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Bioequivalence Guidance Summary
Bioequivalence Guidance SummaryEnter Drug Name Here
Regulatory Body
Study Design
Drug Characteristics
Click here to check the FDA Guidance for Industry: Individual Product Bioequivalence Recommendations
Standards for BioequivalenceUnless otherwise indicated by a specific guidance, this guidance recommends that the traditional BE limit of 80 to 125 percent for non-narrow therapeutic ra
unchanged for the bioavailability measures (AUC and Cmax) of narrow therapeutic range drugs. (1)
*90%CI of ln-Cmax, ln-AUCt, ln-AUCinf within 80.00-125.00%. Additional PK Parameters: AUC0-t, AUC0-∞, Cmax, Tmax, λz , and t1/2+ (1)
Sampling Scheme CriteriaWe recommend that blood samples be drawn at appropriate times to describe the absorption, distribution, and elimination phases of the drug. For most dru
recommend that 12 to 18 samples, including a predose sample, be collected per subject per dose. This sampling can continue for at least three or more term
the drug. The exact timing for sample collection depends on the nature of the drug and the input from the administered dosage form. The sample collection
such a way that the maximum concentration of the drug in the blood (Cmax) and terminal elimination rate constant (λz) can be estimated accurately. At leas
samples can be obtained during the terminal log-linear phase to obtain an accurate estimate of λz from linear regression. (1) An adequate washout period (e
half lives of the moieties to be measured) would separate each treatment. (1)
Fasting and/or Fed Required?we recommend a BE study under fed conditions for all orally administered immediate-release drug products, with the
following exceptions:
• When both test product and RLD are rapidly dissolving, have similar dissolution profiles, and contain a drug substance with high solubility and high permea
(see footnote 3), or
• When the DOSAGE AND ADMINISTRATION section of the RLD label states that the product should be taken only on an empty stomach, or
• When the RLD label does not make any statements about the effect of food on
absorption or administration. (2)
In ANDAs, BE of the test to the RLD is demonstrated in a single dose crossover study. Both treatments should be sprinkled on one of the soft foods mentione
usually applesauce. The BE data should be analyzed using average BE and the 90 percent CI criteria should be used to declare BE. If there are questions abou
design, or the analysis of such BE studies, the sponsors and/or applicants should contact the Office of Generic Drugs.(2)
Critical Dose Drug
Long Half-life Drug
Highly Variable Drug
Rapid Onset Drug
Non-Linear Kinetics
Modified Release
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Bioequivalence Guidance Summary
Parent and/or Metabolite Required?For BE studies, measurement of only the parent drug released from the dosage form, rather than the metabolite, is generally recommended. The rationale
recommendation is that concentration-time profile of the parent drug is more sensitive to changes in formulation performance than a metabolite, which is
metabolite formation, distribution, and elimination. The following are exceptions to this general approach.
• Measurement of a metabolite may be preferred when parent drug levels are too low to allow reliable analytical measurement in blood, plasma, or serum
length of time. We recommend that the metabolite data obtained from these studies be subject to a confidence interval approach for BE demonstration. If
concern related to efficacy or safety for the parent drug, we also recommend that sponsors and/or applicants contact the appropriate review division to det
the parent drug should be measured and analyzed statistically.
• A metabolite may be formed as a result of gut wall or other presystemic metabolism. If the metabolite contributes meaningfully to safety and/or efficacy,
recommend that the metabolite and the parent drug be measured. When the relative activity of the metabolite is low and does not contribute
meaningfully to safety and/or efficacy, it does not have to be measured. We recommend that the parent drug measured in these BE studies be analyzed
using a confidence interval approach. The metabolite data can be used to provide supportive evidence of comparable therapeutic outcome. (1)
Blinding and Data Analysis Subjects with predose plasma concentrations:
• If the predose concentration is ≤ 5 percent of Cmax value in that subject, the subject’s data without any adjustments can be included in all pharmacokinet
and calculations. We recommend that if the predose value is > than 5 percent of Cmax, the subject be dropped from all BE study evaluations.
