivalence Evaluations, publishedby the Food and Drug Administration (FDA). The Orange Bookis widely accepted as the authoritative source for therapeuticequivalence information based on data submitted to the FDAby manufacturers as part of the drug approval process. Infor-mation from the Orange Book is repackaged into other printand software publications, including the USP DI Volume III:

Approved Drug Products and Legal Requirements from Thom-son Micromedex, Facts and Comparisons Approved Bioequiva- lency Codes , and Thomson PDRs Red Book . Other sources ofproduct substitution information include pharmacy operating

systems, pharmacy databases, wholesaler databases and Websites, manufacturers, the medical and pharmacy literature, andrelated databases (e.g., PubMed). The challenge is to help phar-macists evaluate and assimilate the information to determine

when substitution is appropriate and safe, when it is not, andhow to communicate that information to the patient, health careprovider, and third-party payer.

The Orange BookThe Orange Book is intended to provide public information

and advice to health professionals and state health agencies inorder to promote public education in drug product selection andto foster containment of health care costs. Originally publishedas a printed publication with monthly supplements (bearing anorange coverhence the popular name), the Orange Book isnow in its 27th edition and is available online (the EOB) throughthe FDA Center for Drug Evaluation and Research at www.fda.gov/cder/orange. The EOB is fully searchable, and the querydatabase is updated daily with new product approvals, mak-ing this the most up-to-date therapeutic equivalence resourceavailable. Changes are summarized monthly in a cumulativesupplement, also available on the Web site. Full access to thissite 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 lim-

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ited, the annual edition and monthly cumulative supplementscan be downloaded for reference purposes.

The EOB home page (www.fda.gov/cder/ob) is self-explana-tory 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 cumula-

tive supplement.n Links to search for specic products online.

Pharmacists may search for therapeutic equivalence codesin multiple ways, including entering the active ingredient, pro-prietary name, or other information related to the applicantholder and patents. By entering a drug name, the user is directedto the EOB list with the product and its therapeutic equivalencecode; if the active ingredient query is used, the reference drugand other multisource products codes are also listed.

Orange Book denitions and therapeutic equivalenceinformation. 8 The Orange Book denes a series of termsregarding pharmaceutical and therapeutic equivalents andexplains the therapeutic equivalence coding system in detail:n Pharmaceutical equivalents refer to products with the same

active ingredient, in the same dosage form, with identicalstrength or concentration and route of administration. Dif-ferences may exist with respect to shape, color, etc.

n Therapeutic equivalents are drug products that are (1) phar-maceutically equivalent and (2) can be expected to have thesame clinical effect and safety prole when administered topatients as specied in the labeling.

For the FDA to classify drugs as therapeutically equivalent,the products must be bioequivalent, safe, and effective; have thesame active drug ingredient(s) in the same dosage form and

with the same route of administration; meet dened standardsof strength, quality, purity, and identity; and be manufactured incompliance with current good manufacturing practice regula-tions. The nature of bioequivalence is explored in detail in the EOBintroduction. The FDA considers that drug products classied astherapeutically equivalent may be substituted for one another

with the full expectation that the alternative product will pro-duce the same clinical effect and safety prole as the prescribedproduct. Conversely, products classied as not therapeuticallyequivalent should not be expected to produce the same effects. Itshould be noted that Orange Book therapeutic equivalence evalu-ations encompass a comparison only of products with the sameactive ingredient(s) within a therapeutic category.

Brand-name products are usually identied as the referencelisted drug product within a category, with which multisourcedrugs are compared. Some categories have more than one ref-erence drug (e.g., when different release mechanisms producedifferent clinical effects). In the case of extended-release nife-dipine, Bayers Adalat CC and Pzers Procardia XL are eachreference drugs, but they are not considered therapeutically

equivalent.Therapeutic equivalence ratingsA codes. Therapeutic

equivalence codes are designated by a short series of lettersand in some cases numbers (e.g., AA, AB, AN, AB2, BX). A-codes designate therapeutic equivalence. AA refers to productsin conventional dosage forms without potential bioequivalenceproblems, and AB refers to products for which actual or poten-

tial bioequivalence problems have been resolved with adequateevidence. 8 In other A codes, the second letter in the code cor-responds to the dosage form; thus, therapeutic equivalence fornonconventional dosage forms is designated as A_ (e.g., ANfor solutions and powders for inhalation, AT for topical prod-ucts). Occasionally, when there is more than one referencelisted drug, a third component (a number) is added to the code.When this third component is designated, only products with thecorresponding letters and numbers are interchangeable. 8 In thepreviously mentioned example of extended-release nifedipine,

Adalat CC and Procardia XL each have therapeutically equiva-lent alternatives, coded AB1 and AB2, respectively.

Therapeutic equivalence ratingsB codes. B codes areassigned to drug products that the FDA currently considersnot to be therapeutically equivalent to other pharmaceuticallyequivalent products, namely, those for which actual or potentialbioequivalence problems have not been resolved. 8 These prod-ucts should not be substituted without careful consideration.The second letter in the code indicates the dosage form or otherreason behind the bioequivalence problem (i.e., BC for extended-release products, BP for potential bioequivalence problems, BXfor insufcient data, and BD for documented bioequivalenceproblems). Different products with extended-release dosage

forms containing the same active ingredient in equal strengthsoften are not considered by the FDA to be therapeutically equiv-alent; the same is true for delayed-release products and otherdosage forms (e.g., transdermal, otic) for which equivalence hasnot been demonstrated. The B* rating signies that the FDAhas received new information that raises a signicant ques-tion about therapeutic equivalence, requiring investigation andreview. B-coded products may become AB-coded products ifadequate 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 amongpharmaceutical equivalents are either: (1) generic productsapproved prior to the passage of the Drug Price Competitionand Patent Term Restoration Act of 1984 (Waxman-Hatch

Act) or (2) products approved through new drug applications(NDAs), not abbreviated new drug applications (ANDAs) (DonHare, FDA Ofce of Generic Drugs, oral communication, Janu-ary 2007). Prior to 1984, submission of bioequivalence datacould be deferred; the Waxman-Hatch Act requires ANDAapplicants to submit data demonstrating bioequivalence to theinnovator product prior to approval. Thus, under the currentsystem, ANDAs with insufcient bioequivalence data would not

be approved. Continued on page 336

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Product substitution decision supporttool companion textBox 1Product substitution inquiry

Pharmacist is faced with a decision to determine the appropri-ateness of a potential substitution. This inquiry is often triggered

by third-party rejection messages, patient request for lower costtherapy, or legal mandates requiring generic substitution.

