"
"
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have had their approvals withdrawn for other than safety or efficacy reasons
1
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, 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
ANDA (Generic) Drug
in the List. Tentative approval lists are available at
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.
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
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
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
) and extrapolated to infinity (AUC ), for
(0-t) (0-inf)
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
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
) and extrapolated to infinity (AUC ), for
(0-t) (0-inf)
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
AUC , and Cmax. The observed
(0-t), (0-inf)
average differences between the reference and generic products were + 3.47%
(SD 2.84) for AUC
, + 3.25% (SD 2.97) for AUC , and + 4.29% (SD 3.72)
(0-t) (0-inf)
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.
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 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 approved
under 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 and, in addition,
product information is highlighted in bold face and underlined. Those
products with approved applications that are single-source (i.e., there is
only one approved product available for that active ingredient, dosage form,
route of administration, and strength) are also included on the List, but no
therapeutic equivalence code is included with such products. Any drug product
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
AUC , and Cmax. The observed
(0-t), (0-inf)
average differences between the reference and generic products were + 3.47%
(SD 2.84) for AUC
, + 3.25% (SD 2.97) for AUC , and + 4.29% (SD 3.72)
(0-t) (0-inf)
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.
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 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 approved
under 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 and, in addition,
product information is highlighted in bold face and underlined. Those
products with approved applications that are single-source (i.e., there is
only one approved product available for that active ingredient, dosage form,
route of administration, and strength) are also included on the List, but no
therapeutic equivalence code is included with such products. Any drug product
in the List repackaged and/or distributed by other than the 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
xii
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:
A Drug products that FDA considers to be therapeutically equivalent
to
other pharmaceutically equivalent products, i.e., drug products for which:
(1) there are no known or suspected bioequivalence problems. These are
designated AA, AN, AO, AP, or AT, depending on the dosage form; or
(2) actual or potential bioequivalence problems have been resolved with
adequate in vivo and/or in vitro evidence supporting
bioequivalence. These are designated AB.
B Drug products that FDA at this time, considers not to be
therapeutically equivalent to other pharmaceutically equivalent products,
i.e.,
drug products for which actual or potential bioequivalence problems
have not been resolved by adequate evidence of bioequivalence. Often
the problem is with specific dosage forms rather than with the active
ingredients. These are designated BC, BD, BE, BN, BP, BR, BS, BT, BX,
or B*.
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 bio-equivalence. Drug products designated with an "A" code fall
under one of two main policies:
(1) for those active ingredients or dosage forms for which no in vivo
bioequivalence issue is known or suspected, the information necessary to
show bioequivalence between pharmaceutically equivalent products is
presumed and considered self-evident based on other data in the
application for some dosage forms (e.g., solutions) or satisfied for
solid oral dosage forms by a showing that an acceptable in vitro
dissolution standard is met. A therapeutically equivalent rating is
assigned such products so long as they are manufactured in accordance
with Current Good Manufacturing Practice regulations and meet the other
requirements of their approved applications (these are designated AA, AN,
AO, AP, or AT, depending on the dosage form, as described below); or
(2) for those DESI drug products containing active ingredients or dosage
forms that have been identified by FDA as having actual or potential
bioequivalence problems, and for post-1962 drug products in a dosage
form presenting a potential bioequivalence problem, an evaluation of
therapeutic equivalence is assigned to pharmaceutical equivalents only
if the approved application contains adequate scientific evidence
establishing through in vivo and/or in vitro studies the bioequivalence
of the product to a selected reference product (these products are
designated as AB).
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., Isolyte® S w/ Dextrose 5% in Plastic Container and
Plasma-Lyte® 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:
AA Products in conventional dosage forms not presenting bioequivalence problems
Products coded as AA contain active ingredients and dosage forms that are
not regarded as presenting either actual or potential bioequivalence
problems or drug quality or standards issues. However, all oral dosage
forms must, nonetheless, meet an appropriate in vitro bioequivalence
standard that is acceptable to the Agency in order to be approved.
