Assessing the Effects of

Food on Drugs in INDs

and NDAs — Clinical
Pharmacology
Considerations
Guidance for Industry
DRAFT GUIDANCE
This guidance document is being distributed for comment purposes only.

Comments and suggestions regarding this draft document should be submitted within 60 days of
publication in the Federal Register of the notice announcing the availability of the draft
guidance. Submit electronic comments to http://www.regulations.gov. Submit written
comments to the Dockets Management Staff (HFA-305), Food and Drug Administration, 5630
Fishers Lane, rm. 1061, Rockville, MD 20852. All comments should be identified with the
docket number listed in the notice of availability that publishes in the Federal Register.

For questions regarding this draft document, contact (CDER) Office of Clinical Pharmacology at
CDER_OCP_GPT.

U.S. Department of Health and Human Services

Food and Drug Administration
Center for Drug Evaluation and Research (CDER)

February 2019
Clinical Pharmacology

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Assessing the Effects of
Food on Drugs in INDs
and NDAs — Clinical
Pharmacology
Considerations
Guidance for Industry

Additional copies are available from:

Office of Communications, Division of Drug Information
Center for Drug Evaluation and Research
Food and Drug Administration
10001 New Hampshire Ave., Hillandale Bldg., 4 th Floor
Silver Spring, MD 20993-0002
Phone: 855-543-3784 or 301-796-3400; Fax: 301-431-6353
Email: druginfo@fda.hhs.gov
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm

U.S. Department of Health and Human Services

Food and Drug Administration
Center for Drug Evaluation and Research (CDER)

February 2019
Clinical Pharmacology

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 Contains Nonbinding Recommendations
Draft — Not for Implementation
TABLE OF CONTENTS

I. INTRODUCTION...................................................................................................... 1
II. BACKGROUND ........................................................................................................ 1
III. RECOMMENDATIONS FOR FE STUDIES ............................................................ 3
IV. TIMING OF FE STUDIES ........................................................................................ 3
V. CONSIDERATIONS FOR DESIGNING FE STUDIES............................................ 4
A. Pilot Studies ................................................................................................................. 4
B. Pivotal Studies .............................................................................................................. 4
C. Types of Meals to Evaluate ............................................................................................ 5
D. Subject Selection........................................................................................................... 5
E. Test Doses .................................................................................................................... 6
F. Administration ............................................................................................................. 6
G. Sample Collection ......................................................................................................... 6
VI. OTHER CONSIDERATIONS ................................................................................... 7
A. FE Study Waivers ......................................................................................................... 7
B. Drug Products Labeled for Administration With Soft Foods ............................................ 7
C. Drug Products Labeled for Administration With Special Vehicles .................................... 7
D. Specific Populations ...................................................................................................... 7
E. Fixed-Combination Drug Products................................................................................. 8
VII. DATA ANALYSES AND LABELING....................................................................... 8
A. Data Analyses ............................................................................................................... 8
B. Labeling ...................................................................................................................... 9
APPENDIX 1. COMPOSITION OF A HIGH-FAT MEAL............................................... 11
APPENDIX 2. COMPOSITION OF A LOW-FAT MEAL................................................ 12
APPENDIX 3. LABELING EXAMPLES........................................................................... 13

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1 Assessing the Effects of Food on Drugs in INDs and NDAs —

2 Clinical Pharmacology Considerations
3 Guidance for Industry 1
4
5
6 This draft guidance, when finalized, will represent the current thinking of the Food and Drug
7 Administration (FDA or Agency) on this topic. It does not establish any rights for any person and is not
8 binding on FDA or the public. You can use an alternative approach if it satisfies the requirements of the
9 applicable statutes and regulations. To discuss an alternative approach, contact the FDA staff responsible
10 for this guidance as listed on the title page.
11
12
13
14
15 I. INTRODUCTION
16
17 This guidance provides recommendations to sponsors planning to conduct food-effect (FE)
18 studies for orally administered drug products as part of investigational new drug applications
19 (INDs), new drug applications (NDAs), and supplements to these applications. This guidance
20 revises and replaces part of the 2002 FDA guidance for industry entitled Food-Effect
21 Bioavailability and Fed Bioequivalence Studies. Information on fed bioequivalence (BE)
22 studies to be submitted in abbreviated new drug applications (ANDAs) is now found in the
23 FDA draft guidance for industry entitled Bioequivalence Studies with Pharmacokinetic
24 Endpoints for Drugs Submitted Under an ANDA. 2 Specific recommendations concerning fed
25 comparability trials are now described in the FDA draft guidance for industry entitled
26 Bioavailability Studies Submitted in NDAs or INDs — General Considerations.3
27
28 In general, FDA’s guidance documents do not establish legally enforceable responsibilities.
29 Instead, guidances describe the Agency’s current thinking on a topic and should be viewed only
30 as recommendations, unless specific regulatory or statutory requirements are cited. The use of
31 the word should in Agency guidances means that something is suggested or recommended, but
32 not required.
33
34
35 II. BACKGROUND
36