Data deletion due to vomiting:
• We recommend that data from subjects who experience emesis during the course of a BE study for immediate-release products be deleted from statistica
vomiting occurs at or before 2 times median Tmax. In the case of modified-release products, the data from subjects who experience emesis any time during
dosing interval can be deleted. (1)
Reference ProductFor ANDAs, we also recommend that the BE study be conducted between the test product and reference listed drug using the strength(s) specified in Appro
with Therapeutic Equivalence Evaluations (Orange Book). (1)
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Bioequivalence Guidance Summary
Combining Studies
REFERENCES(1) Guidance for Industry: Bioavailability and Bioequivalence Studies for Orally Administered Drug Products — General Considerations. U.S. Department of H
Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER); March 2003. BP Revision 1.
(2) Guidance for Industry: Food-Effect Bioavailability and Fed Bioequivalence Studies. U.S. Department of Health and Human Services. Food and Drug Admin
for Drug Evaluation and Research (CDER); December 2002. BP.
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Regulatory
BodyFDA TPD
Standards for
BE: Single
Dose Studies
Unless otherwise indicated by a specific guidance, this guidance recommends
that the traditional BE limit of 80 to 125 percent for non-narrow therapeutic
range drugs remain unchanged for the bioavailability measures (AUC and
Cmax) of narrow therapeutic range drugs. (1)
[90%CI of ln-Cmax, ln-AUCt, ln-AUCinf within 80.00-125.00%. Additional PK
Parameters: AUC0-t, AUC0-∞, Cmax, Tmax, λz , and t1/2] (1)
For drugs with uncomplicated characteristics, the follow
in single dose cross-over comparative bioavailability stu
bioequivalence:
a) The 90% confidence interval of the relative mean AU
reference product should be within 80 percent to 125 pe
b) The relative mean measured Cmax of the test to refebetween 80 percent and 125 percent.
These standards must be met on log transformed param
• the measured data, and
• data corrected for measured drug content (percent po
Additional PK Parameters to report: AUCT, AUCI, AUC
Tmax, lambda. (1)
Standards for
BE: Steady
State Studies
For steady-state studies, we recommend that the measurement of total
exposure be the area under the plasma, serum, or blood concentration-time
curve from time zero to time tau over a dosing interval at steady state (AUC0-tau), where tau is the length of the dosing interval. (1)
PK Parameters: Cmin (concentration at the end of a dosing interval), Cav
(average concentration during a dosing interval), degree of fluctuation [(Cmax-
Cmin)/Cav], and swing [(Cmax-Cmin)/Cmin] (1)
The 90% confidence interval of the relative mean AUCta
reference formulation should be within 80% to 125%.
The relative mean measured Cmax at steady state of thformulation should be within 80% to 125%.
The relative mean measured Cmin at steady state of th
formulation should not be less than 80%.
[met on both potency uncorrected and corrected data]
PK Parameters: AUCtau, Cmax, Tmax, Cpd, Cmin, fluc
For steady-state studies of drugs with uncomplicated ch
three consecutive pre-dose concentration levels (Cpd) a
evidence of steady state. Generally, observations of Cp
reference products should be recorded at the same time
these measurements could be taken based on the first s
in which a profile over the dosing interval is being estab
usually achieved when repeated doses of a formulation
period that exceeds five disposition half-lives of the mod
Analysis of Tmax, lambda, and fluctuation should b
raw scale, while calculations for AUCX, AUCT, AUC
and
Rapid Onset
Drugs
RAPID ONSET:
An early exposure measure may be informative on the basis of appropriate
clinical efficacy/safety trials and/or pharmacokinetic/pharmacodynamic studies
that call for better control of drug absorption into the systemic circulation (e.g.,
to ensure rapid onset of an analgesic effect or to avoid an excessive
hypotensive action of an antihypertensive). In this setting, the guidance
recommends use of partial AUC as an early exposure measure. We
recommend
that the partial area be truncated at the population median of Tmax values for
the reference formulation. We also recommend that at least two quantifiable
samples be collected before the expected peak time to allow adequateestimation of the partial area. (1)
RAPID ONSET:
To date this standard has only been applied to two drug
ibuprofen and tablet formulations of sumatriptan. This no
that bioequivalence standards for drugs for which an ea
rate of absorption is important because of therapeutic o
example, an analgesic for rapid relief of pain) are as des
guidelines and policy statements. In addition, the relativ
the test to reference formulation should be within 80 to 1
AUCReftmax for a test product is defined as the area u