AB, AB1, AB2, AB3... Products meeting necessary bioequivalence requirements
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 (see Section 1.2, Therapeutic Equivalence-Related
Terms, Pharmaceutical Equivalents) 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 character 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. Two or
more reference listed drugs are generally selected only when there are at
least two potential reference drug products which are not bioequivalent to
each other. If a study is submitted that demonstrates bioequivalence to a
specific listed drug product, the generic product will be given the same
three-character code as the reference listed drug it was compared against.
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. Generic drug products deemed by FDA to be bioequivalent to
Adalat® CC and Procardia XL® have been approved, 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. (The assignment of an AB1 or AB2 rating to a specific product does
not imply product preference.) Even though drug products of distributors
and/or repackagers are not included in the List, they are considered
therapeutically equivalent to the application holder's drug product if the
application holder's drug product is rated either with an AB or three-
character code or is single source in the List. Drugs coded as AB under a
heading are considered therapeutically equivalent only to other drugs
coded as AB under that heading. Drugs coded with a three-character code
under a heading are considered therapeutically equivalent only to other
drugs coded with the same three-character code under that heading.
AN Solutions and powders for aerosolization
Uncertainty regarding the therapeutic equivalence of aerosolized products
arises primarily because of differences in the drug delivery system.
Solutions and powders intended for aerosolization that are marketed for
use in any of several delivery systems are considered to be
pharmaceutically and therapeutically equivalent and are coded AN. Those
products that are compatible only with a specific delivery system or those
products that are packaged in and with a specific delivery system are
coded BN, unless they have met an appropriate bioequivalence standard.
Solutions or suspensions in a specific delivery system will be coded AN if
the bioequivalence standard is based upon in vitro methodology, if
bioequivalence needs to be demonstrated by in vivo methodology then the
drug products will be coded AB.
AO Injectable oil solutions
The absorption of drugs in injectable (parenteral) oil solutions may vary
substantially with the type of oil employed as a vehicle and the
concentration of the active ingredient. Injectable oil solutions are
therefore considered to be pharmaceutically and therapeutically equivalent
only when the active ingredient, its concentration, and the type of oil
used as a vehicle are all identical.
AP Injectable aqueous solutions and, in certain instances, intravenous non-aqueous
solutions
It should be noted that even though injectable (parenteral) products under
a specific listing may be evaluated as therapeutically equivalent, there
may be important differences among the products in the general category,
Injectable; Injection. For example, some injectable products that are
rated therapeutically equivalent are labeled for different routes of
administration. In addition, some products evaluated as therapeutically
equivalent may have different preservatives or no preservatives at all.
Injectable products available as dry powders for reconstitution,
concentrated sterile solutions for dilution, or sterile solutions ready
for injection are pharmaceutical alternative drug products. They are not
rated as therapeutically equivalent (AP) to each other even if these
pharmaceutical alternative drug products are designed to produce the same
concentration prior to injection and are similarly labeled. Consistent
with accepted professional practice, it is the responsibility of the
prescriber, dispenser, or individual administering the product to be
familiar with a product's labeling to assure that it is given only by the
route(s) of administration stated in the labeling.
Certain commonly used large volume intravenous products in glass
containers are not included on the List (e.g., dextrose injection 5%,
dextrose injection 10%, sodium chloride injection 0.9%) since these
products are on the market without FDA approval and the FDA has not
not imply product preference.) Even though drug products of distributors
and/or repackagers are not included in the List, they are considered
therapeutically equivalent to the application holder's drug product if the
application holder's drug product is rated either with an AB or three-
character code or is single source in the List. Drugs coded as AB under a
heading are considered therapeutically equivalent only to other drugs
coded as AB under that heading. Drugs coded with a three-character code
under a heading are considered therapeutically equivalent only to other
drugs coded with the same three-character code under that heading.
AN Solutions and powders for aerosolization
Uncertainty regarding the therapeutic equivalence of aerosolized products
arises primarily because of differences in the drug delivery system.