1
This guidance has been prepared by the Office of Clinical Pharmacology in the Center for Drug Evaluation and
Research at the Food and Drug Administration.
2
We update guidances periodically. To make sure you have the most recent version of guidance, check the FDA
Drugs guidance Web page at
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm. When final, this
guidance will represent the FDA’s current thinking on this topic
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37 Food-drug interactions can have a significant impact on the safety and efficacy of the drug.
38 These effects can be manifested in different ways. In some cases, co-administration of a drug
39 with food can increase the systemic exposure of the drug, leading to improved efficacy or
40 higher rates of adverse reactions. In other cases, administration of a drug with food can lower
41 the systemic absorption of a drug, thereby reducing the efficacy. Hence, assessing the effect
42 of food on the absorption of a drug is critical to optimize the safety and efficacy of the product
43 and to determine optimum instructions for drug administration in relation to food. Because
44 diets vary with respect to the amount and type of food, and maintaining strict control over the
45 daily content of food can be difficult, developing drug formulations that are not affected by
46 food is strongly encouraged. However, when developing such formulations is not possible,
47 well-conducted FE trials can inform how, when, and why drugs should or should not be
48 administered with food.
49
50 During new drug development, pharmacokinetic studies to assess the effect of food on the
51 systemic exposure of the drug are conducted to determine: (1) if, and to what extent, food
52 impacts the systemic exposure of the drug; (2) whether food increases or decreases the variability
53 of the systemic exposure of the drug; and (3) if the effect of food is different across meals with
54 different fat or caloric contents. For example, the absorption of a drug can increase when the
55 drug is given with a high-fat meal, while a low-fat meal has inconsequential effects on the
56 absorption of the same drug. To provide dosing instructions in relation to food, FE studies that
57 include additional meal types that may not result in a clinically relevant food effect can be
58 beneficial and provide useful labeling information.
59
60 It is important to have a detailed understanding of the exposure-response relationships of the
61 drug to interpret the results of FE studies. For example, the observed increase or decrease in
62 the systemic exposures of some drugs in the presence of food may not be clinically relevant
63 based on exposure-response information. If appropriately conducted FE studies indicate that
64 food does not have a clinically significant impact on the pharmacokinetics (PK) of the drug,
65 the sponsor can conduct pivotal trials without regard to food, and the labeling can state that the
66 drug can be taken with or without food.
67
68 In other cases, the clinical pharmacology characteristics of the drug may suggest that it should
69 be administered only under fasted conditions (e.g., when higher exposures under fed
70 conditions raise the risk of a clinically significant adverse reaction). In such cases, the drug
71 should be administered without food in clinical trials, and the sponsor should determine a
72 realistic interval between drug administration and meals that patients can practically
73 implement to include in the product labeling. On the other hand, some drugs have undesired
74 side effects that can be alleviated when taken with a meal. For example, drugs that cause
75 localized gastric irritation can adversely impact patient compliance or lead to loss of the dose
76 from vomiting. In such cases, administration of drugs with food can often alleviate the gastric
77 discomfort and improve compliance. However, if food also has a significant effect on the
78 exposure of the drug, then the evaluation of the effect of additional meal types on the PK of
79 the drug may be helpful. Lastly, in some circumstances, food may increase absorption, and
80 co-administration with food may be the only practical means of enhancing the efficacy of the
81 drug in patients.
82
83