Box 2Information gatheringGather necessary information from the patient to factor into

product substitution decision:n Is this a prescription for new therapy or continuation of on-

going 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 fac-

tors 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 bioengineeredproducts (includes boxes 3, 8, 9, and 14)

Critical dose and narrow therapeutic index drugs. Criticaldose 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 signicanttherapeutic differencesincluding efcacy and/or toxicityevenamong equivalent products; caution should be exercised with sub-stitution of any of these products.

Therapeutic equivalence (TE) information located in the Foodand Drug Administrations (FDA) Approved Drug Products WithTherapeutic Equivalence Evaluations (the Orange Book), available

Figure 1. Patient-centered product substitution decision support tool for pharmacists

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at www.fda.gov/cder/orange, provides important guidance to healthprofessionals related to this category of drugs. If a product is A-codedand substitution is required, all parties (i.e., prescriber, patient, casemanager, and caregivers) should be notied in advance. A plan formonitoring patient response and follow-up should be dened and

implemented; the patient should be monitored as necessary basedon clinical response. Products that are not rated therapeuticallyequivalent should not be substituted. 2

Examples: Lithium, cyclosporine, warfarin, phenytoin, levothy-roxine, carbamazepine, digoxin, quinidine, theophylline.

Levothyroxine products. The Orange Book provides a separatesection in the introduction detailing which products are bioequiva-lent, because the TE coding of these products is complicated (e.g,

AB1, AB2, AB3, AB4, BX) and bioequivalence data for these productshave become available through new drug applications (NDAs) andabbreviated new drug applications (ANDAs) in recent years. In gen-eral, only AB products with corresponding numbers are equivalent(i.e., a product with an AB1 code is equivalent to other AB1-ratedproducts, but not to AB3-rated products.) Some levothyroxine prod-

ucts have multiple three-letter codes indicating they have demon-strated bioequivalence to more than one reference listed drug (e.g.,Levo-T is rated AB2 and AB3, therefore it would be considered thera-peutically equivalent to any of the other products rated AB2 or AB3,but not to products rated AB4). To be considered therapeuticallyequivalent, two products must share at least one common TE code.

Although some overlap among categories exists, there is no transi-tive property of bioequivalence that transfers bioequivalence acrosscategories without the actual designation. For example, referring tothe list of TE ratings of multisource levothyroxine products, note thatboth Mylans generic levothyroxine and Abbotts Synthroid brandof levothyroxine have AB1 ratings and are considered equivalent. 3 Synthroid is not equivalent to Levothroid (Lloyds AB4-rated prod-uct), even though Mylans levothyroxine product is equivalent; thiscould be a result of the additive bioavailability dif ferences extendingbeyond acceptable limits between the rst and third products. Whilean Electronic Orange Book search would reveal the list of TE codesfor each manufacturers product, sorted by manufacturer, the FDAprovides a reference table, sorted by TE code to aid in interpretingtherapeutic equivalence among products.

Biotechnology products. Bioengineered, large protein prod-ucts, also referred to as therapeutic biological proteins, have thepotential to generate wide variability in response; therefore switch-ing among products may result in serious consequences for patients(e.g., severe immunological response). 4,5 This variability stemsfrom the complex structure of these products, which are usually notas fully characterized as chemically synthesized, small molecular

weight drugs. As such, the FDA considers each product distinct andnot interchangeable. 5 In fact, manufacturers that adjust manufactur-ing processes for a product must demonstrate equivalence to theiroriginal product. 4,6

In recent years, oversight of many of these products has movedfrom the FDA Center for Biologics Evaluation and Research to theFDA Center for Drug Evaluation and Research; as a result of thischange, some of these products are included in the Orange Book.

While some researchers 7 have explored the outcomes of mid-therapy interchange among different manufacturers products, theFDAs strong position on this issuebacked by the potential for seri-ous patient consequencesobliges health professionals not to sub-stitute biological proteins without compelling data supporting theirtherapeutic equivalence and without very close monitoring. 5

Examples: Recombinant human insulin, recombinant somatro-pin, urokinase, alteplase, lgrastim, iniximab.

Therapeutic equivalence ratings of multisourcelevothyroxine products 3 Orange BookBrand name Applicant TE codeUnithroid Stevens J AB1Levothyroxine sodium Mylan AB1Levoxyl Jones Pharma AB1Synthroid Abbott AB1Synthroid Abbott AB2Levothyroxine sodium Mylan AB2Levo-T Alara Pharm AB2Unithroid Stevens J AB2Levothyroxine sodium Genpharm AB2Levoxyl Jones Pharma AB3Levo-T Alara Pharm AB3Unithroid Stevens J AB3Levothyroxine sodium Mylan AB3Levothyroxine sodium Genpharm AB3Levothroid Lloyd AB4Levothyroxine sodium Mylan AB4Novothyrox Genpharm BXLevolet Vintage BX

Box 4 branchControlled-release, delayed-release,extended-release, topical absorption, or hormonalproducts (includes boxes 4, 10, 11, and 1518)

Various manufacturers employ different approaches to achievedelayed, extended, or sustained release. Accordingly, the rate andextent of absorption of productseven with the same active ingredi-ent in the same dosemay vary signicantly. With these bioavail-

ability differences, substitution would be expected to generate adifferent response. The FDA rates these products as not therapeuti-cally 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, thensubstitution is appropriate. Review the patient prole for allergiesto excipients (e.g., red dye). Educate the patient, and communicateas necessary with the prescriber.

