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`CENTER FOR DRUG EVALUATION AND RESEARCH
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`APPLICATION NUMBER:
`22511Orig1s000
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`MEDICAL REVIEW(S)
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`

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`CLINICAL REVIEW
`
`Application Type 505(b)(2)
`Application Number(s) 22-511
`Priority or Standard Standard
`
`June 30, 2009
`Submit Date(s)
`July 7, 2009
`Received Date(s)
`PDUFA Goal Date April 30, 2010
`Division / Office Division of Gastroenterology
`
`Reviewer Name(s) Erica L. Wynn, MD MPH through
`Ruyi He, MD
`Review Completion Date April 2, 2010
`
`Established Name Naproxen/Esomeprazole
`Magnesium
`Trade Name Vimovo
`Therapeutic Class Combination NSAID and Proton
`Pump Inhibitor
`Applicant Pozen Inc
`Formulation(s) Oral tablet
`Dosing Regimen Naproxen (500 or 375mg) and
`Esomeprazole (20mg) twice daily
`Indication(s) Treatment of signs and symptoms
`of osteoarthritis, rheumatoid
`arthritis, and ankylosing
`spondylitis in participants are risk
`for developing NSAID-associated
`gastric ulcers.
`Intended Population(s) Adults 18 years and above
`Template Version: March 6, 2009
`
`

`

`Clinical Review of Safety and Efficacy
`Erica L. Wynn, MD MPH
`NDA 022511
`Vimovo Naproxen/Esomeprazole Magnesium
`
`
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`
`Table of Contents
`
`2
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`1 RECOMMENDATIONS/RISK BENEFIT ASSESSMENT......................................... 9
`1.1 Recommendation on Regulatory Action ............................................................. 9
`1.2 Risk Benefit Assessment.................................................................................... 9
`1.3 Recommendations for Postmarketing Risk Evaluation and Mitigation Strategies
`......................................................................................................................... 11
`1.4 Recommendations for Postmarketing Requirements and Commitments ......... 11
`INTRODUCTION AND REGULATORY BACKGROUND ...................................... 12
`2.1 Product Information .......................................................................................... 12
`2.2 Tables of Currently Available Treatments for Proposed Indications ................. 13
`2.3 Availability of Proposed Active Ingredient in the United States ........................ 19
`2.4
`Important Safety Issues With Consideration to Related Drugs......................... 19
`2.5 Summary of Presubmission Regulatory Activity Related to Submission .......... 20
`2.6 Other Relevant Background Information .......................................................... 23
`3 ETHICS AND GOOD CLINICAL PRACTICES....................................................... 23
`3.1 Submission Quality and Integrity ...................................................................... 23
`3.2 Compliance with Good Clinical Practices ......................................................... 23
`3.3 Financial Disclosures........................................................................................ 24
`4 SIGNIFICANT EFFICACY/SAFETY ISSUES RELATED TO OTHER REVIEW
`DISCIPLINES ......................................................................................................... 24
`4.1 Chemistry Manufacturing and Controls ............................................................ 24
`4.2 Clinical Microbiology......................................................................................... 24
`4.3 Preclinical Pharmacology/Toxicology ............................................................... 25
`4.4 Clinical Pharmacology...................................................................................... 26
`4.4.1 Mechanism of Action.................................................................................. 26
`4.4.2 Pharmacodynamics.................................................................................... 26
`4.4.3 Pharmacokinetics....................................................................................... 26
`5 SOURCES OF CLINICAL DATA............................................................................ 27
`5.1 Table of Clinical Studies/Trials......................................................................... 27
`5.2 Review Strategy ............................................................................................... 35
`5.3 Discussion of Individual Studies/Clinical Trials................................................. 35
`5.3.1 Overview of Protocols Submitted with Application ..................................... 35
`5.3.2 Clinical Overview of Trial PN400-301......................................................... 41
`5.3.3 Clinical Overview of Trial PN400-302......................................................... 56
`5.3.4
` Clinical Overview of Trial PN400-304........................................................ 69
