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Approved Drug Products |
U.S. Food and Drug Administration • Center for Drug Evaluation and Research |
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Approved Drug Products |
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Food and Drug Administration PREFACE TO TWENTY SECOND EDITION
The publication, Approved Drug Products with Therapeutic Equivalence Evaluations (the List), 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., Donnatal7 Tablets and Librax7 Capsules] or pre-1938 drugs [e.g., Phenobarital 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of any product is that the product is the subject of an application with an effective approval that has not been withdrawn for safety or efficacy reasons.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 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), 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 approved multisource prescription drug products on the List. 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 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 Data Management and Services, Office of Information Technology, Center for Drug and Evaluation and Research, HFD-90, 5600 Fishers Lane, Rockville, MD 20857. Comments received are publicly available to the extent allowable under the Freedom of Information regulations. 1. INTRODUCTIONThe 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, have been discontinued from marketing, or have had their approvals withdrawn for other than safety or efficacy reasons subsequent to being discontinued from marketing. 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 and OTC 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. This publication also includes additional information, such as Orphan Drug Product Designations and other data 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 were given tentative approval. Prior to the effective date, the Agency will not include drug products with tentative approval in the List; however, they are available in the FDA Drug Product Approvals List on the Internet World Wide Web. 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, effective 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 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- 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; and (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 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)(7)(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:
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 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 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. 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 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 multiple NDAs 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 an NDA listed drug that is not designated as the reference listed 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 NDA 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... SS 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 determination of bioequivalence may be granted. The second situation occurs when the bioequivalence of two NDA drug 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 judgement 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. Acyclovir 200mg Tablet-Reference Listed Drug. Novopharm’s single source acyclovir tablets have been declared to be a reference listed drug for the 200 mg tablet in addition to the acylcovir (Zovirax) 800 mg tablet of the innovator. A generic firm wishing to submit an ANDA for a duplicate of the 200 mg acyclovir tablet will be eligible for a waiver of the in vivo determination of bioequivalence (1) if their product is proportionally similar in its active and inactive ingredients to their own 800 mg acyclovir tablet and (2) by doing an acceptable comparative dissolution test (dissolution profile) against Novopharm’s 200 mg acyclovir reference listed drug. Before a waiver of the in vivo determination of bioequivalence can be granted for the 200 mg acyclovir tablet, the generic firm must have completed an acceptable fasting and fed study comparing their acyclovir 800 mg tablet against the Zovirax 800 mg tablet. For further information on the study designs, you should contact the Division of Bioequivalence, Office of Generic Drugs. 1.5 General Policies and Legal Status The List contains public information and advice. It does not mandate the drug products which may be 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 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. FDA has evaluated for therapeutic equivalence only multisource prescription drug products, 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 and route of administration) 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 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, although not identified in the List, distributors or repackagers of an application holder's drug product are considered to have the same code as the application holder. 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. 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 most 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 List, and hence to a specific approved drug product. In such cases, to assure that the product in question is the subject of an approved application, the firm named on the label should be contacted. To relate trade name (proprietary name) information on a product label to that on the List, the following should be noted: if the applicant is the marketer, its name appears on the List and on the label; if the Agency is aware of a corporate relationship between the applicant and the marketer, the trade name (proprietary name) of the drug product (established drug name if no trade name exists) appears on the List. If a corporate relationship exists between an application holder and a marketer and both firms are distributing the drug product, the FDA reserves the right to select the trade name of either the marketer or the application holder to appear on the List. If there is no known corporate relationship between the applicant and the marketer, the established drug name appears on the List. Every product on the List is subject at all times to regulatory action. From time to time, approved products may be found in violation of one or more provisions of the Act. In such circumstances, the Agency will commence appropriate enforcement action to correct the violation, if necessary, by securing removal of the product from the market by voluntary recall, seizure, or other enforcement actions. Such regulatory actions are, however, independent of the inclusion of a product on the List. The main criterion for inclusion of a product is that it has an application with an effective approval that has not been withdrawn for safety or efficacy reasons. FDA believes that retention of a violative product on the List will not have any significant adverse health consequences, because other legal mechanisms are available to the Agency to prevent the product's actual marketing. FDA may however, change a product's therapeutic equivalence rating if the circumstances giving rise to the violation change or otherwise call into question the data upon which the Agency's assessment of whether a product meets the criteria for therapeutic equivalence was made.
