guidelines for therapeutic interchange—2004: american college of clinical pharmacy

Guidelines for Therapeutic Interchange—2004

American College of Clinical Pharmacy

Thomas Gray, Pharm.D., Karen Bertch, Pharm.D., FCCP, Kimberly Galt, Pharm.D., Michael Gonyeau, Pharm.D., Emilie Karpiuk, Pharm.D., Lance Oyen, Pharm.D.,

Mary Jane Sudekum, Pharm.D., and Lee C. Vermeulen, M.S.

Key Words: therapeutic interchange, guidelines, drug policies, drugprocedures, pharmacy and therapeutics committee, patient care, cost-effectivetherapy, American College of Clinical Pharmacy, ACCP, position statement.(Pharmacotherapy 2005;25(11):1666–1680)

This publication is an update of the AmericanCollege of Clinical Pharmacy (ACCP) PositionStatement on “Guidelines for TherapeuticInterchange,”1 originally published in 1993.

The ACCP supports the practice of therapeuticinterchange, in which pharmacists collaboratewith physicians and other health careprofessionals to develop policies and implementprograms that improve drug use to provide thebest possible patient care at the most affordablecost. The ACCP has established the followingguidelines for implementing therapeuticinterchange policies and procedures withinhealth care organizations and other appropriatepatient care settings:

• Guideline I: Therapeutic interchange isappropriate in institutional and ambulatorysettings that have a functioning formularysystem and pharmacy and therapeuticscommittee or equivalent drug use policy-setting bodies.

• Guideline II: Organizations implementingtherapeutic interchange programs mustaccept the obligation to measure their impacton the clinical, economic, and humanistic

outcomes of care.• Guideline III: Therapeutic interchange, as

defined herein, may be executed bypharmacists when prescribers have beenadvised of the policy set forth by thepharmacy and therapeutics committee or itsequivalent. Notification to each individualprescriber need not occur for each inter-change when institutional or organizationalpolicies do not require such. In other cases,prescribers should be notified within areasonable time frame through written, oral,or electronic communication. Use of tech-nology to aid in managing the therapeuticinterchange policy is highly desirable.

• Guideline IV: The pharmacy and therapeuticscommittee or an equivalent body shouldensure that professional staff is educatedregarding the policies, procedures, objectives,and rationale for therapeutic interchange.The policies should include provisions fordisclosure of therapeutic interchangepractices to patients as appropriate to thesetting in which therapeutic interchange willoccur.

• Guideline V: Therapeutic interchangepolicies should define a mechanism thatpermits exceptions to the policy and proce-dures when necessary and/or appropriate.

Definition

Therapeutic interchange is defined as thedispensing of a drug that is therapeuticallyequivalent to but chemically different from the

The guidelines were written by the 2003 ACCPPublications Committee: Thomas Gray, Pharm.D., Chair;Karen Bertch, Pharm.D., FCCP; Kimberly Galt, Pharm.D.;Michael Gonyeau, Pharm.D.; Emilie Karpiuk, Pharm.D.;Lance Oyen, Pharm.D.; Mary Jane Sudekum, Pharm.D.; andLee C. Vermeulen, M.S. Received by the ACCP Board ofRegents on August 7–8, 2003.

Address reprint request to the American College ofClinical Pharmacy, 3101 Broadway, Suite 380, Kansas City,MO 64111; e-mail: [email protected]; or download fromhttp://www.accp.com.

ACCP POSITION STATEMENT

GUIDELINES FOR THERAPEUTIC INTERCHANGE—2004 ACCP

drug originally prescribed by a physician or otherauthorized prescriber. Although usually of thesame pharmacologic class, drugs appropriate fortherapeutic interchange may differ in chemistryor pharmacokinetic properties, and may possessdifferent mechanism of action, adverse-reaction,toxicity, and drug interaction profiles. In mostcases, the interchanged drugs have closesimilarity in efficacy and safety profiles.

Overview of Therapeutic Interchange

The role of therapeutic interchange hasincreased substantially in recent years as a resultof two primary influences: the rapid expansionin the number of drugs within the same orcomparable therapeutic classes, and the need tocontrol drug and related health care costs whilepromoting more rational drug therapy.Therapeutic interchange policies and programsgrant pharmacists the authority to interchangedrugs without prior consent from the prescriber,according to procedures outlined in a specificpolicy. Prescribers may include physicians,physician assistants, nurse practitioners, andother health care professionals who areauthorized to prescribe.

Therapeutic interchange policies andprocedures within a health care deliveryorganization usually are developed and guided bya group responsible for establishing drug usepolicies, such as the pharmacy and therapeuticscommittee. This committee is composed ofphysicians, pharmacists, and other healthprofessionals whose combined and comple-mentary expertise, knowledge, and experienceare used to develop policies and procedures toguide the professional staff and administration ofan organization on matters related to thetherapeutic use of drugs. Among other duties,the committee serves in an advisory capacity tothe medical staff and administration in allmatters pertaining to the use of drugs, includingtherapeutic interchange; establishes programsand procedures that help ensure cost-effectivedrug therapy; establishes or plans suitableeducational programs for the professional staff onmatters related to drug use; participates incontinuous quality improvement activities; andinitiates or directs drug use evaluation programsand reviews their results.2 A successful andeffective therapeutic interchange policy is directlyrelated to the effectiveness of the pharmacy andtherapeutics committee in performing itsfunctions, as well as the input of other health

care professionals involved with implementingand maintaining the policy.

The ACCP Guidelines and Rationale forTherapeutic Interchange

As stated, the ACCP supports the concept andpractice of therapeutic interchange. The policiesshould result from a synergistic combination ofthe expertise and knowledge of pharmacists andphysicians whose common goal is to ensureoptimum patient care. They should not beinterpreted as “bestowing independent pre-scribing authority on pharmacists.” Althoughthe policies may vary in complexity, most involvethe interchange of one drug for another that isdeemed to be therapeutically equivalent. Theyshould not be viewed as or become blanketpolicies allowing pharmacists to choose analternative drug from an entire class or categoryof drugs.

This section describes the rationale for eachACCP-supported guideline for implementingtherapeutic interchange policies and procedureswithin health care organizations.