`6 REVIEW OF EFFICACY......................................................................................... 84
`Efficacy Summary...................................................................................................... 84
`6.1
`Indication .......................................................................................................... 84
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`

`Clinical Review of Safety and Efficacy
`Erica L. Wynn, MD MPH
`NDA 022511
`Vimovo Naproxen/Esomeprazole Magnesium
`
`
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`
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`6.1.1 Methods ..................................................................................................... 85
`6.1.2 Demographics............................................................................................ 85
`6.1.3 Subject Disposition .................................................................................... 89
`6.1.4 Analysis of Primary Endpoint(s) ................................................................. 90
`6.1.5 Analysis of Secondary Endpoints(s)........................................................... 94
`6.1.6 Other Endpoints ......................................................................................... 95
`6.1.7 Subpopulations .......................................................................................... 95
`6.1.8 Analysis of Clinical Information Relevant to Dosing Recommendations .... 99
`6.1.9 Discussion of Persistence of Efficacy and/or Tolerance Effects................. 99
`6.1.10 Additional Efficacy Issues/Analyses......................................................... 100
`7 REVIEW OF SAFETY........................................................................................... 100
`Safety Summary ...................................................................................................... 100
`7.1 Methods.......................................................................................................... 102
`7.1.1 Studies/Clinical Trials Used to Evaluate Safety ....................................... 102
`7.1.2 Categorization of Adverse Events............................................................ 103
`7.1.3 Pooling of Data Across Studies/Clinical Trials to Estimate and Compare
`Incidence.................................................................................................. 104
`7.2 Adequacy of Safety Assessments .................................................................. 104
`7.2.1 Overall Exposure at Appropriate Doses/Durations and Demographics of
`Target Populations................................................................................... 105
`7.2.2 Explorations for Dose Response.............................................................. 110
`7.2.3 Special Animal and/or In Vitro Testing ..................................................... 111
`7.2.4 Routine Clinical Testing ........................................................................... 111
`7.2.5 Metabolic, Clearance, and Interaction Workup ........................................ 111
`7.2.6 Evaluation for Potential Adverse Events for Similar Drugs in Drug Class 112
`7.3 Major Safety Results ...................................................................................... 112
`7.3.1 Deaths...................................................................................................... 112
`7.3.2 Nonfatal Serious Adverse Events ............................................................ 112
`7.3.3 Dropouts and/or Discontinuations ............................................................ 118
`7.3.4 Significant Adverse Events ...................................................................... 135
`7.3.5 Submission Specific Primary Safety Concerns ........................................ 135
`7.4 Supportive Safety Results .............................................................................. 140
`7.4.1 Common Adverse Events ........................................................................ 140
`7.4.2 Laboratory Findings ................................................................................. 154
`7.4.3 Vital Signs................................................................................................ 157
`7.4.4 Electrocardiograms (ECGs) ..................................................................... 157
`7.4.5 Special Safety Studies/Clinical Trials....................................................... 157
`7.4.6
`Immunogenicity........................................................................................ 157
`7.5 Other Safety Explorations............................................................................... 158
`7.5.1 Dose Dependency for Adverse Events .................................................... 158
`7.5.2 Time Dependency for Adverse Events..................................................... 161
`7.5.3 Drug-Demographic Interactions ............................................................... 167