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84 III. RECOMMENDATIONS FOR FE STUDIES
85
86 Sponsors should conduct FE studies for all new chemical entities and should consider conducting
87 FE studies in other scenarios, such as but not limited to, modified-release or combination
88 products of new or approved drugs. Sponsors are strongly encouraged to engage FDA staff early
89 in the development of a new drug regarding the strategy and details of FE studies. The general
90 recommendations for these FE studies are as follows:
91
92 • Sponsors should assess the effect of food on the PK of a new drug early in development
93 to inform the overall drug development program and final product labeling.
94
95 • Sponsors should test the effect of food on a new drug in clinical trials (see section IV)
96 before conducting the pivotal safety and efficacy trials to provide informed decisions
97 regarding dosing with respect to food.
98
99 • The sponsor should conduct a pivotal FE trial using the to-be-marketed formulation when
100 it is different than the clinical trial formulation used in the pivotal safety and efficacy trial
101 (see the FDA guidance for industry entitled Bioavailability Studies Submitted in NDAs or
102 INDs — General Considerations 4 for more information).
103
104 • In some situations, sponsors should assess the effects of different types of meals on a new
105 drug, as discussed above.
106
107 • When the efficacy or safety of a new drug is adversely impacted by food, and fasted
108 dosing is necessary, the sponsor should conduct FE studies to determine a realistic time
109 interval between drug administration and meals, which depends on the characteristics of
110 the drug (e.g., 2 hours before a meal, and 1 hour after).
111
112
113 IV. TIMING OF FE STUDIES
114
115 This section of the guidance provides recommendations on when FE studies should be conducted
116 during the development of a new drug:
117
118 • Preliminary assessments of the effects of food on a new drug can occur in phase 1 pilot
119 trials (e.g., as part of the first-in-human trials (see section V)) and help determine whether
120 a drug should be administered with food in clinical trials until a to-be-marketed
121 formulation is identified.
122
123 • The sponsor should also conduct a pivotal FE study using the formulation to be used in
124 the pivotal efficacy and safety trial and in some cases the to-be-marketed formulation, if
125 different, to guide dosing in clinical trials and provide adequate labeling instructions (see
126 section V and the FDA guidance for industry entitled Bioavailability Studies Submitted in

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127 NDAs or INDs — General Considerations5).
128
129
130 V. CONSIDERATIONS FOR DESIGNING FE STUDIES
131
132 This section provides general considerations for designing FE studies. Sponsors can propose
133 alternative trial designs and data analyses. The sponsor should provide the scientific rationale
134 and justifications for any alternative trial designs and analyses in the study protocol.
135
136 A. Pilot Studies
137
138 The sponsor should conduct a pilot study to provide a preliminary assessment of the effect of a
139 high-fat meal on the systemic exposure of the drug. To ensure the safety of the subject
140 population, sponsors should carefully choose the dose for the FE assessment to account for any
141 potential significant effects of food on the exposure of the drug that might increase the number or
142 severity of adverse events.
143
144 B. Pivotal Studies
145
146 The sponsor should use a randomized, balanced, single-dose, two-treatment (i.e., fed versus
147 fasted), two-period, crossover design to study the effects of food on either an immediate-release
148 or a modified-release drug product. The formulation to be tested should be administered on an
149 empty stomach during one period and the high-fat test meal during the alternate period. For
150 other types of meals, see section C below. A washout period of five elimination half-lives of the
151 drug should separate the treatments in the FE study.
152
153 For drugs with long elimination half-lives (i.e., longer than 24 hours), a single-dose, parallel
154 study design can be more practical. In these studies, the sponsor should administer each
155 treatment (i.e., fasted, food-drug combination) to a separate group of subjects with similar
156 demographics.
157
158 The sponsor should enroll an adequate number of subjects to sufficiently characterize the effect
159 of food on the PK of the drug. The pharmacokinetic variability of the drug will affect the sample
160 size for each group. At a minimum, 12 subjects should be enrolled in each treatment arm.
161
162 If a conventional FE study with rich pharmacokinetic sampling cannot be performed, the sponsor
163 should consider conducting a well-designed and well-controlled population pharmacokinetic
164 study to assess the potential effects of food on a new drug. However, these types of analyses are
165 often hampered by a lack of reliable information regarding drug dosing relative to the type and
166 amount of food as well as adequate sampling of each subject’s drug levels to sufficiently
167 characterize the absorption phase of the drug. Sponsors are strongly encouraged to seek FDA
168 input early in the conceptual stage of population pharmacokinetic studies that assess the effect of
169 food on a drug to ensure careful planning and execution of such studies.
170