Guideline I

Therapeutic interchange is appropriate ininstitutional and ambulatory settings that have afunctioning formulary system and pharmacy andtherapeutics committee or equivalent drug usepolicy-setting bodies.

Rationale

The success of any therapeutic interchangeprogram is related to the effectiveness of thepharmacy and therapeutics committee or itsequivalent body, and the organization’s formularysystem. An effective committee uses theprinciples of quality management to governtherapeutic interchange policies and processes ofthe formulary system. This committee shouldrepresent both the pharmacy and medical staffs.It must develop, implement, review, and changepolicies and procedures to ensure optimumpatient care while managing costs. Similarly, itshould recommend and assist in educating healthprofessionals regarding policies and approvedexceptions to them, assessing organizationaleffectiveness of the program, and evaluating thepatient care outcomes associated with theirimplementation.2–4

The pharmacy and therapeutics committeeshould establish or assign a subcommittee or

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department to monitor the effectiveness oftherapeutic interchange policies and procedures.Audits or reviews should be conducted accordingto set policies. Criteria should be developed andused to determine when and why the therapeuticinterchange policies may be ineffective (seeGuideline II). The issues identified should beaddressed and the health professionals notified ofresulting changes to policies and procedures.

The specific types of institutional orambulatory settings for which therapeuticinterchange policies are most likely to be effectiveare those that have drug formularies with afunctioning pharmacy and therapeuticscommittee or its equivalent. This may include,but is not limited to, hospice settings, healthmaintenance organizations, community hospitals,university hospitals, and ambulatory clinicsaffiliated with a hospital. Community phar-macists, including home care, and long-term carefacility consultant pharmacists also mayparticipate in therapeutic interchange programsin some cases.5, 6 If the policies dictate thatlaboratory or medical record data should bereadily available to pharmacists beforerecommending the use of or dispensing atherapeutic alternative, the setting must provideaccess to this information. Regardless of thesetting, pharmacists and physicians must have agood working relationship and a mutual goal toprovide excellent medical care while containingcosts.

Therapeutic interchange recently has become acommon method used by some health plans,pharmacy benefits management companies, andinsurers as part of the effort to control drugexpenditures. When therapeutic interchange isadopted by these entities, it is important that apharmacist who is directly responsible for thecare of the patient evaluate the practical impacton the patient that is likely to result. Thepharmacist who is directly responsible for thepatient’s care should act as an advocate for thepatient. Patient advocacy by the pharmacistincludes, but is not limited to, education of thepatient about the potential impact of theinterchange, and communication with theprescriber whose orders or prescriptions areaffected. Pharmacists should use their expertiseto assist both the patient and the prescriber withdecisions related to therapeutic interchange.7

The institutional setting provides a controlledand continuously supervised health care environ-ment, allowing for oversight and assurance ofaccurate drug therapy administration. When a

patient is moved from the institutional setting toanother institutional or alternative health caresetting, the change in the commercial product ismore readily apparent to the patient. When atherapeutic interchange occurs, patients willoften notice that the specific product or dosageform has changed. Although drugs that havebeen determined to be therapeuticallyinterchangeable are typically comparable inefficacy, some drug product attributes (e.g.,administration frequency or product appearance)may be substantially different and requiremodified behavior on the part of the patient.Pharmacists should educate patients about anychanges that will be apparent to patients as aresult of the interchange.

There is less evidence about patient outcomesassociated with a change in care facilities, orwhen a patient transitions from one care settingto another. In general, the principal findings ofthe limited number of studies performed suggestthat patient clinical and humanistic outcomes areneutral and pharmacoeconomic outcomes arepositive.8–12 The pharmacist responsible for thepatient should ensure that a process or procedureis in place related to therapeutic interchange tominimize potential problems for patients whentransitioning between care settings. An exampleof a procedure that improves the patient’sexperience of uninterrupted and appropriatetherapy upon hospital discharge includesdocumentation of the patient’s home drug on theelectronic drug administration record.13

The lack of accumulated evidence about theimpact of therapeutic interchange on patientswho transition to new care settings is argumentfor the importance of ongoing surveillance andreporting.9 The United States Food and DrugAdministration (FDA) encourages practitionersto report any untoward events thought to beassociated with therapeutic interchange to theMedWatch program.

Guideline II

Organizations implementing therapeuticinterchange programs must accept the obligationto measure the impact of those initiatives on theclinical, economic, and humanistic outcomes ofcare.

Rationale

The approval of a therapeutic interchangeprogram is prefaced by acceptance of clinicalequivalence of drugs within an interchange

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category by an organization‘s medical staff,pharmacy and therapeutics committee, or otherpolicy-setting body. The evidence supportingequivalence should be derived from clinical trialspublished in peer-reviewed literature. In somecircumstances, organizations may choose toimplement therapeutic interchange initiativeswith substantially less supportive evidence (e.g.,drawing evidence from disparate trials withcommon design and comparator groups). Ineither case, the implementation of therapeuticinterchange may not result in positive economic,clinical, or humanistic outcomes for patientstreated under the policy, and demonstration oftrue equivalence of outcomes associated withtherapeutic interchange is of great importance.

The ideal criteria for establishing clinicalequivalence not only must include evidence ofequal efficacy (drawing data from randomizedclinical trials and answering the question, “Canthese drugs produce similar outcomes?”), butalso must consider evidence of equal effective-ness (answering the question, “Do these drugsproduce similar outcomes?”). Evidence ofeffectiveness is obtained from patients receivingcare under usual patient care conditions, not inthe artificial environment of a clinical trial.Furthermore, equivalence of outcome must beshown in a variety of dimensions: clinical,economic, and humanistic.

In economic terms, organizations implementingtherapeutic interchange will enjoy lower drugacquisition costs. Therapeutic interchangesuccessfully decreases drug acquisition costswhen implemented in a variety of settings. Aswith all economic evaluations, it is essential thatthe total cost of care be evaluated to assess theimpact of individual interchange initiatives andensure that the total cost of care is reduced whena less expensive drug is administered in place of amore costly one.