`7.5.4 Drug-Disease Interactions........................................................................ 168
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`Clinical Review of Safety and Efficacy
`Erica L. Wynn, MD MPH
`NDA 022511
`Vimovo Naproxen/Esomeprazole Magnesium
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`7.5.5 Drug-Drug Interactions............................................................................. 168
`7.6 Additional Safety Evaluations ......................................................................... 169
`7.6.1 Human Carcinogenicity............................................................................ 169
`7.6.2 Human Reproduction and Pregnancy Data.............................................. 169
`7.6.3 Pediatrics and Assessment of Effects on Growth .................................... 169
`7.6.4 Overdose, Drug Abuse Potential, Withdrawal and Rebound.................... 169
`7.7 Additional Submissions / Safety Issues.......................................................... 170
`8 POSTMARKETING EXPERIENCE ...................................................................... 170
`
`9 APPENDICES ...................................................................................................... 172
`9.1 Literature Review/References ........................................................................ 172
`9.2 Labeling Recommendations........................................................................... 172
`9.3 Advisory Committee Meeting.......................................................................... 177
`9.4 Details Individual Trial Designs........................................................................ 178
`9.4.1 Final Trial Protocols for PN 400-301 and PN400-302 ................................. 178
`9.4.2 Final Trial Protocol for Trial PN400-304 ...................................................... 187
`9.5 APTC Endpoints and non-APTC MACE Endpoints: Cardiovascular SAEs........ 194
`10 REFERENCES....................................................................................................... 195
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`

`Clinical Review of Safety and Efficacy
`Erica L. Wynn, MD MPH
`NDA 022511
`Vimovo Naproxen/Esomeprazole Magnesium
`
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`
`Table of Tables
`Table 1 Products Approved for the Risk Reduction of NSAID-associated Gastric Ulcers#
`....................................................................................................................... 14
`Table 2 Drugs Approved for the Treatment of Osteoarthritis and/or Rheumatoid Arthritis
`....................................................................................................................... 15
`Table 3 Drugs Approved for the Treatment of Ankylosing Spondylitis .......................... 17
`Table 4 Table of Clinical Trials ...................................................................................... 28
`Table 5 Reviewer’s Summary of Trial Protocol PN400-301 .......................................... 36
`Table 6 Reviewer's Summary of Trial Protocol PN400-302........................................... 38
`Table 7 Reviewers Summary of Trial Protocol PN400-304 ........................................... 40
`Table 8 Baseline Demographics Trial PN400-301 (ITT Population).............................. 41
`Table 9 Cumulative Incidence of Patients Developing Gastric Ulcers at 1, 3, & 6 months
`Trial PN400-301............................................................................................. 43
`Table 10 Overview of Adverse Events Safety Population Trial PN400-301 .................. 46
`Table 11 Serious Adverse Events for Trial PN400-301................................................. 48
`Table 12 Baseline Demographics Trial PN400-302 (ITT Population)............................ 57
`Table 13 Cumulative Incidence of Patients Developing Gastric Ulcers at 1, 3, & 6
`months Trial PN400-302 ................................................................................ 58
`Table 14 Overview of Adverse Events Safety Population Trial PN400-302 .................. 61
`Table 15 Serious Adverse Events for Trial PN400-302................................................. 62
`Table 16 Overview of Adverse Events Trial PN400-304 ............................................... 70
`Table 17 Serious Adverse Events for Trial PN400-304................................................. 72
`Table 18 Adverse Events Leading to Discontinuation in Trial PN400-304 .................... 82
`Table 19 Trial PN400-304 Laboratory Shifts from Baseline Using Expanded Laboratory
`Normal Range................................................................................................ 83
`Table 20 Baseline Demographic Distribution Across Pivotal Trials (ITT Populations)... 87
`Table 21 Low-Dose Aspirin Use Pivotal Trials PN400-301 and PN400-302 ................. 88
`Table 22 Accountability and Disposition of Trial Enrollees Trial PN400-301 and PN400-
