`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` APPROVED
`
`
` DRUG
`
`PRODUCTS
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` WITH
`
`
`
`
` THERAPEUTIC
`
`
` EQUIVALENCE
`
`
` EVALUATIONS
`
` 36th EDITION
`
`
`
`
`
`
`
`
`
`
`
`
`THE PRODUCTS IN THIS LIST HAVE BEEN APPROVED UNDER
`
`SECTION 505 OF THE FEDERAL FOOD, DRUG, AND COSMETIC ACT.
`
`
`
` U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES
`
`
` FOOD AND DRUG ADMINISTRATION
`
` OFFICE OF MEDICAL PRODUCTS AND TOBACCO
`
`
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`
`
` OFFICE OF GENERIC DRUGS
`OFFICE OF GENERIC DRUG POLICY
`
`
`
`
`2016
`
`
`MYLAN - EXHIBIT 1091
`Mylan Laboratories Limited v. Aventis Pharma S.A.
`IPR2016-00712
`
`

`

`
`
` APPROVED DRUG PRODUCTS
`
`
` with
`
` THERAPEUTIC EQUIVALENCE EVALUATIONS
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` The products in this list have been approved under section 505 of the
` Federal Food, Drug, and Cosmetic Act. This volume is current through
`
`
`
` December 31, 2015.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` 36th EDITION
`
`
`
`
`
`
`
` U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES
`
`
` FOOD AND DRUG ADMINISTRATION
`
` OFFICE OF MEDICAL PRODUCTS AND TOBACCO
`
`
` CENTER FOR DRUG EVALUATION AND RESEARCH
`
`
`
` OFFICE OF GENERIC DRUGS
`
` OFFICE OF GENERIC DRUG POLICY
`
`
`
`
`
` 2016
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`

`

`
`
`
`
`FOOD AND DRUG ADMINISTRATION
`
`
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`
`APPROVED DRUG PRODUCTS
`
`
`with
`
`
`Therapeutic Equivalence Evaluations
`
`
` CONTENTS
`
`
`
`
`
` PAGE
`
`
`
`
`
`
` PREFACE TO THIRTY SIXTH EDITION……….………………………………..…................iv
`
`
`
`
`
` 1 INTRODUCTION................................................................................................................ vi
`
`
`
`
`
` 1.1 Content and Exclusion ................................................................................................... vi
`
`
`
`
`
`1.2
` Therapeutic Equivalence-Related Terms ....................................................................... vi
`
`
`
`
`
`
`
` 1.3 Further Guidance on Bioequivalence ............................................................................. ix
`
`
`
`
`
`
`1.4
` Reference Listed Drug ................................................................................................... ix
`
`
`
`
`
`
` 1.5 General Policies and Legal Status .................................................................................. x
`
`
`
`
`1.6
`Practitioner/User Responsibilities ................................................................................... x
`
`
`
`
`Therapeutic Equivalence Evaluations Codes .................................................................xii
`
`1.7
`
`
`
`1.8
` Description of Certain Special Situations ...................................................................... xx
`
`
`
`
`
`1.9
`Therapeutic Equivalence Code Change for a Drug Entity ............................................ xxii
`
`
`
`
`
`1.10 Change of the Therapeutic Equivalence Evaluation for a Single Product ..................... xxii
`
`
`
`
`
`
`1.11 Discontinued Section .................................................................................................. xxiii
`
`
`
`
`
`1.12 Changes to the Orange Book...................................................................................... xxiii
`
`
`
`
`
`
`1.13 Availability of the Edition .............................................................................................xxiv
`
`
`
`
`
`
`
`
`
`2
`
`
`2.1
`
`2.2
`
`2.3
`
`
` HOW TO USE THE DRUG PRODUCTS LISTS ..............................................................2-1
`
`
`
`
`
`Key Sections for Using the Drug Product Lists …………………….….………………......2-1
`
`
`
`Drug Product Illustration ……………………………………………..….…………….……..2-3
`
`
`
`
`Therapeutic Equivalence Evaluations Illustration ………………….….…………..………2-4
`
`
`
`
`DRUG PRODUCT LISTS
`
`
`Prescription Drug Product List ……………………………………….…………….………………...3-1
`
`
`
`OTC Drug Product List ……………………………………………….…………….…………………4-1
`
`
`
`Drug Products with Approval under Section 505 of the FD&C Act Administered
`
`
`
`
`by the Center for Biologics Evaluation and Research List ...……….…….………………...5-1
`
`
`
`
`
`Discontinued Drug Product List .…………………………………………….…….………………....6-1
`
`
`
`
`Orphan Products Designations and Approvals List …………….………….…….………………..7-1
`
`
`
`
`Drug Products Which Must Demonstrate in vivo Bioavailability
`
`
`
`
`
`Only if Product Fails to Achieve Adequate Dissolution …………………..………………………..8-1
`
`
`
`
`APPENDICES
`
`A. Product Name Index ……….…...………………………….………..……………………A-1
`
`
`B. Product Name Index Listed by Applicant ………………….……..……………………..B-1
`
`
`
`C. Uniform Terms …………………………………………….………..…………...………...C-1
`
`
`
`
`
`
`PATENT AND EXCLUSIVITY INFORMATION ADDENDUM ……….……..………………..........AD1
`
`
`A. Patent and Exclusivity Lists …………………………….…..……..……………..……ADA1
`
`
`
`B. Patent and Exclusivity Terms ...……………………….….………...…………………ADB1
`
`
`
`
`
`
`

