In February 2013, GlaxoSmithKline (GSK) announced a ... · PDF fileIn February 2013, GlaxoSmithKline (GSK) announced a commitment to further clinical transparency through the public

In February 2013, GlaxoSmithKline (GSK) announced a commitment to further clinical transparency through the public disclosure of GSK Clinical Study Reports (CSRs) on the GSK Clinical Study Register.

The following guiding principles have been applied to the disclosure: Information will be excluded in order to protect the privacy of patients and all namedpersons associated with the study

Patient data listings will be completely removed* to protect patient privacy. Anonymized data from each patient may be made available subject to an approved research proposal. For further information please see the Patient Level Data section of the GSK Clinical Study Register.

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numbered

CONFIDENTIAL PM2002/00022/00BRL-025000/643

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The GlaxoSmithKline group of companies

A Study to Determine the Bioequivalence of ReformulatedAUGMENTIN ES-600* for Oral Suspension (improved flavor) toStandard Marketed Suspension

Clinical Study Report for Study BRL-025000/643(Development Phase I)

Document Number: PM2002/00022/00 Compound Number: BRL-025000

Investigational Product: AUGMENTIN Generic Drug Name: Amoxicillin

ES-600 and Clavulanate

Initiation Date: 25Jan2002

Completion Date: 25Jul2002

Early Termination Date: None

Date of Report: April 2003

Sponsor Signatory:(and Medical Officer)

MD, PhDFull DevelopmentGlaxoSmithKline

This study was performed in compliance with Good Clinical Practices includingthe archiving of essential documents.

Copyright 2003 the GlaxoSmithKline group of companies. All rights reserved.Unauthorised copying or use of this information is prohibited.

CONFIDENTIAL PM2002/00022/00 BRL-025000/643

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Synopsis

Document Number: PM2002/00022/00 Study Number: BRL-025000/643

Title: A Study to Determine the Bioequivalence of Reformulated AUGMENTIN ES-600* for OralSuspension (improved flavor) to Standard Marketed Suspension

Investigator(s): The principal investigator was MD. Sub-investigators were MD, FACP, MD, MD, MD,

MSN, CRNP, MD, MD, MD, PhD, MD, PhD, MD, MSN, CRNP,

MSN, CRNP, PA-C, MSN, CRNP, RN, BSN and MS.

Study center(s): The study was conducted at the The clinical laboratory facility

at Quest Diagnostic, Inc, 900 Business Center Dr, Horsham, PA 19044 was also utilized.

Publication(s): None as of April 2003.

Study period: 25Jan2002 - 25Jul2002 Phase of Development: I

Objectives: The primary objective was to demonstrate the bioequivalence of a new reformulatedES-600 mg/5 mL suspension of AUGMENTIN† (amoxicillin/clavulanate potassium) to themarketed ES-600 mg/5 mL suspension of AUGMENTIN. The secondary objective was toassess the safety and tolerability of the new reformulated ES-600mg/5 mL suspension ofAUGMENTIN in healthy adult volunteers in this study.

Methodology: Subjects were required to stay in the for approximately 14 hours during eachstudy session. On the first day of each study session, subjects reported to the

at approximately 07:00 AM following an overnight fast of at least 8 hours.Prior to dosing, an intravenous cannula for collection of blood samples was inserted into oneantecubital vein and kept patent with a dilute heparin solution (≤ 100 U/mL) for up to 14 hours.Procedures performed are listed in the table below.


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Procedures Time(Hours from Morning Dosing)

Review of prior (Session 1 only) or Concomitantmedications

Predose

Review of medical history (Session 1 only) PredoseBlood (approximately 6 mL) and urine samples forclinical laboratory tests (4-hour fast)1,2 [Protocol]

Predose

Study medication administration with 240 mL of water3 0 hour (approximately 8:00 AM)Meals (breakfast, lunch, dinner)4 5 minutes, 5, and 10 hour after

dosingBaseline signs/symptoms or Adverse Experiences5 Predose and at 5 minutes, 5, 10, and

12 hours after dosingBlood samples for pharmacokinetics (approximately 3mL)6

Predose and at 0.25, 0.5, 0.75, 1,1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 10, and 12hours after dosing

1. Clinical chemistry, hematology, and urinalysis were obtained prior to dosing during study session 1.2. A serum β-hCG for women was obtained prior to dosing in all study sessions. Results of the serum β-hCG

test were reported prior to dosing with study medication. A urine drug/alcohol screen was also obtained priorto dosing during each session. Results of the urine drug/alcohol screen were not required to be reported priorto dosing with study medication

3. Study medication was administered as 600 mg amoxicillin/ 42.9 mg clavulanate per 5 mL oral suspension4. Meals were standardized across sessions.5. Adverse events were assessed by asking a non-leading question such as "How do you feel?"6. Blood samples for PK analysis were collected in EDTA tubes

A follow–up visit was to occur 24-48 hours after dosing in Session 4.

Number of subjects: Thirty-six subjects were enrolled and 31 subjects completed the study.

Diagnosis and main criteria for inclusion: Subjects were healthy adult males and femalesbetween the ages of 18 and 60 years, inclusive.

Treatment administration: In each session, subjects received a single dose of one of the twoformulations (reformulated or marketed AUGMENTIN ES-600*). Each formulation wasadministered during two study sessions according to the randomization schedule. The studymedication (5 mL volume in an oral syringe) was administered orally, at approximately 08:00AM. Following administration of study medication, approximately 5-6 mL tepid water was drawninto the oral syringe and the liquid was administered. Flushing the syringe was necessary toensure that the full dose of the study medication was administered. Subjects were asked todrink approximately 240 mL tepid water (in total) with each dose of study medication. A lightstandardized breakfast (muffin or bagel, fruit juice) was served immediately (i.e., within 5minutes) following the administration of the study medication and was to be consumed within 30minutes.


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Criteria for evaluation:

Pharmacokinetic: AUC(0-∞) and Cmax of both amoxicillin and clavulanate were the primarypharmacokinetic parameters. The secondary pharmacokinetic parameters were AUC(0-t) and tmax

for amoxicillin and clavulanate.

Safety: All subjects who received at least one dose of study medication were included in theevaluation of clinical safety and tolerability. Adverse events and laboratory data were reviewedby the study physician for all subjects who received at least one dose of study medication. Noformal statistical analysis of the safety data was planned.

Statistical methods: Following loge-transformation, AUC(0-∞), AUC(0-t) and Cmax for bothamoxicillin and clavulanate were separately analyzed by fitting a mixed effects model consistentwith the FDA guidelines. Point estimates and 90% confidence intervals (CIs) for the ratio offormulations (A:B) were constructed. Bioequivalence was to be demonstrated if the 90% CIs forboth AUC(0-∞) and Cmax of amoxicillin and clavulanate were completely contained in the interval(0.80, 1.25). Tmax was analyzed non-parametrically under an estimation approach. The mediandifferences between formulations (A-B) and a corresponding 95% CI were calculated.

Summary:

Pharmacokinetic: The 90% confidence intervals for the ratio of adjusted geometric means forAUC(0-∞) and Cmax of amoxicillin were within the 90% confidence interval (CI) range of 0.80 to1.25, meeting the criteria of bioequivalence. However, the 90% confidence intervals for the ratioof adjusted geometric means for AUC(0-∞) and Cmax of clavulanate included values above theupper limits of the bioequivalence range of 0.80 to 1.25. Therefore, the study failed todemonstrate bioequivalence of reformulated AUGMENTIN ES-600 suspension and standardmarketed AUGMENTIN ES-600 suspension for clavulanate.

Comparisons Between Formulations for Amoxicillin

Parameter FormulationA3

FormulationB3

Comparison PointEstimate

90% C.I. CV resid(%)

AUC(0-∞)1 26.8 26.2 A:B 1.02 (1.00, 1.04) 7.65Cmax1 7.17 7.07 A:B 1.02 (0.96, 1.08) 20.27AUC(0-t)1 26.3 26.0 A:B 1.01 (0.98, 1.04) 10.76tmax (h)2 A-B -0.13 (-0.38, 0.12)1. Point estimate represents the ratio of the adjusted geometric means2. Point estimate represents the estimated median difference. 95% C.I. provided for tmax3. Represents backtransformed Least square means (adjusted geometric means)A: Reformulated Strawberry/CMC 600 Suspension (Test)B: Standard Marketed Raspberry/Orange 600 Suspension (Reference)


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Comparisons Between Formulations for Clavulanate


FormulationB3


90% C.I. CV resid(%)

AUC(0-∞)1 1.607 1.381 A:B 1.16 (1.06, 1.28) 31.44Cmax1 0.643 0.541 A:B 1.19 (1.06, 1.33) 39.84AUC(0-t)1 1.437 1.182 A:B 1.22 (1.08, 1.37) 42.82tmax (h)2 A-B -0.06 (-0.17, 0.06)1. Point estimate represents the ratio of the adjusted geometric means2. Point estimate represents the estimated median difference. 95% C.I. provided for tmax3. Represents backtransformed Least square means (adjusted geometric means)A: Reformulated Strawberry/CMC 600 Suspension (Test)B: Standard Marketed Raspberry/Orange 600 Suspension (Reference)

Safety: Both formulations were generally well tolerated. Summary details for all treatment-emergent AEs reported during the study are listed by regimen in the table below.

ReformulatedAUGMENTIN

ES-600

MarketedAUGMENTIN

ES-600

Total

Most Frequent AE (headache) 7 1 7Total Number of AEs 17 8 25Number of Subjects with AEs 11 6 14Number of Subjects Exposed 34 36 36

There were no deaths or serious adverse events during the study. One subject was withdrawnfrom the study due to an adverse event, an mild injury, that she sustained due to a fallapproximately 1 week and 4 days after the third dosing session. One AE, mild vomiting, whichoccurred approximately 7½ hours after administration of reformulated AUGMENTIN ES-600,was suspected of being related to the study medication by the investigator and resolved beforethe completion of the study. Three subjects had post-dose clinical laboratory values of potentialclinical concern during the study. They were asymptomatic and considered unrelated to thestudy medication by the investigator.


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Conclusions:

• The 90% confidence intervals for the ratio of adjusted geometric means for AUC(0-∞) andCmax of amoxicillin were within the bioequivalence range of 0.80 to 1.25 when comparingthe reformulated AUGMENTIN ES-600 suspension to the standard marketed AUGMENTINES-600 suspension.

• Reformulated AUGMENTIN ES-600 suspension failed to demonstrate bioequivalence tothe standard marketed AUGMENTIN ES-600 suspension as the 90% confidence intervalfor the clavulanate (AUC(0-∞) and Cmax) ratio were not completely contained within thebioequivalence range of 0.80 to 1.25. There was a 16% increase in clavulanate AUC(0-∞)

and a 19% increase in Cmax for the reformulated suspension relative to the standardmarketed suspension.

• Reformulated and marketed AUGMENTIN ES-600 were generally safe and well toleratedby healthy adult male and female subjects.

Date of Report: April 2003


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TABLE OF CONTENTS

PageSynopsis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2

LIST OF TABLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10

LIST OF FIGURES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11

Abbreviations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12

1. ETHICS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 141.1. Independent Ethics Committee (IEC) or Institutional Review Board

(IRB) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 141.2. Ethical Conduct of the Study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 141.3. Subject Information and Consent . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14

2. INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE . . . . . . 14

3. INTRODUCTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 153.1. Background . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 153.2. Rationale . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15

4. STUDY OBJECTIVE(S). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 164.1. Primary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 164.2. Secondary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16

5. INVESTIGATIONAL PLAN . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 175.1. Study Design . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 175.2. Protocol Amendment(s) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 175.3. Selection of Study Population . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17

5.3.1. Inclusion Criteria. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 175.3.2. Exclusion Criteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 185.3.3. Predetermined Criteria for Subject Withdrawal . . . . . . . . . . . . 18

5.4. Investigational Product(s). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 195.4.1. Description of Investigational Product(s) . . . . . . . . . . . . . . . . . 195.4.2. Dosages and Administration . . . . . . . . . . . . . . . . . . . . . . . . . . 205.4.3. Dose Rationale . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 205.4.4. Blinding. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 205.4.5. Treatment Assignment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 215.4.6. Assessment of Compliance . . . . . . . . . . . . . . . . . . . . . . . . . . . 215.4.7. Treatment of Investigational Product Overdose . . . . . . . . . . . . 21

5.5. Prior and Concomitant Medications and Non-Drug Therapies . . . . . 225.5.1. Permitted Medications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 225.5.2. Prohibited Medications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22

5.6. Study Assessments and Procedures . . . . . . . . . . . . . . . . . . . . . . . . . 225.6.1. Demographic and Baseline Assessments . . . . . . . . . . . . . . . . 235.6.2. Pharmacokinetic Assessments . . . . . . . . . . . . . . . . . . . . . . . . 265.6.3. Safety Assessments. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26

5.7. Data Quality Assurance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29


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5.8. Data Analysis Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 295.8.1. Timings of Planned Analyses . . . . . . . . . . . . . . . . . . . . . . . . . . 295.8.2. Sample Size Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . 295.8.3. Analysis Populations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 305.8.4. Treatment Comparisons. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 305.8.5. General Considerations for Data Analyses . . . . . . . . . . . . . . . 305.8.6. Data Handling Conventions . . . . . . . . . . . . . . . . . . . . . . . . . . . 315.8.7. Study Population . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 335.8.8. Pharmacokinetic Analyses . . . . . . . . . . . . . . . . . . . . . . . . . . . . 335.8.9. Statistical Analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 345.8.10. Safety Analyses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35

6. STUDY POPULATION RESULTS. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 366.1. Disposition of Subjects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 366.2. Protocol Deviations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 366.3. Populations Analyzed. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 376.4. Demographics and Other Baseline Characteristics . . . . . . . . . . . . . . 37

6.4.1. Demographic Characteristics . . . . . . . . . . . . . . . . . . . . . . . . . . 376.4.2. Baseline Characteristics. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 376.4.3. Other Current Medical Conditions . . . . . . . . . . . . . . . . . . . . . . 376.4.4. Previous Medications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 376.4.5. Other Factors Affecting Response to Therapy . . . . . . . . . . . . . 38

6.5. Concomitant Medications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 386.6. Treatment Compliance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38

7. PHARMACOKINETIC RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 387.1. Pharmacokinetic Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45

8. SAFETY RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 468.1. Extent of Exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 468.2. Adverse Events . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46

8.2.1. Post-dose Adverse Events . . . . . . . . . . . . . . . . . . . . . . . . . . . . 468.2.2. Treatment-Related Adverse Events . . . . . . . . . . . . . . . . . . . . . 47

8.3. Serious Adverse Events . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 478.4. Adverse Events Leading to Premature Discontinuation of

Investigational Product and/or Study . . . . . . . . . . . . . . . . . . . . . . . . . 478.5. Other Relevant Adverse Events . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47

8.5.1. Adverse Events Requiring Concomitant Therapy . . . . . . . . . . 478.6. Pregnancies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 478.7. Clinical Laboratory Evaluations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47

8.7.1. Laboratory Values Over Time . . . . . . . . . . . . . . . . . . . . . . . . . 478.7.2. Abnormalities of Potential Clinical Concern . . . . . . . . . . . . . . . 47

8.8. Other Safety Evaluations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 488.9. Safety Conclusion(s) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48

9. DISCUSSION AND CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49

10. REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51


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11. SOURCE TABLES. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53

12. OTHER DATA SOURCE FIGURE AND TABLES . . . . . . . . . . . . . . . . . . . 522


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LIST OF TABLES

PageTable 1 Study Medication Regimens. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17Table 2 Study Medication Formulations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19Table 3 Study Medications Used. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20Table 4 Study Medication Regimens. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21Table 5 Study Procedures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23Table 6 Within-Subject CV% from Study 25000/560. . . . . . . . . . . . . . . . . . . . 29Table 7 Values of Potential Clinical Concern . . . . . . . . . . . . . . . . . . . . . . . . . 32Table 8 Subject Disposition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36Table 9 Protocol Deviations. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36Table 10 Demographic Characteristics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37Table 11 Missing AUC(0-Infinity) Data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38Table 12 Number of Evaluable Subjects by Pharmacokinetic Endpoint . . . . . 39Table 13 Comparisons between Formulations for Amoxicillin. . . . . . . . . . . . . 39Table 14 Comparisons between Formulations for Clavulanate. . . . . . . . . . . . 40Table 15 Summary pharmacokinetic parameters for amoxicillin (arithmetic

mean, [geometric mean] (range)) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41Table 16 Summary pharmacokinetic parameters for clavulanate (arithmetic

mean [geometric mean] (range)). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43Table 17 Pooled Residual Coefficients of Variation (CVresid%) . . . . . . . . . . . 44Table 18 Within-subject Coefficients of Variation by Formulation (CVform%) 44Table 19 Post-Dose Adverse Events. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46Table 20 Clinical Laboratory Values of Potential Clinical Concern . . . . . . . . . 48


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LIST OF FIGURES

PageFigure 1 Median Plasma Concentration-time Profile for Amoxicillin. . . . . . . . 40

Figure 2 Median Plasma Concentration-time profile for clavulanate . . . . . . . . 42


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Abbreviations

AE Adverse EventANOVA analysis of varianceAUC(0-∞) area under the plasma concentration-time curve (from time

zero extrapolated to infinity)AUC(0-t) area under the plasma concentration-time curve (from time

zero to the last measurable concentration)%AUCex percentage of AUC(0-∞) obtained by extrapolationCI confidence intervalCmax maximum concentrationCPDM Clinical Pharmacology and Discovery MedicineCPSP Clinical Pharmacology Statistics and Programming

CRF case report formCt last observed quantifiable concentrationCV coefficients of variationCVb between-subject coefficients of variationCVform% within-subject coefficients of variation by formulationCVresid% pooled within-subject coefficients of variationCVw within-subject coefficients of variationECG electrocardiographFDA Food and Drug AdministrationFSH follicle-stimulating hormoneGCP good clinical practicesGSK GlaxoSmithKlineHDPE high density polyethyleneHIV human immunodeficiency virusIUD intrauterine deviceLLQ lower limit of quantificationMFSSE mean squared formulation-by-subject (within sequence) error

from the modelMSE residual mean squared error from the modelNa CMC sodium carboxymethylcelluloseNQ not quantifiablepKa negative log of the acid dissociation constantPKU phenylketonuriaPPT/LC-MS/MS protein precipitation combined with liquid chromatography

with tandem mass spectrometric detectionPPT/LLE-LC-MS/MS protein precipitation/liquid-liquid extraction combined with

liquid chromatography with tandem mass spectrometricdetection

q 8 hr every 8 hoursQC quality controlR&D research and developmentSAE serious adverse eventSQRT square root


12


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SUPAC scale-up and post-approval changest½ half-lifetmax time of maximum concentrationUK United KingdomUS United StatesUSP United States Pharmacopeiaw/v weight/volumeβ-hCG beta-human chorionic gonadotropinλ/z terminal phase rate constant


13


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1. ETHICS

1.1. Independent Ethics Committee (IEC) or Institutional ReviewBoard (IRB)

The protocol, the informed consent, and other information that required pre-approvalwere reviewed and approved by on 22 January 2002.

1.2. Ethical Conduct of the Study

This study was conducted in accordance with "good clinical practice" (GCP) and allapplicable regulatory requirements, including, where applicable, the 1996 version of theDeclaration of Helsinki.

1.3. Subject Information and Consent

Written informed consent was obtained from each subject prior to the performance of anystudy-specific procedures. Case report forms were provided for each subject’s data to berecorded.

2. INVESTIGATORS AND STUDY ADMINISTRATIVESTRUCTURE

The principal investigator was MD. Sub-investigators were MD, FACP, MD, MD, MD,

MSN, CRNP, MD, MD, MD, PhD, MD, PhD, MD, MSN, CRNP, MSN, CRNP, PA-C,

MSN, CRNP, RN, BSN and MS. Thestudy was conducted at the

The clinical laboratoryfacility at Quest Diagnostic, Inc, 900 Business Center Dr, Horsham, PA 19044 was alsoutilized.


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3. INTRODUCTION

3.1. Background

AUGMENTIN† (amoxicillin/clavulanate potassium) is a broad-spectrum antibiotic forthe treatment and prophylaxis of a wide range of bacterial infections. AUGMENTIN is acombination product containing the broad-spectrum penicillin, amoxicillin, and the β-lactamase inhibitor, clavulanate. It was first launched in 1981 but is now available world-wide in a wide range of injectable (I.V.) and/or oral presentations which meet thetreatment needs of adults and pediatric patients, in general practice and in the hospital.The daily therapeutic dose extends up to 12 g of amoxicillin and 1200 mg of clavulanateintravenously, in adults.

AUGMENTIN is generally well tolerated, with the majority of side effects observed inclinical trials being of a mild and transient nature. The most frequently reported adverseeffects include diarrhea, nausea, skin rashes, pruritis, urticaria, vomiting and vaginitis.Changes in liver function tests have been noted in some patients and there have been rarereports of hepatitis and cholestatic jaundice although these hepatic effects are usuallyreversible and have mainly been associated with prolonged dosing in elderly patients.

3.2. Rationale

The shelf life of AUGMENTIN ES-600* suspension is limited by the stability ofclavulanic acid after constitution. The major factor impacting clavulanate stability in theconstituted product is pH. In the orange-raspberry oral suspension product, succinic acidand raspberry flavor excipients contribute most to lowering the initial pH of theconstituted product. Laboratory batches of AUGMENTIN ES-600 oral suspensionproduct with these excipients removed were manufactured and tested for 10 dayclavulanate stability. Removal of succinic acid and raspberry flavor increases pH andimproves stability in suspension (data on file). As an alternative to the orange-raspberryflavoring, strawberry flavoring has been added to the suspension product. Previousstudies suggested a strawberry cream flavor is more palatable to the current flavoring(data on file, GSK). This alternative flavoring of the AUGMENTIN ES-600 suspensionformulation may contribute to improved reconstituted stability of this formulation.

Based on the FDA Guidance on Scale-up and Postapproval Changes (SUPAC), the sumof the adjustments made to the original formula of the ES-600 mg amoxicillin/49.2 mgclavulanate per 5 mL oral suspension are of an extent that it is categorized as a level 3change. Level 3 changes require the performance of an in vivo bioequivalence study.

† AUGMENTIN is a Trade Mark of the GlaxoSmithKline group of companies. Registered in US Patentand Trademark Office.

* AUGMENTIN ES-600 is a Trade Mark of the GlaxoSmithKline group of companies.


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This study was performed to demonstrate the bioequivalence between the more stablereformulated strawberry flavored ES-600 mg/5 mL AUGMENTIN suspension (withoutsuccinic acid and raspberry flavor) and the current marketed ES-600 mg/5 mLAUGMENTIN suspension (containing succinic acid and raspberry flavor).

4. STUDY OBJECTIVE(S)

4.1. Primary

1. To demonstrate the bioequivalence of a new reformulated ES-600 mg/5 mLsuspension of AUGMENTIN to the marketed ES-600 mg/5 mL suspension ofAUGMENTIN.

4.2. Secondary

1. To assess the safety and tolerability of the new reformulated ES-600mg/5 mLsuspension of AUGMENTIN in healthy adult volunteers in this study.


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5. INVESTIGATIONAL PLAN

5.1. Study Design

This was an open-label, randomized, period balanced, replicate, four-period crossoverstudy. Each subject was to participate in four study sessions, separated by at least threedays each. Subjects were to receive a single dose of the new suspension formulation intwo study sessions and a single dose of the standard suspension formulation in the othertwo study sessions. The regimens are described in Table 1 below.

Table 1 Study Medication Regimens

RegimenCode

Study Medication

A Reformulated Strawberry/CMC formulation 600 mg amoxicillin / 42.9 mgclavulanate per 5 mL oral suspension

B Marketed Raspberry/Orange 600 mg amoxicillin / 42.9 mg clavulanate per 5mL oral suspension

5.2. Protocol Amendment(s)

There were no amendments to the protocol. The protocol was modified to change thetime of the follow-up visit to 24-48 hours after dosing in Session 4. This protocolmodification was approved by on 07 May 2002.

5.3. Selection of Study Population

Thirty-six subjects were to be enrolled so that a minimum of 30 subjects completed thestudy. Only subjects who the primary or sub-investigators believed would be able tocomply with the requirements of the protocol were included in the study. An attempt wasmade to enroll equal number of male and female subjects.

5.3.1. Inclusion Criteria

A subject was considered eligible for inclusion in this study only if all of the followingcriteria applied:

1. Healthy adult males and non-pregnant, non-lactating females who were between 18and 60 years of age, inclusive.

2. Body weight ≥50 kg and within ±35% ideal weight based on gender, height and bodyframe (Protocol).


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5.3.2. Exclusion Criteria

A subject was not eligible for inclusion in this study if any of the following criteriaapplied:

1. History of phenylketonuria (PKU) (i.e., subjects on phenylalanine restricted diet).

2. Any condition (including a history of hypersensitivity or allergy to β-lactamantibiotics or any component of the formulation or a history of AUGMENTINassociated cholestatic jaundice or hepatic dysfunction) which, in the opinion of theinvestigator, contraindicates the administration of AUGMENTIN.

3. The presence of any clinically significant and relevant abnormality identified on thescreening medical assessment or laboratory examination.

4. Positive urine drug/alcohol screen.

5. History of regular alcohol consumption exceeding 7 drinks/week for women or 14drinks/week for men (1 drink = 5 ounces of wine or 12 ounces of beer or 1.5 ouncesof hard liquor) within 6 months of screening.

6. Treatment with an investigational drug within 30 days or 5 half-lives (whichever islonger) preceding the first dose of study medication.

7. Pregnant or nursing women; women of childbearing potential who were unwilling orunable to use an appropriate method of contraception as outlined in Section 5.6.1.3(Contraception) from at least 14 days prior to study medication administration untilcompletion of follow-up procedures.

8. Use of prescription (other than oral contraceptives, thyroid replacement therapy andhormone replacement therapy) or non-prescription drugs (other than acetaminophenin doses ≤ 2 grams/day and multivitamins), herbal and dietary supplements withinseven days or 5 half-lives (whichever is longer) prior to the first dose of studymedication. Use of injectable progesterone, progestin subdermal implants,progesterone-releasing IUDs, and postcoital contraception methods and within sevendays or 5 half-lives (whichever is longer) prior to the first dose of study medicationis prohibited. Depo-Provera† (medroxyprogesterone acetate) must have beendiscontinued at least 6 months prior to the first dose of study medication.

9. Donation of blood in excess of 500 mL within 56 days prior to dosing.

10. History of sensitivity to heparin or heparin-induced thrombocytopenia.

5.3.3. Predetermined Criteria for Subject Withdrawal

Subjects may have withdrawn from the study at any time at their own request, or theymay have been withdrawn at any time at the discretion of the investigator for safety,behavioral, or administrative reasons. Subjects who became pregnant during the studywere to be withdrawn from the study immediately.

† Depo-Provera is a Trade Mark of Pharmacia & Upjohn Company. Registered in US Patent andTrademark Office


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Only subjects who were withdrawn from the study prior to administration of studymedication in Session 1 may have been replaced with another subject who would havebeen assigned to the same randomization schedule as the individual who was withdrawn.Subjects who were withdrawn from the study following administration of studymedication were not replaced. If the subject was withdrawn following administration ofstudy medication but prior to study completion, all follow-up procedures should havebeen performed, if possible.

5.4. Investigational Product(s)

5.4.1. Description of Investigational Product(s)

The study medication was supplied by GlaxoSmithKline Pharmaceuticals. The twoformulations of AUGMENTIN ES-600 that were provided are described in Table 2 andTable 3 below.

Table 2 Study Medication Formulations

INGREDIENTOriginal(Marketed)Formulation(mg/5 mL)

Strawberry/CMC(Reformulated)Formulation(mg/5mL)

Amoxicillin Trihydrate1 600.000697.674

600.000697.674

Clavulanate Potassium/Silicon Dioxide1:1 Blend1

42.900113.005(includes 8%overage)

42.900113.005(includes 8%overage)

Xanthan Gum, NF 12.500 3.000Aspartame, NF 12.500 12.500Silicon Dioxide, NF2 86.336 92.821Succinic Acid, Food Grade (Milled) 0.835 -Colloidal Silicon Dioxide, NF 25.000 35.00Hydroxypropyl Methylcellulose, 2910,5cps , USP

79.650 -

Sodium Carboxymethylcellulose, NF - 30.00Orange Flavor # 249792 15.000 -Orange Flavor # 9/79J839 11.250 -Golden Syrup Flavor # 52.927/APO5.51 23.750 -Raspberry Flavor # DYO4447 22.500 -Strawberry Flavor - 26.0Total Dry Powder Fill Weight per Dose 1100 10101. Based on amoxicillin trihydrate at 86% amoxicillin (free acid) content and clavulanate

potassium/silicon dioxide 1:1 blend at 41% clavulanic acid content.2. The quantity of silicon dioxide was adjusted per the amoxicillin trihydrate and clavulanate

potassium/silicon dioxide blend active contents in order to maintain a constant dose weight


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Table 3 Study Medications Used

Study Drugs Appearance Formulation Dose Unit Batch/LotNumbers

Original(Marketed)Formulation

off-white to tan in color;slowly deposits a slightwhite sediment onstanding

Suspension 600 mgamoxicillin/42.9 mgclavulanateper 5 mL

Strawberry/CMC(Reformulated)Formulation

off-white to tan in color;slowly deposits a slightwhite sediment onstanding

Suspension 600 mgamoxicillin/42.9 mgclavulanateper 5 mL

Source: Certificates of Analysis

Both the reformulated and the standard AUGMENTIN ES-600 oral suspensionformulations were supplied in 240 mL HDPE bottles.

5.4.2. Dosages and Administration

In each session, subjects received a single dose of one of the two formulations. Eachformulation was administered during two study sessions according to the randomizationschedule.

The study medication (5 mL volume in an oral syringe) was administered orally, atapproximately 08:00. Following this, approximately 5-6 mL tepid water was drawn intothe oral syringe and the liquid was administered. Flushing the syringe was necessary toensure that the full dose of the study medication was administered. Subjects were askedto drink approximately 240 mL tepid water (in total) with each dose of study medication.A light breakfast (muffin or bagel, fruit juice) was served immediately (i.e., within 5minutes) following the administration of the study medication. Subjects were required toconsume the entire meal within 30 minutes. Breakfast was standardized across sessions.

5.4.3. Dose Rationale

The maximum total dose of amoxicillin (600 mg) and clavulanate (42.9 mg) is withinapproved product labeling for AUGMENTIN ES-600 and was adequate to assess thepharmacokinetic parameters of both components. The daily therapeutic dose extends upto 12 g of amoxicillin and 1200 mg clavulanate intravenously and oral doses of 2-3 g areindicated for prophylaxis of endocarditis [Le Dictionnaire, 2001].

5.4.4. Blinding

Treatments were not blinded.


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5.4.5. Treatment Assignment

Subjects were randomly assigned to receive one of two possible sequences (ABAB orBABA) in a 1:1 ratio, in accordance with the randomization schedule prepared prior tothe study start by Clinical Pharmacology Statistics and Programming (CPSP) using theCoding Memo System. Actual dosing details are displayed in Table 11.1. There were nodeviations between the randomization schedule of intent and the actual dosing schedule.The formulations are described in Table 4.

Table 4 Study Medication Regimens

RegimenCode

Study Medication

A Reformulated Strawberry/CMC formulation 600 mg amoxicillin / 42.9 mgclavulanate per 5 mL oral suspension

B Marketed Raspberry/Orange 600 mg amoxicillin / 42.9 mg clavulanate per 5mL oral suspension

5.4.6. Assessment of Compliance

Study medication was administered under the supervision of the study personnel. Theoral syringe used for study drug administration was flushed with water to ensure that theentire dose was administered.

5.4.7. Treatment of Investigational Product Overdose

An overdose is defined as an excessive dose taken by a subject, either accidentally orintentionally, irrespective of whether it involves study medication or non-studymedication. Overdose may have been suspected or confirmed and may or may not havebeen associated with clinical signs and symptoms.

It would include, but not be limited to, those events which, based on the investigatorsclinical judgement, were considered to be of medical concern and/or require clinicalobservation and/or medical intervention.

As a guide, an overdose would include any dose greater than the highest daily doseincluded in the protocol or prescribing information (for marketed products).

5.4.7.1. Reporting of Overdose

For all overdoses the Serious AE form would have been completed and reported within24 hours as for any other serious AE (see Section 5.6.3.2). The documentation must haveincluded details of any associated signs/symptoms or if the overdose was asymptomaticthis must have been stated.


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5.4.7.2. Further Information on Overdose

For further information of any known signs or symptoms of overdosage and appropriatetreatment, together with details of any antidote, the investigator was referred to theprotocol/Investigator Brochure or the product label.

5.5. Prior and Concomitant Medications and Non-Drug Therapies

5.5.1. Permitted Medications

Permitted medications included contraceptives, hormone replacement therapy, thyroidreplacement therapy, acetaminophen at doses of ≤ 2 grams/day and multivitamins.