The clinical outcomes of interest will dependon the condition being managed by the drugsbeing interchanged. Recognizing that outcomesdocumented in clinical trials often are notachieved under routine clinical practice condi-tions is essential. Once an interchange isimplemented, measurement of treatment successis required. Humanistic outcomes, includingquality of life, functional status, and patientsatisfaction, also are important and should beincluded in an evaluation of the success of atherapeutic interchange initiative.

Organizations must be willing to accept theresponsibility for conducting postimplementation

outcome evaluations in return for the savingsthat they enjoy from therapeutic interchange,particularly in the event they implementtherapeutic interchange initiatives with imperfector less than ideal data supporting clinicalequivalence. Most organizations have respon-sibility for conducting drug use evaluations tosatisfy Joint Commission on Accreditation ofHealthcare Organizations (JCAHO) requirements,and evaluations of postinterchange outcomes caneasily be tailored to fit the framework oftraditional drug use evaluation.14 Excellentexamples of published outcomes evaluations areavailable in the peer-reviewed literature and canserve as templates for similar projects in otherhealth systems.9, 11, 15

Guideline III

Therapeutic interchange, as defined herein,may be executed by pharmacists when pre-scribers have been advised of the policy set forthby the pharmacy and therapeutics committee orits equivalent. Notification to each individualprescriber need not occur for each interchangewhen institutional or organizational policies donot require such. In other cases, prescribersshould be notified within a reasonable time framethrough written, oral, or electronic communi-cation. Use of technology to aid in managing thetherapeutic interchange policy is highly desirable.

Rationale

Therapeutic interchange policies and proce-dures should describe in detail the conditionsand processes for interchanging drugs. Theseshould include who has authority to enact theinterchange, special exceptions to a policy, orprocedure and criteria to be evaluated before andafter the interchange occurs. Solicitation ofapproval from individual prescribers is notnecessary, providing the interchange is performedaccording to the policies and procedures set forthby the pharmacy and therapeutics committee orcomparable oversight body. However, notifica-tion of interchanges to all health care profes-sionals involved in patient care is paramount tothe acceptance and management of the policy.Notification may occur in various ways, includingwritten, oral, or electronic orders recorded in themedical record; e-mail communication; directinterface into drug administration records; orincorporation into the prescribing processthrough the use of computerized physician orderentry.

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Use of computerized physician order entryprovides a distinct opportunity in the manage-ment of therapeutic interchange policies.Computerized information systems are powerfultools for structuring, collecting, and managingdata. When applied to the setting of drugprescriptions, they have the potential to alterphysician prescribing practices substantially.15, 16

The greatest advantages to computerizedphysician order entry lie in the ability of thesystem to offer only those drugs listed on theinstitution’s or health care system’s formulary, orto highlight those preferred drugs approved bythe pharmacy and therapeutics committee fortherapeutic interchange. Guidelines for drug use,and the rationale for substitution, can bedisplayed in real time at the critical point ofphysician initiation. This not only increasesadherence to the therapeutic interchange policy,but also allows immediate prescriber notificationof the drug to be interchanged.

There are many studies documenting increasesin therapeutic interchange policy adherencethrough the use of computerized physician orderentry.15–19 Statistically significant increases in useof formulary drugs and statistically significantdecreases in orders exceeding the maximumrecommended dose have been demonstrated.15

However, there must always be a process bywhich a prescriber may override a therapeuticinterchange recommendation built into thecomputerized physician order entry system.Computerized physician order entry allowspharmacists to manage a therapeutic interchangepolicy proactively through the use of computerizedwarnings, dosage guidance tools, and recommen-dations of preferred drugs within a class.

Guideline IV

The pharmacy and therapeutics committee oran equivalent body should ensure thatprofessional staff is educated regarding thepolicies, procedures, objectives, and rationale fortherapeutic interchange. The policies shouldinclude provisions for disclosure of therapeuticinterchange practices to patients as appropriate tothe setting in which therapeutic interchange willoccur.

Rationale

Proper educational methods should bedeveloped, implemented, reviewed, and revisedas necessary to inform the professional staff

regarding the rationale, procedures, andmonitoring criteria for therapeutic interchange.These methods may include newsletters, fliers,departmental meetings, meeting minutes,electronic media, and publication of therapeuticinterchange policies, such as in an organization’sformulary. Physicians should be informed of thepolicies prospectively, and a list of active policiesshould be readily available to the professionalstaff. As part of ongoing education regardingtherapeutic interchange, the professional staffshould be informed of results from drug useevaluations pertaining to therapeutic interchange.Computerized physician order entry wouldprovide immediate notification of specifictherapeutic interchanges and may serve as aconstant reminder that such policies exist.16, 19

Patient disclosure and educational materialsmay be developed in written or audiovisualformat as appropriate to introduce the concept oftherapeutic interchange, address the potentialimpact to their care, and promote drug adherence.Managed care plans must prospectively notify ordisclose to enrollees information regarding thepolicies and limitations or restrictions on thebenefits package (which should includeprescription coverage and policies of therapeuticinterchange).20 These therapeutic interchangepolicies are again reinforced at a moreindividualized level when prescriptions are filled.Issues of appropriate use, dosage, and adverseeffects are routinely part of patient informationsheets provided with a prescription. If a drug istherapeutically interchanged for another,however, there remains the need to ensure thepatient understands that one drug has replacedanother and is not an addition to therapy.Changes in drug regimens can be sources ofconfusion and may lead to compliance issues,5

potential omissions, or duplication of therapy.Ongoing patient education and follow-up bypharmacists and physicians are essential toprevent these problems.4, 21

The pharmacist plays a critical role in thera-peutic interchange program management andmust be well prepared to communicate effectivelywith both patients and physicians regarding theconcepts of therapeutic interchange.21

Knowledge of all relevant policies and proceduresfor therapeutic interchange is essential. Aprogram to assess pharmacists’ understanding ofthe therapeutic interchange program should be apart of the regular performance evaluationprocesses of the organization.

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Guideline V

Therapeutic interchange policies should definea mechanism that permits exceptions to thepolicy and procedures when necessary and/orappropriate.

