ORANGE BOOK: by Nishath fathima M. pharm(QA) SUUCP HYDERABAD ORANGE BOOK Introduction: Introduction Its official title is Approved Drug Products with Therapeutic Equivalence Evaluations . Commonly known as the Orange Book due to the orange cover of the original print version, it is the Food and Drug Administration's list of all drugs approved in the United States as safe and effective. In addition to listing all approved drugs, the Orange Book is also the authoritative source of information on the therapeutic equivalence of drug products. History: History In the middle of the past century, many states enacted laws banning the substitution of drugs in an attempt to prevent the spread of inferior or counterfeit products. By the 1970s, however, economic pressures had led to the repeal of these anti-substitution laws, and states, beginning with New York, began looking to the Federal government for guidance in creating formularies to regulate substitution. In response to such requests, the FDA announced its intention to create a list of approved drugs and therapeutic equivalence determinations. The first edition appeared in October, 1980. A new edition is published each year and cumulative supplements are made available on a monthly basis. Content : Content The Orange Book consists of five main sections: an introduction, a “how to use” section, the drug product lists, appendices, and a patent exclusivity information addendum. Definitions: Definitions Pharmaceutical Equivalents are drug products which contain the same active ingredients in the same strength and dosage form delivered by the same route of administration. Bioequivalent Drug Products are those which have shown comparable bioavailability when studied under similar conditions (e.g., the rate and extent of absorption of a test drug does not significantly differ from that of the reference drug). Therapeutic Equivalents are Pharmaceutical Equivalents that are Bioequivalent . Only drug products which are Therapeutic Equivalents may be legally substituted for FDA approved drugs in Orange Book. TE Codes: TE Codes TE codes are divided into two categories, A and B ‘A’ Drugs are those which the FDA considers to be therapeutically equivalent and, therefore, substitutable where permitted by the prescriber. They are further divided as follows: AA: there are no known or suspected bioequivalence problems. These are designated AA, AN, AO, AP, or AT, depending on the dosage form: AN for aerosolized drugs, AO for injectable oil solutions, AP for injectable aqueous solutions, and AT for topical products. AB: actual or potential bioequivalence problems have been resolved through adequate in vivo and/or in vitro testing. ‘B’ Drugs are those which the FDA considers NOT to be therapeutically equivalent due to actual or potential bioequivalence problems which have not been resolved. B-rated drugs are not legally substitutable. Reference Listed Drugs: Reference Listed Drugs 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. A condition of approval is that bioequivalence to the innovator drug product must be proven. Once approved, the generic drug is listed in the Orange Book . 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. Multisource And Single Source Drug Products: Multisource And Single Source Drug Products Section 505 of the Act, which in most instances means those pharmaceutical equivalents available from more than one manufacturer. For such products, a therapeutic equivalence code is included. Those products with approved applications that are single-source (i.e., there is only one approved product available for that active ingredient, dosage form, route of administration, and strength) are also included on the List, but no therapeutic equivalence code is included with such products. Any drug product in the List repackaged and/or distributed by other than the application holder is considered to be therapeutically equivalent to the application holder's drug product, distributors or repackagers of an application holder's drug product are considered to have the same code as the application holder. A CODE:
A CODE Multisource drug products listed under the same heading (i.e., identical active ingredients(s), dosage form, and route(s) of administration) and having the same strength generally will be coded AB if a study is submitted demonstrating bioequivalence. In certain instances, a number is added to the end of the AB code to make a three
code (i.e., AB1, AB2, AB3, etc. ). Three-character codes are assigned only in situations when more than one reference listed drug of the same strength has been designated under the same heading. For example, Adalat ® CC (Miles) and Procardia XL® (Pfizer), extended-release tablets, are listed under the active ingredient nifedipine . These drug products, listed under the same heading, are not bioequivalent to each other. Adalat ® CC and Procardia XL® have been assigned ratings of AB1 and AB2, respectively. The generic drug products bioequivalent to Adalat ® CC would be assigned a rating of AB1 and those bioequivalent to Procardia XL® would be assigned a rating of AB2 .