5.5.2. Prohibited Medications

Any medications the subject received within 7 days prior to dosing of study medicationswere recorded as a prior medication. Subjects were to abstain from using prescription ornon-prescription drugs, except those listed in 5.5.1 above, and herbal and dietarysupplements within 7 days or 5 half-lives (whichever was longer) prior to the first dose ofstudy medication and throughout the study. All concomitant medication taken during thestudy were recorded with indication, daily dose, and start and stop dates of administrationin the Case Report Form (CRF) or electronic equivalent.

5.6. Study Assessments and Procedures

Subjects were required to stay in the forapproximately 14 hours during each study session.

On the first day of each study session, subjects reported to the at approximately07:00 following an overnight fast of at least 8 hours.

Prior to dosing, an intravenous cannula for collection of blood samples was inserted intoone antecubital vein and kept patent with a dilute heparin solution (≤ 100 U/mL) for up to14 hours.

Procedures performed are listed in Table 5 below.


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Table 5 Study Procedures

Procedures Time(Hours from Morning Dosing)

Review of prior (Session 1 only) or Concomitantmedications

Predose

Review of medical history (Session 1 only) PredoseBlood (approximately 6 mL) and urine samples forclinical laboratory tests (4-hour fast)1,2 [Protocol]

Predose

Study medication administration with 240 mL ofwater3

0 hour (approximately 8:00 AM)

Meals (breakfast, lunch, dinner)4 5 minutes, 5, and 10 hours afterdosing

Baseline signs/symptoms or Adverse Experiences5 Predose and at 5 minutes, 5, 10,and 12 hours after dosing

Blood samples for pharmacokinetics (approximately3 mL)6

Predose and at 0.25, 0.5, 0.75, 1,1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 10, and12 hours after dosing

1. Clinical chemistry, hematology, and urinalysis were obtained prior to dosing during study session 1.2. A serum β-hCG for women was obtained prior to dosing in all study sessions. Results of the serum β-

hCG test were reported prior to dosing with study medication. A urine drug/alcohol screen was alsoobtained prior to dosing during each session. Results of the urine drug/alcohol screen are not required tobe reported prior to dosing with study medication.

3. Study medication was administered as 5 mL of 600 mg amoxicillin/ 42.9 mL clavulanate per 5 mL oralsuspension

4. Meals were standardized across sessions.5. Adverse events were assessed by asking a non-leading question such as "How do you feel?"6. Blood samples for PK analysis were collected in EDTA tubes

5.6.1. Demographic and Baseline Assessments

5.6.1.1. Screening Visit

Subjects were screened within 30 days prior to administration of study medication toconfirm that they met the entrance criteria for the study. The study investigator or a sub-investigator discussed with each subject the nature of the study, its requirements and itsrestrictions. Written informed consent was obtained prior to performance of any protocolspecific procedures. The following procedures were performed:

• A medical history (including a gynecological history for women and contraceptivepractices where indicated)

• Complete medication history of all drugs taken at least 30 days prior to screeningprocedures

• A history of alcohol use


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• Standard 12-lead electrocardiogram (ECG) (if not completed within previous 6months)

• Physical examination including height and weight, blood pressure and heart rate

• Following at least a 4 hour fast, blood (approximately 15 mL) and urine specimensfor clinical laboratory safety tests (Protocol) were collected, in addition to thefollowing:

• Serum beta-human chorionic gonadotropin (β-hCG) for all females

• Urine drug/alcohol screen

• HIV Test

• Hepatitis B and C Test

• Follicle stimulating hormone (FSH) and estradiol levels for postmenopausalwomen

To prepare for study participation, subjects were instructed on the use of ConcomitantMedications (Section 5.5.2) and Lifestyle Guidelines (Section 5.6.1.2).

Subjects previously screened for another study may have participated in this studyprovided they met the entry criteria outlined above. In such situations, written consentfor this study was obtained prior to any protocol-specified procedures being performed.Screening data from the previous study was considered sufficient to satisfy therequirements of this study, and only those procedures required by this protocol, but notperformed for the other study, were done. All screening data was obtained within 30days prior to administration of study medication, as stipulated above.

5.6.1.2. Lifestyle Guidelines

Meals and Dietary Restrictions

• Subjects were to fast from all food and drink at least 4 hours prior to any laboratorysafety evaluations and 8 hours prior to the start of pharmacokinetic collections.Water was permitted until 1 hour prior to study drug administration.

• Water and soft drinks or fruit juices (except grapefruit juice) were consumed adlibitum after dosing.

• Breakfast was provided immediately (i.e. within 5 minutes) after dosing. Subjectswere required to consume the entire meal within 30 minutes.

• Lunch was provided approximately 5 hours after dosing.

• Dinner was provided at approximately 9 to 10 hours after dosing.

• Meals were standardized across sessions.

Alcohol and Tobacco

• During each dosing session, subjects were to abstain from alcohol for 24 hours priorto the start of dosing until collection of the final pharmacokinetic sample.


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• Subjects who use tobacco products were instructed that use of nicotine-containingproducts was not permitted for 12 hours prior to dosing and until collection of thefinal pharmacokinetic sample during each session.

Activity

Subjects were to abstain from strenuous exercise for 24 hours prior to each bloodcollection for clinical laboratory tests. Subjects may have participated in lightrecreational activities (e.g., watch television, read).

5.6.1.3. Contraception

Women of childbearing potential included the following:

• Post-menopausal females who had been amenorrheic for less than 1 year

• Pre-menopausal females without a documented hysterectomy

Appropriate contraceptive methods for female subjects of childbearing potential includedone of the following:

1. Abstinence

2. One of the following methods:

• documented tubal ligation

• documented placement of a copper-containing intrauterine device (IUD)

• condom and diaphragm with spermicidal foam/gel/film/cream/suppository

• condom with spermicidal foam/gel/film/cream/suppository

Female subjects who were taking oral contraceptives were to adhere to the contraceptiverequirements listed above. Appropriate contraception was to be used by females for atleast 14 days prior to the first dose of study medication and was to continue untilcompletion of follow-up procedures.

5.6.1.4. Follow-up Visit

A follow–up visit was to occur 24-48 hours after dosing in session 4 or after a subject’spremature withdrawal from the study. At follow-up, the following occurred:

• Information regarding the use of concomitant medication or the occurrence ofadverse events was obtained

• Following at least a 4 hour fast, blood (approximately 6-8 mL) and urine specimenswere obtained for clinical laboratory tests (Protocol).

Following completion of the follow up procedures listed above, all male subjects weredischarged from the study. Female subjects were asked to return to the unit 10-14 daysafter completion of study session 4 for a serum pregnancy test. Female subjects werethen discharged from the study.


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5.6.2. Pharmacokinetic Assessments

5.6.2.1. Collection and preparation of samples

Blood samples (approximately 3 mL) were collected into tubes containing EDTA prior todosing and at 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 10, and 12 hours followingdosing at each study session. As soon as possible after collection, blood samples wereplaced on ice and then centrifuged at 3000 rpm (2000 g) for 10 minutes at approximately4º C. The resultant plasma was divided into two aliquots of equal volume and placed inpolypropylene tubes. Sample tube labels included study number (BRL 25000/643),subject number, and nominal time of sample collection. In addition, tubes were labelledwith either 'amox' (for plasma amoxicillin concentration determination) or 'clav' (forplasma clavulanate concentration determination). The plasma aliquots were frozen atapproximately -70º C until shipment. Samples were received from GSK Harlow, UK inthree shipments on 12 July, 20 July and 2 August 2002 at Quintiles, Edinburgh, Scotland.

5.6.2.2. Assay methods

All samples were received frozen and were stored at approximately -80° C prior toanalysis. Plasma samples were analyzed for amoxicillin by a validated PPT/LC-MS/MSmethod [GlaxoSmithKline Document Number WD2002/00365/00] and for clavulanateby a validated PPT/LLE-LC-MS/MS method [GlaxoSmithKline Document NumberWD2002/00659/00]. The lower limit of quantification (LLQ) was 0.05 ug/mL based on a50 uL aliquot of plasma for both amoxicillin and clavulanate.

Samples were analysed between 7 August 2002 and 26 August 2002 for amoxicillin andbetween 24 October 2002 and 9 December 2002 for clavulanate. Quality control (QC)samples were assayed with each batch of samples against separately prepared calibrationstandards. The results of the QC samples were used to assess the day-to-day performanceof the assay. The QC summary for amoxicillin and clavulanate are presented in Table12.17 and Table 12.18, respectively. All drug analysis data are stored at Quintiles,Edinburgh, under study number 25000/643/DRGP1159.

5.6.3. Safety Assessments

5.6.3.1. Adverse events

An adverse event (AE) is any untoward medical occurrence in a patient or clinicalinvestigation subject, temporally associated with the use of a medicinal product, whetheror not considered related to the medicinal product.

As a consistent method of soliciting adverse events, the subject was asked a non-leadingquestion such as: "How do you feel?"

All AEs occurring after administration of the first dose of study medication and on orbefore the final visit were reported as AEs. All AEs were recorded irrespective ofwhether they were considered drug related.


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At each visit/assessment in the period defined above, AEs were evaluated by theinvestigator and recorded.

Any AEs already documented at a previous assessment and designated as ongoing, werereviewed at subsequent visits as necessary. If these resolved, this was documented. If anAE changed in intensity/frequency then this was recorded as a separate event (i.e., a newrecord was started).

5.6.3.2. Serious adverse events

A serious adverse event (SAE) is any untoward medical occurrence that, at any dose,results in death, is life-threatening, requires hospitalization or prolongation of existinghospitalization, results in disability/incapacity, or, is a congenital anomaly/birth defect.Medical or scientific judgement should have been exercised in deciding whetherreporting was appropriate in other situations, such as important medical events that maynot have been immediately life-threatening or result in death or hospitalization but mayhave jeopardized the subject or may require medical or surgical intervention to preventone of the other outcomes listed in the above definition. These should also have beenconsidered serious. Examples of such events are invasive or malignant cancers, intensivetreatment in an emergency room or at home for allergic bronchospasm, blood dyscrasiasor convulsions that do not result in hospitalization, or development of drug dependencyor drug abuse.

SAEs were reported promptly to GSK as in the protocol once the investigator determinedthat the event meets the protocol definition of an SAE.

5.6.3.3. Pregnancies

5.6.3.3.1. Pregnancy

Should a subject have became pregnant during the study, she would have been withdrawnfrom the study immediately. The subject would have received counseling from theprimary investigator or their designate regarding the nature of the study medication andthe potential risk on fetal development.

5.6.3.3.2. Pregnancy Testing

At screening, prior to dosing with study medication during each study session and atfollow-up, women were tested for serum β-hCG. Results were obtained prior to dosingduring each session. In the case of a positive serum β-hCG test the subject would havebeen withdrawn from the study and follow-up would have been conducted as appropriate.

5.6.3.3.3. Time Period for Collecting Pregnancy Information

Details of all pregnancies in subjects that occurred during the treatment and the follow-upperiod would have been documented and reported to GSK. In addition, any pregnancies


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brought to the attention of the investigator after this period, and where it is known thatstudy medication was taken at the time of conception, would have been reported.

Any pregnancies identified during the screening phase/prior to study medicationadministration were not collected.

5.6.3.3.4. Action to be Taken if Pregnancy Occurred

The investigator, or his/her designee, would have collected pregnancy information on anyfemale subject who became pregnant while participating in this study. The investigator,or his/her designee, would have recorded pregnancy information on the appropriate formand submit it to GSK within 2 weeks of learning of a subject’s pregnancy. The subjectwould have been followed to determine the outcome of the pregnancy. Information onthe status of the mother and child would have been forwarded to GSK. Generally,follow-up would have been no longer than 6 to 8 weeks following the estimated deliverydate. Any premature termination of the pregnancy would have been reported.

While pregnancy itself would not have been considered to be an AE or SAE, anypregnancy complication or elective termination of a pregnancy for medical reasons wouldhave been recorded as an AE or a SAE, as described in the protocol.

A spontaneous abortion is always considered to be a SAE and would have been reportedas described in the protocol. Furthermore, any SAE that occurred as a result of a post-study pregnancy and was considered reasonably related to the investigational product bythe investigator, would have been reported to GSK as described in the protocol. Whilethe investigator was not obligated to actively seek this information in former studyparticipants, he/she may have learned of an SAE through spontaneous reporting.

5.6.3.4. Clinical laboratory evaluations

Clinical laboratory data were reviewed and summarized on an ongoing basis during thestudy to evaluate the safety of subjects. Any clinically relevant abnormalities or valuesof potential clinical concern were described. Safety data were presented in tabular and/orgraphical format and summarized descriptively. The investigator exercised his or hermedical and scientific judgment in deciding whether an abnormal laboratory finding orother abnormal assessment was clinically significant.

5.6.3.5. Other safety assessments

At screening only, vital signs (blood pressure and pulse rate) were measured and eachsubject had a physical examination, standard 12-lead ECG (if not completed within theprevious six months), HIV test, and Hepatitis B and C tests.

Any clinically relevant abnormalities or values of potential clinical concern weredescribed. Safety data were presented in tabular format and summarized descriptively.The investigator exercised his or her medical and scientific judgment in deciding whetheran abnormal laboratory finding or other abnormal assessment was clinically significant.


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5.7. Data Quality Assurance

To ensure compliance with GCP and all applicable regulatory requirements, GSK mayhave conducted a quality assurance audit. Regulatory agencies may have conducted aregulatory inspection of this study. Such audits/inspections could have occurred at anytime during or after completion of the study. If an audit or inspection occurred, theinvestigator and institution agreed to allow the auditor/inspector direct access to allrelevant documents and to allocate his/her time and the time of his/her staff to theauditor/inspector to discuss findings and any relevant issues.

5.8. Data Analysis Methods

5.8.1. Timings of Planned Analyses

5.8.1.1. Interim analyses and data monitoring

No interim analysis was planned for this study.

5.8.1.2. Changes in the conduct of the study or planned analyses

The final statistical analyses of the pharmacokinetic data were performed as per protocol.

5.8.2. Sample Size Considerations

5.8.2.1. Sample Size Assumptions

Thirty-six subjects were to be enrolled in the study to ensure a total of at least 30evaluable subjects.

Estimates of within-subject coefficients of variation (CV) from AUGMENTIN study560 [GlaxoSmithKline Document Number BRL-025000/RSD-101BM1/1] are listed inTable 6.

Table 6 Within-Subject CV% from Study 25000/560

Amoxicillin ClavulanateParameter AUC(0-∞) Cmax AUC(0-∞) CmaxCV 15.9% 20.4% 31.1% 35.1%

Using the largest estimate of within-subject variability (35.1%), it was estimated that asample size of 30 subjects under a replicate design would provide at least 90% power todemonstrate equivalence for AUC(0-∞) and Cmax for both amoxicillin and clavulanate.Bioequivalence is demonstrated when the 90% confidence interval for the ratio oftest:reference (A:B) is completely contained within the range 0.80 to 1.25 for bothAUC(0-∞) and Cmax for both amoxicillin and clavulanate. This range represents a


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symmetric 20% range on the loge-scale. This calculation was based on a two one-sidedtesting procedure with a type I error rate of 5% and assumes a true ratio of unity.

No adjustments were made for multiple comparisons.

5.8.2.2. Sample Size Sensitivity

A sensitivity analysis was conducted based on an assumption of a true ratio of 1.05,which would indicate an increase of 5% for the reformulation suspension compared to thestandard suspension. In this case, a sample size of 30 should provide at least 80% powerto demonstrate bioequivalence for AUC(0-∞) and Cmax for both amoxicillin andclavulanate. This calculation was also based on a two one-sided testing procedure with atype I error rate of 5%.

5.8.2.3. Sample Size Re-estimation

No sample size re-estimation was planned.

5.8.3. Analysis Populations

For each pharmacokinetic endpoint separately, subjects were included in the statisticalanalysis of bioequivalence if pharmacokinetic data were available for at least oneadministration of each formulation. Data from subjects not included in the statisticalanalysis were listed.

All subjects who received at least one dose of study medication were evaluable for safety.

5.8.4. Treatment Comparisons

The primary focus of the statistical analysis was to demonstrate the bioequivalence of thereformulated AUGMENTIN ES-600 oral suspension with respect to the standardmarketed ES-600 pediatric suspension formulation of AUGMENTIN as measured byAUC(0-∞) and Cmax of both amoxicillin and clavulanate. For all primary pharmacokineticendpoints, point estimates and 90% confidence intervals were computed for the ratio ofthe reformulated suspension to standard suspension. Bioequivalence was to bedemonstrated if the 90% confidence interval was completely contained within the range0.80 to 1.25 for both AUC(0-∞) and Cmax of both amoxicillin and clavulanate.

5.8.5. General Considerations for Data Analyses

5.8.5.1. Multiple comparison/multiplicity



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5.8.6. Data Handling Conventions

5.8.6.1. Derived and transformed data

AUC(0-∞), AUC(0-t) and Cmax data were loge-transformed prior to statistical analysis.

5.8.6.2. Values of clinical concern

Table 7 below shows values of potential clinical concern used in this study.


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Table 7 Values of Potential Clinical Concern

HematologyHemoglobin Males: <12.0 or >18.0 g/dL Females: <10.5 or >16.1 g/dLHematocrit Males <36.0 or >54.0% Females: <31.0 or >50.6%Leukocytes >1 K/uL below or >3 K/uL above the limit of the reference rangePlatelets <80 or > 500 K/uLChemistryTotal bilirubin ≥ 1.5 times upper limit of the reference rangeAST >2 times upper limit of the reference rangeALT >2 times upper limit of the reference rangeGGT >2 times upper limit of the reference rangeAlk Phosphatase >1.5 times upper limit of the reference rangeCreatinine >1.8 mg/dLBUN >1.5 times upper limit of the reference rangeGlucose, fasting <60 or >126 mg/dLUric acid >11 mg/dLSodium >5 mEq/L above or below the limits of the reference rangePotassium >0.5 mEq/L above or below the limits of the reference rangeCalcium <7.2 or > 12 mg/dLPhosphate >0.8 mg/dL below or 1.0 mg/dL above the limits of the reference

rangeAlbumin >0.5 g/dL above or below the limits of the reference rangeTotal protein >1.0 g/dL above or below the limits of the reference rangeUrinalysisWBC >15/hpfRBC >15/hpfVital SignsHeart Rate Supine/Sitting: <35 or >120 bpm Erect: <40 or >140 bpmBlood Pressure Systolic >30 mmHg change from baseline in same posture

Diastolic >20 mmHg change from baseline in same postureElectrocardiogramPR interval > 300 msec; >25% increase when baseline > 200 msec;

increase >50% when baseline ≤200 msecQRS interval >200 msec; >25% increase when baseline >100 msec

>50% increase when baseline ≤100 msecQTc interval >500 msec; >15% increase when baseline >440 msec

>30% increase when baseline ≤440 msecThe baseline measurement was taken prior to dosing.


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5.8.7. Study Population

5.8.7.1. Disposition of subjects

Subjects were healthy adult males and females between the ages of 19 and 60 years,inclusive.

5.8.7.2. Protocol deviations

Protocol deviations were recorded as reported.

5.8.7.3. Demographic and baseline characteristics

Demographic characteristics were recorded at screening. Baseline characteristics wererecorded prior to dosing in Session 1.

5.8.7.4. Treatment compliance

Study medication was administered under the supervision of the study personnel. Theoral syringe used for study drug administration was flushed with water to ensure that theentire dose was administered.

5.8.8. Pharmacokinetic Analyses

Amoxicillin and clavulanate plasma concentration-time data for each subject wereanalyzed separately by non-compartmental methods using WinNonlin Professionalversion 3.1 [WinNonlin User’s Guide]. All calculations were based on actual samplingtimes.

Amoxicillin and clavulanate plasma concentration versus time data were tabulated andgraphically presented separately for each subject. For estimation of mean plasmaconcentrations at each time point, where a post-dose value was not quantifiable (NQ), avalue of 1/2 the LLQ (i.e., 0.025 ug/mL) was assigned. Where the calculated mean valuewas less than the LLQ (0.05 ug/mL), the mean for the sampling time was assigned asnon-quantifiable.

The amoxicillin and clavulanate pharmacokinetic parameters calculated for each subjectwere: the maximum observed plasma concentration (Cmax) and the time to reach Cmax

(tmax). The area under the plasma concentration-time curve from time zero to the lastmeasurable concentration, AUC(0-t), was determined using the linear trapezoidal rule forall incremental trapezoids arising from increasing concentrations and the logarithmictrapezoidal method for those arising from decreasing concentrations. The terminal phaserate constant (λz) was determined using unweighted linear least squares regressionanalysis of those points visually assessed to be in the terminal phase. The apparentterminal half-life (t1/2) was calculated as ln 2/λz. The area under the plasmaconcentration-time curve extrapolated to infinity [ AUC(0-∞) ], was calculated as the sum


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of AUC(0-t) and Ct/λz, where, Ct is the last observed quantifiable concentration. Thepercentage of AUC(0-∞) obtained by extrapolation (%AUCex) was calculated as follows:

100)0(

% )0()0( ∗∞−

−= −∞−

AUC

AUCAUCAUCex t

Summary statistics (arithmetic mean, n, standard deviation, median, minimum andmaximum) were calculated for each pharmacokinetic parameter by formulation andadministration.

Pharmacokinetic analysis was performed by Clinical Pharmacokinetics/Modeling andSimulation, CPDM, GlaxoSmithKline, UK. All pharmacokinetic data are stored in theArchives, GSK, R&D, under Protocol 25000/643.

5.8.9. Statistical Analysis

Statistical analyses of the pharmacokinetic data were the responsibility of ClinicalPharmacology Statistics and Programming (CPSP), GlaxoSmithKline, US and werecarried out using the SAS for Windows software package (version 6.12) running underWindows NT.

The main focus of the statistical analysis was to demonstrate bioequivalence of formulaA (reformulated AUGMENTIN ES-600 suspension) relative to formula B (standardmarketed AUGMENTIN ES-600 suspension). For each primary pharmacokineticendpoint separately, point estimates and associated 90% confidence intervals werecomputed for the ratio A:B. Bioequivalence was to be demonstrated when the 90%confidence interval is completely contained within 0.80 to 1.25 for both AUC(0-∞) andCmax [Schuirmann, 1987] of both amoxicillin and clavulanate.

Following loge-transformation, AUC(0-∞) and Cmax of both amoxicillin and clavulanatewere separately analyzed by fitting a mixed effects model consistent with the FDAguidelines [FDA, 2001], including terms for subject, sequence, period and regimen.Point estimates and 90% percent confidence intervals for the difference betweenformulations (A-B) were constructed. These were then exponentially backtransformed toobtain point estimates and confidence intervals for the ratio A:B.

Within-subject variability estimates across formulations and for each formulation werecalculated for AUC(0-∞) and Cmax for both amoxicillin and clavulanate. The pooled within-subject coefficients of variation (CVresid%) across formulations were calculated basedon the loge-normal distribution from an equivalent ANOVA model (details on file), using

the following formula:

CVresid(%)= SQRT[exp(MFSSE) – 1] x 100

where MFSSE is the mean squared formulation-by-subject (within sequence) error fromthe model and represents a pooled measure of within-subject variability acrossformulations, accounting for potential subject-by-formulation interaction.


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For each formulation separately, within-subject coefficients of variation were calculatedfrom an ANOVA model fitting terms for subject and administration, using the followingformula:

CVform(%)= SQRT(exp(MSE) – 1) x 100

where MSE is the residual mean squared error from the model.

Distributional assumptions underlying these analyses were assessed by visual inspectionof normal probability plots.

AUC(0-t) data was analyzed similar to both primary pharmacokinetic endpoints, butbioequivalence was only based on the results for the AUC(0-∞) and Cmax data.

The arithmetic mean value across replicates for each subject and formulation wascalculated for tmax of amoxicillin and clavulanate and then analyzed separately using theWilcoxon matched pairs method [Steinijans, 1983]. A point estimate and 95%confidence interval for the median difference between formulations (A-B) wascalculated. The 95% confidence interval provides a range of plausible values for thedifference in tmax.

Summary statistics (n, mean, std, minimum, median, maximum) were calculated for allpharmacokinetic parameters by formulation and administration. All data for thosesubjects included in the formal statistical analyses were included. For AUC(0-∞), AUC(0-t)

and Cmax of amoxicillin and clavulanate, geometric means and between-subject CVs werecalculated, where:

geometric mean = exp(arith. mean on loge scale)

between-subject CVb(%) = SQRT(exp(SD on loge scale)2 – 1) x 100

Summary statistics by formulation were similarly calculated based on average values forthe two replicates within a subject. For AUC(0-∞), AUC(0-t) and Cmax of amoxicillin andclavulanate, this data was averaged on the loge-scale and back-transformed prior tocalculation of the summary statistics. All data for those subjects included in the formalstatistical analyses were included.

5.8.10. Safety Analyses

All subjects who received at least one dose of study medication were included in theevaluation of clinical safety and tolerability. Clinical monitoring and laboratory datawere reviewed by the study physician and were not formally analyzed. Adverse eventswere summarized by formulation. No formal statistical analysis of the safety data wasperformed.


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6. STUDY POPULATION RESULTS

6.1. Disposition of Subjects

Subject disposition is summarized in Table 8 below.

Table 8 Subject Disposition

Disposition Number of SubjectsTotal Screened 75Total Screened But Not Used: 39Total Randomized/Enrolled 36Total Withdrawn Prior to Dosing 0

Regimen A Regimen B TotalTotal Dosed 34 36 36Total Withdrawn After Dosing 1 4 5-Due to Adverse Event 0 1 1-Other 1 3 4Total Completed 33 32 31Regimen A: Reformulated amoxicillin 600 mg/ 42.9 mg clavulanate per 5 mL; Regimen B: Marketedamoxicillin 600 mg/ 42.9 mg clavulanate per 5 mLSource: Tables 11.2 and 11.3

6.2. Protocol Deviations

Subjects enrolled in the study met protocol-specified eligibility criteria and studyprocedures were performed according to the protocol, except as summarized in Table 9below.

Table 9 Protocol Deviations

Source: Data on file, GSK

In the opinion of the investigator, these deviations did not affect subject safety or theresults of the study.


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6.3. Populations Analyzed

All subjects who received at least one dose of study medication were included in theevaluation of clinical safety and tolerability.

6.4. Demographics and Other Baseline Characteristics

6.4.1. Demographic Characteristics

Summary data for all subjects who were enrolled and dosed in this study are displayed inTable 10 below:

Table 10 Demographic Characteristics

Group Parameter Age Height Weight(years) (m) (kg)

All Subjects Mean 34 1.70 73.4n = 36 SD 11.9 0.10 13.0

Range 19-60 1.46-1.87 50.6-97.950% Female, 50% Male; 39% Black, 50% White, 11% OtherSource: Table 11.2

6.4.2. Baseline Characteristics

One subject reported symptoms prior to dosing with study medication.

The investigator did not consider this symptom sufficientto affect the conduct of the study or to represent a potential risk to the subject duringparticipation in the study. Signs and symptoms present prior to the initial dose of studymedication are displayed in Table 11.4.

6.4.3. Other Current Medical Conditions

All subjects were healthy adult volunteers.

6.4.4. Previous Medications

The protocol required that subjects refrain from using prescription (excludingcontraceptives, hormone replacement therapy and thyroid replacement therapy) and non-prescription medications (except acetaminophen at doses of ≤ 2 grams/day andmultivitamins) within 7 days or 5 half-lives (whichever was longer) prior to the first doseof study medication.


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6.4.5. Other Factors Affecting Response to Therapy

No other reported factors affected subjects’ response to therapy.

6.5. Concomitant Medications

The protocol required that subjects refrain from using prescription (excludingcontraceptives, hormone replacement therapy and thyroid replacement therapy) and non-prescription medications (except acetaminophen at doses of ≤ 2 grams/day andmultivitamins) within 7 days or 5 half-lives (whichever was longer) throughout the study.Despite this restriction, two subjects took prohibited medications during the study.

6.6. Treatment Compliance

Subjects were 100% compliant with taking study medication, which was administeredunder the supervision of the study personnel.

7. PHARMACOKINETIC RESULTS

Thirty-six subjects were enrolled and dosed in the study.

Thirty-four subjects were considered evaluable for pharmacokinetic parametersand their data were included in the statistical analysis.

Asthey contributed pharmacokinetic data from both formulation treatments and contributedto the comparison of interest, their data were included in the statistical analyses.

However, as all of these subjectscontributed to the rest of the pharmacokinetic parameter comparisons of interest, all oftheir available data was included in the statistical analyses. Table 11 lists which subjectswere missing AUC(0-∞) data. Table 12 lists the number of total evaluable subjects bypharmacokinetic endpoint.

Table 11 Missing AUC(0-Infinity) Data

Source: Data on file, GSK


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Table 12 Number of Evaluable Subjects by Pharmacokinetic Endpoint

Pharmacokinetic EndpointAUC(0-∞) AUC(0-t) Cmax

Amoxicillin 34 34 34Clavulanate 33 34 34Source: Data on file, GSK

The 90% confidence intervals for the ratio of adjusted geometric means for AUC(0-∞) andCmax of amoxicillin were within the bioequivalence range of 0.80 to 1.25. ReformulatedAUGMENTIN ES-600 suspension failed, however, to demonstrate bioequivalence to thestandard marketed AUGMENTIN ES-600 suspension as the 90% confidence intervalsfor the ratio of adjusted geometric means for AUC(0-∞) and Cmax of clavulanate includedvalues above the upper limits of the bioequivalence range of 0.80 to 1.25. On average,there was a 16% increase in clavulanate AUC(0-∞) and a 19% increase in Cmax for thereformulated AUGMENTIN ES-600 suspension, relative to the standard marketedAUGMENTIN ES-600 suspension. Tmax was similar across formulations for bothamoxicillin and clavulanate. Point estimates and corresponding 90% CI are presented inTable 13 and Table 14.

Table 13 Comparisons between Formulations for Amoxicillin


FormulationB3


90%C.I.

CV resid(%)

AUC(0-∞)1 26.8 26.2 A:B 1.02 (1.00,1.04)

7.65

Cmax1 7.17 7.07 A:B 1.02 (0.96,1.08)

20.27

AUC(0-t)1 26.3 26.0 A:B 1.01 (0.98,1.04)

10.76

tmax (h)2 A-B -0.13 (-0.38,0.12)

A: Reformulated Strawberry/CMC 600 Suspension (Test)B: Standard Marketed Raspberry/Orange 600 Suspension (Reference)1. Point estimate represents the ratio of the adjusted geometric means2. Point estimate represents the estimated median difference. 95% C.I. provided for tmax3. Represents backtransformed Least square means (adjusted geometric means)Source: Tables 12.2, 12.19-12.22; Data on file, GSK


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Table 14 Comparisons between Formulations for Clavulanate


FormulationB3


90%C.I.

CV resid(%)

AUC(0-∞)1 1.607 1.381 A:B 1.16 (1.06,1.28)

31.44

Cmax1 0.643 0.541 A:B 1.19 (1.06,1.33)

39.84

AUC(0-t)1 1.437 1.182 A:B 1.22 (1.08,1.37)

42.82

tmax (h)2 A-B -0.06 (-0.17,0.06)

A: Reformulated Strawberry/CMC 600 Suspension (Test)B: Standard Marketed Raspberry/Orange 600 Suspension (Reference)1. Point estimate represents the ratio of the adjusted geometric means2. Point estimate represents the estimated median difference. 95% C.I. provided for tmax3. Represents backtransformed Least square means (adjusted geometric means)Source: Tables 12.4, 12.23-12.26; Data on file, GSK

The median plasma concentration-time profile for amoxicillin is presented in Figure 1.

Figure 1 Median Plasma Concentration-time Profile for Amoxicillin

0

1

2

3

4

5

6

7

8

0 1 2 3 4 5 6 7 8 9 10 11 12 13

Time after dosing (h)

Med

ian

Am

oxi

cilli

n P

lasm

a C

on

c. (

ug

/mL

)

A1

A2

B1

B2

A1 = Reformulated Strawberry/CMC 600 Suspension (administration 1) [Test]A2 = Reformulated Strawberry/CMC 600 Suspension (administration 2) [Test]B1 = Standard Marketed Raspberry/Orange 600 Suspension (administration 1) [Reference]B2 = Standard Marketed Raspberry/Orange 600 Suspension (administration 2) [Reference]Source: Figure 12.2


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- 34 -

The mean and median plasma concentration-time profiles for amoxicillin are presentedgraphically in Figure 12.1 and Figure 12.2, respectively. The mean (sd) plasmaconcentration-time profiles for amoxicillin are presented in Figure 12.3. Individualplasma concentration-time profiles by subject are presented in Figure 12.13 to Figure12.48 and are detailed in Table 12.13 to Table 12.16. Individual amoxicillinpharmacokinetic parameters (AUC(0-∞), AUC(0-t), Cmax and tmax) with summary statisticsare detailed in Table 12.5 to Table 12.8 and are summarised in Table 15. Individualamoxicillin pharmacokinetic parameters (AUC(0-∞), AUC(0-t) and Cmax) versusformulations and administrations are presented in Figure 12.8 to Figure 12.10.

