CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`
`205103Orig1s000
`
`
`CROSS DISCIPLINE TEAM LEADER REVIEW
`
`

`

`
`
`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 Graft [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 age (2 55) or doc1unented history of gastric
`ulcers.
`
`Cross—Discipline Team Leader Review
`
`
`Date
`September 14, 2016
`From
`Anil Rajpal, MD, MPH, Clinical Team Leader
`Division of Gastroenterolo 3 and Inborn Errors Products
`
`Cross-Discipline Team Leader Review
`Subject
`NDA/ BLA
`
`
`Applicant
`Aralez Pharmaceuticals
`Date of Submission
`March 14, 2016
`
`PDUFA Goal Date
`September 14, 2016
`
`
`Proprietary Name /
`Yosprala (aspirin/omeprazole)
`Established (USAN)
`names
`
`Dosage forms / Strength
`
`Tablet: Delayed Release Aspirin 81 mg or 325 mg; Immediate
`Release Ome razole 40 m -
`
`Proposed Indication
`
`Recommended Action:
`
`Reference ID: 3985627
`
`

`

`CDTL Review ● NDA 205103 ● Yosprala (Aspirin and Omeprazole) ● Aralez Pharmaceuticals
`
`Table of Contents
`
`1. Introduction...........................................................................................................................2
`2. Background........................................................................................................................4
`3. CMC .....................................................................................................................................6
`4. Nonclinical Pharmacology/Toxicology ..............................................................................10
`5. Clinical Pharmacology/Biopharmaceutics..........................................................................16
`6. Clinical Microbiology.........................................................................................................17
`7. Clinical/Statistical - Efficacy..............................................................................................17
`8.
`Safety ...............................................................................................................................18
`9. Advisory Committee Meeting .........................................................................................18
`10. Pediatrics..........................................................................................................................18
`11. Other Relevant Regulatory Issues ....................................................................................24
`12. Labeling ............................................................................................................................25
`13. Recommendations/Risk Benefit Assessment ..................................................................29
`
`1. Introduction
`
`A Complete Response (CR) Letter was sent by the Division on December 16, 2014. This
`resubmission, received March 14, 2016, is a complete response to that letter, and represents
`the third review cycle for this NDA.
`
`Yosprala Tablets: Yosprala tablets are a multilayer orally administered tablet consisting of:
`an enteric-coated (EC) aspirin core (81 mg or 325 mg), and
`
`an immediate release (IR) omeprazole 40 mg film coat.
`
`This is intended to allow for a sequential release, first of omeprazole followed by aspirin
`
`
`Proposed Indication: The proposed indication is as follows:1
`
`“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:
`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,
`
`
`
`
`
`1 The proposed indication is taken from the proposed label in Module 1 of the NDA submission received March
`14, 2016.
`
`2
`
`Reference ID: 3985627
`
`(b) (4)
`
`

`

`CDTL Review ● NDA 205103 ● Yosprala (Aspirin and Omeprazole) ● Aralez Pharmaceuticals
`
`
`
`use in patients who have undergone revascularization procedures (Coronary
`Artery Bypass Graft [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 age (≥ 55) or documented history of gastric ulcers.”
`
`Proposed Dosage and Administration: The proposed dosage and administration is once
`daily.
`
`First Review Cycle: The original 505(b)(2) NDA was submitted by POZEN Inc. on March
`25, 2013. The NDA received a CR action on April 25, 2014 because the Office of
`Compliance had issued an overall “Withhold” recommendation for the
` manufacturing facility where the aspirin component of the tablet is manufactured.
`
`
`
`Second Review Cycle: The NDA was re-submitted by POZEN Inc. on June 30, 2014. The
`NDA again received a CR action on December 16, 2014 because the Office of Compliance
`again issued an overall “Withhold” recommendation for the
`
`manufacturing facility where the aspirin component of the tablet is manufactured.
`
`It should be noted that the current sponsor (Aralez Pharmaceuticals Inc.) was formed by a
`merger of the previous sponsor (POZEN Inc.) and another company (Tribute
`Pharmaceuticals Canada Inc.).2
`
`The primary emphasis of this memorandum is on the issues to be resolved in the current
`review cycle.
`
`2. Background
`2.1 Regulatory History
`
`2.1.1 Overview of Regulatory Activity
`
`For regulatory activities prior to the second cycle NDA submission, see the following:
` First Cycle Clinical Review by Zana Marks, dated March 21, 2014, and Addenda
`dated April 4, 2014, and April 16, 2014.
` First Cycle CDTL Review by Robert Fiorentino dated April 25, 2014
` Second Cycle CDTL Review by Robert Fiorentino dated December 30, 2014
`
`The table below provides an overview of the regulatory activity after the second cycle NDA
`submission.
`
`2 https://aralez.com/about/ (accessed August 24, 2016)
`
`3
`
`Reference ID: 3985627
`
`(b) (4)
`
`(b) (4)
`
`

