CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`
`205103Orig1s000
`
`SUMMARY REVIEW
`
`
`
`
`
`
`
`
`
`
`
`
`

`

`Division Director Review
`
`Summary Review for Regulatory Action
`
`Donna J. Griebel, MD
`From
`
`Subject
`Division Director Summary Review
`NDA#
`205103
`
`
`Applicant Name
`Aralez Pharmaceuticals
`Date of Submission
`March 14, 2016
`
`
`
`Proprietary Name /
`Established
`S ‘
`
`Name
`
`Yosprala/
`as u irin/ome trazole
`
`Proposed Indication(s)
`
`Tablet/ aspirin: 81 mg or 325 mg
`Dosage Forms / Strength
`
`omeprazole 40 mg
`YOSPRALA, a combination of aspirin and
`omeprazole, is indicated for patients who require
`aspirin for secondary prevention of cardiovascular and
`cerebrovascular events and who are at risk of
`
`developing aspirin associated gastric ulcer.
`
`The aspirin component of YOSPRALA is indicated
`for:
`
`o
`
`reducing the combined risk of death and nonfatal
`stroke in patients who have had ischemic stroke or
`transient ischemia of the brain due to fibrin
`
`platelet emboli,
`reducing the combined risk of death and nonfatal
`MI in patients with a previous MI or unstable
`angina pectoris,
`
`reducing the combined risk of MI and sudden
`death in patients with chronic stable angina
`pectoris,
`use in patients who have undergone
`revascularization procedures (Coronary Artery
`Bypass Grafl [CABG] or Percutaneous
`Transluminal Coronary Angioplasty [PTCA])
`when there is a pre-existing condition for which
`aspirin is already indicated.
`
`The omeprazole component of YOSPRALA is
`indicated for decreasing the risk of developing
`aspirin-associated gastric ulcers in patients at risk
`for developing aspirin-associated gastric ulcers due
`to a e Z 55 or documented histo of astric
`
`Page 1 of 15
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`Reference ID: 3985702
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`

`

`
`
`Division Director Review
`
`Action:
`
`A roval
`
`
`
`Material Reviewed/Consulted
`
`0ND Action Package, including:
`Names of discipline reviewers
`
`Medical Officer Review
`Cycle 1: Zana Marks, MD
`Statistical Review
`Cycle 1: Milton C. Fan, PhD/Freda Cooner, PhD
`
`Pharmacology Toxicology Review
`Tamal Chakraborti, PhD/Sushanta Chakder, PhD
`0P9 Review
`Current Cycle: See table below
`Clinical Pharmacology Review
`Dilara Jamar, PhD/Sue-Chjh Lee, PhD
`DPMI-I
`Erica Radden, MD/Donna Snyder, MD/John Alexander,
`MD, MPH
`
`
`
`
`
`Christos Mastroyannis, MD/Tamara Johnson, IVID,
`
`MS/Lynne Yao, MD
`Meeta Patel, PhalmD
`OPDP
`OSIS
`Shila Nkah/
`
`Hasan Irier, PhD/Young Moon Choi, PhD
`Current Cycle: Anil Rajpal, IVfl)
`Cycles 1 and 2: Robert Fiorentino, IVID
`Sherly Abraham, RPH/Mishale Mistry, PharmD
`Joel L. Weissfeld, MD, MPH/Simone P. Pinheiro, ScD
`MSc
`
`OSE/DMEPA
`OSE/DEPI I
`
`CDTL Review
`
`DMPP
`
`Karen Dowdy, RN, BSN/LaShawn Griffiths, MSHS-
`PH, BSN, RN
`
`0ND=0flice ofNew Drugs
`OPDP=Division of Drug Marketing, Advertising and Communication
`DPMH=Division ofPediatric and Maternal Health
`0PQ=Ofiice ofPharmaceutical Quality
`OSE= Ofice of Surveillance and Epidemiology
`DMEPA=Division ofMedication Error Prevention and AnalysisDEPI=Division of Epidemiology I
`OSIS=0$ce of Study Integrity and Surveillance
`DMPP=Division ofMedical Policy Programs
`CD'IIFCross-Discipline Team Leader
`
`“m BRANCH/DIVISION
`
`Drug Product
`
`Zhengfang Ge, Ph.D.
`
`OMPT/CDER/OPQ/ONDP/D— ND Pm
`
`ND API/NDBII
`
`IA/BII
`
`Microbiology
`
`Jingbo Xiao Ph.D.
`
`Facility
`
`Christina Capacci-Daniel,
`Ph.D.
`
`OMPT/CDER/OPQ/OPF/DIA/
`IA/BII
`
`OMPT/CDER/OPQ/OPF/DIA/
`IA/BII
`
`OMPT/CDER/OPQ/OPF/DIA/
`
`Page 2 of 15
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`Reference ID: 3985702
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`

