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Understanding the laws and principles of therapeutic equivalence and when substitution is allowable are important aspects of pharmacy technicians' training. Technicians need to be aware of when substitution is permitted and how these options can help patients and payers. Therapeutic substitution can be an important aspect of medication therapy management (MTM). By understanding more about therapeutic equivalence, technicians who participate in MTM will be better able to:

• conduct reconciliation and refine the personal medication list
• detect potential duplication of prescriptions
• assist pharmacists in determining substitution options as part of MTM
• have a better understanding of the laws governing their particular state

This module will review the terminology and procedures related to equivalence and substitution of medications, with an emphasis on relevance to MTM.

Defining the Terms Related to Equivalence and Substitution

Pharmaceutical Equivalents

Drug products are "pharmaceutical equivalents" if they meet all of the following criteria:

1. Contain the same active ingredient(s)
2. Have the same dosage form and route of administration
3. Are identical in strength or concentration

The drugs may differ in characteristics such as shape, release mechanism, labeling (to some extent), scoring, and excipients (e.g., colors, flavors, preservatives).¹

Pharmaceutical Alternatives

Drugs are considered "pharmaceutical alternatives" if they contain the same therapeutic moiety, but:

• are different salts, esters, or complexes (e.g., tetracycline hydrochloride and tetracycline phosphate complex)
• have different dosage forms (e.g., capsules vs. tablets)or strengths. (Data are generally not available for FDA to make the determination of tablet to capsule)

Different dosage forms or strengths of a given drug by a single manufacturer are also considered pharmaceutical alternatives. So are extended–release products relative to immediate– or standard– release formulations of the same active ingredient.¹

Bioavailability

Bioavailability refers to the rate (how quickly) and extent (how much of the product) to which an active ingredient is absorbed after administration and becomes available at the drug's site of action.

Bioequivalence

Bioequivalence of drug products is determined based on the drug's pharmacokinetics—how it is absorbed in the body. Drugs are deemed bioequivalent if:

1. The rate and extent of absorption of the test drug (usually a generic) are not significantly different from those of the reference drug (brand) when they are administered at the same molar dose under similar conditions, in either a single dose or multiple doses; or
2. The extent of absorption of the test drug does not differ significantly from that of the reference drug (as described above). There may be a difference in the rate of absorption, but this is intentional, is reflected in the product labeling, is not essential to the attainment of effective body drug concentrations during chronic use, and is considered medically insignificant for the drug. This might mean that a generic would need to be taken two times a day instead of once daily, but with regular use its effects would be equivalent.¹

Biosimilars

Biosimilars are considered by many to be the "generic" equivalent of bioengineered pharmaceutical products (biologic drugs). However, they are not generic copies because they are biologic products derived from a different cell line. According to the FDA, biosimilars are:²

• subsequent versions of an innovative biopharmaceutical product
• highly similar to the already FDA–approved biological "reference product"
• have been shown to have no clinically meaningful differences from the reference product.

Therapeutic Equivalence

Drug products are considered to be "therapeutic equivalents" only if:

• they are pharmaceutical equivalents and
• they can be expected to have the same clinical effect and safety profile when administered to patients under the conditions specified in the labeling.

The FDA's criteria for therapeutically equivalent products include:¹

1. The drug is approved as safe and effective
2. They are pharmaceutical equivalents which (a) contain identical amounts of the same active ingredient in the same dosage form and route of administration, and (b) meet required standards of strength, quality, purity, and identity
3. They are bioequivalent. Either the drugs (a) do not present a known or potential bioequivalence problem and meet an acceptable in vitro standard, or (b) may present a known or potential problem bioequivalence problem but it is within acceptable bioequivalence standards
4. There is adequate labeling
5. They are manufactured in compliance with Current Good Manufacturing Practice regulations.