`

`CDTL Review ● NDA 205103 ● Yosprala (Aspirin and Omeprazole) ● Aralez Pharmaceuticals
`
`Table 1. Pertinent Regulatory History of Yosprala (NDA 205103)*
`Date
`Event
`December 16, 2014 CR Letter issued
`January 28, 2015
`Teleconference with Sponsor about requirements to resolve issues in CR Letter
`March 14, 2016
`Current Resubmission for NDA 205103 received
`*IND 78,747
`
`2.1.2 Key Comments Communicated to the Sponsor
`
`Key comments communicated to the sponsor included the following:
`
`Complete Response Letter (Second Cycle)
`
`On December 14, 2014, a Complete Response (CR) Letter was issued that included the
`following:
`
`“We have completed our review of this application, as amended, and have determined
`that we cannot approve this application in its present form. We have described our
`reasons for this action below and, where possible, our recommendations to address
`these issues.
`
`FACILITY INSPECTIONS
`
` manufacturing
`1. During a recent inspection of the
`facility for this application, our field investigator conveyed deficiencies to the
`representative of the facility. Satisfactory resolution of these deficiencies is
`required before this application may be approved.”
`
`Teleconference with Sponsor
`
`On January 28, 2015, a teleconference with the Sponsor occurred to discuss the issues in the
`CR Letter. Key discussion comments from the minutes of the meeting are shown below.
`“Pozen asked if Yosprala can be approved as a safe and effective therapy prior to final
`resolution of the issues raised in the 483. FDA responded, no. A recommendation of
`approval is based on multiple disciplinary reviews including Compliance and so the
`issues raised during the inspection must be adequately addressed.”
`
`2.2
`
`Current Submission
`
`This NDA resubmission was received on March 14, 2016. It was classified as a six-month
`submission with a PDUFA deadline of September 14, 2016. No Advisory Committee
`meeting was convened to discuss this application.
`
`The relevant review disciplines have written review documents. The primary review
`documents relied upon were the following:
`(1) Office of Pharmaceutical Quality (OPQ) Review by Moo-Jhong Rhee dated August 18,
`2016 which incorporates the following disciplines/reviews:
`4
`
`Reference ID: 3985627
`
`(b) (4)
`
`