time of the maximum concentration of the reference pro
each study subject. We reiterate that this notice appliesbioavailability (bioequivalence) studies only. Submission
comparative (superiority) claims, such that time to onse
may need additional pharmacokinetic-pharmacodynamic
BA/BE Guidelines
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Specifics for
Modified
Release Drugs
MODIFIED RELEASE:
For modified-release products submitted as ANDAs, the following studies are
recommended: (1) a single-dose, nonreplicate, fasting study comparing the
highest strength of the test and reference listed drug product and (2) a food-
effect, nonreplicate study comparing the highest strength of the test and
reference product (see section VI.A). Because single-dose studies are
considered more sensitive in addressing the primary question of BE (i.e.,
release of the drug substance from the drug product into the systemic
circulation), multiple-dose studies are generally not recommended, even in
instances where nonlinear kinetics are present. (1)
Extra PK parameters:
• Lag-time (tlag) for modified-release products, if present (2)
MODIFIED RELEASE (APPLIES TO SINGLE DOSE)
PK Parameters: AUCX, AUCT, AUCI, AUCX/AUCI, A
lambda. For formulations that are likely to accumulate
(i.e., AUCX/AUCI < 0.8), safety requires that steady-st
in addition to the single-dose studies. Where the AUCX
be reliably determined, accumulation must be assume
Standards for
BE: High
variability
drugs
Non-Linear
Kinetics
(Report C)
NON-LINEAR KINETICS:
These requirements must be met in both the fasting a
where it has been demonstrated that food does not mo
doses within the range of strengths to be marketed. (8
The following pharmacokinetic parameters should be
dose studies: AUCX, AUCI, Cmax and, where possible
parameters should be calculated from steady state stuCpd, and Cmin.
STANDARDS FOR NON-LINEAR KINETICS DRUGS
Single Dose: Standards for bioavailability and bioequiv
described in Report A: "Bioavailability of Oral Dosage
Used for Systemic Effects".
Chronic Dose: For drugs requiring chronic dose studie
bioavailability and bioequivalence standards are requir
1. The 90% confidence interval of the relative mean AU
reference formulation should be within 80 to 125%.
2. The relative mean measured Cmax of the test to re
should be within 80 to 125%.
3. The relative mean measured Cmin of the test to ref
be within 80 to 125%.
AUCtau* is defined as the area under the plasma conc
after several doses indicating
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Long Half-Life
LONG HALF-LIFE DRUGS:
In a BA or pharmacokinetic study involving an oral product with a long half-life
drug, adequate characterization of the half-life calls for blood sampling over a
long period of time. For a BE determination of an oral product with a long half-
life drug, a nonreplicate, single-dose, crossover study can be conducted,
provided an adequate washout period is used. If the crossover study is
problematic, a BE study with a parallel design can be used. For either a
crossover or parallel study, we recommend that sample collection time be
adequate to ensure completion of gastrointestinal transit (approximately 2 to 3
days) of the drug product and absorption of the drug substance. Cmax and a
suitably truncated AUC can be used to characterize peak and total drug
exposure,
respectively. For drugs that demonstrate low intrasubject variability indistribution and clearance, an AUC truncated at 72 hours (AUC0-72 hr) can be
used
in place of AUC0-t or AUC0-∞. For drugs demonstrating high intrasubject
variability in distribution and clearance, AUC truncation warrants caution. In such
cases, we also recommend that sponsors and/or applicants consult the
appropriate review staff. (1)
LONG HALF-LIFE DRUGS:
This notice serves to clarify that for drugs which exhibi
half-life greater than 24 hours, bioequivalence standar
bioavailability studies will be applied to AUC0-72h. For
bioequivalence assessment, it will not be necessary to
hours post-dose, regardless of the half-life. Alternate d
studies could be considered. (3)
Standards for
BE: Critical
Dose Drugs
CRITICAL DOSE DRUGS:
Unless otherwise indicated by a specific guidance, this guidance recommends
that the traditional BE limit of 80 to 125 percent for non-narrow therapeutic
range drugs remain unchanged for the bioavailability measures (AUC and
Cmax) of narrow therapeutic range drugs. (1)
CRITICAL DOSE DRUGS:
1. The 90% confidence interval of the relative mean AU
reference formulation should be within 90.0 to 112.0%
AUCs
as described in Guidelines A and B are to be determin
2. The 90% confidence interval of the relative mean m
to reference formulation should be between 80.0 and 13. These requirements are to be met in both the fasted
4. These standards should be met on log transformed
from the measured data and from data corrected for m
(percent potency of label claim).