`

`
`
`
`
`
`
`
` FOOD AND DRUG ADMINISTRATION
`
`
` CENTER FOR DRUG EVALUATION AND RESEARCH
`
`APPROVED DRUG PRODUCTS
`
`
`with
`
`Therapeutic Equivalence Evaluations
`
`
`
`
`
` PREFACE TO THIRTY SIXTH EDITION
`
`The publication, Approved Drug Products with Therapeutic Equivalence
`Evaluations (the List, commonly known as the Orange Book), identifies drug
`
`
`products approved on the basis of safety and effectiveness by the Food and
`Drug Administration (FDA) under the Federal Food, Drug, and Cosmetic Act (the
`FD&C Act). Drugs on the market approved only on the basis of safety (covered
`by the ongoing Drug Efficacy Study Implementation [DESI] review [e.g.,
`Donnatal® Tablets and Librax® Capsules] or pre-1938 drugs [e.g.,
`Phenobarbital Tablets]) are not included in this publication. The main
`
`criterion for the inclusion of any product is that the product is the subject
`of an application with an effective approval that has not been withdrawn for
`safety or efficacy reasons. Inclusion of products on the List is independent
`of any current regulatory action through administrative or judicial means
`against a drug product. In addition, the List contains therapeutic
`equivalence evaluations for approved multisource prescription drug products.
`These evaluations have been prepared to serve as public information and
`advice to state health agencies, prescribers, and pharmacists to promote
`public education in the area of drug product selection and to foster
`containment of health care costs. Therapeutic equivalence evaluations in
`this publication are not official FDA actions affecting the legal status of
`products under the FD&C Act.
`
`
`Background of the Publication. To contain drug costs, virtually every
`state has adopted laws and/or regulations that encourage the substitution of
`drug products. These state laws generally require either that substitution
`be limited to drugs on a specific list (the positive formulary approach) or
`that it be permitted for all drugs except those prohibited by a particular
`list (the negative formulary approach). Because of the number of requests in
`the late 1970s for FDA assistance in preparing both positive and negative
`formularies, it became apparent that FDA could not serve the needs of each
`state on an individual basis. The Agency also recognized that providing a
`single list based on common criteria would be preferable to evaluating drug
`products on the basis of differing definitions and criteria in various state
`laws. As a result, on May 31, 1978, the Commissioner of the Food and Drug
`
`Administration sent a letter to officials of each state stating FDA's intent
`to provide a list of all prescription drug products that are approved by FDA
`for safety and effectiveness, along with therapeutic equivalence
`determinations for multisource prescription products.
`
`
`The List was distributed as a proposal in January l979. It included only
`currently marketed prescription drug products approved by FDA through new
`drug applications (NDAs) and abbreviated new drug applications (ANDAs) under
`the provisions of Section 505 of the FD&C Act.
`
`
`
`
`The therapeutic equivalence evaluations in the List reflect FDA's
`application of specific criteria to the multisource prescription drug
`products on the List approved under Section 505 of the FD&C Act. These
`evaluations are presented in the form of code letters that indicate the basis
`
`
`iv
`
`