`

`CDTL Review 0 NDA 205103 0 Yosprala (Aspirin and Omeprazole) o Aralez Pharmaceuticals
`
`(a) Drug Substance (Xavier Ysem)
`(b) Drug Product (Zhengfang Ge)
`(c)
`Process (Jingbo Xiao)
`((1) Facility (Christina Capacci-Daniel)
`(e) Biophannaceutics (Hansong Chen)
`(1) Application Technical Lead manuta Gromek-Woods)
`(g) ORA Lead (Paul Perdue)
`(2) Pharmacology/Toxicology Review by Tamal Chakraborti dated August 5, 2016
`(3) Clinical Pharmacology Review by Dilara Jappar dated August 12, 2016
`(4) Office of Study Integrity and Surveillance (OSIS) Reviews/Memos:
`(a) Decline to Inspect Memo by Shila Nkah dated August 8, 2016
`(b) Review of Establishment Inspection Report (EIR) by Hasan Irier dated August
`19, 201 6
`(5) Division of Epidemiology ODEPI) Review by Joel Weissfeld, dated July 11, 2016
`(6) Division of Pediatric and Maternal Health (DPMH) Reviews:
`(a)
`Pediatric Review by Erica Radden, dated August 11, 2016
`(b) Maternal Health Review by Christos Mastroyannis, dated August 29, 2016
`(7) Labeling Reviews:
`(a)
`Proprietary Name Review by Sherly Abraham dated May 27,2016
`(b) Label and Labeling Review by Sherly Abraham dated July 28, 2016
`(c) Office of Prescription Drug Promotion (OPDP) Review by Meeta Patel dated
`August 8, 2016
`((1) Division of Medical Policy Programs (DMPP) Patient Labeling Review by
`Karen Dowdy dated August 11, 2016
`
`The reviews should be consulted for more specific details of the current application.
`
`3. CMC
`
`The Office of Pharmaceutical Quality (OPQ) Review summarized the quality assessments
`(including biopharmaceutics assessments) as follows.
`
`3.1 Product Overview
`
`The OPQ Review provided an overview of the product as follows.
`
`3.1. I Progosed Drug Product:
`
`“Aspirin and omeprazole are the two active pharmaceutical ingredients of the drug product
`YospralaTM (81 mg or 325 mg aspirin] 40 mg omeprazole) tablets. The proposed drug
`product is an aspirin delayed-release/omeprazole immediate-release tablet. The listed drugs
`for this 505(b)(2) application are Ecotrin® GSK (aspirin) and Prilosec® AstraZeneca
`(omeprazole), both are delayed-release.
`
`Aspirin is provided by
`
`0%)
`
`Reference ID: 3985627
`
`

`

`CDTL Review 0 NDA 205103 e Yosprala (Aspirin and Omeprazole) o Aralez Pharmaceuticals
`
`See the chemical structures of aspirin- components and omeprazole in the OPQ
`Review.
`
`3.1.2 Stability:
`
`“The stability of omeprazole in solution is a fimction of pH; it is rapidly degraded in acid media,
`but has acceptable stability under alkaline conditions. Omeprazole is a racemate of two
`enantiomers,. .
`
`3.1.3 Drug Product Manufacturing:
`
`-
`
`. consist of an as in'n core that is coated
`
`as shown below:”
`
`The figure above is taken from the OPQ Review.
`
`3.2
`
`Quality Assessment Overview
`
`The OPQ Review provided an overview of the quality assessment as follows.
`
`3.2.1 Drug Substance
`
`“The drug substance reviewer, Dr. Xavier Ysem, concludes that the quality of ‘the described
`drug substances is deemed acceptable to support their use in the manufacture of the proposed
`drug product YospralaTM (81 mg or 325 mg asan 40 mg omeprazole) tablets as described
`under Applicant’s NDA 205-103’.”
`
`Reference ID: 3985627
`
`

`

`CDTL Review 0 NBA 205103 e Yosprala (Aspirin and Omeprazole) o Aralez Pharmaceuticals
`
`3.2.2 D_rug Product
`
`Product reviewer, the as iiin mixture s
`
`3.2.3 Stabilig
`
`“No significant differences have been observed for the real time stability results comparing
`the drug products usin. aspirin and drug products using- aspirin (see review #2
`in the previous review cycle). Therefore, the proposed 36 months expiration dating period is
`granted for the drug product stored at USP room temperature condition based on the 36
`months long term stability data for the drug products manufactured with aspirin from
`- Post-approval stability protocol and commitment are adequate.”
`
`3.2.4 Process
`
`information for in-process controls and for the commercial scale-up.”
`
`The firm provided adequate
`
`3.2.5 Microbiology
`
`“Regarding the Microbiology assessment, the review of the original submission dated 08-Jul-
`2013 remains adequate for microbial limit specifications for the drug product, as there are no
`changes in the control of microbial limits in the current resubmission.”
`
`3.2.6 Biopharmaceutics
`
`“Biopharmaceutics Review dated 9-Aug-2016 made a recommendation of approval, but
`raised a concern finding the dmadation at omgragle in the acidic medium at
`stomach: As stated in the review,
`
`‘Ihe dissolution o Yos
`
`
`
`Reference ID: 3985627
`
`