1.7 Therapeutic Equivalence Evaluations Codes
The coding system for therapeutic equivalence evaluations is constructed to allow users to determine quickly whether the Agency has evaluated a particular approved product as therapeutically equivalent to other pharmaceutically equivalent products (first letter) and to provide additional information on the basis of FDA's evaluations (second letter). With few exceptions, the therapeutic equivalence evaluation date is the same as the approval date. The two basic categories into which multisource drugs have been placed are indicated by the first letter as follows:
Individual drug products have been evaluated as therapeutically equivalent to the reference product in accordance with the definitions and policies outlined below:
"A" CODES Drug products that are considered to be therapeutically equivalent to other pharmaceutically equivalent products. "A" products are those for which actual or potential bioequivalence problems have been resolved with adequate in vivo and/or in vitro evidence supporting bioequivalence. Drug products designated with an "A" code fall under one of two main policies:
There are some general principles that may affect the substitution of pharmaceutically equivalent products in specific cases. Prescribers and dispensers of drugs should be alert to these principles so as to deal appropriately with situations that require professional judgment and discretion. There may be labeling differences among pharmaceutically equivalent products that require attention on the part of the health professional. For example, pharmaceutically equivalent powders to be reconstituted for administration as oral or injectable liquids may vary with respect to their expiration time or storage conditions after reconstitution. An FDA evaluation that such products are therapeutically equivalent is applicable only when each product is reconstituted, stored, and used under the conditions specified in the labeling of that product. The Agency will use notes in this publication to point out special situations such as potential differences between two drug products that have been evaluated as bioequivalent and otherwise therapeutically equivalent, when they should be brought to the attention of health professionals. These notes are contained in Section 1.8, Description of Special Situations. For example, in rare instances, there may be variations among therapeutically equivalent products in their use or in conditions of administration. Such differences may be due to patent or exclusivity rights associated with such use. When such variations may, in the Agency's opinion, affect prescribing or substitution decisions by health professionals, a note will be added to Section 1.8. Also, occasionally a situation may arise in which changes in a listed drug product after its approval (for example, a change in dosing interval) may have an impact on the substitutability of already approved generic versions of that product that were rated by the Agency as therapeutically equivalent to the listed product. When such changes in the listed drug product are considered by the Agency to have a significant impact on therapeutic equivalence, the Agency will change the therapeutic equivalence ratings for other versions of the drug product unless the manufacturers of those other versions of the product provide additional information to assure equivalence under the changed conditions. Pending receipt of the additional data, the Agency may add a note to Section 1.8, or, in rare cases, may even change the therapeutic equivalence rating. In some cases (e.g., Isolyte7 S w/ Dextrose 5% in Plastic Container and Plasma-Lyte7 148 and Dextrose 5% in Plastic Container), closely related products are listed as containing the same active ingredients, but in somewhat different amounts. In determining which of these products are pharmaceutically equivalent, the Agency has considered products to be pharmaceutically equivalent with labeled strengths of an ingredient that do not vary by more than 1%. Different salts and esters of the same therapeutic moiety are regarded as pharmaceutical alternatives. For the purpose of this publication, such products are not considered to be therapeutically equivalent. There are no instances in this List where pharmaceutical alternatives are evaluated or coded with regard to therapeutic equivalence. Anhydrous and hydrated entities, as well as different polymorphs, are considered pharmaceutical equivalents and must meet the same standards and, where necessary, as in the case of ampicillin/ampicillin trihydrate, their equivalence is supported by appropriate bioavailability/bioequivalence studies. The codes in this book are not intended to preclude health care professionals from converting pharmaceutically different concentrations into pharmaceutical equivalents using accepted professional practice. Where package size variations have therapeutic implications, products so packaged have not been considered pharmaceutically equivalent. For example, some oral contraceptives are supplied in 21-tablet and 28-tablet packets; the 28-tablet packets contain 7 placebo or iron tablets. These two packaging configurations are not regarded as pharmaceutically equivalent; thus, they are not designated as therapeutically equivalent. Preservatives may differ among some therapeutically equivalent drug products. Differences in preservatives and other inactive ingredients do not affect FDA's evaluation of therapeutic equivalence except in cases where these components may influence bioequivalence or routes of administration. The specific sub-codes for those drugs evaluated as therapeutically equivalent and the policies underlying these sub-codes follow:
