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` APPROVED
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` DRUG
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`PRODUCTS
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` THERAPEUTIC
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` EQUIVALENCE
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`
` EVALUATIONS
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` 37th EDITION
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`THE PRODUCTS IN THIS LIST HAVE BEEN APPROVED UNDER
`SECTION 505 OF THE FEDERAL FOOD, DRUG, AND COSMETIC ACT.
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`
`
`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
`
`
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` 2017
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` APPROVED DRUG PRODUCTS
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` with
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` THERAPEUTIC EQUIVALENCE EVALUATIONS
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` The products in this list have been approved under section 505 of the
` Federal Food, Drug, and Cosmetic Act. This volume is current through
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`
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` December 31, 2016.
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` 37th EDITION
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` 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
`
`
`
`
`
` 2017
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` FOOD AND DRUG ADMINISTRATION
`
`
` CENTER FOR DRUG EVALUATION AND RESEARCH
`
`
` APPROVED DRUG PRODUCTS
`
`
` With
`
` Therapeutic Equivalence Evaluations
`
`
` CONTENTS
`
`
`
`
`
`
`
`
`
`
`
` PAGE
`
`
`
`
` PREFACE TO THIRTY SEVENTH 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 and Reference Standard............................................................ 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 ........................................... xxiii
`
`
`
`
`
` 1.10 Change of the Therapeutic Equivalence Evaluation for a Single Product .................... xxiii
`
`
`
`
`
`
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` 1.11 Discontinued Section ..................................................................................................xxiv
`
`
`
`
`
` 1.12 Changes to the Orange Book......................................................................................xxiv
`
`
`
`
`
`
` 1.13 Availability of the Edition ..............................................................................................xxv
`
`
`
`
`
`
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`
`
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`
`
`
`
`2
` HOW TO USE THE DRUG PRODUCTS LISTS ..............................................................2-1
`
`
`
`
`2.1
`Key Sections for Using the Drug Product Lists …………………….….………………......2-1
`
`
`
`
`
`2.2
`Drug Product Illustration ……………………………………………..….…………….……..2-3
`
`
`
`
`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
`
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`WATSON LABORATORIES, INC. , IPR2017-01622, Ex. 1086, p. 3 of 1400
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`

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`
` FOOD AND DRUG ADMINISTRATION
`
`
` CENTER FOR DRUG EVALUATION AND RESEARCH
`
`
` APPROVED DRUG PRODUCTS
`
`
` With
`
`Therapeutic Equivalence Evaluations
`
`
`
`
`
`
` PREFACE TO THIRTY SEVENTH 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). The main criterion for the inclusion of any product is that the
`product is the subject of an application with an approval that has not been
`withdrawn for safety or efficacy reasons. Inclusion of products in the
`Orange Book is independent of any current regulatory action through
`
`administrative or judicial means against a drug product. In addition, the
`Orange Book 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 Orange Book 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 Orange Book reflect FDA's
`
`application of specific criteria to the multisource prescription drug
`products listed in the Orange Book and approved under Section 505 of the FD&C
`
`Act. These evaluations are presented in the form of code letters that
`indicate the basis for the evaluation made. An explanation of the code
`appears in the Introduction.
`
`
`
`
`
`
`iv
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`WATSON LABORATORIES, INC. , IPR2017-01622, Ex. 1086, p. 4 of 1400
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`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 Orange Book 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 (Hatch-Waxman
`
`
`
`Amendments). The Hatch-Waxman Amendments require that FDA, among other
`
`things, make publicly available a list of approved drug products with monthly
`supplements. The Orange Book and its monthly Cumulative Supplements satisfy
`this requirement. The Addendum to this publication identifies drugs that
`
`qualify under the FD&C Act for periods of exclusivity and provides patent
`information concerning the listed drugs which also may delay the approval of
`ANDAs or 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 and Regulatory
`
`Support, Office of Generic Drug Policy, Office of Generic Drugs, Center for
`Drug Evaluation and Research, 7620 Standish Place, Rockville, MD 20855-2773.
`
`
`Comments received are publicly available to the extent allowable under the
`Freedom of Information Act and FDA regulations.