Rationale

Therapeutic interchange may not be applicableto or appropriate for all patients. Allergies or ahistory of failed therapy or unwanted side effectsmay warrant that another drug be prescribed.Also, a drug being prescribed for an off-labelindication should be allowed if the preferred drugis not appropriate. For example, cimetidine,when prescribed concurrently with a 24-hourcreatinine clearance, is used to improve theaccuracy of the laboratory test. Other histamine2antagonists do not have this pharmacologiceffect.12

In addition, some chronic disease states maynot be amenable to therapeutic interchange.Patients with mental illness, rheumatic disease,and some gastrointestinal disorders may bestabilized or in remission with their current drugregimen. Switching to another drug may havethe potential to cause relapse or deterioration intheir condition.

Consequently, an acceptable method ofexercising exceptions to an organization’stherapeutic interchange procedures must bemade available to prescribers. The physicianshould notify the pharmacist either in writing ororally regarding the desire to override theexisting policy or procedure. Data on the natureand extent of exceptions to the policy andprocedures should be collected and analyzed bythe appropriate oversight body.

Some institutions are now adding a statementto their therapeutic interchange policyauthorizing changes of the preferred drug in caseof a national supply shortage. Changing thepreferred drug in times of national shortageshould be permissible to alleviate distributiondelays and provide continuity of patient care.Implementation of this statement must berestricted to previously authorized drug classesand should not be interpreted as an openinvitation that allows pharmacists to interchangeany prescribed drug at will.

Additional Background and Discussion

Because interest in therapeutic interchange hasbecome broader, it is important for health care

practitioners to be aware of common practicesassociated with therapeutic interchange and thefactors that influence it. This section describescommon practices that are undertaken with atherapeutic interchange program. Typical drugclasses that may be considered for therapeuticinterchange are highlighted. In addition, themultitude of factors that can affect the successand outcome of therapeutic interchange arereviewed.

Common Practices in Therapeutic Interchange

High-quality, cost-effective formularies arerequired because of the increasing complexity ofpharmacotherapy, the associated increase in thenumber of therapeutically equivalent drugs thatoften are considered “me too,” and escalatingdrug costs. Therapeutic interchange is a widelyused option available to accomplish this objectiverelated to formularies while also maintainingoptimal patient care.22 Other benefits oftherapeutic interchange include minimizingtherapeutic duplication, producing positiveclinical outcomes, and controlling costs.23 It alsocan be used as a vehicle to promote appropriateuse of pharmaceuticals, by supporting the highestquality standards of pharmaceutical care tooptimize patient wellness and outcomes.

For health care practitioners to develop andsupport a successful therapeutic interchangeprogram, certain common practices should beassociated with the program.5, 23–25 The practicesto be considered may include, but may not belimited to the following:

• Guidelines should be developed to supportdecisions in the therapeutic interchangeprocess using an evidence-based approach.

• Clinical pathways and other nationalstandardized guidelines should be used tosustain decision-making processes, andinterventions should be performed inaccordance with interchange protocols.

• The need for physician support is paramountto the process. Successful programs designedto influence prescribing must involvephysicians throughout the process. Thisinvolvement may include delineatingprocedures, communicating to othermembers of the medical staff, and assisting inimplementing and setting up the overalloperation of the program.

• Qualified health care personnel are requiredto monitor prescriber compliance withtherapeutic interchange and overall patient

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outcomes affected by the interchangeprogram.

• Effective communication with the medicalstaff and other health care personnel iscritical to executing drug interchangestrategies. Communication vehicles caninclude interactive educational programs,pharmacy newsletters, and direct mailingssuch as “dear doctor” letters.

• Industry involvement is essential to have animpact on the general costs of drugs. Oncean institution or health system determinesthat certain drugs are deemed equivalentwithin a class, a competitive bidding processcan be undertaken with drug manufacturers.By driving market share to a specific drugwithin the class, manufacturers may bepersuaded to offer some price reductions forthat product.

• By standardizing a formulary to one or moreproducts within a therapeutic class, theinstitution can more appropriately manageits inventories. Patient safety can beenhanced by product standardization,allowing for less chance of errors.

• Demonstration of positive clinical outcomescertainly adds support to a therapeuticinterchange program. Although the litera-ture is limited in documenting favorablepatient outcomes from various drugmanagement techniques, demonstrating thattherapeutic interchange did not negativelyaffect clinical outcomes is important.

• Economic outcomes should be consideredwith the recognition that health care is abusiness. Effective fiscal management is vitalfor long-term economic survival of institu-tions and health systems. However, theseconsiderations must be balanced with patientcare outcomes.

• A therapeutic interchange program shouldnot impede patient access to necessary drugsbut, instead, improve patient access to moreaffordable health care.

Determining which drugs to include in atherapeutic interchange program can vary basedon a specific institution’s or health system’sneeds. However, in general, many programsfocus on drugs with high risk, high volume, orhigh costs, or drugs overused in routineconditions.26 Those individuals involved inmaking decisions about the therapeutic inter-change program and which specific drugs toinclude should minimally include physicians,pharmacists, and pharmacy and therapeutics

committee staff. Other health care professionalsincluding nurses and social workers, as well asrisk managers, also may be a part of the decision-making process. Typical classes of drugs forwhich therapeutic interchange may beundertaken are the following5, 22, 26:

• Analgesics: cyclooxygenase-2–selectiveinhibitors, nonsteroidal antiinflammatorydrugs, opiates, opioids

• Antiinfective drugs: aminoglycosides,antifungals, carbapenems, first-, second-, andthird-generation cephalosporins, fluoro-quinolones, macrolides, penicillins

• Cardiovascular drugs: angiotensin-convertingenzyme inhibitors, angiotensin II receptorantagonists, b-blockers, calcium channelblockers, direct thrombin inhibitors,glycoprotein IIb-IIIa receptor antagonists, 3-hydroxy-3-methylglutaryl coenzyme A(HMG-CoA) reductase inhibitors, low-molecular-weight heparins, nitrates andnitrites, thiazide diuretics, thrombolytics

• Central nervous system drugs: benzo-diazepines, neuromuscular blocking drugs,selective serotonin reuptake inhibitors,triptans