The concept of therapeutic equivalence (as defined here) applies only to drug products containing the same active ingredient(s). It does not encompass different therapeutic agents that are used for the same condition (e.g., ibuprofen vs. naproxen for the treatment of pain).¹

The Orange Book: Listing of Therapeutic Equivalents

All 50 states have specific laws or regulations governing whether and how drug products may be substituted with a generic or equivalent agent. Each state sets its own formulary—either a "positive" formulary that lists the agents allowed for substitution, or a "negative formulary "stating that substitution is permitted for all drugs except those listed as specifically prohibited. The FDA provides a comprehensive, up–to–date list of all prescriptions approved as safe and effective, along with therapeutic equivalence determinations. This listing is published in the book Approved Drug Products With Therapeutic Equivalence Evaluations, otherwise known as The Orange Book, which is currently available in its 37th edition and in a free searchable format online at: www.fda.gov/Drugs/InformationOnDrugs/ucm129662.htm.¹ The electronic version on the FDA's website is searchable by active ingredient, the proprietary name of drug, and other fields. The information covers prescription drugs approved by the FDA as well as over–the– counter (OTC) drug products regulated by the FDA, and is updated with the most recently approved drugs.

Reference Listed Drug (RLD)

A reference–listed drug or "reference drug" means that the drug has been identified by the FDA as the product for comparison purposes in the approval of an Abbreviated New Drug Application (ANDA) for a generic equivalent.

Therapeutic Equivalence Evaluation Codes

"A" Rating: Drugs that are therapeutically equivalent to the reference drug, with no known bioequivalence problems. Sub–ratings are based on the dosage form, as shown below:

• AA = conventional dosage forms
• AN = solutions and powders for aerosolization
• AO = injectable oil solutions
• AP = injectable aqueous solutions or IV solutions
• AT = topical products

"AB" Rating: Therapeutically equivalent to each other. Known or potential bioequivalence problems may exist but have been found to meet standards for bioequivalence.

"B" Rating: Not therapeutically equivalent to other pharmaceutical products. Actual or potential bioequivalence problems have not been resolved.

• B* Requires FDA investigation to review therapeutic equivalence
• BC Extended–release dose forms
• BD Active ingredients and dosage forms with documented bioequivalence problems
• BE Delayed–release oral dosage forms
• BN Aerosol–nebulizer delivery systems
• BP Potential bioequivalence problems
• BS Products shown by the FDA to have deficient standards
• BT Topical products (ointments, gels, lotions) that are not bioequivalent
• BX Products for which the data are insufficient to determine therapeutic equivalence

The purpose of generic substitution is to save patients, government, and outside payers on their drug costs. Medicaid, Medicare, managed care plans, and most private insurers specify that certain generic substitutions must be made using therapeutically equivalent products that are on the preferred tiers of their formulary. If a patient or physician requests the branded agent, the patient may need to pay the full cost of the drug or a higher portion of the copayment. Pharmacists must work within state laws when making substitutions. Most states allow pharmacists to make substitutions with a therapeutically equivalent agent as long as the physician or prescriber does not specify the brand using specific wording. Some examples of that wording may include:³

• May Not Substitute (or No Substitution)
• Dispense as Written (or DAW)
• Brand Medically Necessary (or Brand Necessary)
• Substitution Not Permitted

Some states, such as North Carolina, specify that drugs with narrow therapeutic ranges must be dispensed as originally prescribed. Drugs with narrow therapeutic ranges are those for which there is a relatively small difference between the effective dose of the drug and a potentially toxic dose of the drug.

Tips for Techs in MTM

During MTM, the patient's drug regimen can be examined to see:

• if the patient has received duplicate prescriptions of the same drug under different names
• what alternatives may be allowed under the patient's drug reimbursement plan
• if additional cost savings can be found with further therapeutic substitution
• if copayments can be reduced with selection of a different agent

When therapeutic substitutions are made, it is important to include the patient in the decision and educate patients about how this may affect them. These may seem like simple switches to the pharmacy technician who is accustomed to handling medications, but many patients identify closely with the appearance of a medication. Substituting a pink pill for a blue pill or a different shape is likely to cause confusion—even for a highly educated consumer—and often leads the patient to question whether he or she has received an incorrect drug. Changes made through the MTM process need to be thoroughly explained to the patient: does the drug look different? Is it taken at different times of the day?