`302................................................................................................................. 89
`Table 23 Analysis of Cumulative Observed Incidence of Patients Developing Gastric
`Ulcers at 1, 3, and 6 months Intent to Treat Population Trials PN400-301 and
`PN400-302..................................................................................................... 93
`Table 24 Key Secondary Endpoints Primary Safety Population (Trials PN400-301 and
`PN400-302) ................................................................................................... 94
`Table 25 Proportion of ITT Population:Trials PN400-301 and PN400-302 with Gastric
`Ulcer at 6 Months By Low-Dose Aspirin Use ................................................. 97
`Table 26 Cumulative Proportion of Study Enrollees with Gastric Ulcers at 6 months by
`Risk Factors, Combined Trials PN400-301 and PN400-302.......................... 98
`Table 27 Cumulative Proportion of Study Participants ≥ 65 years old ± Low Dose
`Aspirin Use who developed Gastric Ulcers. ................................................... 99
`Table 28 Table of Overall Safety Review of Vimovo Tablets....................................... 101
`Table 29 Pooled Populations for Safety Analysis........................................................ 103
`Table 30 Enumeration of Study Participants for New Drug Development Program .... 105
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`
`Clinical Review of Safety and Efficacy
`Erica L. Wynn, MD MPH
`NDA 022511
`Vimovo Naproxen/Esomeprazole Magnesium
`
`Table 31 Number of Study Participants Exposed to Vimovo by Duration of Study Drug
`Exposure and Total Doses Taken................................................................ 107
`Table 32 Demographic Data From Selected Pooled Populations. .............................. 109
`Table 33 Number of Study Participants who Took Vimovo Tablets (500/20mg) by
`Duration of Study Drug Exposure and Total Number of Doses Taken for All
`Clinical Trials ............................................................................................... 111
`Table 34 Number of SAEs in All of the Phase 3 Trials by Treatment Group ............... 113
`Table 35 Summary of Serious Adverse Events All Phase III Trials ............................. 115
`Table 36 Dropout Profile for All Phase III Trials .......................................................... 118
`Table 37 Patients Withdrawn from Vimovo Treatment Group Due to Elevated Blood
`Pressure or Hypertension ............................................................................ 121
`Table 38 Discontinuations from Vimovo due to Drops in Hemoglobin or Anemia ....... 123
`Table 39 Summary of Treatment Emergent Adverse Events Leading to Trial
`Discontinuation by System Organ Class and Selected Preferred Terms for all
`Phase III Clinical Trials § ............................................................................. 126
`Table 40 Summary of Selected Treatment Emergent Adverse Events Leading to
`Discontinuation by Age Subgroups in all Phase III Trials for Vimovo........... 131
`Table 41 SOC and Selected Preferred Terms of Adverse Events Leading to
`Discontinuation of Vimovo by AE Day of Onset (Expanded Safety Population)
`..................................................................................................................... 133
`Table 42 Listing of Normal Range and Extended Normal Range Laboratory Test Values
`for Liver Function Tests All Phase 3 Trials................................................... 136
`Table 43 Clinically Relevant Hepatic Transaminases from the Expanded Safety
`Population.................................................................................................... 137
`Table 44 Summary of Hepatic Function Tests Patient PN400-302-499-2260............. 139
`Table 45 Common Treatment Emergent Adverse Events, Including Gastric and
`Duodenal Ulcer, Occurring ≥ 2% in the Primary Safety Primary .................. 141
`Table 46 Selected Treatment Emergent Adverse Events By Age (in Decade) Primary
`Safety Population......................................................................................... 145
`Table 47 Treatment Emergent Adverse Events Occurring in ≥2% of Study Participants
`in the Supportive Safety Population............................................................. 150
`Table 48 Treatment Emergent Adverse Events, Including Gastric and Duodenal Ulcers,
`occurring in ≥ 2% of Study Participants in the ESP, PSP, SSP and the LSP
`..................................................................................................................... 152
`Table 49 Comparisons in Hemoglobin Changes between all Phase III Trial Populations
`and Agents................................................................................................... 155
`Table 50 Analysis of increases in serum creatinine ≥ 0.5mg/dl for all Trial Agents ..... 156
`Table 51 Treatment Emergent Adverse Events by Treatment Exposure PN400-304 . 159