Table 15 Summary pharmacokinetic parameters for amoxicillin (arithmeticmean, [geometric mean] (range))1

Parameter Formulation A2 Formulation A2 Formulation B3 Formulation B3

[units] (admin 1) (admin 2) (admin 1) (admin 2)(n=34) (n=31) (n=34) (n=32)

AUC(0-∞) 27.2 27.45 26.8 26.9[ug.h/mL] [26.7]

(18.7 – 42.8)[27.0](20.7 – 36.6)

[26.4](16.0 – 38.3)

[26.5](18.1 – 37.2)

AUC(0-t) 27.0 26.7 26.6 26.7[ug.h/mL] [26.5]

(18.4 – 42.4)[26.1](11.7 – 36.5)

[26.2](16.0 – 38.0)

[26.3](17.9 – 36.8)

Cmax 7.59 7.12 7.43 7.22[ug/mL] [7.38]

(3.96 – 11.53)[6.86](2.37 – 12.11)

[7.20](4.23 – 11.59)

[7.03](4.15 – 10.52)

tmax4

[hours]1.97(0.75 – 3.03)

2.00(0.77 – 3.02)

1.96(0.97 – 3.03)

2.00(0.73 – 4.00)

1. 2. Reformulated Strawberry/CMC 600 Suspension (Test)3. Standard Marketed Raspberry/Orange 600 Suspension (Reference)4. median (range)5. n=30Source: Tables 12.1 and 12.2

In some instances (3 out of 133 plasma concentration-time profiles), amoxicillin AUC(0-∞)

was not determined, as the terminal slopes could not be established. The percentage ofamoxicillin AUC(0-∞) obtained by extrapolation (%AUCex) was less than 3% (Table 12.5).

The median plasma concentration-time profile for clavulanate is presented in Figure 2.


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- 35 -

Figure 2 Median Plasma Concentration-time profile for clavulanate

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0 1 2 3 4 5 6


Mea

n C

lavu

lan

ate

Pla

sma

Co

nc.

(u

g/m

L)

A1

A2

B1

B2

A1 = Reformulated Strawberry/CMC 600 Suspension (administration 1) [Test]A2 = Reformulated Strawberry/CMC 600 Suspension (administration 2) [Test]B1 = Standard Marketed Raspberry/Orange 600 Suspension (administration 1) [Reference]B2 = Standard Marketed Raspberry/Orange 600 Suspension (administration 2) [Reference]Source: Figure 12.3

The mean and median plasma concentration-time profiles for clavulanate are presentedgraphically in Figure12.4 and Figure 12.5, respectively. The mean (sd) plasmaconcentration-time profiles for clavulanate are presented in Figure 12.6. Individualplasma concentration-time profiles by subject are presented in Figure 12.49 to Figure12.84 and are detailed in Table 12.13 to Table 12.16. Individual clavulanatepharmacokinetic parameters (AUC(0-∞), AUC(0-t), Cmax and tmax) with summary statisticsare detailed in Table 12.9 to Table 12.12 and are summarised in Table 16. Individualclavulanate pharmacokinetic parameters (AUC(0-∞), AUC(0-t) and Cmax) versusformulations and administrations are presented in Figure 12.10 to Figure 12.12.


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Table 16 Summary pharmacokinetic parameters for clavulanate (arithmeticmean [geometric mean] (range))1

Parameter[units]

Formulation A2 Formulation A2 Formulation B3 Formulation B3

(admin 1) (admin 2) (admin 1) (admin 2)(n=34) (n=31) (n=34) (n=32)

AUC(0-∞) 1.705 1.806 1.577 1.618

[ug.h/mL] [1.585](0.707 – 3.95)

[1.666](0.672 – 3.30)

[1.477](0.449 – 2.61)

[1.438](0.316 – 2.91)

AUC(0-t) 1.55 1.59 1.35 1.42[ug.h/mL] [1.41]

(0.362 – 3.80)[1.40](0.491 – 3.19)

[1.16](0.133 – 2.53)

[1.20](0.253 – 2.75)

Cmax 0.684 0.686 0.604 0.628[ug/mL] [0.638]

(0.190 – 1.32)[0.620](0.278 – 1.22)

[0.537](0.083 – 1.31)

[0.548](0.162 – 1.37)

tmax4

[hours]1.00(0.70 - 2.52)

1.00(0.50 - 2.00)

1.00(0.50 - 2.02)

1.03(0.50 - 2.02)

1. 2. Reformulated Strawberry/CMC 600 Suspension (Test)3. Standard Marketed Raspberry/Orange 600 Suspension (Reference)4. median (range)5. n=326. n=287. n=308. n=30Source: Tables 12.3 and 12.4

In some instances (10 out of 133 plasma concentration-time profiles), clavulanateAUC(0-∞) was not determined, as the terminal slopes could not be established. Thepercentage of clavulanate AUC(0-∞) obtained by extrapolation (%AUCex) was less than20% (Table 12.9).

Analyses were performed on the affected parameters with and without the potentialoutlying subjects, but without change of statistical inference (details on file). Thus allpresented results and conclusions are based on the full data set including all statisticallyevaluable subjects. No other gross violations of distributional or model assumptionswere observed.

There were significant period effects (p < 0.05) in the analysis of the Cmax of amoxicillin,and the AUC(0-∞), AUC(0-t) and Cmax of clavulanate. These period effects signal that therewere systematic differences in average response to treatment across periods. Given thestudy design and the linear model used in the formal statistical analysis, these systematicdifferences were adjusted for the comparisons between regimens and did not impact theinferences drawn based on the results.


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Pooled residual coefficients of variation (CVresid %) estimates are provided in the Table17.

Table 17 Pooled Residual Coefficients of Variation (CVresid%)

Parameter Cvresid%Within-Subject CV (%)

Amoxicillin AUC(0-∞) 7.65 Cmax 20.27 AUC(0-t) 10.76Clavulanate AUC(0-∞) 31.44 Cmax 39.84 AUC(0-t) 42.82Source: Data on file, GSK

The within-subject coefficients of variation for Cmax and AUC(0-t) of clavulanate in thisstudy were slightly higher than that used in the sample size calculations (35.1%). Post-hoc power was computed based on the highest within-subject variability (clavulanateCmax, CVw=39.84%) observed in this study. Based on this within-subject variabilityestimate and the number of subjects who completed the study (n=34), the statisticalpower to demonstrate bioequivalence was 85%. This calculation was based on a two one-sided testing procedure with a type I error rate of 5%. and assumes a true ratio of unity.Sensitivity analyses were performed prior to study initiation under the assumption thatthe true ratio (reformulated suspension compared to marketed suspension) would notdeviate more than 5%.

Within subject coefficients of variation by formulation (CVform%) estimates areprovided in Table 18. Analysis details for Table 17 and Table 18 are on file.

Table 18 Within-subject Coefficients of Variation by Formulation (CVform%)

Reformulated AUGMENTIN ES-600 Marketed AUGMENTIN ES-600Parameter CVform % CVform % (B)AmoxicillinAUC(0-∞) 7.1% 7.8%Cmax 22.5% 15.3%AUC(0-t) 14.4% 8.0%ClavulanateAUC(0-∞) 22.1% 20.1%Cmax 29.9% 28.4%AUC(0-t) 29.2% 31.1%Source: Data on file, GSK


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7.1. Pharmacokinetic Conclusions

• The 90% confidence intervals for the ratio of adjusted geometric means for AUC(0-∞)

and Cmax of amoxicillin were within the bioequivalence range of 0.80 to 1.25 whencomparing the reformulated AUGMENTIN ES-600 to the standard marketedAUGMENTIN ES-600 suspension.

• Reformulated AUGMENTIN ES-600 suspension failed to demonstratebioequivalence to the standard marketed AUGMENTIN ES-600 suspension as the90% confidence interval for the clavulanate (AUC(0-∞) and Cmax) ratio were notcompletely contained within the bioequivalence range of 0.80 to 1.25. There was a16% increase in clavulanate AUC(0-∞) and a 19% increase in Cmax for thereformulated suspension relative to the standard marketed suspension.


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8. SAFETY RESULTS

8.1. Extent of Exposure

Thirty-six subjects were dosed during this study. Thirty-four subjects received RegimenA, reformulated AUGMENTIN ES-600 and 36 subjects received Regimen B, marketedAUGMENTIN ES-600.

8.2. Adverse Events

8.2.1. Post-dose Adverse Events

A total of 25 adverse events (AEs) in 14 subjects were reported during this study. Therewere 17 AEs in 11 subjects after administration of reformulated AUGMENTIN ES-600and 8 AEs in 6 subjects after administration of marketed AUGMENTIN ES-600. AllAEs were mild in intensity except one injury that was moderate in intensity. The mostfrequent AE was headache. All AEs resolved before the completion of the study. Asummary of all treatment-emergent AEs is presented in Table 19 below.

Table 19 Post-Dose Adverse Events

Adverse Event Number of Subjects(Preferred Term) Regimen A Regimen B TotalHeadache 71 1 72

Dizziness 1 1 2Injury 1 1 2Nausea 0 2 2Anorexia 0 1 1Arthralgia 1 0 1Diarrhea 1 0 1Flushing 1 0 1Injection Site Inflammation 1 0 1Micturition Frequency 0 1 1Pharyngitis 1 1 12

Photosensitivity Reaction 1 0 1Vomiting 1 0 1Total Number of AEs 17 8 25Number of Subjects with AEs 11 6 14Number of Subjects Exposed 34 36 361. One subject experienced the same AE more than once after administration of the same regimen. For the

purposes of this table, no AE was counted more than once for each subject per treatment, but each AE is listedindividually in the source of this table.

2. One subject experienced the same AE after administration of Regimen A and Regimen B.Regimen A: Reformulated amoxicillin 600 mg/ 42.9 mg clavulanate per 5 mL; Regimen B: Marketed amoxicillin 600mg/ 42.9 mg clavulanate per 5 mLSource: Table 11.7


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8.2.2. Treatment-Related Adverse Events

One AE in one subject was suspected of being related to the study medication by theinvestigator.

This AE resolved before thecompletion of the study.

8.3. Serious Adverse Events

There were no serious adverse events (SAEs) during this study.

8.4. Adverse Events Leading to Premature Discontinuation ofInvestigational Product and/or Study

The mild injury, skin abrasion, was due to a fall off a bike and was notrelated to the study medication.

8.5. Other Relevant Adverse Events

8.5.1. Adverse Events Requiring Concomitant Therapy

Six subjects experienced AEs that required concomitant medications during the study.

8.6. Pregnancies

No subjects became pregnant during this study.

8.7. Clinical Laboratory Evaluations

8.7.1. Laboratory Values Over Time

Overall, no notable trends were observed in the laboratory parameters measured duringthe study.

8.7.2. Abnormalities of Potential Clinical Concern

Two subjects had pre-dose laboratory values of potential clinical concern.

Study medication was administered


47


- 41 -

according to the randomization schedule as these values were not considered sufficient toaffect subject safety. Three subjects had post-dose clinical laboratory values of potentialclinical concern during the study as shown in Table 20 below. The values of potentialclinical concern were asymptomatic and considered unrelated to the study medication bythe investigator.

Table 20 Clinical Laboratory Values of Potential Clinical Concern

1.

Regimen A: Reformulated amoxicillin 600 mg/ 42.9 mg clavulanate per 5 mL; Regimen B: Marketed amoxicillin 600mg/ 42.9 mg clavulanate per 5 mLSource: 11.9

See Tables 11.10 and 11.11 for all safety laboratory test results and urine drug/alcoholtest results.

8.8. Other Safety Evaluations

At screening only, vital signs were measured and each subject had a physicalexamination, standard 12-lead ECG (if not completed within the previous six months),HIV test, and Hepatitis B and C tests. No enrolled subjects had screening abnormalitiesin safety parameters that prevented them from entering the study.

8.9. Safety Conclusion(s)

• Reformulated and marketed AUGMENTIN ES-600 were generally safe and welltolerated by healthy adult male and female subjects.


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9. DISCUSSION AND CONCLUSIONS

The apparent enhancement of clavulanate bioavailability cannot be explained by thedifferences in properties of the two suspension products. It is probable that thisanamolous finding resulted from an unusually high incidence of subjects with hightest/reference ratios for the clavulanate pharmacokinetic end-points. The arguments aresummarised hereunder.

The minor formulation or pH differences between the two suspensions are not expectedto affect bioavailability of clavulanate.

• Clavulanate passes rapidly and completely into solution (no dissolution stage prior toabsorption).

• Both the reformulated and standard marketed suspension can be considered to be arapidly dissolving drug product (in vitro dissolution test showed >90% of amoxicillinand clavulanate dissolved in 10 minutes) (USP Apparatus 2, paddle speed 75 rpm,900 mL deionized water at 37° C).

• Both suspensions used in this study were administered freshly constituted each timeprior to dosing and then discarded. Differences in degradation rate during ingestionare also unlikely.

• Previous studies where clavulanate-containing dosage forms of AUGMENTIN wereco-administered with antacids or where formulations of AUGMENTIN containingbuffers were used did not show differences in absorption of either amoxicillin orclavulanate. Also, lower strength of a reformulated AUGMENTIN suspension (200mg amoxicillin/28.5 mg clavulanate), which is compositionally similar to thereformulated AUGMENTIN ES-600 suspension with the exception of flavoringagent and sodium carboxymethylcellulose, was shown to be bioequivalent to themarketed AUGMENTIN suspension (200 mg amoxicillin/28.5 mg clavulanate),which is compositionally similar to the marketed AUGMENTIN ES-600suspension.

The findings could have been a chance result arising from normal statistical variation.

• Exploratory analysis of the data shows that several subjects had high geometric meanof test/reference ratios for the primary pharmacokinetic endpoints of clavulanate.Five out of 34 subjects used in the statistical analysis had geometric mean oftest/reference ratios that were >2.0 for Cmax of clavulanate, and 3 out of 33 subjectshad geometric mean of test/reference ratios that were >2.0 for AUC(0-∞). In contrast,all the remaining subjects had geometric mean of test/reference ratios of amoxicillinthat were close to 1.0 for AUC(0-∞) and Cmax.

• Inter-individual variation of bioavailibility was relatively high, but within-subjectcoefficients of variation for AUC(0-∞) and Cmax were almost identical between thereformulated suspension and the standard marketed suspension, suggesting that thetest product performs as well as the reference product.


49


- 43 -

Even if the reformulated suspension had a higher clavulanate bioavailability than themarketed suspension, the clinical impact of this difference would be small.

• Clavulanate has a broad therapeutic index, and AUGMENTIN formulationsapproved for administration three times a day result in much higher clavulanate dailydose than either the reformulated or marketed AUGMENTIN ES-600 used in thisstudy. Therefore, the apparent <20% average increase in clavulanate AUC(0-∞) andCmax suspension should not be accompanied by additional risk.

• Clavulanate stability is such that losses over the 10 day dosing period are in theregion of 15% in the marketed product (orange-raspberry suspension) and 10% in thereformulated (strawberry cream suspension) formulation. Thus, the impact of a 15%difference in bioavailability would not be significant in the clinical setting.

• The safety profiles appeared similar for both reformulated and marketedAUGMENTIN ES-600. The one treatment-related AE reported during the study(vomiting) is among the most frequently reported adverse events observed aftertreatment with AUGMENTIN [Physician’s Desk Reference, 2002].

In conclusion,

• The 90% confidence intervals for the ratio of adjusted geometric means for AUC(0-∞)

and Cmax of amoxicillin were within the bioequivalence range of 0.80 to 1.25 whencomparing the reformulated AUGMENTIN ES-600 suspension to the standardmarketed AUGMENTIN ES-600 suspension.

• Reformulated AUGMENTIN ES-600 suspension failed to demonstratebioequivalence to the standard marketed AUGMENTIN ES-600 suspension as the90% confidence interval for the clavulanate (AUC(0-∞) and Cmax) ratio were notcompletely contained within the bioequivalence range of 0.80 to 1.25. There was a16% increase in clavulanate AUC(0-∞) and a 19% increase in Cmax for thereformulated suspension relative to the standard marketed suspension.

• Reformulated and marketed AUGMENTIN ES-600 were generally safe and welltolerated by healthy adult male and female subjects.


50


- 44 -

10. REFERENCES

GlaxoSmithKline Document Number BRL-025000/RSD-100NLZ/1. Study 25000/491. Astudy to describe the pharmacokinetic profiles of an intravenous formulation (at doses of1000/100 mg and 2000/200 mg) and an oral tablet formulation (875/125 mg) ofAUGMENTIN in healthy volunteers.

GlaxoSmithKline Document Number BRL-025000/RSD-101BM1/1. Study 25000/560. Astudy to demonstrate bioequivalence of a new pediatric suspension formulation ofAUGMENTIN (800 mg/57 mg per 5 mL) to the standard pediatric suspensionformulation of AUGMENTIN (600 mg/42.9 mg per 5 ml) in healthy volunteers.

GlaxoSmithKline Document Number BRL-025000/RSD-101PTK/1. Study 25000/601. Astudy to determine the bioequivalence of reformulated AUGMENTIN suspension(improved stability) to standard marketed suspension.

GlaxoSmithKline Document Number BRL-025000/RSD-1018M7/1. Study 25000/583.An open, randomised, three way crossover study to investigate the effect of Maalox onthe bioavailability of sustained release oral AUGMENTIN (BRL 25000) in healthy maleand female volunteers.

GlaxoSmithKline Document Number HH-1019/BRL-025000/1. Study 25000/433. Anopen, 5 part crossover study to determine the relative bioavailability and intestinalpermeability effects of AUGMENTIN co-administered with candidate GI toleranceremedial agents compared with AUGMENTIN alone in healthy volunteers.

GlaxoSmithKline Document Number WD2002/00365/00 (Quintiles Study NumberDRGP1149). Validation of an analytical procedure for the determination of BRL-2333(amoxicillin) in human plasma using protein precipitation and liquid-liquid extractionfollowed by HPLC with tandem mass spectrometric detection.

GlaxoSmithKline Document Number WD2002/00659/00.(Quintiles Study NumberDRGP1150). Validation of an analytical procedure for the determination of BRL-14151(clavulanic acid) in human plasma using protein precipitation and liquid-liquid extractionfollowed by HPLC with tandem mass spectrometric detection.

Le Dictionnaire. Editions du Vidal. 77th Edition. Paris, France: Vidal; 2001: 177-179.

Physician’s Desk Reference. 56th Edition. Montvale, NJ: Medical EconomicsCompany; 2002: 1487-1490.

Schuirmann DJ. 1987. A comparison of the two one-sided tests procedure and the powerapproach for assessing the equivalence of average bioavailability. J Pharmacokinet andBiopharm, 15, 657–680.

Steinijans VW, Diletti E. 1983. Statistical Analysis of Bioavailability Studies: Parametricand Nonparametric Confidence Intervals. Eur J Clin Pharmacol, 24, 127–136.


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U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES, FDA, CDER. 2001.Statistical Approaches to Establishing Bioequivalence. Guidance for Industry, FDA,CDER, 2001.

WinNonlin User’s Guide, Pharsight Corporation, Mountain View, CA, USA.


52

11. SOURCE TABLES

PageTable 11.1 Study Medication Administration Record. . . . . . . . . . . . . . . . . . . . 54Table 11.2 Demographic Data. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69Table 11.3 Demographic Data for Volunteers Who Were Screened But Not

Used . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 72Table 11.4 Pre-Study and Baseline Signs and Symptoms . . . . . . . . . . . . . . . 75Table 11.5 Prior Medications by Subject . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 76Table 11.6 Concomitant Medications by Subject . . . . . . . . . . . . . . . . . . . . . . 78Table 11.7 Adverse Experiences by Subject and Treatment . . . . . . . . . . . . . 80Table 11.8 Subjects Withdrawn from the Study . . . . . . . . . . . . . . . . . . . . . . . 89Table 11.9 Subjects Who had Clinical Laboratory Values of Potential Clinical

Concern. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 90Table 11.10 Clinical Laboratory Data by Subject . . . . . . . . . . . . . . . . . . . . . . 91Table 11.11 Clinical Laboratory Data by Subject - Urine Drug Screen . . . . . . 484


53


- 2 -

Table 11.1 Study Medication Administration Record

BRL 25000/643

Subject Session Date/Time Regimen Study Drug

CO

NF

IDE

NT

IAL

PM

2002/00022/00 B

RL-025000/643

54

This section contained data from each individual patient, rather than in aggregate. They have been excluded to protect patient privacy. Anonymized data from each patient may be made available subject to an approved research proposal. For further information please see

the Patient Level Data section of the Sponsor Clinical Study Register.


- 17 -

Table 11.2 Demographic Data

BRL 25000/643

Age Height WeightSubject Sex (years) (m) (kg) Race Study Status

CO

NF

IDE

NT

IAL

PM

2002/00022/00 B

RL-025000/643

69

This section contained data from each individual patient, rather than in aggregate. They have been excluded to protect patient privacy. Anonymized data from each patient may be

made available subject to an approved research proposal. For further information please see the Patient Level Data section of the Sponsor Clinical Study Register.


- 20 -

Table 11.3 Demographic Data for Volunteers Who Were Screened But Not Used

BRL 25000/643

Age Height WeightVol. ID Sex (years) (m) (kg) Race Study Status

CO

NF

IDE

NT

IAL

PM

2002/00022/00 B

RL-025000/643

72

This section contained data from each individual patient, rather than in aggregate. They have been excluded to protect patient privacy. Anonymized data from each patient may be made available subject to an approved research proposal. For further information please see the Patient Level Data section of the

Sponsor Clinical Study Register.


- 23 -

Table 11.4 Pre-Study and Baseline Signs and Symptoms

BRL 25000/643

Date/Time of Start End Intensity/Sub- Preferred Term First Dose of Date/Time Date/Time Rela-ject (Investigator Term) Study Drug of Event of Event Duration Outcome Course tionship

CO

NF

IDE

NT

IAL

PM

2002/00022/00 B

RL-025000/643

75




- 24 -

Table 11.5 Prior Medications by Subject

BRL 25000/643

Total Date/Time of ContinuingSub- Daily Stop First Dose of Duringject Drug Name Dose Route Duration Indication Date/Time Study Drug Study?

Route: PO – Oral

CO

NF

IDE

NT

IAL

PM

2002/00022/00 B

RL-025000/643

76




- 26 -

Table 11.6 Concomitant Medications by Subject

BRL 25000/643

Date/Time ofSub- Frequency Start Stop First Dose ofject Drug Name Dose per Day Route Indication Date/Time Date/Time Study Drug

Route: PO - Oral, TO - Topical

CO

NF

IDE

NT

IAL

PM

2002/00022/00 B

RL-025000/643

78




- 28 -

Table 11.7 Adverse Experiences by Subject and Treatment

BRL 25000/643

Time of Start andOnset End Relationship

Sub- Regi- Ses- Preferred Term After Date/Time Course / Action toject men sion (Investigator Term) 1st Dose of Event Duration Intensity Taken Study Drug Outcome

# = Flag identifying an AE as the cause for withdrawal@ = Corrective therapy given (see Concomitant Medication record for details)A=Reformulated Amox 600mg/42.9mg Clav per 5 mL; B=Marketed Amox 600mg/42.9mg Clav per 5 mL

CO

NF

IDE

NT

IAL

PM

2002/00022/00 B

RL-025000/643

80

This section contained data from each individual patient, rather than in aggregate. They have been excluded to protect patient privacy. Anonymized data from each patient may be made available subject to an approved research proposal. For further information please see the

Patient Level Data section of the Sponsor Clinical Study Register.


- 37 -

Table 11.8 Subjects Withdrawn from the Study

BRL 25000/643

Date/Time Date/Time Actual Reason for Withdrawalof of Last Duration of Number

Subject Withdrawal Last Dose Treatment Treatment of Doses Category Detail

A=Reformulated Amox 600mg/42.9mg Clav per 5 mL; B=Marketed Amox 600mg/42.9mg Clav per 5 mL

CO

NF

IDE

NT

IAL

PM

2002/00022/00 B

RL-025000/643

89




- 38 -

Table 11.9 Subjects Who had Clinical Laboratory Values of Potential Clinical Concern

BRL 25000/643

Time Point ofBaseline Value of Value/Change

Subject Treatment Parameter Reference Range Value Concern (D:H:M)

A=Reformulated Amox 600mg/42.9mg Clav per 5 mL; B=Marketed Amox 600mg/42.9mg Clav per 5 mL

CO

NF

IDE

NT

IAL

PM

2002/00022/00 B

RL-025000/643

90

This section contained data from each individual patient, rather than in aggregate. They have been excluded to protect patient privacy. Anonymized data from each patient may be made available subject to an approved research proposal. For further information please

see the Patient Level Data section of the Sponsor Clinical Study Register.


- 39 -

Table 11.10 Clinical Laboratory Data by Subject

BRL 25000/643

H/L = Above (H) or below (L) limit of the reference range. A = Value abnormal.>/< = Increase (>) or decrease (<) from baseline which exceeds protocol-defined value of concern c = See comment report.* = Exceeds protocol-defined value of concern relative to the reference range.Regimens: A=Reformulated Amox 600mg/42.9mg Clav per 5 mL; B=Marketed Amox 600mg/42.9mg Clav per 5 mL

CO

NF

IDE

NT

IAL

PM

2002/00022/00 B

RL-025000/643

91




- 432 -

Table 11.11 Clinical Laboratory Data by Subject – Urine Drug Screen

BRL 25000/643

H/L = Above (H) or below (L) limit of the reference range. A = Value abnormal.>/< = Increase (>) or decrease (<) from baseline which exceeds protocol-defined value of concern c = See comment report.* = Exceeds protocol-defined value of concern relative to the reference range.Regimens: A=Reformulated Amox 600mg/42.9mg Clav per 5 mL; B=Marketed Amox 600mg/42.9mg Clav per 5 mL

CO

NF

IDE

NT

IAL

PM

2002/00022/00 B

RL-025000/643

484



12. OTHER DATA SOURCE FIGURES AND TABLES

PageFigure 12.1 Mean amoxicillin plasma concentration-time profiles following

single oral dose administrations of Augmentin ES-600 suspension(reformulated and standard) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 529

Figure 12.2 Median amoxicillin plasma concentration-time profiles followingsingle oral dose administrations of Augmentin ES-600 suspension(reformulated and standard) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 530

Figure 12.3 Mean (sd) amoxicillin plasma concentration-time profilesfollowing single oral dose administrations of Augmentin ES-600suspension (reformulated and standard) . . . . . . . . . . . . . . . . . . . . . . . . . 531

Figure 12.4 Mean clavulanate plasma concentration-time profiles followingsingle oral dose administrations of Augmentin ES-600 suspension(reformulated and standard) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 532

Figure 12.5 Median clavulanate plasma concentration-time profiles followingsingle oral dose administrations of Augmentin ES-600 suspension(reformulated and standard) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 533

Figure 12.6 Mean (sd) clavulanate plasma concentration-time profilesfollowing single oral dose administrations of Augmentin ES-600suspension (reformulated and standard) . . . . . . . . . . . . . . . . . . . . . . . . . 534

Figure 12.7 Individual amoxicillin AUC(0-inf) [ug.h/mL] by formulation andadministration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 535

Figure 12.8 Individual amoxicillin AUC(0-t) [ug.h/mL] by formulation andadministration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 536

Figure 12.9 Individual amoxicillin Cmax [ug/mL] by formulation andadministration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 537

Figure 12.10 Individual clavulanate AUC(0-inf) [ug.h/mL] by formulation andadministration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 538

Figure 12.11 Individual clavulanate AUC(0-t) [ug.h/mL] by formulation andadministration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 539

Figure 12.12 Individual clavulanate Cmax [ug/mL] by formulation andadministration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 540

Figure 12.13 Individual amoxicillin plasma concentration-time profiles forSubject following single oral dose administrations of AugmentinES-600 suspension (reformulated and standard) . . . . . . . . . . . . . . . . . . . 541





522

















523

















524



Figure 12.49 Individual clavulanate plasma concentration-time profiles forSubject following single oral dose administrations of AugmentinES-600 suspension (reformulated and standard) . . . . . . . . . . . . . . . . . . . 577














525

















526









Table 12.1 Summary statistics for amoxicillin pharmacokinetic parametersby formulation and administration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 613

Table 12.2 Summary statistics for amoxicillin pharmacokinetic parametersby formulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 614

Table 12.3 Summary statistics for clavulanate pharmacokinetic parametersby formulation and administration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 615

Table 12.4 Summary statistics for clavulanate pharmacokinetic parametersby formulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 616

Table 12.5 Individual amoxicillin AUC(0-inf) [ug.h/mL] (%extrapolation)following single oral dose administrations of Augmentin ES-600suspension (reformulated and standard) . . . . . . . . . . . . . . . . . . . . . . . . . 617

Table 12.6 Individual amoxicillin AUC(0-t) [ug.h/mL] following single oraldose administrations of Augmentin ES-600 suspension (reformulatedand standard) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 618

Table 12.7 Individual amoxicillin Cmax [ug/mL] following single oral doseadministrations of Augmentin ES-600 suspension (reformulated andstandard) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 619

Table 12.8 Individual amoxicillin Tmax [hours] following single oral doseadministrations of Augmentin ES-600 suspension (reformulated andstandard) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 620

Table 12.9 Individual clavulanate AUC(0-inf) [ug.h/mL] (%extrapolation)following single oral dose administrations of Augmentin ES-600suspension (reformulated and standard) . . . . . . . . . . . . . . . . . . . . . . . . . 621


527

Table 12.10 Individual clavulanate AUC(0-t) [ug.h/mL] following single oraldose administrations of Augmentin ES-600 suspension (reformulatedand standard) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 622

Table 12.11 Individual clavulanate Cmax [ug/mL] following single oral doseadministrations of Augmentin ES-600 suspension (reformulated andstandard) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 623

Table 12.12 Individual clavulanate Tmax [hours] following single oral doseadministrations of Augmentin ES-600 suspension (reformulated andstandard) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 624

Table 12.13 Individual plasma concentration [ug/mL] for amoxicillin andclavulanate following a single oral dose administration of reformulatedstrawberry/CMC Augmentin ES-600 suspension (1st administration) . . . 625

Table 12.14 Individual plasma concentration [ug/mL] for amoxicillin andclavulanate following a single oral dose administration of reformulatedstrawberry/CMC Augmentin ES-600 suspension (2nd administration) . . . 634

Table 12.15 Individual plasma concentration [ug/mL] for amoxicillin andclavulanate following a single oral dose administration of standardmarketed raspberry/orange Augmentin ES-600 suspension (1stadministration). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 643

Table 12.16 Individual plasma concentration [ug/mL] for amoxicillin andclavulanate following a single oral dose administration of standardmarketed raspberry/orange Augmentin ES-600 suspension (2ndadministration). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 652

Table 12.17 Plasma concentrations of amoxicillin in quality control samples . 661Table 12.18 Plasma concentrations of clavulanate in quality control samples 666Table 12.19 Analysis of Variance (ANOVA) for Amoxicillin AUC(0-inf)

[ug.h/mL] . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 670Table 12.20 Analysis of Variance (ANOVA) for Amoxicillin AUC(0-t)

[ug.h/mL] . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 673Table 12.21 Analysis of Variance (ANOVA) for Amoxicillin Cmax [ug/mL] . . . 676Table 12.22 Non-parametric Analysis for Amoxicillin Tmax [hours] . . . . . . . . 679Table 12.23 Analysis of Variance (ANOVA) for Clavulanate AUC(0-inf)

[ug.h/mL] . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 680Table 12.24 Analysis of Variance (ANOVA) for Clavulanate AUC(0-t)

[ug.h/mL] . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 683Table 12.25 Analysis of Variance (ANOVA) for Clavulanate Cmax [ug/mL] . . 686Table 12.26 Non-parametric Analysis for Clavulanate Tmax [hours] . . . . . . . 689


528


- 2 -

Figure 12.1 Mean amoxicillin plasma concentration-time profiles following singleoral dose administrations of Augmentin ES-600 suspension(reformulated and standard)

0

1

2

3

4

5

6

7

8

0 1 2 3 4 5 6 7 8 9 10 11 12 13


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A1 = Reformulated Strawberry/CMC 600 Suspension (administration 1) [Test]A2 = Reformulated Strawberry/CMC 600 Suspension (administration 2) [Test]B1 = Standard Marketed Raspberry/Orange 600 Suspension (administration 1) [Reference]B2 = Standard Marketed Raspberry/Orange 600 Suspension (administration 2) [Reference]


529


- 3 -

Figure 12.2 Median amoxicillin plasma concentration-time profiles followingsingle oral dose administrations of Augmentin ES-600 suspension(reformulated and standard)

0

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530


- 4 -

Figure 12.3 Mean (sd) amoxicillin plasma concentration-time profiles followingsingle oral dose administrations of Augmentin ES-600 suspension(reformulated and standard)

0

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531


- 5 -

Figure 12.4 Mean clavulanate plasma concentration-time profiles following singleoral dose administrations of Augmentin ES-600 suspension(reformulated and standard)

0

0.1

0.2

0.3

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532


- 6 -

Figure 12.5 Median clavulanate plasma concentration-time profiles followingsingle oral dose administrations of Augmentin ES-600 suspension(reformulated and standard)

0

0.1

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533


- 7 -

Figure 12.6 Mean (sd) clavulanate plasma concentration-time profiles followingsingle oral dose administrations of Augmentin ES-600 suspension(reformulated and standard)

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

0 1 2 3 4 5 6


Mea

n C

lavu

lan

ate

Pla

sma

Co

nc.