• Eye, ear, nose, and throat preparations:antitussives, decongestants, expectorants,low- and nonsedating antihistamines, nasalcorticosteroids, ophthalmic b-blockers,respiratory corticosteroids

• Gastrointestinal drugs: antacids, serotonin5-HT3 receptor antagonists, histamine2-receptor antagonists, laxatives and stoolsofteners, proton-pump inhibitors

• Hormones and synthetic substitutes:insulins, luteinizing hormone–releasinghormone agonists, oral contraceptives,thyroid drugs

• Metabolic drugs: parenteral amino acids,intravenous fat emulsions

• Skin products: antifungal creams andointments, topical corticosteroids, debridingagents

• Miscellaneous drugs: intravenous immuneglobulins, iron preparations, potassiumsupplements, vitamins

Although this list is quite extensive, the 11drug classes most often used in therapeuticinterchange, as reported by a survey conducted in1999,22 are as follows (listed in descending orderof frequency):

• Histamine2-receptor antagonists• Proton-pump inhibitors

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• Antacids• Fluoroquinolones• Potassium supplements• First-generation cephalosporins• HMG-CoA reductase inhibitors• Second-generation cephalosporins• Insulins• Third-generation cephalosporins• Laxatives and stool softeners

Practitioners at individual institutions andhealth systems should develop a systematicprocess to determine the specific classes toinclude in therapeutic interchange programsconsidering overall value to patient care, clinicaland economic outcomes, and practitionersupport.

There may be barriers to use of therapeuticinterchange or various factors as to whyinstitutions or health systems may not use atherapeutic interchange program. These barriersmay include the potential for physician or otherhealth care practitioner nonacceptance, violationof state law, fear of civil liability, lack of staffresources to set up and implement the program,and the cost of initiating therapeutic interchange,which may be greater than the expected benefit.22

However, initiation costs for most newtherapeutic interchange initiatives occur onlyonce, whereas the benefits and savings associatedwith the initiatives continue for years.

Although there are many advantages forinstitutions or health systems to implement atherapeutic interchange program, there also areassociated disadvantages with a program of thisnature. One study in community pharmaciesshowed that for about 10% of suggestedtherapeutic interchanges, the patient failed tohave the prescription filled, even though themean cost was lower for the interchanged drug.5

Although the number of therapeutic interchangesreported in this study was small, the authorspeculated that it is possible that therapeuticinterchange may contribute to noncompliance.Furthermore, it is not known if the patients whofailed to fill their prescriptions were being treatedfor serious conditions such as congestive heartfailure or diabetes mellitus, or for an acute, self-limiting condition. For the most part,controlling costs related to drug therapy is amajor reason for implementing a therapeuticinterchange program. Although interchangeprograms may decrease costs for institutions andpayers, it may create time-related costs forpatients and pharmacists.5 Patients who haveinterchanged prescriptions are likely to make

additional trips to an ambulatory pharmacy tohave their prescription changed and filled,whereas in the hospital setting, a changedprescription may take more time for health careworkers to process. Therapeutic interchangemay add time to the dispensing process forpharmacists because of the steps involved tomake a change to a prescription and thenecessary patient education. Overall, theadvantages associated with a therapeuticinterchange program appear to outweigh thedisadvantages.

Factors That Influence Therapeutic Interchange

Many factors influence the ability of aninstitution or health system to implement atherapeutic interchange program, and onceimplemented, contribute to and sustain itssuccess. The following is a list of factors thatinfluence therapeutic interchange practices tosome degree. This list may not be exhaustive,but it includes many commonalities seen atvarious institutions and health systems.

• Health care setting3, 4: therapeutic inter-change programs have been used successfullyin the hospital setting for many years. In thissetting, the process is simple, straight-forward, consistent, and ethical because thereusually is only one formulary. In general, asingle formulary simplifies prescribingdecisions as well as the inventory controlprocess. In most ambulatory care settings,the process is not as straightforward orconsistent because there usually are multipleformularies, and inventory is not reduced.

• Unit or area in the institution or healthsystem: therapeutic interchange may bemore conducive to certain units or areas inthe institution due to the types of drugs ordrug classes being prescribed for patients onthese units. Specific units where the potentialfor therapeutic interchange is high includespecialty care units or step-down units,specialty care clinics, coronary care units,and intensive care units.

• Patient types: the suitability of therapeuticinterchange based on drug classes or specificdrugs may depend on whether the patient isa neonate, is elderly, has compromised organfunction, is pregnant, or is at risk due tocomorbid conditions. In addition, healthcare practitioners involved with therapeuticinterchange programs should take intoaccount whether a patient is starting a new

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therapy or is switching therapy. Efficacy,effectiveness, safety, and economic data canbe used in a straightforward manner withregard to establishing therapeutic equivalentdrugs for patients starting a new therapy;however, the situation is more complex whenexamining these issues for switching well-stabilized patients from one drug to another.Care should be exercised when beginningtherapeutic switches for patients who arewell stabilized with a drug regimen comparedwith a patient starting a new regimen.

• Patient preferences: the patient’s acceptanceof therapeutic interchange and his or hercompliance with any change in therapy ifwarranted affect the outcomes of a thera-peutic interchange program. Some patientswant the highest quality drugs, always at thelowest cost. Sometimes this can be a barrier,especially for newer drugs and high-technology biologicals. For example, apatient may want to receive a more costlydrug from a different class of drugs that has asimilar therapeutic effect, but the drug is nota member of the class that is part of thetherapeutic interchange program. Althoughtherapeutic interchange requires clinicalindistinguishability among drugs in aninterchanged class, patients may have adifferent perception on this. They mayequate newer or more expensive drugs withhigher quality.

• Drug characteristics27: a variety of issuesrelated to the specific drug classes and drugswithin them must be considered whendetermining suitability for therapeuticinterchange. The following are some charac-teristics to consider:• Efficacy—refers to the expected partial or

total response or tolerance by a patient to acomplete course of therapy under idealconditions. One must consider the rangesof indications with documented efficacy foreach drug in the group.

• Effectiveness—refers to the expectedpartial or total response or tolerance by apatient to a complete course of therapy inthe usual clinical practice setting.