`

`Division Director Review
`
`Quality Review
`Biopharmaceutics
`Regulatory Business
`Process Manager
`Application Technical Lead
`
`Laboratory (OTR)
`ORA Lead
`
`Environmental Analysis
`(EA)
`
`REVIEWER
`Hansong Chen, Ph.D.
`Truong Quach, Phar. D.
`
`Danuta Gromek-Woods,
`Ph.D.
`NA
`Paul Perdue Jr.
`
`NA
`
`BRANCH/DIVISION
`CDER/OPQ/ONDP/DB II
`OMPT/CDER/OPQ/OPRO/DR
`BPMI/RBPMBI
`OMPT/CDER/OPQ/ONDP/D
`NDPII/BV
`NA
`OGROP/ORA/OO/OMPTO/D
`MPTPO/MDTP
`NA
`
`Page 3 of 15
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`Reference ID: 3985702
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`

`

`Division Director Review
`
`1. Introduction
`
`Division Director Review
`
`This is the third review cycle for this 505(b)(2) NDA for a fixed combination product (aspirin
`and omeprazole). The application was considered approvable by all review disciplines at the
`completion of the first review cycle, with the exception of the CMC reviewers due to a
`Withhold reconnnendation from the Office of Compliance. Deficiencies were found during
`the inspection of the
`ma) Manufacturing facility, which supplied the aspirin
`drug substance for the product. The first CR letter was issued on April 25, 2014. A second
`CR letter was issued on December 16, 2014 due to continued facility deficiencies
`(low
`In this resubmission, the applicant proposes a new supplier for the aspirin drug
`M4) The change in drug
`substance
`substance supplier for the aspirin component of this fixed combination product necessitated
`submission and review of new biophannaceutical data and two relative BA/BE studies
`comparing the PK of the aspirin components of the two aspirin dose levels of the combination
`products produced in the original
`(m4) facility and the new
`(hm) facility.
`
`2. Background
`
`See Introduction above and the detailed regulatory history outlined in the CDTL review. See
`also my two previous Division Director reviews for this NDA. The major review issue
`identified this cycle related to the Biophannaceutics reviewers’ concerns regarding the loss of
`omeprazole when the product was exposed to acid in in vitro dissolution studies. See Section
`3 for details regarding this issue.
`
`The original applicant was Pozen, Inc. The applicant for the current resubmission is Aralez
`Pharmaceuticals, Inc. The latter was formed by a merger between Pozen, Inc. and Tribute
`Pharmaceuticals Canada, Inc.
`
`3. CMC
`
`I concur with the OPQ review team’s conclusions and recommendation for approval. They
`have determined that the applicant provided sufficient information to assure the identity,
`strength, purity and quality of the drug product. The Office of Facility and Process has made a
`final overall “Approve” recommendation based on the inspection of manufacturing facilities.
`OPQ recommends approval with an expiration dating period of 36 months.
`
`Page 4 of 15
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`Reference ID: 3985702
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`

`

`13' ”only
`
`F
`
`.
`
`This fixed combination drug product consists of an aspirin core, which is surrounded by
`coating, a layer ofomeprazole, and external film coats. The product contains .film coats.
`The schematic of the product, reproduced fi'om the OPQ review, is shown below.
`
`Figure 1: Schematic of Yosprala
`
`
`
`As described in Section 1 above, manufacturing facility issues at theF— site, which produced the aspirin drug substance, to issuance oftwo
`
`CR letters. In this submission the
`licant withdrew the site- and replaced it-
`m s- a...5a...W...
`
`onstrate bioequivalence of the products
`orm to
`es
`e BA
`ption o
`or a
`manufactured with aspirin drug substance from the new site vs. flie drug product manufactured
`with aspirin drug substance from the original site.
`
`Although the Biopharmaceutics reviewers have recommended approval, they raised concers
`regarding the degradation of omeprazole in the acidic medium of the stomach, based on the
`results of the in vitro tablet dissolution test results presented in the application. They stated:
`
`“The dissolution o Yos rala tablet in acid medium 0.1 N HCI demonstrated that
`
`
`
`The following figure summarizes these data.
`
`Page 5 of 15
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`Reference ID: 3985702
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`