(u

g/m

L)

A1

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

0 1 2 3 4 5 6


Mea

n C

lavu

lan

ate

Pla

sma

Co

nc.

(u

g/m

L)

A2

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

0 1 2 3 4 5 6


B1

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

0 1 2 3 4 5 6


B2



534


- 8 -

Figure 12.7 Individual amoxicillin AUC(0-inf) [ug.h/mL] by formulation andadministration


535

This section contained data from each individual patient, rather than in aggregate. They have been excluded to protect patient privacy. Anonymized data from each patient may

be made available subject to an approved research proposal. For further information please see the Patient Level Data section of the Sponsor Clinical Study Register.


- 9 -

Figure 12.8 Individual amoxicillin AUC(0-t) [ug.h/mL] by formulation andadministration


536




- 10 -

Figure 12.9 Individual amoxicillin Cmax [ug/mL] by formulation andadministration


537




- 11 -

Figure 12.10 Individual clavulanate AUC(0-inf) [ug.h/mL] by formulation andadministration


538




- 12 -

Figure 12.11 Individual clavulanate AUC(0-t) [ug.h/mL] by formulation andadministration


539




- 13 -

Figure 12.12 Individual clavulanate Cmax [ug/mL] by formulation andadministration


540




- 14 -

Figure 12.13 Individual amoxicillin plasma concentration-time profiles for Subject following single oral dose administrations of Augmentin ES-600

suspension (reformulated and standard)

0

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

0 1 2 3 4 5 6 7 8 9 10 11 12 13


A1

A2

B1

B2

0.01

0.1

1

101515

0 1 2 3 4 5 6 7 8 9 10 11 12 13


A1

A2

B1

B2



541


- 15 -



0

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

0 1 2 3 4 5 6 7 8 9 10 11 12 13


A1

A2

B1

B2

0.01

0.1

1

101515

0 1 2 3 4 5 6 7 8 9 10 11 12 13


A1

A2

B1

B2



542


- 16 -



0

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

0 1 2 3 4 5 6 7 8 9 10 11 12 13


A1

A2

B1

B2

0.01

0.1

1

101515

0 1 2 3 4 5 6 7 8 9 10 11 12 13


A1

A2

B1

B2



543


- 17 -



0

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

0 1 2 3 4 5 6 7 8 9 10 11 12 13


A1

A2

B1

B2

0.01

0.1

1

101515

0 1 2 3 4 5 6 7 8 9 10 11 12 13


A1

A2

B1

B2



544


- 18 -



0

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

0 1 2 3 4 5 6 7 8 9 10 11 12 13


A1

A2

B1

B2

0.01

0.1

1

101515

0 1 2 3 4 5 6 7 8 9 10 11 12 13


A1

A2

B1

B2



545


- 19 -



0

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

0 1 2 3 4 5 6 7 8 9 10 11 12 13


B1

0.01

0.1

1

101515

0 1 2 3 4 5 6 7 8 9 10 11 12 13


B1

B1 = Standard Marketed Raspberry/Orange 600 Suspension (administration 1) [Reference]

Subject completed only one dosing session


546


- 20 -



0

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

0 1 2 3 4 5 6 7 8 9 10 11 12 13


A1

A2

B1

B2

0.01

0.1

1

101515

0 1 2 3 4 5 6 7 8 9 10 11 12 13


A1

A2

B1

B2



547


- 21 -



0

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

0 1 2 3 4 5 6 7 8 9 10 11 12 13


A1

B1

0.01

0.1

1

101515

0 1 2 3 4 5 6 7 8 9 10 11 12 13


A1

B1

A1 = Reformulated Strawberry/CMC 600 Suspension (administration 1) [Test]B1 = Standard Marketed Raspberry/Orange 600 Suspension (administration 1) [Reference]

Subject completed only two dosing sessions


548


- 22 -



0

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

0 1 2 3 4 5 6 7 8 9 10 11 12 13


A1

A2

B1

B2

0.01

0.1

1

101515

0 1 2 3 4 5 6 7 8 9 10 11 12 13


A1

A2

B1

B2



549


- 23 -



0

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

0 1 2 3 4 5 6 7 8 9 10 11 12 13


A1

A2

B1

B2

0.01

0.1

1

101515

0 1 2 3 4 5 6 7 8 9 10 11 12 13


A1

A2

B1

B2



550


- 24 -



0

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

0 1 2 3 4 5 6 7 8 9 10 11 12 13


A1

A2

B1

B2

0.01

0.1

1

101515

0 1 2 3 4 5 6 7 8 9 10 11 12 13


A1

A2

B1

B2



551


- 25 -



0

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

0 1 2 3 4 5 6 7 8 9 10 11 12 13


A1

A2

B1

B2

0.01

0.1

1

101515

0 1 2 3 4 5 6 7 8 9 10 11 12 13


A1

A2

B1

B2



552


- 26 -



0

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

0 1 2 3 4 5 6 7 8 9 10 11 12 13


A1

A2

B1

B2

0.01

0.1

1

101515

0 1 2 3 4 5 6 7 8 9 10 11 12 13


A1

A2

B1

B2



553


- 27 -



0

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

0 1 2 3 4 5 6 7 8 9 10 11 12 13


A1

A2

B1

B2

0.01

0.1

1

101515

0 1 2 3 4 5 6 7 8 9 10 11 12 13


A1

A2

B1

B2



554


- 28 -



0

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

0 1 2 3 4 5 6 7 8 9 10 11 12 13


A1

A2

B1

B2

0.01

0.1

1

101515

0 1 2 3 4 5 6 7 8 9 10 11 12 13


A1

A2

B1

B2



555


- 29 -



0

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

0 1 2 3 4 5 6 7 8 9 10 11 12 13


A1

A2

B1

B2

0.01

0.1

1

101515

0 1 2 3 4 5 6 7 8 9 10 11 12 13


A1

A2

B1

B2



556


- 30 -



0

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

0 1 2 3 4 5 6 7 8 9 10 11 12 13


A1

A2

B1

B2

0.01

0.1

1

101515

0 1 2 3 4 5 6 7 8 9 10 11 12 13


A1

A2

B1

B2



557


- 31 -



0

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

0 1 2 3 4 5 6 7 8 9 10 11 12 13


A1

A2

B1

B2

0.01

0.1

1

101515

0 1 2 3 4 5 6 7 8 9 10 11 12 13


A1

A2

B1

B2



558


- 32 -



0

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

0 1 2 3 4 5 6 7 8 9 10 11 12 13


A1

A2

B1

B2

0.01

0.1

1

101515

0 1 2 3 4 5 6 7 8 9 10 11 12 13


A1

A2

B1

B2



559


- 33 -



0

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

0 1 2 3 4 5 6 7 8 9 10 11 12 13


B1

0.01

0.1

1

101515

0 1 2 3 4 5 6 7 8 9 10 11 12 13


B1




560


- 34 -



0

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

0 1 2 3 4 5 6 7 8 9 10 11 12 13


A1

A2

B1

B2

0.01

0.1

1

101515

0 1 2 3 4 5 6 7 8 9 10 11 12 13


A1

A2

B1

B2



561


- 35 -



0

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

0 1 2 3 4 5 6 7 8 9 10 11 12 13


A1

A2

B1

B2

0.01

0.1

1

101515

0 1 2 3 4 5 6 7 8 9 10 11 12 13


A1

A2

B1

B2



562


- 36 -



0

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

0 1 2 3 4 5 6 7 8 9 10 11 12 13


A1

A2

B1

B2

0.01

0.1

1

101515

0 1 2 3 4 5 6 7 8 9 10 11 12 13


A1

A2

B1

B2



563


- 37 -



0

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

0 1 2 3 4 5 6 7 8 9 10 11 12 13


A1

A2

B1

B2

0.01

0.1

1

101515

0 1 2 3 4 5 6 7 8 9 10 11 12 13


A1

A2

B1

B2



564


- 38 -



0

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

0 1 2 3 4 5 6 7 8 9 10 11 12 13


A1

A2

B1

B2

0.01

0.1

1

101515

0 1 2 3 4 5 6 7 8 9 10 11 12 13


A1

A2

B1

B2



565


- 39 -



0

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

0 1 2 3 4 5 6 7 8 9 10 11 12 13


A1

A2

B1

B2

0.01

0.1

1

101515

0 1 2 3 4 5 6 7 8 9 10 11 12 13


A1

A2

B1

B2



566


- 40 -



0

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

0 1 2 3 4 5 6 7 8 9 10 11 12 13


A1

B1

0.01

0.1

1

101515

0 1 2 3 4 5 6 7 8 9 10 11 12 13


A1

B1




567


- 41 -



0

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

0 1 2 3 4 5 6 7 8 9 10 11 12 13


A1

A2

B1

B2

0.01

0.1

1

101515

0 1 2 3 4 5 6 7 8 9 10 11 12 13


A1

A2

B1

B2



568


- 42 -



0

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

0 1 2 3 4 5 6 7 8 9 10 11 12 13


A1

A2

B1

B2

0.01

0.1

1

101515

0 1 2 3 4 5 6 7 8 9 10 11 12 13


A1

A2

B1

B2



569


- 43 -



0

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

0 1 2 3 4 5 6 7 8 9 10 11 12 13


A1

A2

B1

B2

0.01

0.1

1

101515

0 1 2 3 4 5 6 7 8 9 10 11 12 13


A1

A2

B1

B2



570


- 44 -



0

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

0 1 2 3 4 5 6 7 8 9 10 11 12 13


A1

A2

B1

B2

0.01

0.1

1

101515

0 1 2 3 4 5 6 7 8 9 10 11 12 13


A1

A2

B1

B2



571


- 45 -



0

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

0 1 2 3 4 5 6 7 8 9 10 11 12 13


A1

B1

B2

0.01

0.1

1

101515

0 1 2 3 4 5 6 7 8 9 10 11 12 13


A1

B1

B2

A1 = Reformulated Strawberry/CMC 600 Suspension (administration 1) [Test]B1 = Standard Marketed Raspberry/Orange 600 Suspension (administration 1) [Reference]B2 = Standard Marketed Raspberry/Orange 600 Suspension (administration 2) [Reference]Subject completed only three dosing sessions


572


- 46 -



0

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

0 1 2 3 4 5 6 7 8 9 10 11 12 13


A1

A2

B1

B2

0.01

0.1

1

101515

0 1 2 3 4 5 6 7 8 9 10 11 12 13


A1

A2

B1

B2



573


- 47 -



0

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

0 1 2 3 4 5 6 7 8 9 10 11 12 13


A1

A2

B1

B2

0.01

0.1

1

101515

0 1 2 3 4 5 6 7 8 9 10 11 12 13


A1

A2

B1

B2



574


- 48 -



0

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

0 1 2 3 4 5 6 7 8 9 10 11 12 13


A1

A2

B1

B2

0.01

0.1

1

101515

0 1 2 3 4 5 6 7 8 9 10 11 12 13


A1

A2

B1

B2



575


- 49 -



0

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

0 1 2 3 4 5 6 7 8 9 10 11 12 13


A1

A2

B1

B2

0.01

0.1

1

101515

0 1 2 3 4 5 6 7 8 9 10 11 12 13


A1

A2

B1

B2



576


- 50 -

Figure 12.49 Individual clavulanate plasma concentration-time profiles for Subject following single oral dose administrations of Augmentin ES-600


0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

1.1

1.2

1.3

1.4

1.5

0 1 2 3 4 5 6 7 8


A1

A2

B1

B2

0.01

0.1

1

1.51.5

0 1 2 3 4 5 6 7 8


A1

A2

B1

B2



577


- 51 -



0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

1.1

1.2

1.3

1.4

1.5

0 1 2 3 4 5 6 7 8


A1

A2

B1

B2

0.01

0.1

1

1.51.5

0 1 2 3 4 5 6 7 8


A1

A2

B1

B2



578


- 52 -



0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

1.1

1.2

1.3

1.4

1.5

0 1 2 3 4 5 6 7 8


A1

A2

B1

B2

0.01

0.1

1

1.51.5

0 1 2 3 4 5 6 7 8


A1

A2

B1

B2



579


- 53 -



0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

1.1

1.2

1.3

1.4

1.5

0 1 2 3 4 5 6 7 8


A1

A2

B1

B2

0.01

0.1

1

1.51.5

0 1 2 3 4 5 6 7 8


A1

A2

B1

B2



580


- 54 -



0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

1.1

1.2

1.3

1.4

1.5

0 1 2 3 4 5 6 7 8


A1

A2

B1

B2

0.01

0.1

1

1.51.5

0 1 2 3 4 5 6 7 8


A1

A2

B1

B2



581


- 55 -



0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

1.1

1.2

1.3

1.4

1.5

0 1 2 3 4 5 6 7 8


B1

0.01

0.1

1

1.51.5

0 1 2 3 4 5 6 7 8


B1




582


- 56 -



0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

1.1

1.2

1.3

1.4

1.5

0 1 2 3 4 5 6 7 8


A1

A2

B1

B2

0.01

0.1

1

1.51.5

0 1 2 3 4 5 6 7 8


A1

A2

B1

B2



583


- 57 -



0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

1.1

1.2

1.3

1.4

1.5

0 1 2 3 4 5 6 7 8


A1

B1

0.01

0.1

1

1.51.5

0 1 2 3 4 5 6 7 8


A1

B1




584


- 58 -



0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

1.1

1.2

1.3

1.4

1.5

0 1 2 3 4 5 6 7 8


A1

A2

B1

B2

0.01

0.1

1

1.51.5

0 1 2 3 4 5 6 7 8


A1

A2

B1

B2



585


- 59 -



0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

1.1

1.2

1.3

1.4

1.5

0 1 2 3 4 5 6 7 8


A1

A2

B1

B2

0.01

0.1

1

1.51.5

0 1 2 3 4 5 6 7 8


A1

A2

B1

B2



586


- 60 -



0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

1.1

1.2

1.3

1.4

1.5

0 1 2 3 4 5 6 7 8


A1

A2

B1

B2

0.01

0.1

1

1.51.5

0 1 2 3 4 5 6 7 8


A1

A2

B1

B2



587


- 61 -



0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

1.1

1.2

1.3

1.4

1.5

0 1 2 3 4 5 6 7 8


A1

A2

B1

B2

0.01

0.1

1

1.51.5

0 1 2 3 4 5 6 7 8


A1

A2

B1

B2



588


- 62 -



0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

1.1

1.2

1.3

1.4

1.5

0 1 2 3 4 5 6 7 8


A1

A2

B1

B2

0.01

0.1

1

1.51.5

0 1 2 3 4 5 6 7 8


A1

A2

B1

B2



589


- 63 -



0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

1.1

1.2

1.3

1.4

1.5

0 1 2 3 4 5 6 7 8


A1

A2

B1

B2

0.01

0.1

1

1.51.5

0 1 2 3 4 5 6 7 8


A1

A2

B1

B2



590


- 64 -



0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

1.1

1.2

1.3

1.4

1.5

0 1 2 3 4 5 6 7 8


A1

A2

B1

B2

0.01

0.1

1

1.51.5

0 1 2 3 4 5 6 7 8


A1

A2

B1

B2



591


- 65 -



0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

1.1

1.2

1.3

1.4

1.5

0 1 2 3 4 5 6 7 8


A1

A2

B1

B2

0.01

0.1

1

1.51.5

0 1 2 3 4 5 6 7 8


A1

A2

B1

B2



592


- 66 -



0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

1.1

1.2

1.3

1.4

1.5

0 1 2 3 4 5 6 7 8


A1

A2

B1

B2

0.01

0.1

1

1.51.5

0 1 2 3 4 5 6 7 8


A1

A2

B1

B2



593


- 67 -



0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

1.1

1.2

1.3

1.4

1.5

0 1 2 3 4 5 6 7 8


A1

A2

B1

B2

0.01

0.1

1

1.51.5

0 1 2 3 4 5 6 7 8


A1

A2

B1

B2



594


- 68 -



0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

1.1

1.2

1.3

1.4

1.5

0 1 2 3 4 5 6 7 8


A1

A2

B1

B2

0.01

0.1

1

1.51.5

0 1 2 3 4 5 6 7 8


A1

A2

B1

B2



595


- 69 -



0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

1.1

1.2

1.3

1.4

1.5

0 1 2 3 4 5 6 7 8


B1

0.01

0.1

1

1.51.5

0 1 2 3 4 5 6 7 8


B1




596


- 70 -



0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

1.1

1.2

1.3

1.4

1.5

0 1 2 3 4 5 6 7 8


A1

A2

B1

B2

0.01

0.1

1

1.51.5

0 1 2 3 4 5 6 7 8


A1

A2

B1

B2



597


- 71 -



0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

1.1

1.2

1.3

1.4

1.5

0 1 2 3 4 5 6 7 8


A1

A2

B1

B2

0.01

0.1

1

1.51.5

0 1 2 3 4 5 6 7 8


A1

A2

B1

B2



598


- 72 -



0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

1.1

1.2

1.3

1.4

1.5

0 1 2 3 4 5 6 7 8


A1

A2

B1

B2

0.01

0.1

1

1.51.5

0 1 2 3 4 5 6 7 8


A1

A2

B1

B2



599


- 73 -



0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

1.1

1.2

1.3

1.4

1.5

0 1 2 3 4 5 6 7 8


A1

A2

B1

B2

0.01

0.1

1

1.51.5

0 1 2 3 4 5 6 7 8


A1

A2

B1

B2



600


- 74 -



0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

1.1

1.2

1.3

1.4

1.5

0 1 2 3 4 5 6 7 8


A1

A2

B1

B2

0.01

0.1

1

1.51.5

0 1 2 3 4 5 6 7 8


A1

A2

B1

B2



601


- 75 -



0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

1.1

1.2

1.3

1.4

1.5

0 1 2 3 4 5 6 7 8


A1

A2

B1

B2

0.01

0.1

1

1.51.5

0 1 2 3 4 5 6 7 8


A1

A2

B1

B2



602


- 76 -



0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

1.1

1.2

1.3

1.4

1.5

0 1 2 3 4 5 6 7 8


A1

B1

0.01

0.1

1

1.51.5

0 1 2 3 4 5 6 7 8


A1

B1




603


- 77 -



0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

1.1

1.2

1.3

1.4

1.5

0 1 2 3 4 5 6 7 8


A1

A2

B1

B2

0.01

0.1

1

1.51.5

0 1 2 3 4 5 6 7 8


A1

A2

B1

B2



604


- 78 -



0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

1.1

1.2

1.3

1.4

1.5

0 1 2 3 4 5 6 7 8


A1

A2

B1

B2

0.01

0.1

1

1.51.5

0 1 2 3 4 5 6 7 8


A1

A2

B1

B2



605


- 79 -



0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

1.1

1.2

1.3

1.4

1.5

0 1 2 3 4 5 6 7 8


A1

A2

B1

B2

0.01

0.1

1

1.51.5

0 1 2 3 4 5 6 7 8


A1

A2

B1

B2



606


- 80 -



0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

1.1

1.2

1.3

1.4

1.5

0 1 2 3 4 5 6 7 8


A1

A2

B1

B2

0.01

0.1

1

1.51.5

0 1 2 3 4 5 6 7 8


A1

A2

B1

B2



607


- 81 -



0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

1.1

1.2

1.3

1.4

1.5

0 1 2 3 4 5 6 7 8


A1

B1

B2

0.01

0.1

1

1.51.5

0 1 2 3 4 5 6 7 8


A1

B1

B2

A1 = Reformulated Strawberry/CMC 600 Suspension (administration 1) [Test]B1 = Standard Marketed Raspberry/Orange 600 Suspension (administration 1) [Reference]B2 = Standard Marketed Raspberry/Orange 600 Suspension (administration 2) [Reference]Subject completed only three dosing sessions


608


- 82 -



0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

1.1

1.2

1.3

1.4

1.5

0 1 2 3 4 5 6 7 8


A1

A2

B1

B2

0.01

0.1

1

1.51.5

0 1 2 3 4 5 6 7 8


A1

A2

B1

B2



609


- 83 -



0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

1.1

1.2

1.3

1.4

1.5

0 1 2 3 4 5 6 7 8


A1

A2

B1

B2

0.01

0.1

1

1.51.5

0 1 2 3 4 5 6 7 8


A1

A2

B1

B2



610


- 84 -



0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

1.1

1.2

1.3

1.4

1.5

0 1 2 3 4 5 6 7 8


A1

A2

B1

B2

0.01

0.1

1

1.51.5

0 1 2 3 4 5 6 7 8


A1

A2

B1

B2



611


- 85 -



0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

1.1

1.2

1.3

1.4

1.5

0 1 2 3 4 5 6 7 8


A1

A2

B1

B2

0.01

0.1

1

1.51.5

0 1 2 3 4 5 6 7 8


A1

A2

B1

B2



612


- 2 -

Table 12.1 Summary statistics for amoxicillin pharmacokinetic parameters byformulation and administration

Parameter Formulation Admin. n Arith. s.d. Median Min Max Mean

AUC(0_inf) (ug.h/mL)A 1 34 27.2 5.09 26.8 18.7 42.8 A 2 30 27.4 4.57 28.1 20.7 36.6 B 1 34 26.8 4.92 26.9 16.0 38.3 B 2 32 26.9 4.56 26.8 18.1 37.2

AUC(0_t) (ug.h/mL) A 1 34 27.0 5.05 26.6 18.4 42.4 A 2 31 26.7 5.28 27.5 11.7 36.5 B 1 34 26.6 4.89 26.7 16.0 38.0 B 2 32 26.7 4.53 26.5 17.9 36.8

Cmax (ug/mL) A 1 34 7.59 1.771 7.53 3.96 11.53 A 2 31 7.12 1.833 6.93 2.37 12.11 B 1 34 7.43 1.890 6.84 4.23 11.59 B 2 32 7.22 1.661 7.04 4.15 10.52 Tmax (h) A 1 34 1.85 0.631 1.97 0.75 3.03 A 2 31 1.97 0.699 2.00 0.77 3.02 B 1 34 1.93 0.583 1.96 0.97 3.03 B 2 32 2.10 0.833 2.00 0.73 4.00

Parameter Formulation Admin n Geometric CV(%) Mean

AUC(0_inf) (ug.h/mL) A 1 34 26.7 18.61 A 2 30 27.0 16.86 B 1 34 26.4 18.84 B 2 32 26.5 17.40

AUC(0_t) (ug.h/mL) A 1 34 26.5 18.65 A 2 31 26.1 22.56 B 1 34 26.2 18.84 B 2 32 26.3 17.44

Cmax (ug/mL) A 1 34 7.38 24.49 A 2 31 6.86 29.76 B 1 34 7.20 25.84 B 2 32 7.03 24.00

Formulation Key: A: Reformulated Strawberry/CMC 600 suspension (Test) B: Marketed Raspberry/Orange 600 suspension (Ref)


- 613 -


- 3 -

Table 12.2 Summary statistics for amoxicillin pharmacokinetic parameters byformulation

Parameter Formulation n Arith. s.d. Median Min Max Mean

AUC(0_inf) (ug.h/mL)A 34 27.2 4.68 27.1 18.7 39.6 B 34 26.6 4.69 26.9 16.0 37.7

AUC(0_t) (ug.h/mL) A 34 26.6 4.79 26.5 18.4 39.3 B 34 26.4 4.64 26.7 16.0 37.4

Cmax (ug/mL) A 34 7.31 1.596 7.19 4.70 11.82 B 34 7.26 1.548 7.18 4.49 10.22

Tmax (h) A 34 1.88 0.484 1.84 1.00 2.78 B 34 2.01 0.609 1.99 0.88 3.26

Parameter Formulation n Geometric CV(%) Mean

AUC(0_inf) (ug.h/mL) A 34 26.8 17.39 B 34 26.2 18.27

AUC(0_t) (ug.h/mL) A 34 26.2 18.15 B 34 26.0 18.22

Cmax (ug/mL) A 34 7.14 21.98 B 34 7.10 22.17



- 614 -


- 4 -

Table 12.3 Summary statistics for clavulanate pharmacokinetic parameters byformulation and administration

Parameter Formulation Admin. n Arith. s.d. Median Min Max Mean

AUC(0_inf) (ug.h/mL)A 1 32 1.703 0.6895 1.613 0.707 3.954 A 2 28 1.804 0.7360 1.569 0.672 3.299 B 1 30 1.573 0.5608 1.415 0.449 2.605 B 2 30 1.605 0.7025 1.653 0.316 2.909

AUC(0_t) (ug.h/mL) A 1 34 1.550 0.6958 1.420 0.362 3.803 A 2 31 1.589 0.7768 1.400 0.491 3.193 B 1 34 1.348 0.6341 1.283 0.133 2.531 B 2 32 1.424 0.7210 1.452 0.253 2.753

Cmax (ug/mL) A 1 34 0.684 0.2542 0.625 0.190 1.316 A 2 31 0.686 0.3015 0.572 0.278 1.222 B 1 34 0.604 0.2604 0.599 0.083 1.311 B 2 32 0.628 0.3070 0.606 0.162 1.365

Tmax (h) A 1 34 1.22 0.490 1.00 0.70 2.52 A 2 31 1.14 0.341 1.00 0.50 2.00 B 1 34 1.19 0.373 1.00 0.50 2.02 B 2 32 1.19 0.335 1.03 0.50 2.02

Parameter Formulation Admin n Geometric CV(%) Mean

AUC(0_inf) (ug.h/mL) A 1 32 1.584 39.82 A 2 28 1.659 44.68 B 1 30 1.466 41.73 B 2 30 1.426 57.83

AUC(0_t) (ug.h/mL) A 1 34 1.405 49.05 A 2 31 1.397 57.96 B 1 34 1.158 70.86 B 2 32 1.204 72.39

Cmax (ug/mL) A 1 34 0.638 40.68 A 2 31 0.620 49.38 B 1 34 0.537 59.46 B 2 32 0.548 60.89



- 615 -


- 5 -

Table 12.4 Summary statistics for clavulanate pharmacokinetic parameters byformulation

Parameter Formulation n Arith. s.d. Median Min Max Mean

AUC(0_inf) (ug.h/mL)A 33 1.706 0.6499 1.700 0.672 3.513 B 33 1.523 0.5940 1.489 0.316 2.560

AUC(0_t) (ug.h/mL) A 34 1.553 0.6666 1.443 0.455 3.389 B 34 1.366 0.6272 1.351 0.265 2.408

Cmax (ug/mL) A 34 0.678 0.2401 0.637 0.233 1.265 B 34 0.608 0.2594 0.619 0.142 1.174

Tmax (h) A 34 1.16 0.364 1.01 0.75 2.01 B 34 1.19 0.302 1.23 0.62 2.02

Parameter Formulation n Geometric CV(%) Mean

AUC(0_inf) (ug.h/mL) A 33 1.590 40.17 B 33 1.384 51.62

AUC(0_t) (ug.h/mL) A 34 1.415 47.63 B 34 1.186 65.69

Cmax (ug/mL) A 34 0.636 38.74 B 34 0.544 54.89



- 616 -


- 6 -

Table 12.5 Individual amoxicillin AUC(0-inf) [ug.h/mL] (%extrapolation)following single oral dose administrations of Augmentin ES-600suspension (reformulated and standard)

Geo Mean Test / Test Test Reference Reference Geo Mean Geo Mean Geo MeanSubj Seq Admin 1 Admin 2 Admin 1 Admin 2 Test Reference Reference



- 617 -

This section contained data from each individual patient, rather than in aggregate. They have been excluded to protect patient privacy. Anonymized

data from each patient may be made available subject to an approved research proposal. For further information please see the Patient Level Data

section of the Sponsor Clinical Study Register.


- 7 -

Table 12.6 Individual amoxicillin AUC(0-t) [ug.h/mL] following single oral doseadministrations of Augmentin ES-600 suspension (reformulated andstandard)

Geo Mean Test / Test Test Reference Reference Geo Mean Geo Mean Geo Mean Subj Seq Admin 1 Admin 2 Admin 1 Admin 2 Test Reference Reference



- 618 -

This section contained data from each individual patient, rather than in aggregate. They have been excluded to protect patient privacy.

Anonymized data from each patient may be made available subject to an approved research proposal. For further information please see



- 8 -

Table 12.7 Individual amoxicillin Cmax [ug/mL] following single oral doseadministrations of Augmentin ES-600 suspension (reformulated andstandard)




- 619 -


Anonymized data from each patient may be made available subject to an approved research proposal. For further information please see the Patient Level Data section of the Sponsor Clinical Study Register.


- 9 -

Table 12.8 Individual amoxicillin Tmax [hours] following single oral doseadministrations of Augmentin ES-600 suspension (reformulated andstandard)

Average Test - Test Test Reference Reference Average Average Average Subj Seq Admin 1 Admin 2 Admin 1 Admin 2 Test Reference Reference



- 620 -





- 10 -

Table 12.9 Individual clavulanate AUC(0-inf) [ug.h/mL] (%extrapolation)following single oral dose administrations of Augmentin ES-600suspension (reformulated and standard)

GeoMean Test / Test Test Reference Reference GeoMean GeoMean GeoMeanSub Seq Admin 1 Admin 2 Admin 1 Admin 2 Test Ref Ref



- 621 -


data from each patient may be made available subject to an approved research proposal. For further information please see the Patient Level Data section of the

Sponsor Clinical Study Register.


- 11 -

Table 12.10 Individual clavulanate AUC(0-t) [ug.h/mL] following single oral doseadministrations of Augmentin ES-600 suspension (reformulated andstandard)




- 622 -


Anonymized data from each patient may be made available subject to an approved research proposal. For further information please see the Patient Level Data section of the Sponsor Clinical Study Register.


- 12 -

Table 12.11 Individual clavulanate Cmax [ug/mL] following single oral doseadministrations of Augmentin ES-600 suspension (reformulated andstandard)




- 623 -


Anonymized data from each patient may be made available subject to an approved research proposal. For further information please see the



- 13 -

Table 12.12 Individual clavulanate Tmax [hours] following single oral doseadministrations of Augmentin ES-600 suspension (reformulated andstandard)

Average Test - Test Test Reference Reference Average Average Average Subj Seq Admin 1 Admin 2 Admin 1 Admin 2 Test Reference Reference



- 624 -





- 14 -

Table 12.13 Individual plasma concentration [ug/mL] for amoxicillin and clavulanate following a single oral doseadministration of reformulated strawberry/CMC Augmentin ES-600 suspension (1st administration)

Subject Subject Subject SubjectTime Amoxicillin Clavulanate Time Amoxicillin Clavulanate Time Amoxicillin Clavulanate Time Amoxicillin Clavulanate

[hours] [ug/mL] [ug/mL] [hours] [ug/mL] [ug/mL] [hours] [ug/mL] [ug/mL] [hours] [ug/mL] [ug/mL]

NQ not quantifiable, below lower limit of quantification (<0.05 ug/mL)*concentration values used to determine the terminal elimination phase rate constant

CO

NF

IDE

NT

IAL

PM

2002/00022/00 B

RL-025000/643

- 625 -

This section contained data from each individual patient, rather than in aggregate. They have been excluded to protect patient privacy. Anonymized data from each patient may be made available subject to an approved research proposal. For further

information please see the Patient Level Data section of the Sponsor Clinical Study Register.