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171 C. Types of Meals to Evaluate
172
173 For all orally administered drugs under development, an FE study with a high-fat meal should be
174 conducted. Table 1 provides the definition of various test meals:
175
176 Table 1. Test Meal Definitions
Fat
Meal Type Total Kcal
Kcal Grams Percent
High-Fat 6 800-1000 500-600 55-65 50

Low-Fat 7 400-500 100-125 11-14 25

177
178 The physiological conditions induced by a high-fat meal generally provide the greatest effects on
179 gastrointestinal physiology and the maximum effects on the systemic availability of the drug.
180 For some drugs, the effect observed with a high-fat meal is not observed with a low-fat meal.
181 When drug administration with a high-fat meal causes unacceptable toxicity or a loss of drug
182 efficacy, a low-fat meal can have less or no impact on systemic exposures, improve patient
183 compliance, and alleviate localized gastric irritation. In these circumstances, administration of the
184 drug with a low-fat meal may be more advantageous to patients.
185
186 The sponsor should provide a description of the meal, the caloric and content breakdown
187 (carbohydrates, proteins and fat), and the type of fat (e.g., percent saturated fat and percent unsaturated
188 fat) in the study report. Examples of high- and low-fat meals are provided in the Appendices and
189 can help guide trial design and product labeling.
190
191 D. Subject Selection
192
193 Sponsors can conduct FE studies in healthy adult subjects. Subjects from the patient population
194 can also be appropriate if safety concerns preclude the enrollment of healthy subjects, or if
195 differential effects of food on the drug are expected in the target patient population as compared
196 to healthy subjects because of the underlying disease condition.
197
198 The sponsor should enroll both male and female subjects in the FE study unless the indication is
199 specific to one sex (e.g., oral contraceptives), or if safety concerns preclude the enrollment of
200 one sex (e.g., if the drug is a teratogen, women of child-bearing age should be excluded).
201 Subjects in FE studies should have normal renal and hepatic function. Sponsors should exclude
202 subjects if they cannot refrain from using concomitant drugs that could confound the results of
203 the FE study (e.g., drugs that can alter the absorption of other drugs by affecting gastrointestinal
204 motility or by changing the gastric pH as well as drugs that can increase or decrease the
205 metabolism and excretion of the investigational drug).
206

6
See Appendix 1: Composition of a High-Fat Meal
7
See Appendix 2: Composition of a Low-Fat Meal

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207 E. Test Doses
208
209 The sponsor should use the clinically recommended dose in the pivotal FE study. When
210 several doses of a drug that exhibit linear PK will be marketed, the sponsor should use the
211 highest clinically recommended dose unless safety concerns necessitate a lower dose. When it
212 is unsafe to administer the therapeutic dose to healthy subjects, the sponsor can test the highest
213 strength of the drug formulation in lieu of the highest dose, as long as the PK of the drug over
214 the therapeutic range are linear. For drugs with nonlinear PK across the therapeutic dose
215 range, the sponsor should conduct single-dose FE studies using both the high and low doses
216 listed in the product labeling
217
218 F. Administration
219
220 1. Fasted Conditions
221
222 Following an overnight fast of at least 10 hours, investigators should administer the drug product
223 to study subjects with 240 mL (i.e., 8 fluid ounces) of water. Additional water is permitted ad
224 lib except for the period 1 hour before to 1 hour after administration of the drug product. The
225 study subjects should not consume any food for at least 4 hours after the dose. Subjects should
226 receive standardized meals scheduled at the same time throughout the study.
227
228 2. Fed Conditions
229
230 Following an overnight fast of at least 10 hours, the study subjects should start the recommended
231 meal 30 minutes before administration of the drug product. Trial subjects should eat this meal in
232 30 minutes or less. The study subjects should take the drug product with 240 mL (8 fluid
233 ounces) of water. Additional water is allowed ad lib except for 1 hour before and 1 hour after
234 drug administration. No food is allowed for at least 4 hours after the dose.
235
236 3. Modified Fasted Condition
237
238 When fasted dosing is necessary because food can significantly increase or decrease the exposure
239 of the drug, the standard, overnight, fasted, test condition may not be practical for patient
240 treatment. Furthermore, the results of the overnight fasted condition may not be applicable to
241 shorter periods of fasting in patients. To provide food-drug labeling instructions (e.g., no food
242 should be consumed X hours before or Y hours after drug administration) for such products, the
243 sponsor should conduct FE studies with appropriate separation times between drug
244 administration and food consumption. The sponsor should provide pharmacokinetic data to
245 support pragmatic labeling instructions to prevent food-drug interactions, taking into
246 consideration the frequency of dosing, the patient demographics, and the disease condition, etc.
247
248 G. Sample Collection
249
250 For both fasted and fed treatment periods, the sponsor should collect samples in a biological matrix
251 (e.g. plasma) from the study subjects to characterize the complete plasma concentration versus
252 time profile for the parent drug (e.g., 12-18 samples per subject per period). The sponsor can use