`Table 52 Pre-Specified NSAID-Associated Upper Gastrointestinal Events................. 162
`Table 53 Onset of Selected Treatment Emergent Adverse Events by SOC and/or
`Preferred Term by Treatment Window: 12 month Completers Longterm Safety
`Trial PN400-304........................................................................................... 165
`Table 54 APTC and MACE Events by Trial Drug all Phase III studies ........................ 166
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`
`
`Clinical Review of Safety and Efficacy
`Erica L. Wynn, MD MPH
`NDA 022511
`Vimovo Naproxen/Esomeprazole Magnesium
`
`Table 55 Incidence of Analysis of Selected Cardiorenal Treatment Emergent Adverse
`Events: Expanded Safety Population (All Phase III trials except PN400-303)
`..................................................................................................................... 167
`
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`Clinical Review of Safety and Efficacy
`Erica L. Wynn, MD MPH
`NDA 022511
`Vimovo Naproxen/Esomeprazole Magnesium
`
`
`
`
`
`Table of Figures
`
`Figure 1 Cumulative Observed Incidence of Patients Developing Gastric Ulcers at 1, 3,
`and 6 Months Trial PN400-301 ITT Population (Percentages Reported)....... 42
`Figure 2 Cumulative Observed Incidence of Gastric Ulcers at 1, 3 and 6 months PN400-
`301 Per Protocol Population (Percentages Reported) ................................... 44
`Figure 3 Cumulative Incidence of Patients Developing Gastric Ulcers in Participants >/=
`65 years old with and without Low-Dose Aspirin Use PN400-301 ................. 45
`Figure 4 Study PN400-301 Primary Reason for Withdrawals by Treatment.................. 55
`Figure 5 Cumulative Observed Incidence of Patients Developing Gastric Ulcers at 1, 3,
`and 6 months Trial PN400-302 ITT population (Percentages Reported) ....... 58
`Figure 6 Cumulative Observed Incidence of Patients Developing Gastric Ulcers at 1, 3,
`and 6 months PN400-302 PP Population (Percentages reported)................. 59
`Figure 7 Cumulative Incidence of Patients Developing Gastric Ulcers in Trial
`Participants who are >/= 65 years old with and without Low Dose Aspirin Use
`PN400-302 (Reported in Percentages).......................................................... 60
`Figure 8 Primary Reason for Withdrawal Trial PN400-302............................................ 67
`Figure 9 Summary of Reasons for Withdrawal of Consent Trial PN400-302................. 68
`Figure 10 Primary Reason for Withdrawal Trial PN400-304......................................... 69
`Figure 11 Analysis of Cumulative Observed Incidence of Patients Developing Gastric
`Ulcers (in Percentages) at 1, 3, and 6 months (ITT Population from Combined
`Trials PN400-301 and PN400-302)................................................................ 92
`Figure 12 Kaplan-Meier Plot of Time to Gastric Ulcer (ITT Population PN400-301) ... 161
`Figure 13 Kaplan-Meier Plot of Time to Gastric Ulcer (ITT Population PN400-302) ... 161
`Figure 14 Kaplan Meier Graph Cumulative Incidence of Pre-specified NSAID
`Associated Adverse Events or Duodenal Ulcers Leading to Trial
`Discontinuation :ITT Population Trials PN400-301 and PN400-302 ............ 163
`Figure 15 Kaplan Meier Graph Cumulative Incidence of Pre-Specified NSAID
`Associated Upper Gastrointestinal Adverse Events Leading to Withdrawal :
`Overall Safety Population Long Term Trial PN400-304 ............................... 164
`Figure 16 Visit and Schedule of Assessments for Trial PN400-301 and PN400-302 .. 182
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`Clinical Review of Safety and Efficacy
`Erica L. Wynn, MD MPH
`NDA 022511
`Vimovo Naproxen/Esomeprazole Magnesium
`
`
`
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`1 Recommendations/Risk Benefit Assessment
`
`
`1.1 Recommendation on Regulatory Action
`
`The sponsor has proposed the following indication for Vimovo tablets: relief of signs and
`symptoms of osteoarthritis, ankylosing spondylitis, and rheumatoid arthritis in patients at
`risk of developing NSAID-associated gastric ulcers.
`
`In reference to the reduction of gastric ulcers, based on the data provided, this medical
`reviewer recommends approval for the aforementioned indication. The sponsor has
`provided evidence that Vimovo was superior to the active control (EC Naproxen) in
`decreasing the incidence of NSAID-induced ulcer formation. The proportion of patients
`developing gastric ulcers while taking Vimovo was statistically lower than the proportion
`of patients taking EC Naproxen (5.6% vs. 23.7%). It is important to note that in the
`opinion of this medical officer, it has been well documented that all patients taking
`NSAIDs chronically are at risk of ulcer formation. In this medical officer’s opinion, the
`sponsor has not studied patients at high-risk of developing complications from NSAID-
`induced GI toxicity. The one clinical trial (PN400-303) designed to support this claim
`was terminated early.