Solutions and powders intended for aerosolization that are marketed for
use in any of several delivery systems are considered to be
pharmaceutically and therapeutically equivalent and are coded AN. Those
products that are compatible only with a specific delivery system or those
products that are packaged in and with a specific delivery system are
coded BN, unless they have met an appropriate bioequivalence standard.
Solutions or suspensions in a specific delivery system will be coded AN if
the bioequivalence standard is based upon in vitro methodology, if
bioequivalence needs to be demonstrated by in vivo methodology then the
drug products will be coded AB.
AO Injectable oil solutions
The absorption of drugs in injectable (parenteral) oil solutions may vary
substantially with the type of oil employed as a vehicle and the
concentration of the active ingredient. Injectable oil solutions are
therefore considered to be pharmaceutically and therapeutically equivalent
only when the active ingredient, its concentration, and the type of oil
used as a vehicle are all identical.
AP Injectable aqueous solutions and, in certain instances, intravenous non-aqueous
solutions
It should be noted that even though injectable (parenteral) products under
a specific listing may be evaluated as therapeutically equivalent, there
may be important differences among the products in the general category,
Injectable; Injection. For example, some injectable products that are
rated therapeutically equivalent are labeled for different routes of
administration. In addition, some products evaluated as therapeutically
equivalent may have different preservatives or no preservatives at all.
Injectable products available as dry powders for reconstitution,
concentrated sterile solutions for dilution, or sterile solutions ready
for injection are pharmaceutical alternative drug products. They are not
rated as therapeutically equivalent (AP) to each other even if these
pharmaceutical alternative drug products are designed to produce the same
concentration prior to injection and are similarly labeled. Consistent
with accepted professional practice, it is the responsibility of the
prescriber, dispenser, or individual administering the product to be
familiar with a product's labeling to assure that it is given only by the
route(s) of administration stated in the labeling.
Certain commonly used large volume intravenous products in glass
containers are not included on the List (e.g., dextrose injection 5%,
dextrose injection 10%, sodium chloride injection 0.9%) since these
products are on the market without FDA approval and the FDA has not
published conditions for marketing such parenteral products under approved
NDAs. When packaged in plastic containers, however, FDA regulations
require approved applications prior to marketing. Approval then depends
on, among other things, the extent of the available safety data involving
the specific plastic component of the product. All large volume
parenteral products are manufactured under similar standards, regardless
of whether they are packaged in glass or plastic. Thus, FDA has no reason
to believe that the packaging container of large volume parenteral drug
products that are pharmaceutically equivalent would have any effect on
their therapeutic equivalence.
The strength of parenteral drugs products is defined as the total drug
content of the container. Until recently the strength of liquid
parenteral drug products in the Orange Book have not been displayed. The
concentration of the liquid parenteral drug product in the Orange Book has
been shown as xmg/ml. The amount of dry powder or freeze dried powder in
a container has always been identified as the strength.
With the finalization of the Waxman-Hatch amendments that characterized
each strength of a drug product as a listed drug, it became evident that
the format of the Orange Book should be changed to reflect each strength
of a parenteral solution. To this end the OGD has started to display the
strength of all new approvals of parenteral solutions. Previously we
would have displayed only the concentration of an approved parenteral
solution, e.g. 50mg/ml. If this drug product had a 20 ml and 60 ml
container approved the two products would be shown as 1Gm / 20ml (50mg/ml)
and 3Gm / 60ml (50mg/ml).
AT Topical products
There are a variety of topical dosage forms available for dermatologic,
ophthalmic, otic, rectal, and vaginal administration, including creams,
gels, lotions, oils, ointments, pastes, solutions, sprays and
suppositories. Even though different topical dosage forms may contain the
same active ingredient and potency, these dosage forms are not considered
pharmaceutically equivalent. Therefore, they are not considered
therapeutically equivalent. All solutions and DESI drug products
containing the same active ingredient in the same topical dosage form for
which a waiver of in vivo bioequivalence has been granted and for which
chemistry and manufacturing processes are adequate to demonstrate
bioequivalence, are considered therapeutically equivalent and coded AT.