`

`Division Director Review
`
`re 2:
`
`Fi
`
`gu
`
`(IN)
`
`The Biopharmaceutics reviewers presented their concerns about these data to the overall
`review team, and entered an addendum review stating that they deferred to the nonclinical and
`clinical reviewers to assess the in viva safety of the degradants that would be expected to be
`formed when Yosprala is exposed to stomach acid. The OPQ, Clinical, Clinical Pharmacology
`and Pharmflbx reviewers met in multiple team meetings to discuss the safety issues raised by
`the Biopharmaceutics reviewers.
`
`The Clinical and Clinical Pharmacology reviewers noted that the loss of omeprazole in
`stomach acid does not raise efficacy issues because the clinical trials have established the
`efficacy of the product. Regarding safety issues raised by degradation of omeprazole by
`stomach acid, the OPQ and Phann/Tox reviewers noted that the actual omeprazole acid
`degradation products formed by exposure of Yosprala are unknown. The OPQ reviewers cited
`a publication from Lindberg, et all that included a list of a number of degradant products, with
`structures, that may be formed when omeprazole is exposed to acidic conditions. The team
`could not find data in the literature characterizing the safety of these specific molecules. The
`PharmTox reviewers, including the Associate Director of Pharmacology/Toxicology, Abby
`Jacobs, PhD, strongly stated that the molecular products of omeprazole that result fi‘om
`stomach acid exposure are “metabolites, not degradants” as the exposure to acid occurs within
`the human body, and they stated ICH Q3(B) applies to this situation. They specifically
`referred to the following in ICH Q3(B):
`
`“Qualification is the process of acquiring and evaluating data that establishes the
`biological safety of an individual degradation product or a given degradation profile at
`the levels specified. The applicant should provide a rationale for establishing
`degradation product acceptance criteria that includes safety considerations. The level of
`any degradation product present in a new drug product that has been adequately tested
`in safety and/or clinical studies would be considered qualified. [emphasis added]
`Therefore, it is useful to include any available information on the actual content of
`
`‘1 Lindberg P. Brandstrom A. et a1. Medicinal Research Reviews. Vol 10. No. 1. 1-54 (1990)
`
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`Reference ID: 3985702
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`Division Director Review
`
`degradation products in the relevant batches at the time of use in safety and/or clinical
`studies. Degradation products that are also significant metabolites present in
`animal and/or human studies are generally considered qualified [emphasis
`added]”.
`
`Yosprala has been investigated in two large phase 3 trials and no unusual safety signal was
`identified in the clinical review of those trials during the initial review cycle. The CDTL for
`the current review cycle, Dr. Rajpal, NID, reassessed the Clinical Safety review written by Dr.
`Zana Marks, MD in the first review cycle, and reported that even when viewed from the
`vantage point of this new safety question raised by the Biopharmaceutics reviewers, he
`identified no new safety signal. Furthermore, he evaluated the safety data submitted from the
`BA/BE trials submitted in the current resubmission, and found no safety signal in those data.
`
`The Pharmacology/Toxicology reviewers noted that the applicant had conducted a rat PK
`study comparing
`(m4) omeprazole, which revealed a qualitatively similar
`metabolite profile (plasma and urine)
`(m4) However,
`they pointed out that rodent stomach pH is somewhat higher than human stomach pH, i.e.,
`approximately 3.2 to 3.9, as compared to 1.5 to 3.5 in humans.
`
`The publications by Lindberg, et a12 and by Shin and Kim3 summarizes the physiology of the
`parietal cell and the mechanism of action of proton pump inhibitors in parietal cells. In the
`resting state, the parietal cell contains cytoplasmic tubulovesicles that fuse to form a secretory
`canaliculus when the cell is stimulated. The H+, +-ATPase (proton pump) is localized in the
`lining of the secretory canaliculus. H’r and Cl‘ ions are transported into the canaliculus to the
`stomach lumen, in exchange for entry of K+ into the parietal cell’s cytosol. The environment
`in the canaliculus is an acidic environment, i.e., pH of £1. Intravenously administered 3H-