Specific Cases: Specific Cases 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. These are therapeutically equivalent only when each product is reconstituted, stored, and used under the conditions specified in the labeling of that product. In some cases closely related products are listed as containing the same active ingredients, but in somewhat different amounts. These products considered to be pharmaceutically equivalent with labeled strengths of an ingredient that do not vary by more than 1%. 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 B CODE: B CODE Drug products that FDA, at this time, considers not to be therapeutically equivalent to other pharmaceutically equivalent products. BC Extended-release dosage forms (capsules, injectables and tablets) BD Active ingredients and dosage forms with documented bioequivalence problems BE Delayed-release oral dosage forms BN Products in aerosol-nebulizer drug delivery systems BP Active ingredients and dosage forms with potential bioequivalence problems BR Suppositories or enemas that deliver drugs for systemic absorption BS Products having drug standard deficiencies BT Topical products with bioequivalence issues BX Drug products for which the data are insufficient to determine therapeutic equivalence Special Situations: Special Situations 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. where nitrogen balance is the sole therapeutic objective they may be considered therapeutically equivalent. Follitropin Alfa and Beta. Based on available data derived from physico -chemical tests and bioassay, follitropin alfa and follitropin beta are indistinguishable. Waived exclusivity. If a new drug application (NDA) submitted under section 505(b) of the Federal Food, Drug, and Cosmetic Act (Act) qualifies for exclusivity under sections 505(c)(3)(D) and 505(j)(5)(D), the exclusivity is listed in the Patent and Exclusivity Section of the Orange Book. If a drug product has received this exclusivity, the FDA will delay the approval of a 505(b)(2) application or an abbreviated new drug application (ANDA) under section 505(j) of the Act until the expiration of the exclusivity. TE Code Change For A Drug Entity: TE Code Change For A Drug Entity MULTISOURCE DRUG PRODUCT Specific 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. 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 . 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, the Agency will announce in the Introduction 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. 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 Drug List: Drug List The Prescription and OTC Drug Product Lists, arranged alphabetically by active ingredient(s), contain product identification information for single and multiple ingredient drug products. Also shown are the application number and drug product number and approval dates for those drug products approved on or after January 1, 1982 . The application number preceded by "N" is a New Drug Application (NDA) or commonly the innovator. The application number preceded by an "A" is an Abbreviated New Drug Application (ANDA or commonly the generic). 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 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 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. Patent And Exclusivity Information Addendum: 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. 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 505(b)(1) application except in the case of Orphan Drug exclusivity. Applications qualifying for periods of exclusivity are: A new drug application approved after September 24, 1984, for a drug product all active ingredients (including any ester or salt of the active ingredient) of which had never been approved in any other new drug application under Section 505 (b) of the Act. No subsequent ANDA or application described in Section 505(b)(2) of the Act for the same drug may be submitted for a period of five years from the date of approval of the original application, except that such an application may be submitted after four years if it contains a certification that a patent claiming the drug is invalid or will not be infringed by the product for which approval is sought. Patent And Exclusivity Information Addendum: Patent And Exclusivity Information Addendum A new drug application approved after September 24, 1984, for a drug product containing an active ingredient (including any ester or salt of that active ingredient) that has been approved in an earlier new drug application and that includes reports of new clinical investigations (other than bioavailability studies). Such investigations must have been conducted or sponsored by the applicant and must have been essential to approval of the application. If these requirements are met, the approval of a subsequent ANDA or an application described in Section 505(b)(2) of the Act may not be made effective for the same drug or use, if for a new indication, before the expiration of three years from the date of approval of the original application. If an applicant has exclusivity for a new application or 505(b)(2) application for the drug product with indications or use, this does not preclude the approval of an ANDA or 505(b)(2) application not covered by the exclusivity. A supplement to a new drug application for a drug containing a previously approved active ingredient including (any ester or salt of the active ingredient) approved after September 24, 1984, that contains reports of new clinical investigations (other than bioavailability studies) essential to the approval of the supplement and conducted or sponsored by the applicant. The approval of a subsequent ANDA or 505(b)(2) application for a change approved in the supplement may not be made effective for three years from the date of approval of the original supplement. References: References Approved Drug Products with Therapeutic Equivalence Evaluations . Published by FDA 31 st edition. Slide 18: Thank you