Pharmacy technicians need to be particularly careful about look–alike, sound–alike medications. As more medications are approved, there is a growing potential for similar–sounding names (either brand or generic names) to be confused. The Institute for Safe Medication Practices (ISMP) publishes a List of Confused Drug Names⁴ (updated February 2015) that compares some of the most commonly confused agents, such as Colazal and Clozaril, Zantac and Xanax, and Zyvox and Vioxx. ISMP recommendations for safeguarding against errors in cases of look–alike, sound–alike drugs include:

• using both brand and generic names on prescription labels
• including purpose of the medication on the prescription (e.g. "for hypertension")
• configuring computer selection screens to prevent these drugs from appearing consecutively
• changing the appearance of the name by capitalizing certain letters (e.g. "tall–man" lettering) to emphasize differences in the names. Example include acetaZOLAMIDE and acetaHEXAMIDE, or amLODIPine and aMILoride.⁴
• physically separating the products on the shelf, if they are usually placed in close proximity to each other.

Verifying prescription information is an essential part of the pharmacist's and pharmacy technicians' jobs, and is often necessary in MTM. When referring to a generic name or making a generic substitution, the dosage may be influenced simply by how the drug is written. The U.S. Library of Medicine's recommendation for consistency of drug names calls for removal of the "salt" modifier, unless the generic name has more than one salt.⁵ So, "pseudoephedrine tannate" would be written as "pseudoephedrine. Some medications do have different "salts" and may even call for different dosage schedules. For example, the beta–blocker metoprolol succinate calls for once–daily dosing, while metoprolol tartrate is dosed either twice or three times daily. In these cases, it may be necessary to confirm the correct prescription and dose with the prescriber. In addition, it may be necessary to clarify possible variations in the dosage form for single agent. If montelukast (Singulair) is prescribed for a child, is the prescription for a chewable tablet, or a swallowed tablet?

Educating Patients About Substitution

Although consumer acceptance of generic drugs has increased, there are still many people who believe that the generic is an inferior product and that it may adversely affect their health. A survey of 2,500 people in a large insurance plan showed that most consumers believe generic drugs are a better value than branded drugs, but they did not necessarily prefer them. Among the survey respondents, 56% said that "Americans should use more generics," but only 36% said they preferred to take generics.⁶ Direct–to–consumer advertising of pharmaceuticals can have a strong influence on patients' perceptions of whether they are getting the "best drug" available.^7,8

Patients may have assumptions about generic medications that are based on lack of knowledge about the approval and quality control processes involved in their approval. They may assume the quality or batch–to–batch consistency is lower, the drug might not be absorbed the same way in the body, or that they are more likely to cause side effects than the branded drug.^9,10

Physician prescribing behavior is another factor influencing substitution. Physicians may not prescribe generics due to habit, or due to concerns about the safety and efficacy of the generic product. A study based on data from the National Ambulatory Medical Care Survey found that the majority of physicians refer to drugs by their brand names rather than the generic names.¹¹ In some cases, physicians prescribe a branded drug out of habit, rather than intention.

There are sometimes actual differences between branded and generics that compel physicians to prefer the branded drug:³

• A generic drug can differ from the brand in inactive ingredients, as long as this does not interfere with therapeutic equivalence
• Patient sensitivities or allergies to inactive ingredients may necessitate using a branded version.
• Some health care providers are unwilling to substitute drugs with a narrow therapeutic index.
• Some professional societies have clinical practice guidelines that recommended branded agents for certain conditions. For example, in 2006 the American Academy of Neurology released a statement opposing generic substitution for anticonvulsant drugs used in the treatment of epilepsy without the approval of the attending physician

Tips for educating patients about generics

Patients may have misconceptions about generic medications or ask for the brand because they are concerned about quality. The following points have been provided by the FDA as part of patient education about generics.¹³

• Today nearly 8 out of 10 prescriptions filled in the United States are for generic drugs.
• The Food and Drug Administration's process for approval of a generic requires that the drug meet rigorous standards for strength, quality, purity, and potency.
• Generic drugs are required to have the same active ingredient, strength, dosage form, and route of administration as the brand. They do not need to contain the same inactive ingredients as the brand.
• Generic drugs do not need to have the same expensive clinical trials for safety and efficacy. Instead, manufacturers are required to show that the generic agent is "bioequivalent," meaning that it has same activity in the body.
• All generic manufacturing, packaging, and testing sites must pass the same quality standards as branded drugs.
• There are specific standards set by the FDA for batch–to–batch differences between generics or branded medications. In studies by the FDA, only small variations have been seen between brand and generic and these were not likely to be clinically relevant.
• The FDA does monitor adverse event reports for generics as it does for branded drugs.