`labeled omeprazole has been shown in animal studies to localize to the gastric mucosa, and
`microscopy reveals that the drug localized specifically within parietal cells. Electron
`microscopy has revealed that the omeprazole localizes within the tubulovesicles and the
`secretory canalicular membranes. Omeprazole, a weak base (pKa=4), remains in its base form
`a physiological pH; however, when it diffilses into the secretory canaliculus of the parietal cell,
`the molecule becomes exposed to a very low pH and undergoes protonation, which traps it in
`the acid compartment of the parietal cell. It undergoes further acid conversion to the
`sulfonamide structure which is the inhibitor of the proton pump. Lindberg, et al. describe
`other molecular changes that occur in the presence of acid. Therefore, acid degradation is
`occurring even with coated/acid-protected omeprazole products, after systemic absorption. In
`fact, omeprazole is a prodrug that requires acid conversion to the molecular structure that will
`interact with the proton pump. Presumably, additional molecular products of acid degradation
`of omeprazole are forming in the canaliculus, and some of those degradants may be
`reabsorbed, as the canaliculus opens to the stomach lumen, and the degradants could
`potentially pass into stomach contents. The reviewers identified no data in the literature that
`describe measurement of systemic exposure to various potential omeprazole acid degradation
`products.
`
`2 Lindberg P, Brandstrom A. et al. Medicinal Research Reviews. Vol 10, No. 1. 1-54 (1990)
`3 Shin JM and Kim N. J Neurogastroenterol Motil, Vol 19, No. 1. 25-35 (January 2013)
`
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`Division Director Review
`
`I concur with Dr. Rajpal’s summary of the review team’s conclusions regarding this issue.
`The clinical trials revealed no new safety issues potentially attributable to the acid degradation
`of the omeprazole in Yosprala. The acid degradant issues were thoroughly explored by the
`review team and do not change the risk/benefit assessment of Yosprala from the conclusions of
`the previous review cycles. I concur with the team’s recommendation for PMCs to further
`explore the issue. Two investigations will be included in the Approval letter as PMCs:
`
`3111-1 Conduct an in vitro study to characterize and quantify the degradants of the
`immediate release omeprazole of Yosprala at various pHs (i.e., pH 1, 1.5, 2, 2.5, 3,
`3.5, 4) following a minimum of 1 hour of exposure at 37°C, and evaluate the
`differences in the profiles. Submit the chromatograms and a summary of
`quantitative data generated during the study.
`Final Protocol Submission:
`01/2017
`Study/Trial Completion:
`04/2017
`Final Report Submission:
`06/2017
`
`3111-2 Conduct a clinical PK trial evaluating the systemic exposures of the omeprazole
`degradants that are shown to be present at a higher level at pH <3.0 compared to
`higher pHs in the in vitro studies (PMC #3111-1). This trial will include both
`Yosprala and the reference product for the omeprazole component of Yosprala.
`Compare the individual omeprazole degradant exposures between the two products.
`Final Protocol Submission:
`11/2017
`Study/Trial Completion:
`03/2018
`Final Report Submission:
`06/2018
`
`
`
`The pH range selected for the in vitro study to assure that testing is conducted over a range that
`covers the pH of the rat stomach and humans.
`
`4. Nonclinical Pharmacology/Toxicology
`
`I concur with the conclusions reached by the Pharmacology/Toxicology reviewer that there are
`no outstanding Pharm/Tox issues that preclude approval. No new nonclinical toxicology data
`were submitted in this resubmission. The Pharmacology/Toxicology reviewers worked with
`the DPMH reviewers to assure that the product label conforms to the Pregnancy and Lactation
`Labeling Rule (PLLR). See the description in Section 3 of the Pharm/Tox reviewers’
`contributions to discussions regarding omeprazole acid degradation products.
`
`5. Clinical Pharmacology
`
`I concur with the conclusions reached by the Clinical Pharmacology reviewer that there are no
`outstanding Clinical Pharmacology issues that preclude approval. As stated in Section 1
`Background of my review, in response to the last CR letter, the applicant now proposes to
`
`Page 8 of 15
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`Reference ID: 3985702
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`