`

`
`for the evaluation made. An explanation of the code appears in the
`
`Introduction.
`
`A complete discussion of the background and basis of FDA's therapeutic
`
`equivalence evaluation policy was published in the Federal Register on
`
`
`
`January 12, 1979 (44 FR 2932). The final rule, which includes FDA's
`responses to the public comments on the proposal, was published in the
`Federal Register on October 31, 1980 (45 FR 72582). The first publication,
`October 1980, of the final version of the List incorporated appropriate
`corrections and additions. Each subsequent edition has included the new
`
`approvals and made appropriate changes in data.
`
`On September 24, 1984, the President signed into law the Drug Price
`
`
`Competition and Patent Term Restoration Act of 1984 (1984 Amendments). The
`1984 Amendments require that FDA, among other things, make publicly available
`a list of approved drug products with monthly supplements. The Approved Drug
`
`Products with Therapeutic Equivalence Evaluations publication and its monthly
`
`Cumulative Supplements satisfy this requirement. The Addendum to this
`publication identifies drugs that qualify under the 1984 Amendments for
`periods of exclusivity (during which ANDAs or applications described in
`Section 505(b)(2) of the FD&C Act for those drugs may not be submitted for a
`specified period of time and, if allowed to be submitted, would be
`tentatively approved) and provides patent information concerning the listed
`drugs which also may delay the approval of ANDAs or Section 505(b)(2)
`
`applications. The Addendum also provides additional information that may be
`
`helpful to those submitting a new drug application to the Agency.
`
`The Agency intends to use this publication to further its objective of
`obtaining input and comment on the publication itself and related Agency
`procedures. Therefore, if you have comments on how the publication can be
`improved, please send them to the Director, Division of Legal & Regulatory
`Support, Office of Generic Drugs, Center for Drug and Evaluation and
`
`
`Research, 7620 Standish Place, Rockville, MD 20855-2773. Comments received
`
`are publicly available to the extent allowable under the Freedom of
`
`Information regulations.
`
`
`v
`
`

`

`
`
`
`
` 1. INTRODUCTION
`
`
`
`
`
` 1.1 Content and Exclusion
`
`
`
`The List is composed of four parts: (1) approved prescription drug
`products with therapeutic equivalence evaluations; (2) approved
`over-the-counter (OTC) drug products for those drugs that may not be marketed
`without NDAs or ANDAs because they are not covered under existing OTC
`monographs; (3) drug products with approval under Section 505 of the FD&C Act
`administered by the Center for Biologics Evaluation and Research; and (4) a
`cumulative list of approved products that have never been marketed, are for
`
`exportation, are for military use, have been discontinued from marketing and
`
`we have not determined that they were withdrawn for safety or effectiveness
`reasons, or have had their approvals withdrawn for other than safety or
`efficacy reasons subsequent to being discontinued from marketing.1 This
`
`publication also includes indices of prescription and OTC drug products by
`trade or established name (if no trade name exists) and by applicant name
`
`(holder of the approved application). All established names for active
`ingredients generally conform to official compendial names or United States
`
`
`
`Adopted Names (USAN) as described in (21 CFR 299.4(e)). The latter list
`
`includes applicants’ names as abbreviated in this publication; in addition, a
`
`
`list of uniform terms is provided in Appendix C.
`
`
`An Addendum contains drug patent and exclusivity information for the
`
`
`Prescription, OTC, Discontinued Drug Product Lists, and for the Drug Products
`with Approval under Section 505 of the FD&C Act Administered by the Center
`for Biologics Evaluation and Research. The publication may include
`
`additional information that the Agency deems appropriate to disseminate.
`
`Prior to the 6th Edition, the publication had excluded OTC drug products
`and drug products with approval under Section 505 of the FD&C Act
`
`administered by the Center for Biologics Evaluation and Research. The 1984
`Amendments required the Agency to begin publishing an up-to-date list of all
`marketed drug products, OTC as well as prescription, that have been approved
`
`for safety and efficacy and for which new drug applications are required.
`
`
`Under the FD&C Act, some drug products are given tentative approvals. The
`
`
`
`Agency will not include drug products with tentative approvals in the List.
`Tentative approval lists are available on FDA’s website at Drug Approval
`
`
`
`Reports. When the tentative approval becomes a full approval through a
`subsequent action letter to the applicant, the Agency will list the drug
`
`product and the final approval date in the appropriate approved drug product
`
`list.
`
`Distributors or repackagers of products on the List are not identified.
`Because distributors or repackagers are not required to notify FDA when they
`shift their sources of supply from one approved manufacturer to another, it
`
`is not possible to maintain complete information linking product approval
`
`with the distributor or repackager handling the products.
`
`
`
`
`1.2 Therapeutic Equivalence-Related Terms
`
`
`
` 1 Newly approved products are added to parts 1, 2, or 3, of the List, depending on the dispensing
`requirements (prescription or OTC) or approval authority, unless the Orange Book staff is
`otherwise notified before publication.
`
`
`
`
`
`vi
`
`