`

`CDTL Review 0 NDA 205103 e Yosprala (Aspirin and Omeprazole) o Aralez Pharmaceuticals
`
`
`
`However, in the addendum dated 17-Aug-2016 to the previous Review (9-Aug—2016),
`Biopharmaceutics Team states that safety concern in-vivo about these degradants is beyond
`the Biopharmaceutics purview and is deferred to pre-clinical and clinical teams.”
`
`3.2.7 Facilities Review/Inspection
`
`“The Office of Facility and Process has made a final overall manufacturing Inspection
`‘Approve’ recommendation for the facilities involved in this application,. . .”
`
`3.3
`
`Final Recommendation
`
`The final recommendation/conclusion on approvability by CMC is the following (emphasis
`addeg):
`
`“This applicant has provided sufiicient CMC information to assure the identity,
`strength, purity, and quality of the drug product before the drug administration.
`
`The Office of Facility and Process has made a final overall “Approve”
`recommendation for the manufacturing inspection of facilities involved in this
`application.
`
`Labeling and labels are deemed satisfactory from the CMC perspective.
`
`8
`
`Reference ID: 3985627
`
`

`

`CDTL Review ● NDA 205103 ● Yosprala (Aspirin and Omeprazole) ● Aralez Pharmaceuticals
`
`The issue raised by the Biopharmaceutics Review about acid degradation of
`omeprazole in the stomach is deemed to be beyond the Biopharmaceutics’ purview
`and its safety concern is deferred to Clinical Team, but OPQ will support and
`cooperate with any post approval investigation on this issue, if it be warranted by
`the Clinical Team.
`
`Therefore, from the OPQ perspective, this application is recommended for Approval
`with expiration dating period of 36 months.”
`
`The following postmarketing commitment (PMC) is recommended:
`
`Conduct an in vitro study to characterize and quantify the degradants of 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 across pHs. Submit the chromatograms and a summary of quantitative
`data generated during the study.
`Final Protocol Submission:
`Study/Trial Completion:
`Final Report Submission:
`
`01/2017
`04/2017
`06/2017
`
`It should be noted that the issue is appropriate for a PMC instead of a pre-approval
`requirement because prior clinical experience indicates safety and the issue is a theoretical
`concern. The drug’s safety profile has been adequately assessed in the pre-approval
`program. However, because this product contains non-enteric coated omeprazole which may
`be unstable in acidic pH, there is residual uncertainty regarding potential omeprazole
`degradants in the acidic pH of the stomach. To address this residual uncertainty an in vitro
`study will be conducted to characterize and quantify the degradants of immediate release
`omeprazole of Yosprala at various pH ranges (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 to evaluate the differences in the profiles across
`the pH range; the applicant should submit the chromatograms and summary of quantitative
`data generated in the study..
`
`4. Nonclinical Pharmacology/Toxicology
`
`The Nonclinical Pharmacology/Toxicology Review summarized the nonclinical findings as
`follows.
`
`4.1
`
`Brief Discussion of Nonclinical Findings
`
`The Applicant did not submit any nonclinical study report in this resubmission.
`
`The Nonclinical Pharmacology/Toxicology Reviewer referred to previous nonclinical
`pharmacology/toxicology reviews from the first and second review cycles.
`
`Reference ID: 3985627
`
`9
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`