5. Steady-state studies are not required for ―critical do
warranted by exceptional circumstances. If a steady-s
90% confidence interval of the relative mean measure
reference formulation should also be between 80.0 an
Data to Analyze
Subjects with predose plasma concentrations:
• If the predose concentration is ≤ 5 percent of Cmax value in that subject, the
subject‘s data without any adjustments can be included in all pharmacokinetic
measurements and calculations. We recommend that if the predose value is >
than 5 percent of Cmax, the subject be dropped from all BE study evaluations.
Data deletion due to vomiting:• We recommend that data from subjects who experience emesis during the
course of a BE study for immediate-release products be deleted from statistical
analysis if vomiting occurs at or before 2 times median Tmax. In the case of
modified-release products, the data from subjects who experience emesis any
time during the labeled dosing interval can be deleted. (1)
The analyses should include all data for all subjects (s
outs and Withdrawal of Subjects from a Study") on me
Supplementary analyses may also be carried out with
subjects initially excluded from the analyses. Such exc
It is rarely acceptable to exclude more than 5 percent
than 10 percent of the data for a single subject-formula
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Sampling
Scheme
Criteria
We recommend that blood samples be drawn at appropriate times to describe
the absorption, distribution, and elimination phases of the drug. For most drugs,
we recommend that 12 to 18 samples, including a predose sample, be collected
per subject per dose. This sampling can continue for at least three or more
terminal half lives of the drug. The exact timing for sample collection depends
on the nature of the drug and the input from the administered dosage form. The
sample collection can be spaced in such a way that the maximum concentration
of the drug in the blood (Cmax) and terminal elimination rate constant (λz) can
be estimated accurately. At least three to four samples can be obtained during
the terminal log-linear phase to obtain an accurate estimate of λz from linear
regression. (1)
The duration of blood or urine sampling in a study sho
account for at least 80 percent of the known AUC to in
is usually at least three times the terminal half-life of th
Calculation of the relevant pharmacokinetic parameter
should be collected per subject per dose. There may b
inaccuracies in the estimates of the terminal dispositio
constant is estimated from linear regression using only
these inaccuracies it is preferable that four or more po
the terminal log-linear phase of the curve. (1)
Washout
An adequate washout period (e.g., more than 5 half lives of the moieties to be
measured) would separate each treatment. (1)
The interval should be the same for all subjects and, to
elimination rate between subjects, normally should be mean terminal half-life of the drug. (generally, the inter
should not exceed four weeks). (1,7)
Fasting vs.
Fed: SingleDose
we recommend a BE study under fed conditions for all orally administered
immediate-release drug products, with the
following exceptions:
• When both test product and RLD are rapidly dissolving, have similar
dissolution profiles, and contain a drug substance with high solubility and high
permeability (BCS Class I) (see footnote 3), or
• When the DOSAGE AND ADMINISTRATION section of the RLD label states
that the product should be taken only on an empty stomach, or
• When the RLD label does not make any statements about the effect of food on
absorption or administration. (2)
In ANDAs, BE of the test to the RLD is demonstrated in a single dose crossover
study. Both treatments should be sprinkled on one of the soft foods mentioned
in the labeling, usually applesauce. The BE data should be analyzed using
average BE and the 90 percent CI criteria should be used to declare BE. If
there are questions about other foods, the design, or the analysis of such BE
studies, the sponsors and/or applicants should contact the Office of Generic
Drugs.(2)
For uncomplicated drugs in immediate-release dosage
documented serious safety risk to subjects from single
the drug or drug product in the absence of food, then a
study conducted in the presence of only a sufficient qu
the toxicity may be acceptable for purposes of BE ass
Fasting vs.Fed: Modified
Release
We recommend that food-effect BA and fed BE studies be performed for all
modified release dosage forms.
