CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`205103Orig1s000
`
`CLINICAL REVIEW(S)
`
`
`
`
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`
`
`
`

`

`Clinical Review
`Zana Marks, MD, MPH
`NDA 205103
`Yosprala: Aspirin/Omeprazole
`
`CLINICAL REVIEW
`
`Application Type
`Application Number
`Priority or Standard
`
`505(b)(2)
`NDA 205103
`Standard
`
`Submit Date March 25, 2013
`Received Date March 25, 2013
`PDUFA Goal Date
`April 25, 2014
`Division / Office
`Division of Gastroenterology and Inborn Errors
`Products
`
`Reviewer Name
`Review Completion Date
`
`Zana H. Marks, MD, MPH
`December 16, 2013
`
`Established Name
`(Proposed) Trade Name
`Therapeutic Class
`Applicant
`
`Aspirin/omeprazole
`YOSPRALA
`
`POZEN
`
`Formulation Oral tablet
`Dosing Regimen
`ECASA (325 mg ) and Omeprazole (40mg)
`once a day
`
`Proposed Indications
`
`Intended Population(s)
`
`Adults 18 years and above
`
`Reference ID: 3475586
`
`1
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`(b) (4)
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`

`

`Clinical Review
`Zana Marks, MD, MPH
`NDA 205103
`Yosprala: Aspirin/Omeprazole
`
`Table of Contents
`
`2
`
`1 RECOMMENDATIONS/RISK BENEFIT ASSESSMENT......................................... 8
`1.1 Recommendation on Regulatory Action ............................................................. 8
`1.2 Risk Benefit Assessment.................................................................................... 8
`1.3 Recommendations for Postmarket Risk Evaluation and Mitigation Strategies . 10
`1.4 Recommendations for Postmarket Requirements and Commitments .............. 10
`INTRODUCTION AND REGULATORY BACKGROUND ...................................... 10
`2.1 Product Information .......................................................................................... 10
`2.2 Tables of Currently Available Treatments for Proposed Indications ................. 12
`2.3 Availability of Proposed Active Ingredient in the United States ........................ 13
`2.4
`Important Safety Issues With Consideration to Related Drugs......................... 13
`2.5 Summary of Presubmission Regulatory Activity Related to Submission .......... 14
`2.6 Other Relevant Background Information .......................................................... 17
`3 ETHICS AND GOOD CLINICAL PRACTICES....................................................... 17
`3.1 Submission Quality and Integrity ...................................................................... 17
`3.2 Compliance with Good Clinical Practices ......................................................... 17
`3.3 Financial Disclosures........................................................................................ 17
`4 SIGNIFICANT EFFICACY/SAFETY ISSUES RELATED TO OTHER REVIEW
`DISCIPLINES ......................................................................................................... 18
`4.1 Chemistry Manufacturing and Controls ............................................................ 18
`4.2 Clinical Microbiology......................................................................................... 18
`4.3 Preclinical Pharmacology/Toxicology ............................................................... 18
`4.4 Clinical Pharmacology...................................................................................... 18
`4.4.1 Mechanism of Action.................................................................................. 18
`4.4.2 Pharmacodynamics.................................................................................... 19
`4.4.3 Pharmacokinetics....................................................................................... 19
`5 SOURCES OF CLINICAL DATA............................................................................ 22
`5.1 Tables of Studies/Clinical Trials ....................................................................... 24
`5.2 Review Strategy ............................................................................................... 26
`5.3 Discussion of Individual Studies/Clinical Trials................................................. 26
`5.3.1 Study PA32540-301 and PA32540-302 ........................................................ 26
`5.3.2 Efficacy and Safety Measurements for Studies PA32540-301 and PA32540-
`302............................................................................................................. 35
`6 REVIEW OF EFFICACY......................................................................................... 62
`Efficacy Summary...................................................................................................... 62
`6.1.1 Methods ..................................................................................................... 62
`6.1.2 Demographics............................................................................................ 64
`6.1.3 Subject Disposition .................................................................................... 65
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`Reference ID: 3475586
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`Clinical Review
