APPROVED
`DRUG
`PRODUCTS
`
`WITH
`
`THERAPEUTIC
`EQUIVALENCE
`EVALUATIONS
`33rd 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
`CENTER FOR DRUG EVALUATION AND RESEARCH
`OFFICE OF PHARMACEUTICAL SCIENCE
`OFFICE OF GENERIC DRUGS
`
`2013
`
`CIPLA EXHIBIT 1025
`Page 1 of 34
`
`

`

`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, 2012.
`
`33rd EDITION
`
`U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES
`FOOD AND DRUG ADMINISTRATION
`CENTER FOR DRUG EVALUATION AND RESEARCH
`OFFICE OF PHARMACEUTICAL SCIENCE
`OFFICE OF GENERIC DRUGS
`
`2013
`
`
`
`CIPLA EXHIBIT 1025
`Page 2 of 34
`
`

`

`FOOD AND DRUG ADMINISTRATION
`CENTER FOR DRUG EVALUATION AND RESEARCH
`APPROVED DRUG PRODUCTS
`with
`Therapeutic Equivalence Evaluations
`
`
`
`CONTENTS
`
`PAGE
`
`PREFACE TO THIRTY THIRD EDITION………………………………………..…................iv
`
`INTRODUCTION...................................................................................................................vi
`1
`Content and Exclusion......................................................................................................vi
`1.1
`Therapeutic Equivalence-Related Terms .........................................................................vi
`1.2
`Statistical Criteria for Bioequivalence............................................................................. viii
`1.3
`Reference Listed Drug.......................................................................................................x
`1.4
`General Policies and Legal Status ...................................................................................xi
`1.5
`Practitioner/User Responsibilities.....................................................................................xi
`1.6
`Therapeutic Equivalence Evaluations Codes................................................................. xiii
`1.7
`Description of Special Situations.....................................................................................xx
`1.8
`Therapeutic Equivalence Code Change for a Drug Entity............................................. xxii
`1.9
`1.10 Change of the Therapeutic Equivalence Evaluation for a Single Product.................... xxiii
`1.11 Discontinued Section.................................................................................................... xxiii
`1.12 Changes to the Orange Book....................................................................................... xxiii
`1.13 Availability of the Edition............................................................................................... xxiv
`
` 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 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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`FOOD AND DRUG ADMINISTRATION
`CENTER FOR DRUG EVALUATION AND RESEARCH
`APPROVED DRUG PRODUCTS
`with
`Therapeutic Equivalence Evaluations
`
`PREFACE TO THIRTY THIRD 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
`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 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 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 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.
`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
`iv
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`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 (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 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 Labeling and Program
`Support, HFD-610, Office of Generic Drugs, Center for Drug and Evaluation and
`Research, 7620 Standish Place, Rockville, MD 20855. Comments received are
`publicly available to the extent allowable under the Freedom of Information
`regulations.
`
`v
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`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 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, 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
`prescribed 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.
`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 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 Act administered by
`the Center for Biologics Evaluation and Research because the main purpose of
`the publication was to provide information to states regarding FDA's
`recommendation as to which generic prescription drug products were acceptable
`candidates for drug product selection. 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 1984 Amendments, some drug products are given tentative
`approvals. The Agency will not include drug products with tentative approval
`in the List. Tentative approval lists are available at ANDA (Generic) Drug
`Approvals. When the tentative approval becomes a full approval through a
`subsequent action letter to the application holder, 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
`Pharmaceutical Equivalents. Drug products are considered pharmaceutical
`equivalents if they contain the same active ingredient(s), are of the same
`
`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
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`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). Data are generally not available for FDA
`to make the determination of tablet to capsule bioequivalence. 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.,
`propoxyphene hydrochloride vs. pentazocine hydrochloride for the treatment of
`pain). Any drug product in the List repackaged and/or distributed by other
`than the application holder is considered to be therapeutically equivalent to
`the application holder's drug product even if the application holder's drug
`product is single source or coded as non-equivalent (e.g., BN). Also,
`distributors or repackagers of an application holder's drug product are
`considered to have the same code as the application holder. Therapeutic
`equivalence determinations are not made for unapproved, off-label indications.