`Division Director Review
`
`change to a new supplier of the aspirin drug substance for Yosprala. They have changed from
`(mo to
`M” (referred to here as (am)
`M”). The drug substances
`on»
`summarized in the
`(mo
`
`table below reproduced from the Clinical Pharmacology Review.
`
`Table 1: Comparison of ASA
`(”m (New Source)
`
`(0(4) Sourced From
`
`(m4) (Current Source) and 8
`
`(no)
`
`The applicant submitted the results of two separate BE studies (Study PA8140-104 and Study
`PA32540—119) to bridge the Yosprala drug products manufactured with aspirin drug substance
`made at these two different facilities. One study, PA8140-104 compared the acetylsalicylic
`acid concentrations between Yosprala (81 mg aspirin/40 mg omeprazole) manufactured from
`aspirin supplied from the
`(m4) site vs the
`M(4) site. The other study, PA32540-119,
`compared the acetylsalicylic acid concentrations between Yosprala (325 mg aspirin/40 mg
`omeprazole) manufactured from aspirin supplied from the
`(no) site vs the
`M0 site.
`
`The Clinical Pharmacology reviewer concluded that the aspirin components from the two
`suppliers were bioeguivalent for bothYosprala dose levels.
`
`The Office of Study Integrity and Surveillance (OSIS) inspected the bioanalytical portions of
`Studies PA8140-104 and PA32540-119. OSIS recommended accepting the analytical data
`from both studies for review. The reviewers from 0813 Division of New Drug
`Bioequivalence Evaluation recommended accepting data from the clinical site that conducted
`the BE trials without on-site inspection because the inspectional outcome from a recent
`inspection of the site was No Action Indicated (NAI).
`
`The Clinical Pharmacology reviewer also addressed the relative bioavailability of omeprazole
`in the Yosprala (81 mg aspirin/40 mg omeprazole) product vs. the Prilosec 40 mg reference
`product in this review cycle. Given the available clinical guidelines for aspirin as secondary
`prevention, we anticipate that if Yosprala is prescribed, it is most likely that the lower aspirin
`dose combination will be selected. The reviewers had previously evaluated data comparing the
`omeprazole exposure associated with the Yosprala (325 mg aspirin/omeprazole 40 mg) dose
`level to the Prilosec 40 mg reference product on days 1, 5 and 7 (Study PA32540-112). The
`Day 1 PK had also been compared in Study PA32540-l 13. The reviewers also previously
`evaluated comparative omeprazole PK data between the two aspirin dose levels of Yosprala
`(325 mg/40 mg vs. 81 mg/40 mg) on Day 7 only in Study PA8140-103 (no direct comparison
`to the reference Prilosec product occrured in this study). During this review cycle the Clinical
`Pharmacology reviewer surmnarized the Day 7 omeprazole PK data for the two Yosprala dose
`levels and Prilosec 40 mg from the previously reviewed studies, which are shown in the table
`below (reproduced fiom her review).
`
`Page 9 of 15
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`Reference ID: 3985702
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`