`Zana Marks, MD, MPH
`NDA 205103
`Yosprala: Aspirin/Omeprazole
`
`6.1.4 Analysis of Primary Endpoint(s) ................................................................. 66
`6.1.5 Analysis of Secondary Endpoints(s)........................................................... 68
`6.1.7 Subpopulations .......................................................................................... 70
`6.1.8 Analysis of Clinical Information Relevant to Dosing Recommendations .... 72
`6.1.9 Discussion of Persistence of Efficacy and/or Tolerance Effects................. 72
`6.1.10 Additional Efficacy Issues/Analyses........................................................... 72
`7 REVIEW OF SAFETY............................................................................................. 73
`Safety Summary ........................................................................................................ 73
`7.1 Methods............................................................................................................ 73
`7.1.1 Studies/Clinical Trials Used to Evaluate Safety ......................................... 73
`7.1.2 Categorization of Adverse Events.............................................................. 74
`7.1.3 Pooling of Data Across Studies/Clinical Trials to Estimate and Compare
`Incidence.................................................................................................... 74
`7.2 Adequacy of Safety Assessments .................................................................... 75
`7.2.1 Overall Exposure at Appropriate Doses/Durations and Demographics of
`Target Populations..................................................................................... 76
`7.2.2 Explorations for Dose Response................................................................ 76
`7.2.3 Special Animal and/or In Vitro Testing ....................................................... 77
`7.2.4 Routine Clinical Testing ............................................................................. 77
`7.2.5 Metabolic, Clearance, and Interaction Workup .......................................... 77
`7.2.6 Evaluation for Potential Adverse Events for Similar Drugs in Drug Class .. 77
`7.3 Major Safety Results ........................................................................................ 78
`7.3.1 Deaths........................................................................................................ 78
`7.3.2 Nonfatal Serious Adverse Events .............................................................. 78
`7.3.3 Dropouts and/or Discontinuations .............................................................. 83
`7.3.4 Significant Adverse Events ........................................................................ 86
`7.3.5 Submission Specific Primary Safety Concerns .......................................... 86
`7.4 Supportive Safety Results ................................................................................ 88
`7.4.1 Common Adverse Events .......................................................................... 88
`Source: Electronically reproduced and copied. ISS Table S2.4. Page 1233.......... 89
`Source: Electronically reproduced and copied. ISS Table S2.4. Page 1234.......... 90
`7.4.2
`Laboratory Findings ................................................................................... 92
`7.4.3 Vital Signs.................................................................................................. 92
`7.4.4 Electrocardiograms (ECGs) ....................................................................... 92
`7.4.5 Special Safety Studies/Clinical Trials......................................................... 92
`7.4.6
`Immunogenicity.......................................................................................... 92
`7.5 Other Safety Explorations................................................................................. 92
`7.5.1 Dose Dependency for Adverse Events ...................................................... 93
`7.5.2 Time Dependency for Adverse Events....................................................... 93
`7.5.3 Drug-Demographic Interactions ................................................................. 93
`7.5.4 Drug-Disease Interactions.......................................................................... 93
`7.5.5 Drug-Drug Interactions............................................................................... 94
`7.6 Additional Safety Evaluations ........................................................................... 94
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`Clinical Review
`Zana Marks, MD, MPH
`NDA 205103
`Yosprala: Aspirin/Omeprazole
`
`7.6.1 Human Carcinogenicity.............................................................................. 94
`7.6.2 Human Reproduction and Pregnancy Data................................................ 94
`7.6.3 Pediatrics and Assessment of Effects on Growth ...................................... 94
`7.6.4 Overdose, Drug Abuse Potential, Withdrawal and Rebound...................... 94