- 23 -

Table 12.14 Individual plasma concentration [ug/mL] for amoxicillin and clavulanate following a single oral doseadministration of reformulated strawberry/CMC Augmentin ES-600 suspension(2nd administration)




CO

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- 634 -




- 32 -

Table 12.15 Individual plasma concentration [ug/mL] for amoxicillin and clavulanate following a single oral doseadministration of standard marketed raspberry/orange Augmentin ES-600 suspension(1st administration)



NQ not quantifiable, below lower limit of quantification (<0.05 ug/mL)NR no result*concentration values used to determine the terminal elimination phase rate constant

CO

NF

IDE

NT

IAL

PM

2002/00022/00 B

RL-025000/643

- 643 -




- 41 -

Table 12.16 Individual plasma concentration [ug/mL] for amoxicillin and clavulanate following a single oral doseadministration of standard marketed raspberry/orange Augmentin ES-600 suspension(2nd administration)




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- 652 -




- 50 -

Table 12.17 Plasma concentrations of amoxicillin in quality control samples

Nominal ConcentrationsQC 1 QC 2 QC 3 QC 4

0.1 ug/mL 6. ug/mL 8. ug/mL 20. ug/mLConcentration Accuracy Concentration Accuracy Concentration Accuracy Concentration Accuracy

(ug/mL) (%) (ug/mL) (%) (ug/mL) (%) (ug/mL) (%)W0201392.xls 0.085 85.00 5.534 92.23 7.301 91.26 18.518 92.59

0.100 99.80 5.270 87.83 7.860 98.25 18.626 93.1318.156 90.78

W0201394.xls 0.089 88.80 5.532 92.21 7.578 94.72 19.421 97.100.114 114.20 5.481 91.34 7.668 95.85 20.843 104.21

20.642 103.21W0201396.xls 0.095 95.00 6.575 109.58 8.068 100.85 19.908 99.54

0.102 102.00 5.897 98.28 8.113 101.41 20.458 102.2919.957 99.79

W0201397.xls 0.103 103.00 5.799 96.65 7.828 97.85 19.446 97.230.104 104.00 5.793 96.55 7.558 94.48 18.904 94.52

19.521 97.61W0201399.xls 0.102 102.00 6.034 100.57 7.874 98.43 19.667 98.34

0.112 112.00 6.125 102.08 7.848 98.10 20.080 100.4020.840 104.20

W0201403.xls 0.120 120.00 5.792 96.53 7.915 98.94 22.913 114.570.108 108.00 5.802 96.70 8.627 107.84 23.024 115.12

20.959 104.79W0201404.xls 0.096 96.00 5.621 93.68 7.634 95.43 19.335 96.68

0.099 99.00 5.731 95.52 7.445 93.06 20.988 104.9422.047 110.24

W0201405.xls 0.120 120.00 5.873 97.88 7.416 92.70 20.290 101.450.099 99.00 6.098 101.63 7.263 90.79 21.859 109.30

19.846 99.23W0201406.xls 0.112 112.00 6.048 100.80 7.689 96.11 19.206 96.03

0.115 115.00 6.113 101.88 7.862 98.28 25.942 129.7117.749 88.75

CO

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NT

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2002/00022/00 B

RL-025000/643

- 661 -


- 51 -

Table 12.17 (cont’d) Plasma concentrations of amoxicillin in quality control samples




0.102 102.00 6.127 102.12 7.879 98.49 22.305 111.5320.243 101.21

W0201408.xls 0.095 95.00 5.220 87.00 7.228 90.35 17.616 88.080.097 97.00 5.560 92.67 7.246 90.58 17.793 88.96

18.499 92.50W0201409.xls 0.090 90.00 6.402 106.70 7.568 94.60 20.794 103.97

0.088 88.00 5.594 93.23 7.530 94.13 20.491 102.4620.156 100.78

W0201410.xls 0.109 109.00 6.196 103.27 7.997 99.96 19.378 96.890.117 117.00 6.097 101.62 8.341 104.26 19.566 97.83

21.511 107.56W0201413.xls 0.083 83.00 5.346 89.10 7.242 90.53 18.738 93.69

0.096 96.00 5.289 88.15 6.994 87.43 19.829 99.1519.313 96.56

W0201415.xls 0.113 113.00 6.141 102.35 8.058 100.73 19.637 98.190.106 106.00 6.053 100.88 7.861 98.26 18.530 92.65

20.220 101.10W0201416.xls 0.098 98.00 5.794 96.57 7.916 98.95 19.582 97.91

0.104 104.00 5.705 95.08 7.869 98.36 20.564 102.8220.378 101.89

W0201417.xls 0.093 93.30 5.977 99.62 8.020 100.25 18.836 94.180.101 100.60 5.924 98.73 7.913 98.92 18.390 91.95

19.599 98.00W0201418.xls 0.110 110.10 6.027 100.45 7.908 98.85 18.576 92.88

0.099 99.40 6.052 100.86 7.693 96.16 18.945 94.7223.261 116.31

CO

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NT

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PM

2002/00022/00 B

RL-025000/643

- 662 -


- 52 -





0.111 111.00 5.388 89.80 7.685 96.06 18.766 93.8319.905 99.53

W0201420.xls 0.108 108.00 5.491 91.52 7.615 95.19 15.192 75.960.106 106.00 5.696 94.93 8.005 100.06 19.118 95.59

18.637 93.19W0201421.xls 0.089 89.00 5.359 89.32 7.016 87.70 19.012 95.06

0.089 89.00 4.625 77.08 7.146 89.33 18.785 93.9318.599 93.00

W0201422.xls 0.087 87.00 5.572 92.87 7.159 89.49 19.964 99.820.083 83.00 5.560 92.67 7.266 90.83 19.363 96.82

19.960 99.80W0201424.xls 0.102 102.00 5.651 94.18 7.107 88.84 20.500 102.50

0.100 100.00 5.448 90.80 7.494 93.68 19.455 97.2820.622 103.11

W0201473.xls 0.107 107.20 6.240 104.00 8.079 100.98 19.988 99.940.107 107.20 6.276 104.60 8.139 101.74 19.262 96.31

19.559 97.79W0201476.xls 0.107 107.00 6.605 110.08 8.985 112.31 22.559 112.79

0.107 107.20 6.936 115.61 9.403 117.54 22.690 113.4523.552 117.76

W0201477.xls 0.101 100.80 6.546 109.10 8.948 111.85 21.976 109.880.112 111.60 6.827 113.79 8.377 104.71 21.275 106.37

22.147 110.74W0201479.xls 0.109 108.60 6.609 110.15 8.813 110.16 22.525 112.62

0.101 101.30 6.607 110.12 8.488 106.10 22.610 113.0522.333 111.67

CO

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RL-025000/643

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0.104 104.00 5.757 95.95 7.501 93.76 18.592 92.9619.299 96.50

W0201507.xls 0.112 112.00 5.964 99.40 7.646 95.58 20.438 102.190.095 95.00 5.782 96.37 7.882 98.53 20.073 100.37

20.581 102.91W0201512.xls 0.103 103.00 5.517 91.95 7.302 91.28 18.860 94.30

0.107 107.00 5.645 94.08 7.374 92.18 19.655 98.2819.140 95.70

W0201513.xls 0.092 92.00 5.575 92.92 7.435 92.94 18.286 91.430.092 92.00 5.787 96.45 7.704 96.30 19.758 98.79

18.659 93.30W0201516.xls 0.109 109.00 5.457 90.95 7.794 97.43 18.718 93.59

0.104 104.00 5.470 91.17 7.788 97.35 18.588 92.9418.012 90.06

W0201521.xls 0.096 96.00 5.734 95.57 7.529 94.11 20.223 101.120.101 101.00 5.680 94.67 7.579 94.74 21.405 107.03

20.985 104.93W0201522.xls 0.100 100.00 5.672 94.53 7.670 95.88 21.593 107.97

0.102 102.00 5.981 99.68 8.058 100.73 21.326 106.6321.575 107.87

W0201523.xls 0.103 103.00 6.147 102.45 7.929 99.11 20.886 104.430.107 107.00 6.174 102.90 8.295 103.69 22.894 114.47

22.820 114.10

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0.1 ug/mL 6. ug/mL 8. ug/mL 20. ug/mL

Overall Mean 0.10 5.85 7.78 20.10S.D.(within run means) 0.01 0.43 0.47 1.59

CV % 8.34 7.29 6.01 7.91Average Bias % 2.00 -2.52 -2.70 0.49

n 70 70 70 105Average Within Run Precision (%) 6.20 3.51 2.50 5.66

Between Run Precision (%) 0.95 1.09 0.93 1.16

CO

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Table 12.18 Plasma concentrations of clavulanate in quality control samples

Nominal ConcentrationsQC 1 QC 2 QC 3

0.2 ug/mL 5. ug/mL 8. ug/mLConcentration Accuracy Concentration Accuracy Concentration Accuracy

(ug/mL) (%) (ug/mL) (%) (ug/mL) (%)W0201428.xls 0.204 102.00 5.004 100.08 8.272 103.40

0.199 99.50 5.025 100.50 8.301 103.76W0201429.xls 0.206 103.00 5.010 100.20 8.675 108.44

0.214 107.00 5.629 112.58 8.665 108.31W0201430.xls 0.234 117.00 4.871 97.42 8.514 106.43

0.205 102.50 4.966 99.32 8.194 102.42W0201431.xls 0.200 100.00 5.361 107.22 8.043 100.54

0.204 102.00 4.855 97.10 8.116 101.45W0201432.xls 0.212 106.00 5.469 109.38 8.264 103.30

0.223 111.50 5.426 108.52 8.140 101.75W0201433.xls 0.218 109.00 5.116 102.32 7.507 93.84

0.218 109.00 5.020 100.40 7.632 95.40W0201434.xls 0.167 83.50 5.046 100.92 7.850 98.13

0.184 92.00 5.081 101.62 7.875 98.44W0201435.xls 0.194 97.00 5.709 114.18 9.112 113.90

0.176 88.00 5.655 113.10 9.048 113.10W0201437.xls 0.230 115.00 5.577 111.54 9.100 113.75

0.237 118.50 5.685 113.70 8.875 110.94W0201438.xls 0.233 116.50 5.552 111.04 8.470 105.88

0.224 112.00 5.500 110.00 8.827 110.34W0201439.xls 0.192 96.00 5.488 109.76 9.177 114.71

0.227 113.50 6.048 120.96 9.745 121.81W0201440.xls 0.259 129.50 5.586 111.72 9.195 114.94

0.192 96.00 5.640 112.80 9.193 114.91

CO

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Table 12.18 (cont’d) Plasma concentrations of clavulanate in quality control samples




0.200 100.00 5.094 101.88 8.304 103.80W0201442.xls 0.207 103.50 4.984 99.68 7.940 99.25

0.213 106.50 5.239 104.78 7.988 99.85W0201444.xls 0.174 87.00 4.943 98.86 8.172 102.15

0.186 93.00 4.969 99.38 8.714 108.93W0201445.xls 0.194 97.00 4.740 94.80 8.212 102.65

0.183 91.50 4.760 95.20 8.196 102.45W0201448.xls 0.221 110.50 5.506 110.12 8.473 105.91

0.241 120.50 5.733 114.66 8.804 110.05W0201450.xls 0.179 89.50 4.723 94.46 8.110 101.38

0.207 103.50 5.774 115.48 9.006 112.58W0201452.xls 0.165 82.50 4.556 91.12 7.430 92.88

0.189 94.50 5.433 108.66 8.721 109.01W0201453.xls 0.175 87.50 4.304 86.08 6.642 83.03

0.157 78.50 5.339 106.78 8.438 105.48W0201454.xls 0.165 82.50 4.405 88.10 7.947 99.34

0.196 98.00 5.492 109.84 7.562 94.53W0202094.xls 0.198 99.00 4.984 99.68 7.905 98.81

0.216 108.00 5.250 105.00 9.262 115.78W0202095.xls 0.174 87.00 5.250 105.00 7.705 96.31

0.194 97.00 5.218 104.36 9.000 112.50W0202096.xls 0.166 83.00 4.792 95.84 7.221 90.26

0.180 90.00 4.921 98.42 0.000 0.00

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0.200 100.00 4.763 95.26 7.759 96.99W0202099.xls 0.192 96.00 6.079 121.58 9.821 122.76

0.188 94.00 5.427 108.54 8.862 110.78W0202100.xls 0.213 106.50 5.399 107.98 9.865 123.31

0.203 101.50 4.620 92.40 7.104 88.80W0202165.xls 0.189 94.50 5.602 112.04 7.569 94.61

0.189 94.50 5.267 105.34 7.605 95.06W0202168.xls 0.206 103.00 5.547 110.94 8.471 105.89

0.178 89.00 4.994 99.88 2.196 27.45W0202178.xls 0.200 100.00 5.298 105.96 7.885 98.56

0.188 94.00 4.555 91.10 7.697 96.21W0202184.xls 0.209 104.50 5.421 108.42 8.432 105.40

0.199 99.50 5.166 103.32 7.876 98.45W0202185.xls 0.201 100.50 4.286 85.72 8.013 100.16

0.176 88.00 6.248 124.96 7.442 93.03W0202193.xls 0.256 128.00 5.233 104.66 8.428 105.35

0.197 98.50 4.900 98.00 7.638 95.48W0202194.xls 0.209 104.50 5.839 116.78 7.819 97.74

0.180 90.00 5.073 101.46 7.351 91.89W0202216.xls 0.199 99.50 5.508 110.16 11.996 149.95

0.207 103.50 5.745 114.90 9.002 112.53

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0.2 ug/mL 5. ug/mL 8. ug/mL

Overall Mean 0.20 5.23 8.13S.D.(within run means) 0.02 0.42 1.46

CV % 10.46 7.95 17.97Average Bias % 0.13 4.54 1.68

n 70 70 70Average Within Run Precision (%) 8.01 7.94 16.16

Between Run Precision (%) 1.15 0.06 1.34

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Table 12.19 Analysis of Variance (ANOVA) for Amoxicillin AUC(0-inf) [ug.h/mL]

The MIXED Procedure

Class Level Information

Class Levels Values


- 670 -

This section contained data from each individual patient, rather than in aggregate. They have been excluded to protect patient

privacy. Anonymized data from each patient may be made available subject to an approved research proposal. For further



- 62 -

Table 12.20 Analysis of Variance (ANOVA) for Amoxicillin AUC(0-t) [ug.h/mL]

The MIXED Procedure


Class Levels Values


- 673 -


Anonymized data from each patient may be made available subject to an approved research proposal. For further information please see the Patient Level Data section of the Sponsor Clinical Study

Register.


- 65 -

Table 12.21 Analysis of Variance (ANOVA) for Amoxicillin Cmax [ug/mL]

The MIXED Procedure



- 676 -


Anonymized data from each patient may be made available subject to an approved research proposal. For further information please see the Patient Level Data section of the Sponsor Clinical Study

Register.


- 68 -

Table 12.22 Non-parametric Analysis for Amoxicillin Tmax [hours]

ASSUMES NO PERIOD EFFECT Reform. Strawberry vs. Marketed Rasberry

AMOX : NON-PARAMETRIC CONFIDENCE INTERVAL FOR TREATMENT DIFF.

A B

MEDIAN 1.84 1.99

N 34 34

MEDIAN DIFFERENCE -0.130

95% CONFIDENCE LIMITS -0.380 TO 0.115


- 679 -


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Table 12.23 Analysis of Variance (ANOVA) for Clavulanate AUC(0-inf) [ug.h/mL]

The MIXED Procedure


Class Levels Values


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Table 12.24 Analysis of Variance (ANOVA) for Clavulanate AUC(0-t) [ug.h/mL]

The MIXED Procedure


Class Levels Values


- 683 -


data from each patient may be made available subject to an approved research proposal. For further information please see the Patient Level Data

section of the Sponsor Clinical Study Register.


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Table 12.25 Analysis of Variance (ANOVA) for Clavulanate Cmax [ug/mL]

The MIXED Procedure


Class Levels Values


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- 78 -

Table 12.26 Non-parametric Analysis for Clavulanate Tmax [hours]

ASSUMES NO PERIOD EFFECT Reform. Strawberry vs. Marketed Rasberry

CLAV : NON-PARAMETRIC CONFIDENCE INTERVAL FOR TREATMENT DIFF.

A B

MEDIAN 1.01 1.23

N 34 34

MEDIAN DIFFERENCE -0.055

95% CONFIDENCE LIMITS -0.165 TO 0.058


- 689 -

Confidential

The GlaxoSmithKline group of companies

Augmentin

25000

Study Title: A Study to Determine the Bioequivalence of Reformulated

Augmentin ES-600 for Oral Suspension (improved flavor) to Standard Marketed Suspension

Study Identifier: 643

Final Clinical Protocol

Lead/Co-ordinating Author: MS* Contributing Authors: PhD* MD*,

PhD* PhD, MD*,

Lead/Coordinating Author and Contributing Author(s) Department: *Clinical Pharmacology and Experimental Medicine, #Clinical Pharmacology

Statistics and Data Sciences

Sponsor Signatory: PhD, MD Sponsor Signatory Title: Vice President Clinical Pharmacology and

Experimental Medicine, N.A.

GSK Investigational Product Identifier: BRL-025000/RSD-101PX2/1

Approval Date: 11 January 2002

Copyright 2001 the GlaxoSmithKline group of companies. All rights reserved. Unauthorised copying or use of this information is prohibited.


- 1 -

BRL-025000/RSD-101PX2/1 Page 2 Final

Sponsor Information Page

Title: Study Title: A Study to Determine the Bioequivalence of

Reformulated Augmentin ES-600 for Oral Suspension (improved flavor) to Standard Marketed Suspension

Study Identifier: 25000/643

USA

Telephone Number:

IND Number: 16,896


- 2 -


- 3 -


Investigator Protocol Agreement Page

I agree:

• To assume responsibility for the proper conduct of the study at this site.

• To conduct the study in compliance with this protocol, any future amendments, and with any other study conduct procedures provided by GlaxoSmithKline (GSK).

• Not to implement any changes to the protocol without agreement from the sponsor and prior review and written approval from the Institutional Review Board (IRB) or Independent Ethics Committee (IEC), except where necessary to eliminate an immediate hazard to the subjects, or for administrative aspects of the study (where permitted by all applicable regulatory requirements).

• That I am thoroughly familiar with the appropriate use of the investigational product(s), as described in this protocol, and any other information provided by the sponsor including, but not limited to, the following: the current Clinical Investigator’s Brochure / Investigator’s Brochure (CIB/IB) or equivalent document, CIB/IB supplement (if applicable), and approved product label (if the product is marketed in this country and the label is not already provided as an equivalent to a CIB/IB).

• That I am aware of, and will comply with, “good clinical practices” (GCP) and all applicable regulatory requirements.

• To ensure that all persons assisting me with the study are adequately informed about the GSK investigational product(s) and of their study-related duties and functions as described in the protocol.

That I have been informed that certain regulatory authorities require the Sponsor to obtain and supply, as necessary, details about the investigator’s ownership interest in the Sponsor or the investigational product, and more generally about his/her financial ties with the Sponsor. GSK will use and disclose the information solely for the purpose of complying with regulatory requirements.


- 4 -


- 5 -

Table of Contents

PageProtocol Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9

1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 111.1 Background . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 111.2 Rationale . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11

2 Objective(s). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 122.1 Primary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 122.2 Secondary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12

3 Endpoint(s) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123.1 Primary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123.2 Secondary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13

4 Study Design . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 134.1 Method of Randomization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13

5 Study Population. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 135.1 Number of Subjects. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 135.2 Eligibility Criteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14

5.2.1 Inclusion Criteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 145.2.2 Exclusion Criteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 145.2.3 Other Eligibility Criteria Considerations. . . . . . . . . . . . . . . . . . . 15

6 Study Assessments and Procedures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 156.1 Demographic and Baseline Assessments. . . . . . . . . . . . . . . . . . . . . . 17

6.1.1 Screening Visit . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 176.1.2 Lifestyle Guidelines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 186.1.3 Contraception . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 196.1.4 Follow-up Visit . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19

6.2 Safety . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 206.2.1 Pregnancy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20

6.3 Pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 216.3.1 Sample Preparation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 216.3.2 Assay Methodology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 226.3.3 Planned Pharmacokinetic Evaluation . . . . . . . . . . . . . . . . . . . . 22

7 Investigational Product . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 227.1 Description of Investigational Product . . . . . . . . . . . . . . . . . . . . . . . . . 227.2 Dosage and Administration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 237.3 Dose Rationale . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 247.4 Blinding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 247.5 Treatment Assignment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 247.6 Packaging and Labeling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 247.7 Preparation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 247.8 Handling and Storage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25


6

7.9 Product Accountability. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 257.10 Assessment of Compliance. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 267.11 Treatment of Investigational Product Overdose . . . . . . . . . . . . . . . . 267.12 Occupational Safety . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26

8 Concomitant Medications and Non-Drug Therapies. . . . . . . . . . . . . . . . . . . 27

9 Subject Completion and Withdrawal. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 289.1 Subject Completion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 289.2 Subject Withdrawal . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28

9.2.1 Subject Withdrawal from Study . . . . . . . . . . . . . . . . . . . . . . . . . 289.2.2 Subject Withdrawal from Investigational Product . . . . . . . . . . . 28

10 Adverse Events (AE) and Serious Adverse Events (SAE) . . . . . . . . . . . . . 2810.1 Definition of an AE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2810.2 Definition of a SAE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3010.3 Lack of Efficacy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3110.4 Clinical Laboratory Abnormalities and Other Abnormal

Assessments as AEs and SAEs . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3110.5 Time Period, Frequency, and Method of Detecting AEs and SAEs . 3210.6 Recording of AEs and SAEs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3210.7 Evaluating AEs and SAEs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33

10.7.1 Assessment of Intensity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3310.7.2 Assessment of Causality . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33

10.8 Follow-up of AEs and SAEs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3410.9 Prompt Reporting of SAEs to GSK . . . . . . . . . . . . . . . . . . . . . . . . . . 35

10.9.1 Timeframes for Submitting SAE Reports to GSK . . . . . . . . . . 3510.9.2 Completion and Transmission of the SAE Reports . . . . . . . . . 35

10.10 Regulatory Reporting Requirements for SAEs . . . . . . . . . . . . . . . . 3610.11 Post-Study AEs and SAEs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3710.12 SAEs Related to Study Participation . . . . . . . . . . . . . . . . . . . . . . . . 37

11 Data Analysis and Statistical Considerations . . . . . . . . . . . . . . . . . . . . . . . 3711.1 Hypotheses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3711.2 Treatment Comparisons of Interest. . . . . . . . . . . . . . . . . . . . . . . . . . 38

11.2.1 Primary Comparisons of Interest. . . . . . . . . . . . . . . . . . . . . . . 3811.3 Interim Analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3811.4 Sample Size Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38

11.4.1 Sample Size Assumptions . . . . . . . . . . . . . . . . . . . . . . . . . . . 3811.4.2 Sample Size Sensitivity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3911.4.3 Sample Size Re-Estimation . . . . . . . . . . . . . . . . . . . . . . . . . . 39

11.5 Analysis Populations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3911.6 Safety Analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3911.7 Clinical Pharmacology Data Analyses . . . . . . . . . . . . . . . . . . . . . . . 39

11.7.1 Pharmacokinetic Analyses . . . . . . . . . . . . . . . . . . . . . . . . . . . 39

12 Study Administration. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4012.1 Regulatory and Ethical Considerations . . . . . . . . . . . . . . . . . . . . . . . 40


7

12.1.1 Regulatory Authority Approval . . . . . . . . . . . . . . . . . . . . . . . . 4012.1.2 Ethical Conduct of the Study and Ethics Approval . . . . . . . . . 4012.1.3 Informed consent. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4112.1.4 Investigator Reporting Requirements . . . . . . . . . . . . . . . . . . . 41

12.2 Study Monitoring . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4212.3 Quality Assurance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4212.4 Study and Site Closure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4312.5 Records Retention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4412.6 Provision of Study Results and Information to Investigators. . . . . . . 4412.7 Data Management. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44

13 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45

14 Appendices . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46


8


Protocol Summary

Rationale

The shelf life of Augmentin suspension is limited by the stability of clavulanic

acid after constitution. The major factor impacting clavulanate stability in the constituted product is pH. In the orange-raspberry oral suspension product, succinic acid and raspberry flavor excipients have the largest contribution to lowering the initial pH of the constituted product. Laboratory batches of Augmentin

oral suspension product with these excipients removed were

manufactured and tested for 10 day clavulanate stability. Removal of succinic acid and raspberry flavor increases pH and improves stability in suspension (data on file). As an alternative to the orange-raspberry flavoring, strawberry flavoring has been added to the suspension product. Previous studies suggested a strawberry cream flavor is more palatable to the current flavoring. This alternative flavoring of the Augmentin suspension formulation may contribute to improved reconstituted stability of this formulation.

This study is being performed to demonstrate the bioequivalence between the more stable reformulated strawberry flavored ES-600 mg/5 mL Augmentin

suspension (without succinic acid and raspberry flavor) and the current marketed ES-600 mg/5 mL Augmentin

suspension (containing succinic acid and raspberry

flavor).

Objective(s)

Primary

1. To demonstrate the bioequivalence of a new reformulated ES-600 mg/5 mL suspension of Augmentin

to the marketed ES-600 mg/5 mL suspension of

Augmentin.

Secondary

1. To assess the safety and tolerability of the new reformulated ES-600mg/5 mL suspension of Augmentin

in healthy adult volunteers in this study.


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Endpoint(s)

AUC and Cmax of both amoxicillin and clavulanate will be the primary pharmacokinetic parameters. The secondary pharmacokinetic parameter is Tmax of both amoxicillin and clavulanate.

Study Design

This will be an open-label, randomized, period balanced, replicate, four-period crossover study. Each subject will participate in four study sessions, separated by at least three days each. Subjects will receive a single dose of the new suspension formulation in two study sessions and a single dose of the standard suspension formulation in the other two study sessions:

Regimen Code

Study Medication

A Reformulated Strawberry/CMC formulation 600 mg amoxicillin / 42.9 mg clavulanate per 5 mL oral suspension

B Marketed Raspberry/Orange 600 mg amoxicillin / 42.9 mg clavulanate per 5 mL oral suspension

Study Population

Thirty-six subjects will be enrolled so that a minimum of 30 subjects complete the study. Eligible subjects will be healthy adult subjects between 18 and 60 years of age. An attempt will be made to enroll equal number of male and female subjects.

Study Assessments and Procedures

Subjects will be admitted to the Clinical Research Unit for an approximate 14 hour stay on Day 1 of each study session for dosing, blood sample collection for pharmacokinetic analysis, and safety assessments. Subjects will be discharged at approximately 12 hours after dosing. Follow-up procedures (including recording of information regarding the use of concomitant medication or the occurrence of adverse events and collection of blood and urine specimens for clinical laboratory tests) will be performed approximately 24 hours after dosing in the last study session (Session 4) for all subjects. Female subjects will be required to return to the unit 10-14 days following their last dose of study medication for a serum pregnancy test. The total duration of the study from first dose of study medication until follow-up will be approximately 4 weeks for male subjects and 6 weeks for female subjects.


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Routine safety and tolerability assessments will be made by heart rate and blood pressure measurements, laboratory safety tests (hematology and biochemistry), urinalysis (including urine drug/alcohol screen), adverse event questioning and clinical monitoring.

Investigational Product(s)

The study medication will be supplied by the GlaxoSmithKline Pharmaceuticals.

Two formulations of Augmentin will be provided:

Both the reformulated and the standard Augmentin ES-600 mg oral suspension formulations will be supplied in 240 mL HDPE bottles containing 600 mg amoxicillin as the trihydrate and 42.9 mg clavulanic acid as the potassium salt per 5 mL suspension.

1 Introduction

1.1 Background

Augmentin is a broad-spectrum antibiotic for the treatment and prophylaxis of a

wide range of bacterial infections. Augmentin is a combination product

containing the broad-spectrum penicillin, amoxicillin, and the β-lactamase inhibitor, clavulanate. It was first launched in 1981 but is now available world-wide in a wide range of injectable (I.V.) and/or oral presentations which meet the treatment needs of adults and pediatric patients, in general practice and in the hospital. The daily therapeutic dose extends up to 12 g of amoxicillin and 1200 mg of clavulanate intravenously, in adults.

Augmentin is generally well tolerated, with the majority of side effects observed

in clinical trials being of a mild and transient nature. The most frequently reported adverse effects include diarrhea, nausea, skin rashes, pruritis, urticaria, vomiting and vaginitis. Changes in liver function tests have been noted in some patients and there have been rare reports of hepatitis and cholestatic jaundice although these hepatic effects are usually reversible and have mainly been associated with prolonged dosing in elderly patients.[Appendix 6]

1.2 Rationale

The shelf life of Augmentin suspension is limited by the stability of clavulanic

acid after constitution. The major factor impacting clavulanate stability in the constituted product is pH. In the orange-raspberry oral suspension product,


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succinic acid and raspberry flavor excipients have the largest contribution to lowering the initial pH of the constituted product. Laboratory batches of Augmentin

oral suspension product with these excipients removed were

manufactured and tested for 10 day clavulanate stability. Removal of succinic acid and raspberry flavor increases pH and improves stability in suspension (data on file). As an alternative to the orange-raspberry flavoring, strawberry flavoring has been added to the suspension product. Previous studies suggested a strawberry cream flavor is more palatable to the current flavoring. This alternative flavoring of the Augmentin suspension formulation may contribute to improved reconstituted stability of this formulation.

Based on the FDA Guidance on Scale-up and Postapproval Changes (SUPAC), the sum of the adjustments made to the original formula of the ES-600 mg amoxicillin/49.2 mg clavulanate per 5 mL oral suspension are of an extent that it is categorized as a level 3 change. Level 3 changes require the performance of an in vivo bioequivalence study.

This study is being performed to demonstrate the bioequivalence between the more stable reformulated strawberry flavored ES-600 mg/5 mL Augmentin

suspension (without succinic acid and raspberry flavor) and the current marketed ES-600 mg/5 mL Augmentin

suspension (containing succinic acid and raspberry

flavor).

2 Objective(s)

2.1 Primary

1. To demonstrate the bioequivalence of a new reformulated ES-600 mg/5 mL suspension of Augmentin

to the marketed ES-600 mg/5 mL suspension of

Augmentin.

2.2 Secondary

1. To assess the safety and tolerability of the new reformulated ES-600mg/5 mL suspension of Augmentin

in healthy adult volunteers in this study.

3 Endpoint(s)

3.1 Primary

AUC and Cmax of both amoxicillin and clavulanate will be the primary pharmacokinetic parameters.


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3.2 Secondary

The secondary pharmacokinetic parameter is Tmax of both amoxicillin and clavulanate.

4 Study Design

This will be an open-label, randomized, period balanced, replicate, four-period crossover study. Each subject will participate in four study sessions, separated by at least three days each. Subjects will receive a single dose of the new suspension formulation in two study sessions and a single dose of the standard suspension formulation in the other two study sessions:

Regimen Code

Study Medication



4.1 Method of Randomization

A randomization schedule will be prepared prior to the start of the study by Clinical Pharmacology Statistics and Data Sciences, using the Coding Memo System. Subjects will be randomly allocated to receive one of two possible sequences (ABAB and BABA) in a 1:1 ratio. The formulations will be:

Regimen Code

Study Medication



5 Study Population

5.1 Number of Subjects

Thirty-six subjects will be enrolled so that a minimum of 30 subjects complete the study. Only subjects who the primary or sub-investigators believe will be able to comply with the requirements of the protocol should be included in the study. An attempt will be made to enroll equal number of male and female subjects.


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5.2 Eligibility Criteria

5.2.1 Inclusion Criteria

A subject will be considered eligible for inclusion in this study only if all of the following criteria apply:

1. Healthy adult males and non-pregnant, non-lactating females who are between 18 and 60 years of age, inclusive.

2. Body weight ≥50 kg and within ±35% ideal weight based on gender, height and body frame.(Appendix 2)

5.2.2 Exclusion Criteria

A subject will not be eligible for inclusion in this study if any of the following criteria apply:

1. History of phenylketonuria (PKU) (i.e., subjects on phenylalanine restricted diet)

2. Any condition (including a history of hypersensitivity or allergy to β-lactam antibiotics or any component of the formulation or a history of Augmentin associated cholestatic jaundice or hepatic dysfunction) which, in the opinion of the investigator, contraindicates the administration of Augmentin .

3. The presence of any clinically significant and relevant abnormality identified on the screening medical assessment or laboratory examination

4. Positive urine drug/alcohol screen

5. History of regular alcohol consumption exceeding 7 drinks/week for women or 14 drinks/week for men (1 drink = 5 ounces of wine or 12 ounces of beer or 1.5 ounces of hard liquor) within 6 months of screening

6. Treatment with an investigational drug within 30 days or 5 half-lives (whichever is longer) preceding the first dose of study medication

7. Pregnant or nursing women; women of childbearing potential who are unwilling or unable to use an appropriate method of contraception as outlined in Section 6.1.(Contraception) from at least 14 days prior to study medication administration until completion of follow-up procedures


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8. Use of prescription (other than oral contraceptives, thyroid replacement therapy and hormone replacement therapy) or non-prescription drugs (other than acetaminophen in doses ≤ 2 grams/day and multivitamins), herbal and dietary supplements within seven days or 5 half-lives (whichever is longer) prior to the first dose of study medication. Use of injectable progesterone, progestin subdermal implants, progesterone-releasing IUDs, and postcoital contraception methods and within seven days or 5 half-lives (whichever is longer) prior to the first dose of study medication is prohibited. Depo-Provera must be discontinued at least 6 months prior to the first dose of study medication.

9. Donation of blood in excess of 500 mL within 56 days prior to dosing

10. History of sensitivity to heparin or heparin-induced thrombocytopenia

5.2.3 Other Eligibility Criteria Considerations

To assess any potential impact on subject eligibility with regard to safety, the investigator must refer to the following document(s) for detailed information regarding warnings, precautions, contraindications, adverse events, and other significant data pertaining to the investigational product(s) being used in this study: see Appendix 6.

6 Study Assessments and Procedures

Subjects will be required to stay in the for approximately 14 hours during each study session.

On the first day of each study session, subjects will report to the at approximately 07:00 following an overnight fast of at least

8 hours.

Prior to dosing, an intravenous cannula for collection of blood samples may be inserted into one antecubital vein and kept patent with a dilute heparin solution (≤ 100 U/mL) for up to 14 hours.


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Procedures to be performed are listed in the following table:

Study Procedures

Procedures Time (Hours from Morning Dosing)

Review of prior (Session 1 only) or Concomitant medications

Predose

Review of medical history (Session 1 only) Predose Blood (approximately 6 mL) and urine samples

for clinical laboratory tests (4-hour fast)AB [Appendix 4]

Predose

Study medication administration with 240 mL of water*

0 hour (approximately 8:00 AM)

Meals (breakfast, lunch, dinner)** 5 minutes, 5, and 10 hour after dosing

Baseline signs/symptoms or Adverse Experiences#

Predose and at 5 minutes, 5, 10, and 12 hours after dosing

Blood samples for pharmacokinetics (approximately 3 mL)##

Predose and at 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 10, and 12 hours after dosing

* Study medication will be administered as 5 mL of 600 mg amoxicillin/ 42.9 mL clavulanate per 5 mL oral suspension ** Meals will be standardized across sessions.