`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 particular brand 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.
`Bioavailability. This term means the rate and extent to which the active
`ingredient or active moiety is absorbed from a drug product and becomes
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`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 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.
`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 Statistical Criteria for Bioequivalence
`Under the Drug Price Competition and Patent Term Restoration Act of 1984,
`manufacturers seeking approval to market a generic drug product must submit
`data demonstrating that the drug product is bioequivalent to the pioneer
`(innovator) drug product. A major premise underlying the 1984 law is that
`bioequivalent drug products are therapeutically equivalent, and therefore,
`interchangeable.
`Bioavailability refers to the rate and extent to which the active
`ingredient or therapeutic ingredient is absorbed from a drug product and
`becomes available at the site of drug action (Federal Food, Drug and Cosmetic
`Act, section 505(j)(8)). Bioequivalence refers to equivalent release of the
`same drug substance from two or more drug products or formulations. This
`leads to an equivalent rate and extent of absorption from these formulations.
`Underlying the concept of bioequivalence is the thesis that, if a drug product
`contains a drug substance that is chemically identical and is delivered to the
`site of action at the same rate and extent as another drug product, then it is
`equivalent and can be substituted for that drug product. Methods used to
`define bioequivalence can be found in 21 CFR 320.24, and include (1)
`pharmacokinetic (PK) studies, (2) pharmacodynamic (PD) studies, (3)
`comparative clinical trials, and (4) in-vitro studies. The choice of study
`used is based on the site of action of the drug and the ability of the study
`design to compare drug delivered to that site by the two products.
`The standard bioequivalence (PK) study is conducted using a two-treatment
`crossover study design in a limited number of volunteers, usually 24 to 36
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`adults. Alternately, a four-period, replicate design crossover study may also
`be used.
`Single doses of the test and reference drug products are
`administered and blood or plasma levels of the drug are measured over time.
`Pharmacokinetic parameters characterizing rate and extent of drug absorption
`are evaluated statistically. The PK parameters of interest are the resulting
`area under the plasma concentration-time curve (AUC), calculated to the last
`measured concentration (AUC(0-t)) and extrapolated to infinity (AUC(0-inf)), for
`extent of absorption; and the maximum or peak drug concentrations (Cmax), for
`rate of absorption. Crossover studies may not be practical in drugs with a
`long half-life in the body, and a parallel study design may be used instead.
`Alternate study methods, such as in-vitro studies or equivalence studies with
`clinical or pharmacodynamic endpoints, are used for drug products where plasma
`concentrations are not useful to determine delivery of the drug substance to
`the site of activity (such as inhalers, nasal sprays and topical products
`applied to the skin).
`The statistical methodology for analyzing these bioequivalence studies is
`called the two one-sided test procedure. Two situations are tested with this
`statistical methodology. The first of the two one-sided tests determines
`whether a generic product (test), when substituted for a brand-name product
`(reference) is significantly less bioavailable. The second of the two one-
`sided tests determines whether a brand-name product when substituted for a
`generic product is significantly less bioavailable. Based on the opinions of
`FDA medical experts, a difference of greater than 20% for each of the above
`tests was determined to be significant, and therefore, undesirable for all
`drug products. Numerically, this is expressed as a limit of test-product
`average/reference-product average of 80% for the first statistical test and a
`limit of reference-product average/test-product average of 80% for the second
`statistical test. By convention, all data is expressed as a ratio of the
`average response (AUC and Cmax) for test/reference, so the limit expressed in
`the second statistical test is 125% (reciprocal of 80%).