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253 different sample collection times for the fasted and fed treatments when co-administration of a
254 drug with food is expected to alter the time course of drug concentrations in the plasma. To
255 determine whether to measure other moieties in the plasma, such as active metabolites, sponsors
256 should refer to the FDA guidance for industry entitled Bioavailability Studies Submitted in NDAs
257 or INDs — General Considerations. 8
258
259
260 VI. OTHER CONSIDERATIONS
261
262 A. FE Study Waivers
263
264 Biopharmaceutical Classification 1 (BCS class 1) drugs are typically highly soluble, highly
265 permeable, and rapidly dissolving compounds that are unaffected by food. Internal FDA data
266 indicate that more than 80 percent of BCS class 1 immediate-release drugs are not affected by
267 high-fat meals; therefore, the labeling for these drugs states that they can be administered
268 without regard to food. The remaining BCS class 1 drugs are subject to high first-pass
269 metabolism effects and can be affected by meals. The FDA may waive the requirement for
270 sponsors to conduct an FE study for drugs that are designated as BCS class 1 (i.e., high
271 solubility, high permeability) immediate-release drugs as defined in the FDA guidance for
272 industry entitled Waiver of In Vivo Bioavailability and Bioequivalence (BE) Studies for
273 Immediate-Release Solid Oral Dosage Forms Based on a Biopharmaceutics Classification
274 System that also have a high bioavailability (F ≥ 0.85). Sponsors should consult the FDA
275 regarding the feasibility of an FE study waiver.
276
277 B. Drug Products Labeled for Administration With Soft Foods
278
279 The labeling of certain drugs (e.g., oral granules, or extended-release capsules) recommends that
280 the product be sprinkled on soft foods (e.g., applesauce, pudding, etc.). Some formulations should
281 be swallowed without chewing. For the labeling to indicate that the drug can be sprinkled on soft
282 foods, the sponsor should perform additional in vivo, relative bioavailability studies using the
283 soft foods listed in the labeling (i.e., test treatment). All soft foods intended for labeling should
284 be tested. When the product is also labeled for administration as an intact dosage form (tablets,
285 capsules), the drug administered in the intact form taken with the soft food (i.e., reference
286 treatment) should be compared to the test treatment.
287
288 C. Drug Products Labeled for Administration With Special Vehicles
289
290 The labeling of certain oral products (e.g., cyclosporine oral solution) recommends that the
291 product be mixed with a beverage before administration. The bioavailability of these products
292 can change when mixed with different beverages because of the formation of complex
293 mixtures and other physical, chemical, or physiological factors. Sponsors should contact the
294 FDA to determine what data should be submitted to support the labeling of these products.
295
296 D. Specific Populations
297
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298 1. Geriatrics
299
300 The FDA does not recommend a dedicated FE study in an elderly population (i.e., patients
301 greater than 65 years old). The incidence of certain diseases (e.g., gastro-esophageal reflux
302 disease) increases with age, which can alter the bioavailability of drugs. However, these
303 diseases do not influence the effect of food on the bioavailability of the drug in an age-
304 dependent manner.
305
306 2. Pediatrics
307
308 When a new pediatric formulation is developed, the sponsor should conduct a new FE study
309 with the pediatric formulation in adults and then extrapolate the results to the pediatric
310 population. Sponsors can use foods and quantities of food that are commonly consumed with
311 drugs in a particular pediatric population (e.g., formula for infants and jelly, pudding, or apple
312 sauce for toddlers).
313
314 When the same to-be-marketed formulation that is approved for use in adults is approved for use
315 in a pediatric population, a separate FE study is not necessary. Furthermore, a separate FE study
316 may not be necessary if a pediatric formulation is very similar to the adult formulation (e.g., a
317 reduced strength tablet) and if the pediatric formulation is approved based on in vitro dissolution
318 tests.
319
320 E. Fixed-Combination Drug Products
321
322 The effect of food on each active ingredient or therapeutic drug moiety in a combination drug
323 product can be different from the effect of food when each active drug ingredient or therapeutic
324 drug moiety is administered alone. Therefore, the sponsor should assess the effect of food on the
325 various active ingredients or therapeutic drug moieties of the combination drug product after
326 administration of the combination drug product.
327
328
329 VII. DATA ANALYSES AND LABELING
330
331 A. Data Analyses
332
333 The following exposure measures and pharmacokinetic parameters should be derived from all FE
334 studies and reported:
335
336 • The total exposure of the drug, or area under the concentration-time curve (AUC0-INF,
337 AUC0-t)
338
339 • The partial exposure of the drug, or area -under-the-concentration-time curve (pAUC) for
340 MR products
341
342 • The peak concentration of the drug (Cmax)
343