"B" CODES
Drug products that FDA, at this time, considers not to be therapeutically equivalent to other pharmaceutically equivalent products. "B" products, for which actual or potential bioequivalence problems have not been resolved by adequate evidence of bioequivalence, often have a problem with specific dosage forms rather than with the active ingredients. Drug products designated with a "B" code fall under one of three main policies:
The specific coding definitions and policies for the "B" sub-codes are as follows:
1.8 Description of Special Situations
Certain drugs present special situations that deserve a more complete explanation than can be provided by the two-letter codes used in the List. These drugs have particular problems with standards of identity, analytical methodology, or bioequivalence that are in the process of resolution. The following drugs are in this category: Amino Acid and Protein Hydrolysate Injections. These products differ in the amount and kinds of amino acids they contain and, therefore, are not considered pharmaceutical equivalents. For this reason, these products are not considered therapeutically equivalent. At the same time, the Agency believes that it is appropriate to point out that where nitrogen balance is the sole therapeutic objective and individual amino acid content is not a consideration, pharmaceutical alternatives with the same total amount of nitrogen content may be considered therapeutically equivalent. Diclofenac Sodium Ophthalmic Solution 0.1%. Two NDAs have been approved for diclofenac sodium ophthalmic solution 0.1% (DSOS), (1) Ciba’s NDA 20-037 for Voltaren and (2) Falcon Pharms' (Alcon) NDA 20-809 for DSOS. Alcon was required to do a study comparing their DSOS to Voltaren and to a placebo control in post cataract surgical inflammation. This study was necessary to demonstrate that the different formulation of the Alcon drug product did not affect the safety and/or effectiveness of the proposed drug product for this indication. Prior to the approval of Alcon’s DSOS Ciba did clinical studies and was approved for two additional indications for the temporary relief of pain and photophobia in patients undergoing corneal refractive surgery. Three years of Waxman-Hatch marketing exclusivity was granted to Ciba for these two new uses. Since the treatment of pain has a different site of action than the anti-inflammatory or photophobia indications, the Agency did not have information to support a recommendation that the Alcon and Ciba DSOS are therapeutically equivalent for the treatment of pain. The designation of therapeutic equivalence at this time applies only to the anti-inflammatory indication. The therapeutic equivalence designation will apply to the photophobia indication upon expiration of Ciba’s marketing exclusivity. Follitropin Alfa and Beta. Based on available data derived from physico-chemical tests and bioassay, follitropin alfa and follitropin beta are indistinguishable. Ribavirin 200mg Oral Capsule. Indicated for use and comarketed with interferon alfa-2b, recombinant (Intron A), as Rebetron Combination Therapy. Gaviscon7. Gaviscon7 is an OTC product which has been marketed since September 1970. The active ingredients in this product, aluminum hydroxide and magnesium trisilicate, were reviewed by the Agency's OTC Antacid Panel and were considered to be safe and effective ingredients (Category I) by that Panel. However, the tablet failed to pass the antacid test which is required of all antacid products. The Agency, therefore, placed the tablet in Category III for lack of effectiveness. A full NDA with clinical studies was submitted by Marion Laboratories, Inc., and approved by FDA on December 9, 1983. Gaviscon7 's activity in treating reflux acidity is made possible by the physical-chemical properties of the inactive ingredients, sodium bicarbonate and alginic acid. Therefore, all ANDAs which cite Gaviscon7 tablets as the listed drug must contain the inactive ingredients sodium bicarbonate and alginic acid. A full NDA will be required to support the effectiveness of the drug product if different inactive ingredients are to be substituted for sodium bicarbonate or alginic acid or if different proportions of these ingredients are to be used. Metaxalone Tablets. In Cumulative Supplement 6 of the Approved Drug Products with Therapeutic Equivalence Evaluations, 21st Edition, (the Orange Book), the Agency proposed to reclassifiy metaxalone tablets from a drug product not presenting bioequivalence problems to one that has a known or potential bioequivalence problem that requires an in vivo demonstration of bioequivalence as a condtiion of approval for an ANDA. The Agency solicited comments from interested persons to be received no later than November 30, 2001. No comments were received. Accordingly, the therapeutic equivalence category for metaxalone tablets will be changed from a "nonbioproblem drug" to a "bioproblem drug." An ANDA for metaxalone tablets must include acceptable in vivo bioequivalence study or studies. As long as metaxalone tablets are a single source drug product, no therapeutic equivalence code will be assigned to the product in the Orange Book. If the Agency approves an ANDA for metaxalone tablets, the innovator's NDA for metaxalone (Skelaxin) tablets and the approved ANDA will both be coded as "AB".