`

`
`Pharmaceutical Equivalents. Drug products are considered pharmaceutical
`
`equivalents if they contain the same active ingredient(s), are of the same
`dosage form, route of administration and are identical in strength or
`concentration (e.g., chlordiazepoxide hydrochloride, 5mg capsules).
`Pharmaceutically equivalent drug products are formulated to contain the same
`amount of active ingredient in the same dosage form and to meet the same or
`compendial or other applicable standards (i.e., strength, quality, purity,
`and identity), but they may differ in characteristics such as shape, scoring
`configuration, release mechanisms, packaging, excipients (including colors,
`flavors, preservatives), expiration time, and, within certain limits,
`
`labeling.
`
`Pharmaceutical Alternatives. Drug products are considered pharmaceutical
`
`
`alternatives if they contain the same therapeutic moiety, but are different
`salts, esters, or complexes of that moiety, or are different dosage forms or
`
`strengths (e.g., tetracycline hydrochloride, 250mg capsules vs. tetracycline
`phosphate complex, 250mg capsules; quinidine sulfate, 200mg tablets vs.
`quinidine sulfate, 200mg capsules). Different dosage forms and strengths
`within a product line by a single manufacturer are thus pharmaceutical
`alternatives, as are extended-release products when compared with immediate-
`
`
`release or standard-release formulations of the same active ingredient.
`
`Therapeutic Equivalents. Drug products are considered to be therapeutic
`
`
`equivalents only if they are pharmaceutical equivalents and if they can be
`expected to have the same clinical effect and safety profile when
`administered to patients under the conditions specified in the labeling.
`
`
`FDA classifies as therapeutically equivalent those products that meet the
`following general criteria: (1) they are approved as safe and effective;
`
`(2) they are pharmaceutical equivalents in that they (a) contain identical
`amounts of the same active drug ingredient in the same dosage form and route
`of administration, and (b) meet compendial or other applicable standards of
`
`strength, quality, purity, and identity; (3) they are bioequivalent in that
`(a) they do not present a known or potential bioequivalence problem, and they
`
`meet an acceptable in vitro standard, or (b) if they do present such a known
`or potential problem, they are shown to meet an appropriate bioequivalence
`
`standard; (4) they are adequately labeled; (5) they are manufactured in
`compliance with Current Good Manufacturing Practice regulations. The concept
`of therapeutic equivalence, as used to develop the List, applies only to drug
`products containing the same active ingredient(s) and does not encompass a
`comparison of different therapeutic agents used for the same condition (e.g.,
`meperidine hydrochloride vs. morphine sulfate for the treatment of pain).
`Any drug product in the List repackaged and/or distributed by other than the
`
`
`applicant is considered to be therapeutically equivalent to the applicant’s
`
`drug product even if the applicant’s drug product is single source or coded
`as non-equivalent (e.g., BN). Also, distributors or repackagers of an
`
`applicant’s drug product are considered to have the same code as the
`applicant. Therapeutic equivalence determinations are not made for
`
`unapproved, off-label uses.
`
`
`FDA considers drug products to be therapeutically equivalent if they meet
`the criteria outlined above, even though they may differ in certain other
`characteristics such as shape, scoring configuration, release mechanisms,
`packaging, excipients (including colors, flavors, preservatives), expiration
`date/time and minor aspects of labeling (e.g., the presence of specific
`pharmacokinetic information) and storage conditions. When such differences
`are important in the care of a particular patient, it may be appropriate for
`
`the prescribing physician to require that a specific product be dispensed as
`a medical necessity. With this limitation, however, FDA believes that
`products classified as therapeutically equivalent can be substituted with the
`
`vii
`
`