For products designated with a B code, substitution is not rec-ommended. If a strongly compelling patient or supply issue exists,review the bioequivalence information and conduct a risk/benetanalysis. Clinical practice situations that might compel pharma-cists to consider substituting include when the wholesalers supplyis depleted as a result of a manufacturers product being temporarilyunavailable or when refusal to substitute would create a nancialhardship for the patient (e.g., $120 co-pay or no coverage for high-cost prescription drug vs $0$10 co-pay). In the latter situation,patients sometimes choose no treatment over a treatment they can-not afford.

When deciding whether substitution is appropriate, pharmacistsshould evaluate the clinical signicance of the potential variability.For example, if the patient has been maintained and stabilized on aparticular product, then the clinical pitfalls of substitution may bemore pronouncedas in uctuations in blood pressure levels (e.g.,for antihypertensive agent) or pain control (e.g., for chronic painmanagement)compared with initiation of new therapy. In suchsituations, substitution may compromise control of the patients con-dition or result in actual harm to the patient. In any case, weighingthe potential risks against the potential benets will help achievethe best outcome for the patient. Communicating with the prescriberand the patient is important; they need to understand substitution

options and consequences, compelling issues, what to expect, andrecommended monitoring parameters if substitution is made.

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Examples: Diltiazem, nifedipine, testosterone gel, estrogenpatches, hydrouoroalkane (HFA)-propellant albuterol products,extended-release theophylline capsules and some tablets.

Controlled-release, delayed-release, and extended-releaseproducts not found in the Orange Book. For products not listedin 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 databasesand Medline searches at www.pubmed.com. Although wholesalerdatabases, pharmacy operating systems, and chain pharmacy data-bases may list and link drugs with the same active ingredient in thesame dosage form and strength, such links do not always reect TE.Pharmacists should be aware of how the links are dened beforeassuming that products listed as alternatives are interchangeableparticularly with many of the sustained-release formulations. Someoperating systems include Orange Book TE codes, but this variesamong systems. Pharmacists should base their decisions on avail-able evidence, their clinical expertise, and accepted resources.

When the possible risks outweigh the potential benets of sub-stituting, do not substitute. In this case, particularly if nancial dis-incentives are in place, the pharmacist may be able to work with thephysician to obtain medical necessity prior authorization with thepatients third-party payer.

If, in the pharmacists professional judgment after evaluatingthe evidence, substitution is unlikely to compromise control or causeharm to the patient, and the patient desires to substitute, the phar-macist may determine that substitution is appropriate. In this case,the pharmacist should communicate with both the prescriber andthe patient to develop a plan for adjusting and monitoring therapy.Ensure compliance with state laws and obtain a new prescriptionif necessary.

Hormonal products. Evidence of bioequivalence is lacking withmany hormonal endocrine products. The Orange Book lists sometherapeutic equivalents; many others are B rated. For products notlisted in the Orange Book, consult the available literature to ascer-tain bioequivalence. If a patient is stabilized on a particular productand there are no data demonstrating bioequivalence of the alterna-tive product, it may be in the patients best interest to continue cur-rent therapy without substitution. For B-rated products, substitutionis 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 notsubject to FDA approval; the FDA refers to these as unapproveddrug products. 9,10 Since 1962, federal law has required pharma-ceutical manufacturers to provide safety and efcacy data for drugapproval. Between 1938 and 1962, federal law required manufactur-ers to provide only safety data for the Drug Efcacy Study Implemen-tation (DESI) review; drugs approved during this time are referredto as DESI drugs, noting efforts initiated by the FDA to demonstrateefcacy of these products in the 1960s. 10

Some drug products released prior to 1938 remain on the markettoday; these are not FDA approved, and thus neither safety nor ef-cacy data have been submitted to the FDA. Although some assumethese products have been grandfathered, the FDAs interpretationof grandfathering is very narrow, and to date no product has beenformally recognized as grandfathered by the FDA. 10

Historically, data regarding safety, efcacy, and bioequivalenceof these products have been sparse; however, the FDA is requiringmanufacturers to submit data if they intend to continue marketingthese drugs. In the meantime, health professionals need guidanceto determine when substitution of these products is or is not appro-priate. Sources of data include clinical drug information databases,PubMed searches, pharmaceutical sciences journals, and manu-facturers.

Pancreatic enzyme products (e.g., Creon, Pancrease, Viokase)

used to treat pancreatic insufciency in conditions such as cysticbrosis and pancreatitis serve as an example of products without FDAapproval. The literature documents wide variations in bioavailabilityamong different manufacturers products, resulting in signicantchanges 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 ofadverse reactions, has issued a guidance on this topic, including astatement that substitution of pancreatic enzyme products made bydifferent manufacturers is not recommended. 11-13

Digoxin and levothyroxine products have historically beenincluded in this category, however many of these products havereceived FDA approval through NDAs and ANDAs in recent years(see the Orange Book and Appendix 1 for available TE codes). Even-tually, all unapproved products will either become approved throughNDA or ANDA processes or will be withdrawn or removed from themarket. 9

If the evidence shows that benets outweigh potential risks,substitution may be acceptable. Communicate with the prescriber todevelop 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 othercategories (includes boxes 6, 7, 13, and 1618)

Because the Orange Book is accepted as the authoritativesource of therapeutic equivalency information, health professionalsshould rst look to this source for product substitution guidance.If a product is not immediately found in an Electronic Orange Booksearch (www.fda.gov/cder/ob), refer to the product package to makecertain that the original source manufacturer is referenced for thesearch. Also check that the appropriate search category is beingused (e.g., active ingredient, proprietary name).

In determining therapeutic equivalence (TE), the FDA requiresthe products to be pharmaceutical equivalents (PE) and to be bio-

equivalent (B); thus, TE = PE + B. If products have equivalent A ratings(indicating they are equivalent), the pharmacist can substitute withan expectation that the alternative medication will produce a similarresponse. 14 [Note: The pharmacist should ensure that the patient hasno history of allergies to excipients in the alternative product.] Basedon the products Orange Book TE code, see the following paragraphand 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 prob-lems and would not be expected to produce the same response inpatients. Either do not substitute, or conduct additional research toensure that substitution would be unlikely to reduce control of thecondition being treated or cause harm to the patient.