`7.7 Additional Submissions / Safety Issues............................................................ 95
`8 POSTMARKET EXPERIENCE............................................................................... 95
`9
`LABELING RECOMMENDATIONS ....................................................................... 95
`10 ADVISORY COMMITTEE MEETING ..................................................................... 96
`11 APPENDICES ........................................................................................................ 96
`11.1 Literature Review/References............................................................................ 96
`
`Reference ID: 3475586
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`Clinical Review
`Zana Marks, MD, MPH
`NDA 205103
`Yosprala: Aspirin/Omeprazole
`
`Table of Tables
`
`Table 1 Tabular Description of All Clinical Trials ........................................................... 24
`Table 2: Scheduled Study Assessments for Studies PA32540-301 and PA32540-30236
`Table 3: Subject Disposition......................................................................................... 40
`Table 4. Summary of Major Protocol Violations for Study PA32540-301 (All Randomized
`Subjects) ....................................................................................................................... 41
`Table 5: Data Sets Analyzed for Study PA32540-301................................................... 42
`Table 6: Demographics and Other Baseline Characteristics- ITT Population................ 43
`Table 7: Ulcer History and NSAID Use at Randomization Study PA32540-301............ 44
`Table 8: Cardiovascular and Cerebrovascular Histories, Co-Morbidities, and Clopidogrel
`Use at Randomization-ITT Population........................................................................... 46
`Table 9: Concomitant Medication Use by Class taken by ≥ 10% of Subjects in Either
`Treatment Group Safety Population Study PA32540-301............................................. 48
`Table 10: Analysis of Cumulative Proportion (n %) of Subjects Developing Gastric
`Ulcers through 1, 3, and 6 Months- ITT Population....................................................... 50
`Table 11: Analysis of Cumulative Proportion (n %) of Subjects Developing Gastric
`and/or Duodenal Ulcers through 1, 3, and 6 Months- ITT Population ........................... 51
`Table 12: Proportion of Subjects Discontinuing due to Pre-Specified UGI Adverse
`Events Study PA32540-301 –ITT Population................................................................ 51
`Table 13: Subject Disposition for Study PA32540-302- All Randomized Subjects........ 52
`Table 14: Summary of Major Protocol Violations for Study PA32540-302-All
`Randomized Subjects ................................................................................................... 53
`Table 15 Data Sets Analyzed Study PA32540-302...................................................... 54
`Table 16: Demographics and Other Baseline Characteristics-ITT Population............... 55
`Table 17: Ulcer History and NSAID use at randomization for Study PA32540-302-ITT
`Population ..................................................................................................................... 56
`Table 18: Cardiovascular and cerebrovascular Histories, Co-Morbidities, and
`Clopidogrel Use at Randomization – ITT Population..................................................... 58
`Table 19: Analysis of the Cumulative Proportion (n, %) of Subjects Developing Gastric
`Ulcers............................................................................................................................ 60
`Table 20: Analysis of Cumulative Proportion (n %) of Subjects Developing Gastric
`and/or Duodenal Ulcers through 1, 3, and 6 Months Study PA32540-302 - ITT
`Population ..................................................................................................................... 61
`Table 21: Proportion of Subjects Discontinuing due to Pre-Specified UGI Adverse
`Events Study PA32540-302 –ITT Population................................................................ 61
`Table 22. Conditions Required for Inclusion in Studies PA32540-301 and PA32540-302
`...................................................................................................................................... 63
`Table 23 Demographics in the ITT Population from Studies PA32540-301 and
`PA32540-302 ................................................................................................................ 65
`Table 24 Subject Disposition: All randomized Subjects from Studies 301 and 302....... 65
`Table 25: Analysis of Cumulative Proportion (n %) of Subjects Developing Gastric
`Ulcers through 1, 3, and 6 Months Study PA32540-301- ITT Population...................... 66
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`Clinical Review
`Zana Marks, MD, MPH
`NDA 205103
`Yosprala: Aspirin/Omeprazole
`
`Table 26: Analysis of the Cumulative Proportion (n, %) of Subjects Developing Gastric
`Ulcers............................................................................................................................ 67