`

`
`full expectation that the substituted product will produce the same clinical
`
`effect and safety profile as the prescribed product.
`
`
`
`Strength. Strength refers to the amount of drug substance (active
`
`
`ingredient) contained in, delivered, or deliverable from a drug product. Note
`that if the criteria the Agency establishes for determining and expressing
`
`the amount of drug substance in a product evolves over time, the Agency
`
`generally does not intend to revise the expressions of strength for drug
`
`products already included in the List, but rather intends to apply the
`
`
`criteria prospectively to drug products added to the List.
`
`
`The strength of drug products in the List is generally expressed in terms
`
`of the amount of drug substance (active ingredient) in the drug product, but
`
`is sometimes expressed in terms of the amount of the active moiety. For
`example, certain drug products included in the List include a designation of
`
`
`“EQ” next to their expression of strength. This “EQ” designation generally
`is used in connection with salt drug products to indicate that the strength
`
`of such drug product is being expressed in terms of the equivalent strength
`
`
`
`
`of the active moiety (e.g., “EQ 200MG BASE”), rather than in terms of the
`
`
`strength of the active ingredient.
`
`Bioavailability. This term means the rate and extent to which the active
`
`ingredient or active moiety is absorbed from a drug product and becomes
`available at the site of action. For drug products that are not intended to
`be absorbed into the bloodstream, bioavailability may be assessed by
`measurements intended to reflect the rate and extent to which the active
`
`ingredient or active moiety becomes available at the site of action.
`
`Bioequivalent Drug Products. This term describes pharmaceutical equivalent
`
`or pharmaceutical alternative products that display comparable
`bioavailability when studied under similar experimental conditions. Section
`505 (j)(8)(B) of the FD&C Act describes one set of conditions under which a
`test and reference listed drug (see Section 1.4) shall be considered
`
`bioequivalent:
`
`
`the rate and extent of absorption of the [test] drug do not show a
`significant difference from the rate and extent of absorption of the
`
`[reference] drug when administered at the same molar dose of the
`therapeutic ingredient under similar experimental conditions in either
`
`a single dose or multiple doses; or
`
`the extent of absorption of the [test] drug does not show a significant
`
`difference from the extent of absorption of the [reference] drug when
`administered at the same molar dose of the therapeutic ingredient under
`similar experimental conditions in either a single dose or multiple
`
`doses and the difference from the [reference] drug in the rate of
`absorption of the drug is intentional, is reflected in its proposed
`labeling, is not essential to the attainment of effective body drug
`concentrations on chronic use, and is considered medically
`
`insignificant for the drug.
`
`Where these above methods are not applicable (e.g., for drug products that
`
`are not intended to be absorbed into the bloodstream), other in vivo or in
`
`
`
`vitro test methods to demonstrate bioequivalence may be appropriate.
`
`For example, bioequivalence may sometimes be demonstrated using an in
`
`
`vitro bioequivalence standard, especially when such an in vitro test has been
`
`
`correlated with human in vivo bioavailability data. In other situations,
`bioequivalence may sometimes be demonstrated through comparative clinical
`
`trials or pharmacodynamic studies.
`
`
`
`
`
`viii
`
`