`Division Director Review
`
`Table 2: Cross-study Comparison of Omeprazole Exposure from PA8140, PA32540 and Prilosec
`
`40 mg on Day 7
`
`Treatment
`
`Statistics
`
`Cmax
`(ng/mL)
`
`30
`
`AUC0'24
`(hr*ng/mL)
`
`Source
`(study #)
`
`PA32 540-1 12
`
`PA8140
`
`PA32540
`
`PA32540
`
`.
`Pnlosec 40 mg +
`.
`Ecotnn 325 mg
`
`$1188
`1094
`
`30
`
`;:85
`1051
`
`26
`
`l 196
`
`71
`
`903
`
`26
`
`1345
`
`44
`1218
`
`PA8140-103
`
`PA8140-103
`
`PA32540-112
`
`Upon request during this review cycle, the applicant provided the Day 7 (after once daily
`dosing x 7) geometric mean ratio and associated confidence interval for CMax and AUC
`comparisons for omeprazole between the Yosprala (81mg aspirin/40 111g omeprazole) dose
`level and the reference product, Prilosec 40 mg. The data utilized in this cross study analysis
`came from Study PA32540-112 (Prilosec 40 mg Day 7 data) and Study PA8140—103 (Yosprala
`81 mg aspirin/omeprazole 40 mg Day 7 data). The Clinical Pharmacology reviewer concluded
`that the data from these cross study comparisons were reasonable given that they were
`generated by the same sponsor with similar bioanalytical methodology at the same
`bioanalytical site with one common treatment present in both studies (bridged cross study
`comparison). The Statistical reviewer evaluated the applicant’s statistical methodology for
`calculation of the geometric mean ratio and confidence intervals and concluded the approach
`was reasonable. The results are summarized in the table below (reproduced from the Clinical
`Pharmacology review). The upper bounds for the 90% confidence intervals did not exceed
`125%. The lower bounds fell below 80%; however, this does not raise an efficacy concern
`given that the Yosprala 325 mg aspirin/40 mg omeprazole product was found effective in
`clinical trials, and the omeprazole exposures associated with the two Yosprala dose levels were
`similar when compared head to head in Study PA8140—103.
`
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`