`Table 27: Analysis of Cumulative Proportion of Subjects Developing Gastric Ulcers at 1,
`3, and 6 months- ITT population in the Combined Analysis .......................................... 67
`Table 28: Outcomes of Secondary Efficacy and Tolerability Endpoints-ITT Population
`Studies PA32540-301 and PA32540-302...................................................................... 70
`Table 29: Analysis of Cumulative Proportion of Subjects Developing Gastric Ulcers
`Throughout 6 Months by Age Group- ITT Population in the Combined Analysis .......... 71
`Table 30: Exposure by Population, PA32540 and ECASA 325 mg............................... 75
`Table 31: Extent of Exposure in the Primary Safety Population (PSP).......................... 76
`Table 32: Incidence of Treatment Emergent Adverse Events-Primary Safety Population
`PA32540-301 and PA32540-302 .................................................................................. 79
`Table 33: Incidence of Serious Adverse Events related to Study Drug in Studies
`PA32540-301 and PA32540-302 .................................................................................. 83
`Table 34: Incidence of Treatment Emergent Adverse Events of the SOC of
`Gastrointestinal Disorders Leading to Study Drug Discontinuation in the Primary Safety
`Population (PSP)........................................................................................................... 85
`Table 35: Clinically Relevant Hepatic-Related Changes in the Primary Safety Population
`(PSP)............................................................................................................................. 87
`Table 36: Incidence of Shifts Denoting Worsening Renal Function in the Primary Safety
`Population ..................................................................................................................... 88
`Table 37: Incidence of All Treatment Emergent Adverse Events by System Organ
`Class-Primary Safety Population from Studies 301 and 302......................................... 89
`Table 38: Pre-specified UGI Adverse Events with Proportion of Subjects (≥ 2% in Either
`Treatment Group) in the Primary Safety Population...................................................... 91
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`Clinical Review
`Zana Marks, MD, MPH
`NDA 205103
`Yosprala: Aspirin/Omeprazole
`
`Table of Figures
`
`Figure 1 Aspirin ............................................................................................................. 12
`Figure 2 Omeprazole..................................................................................................... 12
`Figure 3 Pharmacokinetic Profile of PA32540-Acetylsalicylic acid and Omeprazole..... 20
`Figure 4 Pharmacokinetic Profile of PA32540-Acetylsalicylic acid and Omeprazole..... 21
`Figure 5: Plot of Cumulative Incidence of Pre-specified Upper GI Adverse Events
`Leading to Study Discontinuation – ITT Population from Combined Analysis (Studies
`PA32540-301 and 302) ................................................................................................. 69
`
`Reference ID: 3475586
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`Clinical Review
`Zana Marks, MD, MPH
`NDA 205103
`Yosprala: Aspirin/Omeprazole
`
`1
`
`Recommendations/Risk Benefit Assessment
`
`1.1 Recommendation on Regulatory Action
`
`From the clinical standpoint, the submitted clinical data are adequate to support the
`recommendation of marketing approval for Yosprala (enteric coated aspirin 325
`mg/omeprazole 40 mg) for the indication of preventing recurrent cerebrovascular and
`cardiovascular events, in subjects at risk of developing aspirin-associated gastric ulcers.
`
`1.2 Risk Benefit Assessment
`
`The geriatric population is increasing and as such there are more individuals with
`cardiovascular and cerebrovascular disease requiring daily antiplatelet therapy such as
`aspirin. Aspirin produces its antithrombotic effect by irreversible acetylation of a serine
`residue in platelet cyclooxygenase-1 (COX-1), which blocks thromboxane A2 production
`for the life of the platelet, preventing platelet aggregation. Low dose aspirin, commonly
`defined as 75-325 mg daily, is now widely used for primary and secondary prevention of
`cardiovascular (CV) disease.1
`
`However, aspirin has been shown to cause a two to three fold increase in the risk of
`dose related peptic ulcer bleeding.2 Aspirin is thought to cause mucosal damage by
`both topical irritant effects on the epithelium and systemic effects related to the
`suppression of mucosal prostaglandin synthesis. This suppression reduces mucosal
`defenses such as mucus and bicarbonate secretion, blood flow, epithelial cell turnover
`and repair and mucosal immunocyte function.
`
`Aspirin therapy has become an integral part in the primary and secondary prevention of
`cardiovascular disease. It has been associated with a significantly lower risk of
`cardiovascular events, such as myocardial infarction, stroke or vascular death. Even at
`low doses (<100mg) aspirin may be associated with gastrointestinal adverse events3.