`

`
`
`
`
`1.3 Further Guidance on Bioequivalence
`
`
`
`FDA’s regulations and guidance documents provide additional information
`
`regarding bioequivalence and bioavailability, including methodologies and
`statistical criteria used to establish the bioequivalence of drug products.2
`
`
`
`
`
`1.4 Reference Listed Drug
`
`A reference listed drug (21 CFR 314.94(a)(3)) means the listed drug
`identified by FDA as the drug product upon which an applicant relies in
`
`seeking approval of its ANDA.
`
`
`FDA has identified in the Prescription Drug Product and OTC Drug Product
`
`Lists those reference listed drugs to which the in vivo bioequivalence
`
`(reference standard) and, in some instances, the in vitro bioequivalence of
`the applicant's product is compared. By designating a single reference
`listed drug as the standard to which all generic versions must be shown to be
`bioequivalent, FDA hopes to avoid possible significant variations among
`generic drugs and their brand name counterpart. Such variations could result
`
`if generic drugs were compared to different drugs.
`
`
`However, in some instances when a listed drug is not designated as the
`
`reference listed drug and/or not shown to be bioequivalent to the reference
`listed drug, such listed drug may be shielded from generic competition. An
`
`applicant wishing to market a generic version of a listed drug that is not
`
`designated as the reference listed drug may petition the Agency through the
`citizen petition procedure (see 21 CFR 10.25(a) and CFR 10.30). If the
`citizen petition is approved, the listed drug will be designated as an
`
`
`additional reference listed drug, in which case an ANDA citing the designated
`
`reference listed drug may be submitted. Section 1.7, Therapeutic Equivalence
`
`
`
`Evaluations Codes (products meeting necessary bioequivalence requirements)
`
`
`
`explains the character coding system (e.g., AB, AB1, AB2, AB3...) for
`
`multisource drug products listed under the same heading with two reference
`
`listed drugs.
`
`In addition, there are two situations in which two listed drugs that have
`
`been shown to be bioequivalent to each other have both been designated as
`reference listed drugs. The first situation is when the in vivo
`
`determination of bioequivalence is self-evident and a waiver of any in vivo
`bioequivalence may be granted. The second situation is when the
`
`bioequivalence of two listed products may be determined through in vitro
`
`methodology.
`
`
`
`Reference listed drugs are identified by the symbol "+" in the
`Prescription and Over-the-Counter (OTC) Drug Product Lists. These identified
`
`
`reference listed drugs represent the best judgment of the Office of
`
`Bioequivalence at this time. The Prescription and OTC Drug Product Lists
`
`
`2 We note that prior editions of the Preface to the Orange Book included a
`section entitled “Statistical Criteria for Bioequivalence.” Please see FDA’s
`regulations and guidance documents for additional information regarding
`
`bioequivalence and bioavailability. See FDA Drugs guidance Web page at
`http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/de
`fault.htm; FDA Drugs guidance (Product-Specific Recommendations for Generic
`
`Drug Development) Web page at
`http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/uc
`m075207.htm; see generally 21 CFR part 320.
`
`
`
`ix
`
`

`

`
`identify reference drugs for approved drug products. It is recommended that
`
`an applicant planning to conduct an in vivo bioequivalence study, or planning
`
`
`to manufacture a batch of a drug product for which an in vivo waiver of
`
`bioequivalence will be requested, submit a controlled correspondence to the
`
`
`Office of Generic Drugs to confirm the appropriate reference listed drug.
`
`
`
`
`
` 1.5 General Policies and Legal Status
`
`
`
`The List contains public information and advice. It does not mandate the
`drug products that are purchased, prescribed, dispensed, or substituted for
`one another, nor does it, conversely, mandate the products that should be
`avoided. To the extent that the List sets forth FDA's evaluations of the
`therapeutic equivalence of drug products that have been approved, it contains
`FDA's advice to the public, to practitioners, and to the states regarding
`
`drug product selection. These evaluations do not constitute determinations
`that any product is in violation of the FD&C Act or that any product is
`preferable to any other. Therapeutic equivalence evaluations are a
`scientific judgment based upon evidence, while generic substitution may
`involve social and economic policy administered by the states, intended to
`reduce the cost of drugs to consumers. To the extent that the List
`identifies drug products approved under Section 505 of the FD&C Act, it sets
`
`forth information that the Agency is required to publish and that the public
`is entitled to under the Freedom of Information Act. Exclusion of a drug
`product from the List does not necessarily mean that the drug product is
`either in violation of Section 505 of the FD&C Act, or that such a product is
`
`
`
`not safe or effective, or that such a product is not therapeutically
`equivalent to other drug products. Rather, the exclusion is based on the
`fact that FDA has not evaluated the safety, effectiveness, and quality of the
`drug product.
`
`
`
`1.6 Practitioner/User Responsibilities
`
`
`
`Professional care and judgment should be exercised in using the List.
`
`Evaluations of therapeutic equivalence for prescription drugs are based on
`scientific and medical evaluations by FDA. Products evaluated as
`therapeutically equivalent can be expected, in the judgment of FDA, to have
`equivalent clinical effect and no difference in their potential for adverse
`effects when used under the conditions of their labeling. However, these
`products may differ in other characteristics such as shape, scoring
`configuration, release mechanisms, packaging, excipients (including colors,
`flavors, preservatives), expiration date/time, and, in some instances,
`labeling. If products with such differences are substituted for each other,
`there is a potential for patient confusion due to differences in color or
`shape of tablets, inability to provide a given dose using a partial tablet if
`the proper scoring configuration is not available, or decreased patient
`acceptance of certain products because of flavor. For example, there may
`also be allergic reactions in rare cases due to a coloring or a preservative
`ingredient, as well as differences in cost to the patient.
`
`
`
`
`FDA evaluation of therapeutic equivalence in no way relieves practitioners
`
`of their professional responsibilities in prescribing and dispensing such
`products with due care and with appropriate information to individual
`patients. In those circumstances where the characteristics of a specific
`product, other than its active ingredient, are important in the therapy of a
`particular patient, the physician's specification of that product is
`appropriate. Pharmacists must also be familiar with the expiration
`dates/times and labeling directions for storage of the different products,
`particularly for reconstituted products, to assure that patients are properly
`
`advised when one product is substituted for another.
`
`x
`
`