Pharmaceutically equivalent topical products that raise questions of
bioequivalence, including all post-1962 non-solution topical drug
products, are coded AB when supported by adequate bioequivalence data, and
BT in the absence of such data.
"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
ot been resolved by adequate evidence of bioequivalence, often have a problem
ith specific dosage forms rather than with the active ingredients. Drug
roducts designated with a "B" code fall under one of three main policies:
(1) the drug products contain active ingredients or are manufactured in
dosage forms that have been identified by the Agency as having
documented bio-equivalence problems or a significant potential for
such problems and for which no adequate studies demonstrating
NDAs. When packaged in plastic containers, however, FDA regulations
require approved applications prior to marketing. Approval then depends
on, among other things, the extent of the available safety data involving
the specific plastic component of the product. All large volume
parenteral products are manufactured under similar standards, regardless
of whether they are packaged in glass or plastic. Thus, FDA has no reason
to believe that the packaging container of large volume parenteral drug
products that are pharmaceutically equivalent would have any effect on
their therapeutic equivalence.
The strength of parenteral drugs products is defined as the total drug
content of the container. Until recently the strength of liquid
parenteral drug products in the Orange Book have not been displayed. The
concentration of the liquid parenteral drug product in the Orange Book has
been shown as xmg/ml. The amount of dry powder or freeze dried powder in
a container has always been identified as the strength.
With the finalization of the Waxman-Hatch amendments that characterized
each strength of a drug product as a listed drug, it became evident that
the format of the Orange Book should be changed to reflect each strength
of a parenteral solution. To this end the OGD has started to display the
strength of all new approvals of parenteral solutions. Previously we
would have displayed only the concentration of an approved parenteral
solution, e.g. 50mg/ml. If this drug product had a 20 ml and 60 ml
container approved the two products would be shown as 1Gm / 20ml (50mg/ml)
and 3Gm / 60ml (50mg/ml).
AT Topical products
There are a variety of topical dosage forms available for dermatologic,
ophthalmic, otic, rectal, and vaginal administration, including creams,
gels, lotions, oils, ointments, pastes, solutions, sprays and
suppositories. Even though different topical dosage forms may contain the
same active ingredient and potency, these dosage forms are not considered
pharmaceutically equivalent. Therefore, they are not considered
therapeutically equivalent. All solutions and DESI drug products
containing the same active ingredient in the same topical dosage form for
which a waiver of in vivo bioequivalence has been granted and for which
chemistry and manufacturing processes are adequate to demonstrate
bioequivalence, are considered therapeutically equivalent and coded AT.
Pharmaceutically equivalent topical products that raise questions of
bioequivalence, including all post-1962 non-solution topical drug
products, are coded AB when supported by adequate bioequivalence data, and
BT in the absence of such data.
"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
ot been resolved by adequate evidence of bioequivalence, often have a problem
ith specific dosage forms rather than with the active ingredients. Drug
roducts designated with a "B" code fall under one of three main policies:
(1) the drug products contain active ingredients or are manufactured in
dosage forms that have been identified by the Agency as having
documented bio-equivalence problems or a significant potential for
such problems and for which no adequate studies demonstrating
bioequivalence have been submitted to FDA; or
(2) the quality standards are inadequate or FDA has an insufficient basis
to determine therapeutic equivalence; or
(3) the drug products are under regulatory review.
The specific coding definitions and policies for the "B" sub-codes are as
follows:
B* Drug products requiring further FDA investigation and review to determine therapeutic
equivalence
The code B* is assigned to products previously assigned an A or B code
when FDA receives new information that raises a significant question
regarding therapeutic equivalence that can be resolved only through
further Agency investigation and/or review of data and information
submitted by the applicant. The B* code signifies that the Agency will
take no position regarding the therapeutic equivalence of the product
until the Agency completes its investigation and review.
BC Extended-release dosage forms (capsules, injectables and tablets)
Extended-release tablets are formulated in such a manner as to make the
contained medicament available over an extended period of time following
ingestion.