# Adverse events will be assessed by asking a non-leading question such as "How do you feel?" ## Blood samples for PK analysis will be collected in EDTA tubes A Clinical chemistry, hematology, and urinalysis will be obtained prior to dosing during study session 1. B A serum β-hCG for women will be obtained prior to dosing in all study sessions. Results of the serum β-hCG test will be reported prior to dosing with study medication. A urine drug/alcohol screen will also be obtained prior to dosing during each session. Results of the urine drug/alcohol screen are not required to be reported prior to dosing with study medication

Subjects will be discharged from the unit following completion of procedures at 12 hours post-dose.

There will be an interval of at least three days between study sessions. All study sessions will be conducted identically as described above.


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6.1 Demographic and Baseline Assessments

6.1.1 Screening Visit

Subjects will be screened within 30 days prior to administration of study medication to confirm that they meet the entrance criteria for the study. The study investigator or a sub-investigator will discuss with each subject the nature of the study, its requirements, and its restrictions. Written informed consent must be obtained prior to performance of any protocol specific procedures. The following procedures will be performed:

• A medical history (including a gynecological history for women and contraceptive practices where indicated)

• Complete medication history of all drugs taken at least 30 days prior to screening procedures

• A history of alcohol use

• Standard 12-lead electrocardiogram (ECG) (if not completed within previous 6 months)

• Physical examination including height and weight, blood pressure and heart rate

• Following at least a 4 hour fast, blood (approximately 15 mL) and urine specimens for clinical laboratory safety tests (Appendix 4) will be collected, in addition to the following:

• Serum beta-human chorionic gonadotropin (β-hCG) for all females

• Urine drug/alcohol screen

• HIV Test

• Hepatitis B and C Test

• Follicle stimulating hormone (FSH) and estradiol levels for postmenopausal women

To prepare for study participation, subjects will be instructed on the use of Concomitant Medications (Section 7) and Lifestyle Guidelines (Section 6.1.2).


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Subjects previously screened for another study may participate in this study provided they meet the entry criteria outlined above. In such situations, written consent for this study will be obtained prior to any protocol-specified procedures being performed. Screening data from the previous study will be considered sufficient to satisfy the requirements of this study, and only those procedures required by this protocol, but not performed for the other study, will be done. All screening data must be obtained within 30 days prior to administration of study medication, as stipulated above.

6.1.2 Lifestyle Guidelines

Meals and Dietary Restrictions

• Subjects must fast from all food and drink at least 4 hours prior to any laboratory safety evaluations and 8 hours prior to the start of pharmacokinetic collections. Water is permitted until 1 hour prior to study drug administration.

• Water and soft drinks or fruit juices (except grapefruit juice) may be consumed ad libitum after dosing.

• Breakfast will be provided immediately (i.e. within 5 minutes) after dosing. Subjects will be required to consume the entire meal within 30 minutes.

• Lunch will be provided approximately 5 hours after dosing.

• Dinner will be provided at approximately 9 to 10 hours after dosing.

Meals will be standardized across sessions.

Alcohol and Tobacco

• During each dosing session, subjects will abstain from alcohol for 24 hours prior to the start of dosing until collection of the final pharmacokinetic sample during each session.

• Subjects who use tobacco products will be instructed that use of nicotine-containing products will not be permitted for 12 hours prior to dosing and until collection of the final pharmacokinetic sample during each session.


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Activity

Subjects will abstain from strenuous exercise for 24 hours prior to each blood collection for clinical laboratory tests. Subjects may participate in light recreational activities (e.g., watch television, read).

6.1.3 Contraception

Women of childbearing potential include the following:

• Post-menopausal females who have been amenorrheic for less than 1 year

• Pre-menopausal females without a documented hysterectomy

Appropriate contraceptive methods for female subjects of childbearing potential include one of the following:

1. Abstinence

2. One (1) of the following methods:

• documented tubal ligation

• documented placement of a copper-containing intrauterine device (IUD)

• condom and diaphragm with spermicidal foam/gel/film/cream/suppository

• condom with spermicidal foam/gel/film/cream/suppository

Female subjects who are taking oral contraceptives must adhere to the contraceptive requirements listed above. Appropriate contraception must be used by females for at least 14 days prior to the first dose of study medication and continue until completion of follow-up procedures.

6.1.4 Follow-up Visit

A follow–up visit will occur 24 hours after dosing in session 4. At follow-up, the following will occur:

• Information regarding the use of concomitant medication or the occurrence of adverse events will be obtained

• Following at least a 4 hour fast, blood (approximately 6-8 mL) and urine specimens will be obtained for clinical laboratory tests (Appendix 4).


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Following completion of the follow up procedures listed above, all male subjects will be discharged from the study. Female subjects will be asked to return to the unit 10-14 days after completion of study session 4 for a serum pregnancy test. Female subjects will then be discharged from the study.

6.2 Safety

All subjects who receive at least one dose of study medication will be included in the evaluation of clinical safety and tolerability. Blood pressure, pulse rate, and clinical laboratory data will be reviewed and summarized on an ongoing basis during the study to evaluate the safety of subjects. Any clinically relevant abnormalities or values of potential clinical concern will be described. Safety data will be presented in tabular and/or graphical format and summarized descriptively.

6.2.1 Pregnancy

Subjects who become pregnant during the study should discontinue the study immediately. The subject will receive counseling from the primary investigator or their designate regarding the nature of the study medication and the potential risk on fetal development.

6.2.1.1 Pregnancy Testing

At screening, prior to dosing with study medication during each study session and at follow-up, women will be tested for serum β-hCG. Results will be obtained prior to dosing during each session. In the case of a positive serum β-hCG test the subject will be withdrawn from the study and follow-up will be conducted as appropriate.

6.2.1.2 Time Period for Collecting Pregnancy Information

Details of all pregnancies in subjects that occur during the treatment and the follow-up period must be documented and reported to GSK. In addition any pregnancies brought to the attention of the investigator after this period, and where it is known that study medication was taken at the time of conception, must also be reported.

Any pregnancies identified during the screening phase/prior to study medication administration do not need to be collected.


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6.2.1.3 Action to be Taken if Pregnancy Occurs

The investigator, or his/her designee, will collect pregnancy information on any female subject who becomes pregnant while participating in this study. The investigator, or his/her designee, will record pregnancy information on the appropriate form and submit it to GSK within 2 weeks of learning of a subject’s pregnancy. The subject will also be followed to determine the outcome of the pregnancy. Information on the status of the mother and child will be forwarded to GSK. Generally, follow-up will be no longer than 6 to 8 weeks following the estimated delivery date. Any premature termination of the pregnancy will be reported.

While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication or elective termination of a pregnancy for medical reasons will be recorded as an AE or a SAE, as described in Section 10.6, "Recording of AEs and SAEs" and will be followed as described in Section 10.8, "Follow-up of AEs and SAEs."

A spontaneous abortion is always considered to be a SAE and will be reported as described in Section 10, “Adverse Events (AE) and Serious Adverse Events (SAE).” Furthermore, any SAE occurring as a result of a post-study pregnancy and is considered reasonably related to the investigational product by the investigator, will be reported to GSK as described in Section 10.11, "Post-study AEs and SAEs." While the investigator is not obligated to actively seek this information in former study participants, he/she may learn of an SAE through spontaneous reporting.

6.3 Pharmacokinetics

6.3.1 Sample Preparation

On each dosing day approximately 3.0 mL blood samples will be collected into EDTA tubes at pre-dose, and at 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 10 and 12 hours after the administration of study medication. As soon as possible after collection, blood samples will be centrifuged for 10 minutes at approximately 4º C. The resultant plasma will be divided into two aliquots of equal volume and placed in plain polypropylene tubes. Sample tubes labels should include study number (BRL 25000/643), subject number, session, and nominal time of sample collection. In addition, tubes will also be labeled either “amox” (for plasma amoxicillin concentration determination) or “clav” (for


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plasma clavulanate concentration determination). The plasma aliquots will be stored at -70°C until time of shipment.

6.3.2 Assay Methodology

Plasma samples taken for the measurement of amoxicillin and clavulanate concentrations will be stored at -70°C until time of analysis. The plasma samples will be assayed under the management of the Department of Worldwide Bioanalysis, DMPK, Glaxo SmithKline Pharmaceuticals. All drug analysis data will be stored in the GLP archives, Glaxo SmithKline Pharmaceuticals, R&D.

6.3.3 Planned Pharmacokinetic Evaluation

Plasma concentration-time data for amoxicillin and clavulanate will be tabulated and plotted for each subject for each treatment regimen. From the concentration-time data, the following pharmacokinetic parameters will be determined for both amoxicillin and clavulanate if data permit: Maximum observed plasma concentration (Cmax), time to Cmax (Tmax), and area under the plasma concentration-time curve (AUC). Pharmacokinetic parameters will be summarized descriptively.

All pharmacokinetic data will be stored in the GLP archives, Glaxo SmithKline Pharmaceuticals, R&D.

7 Investigational Product

7.1 Description of Investigational Product

The study medication will be supplied by the GlaxoSmithKline Pharmaceuticals.

Two formulations of Augmentin will be provided:


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INGREDIENT

Original Formulation (mg/5 mL)

Strawberry/CMC Formulation (mg/5mL)

*Amoxicillin Trihydrate 600.000 697.674

600.000 697.674

*Clavulanate Potassium/Silicon Dioxide 1:1 Blend

42.900 113.005 (includes 8% overage)

42.900 113.005 (includes 8% overage)

Xanthan Gum, NF 12.500 3.000 Aspartame, NF 12.500 12.500 **Silicon Dioxide, NF 86.336 92.821 Succinic Acid, Food Grade (Milled) 0.835 - Colloidal Silicon Dioxide, NF 25.000 35.00 Hydroxypropyl Methylcellulose, 2910, 5cps , USP

79.650 -

Sodium Carboxymethylcellulose, NF - 30.00 Orange Flavor # 249792 15.000 - Orange Flavor # 9/79J839 11.250 - Golden Syrup Flavor # 52.927/APO5.51 23.750 - Raspberry Flavor # DYO4447 22.500 - Strawberry Flavor - 26.0 Total Dry Powder Fill Weight per Dose 1100 1010 * Based on amoxicillin trihydrate at 86% amoxicillin (free acid) content and clavulanate potassium/silicon dioxide 1:1 blend at 41% clavulanic acid content. ** The quantity of silicon dioxide is adjusted per the amoxicillin trihydrate and clavulanate potassium/silicon dioxide blend active contents in order to maintain a constant dose weight

Both the reformulated and the standard Augmentin oral suspension formulations will be supplied in 240 mL HDPE bottles.

7.2 Dosage and Administration

In each session, subjects will receive a single dose of one of the two formulations. Each formulation will be administered during two study sessions according to the randomization schedule.

The study medication (5 mL volume in an oral syringe) will be administered orally, at approximately 08:00. Following this, approximately 5-6 mL tepid water will be drawn into the oral syringe and the liquid administered. Flushing the syringe is necessary to ensure that the full dose of the study medication is administered. Subjects will be asked to drink approximately 240 mL tepid water (in total) with each dose of study medication. A light breakfast (muffin or bagel, fruit juice) will be served immediately (i.e., within 5 minutes) following the


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administration of the study medication. Subjects will be required to consume the entire meal within 30 minutes. Breakfast will be standardized across sessions.

7.3 Dose Rationale

The maximum total dose of amoxicillin (600 mg) and clavulanate is within approved product label for Augmentin and is adequate to assess the pharmacokinetic parameters of both components. The daily therapeutic dose extends up to 12 g of amoxicillin and 1200 mg clavulanate intravenously and oral doses of 2-3 g are indicated for prophylaxis of endocarditis [2].

7.4 Blinding

Treatments will not be blinded.

7.5 Treatment Assignment

Subjects will be assigned to study treatment in accordance with the randomization schedule prepared prior to the study start by Clinical Pharmacology Statistics and Data Sciences using the Coding Memo System.

7.6 Packaging and Labeling

The contents of the label will be in accordance with all applicable regulatory requirements.

Each bulk bottle will be labeled with the protocol number (BRL 25000/643), drug

name (Augmentin ), strength (600/42.9 mg per 5 mL), dosage form (powder for reconstitution), directions for reconstitution, quantity, storage conditions, directions (“Dispense as Directed”), caution statement, GSK address, batch number, and phenylketonuria warning statement.

7.7 Preparation

Each subject’s study medication will be prepared using the bulk supply of

Augmentin , on the morning of dosing.

Directions for reconstitution:

Tap each bottle until all the powder flows freely. Add approximately 2/3 of the total volume (see below) of water for reconstitution and shake vigorously to suspend the powder. Add the remainder of the water and shake vigorously.


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Standard Augmentin pediatric oral suspension (600 mg/42.9 mg in 5 mL) – Add 130 mL of water to each bottle to make up a final volume of 150 mL.

Reformulated Augmentin pediatric oral suspension (600 mg/42.9 mg in 5 mL) – Add 135 of water to each bottle to make up a final volume of 150 mL.

Each dose (5 mL of the 600 mg amoxicillin/42.9 mg clavulanate per 5 mL suspension) will be drawn into an oral syringe. The syringe will be labeled with the study number (BRL 25000/643), subject number, Regimen Code (“A” or “B”) and Study Session.

Any unused reconstituted study medication will be discarded after the doses for the individual subjects being dosed on each day are prepared.

7.8 Handling and Storage

Investigational product must be dispensed or administered according to procedures described herein. Only subjects enrolled in the study may receive investigational product, in accordance with all applicable regulatory requirements. Only authorized site staff may supply or administer investigational product. All investigational products must be stored in a secure area with access limited to the investigator and authorized site staff and under physical conditions that are consistent with investigational product-specific requirements.

The un-reconstituted bottles of dry powder can be stored at controlled room temperature (20-25°C or 68-77°F). Once reconstituted, the bottles must be stored in the refrigerator (2-8°C ) and for no longer than 10 days. Any pre-filled dosing syringes must be stored in the refrigerator.

7.9 Product Accountability

The investigator or pharmacist is responsible for investigational product accountability, reconciliation, and record maintenance. In accordance with all applicable regulatory requirements, the investigator or designated site staff must maintain investigational product accountability records throughout the course of the study. This person(s) will document the amount of investigational product received from GSK, the amount supplied and/or administered to and returned by subjects, if applicable. The investigator or pharmacist is responsible for storing all study medication securely and according to the conditions specified in the protocol to ensure that the drugs retain their safety and potency for the duration of their assigned shelf-life.


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7.10 Assessment of Compliance

Study medication will be administered under the supervision of the study personnel. The oral syringe used for study drug administration will be flushed with water to ensure that the entire dose is administered.

7.11 Treatment of Investigational Product Overdose

An overdose is defined as an excessive dose taken by a subject, either accidentally or intentionally, irrespective of whether it involves study medication or non-study medication. Overdose may be suspected or confirmed and may or may not be associated with clinical signs and symptoms.

It would include, but not be limited to those events which based on the investigators clinical judgement were considered to be of medical concern and/or require clinical observation and/or medical intervention.

As a guide, an overdose would include any dose greater than the highest daily dose included in the protocol or prescribing information (for marketed products).

Minor deviations to study drug administration (i.e., resulting from poor subject compliance) must be recorded as study medication compliance and not as serious AEs.

Reporting of Overdose

For all overdoses the Serious AE form must be completed and reported within 24 hours as for any other serious AE (see Section 9). The documentation must include details of any associated signs/symptoms or if the overdose is asymptomatic this must be stated.

Further Information on Overdose

For further information of any known signs or symptoms of overdosage and appropriate treatment, together with details of any antidote, if known, refer to protocol/Investigator Brochure or the product label.

7.12 Occupational Safety

Investigational product is not expected to pose significant occupational safety risk to site staff under normal conditions of use and administration. A Material Safety Data Sheet (MSDS) describing occupational hazards and recommended handling


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precautions either will be provided to the investigator, where this is required by local laws, or is available upon request from GSK.

However, precautions are to be taken to avoid direct skin contact, eye contact, and generating aerosols or mists. In the case of unintentional occupational exposure, treat as if the substance contains the active pharmaceutical even though it is absent from placebo formulations, and notify the monitor at

Study personnel with a known allergy to penicillins should avoid contact with study medication. Skin contact with study medication may result in irritation and allergic reactions with symptoms such as itching, redness, or swelling. If occupational skin contact occurs, the contaminated area should be washed thoroughly.

Inhalation of the product could also result in an allergic reaction with symptoms such as rhinitis, sneezing, itching, or symptoms similar to asthma such as coughing, wheezing, or difficulty breathing. There are no specific first aid recommendations for allergic reactions resulting from occupational inhalation of the study medication.

Ingestion of study medication may result in nausea, stomach discomfort, diarrhea, sore or dry mouth, or sore tongue. Life-threatening anaphylactic reactions have occurred in sensitive individuals. In the event of occupational ingestion, medical advice should be sought. Induction of vomiting is not a recommended first-aid procedure.

8 Concomitant Medications and Non-Drug Therapies

Any medications the subject received within 7 days prior to dosing of study medications will be recorded as a prior medication. Subjects will abstain from using prescription (other than contraceptives, hormone replacement therapy and thyroid replacement therapy) or non-prescription drugs (other than acetaminophen at doses of ≤ 2 grams/day and multivitamins), and herbal and dietary supplements within 7 days or 5 half-lives (whichever is longer) prior to the first dose of study medication and throughout the study. All concomitant medication taken during the study must be recorded with indication, daily dose, and start and stop dates of administration in the CRF.


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9 Subject Completion and Withdrawal

9.1 Subject Completion

Subjects who participate in all study sessions will be considered as having completed the study. Subjects for whom safety laboratory and pharmacokinetic specimens have been collected at each study session will be considered as being evaluable subjects.

9.2 Subject Withdrawal

9.2.1 Subject Withdrawal from Study

A subject may withdraw from the study at any time at their own request, or they may be withdrawn at any time at the discretion of the investigator for safety, behavioral, or administrative reasons.

9.2.2 Subject Withdrawal from Investigational Product

Subjects who withdraw from the study following administration of study medication will not be replaced. If the subject should withdraw following administration of study medication but prior to study completion, all follow-up procedures should be performed, if possible. If a subject is withdrawn from the study prior to administration of study medication in Session 1 only for any reason, that individual may be replaced with another subject who will be assigned to the same randomization schedule as the individual who was withdrawn.

10 Adverse Events (AE) and Serious Adverse Events (SAE)

The investigator is responsible for the detection and documentation of events meeting the criteria and definition of an AE or SAE as provided in this protocol. During the study, when there is a safety evaluation, the investigator or site staff will be responsible for detecting AEs and SAEs, as detailed in this section of the protocol.

10.1 Definition of an AE

Any untoward medical occurrence in a patient or clinical investigation subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product.


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An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. For marketed medicinal products, this also includes failure to produce expected benefits (i.e. lack of efficacy), abuse or misuse.

Examples of an AE include:

• Significant or unexpected worsening or exacerbation of the condition/indication under study. See Section 10.3, “Lack of Efficacy”, for additional information.

• Exacerbation of a chronic or intermittent pre-existing condition including either an increase in frequency and/or intensity of the condition.

• New conditions detected or diagnosed after investigational product administration even though it may have been present prior to the start of the study.

• Signs, symptoms, or the clinical sequelae of a suspected interaction.

• Signs, symptoms, or the clinical sequelae of a suspected overdose of either investigational product or a concurrent medication (overdose per se should not be reported as an AE/SAE).

• Significant failure of expected pharmacological or biological action. See Section 10.3, “Lack of Efficacy” for additional information.

Examples of an AE do not include a/an:

• Medical or surgical procedure (e.g., endoscopy, appendectomy); the condition that leads to the procedure is an AE.

• Situations where an untoward medical occurrence did not occur (social and/or convenience admission to a hospital).

• Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or detected at the start of the study that do not worsen.

• The disease/disorder being studied, or expected progression, signs, or symptoms of the disease/disorder being studied, unless more severe than expected for the subject’s condition.


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For GSK clinical studies, AEs may include pre- or post-treatment events that occur as a result of protocol-mandated procedures (i.e., invasive procedures, modification of subject’s previous therapeutic regimen).

10.2 Definition of a SAE

A serious adverse event is any untoward medical occurrence that, at any dose:

a) results in death.

b) is life-threatening.

NOTE: The term ’life-threatening’ in the definition of ’serious’ refers to an event in which the subject was at risk of death at the time of the event. It does not refer to an event, which hypothetically might have caused death, if it were more severe.

c) requires hospitalization or prolongation of existing hospitalization.

NOTE: In general, hospitalization signifies that the subject has been detained (usually involving at least an overnight stay) at the hospital or emergency ward for observation and/or treatment that would not have been appropriate in the physician’s office or out-patient setting. Complications that occur during hospitalization are AEs. If a complication prolongs hospitalization or fulfills any other serious criteria, the event is serious. When in doubt as to whether “hospitalization” occurred or was necessary, the AE should be considered serious.

Hospitalization for elective treatment of a pre-existing condition that did not worsen from baseline is not considered an AE.

d) results in disability/incapacity,

NOTE: The term disability means a substantial disruption of a person’s ability to conduct normal life functions. This definition is not intended to include experiences of relatively minor medical significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, and accidental trauma (e.g. sprained ankle) which may interfere or prevent everyday life functions but do not constitute a substantial disruption.

e) is a congenital anomaly/birth defect.


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f) Medical or scientific judgement should be exercised in deciding whether reporting is appropriate in other situations, such as important medical events that may not be immediately life-threatening or result in death or hospitalization but may jeopardize the subject or may require medical or surgical intervention to prevent one of the other outcomes listed in the above definition. These should also be considered serious. Examples of such events are invasive or malignant cancers, intensive treatment in an emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions that do not result in hospitalization, or development of drug dependency or drug abuse.

10.3 Lack of Efficacy

“Lack of efficacy” per se will not be reported as an AE. The signs and symptoms or clinical sequelae resulting from lack of efficacy will be reported if they fulfill the AE or SAE definition (including clarifications).

10.4 Clinical Laboratory Abnormalities and Other Abnormal Assessments as AEs and SAEs

Abnormal laboratory findings (e.g., clinical chemistry, hematology, urinalysis) or other abnormal assessments (e.g., ECGs, vital signs) that are judged by the investigator as clinically significant will be recorded as AEs or SAEs if they meet the definition of an AE, as defined in Section 10.1 ("Definition of an AE"), or SAE, as defined in Section 10.2 ("Definition of a SAE"). Clinically significant abnormal laboratory findings or other abnormal assessments that are detected during the study or are present at baseline and significantly worsen following the start of the study will be reported as AEs or SAEs. However, clinically significant abnormal laboratory findings or other abnormal assessments that are associated with the disease being studied, unless judged by the investigator as more severe than expected for the subject’s condition, or that are present or detected at the start of the study and do not worsen, will not be reported as AEs or SAEs.

The investigator will exercise his or her medical and scientific judgment in deciding whether an abnormal laboratory finding or other abnormal assessment is clinically significant.


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10.5 Time Period, Frequency, and Method of Detecting AEs and SAEs

Soliciting of Adverse Events

As a consistent method of soliciting AEs, the subject should be asked a non-leading question such as: "How do you feel?"

Any pre-existing conditions or signs and/or symptoms present in a subject prior to the start of the study (i.e., before informed consent) should be recorded as Medical/Surgical History. In addition, any medical occurrence which is reported after informed consent is obtained but prior to starting active or randomized treatment (i.e., Day 1 of Session 1) will be documented as Medical/Surgical History.

Any signs and symptoms present at the time the first dose is administered will be documented as baseline signs and symptoms.

All AEs occurring after administration of the first dose of study medication and on or before the final visit must be reported as Adverse Events. All AEs must be recorded irrespective of whether they are considered drug related.

At each visit/assessment in the period defined above, AEs will be evaluated by the investigator and recorded.

Any AEs already documented at a previous assessment and designated as ongoing, should be reviewed at subsequent visits as necessary. If these have resolved, this should be documented. If an AE changes in intensity/frequency then this should be recorded as a separate event (i.e., a new record started).

For studies in which there is a delay of greater than 30 days between dosing, and during this time no protocol specific procedures are required, AEs will be recorded for a period of 30 days only after each dosage administration.

10.6 Recording of AEs and SAEs

When an AE/SAE occurs, it is the responsibility of the investigator to review all documentation (e.g., hospital progress notes, laboratory, and diagnostics reports) relative to the event. The investigator will then record all relevant information regarding an AE/SAE on the CRF. It is not acceptable for the investigator to send photocopies of the subject’s medical records to GSK in lieu of completion of the appropriate AE/SAE CRF pages. However, there may be instances when copies


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of medical records for certain cases are requested by GSK. In this instance, all subject identifiers will be blinded on the copies of the medical records prior to submission to GSK.

The investigator will attempt to establish a diagnosis of the event based on signs, symptoms, and/or other clinical information. In such cases, the diagnosis should be documented as the AE/SAE and not the individual signs/symptoms.

10.7 Evaluating AEs and SAEs

10.7.1 Assessment of Intensity

The investigator will make an assessment of intensity for each AE and SAE reported during the study. The assessment will be based on the investigator’s clinical judgement. The intensity of each AE and SAE recorded in the CRF should be assigned to one of the following categories:

Mild: An event that is easily tolerated by the subject, causing minimal discomfort and not interfering with everyday activities.

Moderate: An event that is sufficiently discomforting to interfere with normal everyday activities.

Severe: An event that prevents normal everyday activities.

An AE that is assessed as severe should not be confused with a SAE. Severity is a category utilized for rating the intensity of an event; and both AEs and SAEs can be assessed as severe. An event is defined as ‘serious’ when it meets one of the pre-defined outcomes as described in Section 10.2, “Definition of a SAE”.

10.7.2 Assessment of Causality

The investigator is obligated to assess the relationship between investigational product and the occurrence of each AE/SAE. The investigator will use clinical judgement to determine the relationship. Alternative causes, such as natural history of the underlying diseases, concomitant therapy, other risk factors, and the temporal relationship of the event to the investigational product will be considered and investigated. The investigator will also consult the CIB/IB and/or Product Information, for marketed products, in the determination of his/her assessment.


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There may be situations when an SAE has occurred and the investigator has minimal information to include in the initial report to GSK. However, it is very important that the investigator always make an assessment of causality for every event prior to transmission of the SAE CRF to GSK. The investigator may change his/her opinion of causality in light of follow-up information, amending the SAE CRF accordingly. The causality assessment is one of the criteria used when determining regulatory reporting requirements.

Causality should be assessed using the following categories:

Not related: The AE is definitely not related to the drug.

Unlikely: There are other, more likely causes and the drug is not suspected as a cause.

Suspected (reasonable possibility): A direct cause and effect relationship between the drug and the AE has not been demonstrated but there is a reasonable possibility that the event was caused by the drug.

Probable: There is a probable direct cause and effect relationship between the AE and the study drug.

10.8 Follow-up of AEs and SAEs

After the initial AE/SAE report, the investigator is required to proactively follow each subject and provide further information to GSK on the subject’s condition.

All AEs and SAEs documented at a previous visit/contact and are designated as ongoing, will be reviewed at subsequent visits/contacts.

All AEs and SAEs will be followed until resolution, until the condition stabilizes, until the event is otherwise explained, or until the subject is lost to follow-up. Once resolved, the appropriate AE/SAE CRF page(s) will be updated. The investigator will ensure that follow-up includes any supplemental investigations as may be indicated to elucidate the nature and/or causality of the AE or SAE. This may include additional laboratory tests or investigations, histopathological examinations, or consultation with other health care professionals.

GSK may request that the investigator perform or arrange for the conduct of supplemental measurements and/or evaluations to elucidate as fully as possible the nature and/or causality of the AE or SAE. The investigator is obligated to assist. If a subject dies during participation in the study or during a recognized


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follow-up period, GSK will be provided with a copy of any post-mortem findings, including histopathology.

New or updated information will be recorded on the originally completed “SAE” CRF, with all changes signed and dated by the investigator. The updated SAE CRF should be resent to GSK within the time frames outlined in Section 10.9.

10.9 Prompt Reporting of SAEs to GSK

SAEs will be reported promptly to GSK as described in the following table once the investigator determines that the event meets the protocol definition of an SAE.

10.9.1 Timeframes for Submitting SAE Reports to GSK

Initial SAE Reports Follow-up Information on a Previously Reported SAE

Type of SAE Time Frame Documents Time Frame Documents

All SAEs 24 hrs "SAE" CRF pages

24 hrs Updated "SAE" CRF pages

10.9.2 Completion and Transmission of the SAE Reports

Once an investigator becomes aware that an SAE has occurred in a study subject, she/he will report the information to GSK within 24 hours as outlined in Section 10.9, “Prompt Reporting of SAEs to GSK”. The SAE CRF will always be completed as thoroughly as possible with all available details of the event, signed by the investigator (or designee), and forwarded to GSK within the designated time frames. If the investigator does not have all information regarding an SAE, he/she will not wait to receive additional information before notifying GSK of the event and completing the form. The form will be updated when additional information is received.

The investigator will always provide an assessment of causality at the time of the initial report as described in Section 10.7.2, “Assessment of Causality”.

Facsimile transmission of the “SAE” CRF is the preferred method to transmit this information to the project contact for SAE receipt. In rare circumstances and in the absence of facsimile equipment, notification by telephone is acceptable, with a copy of the "SAE" CRF sent by overnight mail. Initial notification via the telephone does not replace the need for the investigator to complete and sign the


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SAE CRF within the time frames outlined in Section 10.9, “Prompt Reporting of SAEs to GSK”.

GSK study contact: MD Telephone number: (8:30 AM - 5:00 PM ET, Mon.-Fri.) Facsimile number: Alternative GSK contact: physician on call Telephone number: (8:30 AM - 5:00 PM ET, Mon.-Fri.) Facsimile number: Emergency 24 hour medical contact: physician on call Telephone number:

10.10 Regulatory Reporting Requirements for SAEs

The investigator will promptly report all SAEs to GSK in accordance with the procedures detailed in Section 10.9, "Prompt Reporting of SAEs to GSK." GSK has a legal responsibility to notify, as appropriate, both the local regulatory authority and other regulatory agencies about the safety of a product under clinical investigation. Prompt notification of SAEs by the investigator to the appropriate project contact for SAE receipt is essential so that legal obligations and ethical responsibilities towards the safety of other subjects are met.

The investigator, or responsible person according to local requirements, will comply with the applicable local regulatory requirements related to the reporting of SAEs to regulatory authorities and the Institutional Review Board (IRB)/Independent Ethics Committee (IEC).

This protocol has been filed under an Investigational New Drug (IND) application with the US Food and Drug Administration (FDA). A given SAE may qualify as an IND Safety Report if the SAE is both attributable to the investigational product and unexpected. In this case, all investigators filed to the IND (and associated INDs for the same compound) will receive an Expedited Investigator Safety Report (EISR), identical in content to the IND Safety Report submitted to the FDA.

EISRs are prepared according to GSK policy and are forwarded to investigators as necessary. An EISR is prepared for a SAE that is both attributable to investigational product and unexpected. The purpose of the EISR is to fulfill


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specific regulatory and Good Clinical Practice (GCP) requirements, regarding the product under investigation.

When a site receives from GSK an Initial or Follow-up EISR or other safety information (e.g., revised Clinical Investigator’s Brochure/Investigator’s Brochure), the responsible person according to local requirements is required to promptly notify his or her IRB or IEC.

10.11 Post-Study AEs and SAEs

A post-study AE/SAE is defined as any event that occurs outside of the AE/SAE detection period defined in Section 10.5, “Time Period, Frequency, and Method of Detecting AEs and SAEs”, of the protocol.

Investigators are not obligated to actively seek AEs or SAEs in former study participants. However, if the investigator learns of any SAE, including a death, at any time after a subject has been discharged from the study, and he/she considers the event reasonably related to the investigational product, the investigator will promptly notify GSK.

10.12 SAEs Related to Study Participation

An SAE considered related to study participation (e.g., procedures, invasive tests, a change in existing therapy), even if it occurs during the pre- or post-treatment period, will be reported promptly to GSK (see Section 10.9, "Prompt Reporting of SAEs to GSK").

11 Data Analysis and Statistical Considerations

Statistical analyses will be performed by, or under the direct auspices of, Clinical Pharmacology Statistics and Data Sciences, GlaxoSmithKline.

11.1 Hypotheses

To demonstrate the bioequivalence of the reformulated Augmentin pediatric suspension with respect to the standard marketed pediatric suspension formulation of Augmentin , point estimates and 90% confidence intervals will be computed for the ratios of AUC and Cmax of the reformulated suspension to standard suspension [1]. Equivalence will be demonstrated if the 90% confidence interval is completely contained within the range 0.80 to 1.25.


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11.2 Treatment Comparisons of Interest

11.2.1 Primary Comparisons of Interest

The primary focus of the statistical analysis is to demonstrate the bioequivalence of the reformulated Augmentin oral suspension with respect to the standard marketed pediatric suspension formulation of Augmentin as measured by AUC and Cmax of both amoxicillin and clavulanate. For both primary endpoints, point estimates and 90% confidence intervals will be computed for the ratio of the reformulated suspension to standard suspension. Equivalence will be demonstrated if the 90% confidence interval is completely contained within the range 0.80 to 1.25 for both AUC and Cmax of both amoxicillin and clavulanate.