• Dosage formulation—refers to convenienceof a preparation and administration,frequency of dosing, range of dosage forms,and stability.

• Safety—includes contraindications, warn-ings, and adverse effects, as well aslookalike and soundalike products.

• Cost—acquisition cost usually is con-sidered. For intravenous dosage formu-lations, other ancillary supplies such asminibags and tubing used to administer thedrugs may need to be factored into overallcosts.

• Changes in reimbursement24, 28: there is aneed to monitor business and reimbursementliterature as well as health care literature ingeneral to keep abreast of changes inreimbursement. Challenges in reducedreimbursement are evident as a result of theBalanced Budget Act of 1997, and theOutpatient Prospective Payment Systemcreated under this act. Payments forservices, especially in the outpatient setting,are based on the Ambulatory PaymentClassification system, which recently hasundergone many changes. Furthermore,there is a need to educate decision makers ingeneral at an institution or health system andthose involved at the federal level withsetting reimbursement rates about drugcosts, by using trend data and benchmarkinginformation. The effects of drug pricingincreases usually are attributable to highprices for new drugs and higher prices forolder drugs that are being used for newindications. Moreover, higher utilizationtrends of certain drugs are evident.

• Insurance providers: outpatient drugprograms may constantly change theirformularies. Patients may change insuranceproviders and, thus, be exposed to differentformularies.

• Pharmacoeconomic variables27: variablesother than price, such as costs for laboratorytests, staff, hospitalizations, and recoverytimes, must be considered when imple-menting a therapeutic interchange program.

• Ethical practices3, 29, 30: when conceived andmanaged properly in hospitals, therapeuticinterchange provides optimal care in anethical fashion and in such a way that it isinvisible to patients and physicians. Outsidethe institution, however, the effects offormulary management, including thera-peutic interchange, on patients and physi-cians are less likely to be invisible. Forexample, financial incentives may be offeredto physicians by health plans to provide anincentive to prescribe lower cost drugs.

• Manufacturer issues: the ability of themanufacturer to supply the drug chosen fortherapeutic interchange is paramount to the

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appropriate functioning of the program. Theinability of a manufacturer to supply theselected product could result in switching toa nonformulary alternative in classes wherethe drugs are deemed equivalent. Manufac-turers that supply products with a variety offormulations offer more choice over productswith limited formulations. This mayultimately affect which drug is chosen fortherapeutic interchange. The willingness ofmanufacturers to offer contracts that providepricing advantages through GroupPurchasing Organizations or to individualinstitutions supports competitive frictionamong drugs within a therapeutic class andultimately may drive overall costs down.

• Direct-to-consumer advertising: patientsmay demand that their prescribers providethem with a specific drug that they haveheard about through various marketingmedia. The requested drug may not be thesuggested drug to be used within thetherapeutic class as a part of a therapeuticinterchange program or a drug on aninstitution’s or health system’s formulary.

• Regulatory issues or regulatory bodies: theinfluence of the FDA (off-label vs labeled useof drugs), JCAHO, National Committee forQuality Assurance, and other regulatorybodies can effect therapeutic interchange. Inaddition, the influence of governmentalagencies on Medicare and Medicaid policiescan affect drugs that are to be interchangedsince reimbursement may be allocated onlyto a specific drug within a class. The effectof regulatory issues or bodies is more fullydescribed in the Legal and Regulatory Issuessection.

• Legislative bodies and policymakers3, 29:legislative restrictions may hinder thera-peutic interchange, especially in theoutpatient setting. Legislators in many stateshave faced decisions as to whether and howto regulate therapeutic interchange practices.In many cases, this is a result of critics oftherapeutic interchange programs chargingthat they expose patients to increased riskswhile resulting in little savings for patients orthe employers responsible for paying theirinsurance premiums. The Legal andRegulatory Issues section provides more in-depth discussion on this topic.

• Appropriate design and implementation of atherapeutic interchange program4: initialdesign of a therapeutic interchange program

must include a plan to monitor patientsaffected by an interchanged drug. Appro-priate follow-up of patients affected by atherapeutic interchange is important to avoidadverse outcomes.

• Clinical practitioners at the institution orhealth system level7, 27, 31: practitioner buy-inor adaptability to a therapeutic interchangeprogram affects its overall success. Anassessment of the impact of the program onstaff workload is critical to determining thedirection. Adherence to the therapeuticinterchange program contributes to itssuccess from a clinical benefit standpoint aswell as the ability to control drugexpenditures.

• Health care administrators (chief executive,operating, and financial officers): varioushealth care administrators may fully supporttherapeutic interchange from a clinical andcost-effective perspective. Seeing the benefitsin lowering costs of therapy, these adminis-trators may not understand the concept of atherapeutic interchange program and maypressure health care practitioners to includedrug classes that are not warranted forinterchange.

• Staff resource availability to design, thenimplement the therapeutic interchangeprogram: the availability of the appropriatetypes of staff and quantities of staff to pursuea therapeutic interchange program will affectits overall success.

Legal and Regulatory Issues

The legal and regulatory issues concerningtherapeutic interchange have evolved, as has thepractice. Early concepts regarding the responsi-bilities of organizations implementing thera-peutic interchanges focused primarily on the useof a pharmacy and therapeutics committee, andits formulary, to clearly require collaboration ofphysicians, pharmacists, and other members ofthe committee.2 Many aspects of drug selectionand the legal issues of interchange to beinstitutional risk management concerns ratherthan a liability risk have been described.32 In lieuof cases to the contrary, this opinion is stilltoday’s legal stance on therapeutic interchange.33

Since the assertion of therapeutic interchangebenefits of risk minimization in 1988, thelandscape of liability as it pertains to therapeuticinterchange has changed to include new issuessuch as pharmaceutical care, managed care, and