Although bioavailability studies have been conducted on these dosage
forms, they may be subject to bioavailability differences, primarily
because firms developing extended-release products for the same active
ingredient rarely employ the same formulation approach. FDA, therefore,
does not consider different extended-release dosage forms containing the
same active ingredient in equal strength to be therapeutically equivalent
unless equivalence between individual products in both rate and extent has
been specifically demonstrated through appropriate bioequivalence studies.
Extended-release products for which such bioequivalence data have not been
submitted are coded BC, while those for which such data are available have
been coded AB.
BD Active ingredients and dosage forms with documented bioequivalence problems
The BD code denotes products containing active ingredients with known
bioequivalence problems and for which adequate studies have not been
submitted to FDA demonstrating bioequivalence. Where studies showing
bioequivalence have been submitted, the product has been coded AB.
BE Delayed-release oral dosage forms
Where the drug may be destroyed or inactivated by the gastric juice or
where it may irritate the gastric mucosa, the use of “enteric” coatings is
indicated. Such coatings are intended to delay the release of the
medication until the tablet has passed through the stomach. Drug products
in delayed-release dosage forms containing the same active ingredients are
subject to significant differences in absorption. Unless otherwise
specifically noted, the Agency considers different delayed-release
products containing the same active ingredients as presenting a potential
bioequivalence problem and codes these products BE in the absence of
in vivo studies showing bioequivalence. If adequate in vivo studies have
demonstrated the bioequivalence of specific delayed-release products, such
products are coded AB.
BN Products in aerosol-nebulizer drug delivery systems
This code applies to drug solutions or powders that are marketed only as a
component of, or as compatible with, a specific drug delivery system.
There may, for example, be significant differences in the dose of drug and
particle size delivered by different products of this type. Therefore,
the Agency does not consider different metered aerosol dosage forms
containing the same active ingredient(s) in equal strengths to be
therapeutically equivalent unless the drug products meet an appropriate
bioequivalence standard, such products are coded AB.
BP Active ingredients and dosage forms with potential bioequivalence problems
FDA's bioequivalence regulations (21 CFR 320.33) contain criteria and
procedures for determining whether a specific active ingredient in a
specific dosage form has a potential for causing a bioequivalence problem.
It is FDA's policy to consider an ingredient meeting these criteria as
having a potential bioequivalence problem even in the absence of positive
data demonstrating inequivalence. Pharmaceutically equivalent products
containing these ingredients in oral dosage forms are coded BP until
adequate in vivo bioequivalence data are submitted, such products are
coded AB. Injectable suspensions containing an active ingredient
suspended in an aqueous or oleaginous vehicle have also been coded BP.
Injectable suspensions are subject to bioequivalence problems because
differences in particle size, polymorphic structure of the suspended
active ingredient, or the suspension formulation can significantly affect
the rate of release and absorption. FDA does not consider pharmaceutical
equivalents of these products bioequivalent without adequate evidence of
bioequivalence, such products would be coded AB.
BR Suppositories or enemas that deliver drugs for systemic absorption
The absorption of active ingredients from suppositories or enemas that are
intended to have a systemic effect (as distinct from suppositories
administered for local effect) can vary significantly from product to
product. Therefore, FDA considers pharmaceutically equivalent systemic
suppositories or enemas bio-equivalent only if in vivo evidence of
bioequivalence is available. In those cases where in vivo evidence is
available, the product is coded AB. If such evidence is not available,
the products are coded BR.
BS Products having drug standard deficiencies
If the drug standards for an active ingredient in a particular dosage form
are found by FDA to be deficient so as to prevent an FDA evaluation of
either pharmaceutical or therapeutic equivalence, all drug products
containing that active ingredient in that dosage form are coded BS. For
example, if the standards permit a wide variation in pharmacologically
active components of the active ingredient such that pharmaceutical
equivalence is in question, all products containing that active ingredient
in that dosage form are coded BS.