`These are more prevalent in patients who are at increased risk, such as older patients,
`those with a previous history of ulcer disease or a GI bleed, steroid or anticoagulation
`medication use, or H. pylori infection. The GI effects of low dose aspirin (LDA) range
`
`
`1 Hirata, Yoshikazu et al Incidence of gastrointestinal bleeding in patients with cardiovascular disease:
`buffered aspirin versus enteric coated aspirin; Scandanavian Journal of Gastroenterology, 2011;46:803-
`809
`2 Laine, L. Review article: Gastrointestinal bleeding with low dose aspirin-what’s the risk?;Ailment
`Pharmacol Ther 2006;24(6):897-908
`3 ibid
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`Clinical Review
`Zana Marks, MD, MPH
`NDA 205103
`Yosprala: Aspirin/Omeprazole
`
`from dyspeptic symptoms and heartburn to serious peptic ulcer complications with
`bleeding and perforation. The risk of gastrointestinal bleeding after a year of aspirin use
`is more than twice that of non-users. Enteric coated and buffered formulations have not
`been shown to lessen the potential for untoward GI events with aspirin use.4
`
`Gastrointestinal bleeding may occur without warning and may lead to discontinuation of
`LDA therapy. Development of symptoms such as dyspepsia or heartburn may also
`result in discontinuing LDA therapy. This is troublesome because discontinuing the
`aspirin may be associated with an increased risk for serious cardiovascular events to
`occur. Having patients continue on aspirin therapy is key to the management of
`cardiovascular disease.5
`
`The benefits of aspirin therapy must be balanced against the increased risk for GI
`adverse events such as dyspepsia and bleeding associated with the use of aspirin.
`Therefore concomitant gastroprotection with a proton pump inhibitor (PPI) is
`recommended for cardiovascular patients who require continuous low dose aspirin
`therapy and are at increased risk for gastrointestinal injury.6
`
`All drugs have both benefit and risk. Treatment must be based on whether the potential
`benefit outweighs the risk of harm. The benefit of aspirin in the treatment of
`cardiovascular disease is well documented as is the risk of GI bleeding associated with
`its use. The challenge to healthcare providers is to determine the risk/benefit balance
`for individual patients.
`
`The expert consensus document developed by the American College of Cardiology
`Foundation (ACCF), the American College of Gastroenterology (ACG) and the
`American Heart Association (AHA) recommend proton pump inhibitors be co-prescribed
`with antiplatelet therapy such as aspirin to reduce the increased risk of GI
`complications. The need for GI protection increases with the number of risk factors for
`severe bleeding, the strongest and most consistent risk factor being a previous upper GI
`bleed (UGIB).
`
`Patients with coronary artery disease and prior UGIB are at a greater risk of
`cardiovascular events and GI bleeds, so concomitant aspirin and PPI therapy may
`provide an acceptable balance of risk and benefit. This is also evident in stable patients
`
`4 Hirata, Yoshikazu et al Incidence of gastrointestinal bleeding in patients with cardiovascular disease:
`buffered aspirin versus enteric coated aspirin; Scandinavian Journal of Gastroenterology, 2011;46:803-
`809
`5 Scheinman, J; Prevention of peptic ulcers with esomeprazole in patients at risk of ulcer development
`treated with low dose acetylsalicylic acid: a randomized, controlled trial (OBERON);Heart 2011;97:797-
`802
`6 Harrington, R et al. ACCF/ACG/AHA 2010 expert consensus document on the concomitant use of
`proton pump inhibitors and thienopyridines: a focused update of the ACCF/ACG/AHA 2008 expert
`consensus document on reducing the GI risks of antiplatelet therapy and NSAID use. Am J Gastroenterl
`2010;105:2533-49
`
`Reference ID: 3475586
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`Clinical Review
`Zana Marks, MD, MPH
`NDA 205103
`Yosprala: Aspirin/Omeprazole
`
`undergoing coronary revascularization who may have had a GI bleed previously. If a
`coronary stent is placed to treat the patient, the risk/benefit also may favor the
`concomitant use of antiplatelet therapy and a PPI.
`
`The other factors that increase the risk of GI bleeding with antiplatelet therapy such as
`advanced age, concomitant use of coumadin, steroids, NSAIDs; or H. pylori infection
`may be mitigated with the combined use of aspirin and PPI therapy.