Products not found in the Orange Book. For products notlisted in the Orange Book, consult data from known sources todetermine the clinical signicance of potential or actual variableresponse. Sources include Medline searches of the pharmacy andmedical literature at www.pubmed.gov, the Journal of Pharmaceuti- cal Sciences (a common source of published bioequivalence studies),clinical pharmacotherapeutic databases, FDA guidance documents,and clinical drug information publications such as APhA DrugInfo- Line, Pharmacists Letter, and The Medical Letter . For a quick Med-line search, enter the keywords, bioequivalence and the chemicalname of the drug under consideration. Although wholesaler data-bases, pharmacy operating systems, and chain pharmacy databasesmay list or group drugs with the same active ingredient in the samedosage form and strength (i.e., pharmaceutical equivalents), thegroupings do not always reect drugs that have been shown to betherapeutically equivalent. Pharmacists should be aware of how thegroups are dened before assuming that items listed as alternativesare interchangeable. Orange Book TE codes are included in someoperating systems, but this varies among systems. Pharmacistsshould rely on the evidence, their clinical expertise, and accepted

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resources. If necessary resources are limited within the practicesetting, pharmacists are encouraged to advocate for changes topharmacy policies that would provide them access to informationand resources required to make professional judgment regardingpatients therapy.

When the possible risks outweigh the potential benets ofsubstituting, do not substitute. For medically necessary productsdenied by a third-party payer, inform the patient, and contact boththe payer and prescriber for medical necessity prior authorization ofthe prescribed product. This collaborative effort may be particularlyhelpful to the patient if nancial disincentives are in place.

If, in the pharmacists professional judgment based on the evi-dence, substitution is unlikely to compromise control or to causepotential 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 aplan for adjusting and monitoring therapy. Ensure compliance withstate 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 ben-ets, do not substitute. In these circumstances, particularly if nan-cial disincentives are in place, the pharmacist may be able to work

with the physician to obtain medical necessity prior authorizationfor the prescribed product with the patients third-party payer.

If, in the pharmacists professional judgment after evaluatingthe available evidence, substitution is unlikely to compromise con-trol or to cause potential harm to the patient, and the patient wishesto substitute, the pharmacist may determine that substitution isappropriate. Communicate with both the prescriber and the patientto develop and implement a clear plan for adjusting therapy, moni-toring, and follow-up evaluation. Ensure compliance with state lawsand obtain a new prescription if necessary.

GlossaryBioengineered 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 oftenproduced through biotechnology and are generally derived from living materialhuman, animal, or microorganism. Theyare complex in structure and usually are not fully characterized (in contrast to chemically synthesized, small molecularweight drugs, which have a well-dened structure and can be thoroughly characterized). 4 Bioengineered products areregulated not only under provisions of section 505 of the Food, Drug, and Cosmetic Act as other drugs are, but many alsoare 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 signicantlydifferent 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 individu-

alized 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 bloodlevel monitoring. Small changes in dose, absorption, or bioavailability may lead to signicant changes in efcacy and/or toxicit y.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 signicantchanges in effectiveness and toxicity they are commonly referred to as having a narrow therapeutic index. 2 Safe and ef-fective use of these drug products requires careful titration and patient monitoring. Many state regulations include a listof 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 identicalstrength or concentration and route of administration are pharmaceutically equivalent. 8 Dif ferences may exist withrespect 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 sameclinical 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 activedrug ingredient(s) in the same dosage form and route of administration; meet dened standards of strength, quality, pu-rity, and identity; and are manufactured in compliance with current good manufacturing practice regulations. Bioequiva-lence is often the variable upon which therapeutic equivalence is determined (TE = PE + B). The FDA states that productsclassied as therapeutically equivalent may be substituted with the full expectation that the substituted product willproduce 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 equivalent s that are Aor AB rated, sharing at least one common A code, are therapeutic equivalents; others, including those designated withB codes or without a common three-character A code (e.g., AB1, AB3), are not. 8 The Orange Book evaluations do not ad-dress 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 Require- ments is available as a companion to USP DI Volume I: DrugInformation for the Health Care Professional and USP DI VolumeII: Advice for the Patient , or for purchase separately. Publishedannually as a single-volume print publication, its current for-mat includes the annual edition of the Orange Book, withoutmonthly supplements. Red Book, widely recognized as a pricingresource, includes Orange Book therapeutic equivalence codesfor all approved products, including those that are repack-aged and distributed by multiple sources. It is available as asingle-volume, soft-cover, annual publication (with or withoutupdates), as a CD-ROM for Windows, and in database format.

Approved Bioequivalency Codes (ABC) is a loose-leaf printedreference with Orange Book therapeutic equivalence codinginformation provided in an alternative tabular format; it is soldas an annual subscription with monthly updates. The mostsignicant limitations of these resources are that they do notprovide signicant bioequivalence information beyond thera-peutic equivalence coding and they do not provide guidance onproducts for which therapeutic equivalence codes are unavail-able. Other sources of information available to support productsubstitution decisionseach with its own set of advantages andlimitationsinclude pharmacy operating systems, drug data-

bases, wholesaler databases and Web sites, manufacturers,and the medical and pharmacy literature and databases (e.g.,Medline available at www.pubmed.gov). Many bioequivalencestudies are published in the Journal of Pharmaceutical Sciences, accessible through Medline. The APhA DrugInfoLine newslet-ter, Pharmacists Letter, and The Medical Letter are additionalresources.