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344 • The time to the peak concentration of the drug (Tmax)
345
346 • The delay in achieving Tmax (tlag)
347
348 • The terminal elimination half-life of the drug (t1/2)
349
350 • The apparent clearance (Cl/F)
351
352 • The apparent volume of distribution (Vd/F)
353
354 Individual subject measurements as well as summary statistics (e.g., group averages, standard
355 deviations, coefficients of variation, ranges) should be reported.
356
357 When an FE bioavailability trial is conducted to assess changes in formulations, an equivalence
358 approach is recommended (refer to the FDA guidance for industry entitled Bioavailability
359 Studies Submitted in NDAs or INDs—General Considerations9). To make a claim of no food
360 effect, the data should be analyzed using an average criterion, with the fasted treatment arm
361 serving as the reference.
362
363 Exposure measurements (AUC and Cmax) should be log-transformed. The 90 percent confidence
364 interval for the ratio of the population geometric means between the fed and fasted conditions
365 should be provided for AUC0-INF, AUC0-t, and Cmax. An absence of a food effect on
366 bioavailability is established if the 90 percent confidence interval for the ratio of the population
367 geometric means between fed and fasted treatments, based on log-transformed data, is contained
368 in the equivalence limits of 80-125 percent for AUC0-INF (AUC0-t when appropriate) and Cmax,
369 unless other criteria based on the established exposure-response relationships for the drug are
370 more appropriate (refer to the FDA guidance for industry entitled Statistical Approaches to
371 Establishing Bioequivalence). When the 90 percent confidence interval for the ratio of the
372 population geometric means of either AUC0-INF (AUC0-t when appropriate) and Cmax between fed
373 and fasted treatments fails to meet the limits of 80-125 percent, the sponsor should provide
374 specific recommendations on the clinical significance of the food effect based on what is known
375 from the total clinical database about the drug’s exposure-response relationships. The clinical
376 relevance of any difference in Tmax and tlag should also be indicated by the sponsor.
377
378 B. Labeling
379
380 Product labeling should include a summary of essential information pertaining to the effect of
381 food on the PK and PD of the drug (if known) that is needed for the safe and effective use of the
382 drug. See the FDA’s guidance for industry entitled Clinical Pharmacology Section of Labeling
383 for Human Prescription Drug and Biological Products — Content and Format. The effect of
384 food on the absorption of orally administered drugs should be described under a subheading
385 called “Effect of Food” under the “Absorption” heading in the Pharmacokinetics subsection of
386 the CLINICAL PHARMACOLOGY section. The “Effect of Food” subheading includes detailed
387 information that informs actionable recommendations that are described in the DOSAGE AND

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388 ADMINISTRATION section of labeling as well as other sections of labeling when pertinent
389 (e.g., WARNINGS AND PRECAUTIONS, PATIENT COUNSELING INFORMATION). See
390 Appendix 3 of this guidance for examples of incorporating FE information in labeling.
391
392

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393 APPENDIX 1. COMPOSITION OF A HIGH-FAT MEAL*

Total Calories 800-1000

Calories from Protein 150

Calories from
250
Carbohydrates

Calories from Fat 500-600

• Two eggs fried in butter

An Example of a High- • Two strips of bacon
Fat Breakfast • Two slices of toast with butter
• Four ounces of hash brown potatoes
• Eight ounces of whole milk.