`Division Director Review
`
`Parameter
`
`Table 3: Geometric Mean Ratios and 90% Confidence Intervals for Cmax, AUC0-t, and AUC0-24 of
`Omeprazole from PA8140 to Prilosec® on Day 7 based on Bridged Cross-Study Comparisons
`PA81401 vs Prilosec 40 mg2 on Day 7
`GLSM Ratio % (90% Confidence Interval)
`89.76 (64.79-124.36)
`74.97 (50.92-110.36)
`75.05 (51.00-110.44)
`
`Cmax (ng/mL)
`AUC0-t (hr*ng/mL)
`AUC0-24 (hr*ng/mL)
`GLSM = geometric least-squares mean.
`1: PA8140 is from study PA8140-103 Treatment A: One tablet of PA8140 (delayed-release aspirin 81 mg and
`immediate release omeprazole 40 mg) administered once daily for 7 consecutive days.
`2: Prilosec 40 mg is from study PA32540-112 Treatment B: One tablet of EC-ASA (Ecotrin®) 325 mg and one
`capsule EC omeprazole (Prilosec®) 40 mg administered once daily for 7 consecutive days.
`
`Refer to the original Clinical Pharmacology review and my first cycle Division Director
`review for details regarding the omeprazole BA/BE PK studies initially submitted with the
`NDA. In the previously reviewed head to head comparison of the two Yosprala dose levels,
`Study PA8140-103, the Day 7 omeprazole GLSM ratio with 90% CI for 81mg/40mg vs. 325
`mg/40 mg for Cmax was 1.04 (0.86-1.27); for AUC 0-t it was 1.27 (1.04,1.54). Study
`PA32540-112, which compared Yosprala 325mg/40mg (the product evaluated in the efficacy
`trials) vs. Prilosec 40 mg revealed that Day 7 omeprazole exposures for Yosprala were
`relatively low compared to Prilosec: Day 7 Cmax = 0.74 (0.59-0.93) and AUC0-24 = 0.57 (0.45-
`0.73).
`
`6. Clinical Microbiology
`
`Not applicable.
`
`7. Clinical/Statistical-Efficacy
`
`There were no new efficacy data submitted for review in this review cycle. See previous
`reviews for discussion of the phase 3 trials conducted to establish the efficacy of the
`omeprazole component of Yosprala for reducing the risk of developing aspirin associated
`gastric ulcers.
`
`8. Safety
`
`See the first cycle CDTL Review for a discussion of the safety findings from the first cycle
`NDA submissions. In the current submission, the applicant submitted the summary safety data
`from the two BA/BE studies conducted in a total of 72 healthy subjects to support change in
`the manufacturing site. The CDTL evaluated those data and identified no new concerns.
`
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`Division Director Review
`
`DEPI I was consulted to review a publication by Miyake, et al, 2015, which described an
`excess of lower GI bleeding risk from concomitant use of PPIs with low-dose aspirin. Lower
`GI bleeding has been reported as an adverse reaction associated with aspirin. The publication
`suggested that concomitant PPI use with aspirin may further increase that risk. The review
`
`team questioned whether this publication should be
` The DEPI reviewer evaluated the publication and
`found evidence of serious risk of bias. He stated that confounding control and/or outcome
`measurement could result in an artificial association between PPI and lower GI bleeding.
`Furthermore, he identified another publication by Nagat, et al, 2015, that did not find an excess
`risk of lower GI bleeding in patients taking PPIs with low-dose aspirin. He concluded that the
`currently available evidence
` The CDTL and I concurred
`with this recommendation.
`
`The Yosprala label was evaluated this cycle to assure that any class labeling relevant to PPIs
`had been included in the product label. Warnings and Precautions were included to be
`consistent with the most recently approved Prilosec label (NDA 22056), including a Warning
`and Precaution for acute interstitial nephritis. A new class Warning and Precaution of
`cutaneous and systemic lupus erythematosus was also included. The reviewers further revised
`the Warning and Precaution for Gastrointestinal Adverse Reactions during this review cycle to
`add the description of serious GI adverse reactions reported in the Yosprala clinical trials, as
`follows (newly added wording presented here in italics):
`“Aspirin is associated with serious gastrointestinal (GI) adverse reactions,
`including inflammation, bleeding ulceration and perforation of the upper and
`lower GI tract. Other adverse reactions with aspirin include stomach pain,
`heartburn, nausea, and vomiting.”
`
`“Serious GI adverse reactions reported in the clinical trials of YOSPRALA
`were: gastric ulcer hemorrhage in one of the 521 patients treated with
`YOSPRALA and duodenal ulcer hemorrhage in one of the 524 patients treated
`with enteric-coated aspirin. In addition, there were two cases of intestinal
`hemorrhage, one in each treatment group, and one patient treated with
`YOSPRALA experienced obstruction of the small bowel.”
`
`In addition, further modifications of Section 6 Adverse Reactions of the label resulted in the
`addition of the following statement:
`“Less Common Adverse Reactions
`In YOSPRALA-treated patients in the clinical trials there were 2 patients with
`GI bleeding (gastric or duodenal) and 2 patients with lower GI bleeding
`(hematochezia and large intestinal hemorrhage) and one additional patient
`experienced obstruction in the small bowel.”
`
`Given that Yosprala is a fixed combination and does not allow reducing the omeprazole dose
`in the setting of a patient who is a CYP2C19 poor metabolizer, Section 8.8 of the label was
`added during this review cycle to state that the product should be avoided in Asian patients
`with unknown CYP2C19 genotype or those who are known to be poor metabolizers. The
`updated label will state:
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`(b) (4)
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`(b) (4)
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`“In studies of healthy subjects, Asians had approximately a four-fold higher
`exposure to omeprazole than Caucasians. CYP2C19, a polymorphic enzyme, is
`involved in the metabolism of omeprazole. Approximately 15% to 20% of
`Asians are CYP2C19 poor metabolizers. Tests are available to identify a