1.9 Therapeutic Equivalence Code Change for a Drug Entity
The Agency will use the following procedures when, in response to a petition or on its own initiative, it is considering a change in the therapeutic equivalence code for approved multi-source drug products. Such changes will generally occur when the Agency becomes aware of new scientific information affecting the therapeutic equivalence of an entire category of drug products in the List (e.g., information concerning the active ingredient or the dosage form), rather than information concerning a single drug product within the category. These procedures will be used when a change in therapeutic equivalence code is under consideration for all drug products found in the Prescription Drug Product List under a specific drug entity and dosage form. The change may be from the code signifying that the drug does not present a bioequivalence problem (e.g., AA) to a code signifying a bioequivalence problem (e.g., BP), or vice versa. This procedure does not apply to a change of a particular product code (e.g., a change from BP to AB or from AB to BX). Before making a change in a therapeutic equivalence code for an entire category of drugs, the Agency will announce in the Introduction to the Cumulative Supplement that it is considering the change, and will invite comment. Comments, along with scientific data, may be sent to the Director, Division of Bioequivalence, Office of Generic Drugs, Center for Drug Evaluation and Research, (MPN-2) HFD-650, 7500 Standish Place, Rockville, MD 20855. The comment period will generally be 60 days in length, and the closing date for comments will be listed in the description of the proposed change for each drug entity. The most useful type of scientific data submission is an in vivo bioavailability/bioequivalence study conducted on batches of the subject drug products. These submissions should present a full description of the analytical procedures and equipment used, a validation of the analytical methodology, including the standard curve, a description of the method of calculating results, and a description of the pharmacokinetic and statistical models used in analyzing the data. Anecdotal or testimonial information is the least useful to the Agency, and such submissions are discouraged. Copies of supporting reports published in the scientific literature or unpublished material, however, are welcome.
1.10 Change of the Therapeutic Equivalence Evaluation for a Single Product
The aforementioned procedure does not apply to a change in a single drug product code. For example, a change in a single drug product's code from BP to AB as a result of the submission of a bioequivalence study ordinarily will not be the subject of notice and comment. Likewise, a change in a single drug product's code from AB to BX (e.g., as a result of new information raising a significant question as to bioequivalence) does not require notice and comment. The Agency's responsibility to provide the public with the Agency's most current information related to therapeutic equivalence may require a change in a drug product's code prior to any formal notice and opportunity for the applicant to be heard. The publication in the Federal Register of a proposal to withdraw approval of a drug product will ordinarily result in a change in a product's code from AB to BX if this action has not already been taken.
1.11 Availability of Internal Policy and Procedure Guides
The Office of Generic Drugs maintains internal policy and procedure guides. Although these guides are designed for Office personnel and are subject to change without public notice, they are available to members of the public who may wish to know more about the Office's policies and procedures. Copies of these guides may be obtained from the FDA, Center for Drug Evaluation and Research, HFD-210, Division of Communications Management, Drug Information Branch, 5600 Fishers Lane, Rockville, MD 20857. The Agency welcomes public comment on the policies, procedures, and practices employed in the approval of generic drugs. Such comments may be sent to the Director, Office of Generic Drugs, (MPN-2) HFD-600, 7500 Standish Place, Rockville, MD 20855.
1.12 Discontinued Section
2. HOW TO USE THE DRUG PRODUCT LISTS
2.1 Key Sections for Using the Drug Product Lists This publication contains illustrations, along with Drug Product Lists, indices, and lists of abbreviations and terms which facilitate their use. Illustrations. The annotated Drug Product Illustration, see Section 2.2, and the Therapeutic Equivalence Evaluations Illustration, see Section 2.3, are offered to provide further clarification. These depict the format found in the Prescription Drug Product List (the only list in which therapeutic equivalence evaluation codes are displayed). Drug Product Lists. The Drug Product Lists, arranged alphabetically by active ingredient, contain product identification information (active ingredients, dosage forms, routes of administration, product names, application holders, strengths) for single and multiple ingredient drug products. Also shown are the application number and drug product number (FDA internal computer data use only) and approval dates for those drug products approved on or after January 1, 1982. If a prescription drug product is available from more than one source (multisource), a therapeutic equivalence code will appear in front of the applicant's name. If a product is therapeutically equivalent to one or more products or to an appropriate reference, it will be designated with a code beginning with "A" and the entry will be underlined and printed in bold font for emphasis. Active ingredient headings for multiple ingredient (combination) drug products are arranged alphabetically. For purposes of this publication, this alphabetical sort takes precedence over United States Pharmacopeia official monograph order (i.e., Reserpine, Hydralazine Hydrochloride, Hydrochlorothiazide). For example, product information labeled as Reserpine, Hydrochlorothiazide and Hydralazine Hydrochloride appears under the active ingredient heading Hydralazine Hydrochloride; Hydrochlorothiazide; Reserpine. A cross-reference