BT Topical products with bioequivalence issues
This code applies mainly to post-1962 dermatologic, ophthalmic, otic,
rectal, and vaginal products for topical administration, including creams,
ointments, gels, lotions, pastes, and sprays, as well as suppositories not
intended for systemic drug absorption. Topical products evaluated as
having acceptable clinical performance, but that are not bioequivalent to
other pharmaceutically equivalent products or that lack sufficient
evidence of bioequivalence, will be coded BT.
BX Drug products for which the data are insufficient to determine therapeutic equivalence
The code BX is assigned to specific drug products for which the data that
have been reviewed by the Agency are insufficient to determine therapeutic
equivalence under the policies stated in this document. In these
situations, the drug products are presumed to be therapeutically
inequivalent until the Agency has determined that there is adequate
information to make a full evaluation of therapeutic equivalence.
1.8 Description of Special Situations
Certain drugs listed in the Orange Book present special situations that
merit further discussion. Following is a description of those 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. 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.
Follitropin Alfa and Beta. Based on available data derived from physico
chemical tests and bioassay, follitropin alfa and follitropin beta are
indistinguishable.
Gaviscon®. Gaviscon® 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.
Gaviscon®’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 Gaviscon® 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.
Levothyroxine Sodium. Because there are multiple reference listed drugs
of levothyroxine sodium tablets and some reference listed drugs' sponsors have
conducted studies to establish their drugs' therapeutic equivalence to other
reference listed drugs, FDA has determined that its usual practice of
assigning two or three character TE codes may be potentially confusing and
inadequate for these drug products. Accordingly, FDA provides the following
explanation and chart of therapeutic equivalence evaluations for levothyroxine
Levothyroxine Sodium (Mylan ANDA 76187) tablets have been determined to be
therapeutically equivalent to corresponding strengths of Unithroid (Jerome
Stevens NDA 021210) tablets.
Levo-T (Alara NDA 021342), Levothyroxine Sodium (Mylan ANDA 76187), Unithroid
(Jerome Stevens NDA 021210), and Levothyroxine Sodium (Merck KGAA ANDA
76752)tablets have been determined to be therapeutically equivalent to
corresponding strengths of Synthroid (Abbott NDA 021402) tablets.
Levo-T (Alara NDA 021342), Unithroid (Jerome Stevens NDA 021210),
Levothyroxine Sodium (Mylan ANDA 076187), and Levothyroxine Sodium (Merck KGAA
ANDA 76752) tablets have been determined to be therapeutically equivalent to
corresponding strengths of Levoxyl (King Pharms NDA 021301) tablets.
Levothyroxine Sodium (Mylan ANDA 76187) tablets have been determined to be
therapeutically equivalent to corresponding strengths of Levothroid (Lloyd NDA
021116) tablets.
The chart outlines TE codes for all 0.025mg products. Other product strengths
may be similar. Therapeutic equivalence has been established between products
that have the same AB+number TE code. More than one TE code may apply to some
products. One common TE code indicates therapeutic equivalence between
products.
Patent Certification(s) Reference Listed Drug based upon a suitability
petition. An abbreviated new drug application that refers to a Reference
Listed Drug (RLD) approved pursuant to a suitability petition must demonstrate
that the proposed product is bioequivalent to the RLD, and it must include
appropriate patent certification(s) and an exclusivity statement with respect
to the listed drug which served as the basis for the approved suitability
petition. This concept also applies to an ANDA applicant that cites a RLD
that was based upon an NDA that is still covered by patent (s) and/or
exclusivity, e.g. a second RLD that was selected when the in vivo
determination of bioequivalence of the original RLD is self evident and the
waiver of the in vivo determination of bioequivalence may be granted.
Waived exclusivity. If a new drug application (NDA) submitted under
section 505(b) of the Federal Food, Drug, and Cosmetic Act (Act) qualifies fo
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. If the
listed drug is also protected by one or more patents, the approval date for
the 505(b)(2) application or ANDA will be determined by the latest expiring
patent or exclusivity listed in the Orange Book. However, the holder of the
NDA may waiver its exclusivity as to any or all 505(b)(2) and ANDA
applications referencing the protected drug product. If an NDA sponsor
waivers its right to the exclusivity protection, qualified 505(b)(2) or ANDA
applications may be approved without regard to the NDA holder's exclusivity.