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corporate responsibility.33

For therapeutic interchange to be a liabilityrisk, an interchange must fulfill the legal criteriaof negligence. Negligence is defined as patientinjury, a clear breach in duty to protect frompotential harm (as it balances with benefit), andthe injury caused by the breach in duty(causation).33 Although patient injury often isobvious, breach in duty and direct causation aredifficult to prove in court. If a standard of care,such as a policy and procedure on therapeuticinterchange, is in place and adhered to, proof ofbreach in duty is almost impossible. Similarly,causation requires the act of interchange to bedirectly responsible for the harm. In most casesof drug-induced toxicity, the link of cause andeffect is not absolute, especially when thealternative drug, if not switched, would likelyhave caused the same possible constellation ofproblems. It is for all these reasons that no legalcases have been successful in arguing againsttherapeutic interchange.33

As originally asserted in the American Societyof Health-System Pharmacists (ASHP) formularymanagement guidelines, the integration of amultidisciplinary pharmacy and therapeuticscommittee with input into formulary and druguse policy remains integral to a low-risktherapeutic interchange process.2 The pharmacyand therapeutics committee sets its institutionalstandard of practice with respect to the use ofdrugs. Therapeutic interchange policies arereviewed and approved by the pharmacy andtherapeutics committee, and this processprovides legal protection for practices that adhereto therapeutic interchange policy and procedure.The formulary represents a blend of clinical andpharmacoeconomic input. As long as theinterchange is devised with patient outcomessuch as patient risk and benefit in mind,formulary decisions can be determined to be astandard of care. The prescriber liability isreduced when policies are clearly delineated ininstitutional therapeutic interchange policies.Therapeutic interchange is a result of acompilation of formulary decisions based onclinical studies, consensus guidelines, packagelabeling, institutional quality information, andany other information the pharmacy andtherapeutics committee deems pertinent.

Health care liability risk is shared by healthcare personnel as well as the health careorganizations where they work. Corporateresponsibility dictates that the organizationproviding patient care have the responsibility to

oversee the quality of caregivers, care providedwithin its walls, safety and maintenance of thefacilities, and drug use policy and processes.33–35

Similar to the prescriber’s use of primaryliterature for risk management, the use of aformulary devised by a pharmacy and thera-peutics committee represents sound drug usevirtues, which protects the organization fromliability. In those patient care settings without aformal collaborative process, there is greater riskof breach in duty and unclear standards of care.The collaborative decisions of an organizedpharmacy and therapeutics committee providestructure and direction for pharmacists inperforming a therapeutic interchange.

Regulatory control of therapeutic interchangehas largely been a role of state boards ofpharmacy, whose rules and regulations differfrom state to state.33 Obvious liability occurswhen any actions are in direct conflict withgovernmental statute or regulation; otherwise,negligence is difficult to prove and piece togetherretrospectively. State law delegates the role ofdrug policy to the inpatient oversight committeesfor the health care organization (e.g., pharmacyand therapeutics committee).36 Rules andregulations in each state often are similar toprescribing and dispensing standards advocatedby professional organizations, such as theAmerican Medical Association (AMA) andASHP.37 Neither federal law (e.g., Food, Drug,and Cosmetics Act) nor the FDA provideinstruction on therapeutic interchange and, thus,have little historical impact on therapeuticinterchange. The role of the FDA in riskmanagement is intended for general populations,whereas physicians manage risk for theirindividual patients. Thus, the FDA has littleoversight of physician prescribing.38, 39 This keydifference limits the FDA’s role in therapeuticinterchange in a specific patient population.

Off-label use of drugs often is of some concernwhen considering drugs suitable for therapeuticinterchange. The likelihood of identical packageinsert indications for any two or more drugsinvolved in a therapeutic interchange isextremely unlikely. Because labeling is an FDAassignment of drug use, labeling is notnecessarily an up-to-date reflection of clinicaldrug application from the literature and may notaccount for more individualized application foreach practice setting. The FDA and packagelabeling are not restrictive of use of the drug,40

and use for off-label medical reasons becomes arisk-benefit analysis for each patient. Physician

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prescribing of drugs for off-label uses is not inviolation of the Food, Drug, and Cosmetic Act,40, 41

and restriction of this practice may limitphysician flexibility in providing optimal andindividualized care.42 Because therapeuticinterchange is still physician prescribing oftherapy per institutional standards of care,therapeutic interchange with drugs of differinglabeled indications is no different from any otheruse of drugs for off-label clinical indications.

Regulation of therapeutic interchange is notexplicit or standardized by accreditation bodiessuch as JCAHO. Therapeutic interchange isdefined, but no standards are mandated in its2002 or proposed 2004 standards.43 Thestandards dealing with selection, procurement,and storage pertain to prudent drug use but arenot unique to therapeutic interchange.

Professional Organizations’ Viewpoints

This section describes position statements ofpharmacy, physician, pharmaceutical industry,and health care organizations developed since theinitial ACCP statement on therapeuticinterchange published in 1993.1 Policies ofpharmacy associations are universally supportiveof therapeutic interchange. The AMA nowsupports therapeutic interchange under specificconditions. However, not all physician organi-zations are supportive. Manufacturers’ associa-tions have no stated position. Health careorganizations—primarily hospitals, integratedhealth systems, and managed care organiza-tions—have widely adopted therapeutic inter-change policies, thus demonstrating theirsupport.

Other Pharmacy Organizations

The ASHP supports therapeutic interchange asone type of policy for administering a formularysystem. It defines therapeutic interchange as “theact of dispensing therapeutic alternates inaccordance with previously established andapproved written guidelines or protocols.”44

Therapeutic alternates are defined as “drugproducts with different chemical structures butwhich are of the same pharmacological and/ortherapeutic class, and usually can be expected tohave similar therapeutic effects and adversereaction profiles when administered to patients intherapeutically equivalent doses.”44 Decisionsregarding formulary inclusion are “based onscientific and economic considerations thatachieve appropriate, safe, and cost-effective drug

therapy,” and include a process for prescribers touse a nonformulary drug “when medicallyindicated.”44

The California and Virginia Societies of Health-System Pharmacists also support therapeuticinterchange under collaborative agreementsamong physicians, pharmacists, and othersresponsible for health care.45, 46

The Academy of Managed Care Pharmacysupports the use of therapeutic interchangeprograms as part of a comprehensive approach tooptimize patient care. These programs should beguided by teams of practitioners who are “expertsin the diagnosis and treatment of disease.”47

The American Society of Consultant Pharmacistssupports therapeutic interchange, defined as “adynamic process that is administered by aninterdisciplinary committee” using establishedcriteria for selection of interchanged drugs.48

Authorization of the prescriber and evaluation ofeach patient before the interchange are required,and patients should be monitored after theinterchange.