`For statistical reasons, all data is log-transformed prior to conducting
`statistical testing. In practice, these statistical tests are carried out
`using an analysis of variance procedure (ANOVA) and calculating a 90%
`confidence interval for each pharmacokinetic parameter (Cmax and AUC). The
`confidence interval for both pharmacokinetic parameters, AUC and Cmax, must be
`entirely within the 80% to 125% boundaries cited above. Because the mean of
`the study data lies in the center of the 90% confidence interval, the mean of
`the data is usually close to 100% (a test/reference ratio of 1). Different
`statistical criteria are sometimes used when bioequivalence is demonstrated
`through comparative clinical trials pharmacodynamic studies, or comparative
`in-vitro methodology.
`The bioequivalence methodology and criteria described above simultaneously
`control for both differences in the average response between test and
`reference, as well as the precision with which the average response in the
`population is estimated. This precision depends on the within-subject (normal
`volunteer or patient) variability in the pharmacokinetic parameters (AUC and
`Cmax) of the two products and on the number of subjects in the study. The
`width of the 90% confidence interval is a reflection in part of the within-
`subject variability of the test and reference products in the bioequivalence
`study. A test product with no differences in the average response when
`compared to the reference might still fail to pass the bioequivalence criteria
`if the variability of one or both products is high and the bioequivalence
`study has insufficient statistical power (i.e., insufficient number of
`subjects). Likewise, a test product with low variability may pass the
`bioequivalence criteria, when there are somewhat larger differences in the
`average response.
`This system of assessing bioequivalence of generic products assures that
`these substitutable products do not deviate substantially in in-vivo
`performance from the reference product. The Office of Generic Drugs has
`conducted two surveys to quantify the differences between generic and brand
`name products. The first survey included 224 bioequivalence studies submitted
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`in approved applications during 1985 and 1986. The observed average
`differences between reference and generic products for AUC was 3.5% (JAMA,
`Sept. 4, 1987, Vol. 258, No. 9). The second survey included 127
`bioequivalence studies submitted to the agency in 273 ANDAs approved in 1997.
`The three measures reviewed include AUC(0-t), AUC(0-inf), and Cmax. The observed
`average differences between the reference and generic products were + 3.47%
`(SD 2.84) for AUC(0-t), + 3.25% (SD 2.97) for AUC(0-inf), and + 4.29% (SD 3.72)
`for Cmax (JAMA, Dec. 1, 1999, Vol. 282, No. 21).
`The primary concern from the regulatory point of view is the protection of
`the patient against approval of products that are not bioequivalent. The
`current practice of carrying out two one-sided tests at the 0.05 level of
`significance ensures that there is no more than a 5% chance that a generic
`product that is not truly equivalent to the reference will be approved.
`
`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 reference listed drugs. However,
`in some instances when listed drugs are approved for a single drug product, a
`product not designated as the reference listed drug and not shown to be
`bioequivalent to the reference listed drug may be shielded from generic
`competition. A firm 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). When the
`Citizen Petition is approved, the second listed drug will be designated as an
`additional reference listed drug and the petitioner may submit an Abbreviated
`New Drug Application citing the designated reference listed drug. Section
`1.7, Therapeutic Equivalence Evaluations Codes products meeting necessary
`bioequivalence requirements explains the (AB, AB1, AB2, AB3... coding system
`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 may both be designated as
`reference listed drugs. The first situation occurs when the in vivo
`determination of bioequivalence is self-evident and a waiver of the in vivo
`bioequivalence may be granted. The second situation occurs when the
`bioequivalence of two listed products may be determined through in vitro
`methodology. The reference listed drug is 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 Division of
`Bioequivalence at this time. The Prescription and OTC Drug Product Lists
`identify reference drugs for oral dosage forms, Injectables, ophthalmics,
`otics, and topical products. It is recommended that a firm 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, contact the Division of Bioequivalence, Office of Generic Drugs, to
`confirm the appropriate reference listed drug.
`
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`1.5 General Policies and Legal Status
`The List contains public information and advice. It does not mandate the
`drug products which is 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 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 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 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. There may also be better
`stability of one product over another under adverse storage conditions, or
`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 thei