An NDA for which the holder has waived its exclusivity as to all 505(b)(2) an
ANDA applications will be coded with a W in the Patent and Exclusivity Sectio
of the Orange Book and be referred to this section. The applicant referencin
this listed drug should indicate in the exclusivity statement that the holder
of the listed drug has waived its exclusivity.
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, HFD-650, 7620 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 fo
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
determination of bioequivalence of the original RLD is self evident and the
waiver of the in vivo determination of bioequivalence may be granted.
Waived exclusivity. If a new drug application (NDA) submitted under
section 505(b) of the Federal Food, Drug, and Cosmetic Act (Act) qualifies fo
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. If the
listed drug is also protected by one or more patents, the approval date for
the 505(b)(2) application or ANDA will be determined by the latest expiring
patent or exclusivity listed in the Orange Book. However, the holder of the
NDA may waiver its exclusivity as to any or all 505(b)(2) and ANDA
applications referencing the protected drug product. If an NDA sponsor
waivers its right to the exclusivity protection, qualified 505(b)(2) or ANDA
applications may be approved without regard to the NDA holder's exclusivity.
An NDA for which the holder has waived its exclusivity as to all 505(b)(2) an
ANDA applications will be coded with a W in the Patent and Exclusivity Sectio
of the Orange Book and be referred to this section. The applicant referencin
this listed drug should indicate in the exclusivity statement that the holder
of the listed drug has waived its exclusivity.
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, HFD-650, 7620 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 fo
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 an acceptable 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 Discontinued Section
Those drug products in the Discontinued Section of the Orange Book in
which a determination has already been made that the products were not
withdrawn for safety or efficacy reasons have “**Federal Register
determination that product was not discontinued or withdrawn for safety or
efficacy reasons**” following the product strength. Those drug products are
only reflective of citizen petitions determinations made since 1995. The
identification of these drug products in the Discontinued Section of the
Orange Book should avoid the submission of multiple citizen petitions for the
same drug product. FR notices no longer applicable are removed from the Annual
Edition (i.e., there is a currently marketed Reference Listed Drug and no
FR Safety or Effectiveness Determinations
applicable patent or exclusivity).
List lists products that have current and removed notices. The list is
updated quarterly. Notices issued during the year are added to the Electronic
Orange Book Query in the month they become effective.
Generally, approved products are added to the Discontinued Section of the
Orange Book when the applicant holder notifies the Orange Book staff of the
products’ not marketed status. Products may also be added if annual reports
indicate the product is no longer marketed or other Agency administrative
action (e.g., Withdrawal of an Application). Changes to the Orange Book are
not affected by the drug registration and listing requirements of Section 510
of the Act.
Every effort is made to ensure the Annual Edition is current and
accurate. Applicant holders are requested to inform the FDA Orange Book Staff
(OBS) of any changes or corrections. Please inform the OBS when products are
no longer marketed. Notification of the Orange Book staff to include the
newly approved product in the Discontinued Drug Product List rather than parts
1, 2 or 3 of the List (as discussed in Section 1.1) must occur by the end of
the month in which the product is approved to ensure that the product is not
included in the “active” portions of the next published Orange Book update
We can be contacted by email at drugproducts@fda.hhs.gov
. Send Changes by
FAX: 240-276-8974; mail to:
FDA/CDER Orange Book Staff
Office of Generic Drugs, HFD-610
7620 Standish Place
Rockville, MD 20855
1.13 Availability of the Edition
th
Commencing with the 25
edition, the Annual Edition and current monthly
Cumulative Supplement are available in a Portable Document Format (PDF) at the
EOB home page, Electronic Orange Book Query
, by clicking on Publications. The
PDF annual format duplicates previous paper versions except for the Orphan
Products Designations and Approvals List. An annual subscription of the PDF
format may be obtained from the U.S. Government Printing Office, 866-512-1800.
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