`

`
`
`
`
`Multisource and single-source drug products. FDA has evaluated for
`
`therapeutic equivalence only multisource prescription drug products approved
`under Section 505 of the FD&C Act, which in most instances means those
`pharmaceutical equivalents available from more than one manufacturer. For
`such products, a therapeutic equivalence code is included and, in addition,
`product information is highlighted in bold face and underlined. Those
`products with approved applications that are single-source (i.e., there is
`only one approved product available for that active ingredient, dosage form,
`route of administration, and strength) are also included on the List, but no
`therapeutic equivalence code is included with such products. Any drug
`
`product in the List repackaged and/or distributed by other than the applicant
`
`(e.g., an authorized generic) is considered to be therapeutically equivalent
`
`
`to the applicant’s drug product even if the applicant’s drug product is
`single source or coded as non-equivalent (e.g., BN). Also, although not
`
`identified in the List, distributors or repackagers of an applicant’s drug
`
`product are considered to have the same code as the applicant. The details
`of these codes and the policies underlying them are discussed in Section 1.7,
`
`Therapeutic Equivalence Evaluations Codes.
`
`
`Products on the List are identified by the names of the holders of
`approved applications (applicants) who may not necessarily be the
`manufacturer of the product. There are numerous entities other than the
`
`
`applicant that may be involved in the development, manufacturing, and/or
`
`
`marketing of a product. The applicant may have had its product manufactured
`
`by a contract manufacturer and may simply be distributing the product for
`which it has obtained approval. In many instances, however, the manufacturer
`of the product is also the applicant. The name of the manufacturer is
`permitted by regulation to appear on the label, even when the manufacturer is
`not the marketer.
`
`
`
`Although the products on the List are identified by the names of the
`applicants, circumstances, such as changing corporate ownership, have
`sometimes made identification of the applicant difficult. The Agency
`believes, based on continuing document review and communication with firms,
`
`that the applicant designations on the List are, in most cases, correct.
`
`To relate firm name information on a product label to that on the List,
`
`the following should be noted: the applicant's name always appears on the
`
`
`List. This applies whether the applicant (firm name on the Form FDA 356h in
`the application) is the marketer (firm name in largest letters on the label)
`or not. However, the applicant's name may not always appear on the label of
`
`the product.
`
`If the applicant is the marketer, its name appears on the List and on the
`label; if the applicant is not the marketer, and the Agency is aware of a
`corporate relationship (e.g., parent and subsidiary) between the applicant
`and the marketer, the name of the applicant appears on the List and both firm
`names may appear on the label. Firms with known corporate relationships are
`displayed in Appendix B. If there is no known corporate relationship between
`the applicant and the marketer, the applicant's name appears on the List;
`however, unless the applicant is the manufacturer, packager, or distributor,
`the applicant's name may not appear on the label. In this case, the
`practitioner, from labeling alone, will not be able to relate the marketed
`product to an applicant cited in the