`

`CDTL Review ● NDA 205103 ● Yosprala (Aspirin and Omeprazole) ● Aralez Pharmaceuticals
`
`4.2
`
`Labeling
`
`The Nonclinical Pharmacology/Toxicology Reviewer concluded that the proposed draft
`labeling of Yosprala® conforms to the content and format of labeling for human prescription
`drug and biological products under 21 CFR 201.57. The Nonclinical
`Pharmacology/Toxicology Reviewer commented that, however, the revisions below are
`recommended.
`
`8.1 Pregnancy
`
`The Nonclinical Pharmacology/Toxicology Reviewer commented that the Applicant’s
`proposed version appears to be acceptable. The Nonclinical Pharmacology/Toxicology
`Reviewer commented that, however, the aspirin data was moved before omeprazole data in
`order to be consistent with Sections 13.1 and 13.2 of the label. The recommended version is
`shown below.
`
`Animal Data
`
`Aspirin:
`Aspirin produced a spectrum of developmental anomalies when administered to
`Wistar rats as single, large doses (500-625 mg/kg) on gestational day (GD) 9, 10, or
`11. These doses (500 to 625 mg/kg) in rats are about 15 to 19 times the maximum
`recommended human dose of aspirin (325 mg/day) based on body surface area. Many
`of the anomalies were related to closure defects and included craniorachischisis,
`gastroschisis and umbilical hernia, and cleft lip, in addition to diaphragmatic hernia,
`heart malrotation, and supernumerary ribs and kidneys. In contrast to the rat, aspirin
`was not developmentally toxic in rabbits.
`
`Omeprazole:
`Reproductive studies conducted with omeprazole in rats at oral doses up to 138
`mg/kg/day (about 34 times an oral human dose of 40 mg on a body surface area basis)
`and in rabbits at doses up to 69.1 mg/kg/day (about 34 times an oral human dose of
`40 mg on a body surface area basis) during organogenesis did not disclose any
`evidence for a teratogenic potential of omeprazole. In rabbits, omeprazole in a dose
`range of 6.9 to 69.1 mg/kg/day (about 3.4 to 34 times an oral human dose of 40 mg
`on a body surface area basis) administered during organogenesis produced dose-
`related increases in embryo- lethality, fetal resorptions, and pregnancy disruptions. In
`rats, dose-related embryo/fetal toxicity and postnatal developmental toxicity were
`observed in offspring resulting from parents treated with omeprazole at 13.8 to 138
`mg/kg/day (about 3.4 to 34 times an oral human dose of 40 mg on a body surface area
`basis), administered prior to mating through the lactation period.
`
`Esomeprazole:
`The data described below was generated from studies using esomeprazole, an
`enantiomer of omeprazole. The animal to human dose multiples are based on the
`assumption of equal systemic exposure to esomeprazole in humans following oral
`administration of either 40 mg esomeprazole or 40 mg omeprazole.
`10
`
`Reference ID: 3985627
`
`