to the product information (for prescription and OTC products) appears for each additional active ingredient in the product. For combination drug products, the ingredient strengths are separated by semicolons and appear in the same relative sequence as the ingredients in the heading. Available strengths of the dosage form from an applicant appear on separate lines. To use the Drug Product Lists, determine by alphabetical order the ingredient under which the product information is listed, using the Product Name Index, if necessary. Then, find the ingredient in the applicable Drug Product List. Proceed to the dosage form and route of administration and compare products within that ingredient heading only. Therapeutic equivalence or inequivalence for prescription products is determined on the basis of the therapeutic equivalence codes provided within that specific dosage form heading. The OTC Drug Product List, Discontinued Drug Product List, and Drug Products with Approval under Section 505 of the Act Administered by the Center for Biologics Evaluation and Research List have their data arranged similarly. The Discontinued Drug Product List contains approved products that have never been marketed, have been discontinued from marketing, or have had their approvals withdrawn for other than safety or efficacy reasons subsequent to being discontinued from marketing. All products having a "@" in the 12th Cumulative Supplement of the 18th Edition List have been added to the Discontinued Drug Product List appearing in the 19th Edition. Orphan Drug Product Designations. Drugs and biologicals that have been granted Orphan Designation pursuant to Section 526 as amended by the Orphan Drug Act [P.L. 97-414, January 4, 1983] are listed in Section 3.5. Product Name Index (Prescription and OTC Drug Product Lists). This is an index of drug products by established or trade name. The second term of each entry indicates the active ingredient name under which product information can be found in the appropriate Drug Product List. For those drug products with multiple active ingredients, only the first active ingredient (in alphabetical order) will appear. OTC products are so designated. Product Name Index Listed by Applicant (Prescription and OTC Drug Product Lists). This is an index that cross-references applicants to drug products. The bolded and underlined entry represents the applicant name abbreviation used in this publication. Each complete applicant name that is represented by the abbreviated name is marked with an asterisk (*). Listed under each complete applicant name is the first alphabetically arranged ingredient under which product information can be found in the appropriate Drug Product List. OTC products are so designated. To use the Drug Product Lists, determine by alphabetical order the ingredient under which the product information is listed, using the Product Name Index, if appropriate. Uniform Terms. To improve readability, uniform terms are used to designate dosage forms, routes of administration, and abbreviations used to express strengths. These terms are listed in Appendix C. In some cases, the terms used may differ from those used in product labels and other labeling.
PATENT AND EXCLUSIVITY INFORMATION ADDENDUM
This Addendum identifies drugs that qualify under the Drug Price Competition and Patent Term Restoration Act (1984 Amendments) for periods of exclusivity, during which abbreviated new drug applications (ANDAs) and applications described in Section 505(b)(2) of the Federal Food, Drug, and Cosmetic Act (the Act) for those drug products may, in some instances, not be submitted or made effective as described below, and provides patent information concerning the listed drug products. Those drugs that have qualified for Orphan Drug Exclusivity pursuant to Section 527 of the Act and those drugs that have qualified for Pediatric Exclusivity pursuant to Section 505A are also included in this Addendum. This section is arranged in alphabetical order by active ingredient name. For those drug products with multiple active ingredients, only the first active ingredient (in alphabetical order) will appear. For an explanation of the codes used in the Addendum, see the Patent and Exclusivity Terms page. Exclusivity prevents the submission or effective approval of ANDAs or applications described in Section 505(b)(2) of the Act. It does not prevent the submission or approval of a second full NDA. Applications qualifying for periods of exclusivity are:
The Act requires that patent information must now be filed with all newly submitted Section 505 drug applications, and that no NDA may be approved after September 24, 1984, without the submission of pertinent patent information to the Agency. The patent numbers and the expiration dates of appropriate patents claiming drug products that are the subject of approved applications will be published in this Addendum or in the monthly Cumulative Supplement to this publication. Patent information on unapproved applications or on patents beyond the scope of the Act (i.e., process or manufacturing patents) will not be published. The patents that FDA regards as covered by the statutory provisions for submission of patent information are: patents that claim the active ingredient or ingredients; drug product patents, which include formulation/composition patents; and use patents for a particular approved indication or method of using the product. NDA holders or applicants amending or supplementing applications with formulation/ composition patent information are asked to declare that the patent(s) is appropriate for publication and refers to an approved product or one for which approval is being sought. The Agency asks all applicants or application holders with use patents to provide information as to the approved indications or uses covered by such patents. This information will be included in the Cumulative Supplement to the List as it becomes available. Since all parts of this publication are subject to changes, additions, or deletions, the Addendum must be used in conjunction with the most current Cumulative Supplement.
FDA/Center for Drug Evaluation and Research |