`
`The use of Yosprala Tablets containing enteric coated aspirin 325 mg and omeprazole
`40 mg would presumably reduce the undesired gastrointestinal effects often associated
`with long term aspirin use. The addition of the omeprazole to the aspirin may result in
`improving adherence to the aspirin therapy by eliminating upper GI adverse events
`often associated with aspirin use such as dyspepsia and heartburn. Increased
`compliance with this medication would enhance therapeutic goals while improving the
`overall risk benefit profile for aspirin in patients being treated for the secondary
`prevention of cardiovascular and cerebrovascular disease who are at risk for developing
`gastric ulcers.
`
`1.3 Recommendations for Postmarket 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. Aspirin, an NSAID, is in a class of drugs called
`salicylates that have a known risk of gastrointestinal adverse events associated with
`chronic or long term use, even at low doses. Therefore a Medication Guide is
`necessary to communicate these risks. A REMS is not recommended.
`
`1.4 Recommendations for Postmarket Requirements and Commitments
`
`The sponsor requested a full waiver from the requirement to conduct studies with
`Yosprala in patients from birth to 18 years of age because the proposed indication in the
`pediatric population is rare, therefore the incidence of aspirin associated gastric ulcers
`would also expected to be rare.. The Pediatric Review Committee convened on
`September 25, 2013 and the waiver request was agreed upon.
`
`2
`
`Introduction and Regulatory Background
`
`2.1 Product Information
`
`Yosprala Tablets are a multilayer tablet consisting of an enteric-coated aspirin core
`(ECASA 325 mg), and an immediate release (IR) omeprazole 40 mg film coat. This
`
`Reference ID: 3475586
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`

`Clinical Review
`
`Zana Marks, MD, MPH
`NDA 205103
`
`Yosprala: Aspirin/Omeprazole
`
`allows for the sequential release, first of omeprazole in the stomach
`followed by the release of aspirin
`Yosprala Tablets are intended for oral administration on a once daily
`regimen to provide the benefits of aspirin with the upper gastrointestinal (UGI)
`protection of the Proton Pump Inhibitor (PPI; omeprazole).
`
`91(4)
`
`(I!) (4)
`
`Omeprazole is a proton pump inhibitor that inhibits the H+IK+ ATPase enzyme system at
`the secretory surface of the gastric parietal cell. The labeled indications include:
`0 Treatment in adults of duodenal ulcer and gastric ulcer
`
`0 Treatment in adults and children of gastroesophageal reflux disease (GERD) and
`maintenance of healing of erosive esophagitis
`The safety and effectiveness of omeprazole in pediatric patients < 1 year of age have
`not been established.
`
`Omeprazole currently does not have an indication for the prevention of gastric or
`duodenal ulcers.
`
`Aspirin is acetylsalicylic acid and is chemically known as benzoic acid, 2-(acetyloxy).
`Aspirin irreversibly inhibits platelet COX-1. Aspirin is available by prescription and over
`the counter (OTC). The professional labeling for aspirin in the Monograph
`(21 CFR343.80) includes the following indications which are all secondary prevention of
`cardiovascular event indications. The dose is in parentheses:
`
`0 Reduction of the combined risk of death and non-fatal stroke in patients who
`have had ischemic stroke or transient ischemia of the brain due to fibrin platelet
`emboli (50-325 mg once a day, continued indefinitely),
`
`0 Reduction of risk of vascular mortality in patients with a suspected acute MI (160-
`162.5 mg once a day for 30 days),
`
`0 Reduction of combined risk of death and non-fatal MI in patients with previous
`Ml or unstable angina pectoris (75-325 mg once a day, continued indefinitely),
`and
`
`0 Reduction of combined risk of MI and sudden death in patients with chronic
`stable angina pectoris (75-325 mg once a day, continued indefinitely).
`
`Aspirin is also indicated for use in revascularization procedures when there is a
`preexisting condition for which aspirin is already indicated. For CABG, 325 mg daily is
`started post— procedure and continue for 1 year. For PTCA, 325 mg is administered pre-
`surgery, and the maintenance dose post-surgery is 160-325 mg daily, continued
`indefinitely. For carotid endarterectomy, the dose ranges from 80 mg once daily to 650
`mg twice daily, continued indefinitely.