Challenges and upstream problemsinuencing product substitutionDrug databases and dispensing/ information systems

Pharmacists should be aware that the data entered intodrug databases, dispensing systems, and wholesaler databasesfor alternative products may be broadly dened and may notreect Orange Book therapeutic equivalence codes. Consis-tent with critical thinking in caring for patients, pharmacistsalso must question the information furnished through thesedatabases and dispensing systems. It is easy to assume thatthe information provided on the screen accurately reects theinformation sought, but pharmacists must evaluate the sourceto ensure their ultimate decisions are based in evidence anddatanot misinformation. A common misperception is that allsystemsdrug databases, wholesalers systems, and dispens-

ing systemsgroup therapeutically equivalent alternatives

when displaying alternative products. The fact is that some doand some do not. Most of these systems display alternatives

with the same active ingredient in the same dosage form andstrength (i.e., pharmaceutical equivalents) without regard toOrange Book therapeutic equivalence codes or other bioequiva-

lence data. Thus, while many may be therapeutically equiva-lent generic products, many wholesaler databases, pharmacyoperating systems, and chain pharmacy databases lists ofalternative products also include products with the same activeingredient that are not therapeutically equivalent to each other.Pharmacists should be aware of how the groups or links aredened and not assume that items listed as alternatives areinterchangeable, recognizing that sometimes those in the posi-tion of entering the data or contracting for preferred productsmay not have a clinical education background. Some pharmacyoperating systems include Orange Book therapeutic equivalencecodes, but this varies among systems. Pharmacists should relyon the evidence, their clinical expertise, and accepted resources.If access to necessary resources is limited within the practicesetting, pharmacists are encouraged to advocate for changes topharmacy policies that would provide them access to informa-tion and resources necessary to make professional judgmentregarding patients therapy.

Limited (or lack of) Internet accessMany employers limit Internet access through pharmacy

computers. This practice, while understandable from a busi-ness standpoint, hinders pharmacists access to important

information and data required for making decisions on behalfof patients. As previously noted, the most timely therapeuticequivalence information is available on the EOB Web site. Fur-thermore, if additional research regarding bioequivalence andsafety is required, access to online clinical data will expediteresearch efforts. Pharmacists are encouraged to nd creativesolutions in collaboration with their employers to meet the infor-mation access needs to care for patients while respecting thecompanys need to minimize and control Internet usage. Sugges-tions include limiting access to a few select links (e.g., EOB Website, PubMed, APhA DrugInfoLine ) or having one stand-alonecomputer in the pharmacy with Internet access. Pharmacistsshould join with work colleagues to draft a proposal to man-agement; the proposal should address anticipated pitfalls andincorporate possible solutions.

Manufacturer and wholesaler supply issuesSometimes when a wholesaler is out of stock on a particular

manufacturers generic product, another manufacturers prod-uct is used to fulll the orders. In many cases, the products aretherapeutic equivalents, and the only difference may be in thecolor or shape of the tablet. However, with critical dose or narrowtherapeutic 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 aparticular manufacturers product may not be switched readilyamong other available products and some wholesaler decisionmakers are unaware of this nuance.

Orange Book limitationThe Orange Book lists approved products only from compa-

nies that have led applications with the FDA, including NDAsand ANDAs. This limitation is signicant for products that aremanufactured by one company and repackaged for distributionby another company. For example, Product X, produced by Com-pany 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 tond the therapeutic equivalence rating of Product Y will not ndCompany Y (nor Product Y) listed in the Orange Book; the phar-macist must identify the original source (i.e., Company X) andlook up the rating for the product manufactured by that com-pany. Source information usually can be found on the productlabel and/or packaging.

Work-ow issuesIn many practices, prescriptions are entered into the phar-

macy computer system by pharmacy technicians (in somecases student pharmacists). Although pharmacists check theseorders, the decision whether to substitute often occurs at thebeginning of the process instead of the point of pharmacist veri-

cation. This underscores the need for communication, training,and decision support among the pharmacy staff. Alerting phar-macy technicians to the special product substitution situations

where pharmacist guidance is necessary will help to ensure thatsubstitutions are appropriate and that unwitting, inappropriatesubstitutions are avoided. The decision points in the algorithmportion of the decision support tool can be useful in educat-ing pharmacy staff about the situations that require additionalresearch and consideration.

Generic misperceptionsThe FDA communicates to consumers and health profes-

sionals that approved generic products are safe, effective, equalalternatives to brand-name products and other approved gener-ics. 15,16 These products are usually available at a lower cost and

with the expectation of equal efcacy. 1517 However, pharmaceu-tical equivalents marketed without a brand name are sometimesmistaken by health professionals and patients to be therapeuti-cally equivalent generics, translating into signicant, yet easilyexplainable, misperceptions in practice. 18 Confusion commonlyresults from products approved through the NDA process andmarketed under the chemical or generic name; their approvalis for a new drug product, not an ANDA approval as therapeuti-

cally equivalent generic alternatives to innovator products and

other approved generics. Although made available by the FDA inapproval announcements and on its Web site, this informationis often overlooked as seemingly insignicant. Furthermore,imprecise understanding of the distinction is a likely sourceof misperceptions among information systems programmers,

database links among alternative products, and wholesalers.

ConclusionMaking sound productsubstitution decisions

Substituting therapeutically equivalent generic medica-tions often results in quality care at lower prescription costsor co-payments. Some drug productseven generics or otherbrand-name products with the same active ingredientsshouldnot be substituted because of differences in bioavailability andthe impact on patients. Determining whether substitution isappropriate in a given situation is a decision that needs to begrounded 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 dispensingprescription medications. Pharmacists must be prepared toidentify situations where the process should be paused becausefurther research is indicated. They also must ensure that phar-macy technicians and student pharmacists know when to seekguidance during order entry. The sources of drug equivalencyinformation found in drug and wholesaler databases and phar-macy operating systems should be conrmed to ensure accuracyof the information and to prevent erroneous assumptions fromnegatively inuencing patient care. To effectively evaluate thera-

peutic equivalence, pharmacists must have access to the neces-sary sources of information, including online resources suchas the EOB and PubMed. Pharmacists are encouraged to usetools such as the algorithm, talking points, table of commonlyprescribed products requiring special consideration, and appli-cation examples in this article to enhance their interdisciplinaryefforts to provide evidence-based, patient-centered care aimedat improving medication use and advancing patient care.