`
`Review of this NDA was done with consultation from the Division of Anesthesiology and
`Rheumatology Products. Per the DAARP consult, superiority of Vimovo to placebo was
`established for the indication of the treatment of the signs and symptoms of
`osteoarthritis based on primary ITT/LOCF analysis and three sensitivity analyses.
`Together, the bioequivalence of the naproxen in Vimovo tablets to the reference drug
`(EC Naproxen) and the superiority of Vimovo to placebo for pain reduction provide
`adequate evidence of efficacy for the proposed indication from DAARPs perspective.
`
`1.2 Risk Benefit Assessment
`
`The current submission is a 505(b)(2) application using Nexium® and EC Naprosyn® as
`the reference listed drugs. The enteric coated naproxen component of Vimovo has been
`shown to be bioequivalent with EC Naprosyn®. The nexium component is immediate
`release and initially has half of the bioavailability of the equivalent dose of Nexium®.
`However, cumulative dosing of Vimovo increases the bioavailability of the Nexium®
`component.
`
`Both of the reference listed drugs have been marketed in the United States for a
`number of years and have been used concurrently in patients at risk of developing
`ulcers due to chronic NSAID use. Given the information that has been provided in the
`sponsor’s application, Vimovo was effective for pain reduction and reduction in ulcer
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`
`Clinical Review of Safety and Efficacy
`Erica L. Wynn, MD MPH
`NDA 022511
`Vimovo Naproxen/Esomeprazole Magnesium
`
`formation. Based on the information provided, it is unlikely that the applicant’s proposed
`Vimovo tablet will cause any more significant harm or put patients in the general
`population at any greater risk of experiencing an adverse event than the currently
`marketed individual components.
`
`Our risk-benefit analysis can not exclude some consideration of the patient’s quality of
`life, which is inherently subjective and difficult to quantify. Gastrointestinal symptoms
`due to peptic ulcer disease can cause absenteeism or reduce productivity while at work,
`therefore causing wider implications for health care systems in terms of costs. It is
`highly probable that the patients that will benefit the most from Vimovo will have more
`than one medical condition and comorbidity. It is also probable that the ease of
`administering the two active components of Vimovo in one tablet will improve patient
`compliance and possibly patient outcomes. One can reasonably anticipate that Vimovo
`will be used chronically. At 6 months, the percentage of patients taking Vimovo who
`developed gastric ulcers was significantly lower than those taking Naproxen (5.6% vs.
`23.7%). In the data that was submitted, overall rates of adverse events favored Vimovo
`(78.3%) over Naproxen® (87.6%). Although patients taking Vimovo experienced more
`cardiac events overall than placebo in the supportive trials (1.2% vs. 0%), the rate of
`cardiac adverse events was similar to the currently marketed Naproxen® (2.4% for
`Vimovo vs. 2.2% for Naproxen®). The 12 month long-term study did not show an
`increase in the rate of myocardial infarction (a known risk associated with NSAID use).
`Only 1 patient in the entire clinical development program experienced a myocardial
`infarction. Likewise, there does not appear to be an increase in the rate of
`cerebrovascular events. No patient in the clinical development program experienced a
`stroke. Three patients experienced a transient ischemic attack in the Vimovo group
`(0.25%). No one experienced a TIA in the control groups. Although there were no cases
`meeting criteria for Hy’s Law, there were 2 cases of elevated hepatic enzymes > 10X
`the upper limit of normal. All of these side effects are known to be associated with either
`NSAID or PPI use and found in the current labeling for the respective components of
`Vimovo.
`
`Nexium is only approved for 6 months for the risk reduction of NSAID induced ulcers.