11.3 Interim Analysis

No interim analyses are planned.

11.4 Sample Size Considerations

11.4.1 Sample Size Assumptions

Thirty-six subjects will be enrolled into the study to ensure a total of at least 30 evaluable subjects.

Estimates of within-subject coefficients of variation (CV) from Augmentin study 560 are listed in the table below [3].

Amoxicillin Clavulanate Parameter AUC Cmax AUC Cmax CV 15.9% 20.4% 31.1% 35.1%

Using the largest estimate of within-subject variability (35.1%), it is estimated that a sample size of 30 subjects under a replicate design will provide at least 90% power to demonstrate equivalence for AUC and Cmax for both amoxicillin and clavulanate. Equivalence is demonstrated when the 90% confidence interval for the ratio of test:reference (A:B) is completely contained within the range 0.80 to 1.25 for both AUC and Cmax for both amoxicillin and clavulanate. This range represents a symmetric 20% range on the loge-scale. This calculation was based on a two one-sided testing procedure with a type I error rate of 5% and assumes a true ratio of unity.



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11.4.2 Sample Size Sensitivity

A sensitivity analysis was conducted based on an assumption of a true ratio of 1.05, which would indicate an increase of 5% for the reformulation suspension compared to the standard suspension. In this case, a sample size of 30 should provide at least 80% power to demonstrate equivalence for AUC and Cmax for both amoxicillin and clavulanate. This calculation was also based on a two one-sided testing procedure with a type I error rate of 5%.

11.4.3 Sample Size Re-Estimation

No sample size re-estimation is planned for this study.

11.5 Analysis Populations

Subjects will be included in the statistical assessment of bioequivalence should pharmacokinetic data be available for administration of each formulation. Data from subjects not included in the statistical analysis will be listed, and the impact of subjects with incomplete data will be assessed.

All subjects who receive at least one dose of study medication will be evaluable for safety.

11.6 Safety Analysis

All subjects who receive at least one dose of study medication will be included in the evaluation of clinical safety and tolerability. Clinical monitoring and laboratory data will be reviewed by the study physician and will not be formally analyzed. Adverse events will be summarized by formulation. No formal statistical analysis of the safety data will be performed.

11.7 Clinical Pharmacology Data Analyses

11.7.1 Pharmacokinetic Analyses

Following loge-transformation, AUC and Cmax of both amoxicillin and

clavulanate will be analyzed separately by fitting a mixed effects model consistent with the FDA guidelines,[1] including terms for subject, sequence, period and regimen. Point estimates and 90% percent confidence intervals for the difference between formulations (A-B) will be constructed. These will be exponentially backtransformed to obtain point estimates and confidence intervals for the ratio A:B.


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Within-subject variability estimates for each formulation will be calculated for AUC and Cmax for both amoxicillin and clavulanate.

Distributional assumptions underlying these analyses will be assessed by inspection of normal probability plots. Should data indicate that the normality assumption is grossly violated, an appropriate nonparametric procedure will be used to construct 90% confidence intervals, and statistical inference will be based on these results.

The mean value for each subject and formulation will be calculated for Tmax of amoxicillin and clavulanate and then analyzed separately using the Wilcoxon matched pairs method [4]. A point estimate and 95% confidence interval for the median difference between formulations (A-B) will be calculated. The 95% confidence interval will provide a range of plausible values for the difference in Tmax.

Summary statistics will be calculated by session and treatment regimen for all pharmacokinetic parameters. Geometric means and between-subject coefficients of variation will be calculated for the loge-transformed parameters where:

geometric mean = exp(mean on log scale)

between-subject CV = SQRT[exp(S.D. on log scale)2-1] x 100.

12 Study Administration

12.1 Regulatory and Ethical Considerations

12.1.1 Regulatory Authority Approval

GSK will obtain approval to conduct the study from the appropriate regulatory agency in accordance with any applicable country-specific regulatory requirements prior to a site initiating the study in that country.

12.1.2 Ethical Conduct of the Study and Ethics Approval

This study will be conducted in accordance with "good clinical practice" (GCP) and all applicable regulatory requirements, including, where applicable, the Declaration of Helsinki, as amended in South Africa in October, 1996, (Protocol Appendix 3).


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The investigator (or sponsor, where applicable) is responsible for ensuring that this protocol, the site’s informed consent form, and any other information that will be presented to potential subjects (e.g., advertisements or information that supports or supplements the informed consent) are reviewed and approved by the appropriate IEC/IRB. The investigator agrees to allow the IEC/IRB direct access to all relevant documents. The IEC/IRB must be constituted in accordance with all applicable regulatory requirements. GSK will provide the investigator with relevant document(s)/data that are needed for IEC/IRB review and approval of the study. Before investigational product(s) and CRFs can be shipped to the site, GSK must receive copies of the IEC/IRB approval, the approved informed consent form, and any other information that the IEC/IRB has approved for presentation to potential subjects.

If the protocol, the informed consent form, or any other information that the IEC/IRB has approved for presentation to potential subjects is amended during the study, the investigator is responsible for ensuring the IEC/IRB reviews and approves, where applicable, these amended documents. The investigator must follow all applicable regulatory requirements pertaining to the use of an amended informed consent form including obtaining IEC/IRB approval of the amended form before new subjects consent to take part in the study using this version of the form. Copies of the IEC/IRB approval of the amended informed consent form/other information and the approved amended informed consent form/other information must be forwarded to GSK promptly.

12.1.3 Informed consent

Informed consent will be obtained before the subject can participate in the study. The contents and process of obtaining informed consent will be in accordance with all applicable regulatory requirements.

12.1.4 Investigator Reporting Requirements

As indicated in Section 10.10, the investigator (or sponsor, where applicable) is responsible for reporting SAEs to the IEC/IRB, in accordance with all applicable regulations. Furthermore, the investigator may be required to provide periodic safety updates on the conduct of the study at his or her site and notification of study closure to the IEC/IRB. Such periodic safety updates and notifications are the responsibility of the investigator and not of GSK.


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12.2 Study Monitoring

In accordance with applicable regulations, GCP, and GSK procedures, GSK monitors will contact the site prior to the subject enrollment to review the protocol and data collection procedures with site staff. In addition, the monitor will periodically contact the site, including conducting on-site visits. The extent, nature and frequency of on-site visits will be based on such considerations as the study objective and/or endpoints, the purpose of the study, study design complexity, and enrollment rate.

During these contacts, the monitor will:

• Check the progress of the study.

• Review study data collected.

• Conduct source document verification.

• Identify any issues and address their resolution.

This will be done in order to verify that the:

• Data are authentic, accurate, and complete.

• Safety and rights of subjects are being protected.

• Study is conducted in accordance with the currently approved protocol (and any amendments), GCP, and all applicable regulatory requirements.

The investigator agrees to allow the monitor direct access to all relevant documents and to allocate his/her time and the time of his/her staff to the monitor to discuss findings and any relevant issues.

At study closure, monitors will also conduct all activities described in Section 12.4, "Study and Site Closure."

12.3 Quality Assurance

To ensure compliance with GCP and all applicable regulatory requirements, GSK may conduct a quality assurance audit. Regulatory agencies may also conduct a regulatory inspection of this study. Such audits/inspections can occur at any time during or after completion of the study. If an audit or inspection occurs, the investigator and institution agree to allow the auditor/inspector direct access to all


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relevant documents and to allocate his/her time and the time of his/her staff to the auditor/inspector to discuss findings and any relevant issues.

12.4 Study and Site Closure

Upon completion of the study, the monitor will conduct the following activities in conjunction with the investigator or site staff, as appropriate:

• Return of all study data to GSK.

• Data queries.

• Accountability, reconciliation, and arrangements for unused investigational product(s.)

• Review of site study records for completeness.

• Return of treatment codes to GSK.

• Shipment of PK/PD/biomarker/PG samples to assay laboratory(ies).

In addition, GSK reserves the right to temporarily suspend or prematurely discontinue this study either at a single site or at all sites at any time for reasons including, but are not limited to, safety or ethical issues or severe non-compliance. If GSK determines such action is needed, GSK will discuss this with the Investigator (including the reasons for taking such action) at that time. When feasible, GSK will provide advance notification to the investigator of the impending action prior to it taking effect.

GSK will promptly inform all other investigators and/or institutions conducting the study if the study is suspended or terminated for safety reasons, and will also inform the regulatory authorities of the suspension or termination of the study and the reason(s) for the action. If required by applicable regulations, the investigator must inform the IEC/IRB promptly and provide the reason for the suspension or termination.

If the study is prematurely discontinued, all study data must be returned to GSK. In addition, arrangements will be made for all unused investigational product(s) in accordance with the applicable GSK procedures for the study.

Financial compensation to investigators and/or institutions will be in accordance with the agreement established between the investigator and GSK.


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12.5 Records Retention

Following closure of the study, the investigator must maintain all site study records in a safe and secure location. The records must be maintained to allow easy and timely retrieval, when needed (e.g., audit or inspection), and, whenever feasible, to allow any subsequent review of data in conjunction with assessment of the facility, supporting systems, and staff. Where permitted by local laws/regulations or institutional policy, some or all of these records can be maintained in a format other than hard copy (e.g., microfiche, scanned, electronic); however, caution needs to be exercised before such action is taken. The investigator must assure that all reproductions are legible and are a true and accurate copy of the original, and meet accessibility and retrieval standards, including re-generating a hard copy, if required. Furthermore, the investigator must ensure there is an acceptable back-up of these reproductions and that an acceptable quality control process exists for making these reproductions.

GSK will inform the investigator of the time period for retaining these records to comply with all applicable regulatory requirements. The minimum retention time will meet the strictest standard applicable to that site for the study, as dictated by any institutional requirements or local laws or regulations, or GSK standards/procedures; otherwise, the retention period will default to 15 years.

The investigator must notify GSK of any changes in the archival arrangements, including, but not limited to, the following: archival at an off-site facility, transfer of ownership of the records in the event the investigator leaves the site.

12.6 Provision of Study Results and Information to Investigators

When a clinical study report is completed, GSK will provide the major findings of the study to the investigator.

12.7 Data Management

Subject data are collected by the investigator or designee using the Case Report Form (CRF) defined by GSK. Subject data necessary for analysis and reporting will be entered/transmitted into a validated database or data system. Clinical data management will be performed in accordance with applicable GSK standards and data cleaning procedures. Database freeze will occur when data management quality control procedures are completed. Original CRFs will be retained by GSK, while the investigator will retain a copy.


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13 References

1. Guidance for Industry, Statistical Approaches to Establishing Bioequivalence, U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), January 2001

2. 2001. Editions du Vidal. Le Dictionnaire, 77 Edition/pp 177-179. Paris, France: Vidal.

3. BRL-025000/RSD-101BM1/1. A study to demonstrate bioequivalence of a new pediatric suspension formulation of Augmentin (800 mg/57 mg per 5 mL) to the standard pediatric suspension formulation of Augmentin (600 mg/42.9 mg per 5 ml) in healthy volunteers. BSc, PhD, PharmD, MSc, PhD,

BSc, MD*. report in progress.

4. STEINIJANS VW, DILETTI E.. 1983. Statistical Analysis of Bioavailability Studies: Parametric and Nonparametric Confidence Intervals. Eur J Clin Pharmacol, 24, 127-136.


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14 Appendices


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Appendix 1 Schedule of Study Procedures

Screening: medical and medication histories, physical examination, sitting blood pressure and heart rate measurements, standard 12-lead ECG (if not completed within previous 6 months), safety laboratory tests (including HIV and Hepatitis B and C tests), urine drug/alcohol screen and, for all females, a serum pregnancy test as well as FSH and estradiol for all postmenopausal women. [Appendix 4] Study Periods 1, 2, 3 and 4 Time After Dose (Hours) Predose 0 0.08 0.25 0.5 0.75 1 1.5 2 2.5 3 4 5 6 7 8 10 12 Admission to (fasting) X Medical/Medication History* X Meal Served X X X Medication Administration X Clinical lab tests X# Baseline Signs/Symptoms or Adverse Events

X X X X X

PK Blood Samples X X X X X X X X X X X X X X X X Discharge from X * During Study Session 1 only, during subsequent sessions only medication history will be updated. # Clinical Lab Tests obtained prior to dosing during session 1 [Appendix 4]. A serum β-hCG for women will be obtained prior to dosing in all study sessions. Results of the serum β-hCG test will be reported prior to dosing with study medication. A urine drug/alcohol screen will also be obtained prior to dosing during each session. Results of the urine drug/alcohol screen are not required to be reported prior to dosing with study medication. Follow-up: Follow–up visit will occur 24 hours after dosing in session 4. Procedures to be performed at follow up include clinical laboratory tests [Appendix 4]and recording of adverse events/concomitant medications. All male subjects will then be discharged from the study. Females will report to the for a follow up serum pregnancy test 10-14 days following the last dose of study medication.

CO

NF

IDE

NT

IAL

PM

2002/00022/00 B

RL-025000/643

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Appendix 2 Metropolitan Weight Tables

1996 Metropolitan Insurance Company Weight Tables by Height, Size, and Frame

The following are the 1996 Metropolitan Life Insurance Company weight standard tables by height and size of frame (small, medium or large), for people aged 25 to 59, in shoes and wearing five pounds of indoor clothing for men, three pounds for women.

WEIGHT (lbs.) Height Small Medium Large MEN 5’2" 128-134 131-141 138-150 5’3" 130-136 133-143 140-153 5’4" 132-138 135-145 142-156 5’5" 134-140 137-148 144-160 5’6" 136-142 139-151 146-164 5’7" 138-145 142-154 149-168 5’8" 140-148 145-157 152-172 5’9" 142-151 148-160 155-176 5’10" 144-154 151-163 158-180 5’11" 146-157 154-166 161-184 6’0" 149-160 157-170 164-188 6’1" 152-164 160-174 168-192 6’2" 155-168 164-178 172-197 6’3" 158-172 167-182 176-202 6’4" 162-176 171-187 181-207 WOMEN 4’10" 102-111 109-121 118-131 4’11" 103-113 111-123 120-134 5’0" 104-115 113-126 122-137 5’1" 106-118 115-129 125-140 5’2" 108-121 118-132 128-143 5’3" 111-124 121-135 131-147 5’4" 114-127 124-138 134-151 5’5" 117-130 127-141 137-155 5’6" 120-133 130-144 140-159 5’7" 123-136 133-147 143-163 5’8" 126-139 136-150 146-167 5’9" 129-142 139-153 149-170 5’10" 132-145 142-156 152-173 5’11" 135-148 145-159 155-176 6’0" 138-151 148-162 158-179


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Appendix 3 Declaration of Helsinki

Declaration of Helsinki/Elements of Informed Consent

World Medical Association DECLARATION OF HELSINKI

Recommendations Guiding Physicians in Biomedical Research Involving Human Subjects

Adopted by the 18th World Medical Assembly Helsinki, Finland, June 1964

and amended by the 29th World Medical Assembly Tokyo, Japan, October 1975

35th World Medical Assembly Venice, Italy, October 1983

41st World Medical Assembly Hong Kong, September 1989

and the 48th General Assembly

Somerset West, Republic of South Africa, October 1996.

INTRODUCTION

It is the mission of the physician to safeguard the health of the people. His or her knowledge and conscience are dedicated to the fulfillment of this mission.

The Declaration of Geneva of the World Medical Association binds the physician with the words, "The health of my patient will be my first consideration," and the International Code of Medical Ethics declares that, "A physician shall act only in the patient’s interest when providing medical care which might have the effect of weakening the physical and mental condition of the patient."

The purpose of biomedical research involving human subjects must be to improve diagnostic, therapeutic and prophylactic procedures and the understanding of the etiology and pathogenesis of disease.

In current medical practice most diagnostic, therapeutic or prophylactic procedures involve hazards. This applies especially to biomedical research.


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Medical progress is based on research which ultimately must rest in part on experimentation involving human subjects.

In the field of biomedical research a fundamental distinction must be recognized between medical research in which the aim is essentially diagnostic or therapeutic for a patient, and medical research, the essential object of which is purely scientific and without implying direct diagnostic or therapeutic value to the person subjected to the research.

Special caution must be exercised in the conduct of research which may affect the environment, and the welfare of animals used for research must be respected.

Because it is essential that the results of laboratory experiments be applied to human beings to further scientific knowledge and to help suffering humanity, the World Medical Association has prepared the following recommendations as a guide to every physician in biomedical research involving human subjects. They should be kept under review in the future. It must be stressed that the standards as drafted are only a guide to physicians all over the world. Physicians are not relieved from criminal, civil and ethical responsibilities under the laws of their own countries.

I. BASIC PRINCIPLES

1. Biomedical research involving human subjects must conform to generally accepted scientific principles and should be based on adequately performed laboratory and animal experimentation and on a thorough knowledge of the scientific literature.

2. The design and performance of each experimental procedure involving human subjects should be clearly formulated in an experimental protocol which should be transmitted for consideration, comment and guidance to a specially appointed committee independent of the investigator and the sponsor provided that this independent committee is in conformity with the laws and regulations of the country in which the research experiment is performed.


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3. Biomedical research involving human subjects should be conducted only by scientifically qualified persons and under the supervision of a clinically competent medical person. The responsibility for the human subject must always rest with a medically qualified person and never rest on the subject of the research, even though the subject has given his or her consent.

4. Biomedical research involving human subjects cannot legitimately be carried out unless the importance of the objective is in proportion to the inherent risk to the subject.

5. Every biomedical research project involving human subjects should be preceded by careful assessment of predictable risks in comparison with foreseeable benefits to the subject or to others. Concern for the interests of the subject must always prevail over the interest of science and society.

6. The right of the research subject to safeguard his or her integrity must always be respected. Every precaution should be taken to respect the privacy of the subject and to minimize the impact of the study on the subject’s physical and mental integrity and on the personality of the subject.

7. Physicians should abstain from engaging in research projects involving human subjects unless they are satisfied that the hazards involved are believed to be predictable. Physicians should cease any investigation if the hazards are found to outweigh the potential benefits.

8. In publication of the results of his or her research, the physician is obliged to preserve the accuracy of the results. Reports of experimentation not in accordance with the principles laid down in this Declaration should not be accepted for publication.


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9. In any research on human beings, each potential subject must be adequately informed of the aims, methods, anticipated benefits and potential hazards of the study and the discomfort it may entail. He or she should be informed that he or she is at liberty to abstain from participation in the study and that he or she is free to withdraw his or her consent to participation at any time. The physician should then obtain the subject’s freely-given informed consent, preferably in writing.

10. When obtaining informed consent for the research project the physician should be particularly cautious if the subject is in a dependent relationship to him or her or may consent under duress. In that case the informed consent should be obtained by a physician who is not engaged in the investigation and who is completely independent of this official relationship.

11. In case of legal incompetence, informed consent should be obtained from the legal guardian in accordance with national legislation. Where physical or mental incapacity make it impossible to obtain informed consent, or when the subject is a minor, permission from the responsible relative replace that of the subject in accordance with national legislation.

Whenever the minor child is in fact able to give consent, the minor’s consent must be obtained in addition to the consent of the minor’s legal guardian.

12. The research protocol should always contain a statement of the ethical considerations involved and should indicate that the principles enunciated in the present Declaration are complied with.

II. MEDICAL RESEARCH COMBINED WITH PROFESSIONAL CARE (Clinical Research)

1. In the treatment of the sick person, the physician must be free to use a new diagnostic and therapeutic measure, if in his or her judgement it offers hope of saving life, reestablishing health or alleviating suffering.


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2. The potential benefits, hazards and discomfort of a new method should be weighed against the advantages of the best current diagnostic and therapeutic methods.

3. In any medical study, every patient - including those of a control group, if any - should be assured of the best-proven diagnostic and therapeutic method. This does not exclude the use of inert placebo in studies where no proven diagnostic or therapeutic method exists.

4. The refusal of the patient to participate in a study must never interfere with the physician-patient relationship.

5. If the physician considers it essential not to obtain informed consent, the specific reasons for this proposal should be stated in the experimental protocol for transmission the independent committee (see I,2).

6. The physician can combine medical research with professional care, the objective being the acquisition of new medical knowledge, only to the extent that medical research is justified by its potential diagnostic or therapeutic value for the patient.

III. NON-THERAPEUTIC BIOMEDICAL RESEARCH INVOLVING HUMAN SUBJECTS (Non-Clinical Biomedical Research)

1. In the purely scientific application of medical research carried out on a human being, it is the duty of the physician to remain the protector of the life and health of that person on whom biomedical research is being carried out.

2. The subjects should be volunteers -- either healthy persons or patients for whom the experimental design is not related to the patient’s illness.

3. The investigator of the investigation team should discontinue the research if in his/her or their judgement it may, if continued, be harmful to the individual.


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4. In research on man, the interest of science and society should never take precedence over considerations related to the well-being of the subject.


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ELEMENTS OF INFORMED CONSENT

(21 CFR 50.25)

Basic Elements of Informed Consent

1. A statement that the study involves research, an explanation of the purposes of the research and the expected duration of the subject’s participation, a description of the procedures to be followed, and identification of any procedures which are experimental.

2. A description of any reasonably foreseeable risks or discomforts to the subject.

3. A description of any benefits to the subject or to others which may reasonably be expected from the research.

4. A disclosure of appropriate alternative procedures or courses of treatment, if any, that might be advantageous to the subject.

5. A statement describing the extent, if any, to which confidentiality of records identifying the subject will be maintained and that notes the possibility that the Food and Drug Administration may inspect the records.

6. For research involving more than minimal risk, an explanation as to whether any compensation and an explanation as to whether any medical treatments are available if injury occurs and, if so, what they consist of, or where further information may be obtained.

7. An explanation of whom to contact for answers to pertinent questions about the research and research subjects’ rights, and whom to contact in the event of a research-related injury to the subject.

8. A statement that participation is voluntary, that refusal to participate will involve no penalty or loss of benefits to which the subject is otherwise entitled, and that the subject may discontinue participation at any time without penalty or loss of benefits to which the subject is otherwise entitled.


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Additional Elements of Informed Consent

1. A statement that the particular treatment or procedure may involve risks to the subject (or to the embryo or fetus, if the subject is or may become pregnant) which are currently unforeseeable.

2. Anticipated circumstances under which the subjects’ participation may be terminated by the investigator without regard to the subjects’ consent.

3. Any additional costs to the subject that may result from participation in the research.

4. The consequences of a subjects’ decision to withdraw from the research and procedures for orderly termination of participation by the subject.

5. A statement that significant new findings developed during the course of the research which may relate to the subjects’ willingness to continue participation will be provided to the subject.

6. The approximate number of subjects involved in the study.


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Appendix 4 Clinical Laboratory Tests

Hematology

Complete blood count (CBC) with RBC indices and WBC differential

Platelet count

Chemistry

BUN

Creatinine

Glucose, fasting

Sodium

Potassium

Chloride

Total CO2

Calcium

AST

ALT

GGT

Alkaline Phosphatase

Total Bilirubin

Uric Acid

Albumin

Total Protein

Urinalysis

Specific gravity

pH, glucose, protein, blood and ketones by dipstick

Microscopic examination (if dipstick is positive for blood or protein)

Other tests

Urine Drug/Alcohol Screen (screening and prior to dosing during each session)

HIV, Hepatitis B and C Test (screening only)

Serum HCG Pregnancy Test (females only) [screening, prior to dosing each session, and at follow-up]

Follicle stimulating hormone (FSH) and estradiol levels (post menopausal females only at screening)


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Appendix 5 Values of Potential Clinical Concern

Hematology

Hemoglobin Males: <12.0 or >18.0 g/dL Females: <10.5 or >16.1 g/dL

Hematocrit Males <36.0 or >54.0% Females: <31.0 or >50.6%

Leukocytes >1 K/uL below or >3 K/uL above the limit of the reference range

Platelets <80 or > 500 K/uL

Chemistry

Total bilirubin ≥ 1.5 times upper limit of the reference range

AST >2 times upper limit of the reference range

ALT >2 times upper limit of the reference range

GGT >2 times upper limit of the reference range

Alk Phosphatase >1.5 times upper limit of the reference range

Creatinine >1.8 mg/dL

BUN >1.5 times upper limit of the reference range

Glucose, fasting <60 or >126 mg/dL

Uric acid >11 mg/dL

Sodium >5 mEq/L above or below the limits of the reference range

Potassium >0.5 mEq/L above or below the limits of the reference range

Calcium <7.2 or > 12 mg/dL

Phosphate >0.8 mg/dL below or 1.0 mg/dL above the limits of the reference range

Albumin >0.5 g/dL above or below the limits of the reference range

Total protein >1.0 g/dL above or below the limits of the reference range

Urinalysis

WBC >15/hpf

RBC >15/hpf

Vital Signs

Heart Rate Supine/Sitting: <35 or >120 bpm Erect: <40 or >140 bpm

Blood Pressure Systolic >30 mmHg change from baseline in same posture

Diastolic >20 mmHg change from baseline in same posture

Electrocardiogram

PR interval > 300 msec; >25% increase when baseline > 200 msec;

increase >50% when baseline ≤200 msec

QRS interval >200 msec; >25% increase when baseline >100 msec

>50% increase when baseline ≤100 msec

QTc interval >500 msec; >15% increase when baseline >440 msec

>30% increase when baseline ≤440 msec


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Appendix 6 Prescribing Information

AUGMENTIN amoxicillin/clavulanate potassium

Powder for Oral Suspension and Chewable Tablets

DESCRIPTION

Augmentin is an oral antibacterial combination consisting of the semisynthetic antibiotic amoxicillin and the β−lactamase inhibitor, clavulanate potassium (the potassium salt of clavulanic acid). Amoxicillin is an analog of ampicillin, derived from the basic penicillin nucleus, 6-aminopenicillanic acid. The amoxicillin molecular formula is C16H19N3O5S•3H2O and the molecular weight is 419.46.

Chemically, amoxicillin is (2S,5R,6R)-6-[(R)-(-)-2-Amino-2-(p-hydroxyphenyl)acetamido]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid trihydrate and may be represented structurally as:

Clavulanic acid is produced by the fermentation of Streptomyces clavuligerus. It is a β−lactam structurally related to the penicillins and possesses the ability to inactivate a wide variety of β−lactamases by blocking the active sites of these enzymes. Clavulanic acid is particularly active against the clinically important plasmid mediated β−lactamases frequently responsible for transferred drug resistance to penicillins and cephalosporins. The clavulanate potassium molecular formula is C8H8KNO5 and the molecular weight is 237.25. Chemically

clavulanate potassium is potassium (Z)-(2R,5R)-3-(2-hydroxyethylidene)-7-oxo-4-oxa-1-azabicyclo[3.2.0]-heptane-2-carboxylate and may be represented structurally as:


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Inactive Ingredients: Powder for Oral Suspension—Colloidal silicon dioxide, flavorings (See HOW SUPPLIED), succinic acid, xanthan gum, and one or more of the following: aspartame•, hydroxypropyl methylcellulose, mannitol, silica gel, silicon dioxide and sodium saccharin. Chewable Tablets—Colloidal silicon dioxide, flavorings (See HOW SUPPLIED), magnesium stearate, mannitol and one or more of the following: aspartame•, D&C Yellow No. 10, FD&C Red No. 40, glycine, sodium saccharin and succinic acid.

• See PRECAUTIONS–Information for Patients.

Each 125 mg chewable tablet and each 5 mL of reconstituted Augmentin 125 mg/5 mL oral suspension contains 0.16 mEq potassium. Each 250 mg chewable tablet and each 5 mL of reconstituted Augmentin 250 mg/5 mL oral suspension contains 0.32 mEq potassium. Each 200 mg chewable tablet and each 5 mL of reconstituted Augmentin 200 mg/5 mL oral suspension contains 0.14 mEq potassium. Each 400 mg chewable tablet and each 5 mL of reconstituted Augmentin 400 mg/5 mL oral suspension contains 0.29 mEq of potassium.

CLINICAL PHARMACOLOGY

Amoxicillin and clavulanate potassium are well absorbed from the gastrointestinal tract after oral administration of Augmentin. Dosing in the fasted or fed state has minimal effect on the pharmacokinetics of amoxicillin. While Augmentin can be given without regard to meals, absorption of clavulanate potassium when taken with food is greater relative to the fasted state. In one study, the relative bioavailability of clavulanate was reduced when Augmentin was dosed at 30 and 150 minutes after the start of a high fat breakfast. The safety and efficacy of Augmentin have been established in clinical trials where Augmentin was taken without regard to meals.

Oral administration of single doses of 400 mg Augmentin chewable tablets and 400 mg/5 mL suspension to 28 adult volunteers yielded comparable pharmacokinetic data:


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Dose† AUC0- ¥ (µg.hr./mL) Cmax (µg/mL)‡

(amoxicillin/clavulanate potassium)

amoxicillin (±S.D.)

clavulanate potassium (±S.D.)

amoxicillin (±S.D.)

clavulanate potassium (±S.D.)

400/57 mg (5 mL of suspension)

17.29 ± 2.28 2.34 ± 0.94 6.94 ± 1.24 1.10 ± 0.42

400/57 mg (one chewable tablet)

17.24 ± 2.64 2.17 ± 0.73 6.67 ± 1.37 1.03 ± 0.33

† Administered at the start of a light meal. ‡ Mean values of 28 normal volunteers. Peak concentrations occurred

approximately 1 hour after the dose.

Oral administration of 5 mL of Augmentin 250 mg/5 mL suspension or the equivalent dose of 10 mL Augmentin 125 mg/5 mL suspension provides average peak serum concentrations approximately 1 hour after dosing of 6.9 µg/mL for amoxicillin and 1.6 µg/mL for clavulanic acid. The areas under the serum concentration curves obtained during the first 4 hours after dosing were 12.6 µg.hr./mL for amoxicillin and 2.9 µg.hr./mL for clavulanic acid when 5 mL of Augmentin 250 mg/5 mL suspension or equivalent dose of 10 mL of Augmentin 125 mg/5 mL suspension was administered to adult volunteers. One Augmentin 250 mg chewable tablet or 2 Augmentin 125 mg chewable tablets are equivalent to 5 mL of Augmentin 250 mg/5 mL suspension and provide similar serum levels of amoxicillin and clavulanic acid.

Amoxicillin serum concentrations achieved with Augmentin are similar to those produced by the oral administration of equivalent doses of amoxicillin alone. The half-life of amoxicillin after the oral administration of Augmentin is 1.3 hours and that of clavulanic acid is 1.0 hour. Time above the minimum inhibitory concentration of 1.0 µg/mL for amoxicillin has been shown to be similar after corresponding q12h and q8h dosing regimens of Augmentin in adults and children.

Approximately 50% to 70% of the amoxicillin and approximately 25% to 40% of the clavulanic acid are excreted unchanged in urine during the first 6 hours after administration of 10 mL of Augmentin 250 mg/5 mL suspension.


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Concurrent administration of probenecid delays amoxicillin excretion but does not delay renal excretion of clavulanic acid.

Neither component in Augmentin is highly protein-bound; clavulanic acid has been found to be approximately 25% bound to human serum and amoxicillin approximately 18% bound.

Amoxicillin diffuses readily into most body tissues and fluids with the exception of the brain and spinal fluid. The results of experiments involving the administration of clavulanic acid to animals suggest that this compound, like amoxicillin, is well distributed in body tissues.

Two hours after oral administration of a single 35 mg/kg dose of Augmentin suspension to fasting children, average concentrations of 3.0 µg/mL of amoxicillin and 0.5 µg/mL of clavulanic acid were detected in middle ear effusions.

Microbiology: Amoxicillin is a semisynthetic antibiotic with a broad spectrum of bactericidal activity against many gram-positive and gram-negative microorganisms. Amoxicillin is, however, susceptible to degradation by β−lactamases and, therefore, the spectrum of activity does not include organisms which produce these enzymes. Clavulanic acid is a β−lactam, structurally related to the penicillins, which possesses the ability to inactivate a wide range of β−lactamase enzymes commonly found in microorganisms resistant to penicillins and cephalosporins. In particular, it has good activity against the clinically important plasmid mediated β−lactamases frequently responsible for transferred drug resistance.

The formulation of amoxicillin and clavulanic acid in Augmentin protects amoxicillin from degradation by β−lactamase enzymes and effectively extends the antibiotic spectrum of amoxicillin to include many bacteria normally resistant to amoxicillin and other β−lactam antibiotics. Thus, Augmentin possesses the distinctive properties of a broad-spectrum antibiotic and a β−lactamase inhibitor.

Amoxicillin/clavulanic acid has been shown to be active against most strains of the following microorganisms, both in vitro and in clinical infections as described in the INDICATIONS AND USAGE section.

GRAM-POSITIVE AEROBES

Staphylococcus aureus (β−lactamase and non-β−lactamase producing)§


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§ Staphylococci which are resistant to methicillin/oxacillin must be considered resistant to amoxicillin/clavulanic acid.

GRAM-NEGATIVE AEROBES

Enterobacter species (Although most strains of Enterobacter species are resistant in vitro, clinical efficacy has been demonstrated with Augmentin in urinary tract infections caused by these organisms.)

Escherichia coli (β−lactamase and non-β−lactamase producing)

Haemophilus influenzae (β−lactamase and non-β−lactamase producing)

Klebsiella species (All known strains are β−lactamase producing.)