References 1. Generic Pharmaceutical Association. Statistics. Available at:

www.gphaonline.org/Content/NavigationMenu/AboutGener-ics/Statis tics/default.htm. Accessed January 16, 2007.

2. American Pharmaceutical Association. Substitution of Criti-cal Dose Drugs: Issues, Analysis, and Decision Making. 2000.Available at: www.pharmacist.com/pdf/critical_dose.pdf. Ac-cessed October 12, 2006.

3. Food and Drug Administration. Approved Drug Products WithTherapeutic Equivalence Evaluations. 26th ed. CumulativeSupplement 12. December 2006;viiiix. Available at: www.fda.gov/cder/orange/obcs.pdf. Accessed January 16, 2007.

4. Food and Drug Administration. Frequently Asked QuestionsAbout 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: Dis-cussion by National Regulatory Authorities With World HealthOrganization (WHO) on Possible International Non-proprietaryName (INN) Policies for Biosimilars. September 1, 2006.

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6. Food and Drug Administration. FDA Guidance ConcerningDemonstration of Comparability of Human Biological ProductsIncluding Therapeutic Biotechnology-Derived Products. Avail-able at: www.fda.gov/cder/guidance/compare.htm. AccessedNovember 2, 2006.

7. Thames WA, Smith SL, Scheifele AC, et al. Evaluation of theU.S. Oncology Networks recommended guidelines for thera-peutic substitution with darbepoetin alfa 200 mg every 2 weeks

in both naive patients and patients switched f rom 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 a t: w ww.fda.gov/cder/orange/obannual.pdf. Ac-cessed August 14, 2006, to January 16, 2007.

9. Food and Drug Administration. Guidance for FDA Staff andIndustry: Marketing Unapproved DrugsCompliance PolicyGuide. June 2006. Available at: www.fda.gov/cder/guidance/ 6911fnl.pdf. Accessed October 22, 2006.

10. Food and Drug Administration. Questions and Answers on theUnapproved Drug Compliance Policy Guide. 2003. Availableat: www.fda.gov/cder/compliance/CPG_QandA.htm. AccessedOctober 23, 2006.

11. Food and Drug Administration. Guidance for Industry: ExocrinePancreatic Insufciency Drug ProductsSubmitting NDAs.

April 28, 2004. Available at: www.fda.gov/cder/guidance/ 6275fnl.pdf. Accessed December 2, 2006.

12. Exocrine Pancreatic Insufciency Drug Products: Draft Guid-ance for Submitting NDAs, Notices, 69 Federal Register 234104 (2004).

13. Food and Drug Administration. Questions and Answers onPancreatic Insufciency Drug Products. April 27, 2004. Avail-able 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 que-ries.

15. Food and Drug Administration. FDA Ensures Equivalence ofGeneric Drugs. 2003. Available at: www.fda.gov/cder/consum-erinfo/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 EveryoneShould Know. 2005. Available at: www.fda.gov/cder/consum-erinfo/generic-what_everyone_should_know.htm. AccessedJanuary 16, 2007.

18. Wisniewski L, Holquist C. The absence of a trade name does notequal a generic drug. Drug Topics. October 10, 2005;52.Avail-able at: www.fda.gov/cder/drug/MedErrors/no_tradename. pdf.Accessed January 5, 2007.

Appendix 1. Therapeutic equivalence codes of select commonly prescribed medications 14

Generic and brand names

Dosage form and strengths (if TE varies) Applicant/manufacturer (grouped by TE code, listed alphabetically) TE code

Special consideration category andnotes

Bupropion HCl: Wellbutrin SR 100 mg, 150 mg, 200 mg extended-release tablets GlaxoSmithKline (Wellbutrin SR) Impax Sandoz

AB1AB1AB1

Extended release

Bupropion HCl: Zyban 150 mg extended-release tablets GlaxoSmithKline (Zyban) Impax Sandoz

AB2AB2AB2

Extended release

Bupropion HCl: Wellbutrin XL 150 mg, 300 mg extended-release tablets Anchen Impax (300 mg only)

SmithKline Beecham (Wellbutrin XL)

AB3AB3

AB3

Extended release

Bupropion HCl: Wellbutrin SR 50 mg extended-release tablet (GlaxoSmithKline)

[Not ra ted] Extended releaseNo therapeutic equivalents

Digoxin 0.125 mg and 0.25 mg oral tablets Actavis Totowa Caraco SmithKline Beecham (Lanoxin) Stevens J

ABABABAB

Critical dose/NTI

Continued on next page

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Continued on page 340

Appendix 1. Therapeutic equivalence codes of select commonly prescribed medications 14 (continued) Generic and brand names

Dosage form and strengths (if TE varies) Applicant/manufacturer (grouped by TE code, listed alphabetically)

TE codeSpecial consideration category andnotes

Diltiazem HCl extended-release capsules all strengths except 360 mg Andrx (diltiazem) Mylan Torpharm (diltiazem) Watson Labs (Dilacor XR)

AB2AB2AB2AB2

Extended release

Actavis Elizabeth Andrx Pharms (Cartia XT) Biovail (diltiazem) Biovail (Cardizem CD) Torpharm (Dilt-CD)

AB3AB3AB3AB3AB3

Extended release

Andrx Pharms (Taztia XT) Apotex (Diltzac) Biovail (Tiazac) KV Pharm

AB4AB4AB4AB4

Extended release

Diltiazem HCl: Cardizem CD360 mg extended-release capsules (Bioavail) BC

Extended release

Diltiazem HCl: Cardizem LAextended-release capsules (Biovail)

[Not rated] No equivalents yet

Estradiol lm extended release; transdermal Berlex (Climara) Mylan Technologies (estradiol)

ABAB

Transdermal, hormonal, extendedrelease

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)

AB1AB1AB1AB1


Berlex (Climara) Mylan Technologies (estradiol)

AB2AB2


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)