A second or subsequent market entry MR formulation
the Group I or II MR product with which bioequivalence
formulations should be administered as single doses.
studies is to evaluate the bioequivalence of the test an
products under both fasting and fed conditions. Howevmay require that an investigation be conducted after th
appropriate meal at a specified time before taking the
manufacturers should consult with Health Canada befo
(7)
Fasting vs.
Fed: Critical
Dose
CRITICAL DOSE:
In general BE should be demonstrated under both fast
For complicated drugs in immediate-release dosage fo
modified-release dosage forms [#5.3], if there is a doc
risk to subjects from single-dose administration of the
either the absence or presence of food, then an appro
conducted in the indicated condition of use (fed or fast
acceptable for purposes of BE assessment. (5)
Blinding
If possible, the study should be conducted in such a w
aware of which product is administered. Furthermore,
adverse reactions and the person conducting the anal
know which product was administered. Other individua
administration of the drugs, the surveillance of the pat
plasma (or blood, or serum) data should not know whic
administered. (1)
Reference
Product
For ANDAs, we also recommend that the BE study be conducted between the
test product and reference listed drug using the strength(s) specified in
Approved Drug Products with Therapeutic Equivalence Evaluations (Orange
Book). (1)
• a drug product that has been issued a notice of comp
section C.08.004 of the Food and Drug Regulations, a
in Canada by the innovator, or
• a drug product acceptable to the Director. (1)
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Metabolites
For BE studies, measurement of only the parent drug released from the dosage
form, rather than the metabolite, is generally recommended. The rationale for
this recommendation is that concentration-time profile of the parent drug is
more sensitive to changes in formulation performance than a metabolite, which
is more reflective of metabolite formation, distribution, and elimination. The
following are exceptions to this general approach.
• Measurement of a metabolite may be preferred when parent drug levels are
too low to allow reliable analytical measurement in blood, plasma, or serum for
an adequate length of time. We recommend that the metabolite data obtained
from these studies be subject to a confidence interval approach for BE
demonstration. If there is a clinical concern related to efficacy or safety for the
parent drug, we also recommend that sponsors and/or applicants contact the
appropriate review division to determine whether the parent drug should be
measured and analyzed statistically.• A metabolite may be formed as a result of gut wall or other presystemic
metabolism. If the metabolite contributes meaningfully to safety and/or efficacy,
we also recommend that the metabolite and the parent drug be measured.
When the relative activity of the metabolite is low and does not contribute
meaningfully to safety and/or efficacy, it does not have to be measured. We
recommend that the parent drug measured in these BE studies be analyzed
using a confidence interval approach. The metabolite data can be used to
provide supportive evidence of comparable therapeutic outcome. (1)
Determination of bioequivalence should be based on d
Waiver of the measurement of the parent drug will not
concentrations of the parent drug cannot be reliably m
parent drug is not detectable due to rapid biotransform
available assay methodology. In such instances, the u
be acceptable. The measured metabolite should be a
major one, and appropriate scientific justification for a
measurement of the parent drug and the use of metab
provided. The choice of using the metabolite instead o
clearly stated, a priori, in the objective of the study in t
For the purpose of this guidance, a pro-drug is to be tr
That is, if the substance released from the dosage formis reliably measurable in the systemic circulation, it sho
assessment of bioequivalence. It is not generally cons
measure both
parent drug and metabolite levels for the purpose of b
assessment. However, quantitation of metabolite level
helpful, e.g., to explain extreme values caused by meta
subject. In those rare situations where use of drug con
justifiable for the assessment of relative bioavailability
concentrations may be used. That is, use of metabolite
Combining
Studies
If two or more studies have been completed, they may
requirements are met.
a) The same protocol must be used for all studies.
Specifically, this means that the same analytical metho
samples drawn at the same time, and the same lots o
used.b) Two consistency tests must be done on the studies
meaningful.
The first test is the test of equality of the residual mean
of the residual from the first study to the residual for ea
(For each ratio, the smaller of the two residuals must b
denominator.) This ratio is compared to an F statistic,
freedom associated with the residuals. If the ratio is gr
value, the studies may not be combined. The second t
study interaction and is carried out as shown in Table 7
Sources:
(1) Guidance for Industry: Bioavailability and Bioequivalence Studies for Orally
Administered Drug Products — General Considerations. U.S. Department of
Health and Human Services, Food and Drug Administration, Center for DrugEvaluation and Research (CDER); March 2003. BP Revision 1.