The American Pharmacists Associationcontinues to support the concept of therapeuticinterchange “under arrangements in whichpharmacists and authorized prescribersinterrelate on behalf of the care of patients.”49 Ina statement developed in 1987, they supportcontinuing dialogue with other health careorganizations with regard to the role of thepharmacist.49

The American Association of Colleges ofPharmacy has no policy statement but includestherapeutic interchange in the educationaloutcomes that are expected of pharmacy studentsas part of the strategies that are used to manage aformulary system.50

The International Pharmaceutical Federationstates that “the concept of therapeutic inter-change…should be promoted.”51 Therapeuticinterchange is defined as dispensing “a medicinalproduct containing different active ingredientsbut which are of the same pharmacologicalclass…in accordance with a protocol previouslyestablished…or after individual prior consul-tation with the prescriber…designed to achievemaximum therapeutic benefit for the patient andto ensure the safest, most effective and economicuse of medicinal products.”51

The National Association of Boards ofPharmacy (NABP) adopted a resolution in 1993that encourages state boards of pharmacy toprovide a legislative basis for therapeuticinterchange, which “ensures that the patient

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receives the most appropriate drug therapy,” andthat NABP should encourage state boards to“work cooperatively with State Drug Use ReviewBoards to establish protocols based upon theguidelines identified by the Task Force onTherapeutic Interchange that would allowtherapeutic interchange by pharmacists in allpractice settings.”52

Physician and Other Health Organizations

The AMA has reversed its previous stance1 andnow supports therapeutic interchange, defined as“the authorized exchange of therapeuticalternates in accordance with previouslyestablished and approved written guidelines orprotocols within a formulary system.”53

Formulary systems are considered acceptable ininpatient hospital and outpatient settings thathave an organized medical staff and a functioningpharmacy and therapeutics committee. Specificstandards are defined for both the formularysystem and the pharmacy and therapeuticscommittee, including surveillance to monitorcompliance with the policy and clinicaloutcomes, a mechanism for the prescriber tooverride the system when necessary for patientcare, and objective evaluation of usefulness andcost of pharmaceuticals.

The American College of Physicians–AmericanSociety of Internal Medicine continues to supporttherapeutic interchange in hospitals that have afunctioning formulary system and pharmacy andtherapeutics committee. Their position includesa statement that “immediate prior consent fromthe authorized prescriber” should be obtained.54

If this statement is interpreted literally, it couldhinder the effectiveness of an interchange policybecause of the pharmacists’ time and theprescribers’ patience that are required to carryout notification, which may cancel out or evenexceed any financial benefit expected. Inpractice, most organizations inform the medicalstaff about formulary policies as they aredeveloped, and many notify individualprescribers through a progress note, oral notice,or a note on the drug administration record foreach act of therapeutic interchange.

The American Psychiatric Association has abrief statement opposing therapeutic interchangewithout the approval of the treating physician.55

The American Heart Association states that itopposes legislation that would permit pre-scription therapeutic interchange by pharmacistsbecause the pharmacist does not have all the

available clinical information for specificpatients.56 The National Kidney Foundationstates, “No therapeutic drug substitution of acritical dose drug should be allowed without theapproval of the prescribing physician orpatient.”57 The latter statement is in the contextof a discussion about generic drug substitution,but the wording and the intent suggest thattherapeutic interchange should similarly berestricted. All of these organizations opposetherapeutic interchange without physicianapproval. However, none of these groups states aposition specifically in relation to organizedhealth care.

Pharmaceutical Industry

Neither the Generic Pharmaceutical Associationnor the Pharmaceutical Research and Manufac-turers of America has a stated position ontherapeutic interchange. In the past, theyopposed efforts of health care organizations tolimit prescribing to certain products.58, 59

However, contracts developed by health careorganizations and buying groups with manufac-turers for products often include clauses thatrequire the organization to limit formularyproducts to a certain product or group ofproducts to achieve a favorable economic benefit.

Health Care Provider Organizations

The prevalence of therapeutic interchange hasincreased over the past decade. In 1994, theASHP survey of hospital pharmacy services foundthat therapeutic interchange was practiced in67.4% of hospitals.60 In 1996, the number hadincreased to 74.5%.61 In 1999, a survey of 463hospitals of more than 100 beds found that 88%of teaching hospitals, 89% of nonteachinghospitals, and 100% of investor-owned hospitalsused therapeutic interchange.22 A survey ofCanadian hospitals also found a prevalence rateof 89%.62 These findings suggest widespreadacceptance of the practice in hospitals, althoughthe extent of the practice varies widely.

Economic pressure has led to similar policiesin managed care settings. Inclusion ofprescription benefits in health insurance planshas increased, along with the use of tieredsystems that encourage the use of preferred drugproducts. Seeking permission to dispense adifferent product than that prescribed incommunity pharmacies as required by patients’insurance coverage is not well studied. A surveybased on a convenience sample in Virginia found

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that the rate of suggested interchanges was4.6/1000 prescriptions. In areas of the countrywhere the presence of health maintenanceorganizations is greater, the rate may be higher.5

In 1999, use of therapeutic interchange hadincreased to 38% in health maintenanceorganizations and to 56% of employer-sponsoredplans. About 75% of pharmacy benefit managersoffered such programs in 1997. However, thecurrent extent of use is not known.63

Hospitals, health systems, and managed careorganizations have conducted assessments oftherapeutic interchange policies in accordancewith recommendations from professionalorganizations. Hospitals also have begun toassess the impact of a therapeutic interchange onpatients’ access to drugs and continuity of careonce the patient has been discharged.6, 8, 13 Theseassessments have demonstrated both positive andnegative effects on patient care as well as costsavings, both of which are of great interest tohealth care organizations in a time when they aresqueezed between controlling costs and ensuringpatient safety.

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