Source: Food and Drug Administration. Facts About Generic Drugs. June 2016.¹³

Conclusion

The goal of MTM is to ensure that patients are receiving the best and most affordable medication regimen available. Pharmacy technicians have expanding roles as "pharmacist extenders," which may include interaction with patients for screening purposes, reviewing records to determine areas for streamlining or substituting certain drug regimens, and keeping records to ensure that the medication list is accurate. Many pharmacy technicians have knowledge that is highly relevant to this goal, including the formulary tiers for various payers, copayment structures for patients. In addition, patients often provide the pharmacy technician with information they may provide clues about medication adverse effects or adherence issues. The patient may say, "when I took that drug last night it made me nauseated," or, "I haven't been taking this medication because it makes me too tired." This type of information should be escalated to the pharmacist for consideration about decision–making in MTM.

References

1. U.S. Food and Drug Administration. Orange Book Preface. In: Approved Drug Products With Therapeutic Equivalence Evaluations, 37th ed. FDA Center for Drug Evaluation and Research. Available at: http://www.fda.gov/Drugs/DevelopmentApprovalProcess/ucm079068.htm.
2. U.S. Food and Drug Administration. Information for Consumers (Biosimilars). Updated 8/27/2015. Available at: https://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/TherapeuticBiologicApplications/Biosimilars/ucm241718.htm
3. U.S. Department of Health & Human Services. Assistant Secretary for Planning and Evaluation. Expanding the use of generic drugs. ASPE Issue Brief. Dec 1, 2010. Available at: http://aspe.hhs.gov/basic–report/expanding–use–generic–drugs – Trends.
4. Institute for Safe Medication Practices. ISMP's List of Confused Drug Names. Updated February 2015. Available at: http://www.ismp.org/Tools/confuseddrugnames.pdf.
5. Peters L, Kapusnik–Uner JE, Bodenreider O. Methods for managing variation in clinical drug names. AMIA Annu Symp Proc. 2010;2010:637–641.
6. Shrank WH, Cox ER, Fischer MA, et al. Patients' perceptions of generic medications. Health Aff (Millwood). 2009;28(2):546–556.
7. Ventola CL. Direct–to–Consumer Pharmaceutical Advertising: Therapeutic or Toxic? P T. 2011;36(10):669–684.
8. Aikin KJ, Swasy JL, Braman AC. Patient and physician attitudes and behaviors associated with DTC promotion of prescription drugs. Summary of FDA survey research results. Food and Drug Administration, Nov 19, 2004. Available at: https://www.fda.gov/downloads/AboutFDA/CentersOffices/CDER/ucm109877.pdf.
9. Al–Gedadi NA, Hassali MA, Shafie AA. A pilot survey on perceptions and knowledge of generic medicines among consumers in Penang, Malaysia. Pharm Pract (Granada). 2008;6(2):93–97.
10. Hassali MA, Shafie AA, Jamshed S, et al. Consumers' views on generic medicines: a review of the literature. Int J Pharm Pract. 2009;17(2):79–88.
11. Steinman MA, Chren MM, Landefeld CS. What's in a name? Use of brand versus generic drug names in United States outpatient practice. J Gen Intern Med. 2007;22(5):645–648.
12. American Academy of Neurology. Position Statement on the Coverage of Anticonvulsant Drugs for the Treatment of Epilepsy. November 2006. Available at: https://www.ncbi.nlm.nih.gov/pubmed/17438213
13. Food and Drug Administration. Facts about generic drugs. Updated Oct 6, 2017. Available at: https://www.fda.gov/drugs/resourcesforyou/consumers/buyingusingmedicinesafely/understanding genericdrugs/ucm167991.htm

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