`
`
`
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`
`
`
` 1. INTRODUCTION
`
`
`
`
`
` 1.1 Content and Exclusion
`
`
`
`
` The Orange Book 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 name (proprietary name) 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 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 Hatch-
`
`Waxman 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 Orange
`Book. Tentative approval lists are available on FDA’s website at Drug
`
`
`
`
`
`Approval Reports. When the tentative approval becomes a final approval
`
`through a subsequent action letter to the applicant, the Agency will list the
`
`
`drug product and the date of approval in the appropriate approved drug
`
`product list.
`
`
`Distributors or repackagers of products listed in the Orange Book 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 Orange Book, depending on the
`dispensing requirements (prescription or OTC) or approval authority, unless the Orange Book staff
`is otherwise notified before publication.
`
`
`
`
`
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`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 formulated to contain the same
`
` amount of active ingredient, and to meet the same or compendial or other
`applicable standards (i.e., strength, quality, purity, and identity). 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 for which
`
`bioequivalence has been demonstrated, 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.
`
`
`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; and (5) they are manufactured in
`
`compliance with Current Good Manufacturing Practice regulations. The concept
`of therapeutic equivalence, as used to develop the Orange Book, 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 Orange Book 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.
`
`
`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
`full expectation that the substituted product will produce the same clinical
`effect and safety profile as the prescribed product.
`
`
`
`
`vii
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`
` Strength. Strength refers to the amount of drug substance contained in,
`
`
`delivered, or deliverable from a drug product, which includes: (1)(a) the
`total quantity of drug substance in mass or units of activity in a dosage
`unit or container closure (e.g., weight/unit dose, weight/volume or
`weight/weight in a container closure, or units/volume or units/weight in a
`container closure); and/or, as applicable, (b) the concentration of the drug
`substance in mass or units of activity per unit volume or mass (e.g., weight/
`weight, weight/volume, or units/volume); or (2) such other criteria the
`Agency establishes for determining the amount of drug substance contained in,
`delivered, or deliverable from a drug product if the weights and measures
`described in clause (1)(a) do not apply (e.g., certain drug-device
`combination products for which the amount of drug substance is emitted per
`use or unit time). 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 Orange Book, but rather
`
`intends to apply the criteria prospectively to drug products added to the
`
`Orange Book.
`
`
`The strength of drug products in the Orange Book 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 Orange Book
`
`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 drug action. For drug products that are not
`intended to be absorbed into the bloodstream, bioavailability may be assessed
`by scientifically valid measurements intended to reflect the rate and extent
`to which the active ingredient or active moiety becomes available at the site
`of drug 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.
`
`
`
`
`
`
`
`viii
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`WATSON LABORATORIES, INC. , IPR2017-01622, Ex. 1086, p. 8 of 1400
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`

`
`Where these above methods are not applicable (e.g., for drug products that
`are not intended to be absorbed into the bloodstream), other scientifically
`
` valid 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.
`
`
`
`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 and Reference Standard
`
`
`
`
`A reference listed drug (21 CFR 314.3(b)) means the listed drug identified
`by FDA as the drug product upon which an applicant relies in seeking approval
`of its ANDA. Generally, a reference listed drug is a drug product approved
`
`in a new drug application under section 505(c) of the FD&C Act based on full
`reports of investigations of safety and effectiveness. A reference standard
`
`is the drug product selected by FDA that an applicant seeking approval of an
`
`ANDA must use in conducting an in vivo bioequivalence study required for
`
`
`approval. FDA generally selects a single reference standard that ANDA
`applicants must use in in vivo bioequivalence testing. Ordinarily, FDA will
`
`select the reference listed drug as the reference standard. However, in some
`
`
`instances (e.g., where the reference listed drug has been withdrawn from sale
`
`and an ANDA is selected as the reference standard), the reference listed drug
`
`
`
`and the reference standard may be different.
`
`
`FDA has identified reference listed drugs in the Prescription Drug Product
`
`and OTC Drug Product Lists. Forthcoming, FDA will identify reference listed
`
`
`drugs in the Discontinued Drug Product List. These identified reference
`
`
`listed drugs represent drug products upon which an applicant can rely in
`seeking approval of an ANDA. FDA intends to update periodically the
`reference listed drugs identified in the Prescription Drug Product, OTC Drug
`
`Product, and Discontinued Drug Product Lists, as appropriate.