394 *50 percent of calories are derived from fat. Substitutions can be made to this meal, if the content, volume, and
395 viscosity are maintained.

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396 APPENDIX 2. COMPOSITION OF A LOW-FAT MEAL

Total Calories 400-500

Fat (g) 11-14

Percent Calories from

25
Fat

An Example of a Low- • Eight ounces milk (1 percent fat)

Fat Breakfast* • One boiled egg
• One packet flavored instant oatmeal made with water

397 *This low-fat breakfast contains 387 calories and has 10 grams of fat

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398 APPENDIX 3. LABELING EXAMPLES
399
400 Example 1
401 2 DOSAGE AND ADMINISTRATION
402 2.1 Recommended Dosage
403 The recommended dosage for DRUG-X is 500 mg orally once daily on an empty
404 stomach. Do not consume food 2 hours before each dose or 1 hour after each dose
405 [see Clinical Pharmacology (12.3)].
406
407 12 CLINICAL PHARMACOLOGY
408 …
409 12.3 Pharmacokinetics
410 Absorption
411 Effect of Food
412 Following administration of DRUG-X to healthy volunteers, the Cmax increased
413 57% and the AUC increased 45% with a high-fat meal (1000 calories, 50% fat;
414 compared to fasted conditions [see Dosage and Administration (2.1)].
415
416 Example 2
417
418 2 DOSAGE AND ADMINISTRATION
419 2.1 Recommended Dosage
420 The recommended dosage for DRUG-X is 250 mg orally twice daily with a low-fat
421 meal (400 calories, 25% fat) or on an empty stomach Do not take DRUG-X with
422 high fat meals (1000 calories, 50% fat) [see Clinical Pharmacology (12.3)].
423
424 12 CLINICAL PHARMACOLOGY
425 …
426 12.3 Pharmacokinetics
427 Absorption
428 Effect of Food
429 Following administration of DRUG-X to healthy volunteers, the Cmax increased
430 74%, and the AUC increased 87% with a high-fat meal (1000 calories, 50% fat)
431 compared to fasted conditions [see Dosage and Administration (2.1)].
432
433 Following administration of DRUG-X in healthy volunteers, the Cmax increased
434 12%, and the AUC increased 14% with a low-fat meal (400 calories, 25% fat)
435 compared to fasted conditions. These exposure changes are not clinically-
436 significant.
437
438 Example 3
439
440 2 DOSAGE AND ADMINISTRATION
441 2.1 Recommended Dosage
442 The recommended dosage for DRUG-X is 400 mg orally once daily with meals
443 (i.e., 400-1000 calories, 25-50% fat) [see Clinical Pharmacology (12.3)].
444
445 12 CLINICAL PHARMACOLOGY
446 …
447 12.3 Pharmacokinetics

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448 Absorption
449 Effect of Food
450 Following administration of DRUG-X to healthy volunteers, the Cmax
451 increased 15%, and the AUC increased 65% with a low-fat meal (400 calories,
452 25% fat) compared to fasted conditions. The Cmax increased 17%, and the AUC
453 increased 73% with a high-fat meal (1000 calories, 50% fat) compared to fasted
454 conditions [see Dosage and Administration (2.1)].
455
456 Example 4
457
458 2 DOSAGE AND ADMINISTRATION
459 2.1 Recommended Dosage
460 The recommended dosage for DRUG-X is 800 mg orally twice daily with or
461 without meals [see Clinical Pharmacology (12.3)].
462
463 12 CLINICAL PHARMACOLOGY
464 …
465 12.3 Pharmacokinetics
466 Absorption
467 Effect of Food
468 Following administration of DRUG-X to healthy volunteers, the Cmax
469 decreased 15%, while the AUC remained unchanged with a high-fat meal (1000
470 calories, 50% fat) compared to fasted conditions. This concentration decrease is
471 not clinically significant [see Dosage and Administration (2.1)].
472

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