`

`CDTL Review ● NDA 205103 ● Yosprala (Aspirin and Omeprazole) ● Aralez Pharmaceuticals
`
`No effects on embryo-fetal development were observed in reproduction studies with
`esomeprazole magnesium in rats at oral doses up to 280 mg/kg/day (about 68 times
`an oral human dose of 40 mg on a body surface area basis) or in rabbits at oral doses
`up to 86 mg/kg/day (about 42 times an oral human dose of 40 mg esomeprazole or
`omeprazole on a body surface area basis) administered during organogenesis.
`
`A pre- and postnatal developmental toxicity study in rats with additional endpoints to
`evaluate bone development was performed with esomeprazole magnesium at oral
`doses of 14 to 280 mg/kg/day (about 3.4 to 68 times an oral human dose of 40 mg
`esomeprazole or omeprazole on a body surface area basis). Neonatal/early postnatal
`(birth to weaning) survival was decreased at doses equal to or greater than 138
`mg/kg/day (about 34 times an oral human dose of 40 mg esomeprazole or omeprazole
`on a body surface area basis). Body weight and body weight gain were reduced and
`neurobehavioral or general developmental delays in the immediate post-weaning
`timeframe were evident at doses equal to or greater than 69 mg/kg/day (about 17
`times an oral human dose of 40 mg esomeprazole or omeprazole on a body surface
`area basis). In addition, decreased femur length, width and thickness of cortical bone,
`decreased thickness of the tibial growth plate and minimal to mild bone marrow
`hypocellularity were noted at doses equal to or greater than 14 mg/kg/day (about 3.4
`times an oral human dose of 40 mg esomeprazole or omeprazole on a body surface
`area basis). Physeal dysplasia in the femur was observed in offspring of rats treated
`with oral doses of esomeprazole magnesium at doses equal to or greater than 138
`mg/kg/day (about 34 times an oral human dose of 40 mg esomeprazole or omeprazole
`on a body surface area basis).
`
`Effects on maternal bone were observed in pregnant and lactating rats in the pre- and
`postnatal toxicity study when esomeprazole magnesium was administered at oral
`doses of 14 to 280 mg/kg/day (about 3.4 to 68 times an oral human dose of 40 mg
`esomeprazole or omeprazole on a body surface area basis). When rats were dosed
`from gestational day 7 through weaning on postnatal day 21, a statistically significant
`decrease in maternal femur weight of up to 14% (as compared to placebo treatment)
`was observed at doses equal to or greater than 138 mg/kg/day (about 34 times an oral
`human dose of 40 mg esomeprazole or omeprazole on a body surface area basis).
`
`A pre- and postnatal development study in rats with esomeprazole strontium (using
`equimolar doses compared to esomeprazole magnesium study) produced similar
`results in dams and pups as described above.
`
`8.4 Pediatric Use
`
`The Nonclinical Pharmacology/Toxicology Reviewer commented that the Applicant’s
`proposed version appears to be acceptable. The Nonclinical Pharmacology/Toxicology
`Reviewer commented that, however, multiples of human exposure values were corrected in
`appropriate places. The recommended version is shown below.
`
`Reference ID: 3985627
`
`11
`
`

`

`CDTL Review ● NDA 205103 ● Yosprala (Aspirin and Omeprazole) ● Aralez Pharmaceuticals
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`In a juvenile rat toxicity study, esomeprazole was administered with both magnesium
`and strontium salts at oral doses about 17 to 67 times a daily human dose of 40 mg
`based on body surface area. Increases in death were seen at the high dose, and at all
`doses of esomeprazole, there were decreases in body weight, body weight gain, femur
`weight and femur length, and decreases in overall growth [see Nonclinical Toxicology
`(13.2)].
`
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`The Nonclinical Pharmacology/Toxicology Reviewer had the following comments:
` Findings of genotoxicity studies and fertility and reproductive performance studies
`with omeprazole were duplicated in the Applicant’s proposed label.
` Multiples of human exposure values were corrected in appropriate places.
`“No” was added in front of the sentence “astrocytomas were observed in female rats
`
`in this study”.
`In addition, the following paragraph was not incorporated in the label and was added.
`
`
`
`The recommended version is shown below.
`
`Studies to evaluate the potential effects of YOSPRALA on carcinogenicity,
`mutagenicity, or impairment of fertility have not been conducted.
`
`Aspirin
`
`Administration of aspirin for 68 weeks at 0.5% in the feed of rats was not
`carcinogenic.
`
`In the Ames Salmonella assay, aspirin was not mutagenic; however, aspirin did
`induce chromosome aberrations in cultured human fibroblasts.
`
`Aspirin inhibits ovulation in rats.
`
`Omeprazole
`
`In two 24-month carcinogenicity studies in rats, omeprazole at daily doses of 1.7, 3.4,
`13.8, 44.0 and 140.8 mg/kg/day (about 0.35 to 34 times the human dose of 40 mg per
`day, based on body surface area) produced gastric ECL cell carcinoids in a dose-
`related manner in both male and female rats; the incidence of this effect was
`markedly higher in female rats, which had higher blood levels of omeprazole. Gastric
`12
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`Reference ID: 3985627
`
`