`patient’s CYP2C19 genotype. Avoid use in Asian patients with unknown
`CYP2C19 genotype or those who are known to be poor metabolizers…”
`
`9. Advisory Committee Meeting
`
`There was no advisory committee meeting to discuss this application.
`10.
`Pediatrics
`
`See my previous reviews. PREA will be waived because studies would be impossible or
`highly impractical, "because the proposed indication in the pediatric population is rare,
`therefore the incidence of aspirin associated gastric ulcers would also expected to be rare."
`
`In the current review cycle, the DPMH reviews recommended labeling revisions to assure that
`the label complied with PLLR. Those revisions were incorporated. In addition, DPMH
`recommended modification of the wording in Section 8.4 to provide consistency with the
`Contraindication for pediatric use in Section 4 of the product label. Section 17 Patient
`Counseling Information was also updated to correspond to the changes in Sections 8.1, 8.2 and
`8.3 related to PLLR.
`
`11.
`
`Other Relevant Regulatory Issues
`
`See previous reviews from earlier review cycles for information on DSI audits and financial
`disclosures.
`
`12.
`
`Labeling
`
`DMEPA and OPDP concluded that the proprietary name “Yosprala” was acceptable during
`this review cycle.
`
`See Sections 8 and 10 above and previous reviews from earlier cycles for additional labeling
`review issues. In addition, during this cycle, Section 7 Drug Interactions of the product label
`was revised to present the information in tabular format.
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`See the CDTL review for a more detailed and comprehensive description of the labeling
`revisions that occurred during this review cycle.
`
`13.
`
`Decision/Action/Risk Benefit Assessment
`
` Regulatory Action - Approval
`
` Risk Benefit Assessment
`As stated in my Risk Benefit Assessment from the initial review cycle, “Both
`components of this fixed combination are approved drugs and the applicant presented
`substantial evidence that the omeprazole component of the fixed combination reduces
`the risk for gastric ulcers induced by enteric coated aspirin 325 mg. The applicant also
`established bioequivalence based on the active moiety of ASA, i.e., acetylsalicylic acid,
`for both combination presentations (ASA 325 mg/omeprazole 40 mg; ASA 81
`mg/omeprazole 40 mg). Based on the monograph for aspirin professional labeling (21
`CFR 343.80), the secondary cardiovascular prevention indications can be included in
`the Yosprala label.
`
`Although no adequate and well controlled trials that evaluated the efficacy of the ASA
`81mg + IR omeprazole 40mg Yosprala tablet (PA8140) were submitted for review, I
`concur with the CDTL that there is adequate evidence to support the approval of the
`lower ASA dose combination, since there is no reason to believe that ASA 81 mg
`would have a greater risk for development of gastric ulcers, making it more difficult for
`the omeprazole to reduce the risk of ulcers, and given that there is evidence in the
`literature indicating that there is in fact a risk for developing upper gastrointestinal
`injury, including ulcers, with aspirin doses lower than 325 mg. Furthermore, PK data
`from a relative bioavailability study (Study PA 8140-103) established that the
`bioavailability of the omeprazole component of the lower ASA dose fixed combination
`product (81/40) was not lower than that of the fixed combination tested in the two
`phase 3 trials (325/40).
`
`The DCRP concerns regarding marketing a combination that includes a 325 mg dose of
`aspirin when lower doses of aspirin have been found to be effective for secondary
`prevention were carefully considered, including the concerns about increasing risk for
`bleeding with increasing doses of aspirin. These issues were discussed with OND and
`CDER leadership, and in light of inclusion of the ASA 325 mg dose in 21 CFR343.80,
`a decision to limit approval to the 81 mg ASA combination was not supported.
`Presumably, when practice of medicine aligns with clinical guidelines for secondary
`prevention, based on comparable efficacy and apparent improved safety for lower ASA
`doses, the lower dose combination product presentation will be selected for use by
`clinicians. The review team has worked to assure that Yosprala labeling will address
`DCRP concerns. The Dosage and Administration section will encourage prescribers to
`consider current practice guidelines and the potential for an increased risk of bleeding
`with increasing aspirin doses when selecting the Yosprala aspirin dose. A Limitation
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`of Use in the indication will state that the omeprazole component has not been shown
`to reduce the risk of upper GI bleeding. In fact, upper gastrointestinal hemorrhage
`occurred in the trials submitted for review (an SAE in each treatment arm). An
`additional Limitation of Use statement will inform prescribers that Yosprala is not
`appropriate for use in an acute cardiovascular event setting due to the delayed release
`characteristics of the aspirin component.
`
`Safety labeling associated with currently approved omeprazole and NSAID products
`will be included in the Yosprala product label. These have been discussed in my
`review and include new animal safety data and pregnancy warnings for Prilosec, as
`well as an interaction with clopidogrel.”
`
`During this review cycle, the applicant has provided BA/BE studies to establish that
`the manufacturing change for the aspirin drug substance does not impact our previous
`conclusion regarding the safety and efficacy of the aspirin component of Yosprala.
`The risk/benefit conclusion from the original submission has also not changed for the
`overall fixed combination product. The label was updated to include new class labeling
`for the omeprazole PPI component of Yosprala in the Warnings and Precautions
`section. These new class Warnings do not change my Risk Benefit conclusions that
`benefits of the product outweigh the risks. A Limitati