`
`Reference ID: 3475586
`
`1 1
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`

`

`Clinical Review
`
`Zana Marks, MD, MPH
`NDA 205103
`
`Yosprala: Aspirin/Omeprazole
`
`Patients in the studies submitted in support of this application used Omeprazole in an
`immediate release formulation at 40mg combined in a single tablet with delayed release
`aspirin at 325 mg.
`
`Structural Formulas
`
`Figure 1 Aspirin
`0
`
`do“0
`0%CH3
`
`Figure 2 Omeprazole
`
`:4
`
`5—CHWeir?I;
`
`ocn,
`
`cu,
`
`Molecular Formula
`
`The empirical formula of aspirin is CQH304. The empirical formula of omeprazole is
`C17H19N303S.
`
`Molecular Weight
`
`The molecular weight of aspirin is 180.16. The molecular weight of omeprazole is 345.4.
`
`2.2 Tables of Currently Available Treatments for Proposed Indications
`
`There is no FDA approved drug for the proposed indication
`
`M"
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`Reference ID: 3475586
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`Clinical Review
`Zana Marks, MD, MPH
`NDA 205103
`Yosprala: Aspirin/Omeprazole
`
`2.3 Availability of Proposed Active Ingredient in the United States
`
`Prilosec® (Omeprazole) is currently approved for use in adult and pediatric (greater than
`one year of age) patients for various indications. Primarily it is used to treat duodenal
`and gastric ulcers in adults. It is also used to treat gastroesophageal reflux disease
`(GERD) and maintenance of healing of erosive esophagitis in adults and children.
`
`Aspirin is available by prescription and over the counter (OTC).
`
`2.4 Important Safety Issues With Consideration to Related Drugs
`
`PPIs are widely used and have generally been found to be safe and well-tolerated.
`Current PPI labeling includes the following warnings and precautions:
`
` Symptomatic response does not preclude the presence of gastric malignancy
` Atrophic gastritis has been noted with long-term therapy
` PPI therapy may be associated with the increased risk of Clostridium difficile
`associated diarrhea.
` Avoid concomitant use of Prilosec with clopidogrel
` Bone fracture: Long term and multiple daily dose PPI therapy may be associated
`with an increased risk for osteoporosis-related fractures of the hip, wrist, or spine.
` Hypomagnesemia has been reported rarely with prolonged treatment with PPIs.
` Avoid concomitant use of Prilosec® with St. John’s Wort or rifampin due to the
`potential reduction in omeprazole concentrations
`Interactions with diagnostic investigations for Neuroendocrine Tumors: Increase
`in intragastric pH may result in hypergastrinemia and enterochromaffin-like cell
`hyperplasia and increased Chromogranin A levels which may interfere with
`diagnostic investigations for neuroendocrine tumors.
`
`
`
`Additionally, prescribers should be warned against concomitant use of certain
`antiretroviral drugs and drugs for which the gastric pH may affect bioavailability. See
`individual product labeling for further details.
`
`Aspirin is also widely used and patients who consume three or more alcoholic drinks
`everyday should be counseled regarding the bleeding risks involved with chronic, heavy
`alcohol use while taking aspirin. Low doses of aspirin can inhibit platelet function
`leading to an increase in bleeding time. This can adversely affect patients with inherited
`and acquired bleeding disorders. Some of the possible major gastrointestinal side
`effects with aspirin use include stomach pain, heartburn, nausea, vomiting, and frank GI
`bleeding. Although minor upper GI symptoms such as dyspepsia are common and may
`occur at any time during therapy with aspirin use, physicians should be vigilant for signs
`
`Reference ID: 3475586
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`Clinical Review
`Zana Marks, MD, MPH
`NDA 205103
`Yosprala: Aspirin/Omeprazole
`
`of ulceration and bleeding, even in the absence of previous GI symptoms. Aspirin
`should be avoided in patients with severe renal failure and severe hepatic insufficiency.
`For more information please see