`Prolonged use of PPIs has been associated with bacterial overgrowth, fractures,
`hypergastrinemia and other complications. (See Section 2.4) Although the naproxen
`component of Vimovo has two strengths (375mg and 500mg), the esomeprazole
`component of both dosage forms of Vimovo is fixed at 20mg. To ensure that the
`benefits of drug use overweigh the risks, the medical officer suggests that physicians
`consider daily use of this medication for no more than 6 months or use the lowest dose
`that will relieve patient symptoms for as short of a duration as possible. Additional
`recommendations for the safe use of this drug are reflected in the labeling section
`below.
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`Clinical Review of Safety and Efficacy
`Erica L. Wynn, MD MPH
`NDA 022511
`Vimovo Naproxen/Esomeprazole Magnesium
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`1.3 Recommendations for Postmarketing Risk Evaluation and Mitigation
`Strategies
`
`As of 2005, all prescription NSAIDs have been required to include a Box Warning and
`Medication Guide as parts of the product label due to the risk of cardiovascular and
`gastrointestinal adverse events. A Medication Guide only REMS is necessary to ensure
`that the benefits of Vimovo outweigh its risks of cardiovascular and gastrointestinal
`adverse events. These risks are included in the label of Vimovo and all members of the
`class of Nonsteroidal Anti-Inflammatory Drugs.
`
`1.4 Recommendations for Postmarketing Requirements and Commitments
`
`The sponsor has requested a full waiver from the requirement to conduct studies with
`Vimovo in patients from birth to 18 years of age.
`
`. The proposed
`indication is for “the treatment of osteoarthritis, rheumatoid arthritis, and ankylosing
`spondylitis in patients at risk of developing NSAID-associated ulcers.” Essentially all
`patients on NSAID therapy are at risk of developing ulcers. In general the histology of
`pediatric gastric ulcers is similar to adults. While esomeprazole, a component of
`Vimovo, is approved for use in children as young as 1 year of age, there are no dosing
`recommendations for the sponsor’s proposed indication. Gastrointestinal toxicity from
`NSAIDs in children does exist but estimates of prevalence vary. Several papers using
`varying protocols and study participants have attempted to discern the prevalence of
`NSAID gastropathy in children, with varying conclusions. The percentage of pediatric
`patients who experience NSAID toxicity and the severity of the adverse effects in
`children appear to be less than that seen in adults. However, use of these medications
`on a chronic basis can still lead to potentially significant issues.1
`
`Juvenile Idiopathic Arthritis (previously known as juvenile rheumatoid arthritis) and other
`forms of inflammatory chronic arthritis represent the most frequently occurring
`indications for chronic use of NSAIDs in children.1 No individual NSAID has been shown
`to have a clear advantage over others in treating arthritis or the fever associated with
`systemic arthritis.1 Although it is difficult to determine the prevalence and incidence of
`the childhood arthropathies, approximately 300,000 children in the United States are
`estimated to have some type of arthritis.2 Studies have been performed successfully in
`pediatric patients with JIA to establish a treatment indication. Naproxen is currently
`available in a suspension form for the treatment of JRA and seems to be the standard
`NSAID of choice in the pediatric rheumatology community.3
`
`Although a COX-2 inhibitor, is an available option for pediatric patients on NSAIDs who
`require gastro-protective therapy, having additional options for children with JIA and
`those who do not respond to other therapies would be beneficial. Pediatric health care
`providers may also welcome an additional alternative NSAID preparation that decreases
`GI toxicity and perhaps has less potential for adverse events.
`
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`Clinical Review of Safety and Efficacy
`Erica L. Wynn, MD MPH
`NDA 022511
`Vimovo Naproxen/Esomeprazole Magnesium
`
`
`
`
`
` A
`
` pediatric consult was obtained. On April 14, 2010, the medical officer’s
`recommendation for deferral of pediatric studies was presented to the Pediatric Review
`Committee. The PeRC committee concurred with the opinion of the review team. The
`efficacy of Vimovo tablets for juvenile arthritis and peptic ulcer disease can be
`e