BXBXBXBXBXBX


Fentanyl transdermal patch: Duragesic Alza (Duragesic) Multisource

ABAB

TransdermalAll approved products AB rated

Glipizide: Glucotrol and Glucotrol XL tablet s and extended-release tablets Pzer (Glucotrol) Multisource generics

ABAB

All approved products in like dosageforms are AB rated

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Appendix 1. Therapeutic equivalence codes of select commonly prescribed medications 14 (continued)

Generic and brand names



Glyburide: Micronase

Pharmacia and Upjohn (Micronase) Sano Aventis (DiaBeta) Multisource generics

ABBXAB

All current generics rated AB,

equivalent to Micronase brandNo generic equivalents to DiaBetabrand

Levothyroxine sodium: Various brand names tablets, all strengths Abbott (Synthroid) Jones Pharma (Levoxyl) Mylan Stevens J (Unithroid)

AB1AB1AB1AB1

Critical dose/NTI drug

Abbott (Synthroid) Alara Pharm (Levo-T)

Genpharm (levothyroxine sodium) Mylan Stevens J (Unithroid)

AB2AB2

AB2AB2AB2

Critical dose/NTI

Alara Pharm (Levo-T) Genpharm (levothyroxine sodium) Jones Pharma (Levoxyl) Mylan Stevens J (Unithroid)

AB3AB3AB3AB3AB3

Critical dose/NTI

Lloyd (Levothroid) Mylan

AB4AB4

Critical dose/NTI

Genpharm (Novothyrox)

Vintage (Levolet)

BX

BX

Critical dose/NTI

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

ABABABABABABABABAB

ABABABABABABAB

Extended release

Andrx Labs (Fortamet) Depomed (Glumetza)

BXBX


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Nifedipine: Adalat CC, Procardia XL

oral; extended-release tablets Bayer Pharms (Adalat CC) Biovail Watson Labs (Afeditab CR)

AB1AB1AB1

Extended release

Pzer (Procardia XL) Biovail Martec USA Osmotica Pharm

AB2AB2AB2AB2

Pancreatic enzyme products, pancrelipase McNeil (Pancrease, Pancrease MT) Organon (Cotazym, Cotazym-S) Solvay (Creon) Various (all distinct products)

[Not rated] Pre-DESI; high variability among prod-ucts with profound clinical differencespossible; none are bioequivalent; do notinterchange products

Phenobarbital Multisource

[Not rated] Pre-DESI; some older studies showbioequivalence among multisourceproducts

Theophylline extended-release capsules Inwood Labs UCB, Inc. (Theo-24)

BCBC

Extended release

Theophylline extended-release tablets Inwood Labs (Theochron) Nostrum Pliva Purdue Frederick (Uniphyl)

ABABABAB

Extended release

Monarch Pharms (Quibron-T/SR) BC Extended release

Tizanidine: Zanaex capsules Acorda (Zanaex)

[Not rated] Different dosage forms are not inter-changeable; reports of confusion con-cerning interchangeability of generic tablets for brand-name capsules

Tizanidine: Zanaex tablet s

Acorda (Zanaex) Acatavis Elizabeth Actavis Totowa Alphapharm Barr Caraco Corepharma Dr. Reddys Labs Inc. Ivax Pharms Mylan Sandoz Teva Torpharm

ABABABABABABABABABABABABAB

All generic and brand-name tabletsare AB rated; may not substitute for

capsules

Continued on page 342

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Warfarin sodium: Coumadinoral tablets Barr Bristol-Myers Squibb (Coumadin) Genpharm Pliva Sandoz Taro USL Pharma Zydus Pharms USA

ABABABABABABABAB

Critical dose/NTI

Abbreviations used: DESI = Drug Ef cacy Study Implementation; NTI = narrow t herapeutic index; TE = therapeutic equivalence.

Source: Reference 14.

Appendix 2. Communicating with patients about product substitution issues

Talking points and outline Comments/suggested languageBegin with an advocacy statement . Use the dialogue as an opportunity to reinforce the pharmacist s role

as a member of the health care team to help patients use medicationsappropriately. Explain to patient the importance of staying with onepharmacy.

Use patient language. Be aware of the patients literacy, health literacy, and cultural inu -ences. Target language in the 4th8th grade range, avoid technical

terms, and be sensit ive 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 di fferences and addi tional 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 encouragepatients 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 substitut ing. Ifa formulary agent cannot be used, let the patient know what else canbe done. [Offer to help facilita te medical necessity prior approval with the patient s prescriber and payer as noted in box 18 of the decisionsupport tool.]


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

Talking points and outline Comments /suggested languageHelp the patient understand the clinical implications Patients need to understand how their condition may be inuenced by aof substitut ing (or not substitut ing). 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 toensure that they are equal to the brand-name product. [Many patienteducation resources on safety, efcacy, and bioequivalence of genericsare available on the FDA Ofce of Generic Drugs Web site www.fda.gov/ogd.]

Mention co-pay difference.Discuss risksE xplain why substituting is For a patient desiring generic substitut ion when the product cannot benot 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 andwhy you are not recommending substitution.

What other options are there? Outline other options available to the patient, including medicalnecessity prior authorization and getting a new prescription withcareful monitoring.

Involve the patient in nding a solution; outline logistics and what thepatient may expect, including timing for each option.

Explore prior authorization options. Explain medical necessity prior authorization. Briey outline logisticsand what the patient may expect, including timing. Sample phrasing:

It seems that substitut ing a generic might not be safe for you at thispoint. 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 monitoringmay be required (if substitut ing with a product that may havebioequivalence differences).

Patient counseling: Medication-specic parameters Educate the patient about medication-specic information, includingand 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 issues a

Talking points and outline Comments /suggested languagePlan for efcient, organized, professional, Create a communication plan with concrete recommendations.patient-centered, and solution-oriented

interdisciplinary interchange. Call the ofce.

Build rapport by being organized and emphasizing the patient , not the prescriptionor product.