Moraxella catarrhalis (β−lactamase and non-β−lactamase producing)

The following in vitro data are available, but their clinical significance is unknown.

Amoxicillin/clavulanic acid exhibits in vitro minimal inhibitory concentrations (MICs) of 0.5 µg/mL or less against most (≥90%) strains of Streptococcus

pneumoniaeII; MICs of 0.06 µg/mL or less against most (≥90%) strains of Neisseria gonorrhoeae; MICs of 4 µg/mL or less against most (≥90%) strains of staphylococci and anaerobic bacteria; and MICs of 8 µg/mL or less against most (≥90%) strains of other listed organisms. However, with the exception of organisms shown to respond to amoxicillin alone, the safety and effectiveness of amoxicillin/clavulanic acid in treating clinical infections due to these microorganisms have not been established in adequate and well-controlled clinical trials.

II Because amoxicillin has greater in vitro activity against Streptococcus pneumoniae than does ampicillin or penicillin, the majority of S. pneumoniae strains with intermediate susceptibility to ampicillin or penicillin are fully susceptible to amoxicillin.

GRAM-POSITIVE AEROBES

Enterococcus faecalis¶

Staphylococcus epidermidis (β−lactamase and non-β−lactamase producing)

Staphylococcus saprophyticus (β−lactamase and non-β−lactamase producing)


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Streptococcus pneumoniae¶**

Streptococcus pyogenes¶**

viridans group Streptococcus¶**

GRAM-NEGATIVE AEROBES

Eikenella corrodens (β−lactamase and non-β−lactamase producing)

Neisseria gonorrhoeae¶ (β−lactamase and non-β−lactamase producing)

Proteus mirabilis¶ (β−lactamase and non-β−lactamase producing)

ANAEROBIC BACTERIA

Bacteroides species, including Bacteroides fragilis (β−lactamase and non-β−lactamase producing)

Fusobacterium species (β−lactamase and non-β−lactamase producing)

Peptostreptococcus species**

¶ Adequate and well-controlled clinical trials have established the effectiveness of amoxicillin alone in treating certain clinical infections due to these organisms.

** These are non-β−lactamase-producing organisms and, therefore, are susceptible to amoxicillin alone.

SUSCEPTIBILITY TESTING

Dilution Techniques: Quantitative methods are used to determine antimicrobial minimal inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized procedure. Standardized procedures are based on a dilution method1 (broth or agar) or equivalent with standardized inoculum concentrations and standardized concentrations of amoxicillin/clavulanate potassium powder.

The recommended dilution pattern utilizes a constant amoxicillin/clavulanate potassium ratio of 2 to 1 in all tubes with varying amounts of amoxicillin. MICs are expressed in terms of the amoxicillin concentration in the presence of


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clavulanic acid at a constant 2 parts amoxicillin to 1 part clavulanic acid. The MIC values should be interpreted according to the following criteria:

RECOMMENDED RANGES FOR AMOXICILLIN/CLAVULANIC ACID SUSCEPTIBILITY TESTING

For gram-negative enteric aerobes:

MIC (µg/mL) Interpretation

≤ 8/4 Susceptible (S)

16/8 Intermediate (I)

≥ 32/16 Resistant (R)

For Staphylococcus†† and Haemophilus species:


≤ 4/2 Susceptible (S)


†† Staphylococci which are susceptible to amoxicillin/clavulanic acid but resistant to methicillin/oxacillin must be considered as resistant.

For Streptococcus pneumoniae: Isolates should be tested using amoxicillin/clavulanic acid and the following criteria should be used:


≤ 0.5/0.25 Susceptible (S)

1/0.5 Intermediate (I)



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A report of “Susceptible” indicates that the pathogen is likely to be inhibited if the antimicrobial compound in the blood reaches the concentration usually achievable. A report of “Intermediate” indicates that the result should be considered equivocal, and, if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where high dosage of drug can be used. This category also provides a buffer zone that prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of “Resistant” indicates that the pathogen is not likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable; other therapy should be selected.

Standardized susceptibility test procedures require the use of laboratory control microorganisms to control the technical aspects of the laboratory procedures. Standard amoxicillin/clavulanate potassium powder should provide the following MIC values:

Microorganism MIC Range (µg/mL)‡‡

Escherichia coli ATCC 25922 2 to 8

Escherichia coli ATCC 35218 4 to 16

Enterococcus faecalis ATCC 29212 0.25 to 1.0

Haemophilus influenzae ATCC 49247 2 to 16

Staphylococcus aureus ATCC 29213 0.12 to 0.5

Streptococcus pneumoniae ATCC 49619 0.03 to 0.12

‡‡ Expressed as concentration of amoxicillin in the presence of clavulanic acid at a constant 2 parts amoxicillin to 1 part clavulanic acid.

Diffusion Techniques: Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to

antimicrobial compounds. One such standardized procedure2 requires the use of standardized inoculum concentrations. This procedure uses paper disks impregnated with 30 µg of amoxicillin/clavulanate potassium (20 µg amoxicillin plus 10 µg clavulanate potassium) to test the susceptibility of microorganisms to amoxicillin/clavulanic acid.


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Reports from the laboratory providing results of the standard single-disk susceptibility test with a 30 µg amoxicillin/clavulanate potassium (20 µg amoxicillin plus 10 µg clavulanate potassium) disk should be interpreted according to the following criteria:

RECOMMENDED RANGES FOR AMOXICILLIN/CLAVULANIC ACID SUSCEPTIBILITY TESTING

For Staphylococcus§§ species and H. influenzaea:

Zone Diameter (mm) Interpretation

≥ 20 Susceptible (S)

≤ 19 Resistant (R)

For other organisms except S. pneumoniaeb and N. gonorrhoeaec:

Zone Diameter (mm) Interpretation

≥ 18 Susceptible (S)

14 to 17 Intermediate (I)

≤ 13 Resistant (R)

§§ Staphylococci which are resistant to methicillin/oxacillin must be considered as resistant to amoxicillin/clavulanic acid.

a A broth microdilution method should be used for testing H. influenzae. β-lactamase negative, ampicillin-resistant strains must be considered resistant to amoxicillin/clavulanic acid.

b Susceptibility of S. pneumoniae should be determined using a 1 µg oxacillin disk. Isolates with oxacillin zone sizes of ≥20 mm are susceptible to amoxicillin/clavulanic acid. An amoxicillin/clavulanic acid MIC should be determined on isolates of S. pneumoniae with oxacillin zone sizes of ≤19 mm.


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c A broth microdilution method should be used for testing N. gonorrhoeae and interpreted according to penicillin breakpoints.

Interpretation should be as stated above for results using dilution techniques. Interpretation involves correlation of the diameter obtained in the disk test with the MIC for amoxicillin/clavulanic acid.

As with standardized dilution techniques, diffusion methods require the use of laboratory control microorganisms that are used to control the technical aspects of the laboratory procedures. For the diffusion technique, the 30 µg amoxicillin/clavulanate potassium (20 µg amoxicillin plus 10 µg clavulanate potassium) disk should provide the following zone diameters in these laboratory quality control strains:

Microorganism Zone Diameter (mm)

Escherichia coli ATCC 25922 19 to 25 mm

Escherichia coli ATCC 35218 18 to 22 mm

Staphylococcus aureus ATCC 25923 28 to 36 mm

INDICATIONS AND USAGE

Augmentin is indicated in the treatment of infections caused by susceptible strains of the designated organisms in the conditions listed below:

Lower Respiratory Tract Infections–caused by β−lactamase-producing strains of Haemophilus influenzae and Moraxella (Branhamella) catarrhalis.

Otitis Media–caused by β−lactamase-producing strains of Haemophilus influenzae and Moraxella (Branhamella) catarrhalis.

Sinusitis–caused by β−lactamase-producing strains of Haemophilus influenzae and Moraxella (Branhamella) catarrhalis.

Skin and Skin Structure Infections–caused by β−lactamase-producing strains of Staphylococcus aureus, Escherichia coli and Klebsiella spp.

Urinary Tract Infections–caused by β−lactamase-producing strains of Escherichia coli, Klebsiella spp. and Enterobacter spp.


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While Augmentin is indicated only for the conditions listed above, infections caused by ampicillin-susceptible organisms are also amenable to Augmentin treatment due to its amoxicillin content. Therefore, mixed infections caused by ampicillin-susceptible organisms and β−lactamase-producing organisms susceptible to Augmentin should not require the addition of another antibiotic. Because amoxicillin has greater in vitro activity against Streptococcus pneumoniae than does ampicillin or penicillin, the majority of S. pneumoniae strains with intermediate susceptibility to ampicillin or penicillin are fully susceptible to amoxicillin and Augmentin. (See Microbiology subsection.)

Bacteriological studies, to determine the causative organisms and their susceptibility to Augmentin, should be performed together with any indicated surgical procedures.

Therapy may be instituted prior to obtaining the results from bacteriological and susceptibility studies to determine the causative organisms and their susceptibility to Augmentin when there is reason to believe the infection may involve any of the β−lactamase-producing organisms listed above. Once the results are known, therapy should be adjusted, if appropriate.

CONTRAINDICATIONS

Augmentin is contraindicated in patients with a history of allergic reactions to any penicillin. It is also contraindicated in patients with a previous history of Augmentin-associated cholestatic jaundice/hepatic dysfunction.

WARNINGS

SERIOUS AND OCCASIONALLY FATAL HYPERSENSITIVITY (ANAPHYLACTIC) REACTIONS HAVE BEEN REPORTED IN PATIENTS ON PENICILLIN THERAPY. THESE REACTIONS ARE MORE LIKELY TO OCCUR IN INDIVIDUALS WITH A HISTORY OF PENICILLIN HYPERSENSITIVITY AND/OR A HISTORY OF SENSITIVITY TO MULTIPLE ALLERGENS. THERE HAVE BEEN REPORTS OF INDIVIDUALS WITH A HISTORY OF PENICILLIN HYPERSENSITIVITY WHO HAVE EXPERIENCED SEVERE REACTIONS WHEN TREATED WITH CEPHALOSPORINS. BEFORE INITIATING THERAPY WITH AUGMENTIN, CAREFUL INQUIRY SHOULD BE MADE CONCERNING PREVIOUS HYPERSENSITIVITY REACTIONS TO PENICILLINS, CEPHALOSPORINS OR OTHER ALLERGENS. IF AN ALLERGIC REACTION OCCURS, AUGMENTIN SHOULD BE DISCONTINUED AND


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THE APPROPRIATE THERAPY INSTITUTED. SERIOUS ANAPHYLACTIC REACTIONS REQUIRE IMMEDIATE EMERGENCY TREATMENT WITH EPINEPHRINE. OXYGEN, INTRAVENOUS STEROIDS AND AIRWAY MANAGEMENT, INCLUDING INTUBATION, SHOULD ALSO BE ADMINISTERED AS INDICATED.

Pseudomembranous colitis has been reported with nearly all antibacterial agents, including Augmentin, and has ranged in severity from mild to life-threatening. Therefore, it is important to consider this diagnosis in patients who present with diarrhea subsequent to the administration of antibacterial agents.

Treatment with antibacterial agents alters the normal flora of the colon and may permit overgrowth of clostridia. Studies indicate that a toxin produced by Clostridium difficile is one primary cause of “antibiotic associated colitis.”

After the diagnosis of pseudomembranous colitis has been established, appropriate therapeutic measures should be initiated. Mild cases of pseudomembranous colitis usually respond to drug discontinuation alone. In moderate to severe cases, consideration should be given to management with fluids and electrolytes, protein supplementation and treatment with an antibacterial drug clinically effective against Clostridium difficile colitis.

Augmentin should be used with caution in patients with evidence of hepatic dysfunction. Hepatic toxicity associated with the use of Augmentin is usually reversible. On rare occasions, deaths have been reported (less than 1 death reported per estimated 4 million prescriptions worldwide). These have generally been cases associated with serious underlying diseases or concomitant medications. (See CONTRAINDICATIONS and ADVERSE REACTIONS–Liver.)

PRECAUTIONS

General: While Augmentin possesses the characteristic low toxicity of the penicillin group of antibiotics, periodic assessment of organ system functions, including renal, hepatic and hematopoietic function, is advisable during prolonged therapy.

A high percentage of patients with mononucleosis who receive ampicillin develop an erythematous skin rash. Thus, ampicillin class antibiotics should not be administered to patients with mononucleosis.


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The possibility of superinfections with mycotic or bacterial pathogens should be kept in mind during therapy. If superinfections occur (usually involving Pseudomonas or Candida), the drug should be discontinued and/or appropriate therapy instituted.

Information for the Patient: Augmentin may be taken every 8 hours or every 12 hours, depending on the strength of the product prescribed. Each dose should be taken with a meal or snack to reduce the possibility of gastrointestinal upset. Many antibiotics can cause diarrhea. If diarrhea is severe or lasts more than 2 or 3 days, call your doctor.

Make sure your child completes the entire prescribed course of treatment, even if he/she begins to feel better after a few days. Keep suspension refrigerated. Shake well before using. When dosing a child with Augmentin suspension (liquid), use a dosing spoon or medicine dropper. Be sure to rinse the spoon or dropper after each use. Bottles of Augmentin suspension may contain more liquid than required. Follow your doctor’s instructions about the amount to use and the days of treatment your child requires. Discard any unused medicine.

Phenylketonurics: Each 200 mg Augmentin chewable tablet contains 2.1 mg phenylalanine; each 400 mg chewable tablet contains 4.2 mg phenylalanine; each 5 mL of either the 200 mg/5 mL or 400 mg/5 mL oral suspension contains 7 mg phenylalanine. The other Augmentin products do not contain phenylalanine and can be used by phenylketonurics. Contact your physician or pharmacist.

Drug Interactions: Probenecid decreases the renal tubular secretion of amoxicillin. Concurrent use with Augmentin may result in increased and prolonged blood levels of amoxicillin. Co-administration of probenecid cannot be recommended.

The concurrent administration of allopurinol and ampicillin increases substantially the incidence of rashes in patients receiving both drugs as compared to patients receiving ampicillin alone. It is not known whether this potentiation of ampicillin rashes is due to allopurinol or the hyperuricemia present in these patients. There are no data with Augmentin and allopurinol administered concurrently.

In common with other broad-spectrum antibiotics, Augmentin may reduce the efficacy of oral contraceptives.


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Drug/Laboratory Test Interactions: Oral administration of Augmentin will result in high urine concentrations of amoxicillin. High urine concentrations of ampicillin may result in false-positive reactions when testing for the presence of glucose in urine using Clinitest®, Benedict’s Solution or Fehling’s Solution. Since this effect may also occur with amoxicillin and therefore Augmentin, it is recommended that glucose tests based on enzymatic glucose oxidase reactions (such as Clinistix® or Tes-Tape®) be used.

Following administration of ampicillin to pregnant women a transient decrease in plasma concentration of total conjugated estriol, estriol-glucuronide, conjugated estrone and estradiol has been noted. This effect may also occur with amoxicillin and therefore Augmentin.

Carcinogenesis, Mutagenesis, Impairment of Fertility: Long-term studies in animals have not been performed to evaluate carcinogenic potential.

Mutagenesis: The mutagenic potential of Augmentin was investigated in vitro with an Ames test, a human lymphocyte cytogenetic assay, a yeast test and a mouse lymphoma forward mutation assay, and in vivo with mouse micronucleus tests and a dominant lethal test. All were negative apart from the in vitro mouse lymphoma assay where weak activity was found at very high, cytotoxic concentrations.

Impairment of Fertility: Augmentin at oral doses of up to 1200 mg/kg/day (5.7 times the maximum human dose, 1480 mg/m2/day, based on body surface area) was found to have no effect on fertility and reproductive performance in rats, dosed with a 2:1 ratio formulation of amoxicillin:clavulanate.

Teratogenic effects. Pregnancy (Category B): Reproduction studies performed in pregnant rats and mice given Augmentin at oral dosages up to 1200 mg/kg/day,

equivalent to 7200 and 4080 mg/ m2/day, respectively (4.9 and 2.8 times the maximum human oral dose based on body surface area), revealed no evidence of harm to the fetus due to Augmentin. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Labor and Delivery: Oral ampicillin class antibiotics are generally poorly absorbed during labor. Studies in guinea pigs have shown that intravenous administration of ampicillin decreased the uterine tone, frequency of contractions, height of contractions and duration of contractions. However, it is not known


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whether the use of Augmentin in humans during labor or delivery has immediate or delayed adverse effects on the fetus, prolongs the duration of labor, or increases the likelihood that forceps delivery or other obstetrical intervention or resuscitation of the newborn will be necessary.

Nursing Mothers: Ampicillin class antibiotics are excreted in the milk; therefore, caution should be exercised when Augmentin is administered to a nursing woman.

Pediatric Use: Because of incompletely developed renal function in neonates and young infants, the elimination of amoxicillin may be delayed. Dosing of Augmentin should be modified in pediatric patients younger than 12 weeks (3 months). (See DOSAGE AND ADMINISTRATION–Pediatric.)

ADVERSE REACTIONS

Augmentin is generally well tolerated. The majority of side effects observed in clinical trials were of a mild and transient nature and less than 3% of patients discontinued therapy because of drug-related side effects. From the original premarketing studies, where both pediatric and adult patients were enrolled, the most frequently reported adverse effects were diarrhea/loose stools (9%), nausea (3%), skin rashes and urticaria (3%), vomiting (1%) and vaginitis (1%). The overall incidence of side effects, and in particular diarrhea, increased with the higher recommended dose. Other less frequently reported reactions include: abdominal discomfort, flatulence and headache.

In pediatric patients (aged 2 months to 12 years), one U.S./Canadian clinical trial was conducted which compared Augmentin 45/6.4 mg/kg/day (divided q12h) for 10 days versus Augmentin 40/10 mg/kg/day (divided q8h) for 10 days in the treatment of acute otitis media. A total of 575 patients were enrolled, and only the suspension formulations were used in this trial. Overall, the adverse event profile seen was comparable to that noted above. However, there were differences in the rates of diarrhea, skin rashes/urticaria, and diaper area rashes. (See CLINICAL STUDIES.)

The following adverse reactions have been reported for ampicillin class antibiotics:

Gastrointestinal: Diarrhea, nausea, vomiting, indigestion, gastritis, stomatitis, glossitis, black “hairy” tongue, mucocutaneous candidiasis, enterocolitis, and hemorrhagic/pseudomembranous colitis. Onset of pseudomembranous colitis symptoms may occur during or after antibiotic treatment. (See WARNINGS.)


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Hypersensitivity Reactions: Skin rashes, pruritus, urticaria, angioedema, serum sickness-like reactions (urticaria or skin rash accompanied by arthritis, arthralgia, myalgia and frequently fever), erythema multiforme (rarely Stevens-Johnson Syndrome) and an occasional case of exfoliative dermatitis (including toxic epidermal necrolysis) have been reported. These reactions may be controlled with antihistamines and, if necessary, systemic corticosteroids. Whenever such reactions occur, the drug should be discontinued, unless the opinion of the physician dictates otherwise. Serious and occasional fatal hypersensitivity (anaphylactic) reactions can occur with oral penicillin. (See WARNINGS.)

Liver: A moderate rise in AST (SGOT) and/or ALT (SGPT) has been noted in patients treated with ampicillin class antibiotics but the significance of these findings is unknown. Hepatic dysfunction, including increases in serum transaminases (AST and/or ALT), serum bilirubin and/or alkaline phosphatase, has been infrequently reported with Augmentin. It has been reported more commonly in the elderly, in males, or in patients on prolonged treatment. The histologic findings on liver biopsy have consisted of predominantly cholestatic, hepatocellular, or mixed cholestatic-hepatocellular changes. The onset of signs/symptoms of hepatic dysfunction may occur during or several weeks after therapy has been discontinued. The hepatic dysfunction, which may be severe, is usually reversible. On rare occasions, deaths have been reported (less than 1 death reported per estimated 4 million prescriptions worldwide). These have generally been cases associated with serious underlying diseases or concomitant medications.

Renal: Interstitial nephritis and hematuria have been reported rarely.

Hemic and Lymphatic Systems: Anemia, including hemolytic anemia, thrombocytopenia, thrombocytopenic purpura, eosinophilia, leukopenia and agranulocytosis have been reported during therapy with penicillins. These reactions are usually reversible on discontinuation of therapy and are believed to be hypersensitivity phenomena. A slight thrombocytosis was noted in less than 1% of the patients treated with Augmentin. There have been reports of increased prothrombin time in patients receiving Augmentin and anticoagulant therapy concomitantly.

Central Nervous System: Agitation, anxiety, behavioral changes, confusion, convulsions, dizziness, insomnia, and reversible hyperactivity have been reported rarely.


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OVERDOSAGE

Most patients have been asymptomatic following overdosage or have experienced primarily gastrointestinal symptoms including stomach and abdominal pain, vomiting, and diarrhea. Rash, hyperactivity, or drowsiness have also been observed in a small number of patients.

In the case of overdosage, discontinue Augmentin, treat symptomatically, and institute supportive measures as required. If the overdosage is very recent and there is no contraindication, an attempt at emesis or other means of removal of drug from the stomach may be performed. A prospective study of 51 pediatric patients at a poison center suggested that overdosages of less than 250 mg/kg of amoxicillin are not associated with significant clinical symptoms and do not

require gastric emptying.3

Interstitial nephritis resulting in oliguric renal failure has been reported in a small number of patients after overdosage with amoxicillin. Renal impairment appears to be reversible with cessation of drug administration. High blood levels may occur more readily in patients with impaired renal function because of decreased renal clearance of both amoxicillin and clavulanate. Both amoxicillin and clavulanate are removed from the circulation by hemodialysis.

DOSAGE AND ADMINISTRATION

Dosage:

Pediatric Patients: Based on the amoxicillin component, Augmentin should be dosed as follows:

Neonates and infants aged < 12 weeks (3 months)

Due to incompletely developed renal function affecting elimination of amoxicillin in this age group, the recommended dose of Augmentin is 30 mg/kg/day divided q12h, based on the amoxicillin component. Clavulanate elimination is unaltered in this age group. Experience with the 200 mg/5 mL formulation in this age group is limited and, thus, use of the 125 mg/5 mL oral suspension is recommended.

Patients aged 12 weeks (3 months) and older


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INFECTIONS DOSING REGIMEN

q12hII II q8h

200 mg/5 mL or 400 mg/5 mL oral suspension¶¶

125 mg/5 mL or 250 mg/5 mL oral suspension¶¶

Otitis media***, sinusitis, lower respiratory tract infections, and more severe infections

45 mg/kg/day q12h 40 mg/kg/day q8h

Less severe infections 25 mg/kg/day q12h 20 mg/kg/day q8h

The q12h regimen is recommended as it is associated with significantly less diarrhea. (See CLINICAL STUDIES.) However, the q12h formulations (200 mg and 400 mg) contain aspartame and should not be used by phenylketonurics.

Each strength of Augmentin suspension is available as a chewable tablet for use by older children.

*** Duration of therapy studied and recommended for acute otitis media is 10 days.

Pediatric patients weighing 40 kg and more should be dosed according to the following adult recommendations: The usual adult dose is 1 Augmentin 500 mg tablet every 12 hours or 1 Augmentin 250 mg tablet every 8 hours. For more severe infections and infections of the respiratory tract, the dose should be 1 Augmentin 875 mg tablet every 12 hours or 1 Augmentin 500 mg tablet every 8 hours. Among adults treated with 875 mg every 12 hours, significantly fewer experienced severe diarrhea or withdrawals with diarrhea vs. adults treated with 500 mg every 8 hours. For detailed adult dosage recommendations, please see complete prescribing information for Augmentin Tablets.

Hepatically impaired patients should be dosed with caution and hepatic function monitored at regular intervals. (See WARNINGS.)

Adults: Adults who have difficulty swallowing may be given the 125 mg/5 mL or 250 mg/5 mL suspension in place of the 500 mg tablet. The 200 mg/5 mL


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suspension or the 400 mg/5 mL suspension may be used in place of the 875 mg tablet. See dosage recommendations above for children weighing 40 kg or more.

The Augmentin 250 mg tablet and the 250 mg chewable tablet do not contain the same amount of clavulanic acid (as the potassium salt). The Augmentin 250 mg tablet contains 125 mg of clavulanic acid, whereas the 250 mg chewable tablet contains 62.5 mg of clavulanic acid. Therefore, the Augmentin 250 mg tablet and the 250 mg chewable tablet should not be substituted for each other, as they are not interchangeable.

Due to the different amoxicillin to clavulanic acid ratios in the Augmentin 250 mg tablet (250/125) versus the Augmentin 250 mg chewable tablet (250/62.5), the Augmentin 250 mg tablet should not be used until the child weighs at least 40 kg and more.

DIRECTIONS FOR MIXING ORAL SUSPENSION

Prepare a suspension at time of dispensing as follows: Tap bottle until all the powder flows freely. Add approximately 2/3 of the total amount of water for reconstitution (see table below) and shake vigorously to suspend powder. Add remainder of the water and again shake vigorously.

Augmentin 125 mg/5 mL Suspension

Bottle Size Amount of Water Required for Reconstitution

75 mL 67 mL

100 mL 90 mL

150 mL 134 mL

Each teaspoonful (5 mL) will contain 125 mg amoxicillin and 31.25 mg of clavulanic acid as the potassium salt.


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50 mL 47 mL

75 mL 69 mL

100 mL 91 mL




75 mL 65 mL

100 mL 87 mL

150 mL 130 mL




50 mL 44 mL

75 mL 66 mL

100 mL 87 mL


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Note: SHAKE ORAL SUSPENSION WELL BEFORE USING.

Reconstituted suspension must be stored under refrigeration and discarded after 10 days.

Administration: Augmentin may be taken without regard to meals; however, absorption of clavulanate potassium is enhanced when Augmentin is administered at the start of a meal. To minimize the potential for gastrointestinal intolerance, Augmentin should be taken at the start of a meal.

HOW SUPPLIED

AUGMENTIN 125 MG/5 ML FOR ORAL SUSPENSION: Each 5 mL of reconstituted banana-flavored suspension contains 125 mg amoxicillin and 31.25 mg clavulanic acid as the potassium salt.

NDC 0029-6085-39 75 mL bottle NDC 0029-6085-22 150 mL bottle

NDC 0029-6085-23 100 mL bottle

AUGMENTIN 200 MG/5 ML FOR ORAL SUSPENSION: Each 5 mL of reconstituted orange-raspberry-flavored suspension contains 200 mg amoxicillin and 28.5 mg clavulanic acid as the potassium salt.


NDC 0029-6087-39 75 mL bottle

AUGMENTIN 250 MG/5 ML FOR ORAL SUSPENSION: Each 5 mL of reconstituted orange-flavored suspension contains 250 mg amoxicillin and 62.5 mg clavulanic acid as the potassium salt.


NDC 0029-6090-23 100 mL bottle

AUGMENTIN 400 MG/5 ML FOR ORAL SUSPENSION: Each 5 mL of reconstituted orange-raspberry-flavored suspension contains 400 mg amoxicillin and 57 mg clavulanic acid as the potassium salt.


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NDC 0029-6092-39 75 mL bottle

AUGMENTIN 125 MG CHEWABLE TABLETS: Each mottled yellow, round, lemon-lime-flavored tablet, debossed with BMP 189, contains 125 mg amoxicillin as the trihydrate and 31.25 mg clavulanic acid as the potassium salt.

NDC 0029-6073-47 carton of 30 tablets

AUGMENTIN 200 MG CHEWABLE TABLETS: Each mottled pink, round, biconvex, cherry-banana-flavored tablet contains 200 mg amoxicillin as the trihydrate and 28.5 mg clavulanic acid as the potassium salt.


AUGMENTIN 250 MG CHEWABLE TABLETS: Each mottled yellow, round, lemon-lime-flavored tablet, debossed with BMP 190, contains 250 mg amoxicillin as the trihydrate and 62.5 mg clavulanic acid as the potassium salt.


AUGMENTIN 400 MG CHEWABLE TABLETS: Each mottled pink, round, biconvex, cherry-banana-flavored tablet contains 400 mg amoxicillin as the trihydrate and 57.0 mg clavulanic acid as the potassium salt.


AUGMENTIN is also supplied as:

AUGMENTIN 250 MG TABLETS (250 mg amoxicillin/125 mg clavulanic acid):

NDC 0029-6075-27 bottles of 30 NDC 0029-6075-31 100 Unit Dose tablets






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Store tablets and dry powder at or below 25°C (77°F). Dispense in tightly closed, moisture-proof containers. Store reconstituted suspension under refrigeration. Discard unused suspension after 10 days.

CLINICAL STUDIES

In pediatric patients (aged 2 months to 12 years), one U.S./Canadian clinical trial was conducted which compared Augmentin 45/6.4 mg/kg/day (divided q12h) for 10 days versus Augmentin 40/10 mg/kg/day (divided q8h) for 10 days in the treatment of acute otitis media. Only the suspension formulations were used in this trial. A total of 575 patients were enrolled, with an even distribution among the two treatment groups and a comparable number of patients were evaluable (i.e., ≥84%) per treatment group. Strict otitis media-specific criteria were required for eligibility and a strong correlation was found at the end of therapy and follow-up between these criteria and physician assessment of clinical response. The clinical efficacy rates at the end of therapy visit (defined as 2-4 days after the completion of therapy) and at the follow-up visit (defined as 22-28 days post-completion of therapy) were comparable for the two treatment groups, with the following cure rates obtained for the evaluable patients: At end of therapy, 87.2% (n=265) and 82.3% (n=260) for 45 mg/kg/day q12h and 40 mg/kg/day q8h, respectively. At follow-up, 67.1% (n=249) and 68.7% (n=243) for 45 mg/kg/day q12h and 40 mg/kg/day q8h, respectively.

The incidence of diarrhea††† was significantly lower in patients in the q12h treatment group compared to patients who received the q8h regimen (14.3% and 34.3%, respectively). In addition, the number of patients with either severe diarrhea or who were withdrawn with diarrhea was significantly lower in the q12h treatment group (3.1% and 7.6% for the q12h/10 day and q8h/10 day, respectively). In the q12h treatment group, 3 patients (1.0%) were withdrawn with an allergic reaction, while 1 patient (0.3%) in the q8h group was withdrawn for this reason. The number of patients with a candidal infection of the diaper area was 3.8% and 6.2% for the q12h and q8h groups, respectively.

It is not known if the finding of a statistically significant reduction in diarrhea with the oral suspensions dosed q12h, versus suspensions dosed q8h, can be extrapolated to the chewable tablets. The presence of mannitol in the chewable tablets may contribute to a different diarrhea profile. The q12h oral suspensions are sweetened with aspartame only.


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††† Diarrhea was defined as either: (a) three or more watery or four or more loose/watery stools in one day; OR (b) two watery stools per day or three loose/watery stools per day for two consecutive days.

REFERENCES

National Committee for Clinical Laboratory Standards. Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically – Third Edition. Approved Standard NCCLS Document M7-A3, Vol. 13, No. 25. NCCLS, Villanova, PA, Dec. 1993.

National Committee for Clinical Laboratory Standards. Performance Standard for Antimicrobial Disk Susceptibility Tests – Fifth Edition. Approved Standard NCCLS Document M2-A5, Vol. 13, No. 24. NCCLS, Villanova, PA, Dec. 1993.

Swanson-Biearman B, Dean BS, Lopez G, Krenzelok EP. The effects of penicillin and cephalosporin ingestions in children less than six years of age. Vet Hum Toxicol 1988;30:66-67.

DATE OF ISSUANCE MAR. 1999 (c) SmithKline Beecham, 1999 SmithKline Beecham Pharmaceuticals Philadelphia, PA 19101 AG:PL6A Printed in U.S.A.


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This section contained Principal Investigator’s Curriculum Vitae and has been excluded to

protect Principal Investigator privacy.











CONFIDENTIAL

d:\esps\coredoss\temp\esps00000.docDRAFT 04 Apr 03 - 1 -

RANDOMIZATION SCHEDULE OF INTENT

Regimen ListingProject: 25000 Protocol: 643Date Prepared: 07-Jan-2003/12:11 Prepared By: Addendum: 0 Date Schedule Created: 05-Jun-2002/11:27Created By:

Random Number RegimenBABAABABABABBABAABABBABABABAABABABABBABABABAABABBABAABABABABBABABABAABABABABBABABABAABABABABBABAABABBABABABAABABBABAABABBABAABAB


CONFIDENTIAL


RANDOMIZATION SCHEDULE OF INTENT (CONT.)

Random Number RegimenBABAABABABABBABABABAABABBABAABABBABAABABABABBABA

Regimen Listing

Regimen Regimen NameA REFORMULATED STRAWBERRY 600 SUSPENSIONB MARKETED RASPBERRY ORANGE 600

SUSPENSION

Stratification Listing

Stratification Start Number Last NumberMALEFEMALE


CONFIDENTIAL


ACTUAL DOSING SCHEDULE

Random Number RegimenBABAABABABABBABAABABBABABABAABABABABBABABABAABABBABAABABABABBABABABAABABABABBABABABAABABABABBABAABABBABABABAABABBABAABABBABAABABBABAABABABABBABABABAABABBABAABAB

Regimen Regimen NameA REFORMULATED STRAWBERRY 600 SUSPENSIONB MARKETED RASPBERRY ORANGE 600 SUSPENSION