`
`
`FDA also has identified in the Prescription Drug Product and OTC Drug
`
`Product Lists reference standards to which the in vivo bioequivalence is
`
`
`compared. These identified reference standards represent the FDA’s best
`
`judgment at this time as to the appropriate comparator for purposes of in
`vivo bioequivalence testing.
`
`
`
`In some instances when a listed drug is not designated as a reference
`
`listed drug, such listed drug may be shielded from generic competition. If
`FDA has not designated a reference listed drug for a drug product the
`
`applicant intends to duplicate, the potential applicant may ask FDA to
`
`
`
` 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/default.htm; FDA Drugs
`guidance (Product-Specific Recommendations for Generic Drug Development) Web page at
`
`http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm075207.htm; see
`generally 21 CFR part 320.
`
`
`
`ix
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`WATSON LABORATORIES, INC. , IPR2017-01622, Ex. 1086, p. 9 of 1400
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`

`

`
`designate a reference listed drug for that drug product. Potential
`
`applicants should consult agency guidance related to referencing approved
`drug products in ANDA submissions for information on submitting such a
`request. If the request is granted, the listed drug will be designated as a
`
`reference listed drug, in which case an ANDA citing the designated reference
`
`
`listed drug may be submitted. Section 1.7, Therapeutic Equivalence
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`
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`Evaluations Codes (products meeting necessary bioequivalence requirements)
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`explains the character coding system (e.g., AB, AB1, AB2, AB3...) for
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`
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`multisource drug products listed under the same heading with two reference
`listed drugs.
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`A potential applicant should consult agency guidance related to
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`referencing approved drug products in ANDA submissions for information on
`submitting a request for selection of a reference standard. FDA may, on its
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`own initiative, select a new reference standard when doing so will help to
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`
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`ensure that potential applicants have adequate information required for in
`vivo bioequivalence studies, e.g., in the event that the listed drug
`currently selected as the reference standard has been withdrawn from sale for
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`other than safety and efficacy reasons. Historically, there were two
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`situations in which two listed drugs that had been shown to be bioequivalent
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`to each other had both been identified by the symbol “+” in the Orange Book.
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`
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`The first situation was when the in vivo determination of bioequivalence is
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`self-evident and a waiver of any in vivo bioequivalence may be granted. The
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`second situation was when the bioequivalence of two listed products may be
`determined through in vitro methodology.
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`
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`If an applicant has a question related to the appropriate reference
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`standard, it is recommended that an applicant planning to conduct an in vivo
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`bioequivalence study submit a controlled correspondence to the Office of
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`Generic Drugs.
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`
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`1.5 General Policies and Legal Status
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`
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`The Orange Book contains public information and advice. It does not
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`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 Orange Book sets forth FDA's
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`evaluations of the therapeutic equivalence of drug products that have been
`approved, it contains FDA's advice to the public, to practitioners, and to
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`the states regarding drug product selection. These evaluations do not
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`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 Orange Book 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 Orange Book does not necessarily
`
`mean that the drug product is either in violation of Section 505 of the FD&C
`
`
`Act, 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.
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`
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`1.6 Practitioner/User Responsibilities
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`
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`Professional care and judgment should be exercised in using the Orange
`Book. Evaluations of therapeutic equivalence for prescription drugs are based
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`
`x
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`WATSON LABORATORIES, INC. , IPR2017-01622, Ex. 1086, p. 10 of 1400
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`
`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.
`
`Multisource and single-source drug products. In the Orange Book, 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 in the Orange Book, but no therapeutic equivalence code is included
`
`with such products. Any drug product in the Orange Book repackaged and/or
`
`
`distributed by other than the applicant (e.g., an authorized generic) is
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`considered to be therapeutically equivalent to the applicant’s drug product
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`even if the applicant’s drug product is single source or coded as non-
`equivalent (e.g., BN). Also, although not identified in the Orange Book,
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`distributors or repackagers of an applicant’s drug product are considered to
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`have the same code as the applicant. The details of these codes and the
`
`policies underlying them are discussed