Flow of information: (1) Quickly introduce the substitut ion problem, (2) follow upimmediately with your recommendation; (3) back up the recommendation with howit will impact the patient clinically, using data as necessary.

Be prepared to fax a writ ten recommendation to follow up the phone call.

Format the fax communication with bullets, including necessary clinicalbackground as outlined below.

Avoid unintentionally putt ing the When presenting a problem with the prescribed medication, keep language inprescriber on the defensive. third person (e.g., A problem with the medication the patient was prescribed)

instead of second person, which confronts the physician personally (e.g., Aproblem with the medication you prescribed).

Emphasize data as they relate directly Instead of hearing about numbers, data, and statis tics, physicians want to know to the patient. how the patient will be af fected.Explain upstream issues that may be Help the physician understand the reason for the recommendation to changedriving the request. therapy. For example: Wholesaler product disruption scenario: Wholesalers may

experience drug shortages from different manufacturers. Most physicians areunaware of issues related to the drug supply chain. If this situat ion applies, share

it (briey) with the physician to put your request to change therapy into context; then formulate a plan for switching and any necessar y monitoring. Patientnancial constraint scenario: A tiered co-pay system may be preventing a patientfrom af fording the medication, thereby forcing him or her to make a decision toeither forgo any treatment or switch to an alternative treatment.

Suggested outline: Sample phrasing: Provide a brief introduction of yourself. [Greeting and introduce yourself.] I am calling in regard to [patient name]. Indicate you are calling on behalf of the (Instead of: ...calling about a prescription you wrote for [patient name] .)patient.Provide a succinct description of the There seems to be a problem [briey describe formulary conict/supply issue/ problem (including upstream issues) and substitution problem] with the medication the patient was prescribed.how it impacts the patient.Make a recommendat ion to remedy the I recommend we [succinct recommendation] . It will help [patient] by [add problem. specics related to justify change and link your recommendation to its impact on Explain how this potential solution impacts the patient]. the patient .

Offer to take verbal order and follow up with fax.

aMany product substitutions occur without the need to communicate directly wit h 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 substi tution requiring authorizat ion; or wholesaler

supply shortages require substitution wit h another manufacturers producteven when substitution is not idealto avoid interruption in therapy for certain chronic conditions. In these and

similar situations, the followi ng approach for communication with prescribers is suggested. (Of ten, initial communication occurs with a nurse or other staf f member who relays information

to the pr escribe r; i t is impor tant t o ensure t hat thi s middle pe rson und erst ands the r eason for y our recomm endatio n.)

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Appendix 4.Patient-centered product substi tution decision support tool for pharmacistsApplication examples

Thousands of times every day in the United States, generic and alternative brand-name products are safely and appropriatelysubstituted for the prescribed medication. The following application examples are intended to illustrate how this decision support tool, as a complement to pharmacist s professional judgment , may be applied to identify special situations that warrant the acquisi-

tion of addit ional patient and bioequivalence information to determine the potential impact of substitution on the patients clinicalcondition. The examples also raise nancial, legal, and supply-chain issues, as well as educational and communication consider-ations 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 physi-

cal 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 pat ient has a new prescription drug card and suspects that generics may be man-dated. During order entry for the brand name, the pharmacist receives the following rejectionmessage: Not covered; generic substitution required. Referring to the Product Substi tutionDecision Support Tool, the pharmacist scans the algorithm and sees that she has most of the information (from the init ial intake of the prescription by the technician and the patientsprole) 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 writ ten, however, that thepatient said he wanted the brand-name product. From the prole, she determines that this isa product the patient has been taking for the past few months, af ter rst t rying three otherantihypertensives during the preceding year.

Scanning for special considerations. Proceeding past box 3 (the prescription is not fora critical dose drug), the pharmacist stops at box 4 noting that this is an extended-releaseproduct and follows the Yes arrow to box 10:

Ascertaining therapeutic equivalence. To nd the therapeutic equivalence rating, thepharmacist consults the Electronic Orange Book at www.fda.gov/cder/ob and nds thatCardizem CD is rated AB3, therefore only AB3-rated generics are equivalent to the prescribedproduct. 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 brandn Cardizem LA, a Biovail brandn Diltiazem hydrochloride, a Mylan genericn Tiazac, a Biovail generic diltiazem hydrochloriden Cartia XT, an Andrx generic diltiazem hydrochlorideReaching 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 talkwith 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 therapeut ic equivalence with generic products. Appendix 2 list s tips for communicating with pat ientsabout 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 seeingyou 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 myprescription?

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 thehospital?!

Pharmacist: It is frustrating to have our choices limited. [Pause.] Did you know that generics go through an FDA approval pro-cess? 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 andworks 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 mechanismsvary and the products are not therapeutically equivalent. Andrx markets three different diltiazem products, each with different TEcodes. Cardizem CD and Cardizem LA also are not equivalent to each other. Because of the variability of coding among products, thepharmacist also may choose to document with the prescriber that the patient is taking Cartia XT and complete the continuity of careloop.

Application example 2. Thyroid replacement and critical dose/narrow therapeutic index drug selectionA.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 at tempts to dispense the medication only to discover that thereis none on the pharmacy shelf. When he goes to pull the supply from the order that just arrived from the wholesaler, he sees thatLevoxyl is on backorder and that Levothroid (Lloyd) was substituted by the wholesaler in fullling their stock order. The pharmacistknows that substitution of levothyroxine products may cause problems, so he consults the Product Substitution Decision SupportTool. Box 2 says:

He already has the initial patient informationneeded to proceed, scans the algorithm, and stopsright away at box 3levothyroxine is a crit ical dosedrug, also referred to as a narrow therapeutic index(NTI) product. Following the Yes arrow to box 8:

The pharmacist consults the Electronic OrangeBook at www.fda.gov/cder/ob and discovers thatLevoxyl 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-charactercode to be equivalent. Following the No arrow to box 9 (because the products are not equivalent), the recommended action is not tosubstitute. 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 completelyout 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., bothproducts share the AB1 code), he decides to

10.1331_JAPhA.2007.07502

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