(1) Guidance for Industry: Conduct and Analysis of Bio
Bioequivalence Studies - Part A: Oral Dosage Formula
Effects. Health Products and Food Branch Guidance D
(2) Guidance for Industry: Food-Effect Bioavailability and Fed Bioequivalence
Studies. U.S. Department of Health and Human Services. Food and Drug
Administration. Center for Drug Evaluation and Research (CDER); December
2002. BP.
(2) DRAFT GUIDANCE FOR INDUSTRY: Use of Meta
Comparative Bioavailability Studies. Health Products a
2004/05/05.
(3) NOTICE TO INDUSTRY: Bioequivalence Requirem
Drugs. file 05-113899-750. June 22, 2005.
(4) NOTICE TO INDUSTRY: Bioequivalence Requirem
an Early Time of Onset or Rapid Rate of Absorption Is
drugs). 05-113913-859. June 22, 2005.
(5) GUIDANCE FOR INDUSTRY: Bioequivalence Req
Bioavailability Studies Conducted in the Fed State. He
Branch. 05-114865-164. July 21, 2005.
(6) GUIDANCE FOR INDUSTRY: Bioequivalence Req
Drugs. Health Products and Food Branch. 06-112871-
(7) GUIDANCE FOR INDUSTRY: Conduct and Analys
Bioequivalence Studies - Part B: Oral Modified Releas
Products and Food Branch Guidance Document. 1996
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Canadian BA/BE Drug Classification System
Critical Dose Drugs
Cyclosporine C - Critical Dose Drug
Digoxin C - Critical Dose Drug
Flecainide C - Critical Dose Drug
Lithium C - Critical Dose Drug
Phenytoin C - Critical Dose Drug
Sirolimus C - Critical Dose Drug
Tacrolimus C - Critical Dose Drug
Theophylline C - Critical Dose Drug
Warfarin C - Critical Dose Drug
Drugs with Non-Linear Kinetics
Acetylsalicylic acid C - Non-Linear Kinetics (For TPD, chronic dose studies may be required)
Acyclovir C - Non-Linear Kinetics (For TPD, chronic dose studies may be required)
Carbamazepine C - Non-Linear Kinetics (For TPD, chronic dose studies may be required)
Cephalosporins C - Non-Linear Kinetics (For TPD, chronic dose studies may be required)Disopyramide C - Non-Linear Kinetics (For TPD, chronic dose studies may be required)
Fluorouracil C - Non-Linear Kinetics (For TPD, chronic dose studies may be required)
Glucocorticosteroids C - Non-Linear Kinetics (For TPD, chronic dose studies may be required)
Griseofulvin C - Non-Linear Kinetics (For TPD, chronic dose studies may be required)
Levodopa C - Non-Linear Kinetics (For TPD, chronic dose studies may be required)
Phenytoin C - Non-Linear Kinetics (For TPD, chronic dose studies may be required)
Propranolol C - Non-Linear Kinetics (For TPD, chronic dose studies may be required)
Rifampin C - Non-Linear Kinetics (For TPD, chronic dose studies may be required)
Valproic acid C - Non-Linear Kinetics (For TPD, chronic dose studies may be required)
Verpamil C - Non-Linear Kinetics (For TPD, chronic dose studies may be required)
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FDA Special Guidances/Exceptions: Bioequivalence
FDA Special Guidances:
Clozapine Steady-state study in patients required at 100 mg. See http://www.fda.gov/CDE
Potassium Chloride Steady-state study required. See http://www.fda.gov/CDER/GUIDANCE/old195f
FDA Exceptions:
Source: http://www.fda.gov/cder/orange/obannual.pdf
The following drugs are defined by the 2008 FDA Orange Book as, "DRUG PRODUCTS WHICH
MUST DEMONSTRATE IN VIVO BIOAVAILABILITY
ONLY IF PRODUCT FAILS TO ACHIEVE ADEQUATE DISSOLUTION"
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R/GUIDANCE/6077fnl.pdf
n.pdf
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