`

`CDTL Review ● NDA 205103 ● Yosprala (Aspirin and Omeprazole) ● Aralez Pharmaceuticals
`
`carcinoids seldom occur in the untreated rat. In addition, ECL cell hyperplasia was
`present in all treated groups of both sexes. In one of these studies, female rats were
`treated with 13.8 mg omeprazole/kg/day (about 3.4 times the human dose of 40 mg
`per day, based on body surface area) for one year, then followed for an additional
`year without the drug. No carcinoids were seen in these rats. An increased incidence
`of treatment-related ECL cell hyperplasia was observed at the end of one year (94%
`treated vs 10% controls). By the second year the difference between treated and
`control rats was much smaller (46% vs 26%) but still showed more hyperplasia in the
`treated group. Gastric adenocarcinoma was seen in one rat (2%). No similar tumor
`was seen in male or female rats treated for two years. For this strain of rat no similar
`tumor has been noted historically, but a finding involving only one tumor is difficult
`to interpret. In a 52-week toxicity study in Sprague-Dawley rats, brain astrocytomas
`were found in a small number of males that received omeprazole at dose levels of 0.4,
`2, and 16 mg/kg/day (about 0.1 to 3.2 times the human dose of 40 mg/day, based on
`body surface area). No astrocytomas were observed in female rats in this study. In a
`2-year carcinogenicity study in Sprague-Dawley rats, no astrocytomas were found in
`males and females at the high dose of 140.8 mg/kg/day (about 34 times the human
`dose of 40 mg per day, based on body surface area). A 78-week mouse
`carcinogenicity study of omeprazole did not show increased tumor occurrence, but
`the study was not conclusive. A 26-week p53 (+/-) transgenic mouse carcinogenicity
`study was not positive.
`
`Omeprazole was positive for clastogenic effects in an in vitro human lymphocyte
`chromosomal aberration assay, in one of two in vivo mouse micronucleus tests, and in
`an in vivo bone marrow cell chromosomal aberration assay. Omeprazole was
`negative in the in vitro Ames Salmonella typhimurium assay, an in vitro mouse
`lymphoma cell forward mutation assay and an in vivo rat liver DNA damage assay.
`
`Omeprazole at oral doses up to 138 mg/kg/day (about 34 times the human dose of 40
`mg per day, based on body surface area) was found to have no effect on fertility and
`reproductive performance.
`
`In 24-month carcinogenicity studies in rats, a dose-related significant increase in
`gastric carcinoid tumors and ECL cell hyperplasia was observed in both male and
`female animals. Carcinoid tumors have also been observed in rats subjected to
`fundectomy or long-term treatment with other proton pump inhibitors or high doses
`of H2-receptor antagonists.
`
`13.2 Animal Toxicology and/or Pharmacology
`
`The Nonclinical Pharmacology/Toxicology Reviewer commented that the Applicant’s
`proposed version appears to be acceptable. The Nonclinical Pharmacology/Toxicology
`Reviewer commented that, however, multiples of human exposure values were corrected in
`appropriate places. The recommended version is shown below.
`
`Aspirin
`
`13
`
`Reference ID: 3985627
`
`

`

`CDTL Review ● NDA 205103 ● Yosprala (Aspirin and Omeprazole) ● Aralez Pharmaceuticals
`
`The acute oral 50% lethal dose in rats is about 1.5 g/kg and in mice 1.1 g/kg. Renal
`papillary necrosis and decreased urinary concentrating ability occur in rodents
`chronically administered high doses. Dose-dependent gastric mucosal injury occurs in
`rats and humans. Mammals may develop aspirin toxicosis associated with GI
`symptoms, circulatory effects, and central nervous system depression [see
`Overdosage (10)].
`
`Omeprazole
`
`Reproductive Toxicology Studies
`
`Reproductive studies conducted with omeprazole in rats at oral doses up to 138
`mg/kg/day (about 34 times the human dose on a body surface area basis) and in
`rabbits at doses up to 69 mg/kg/day (about 34 times the human dose on a body
`surface area basis) did not disclose any evidence for a teratogenic potential of
`omeprazole. In rabbits, omeprazole in a dose range of 6.9 to 69.1 mg/kg/day (about
`3.4 to 34 times the human dose on a body surface area basis) produced dose-related
`increases in embryo-lethality, fetal resorptions, and pregnancy disruptions. In rats,
`dose-related embryo/fetal toxicity and postnatal developmental toxicity were
`observed in offspring resulting from parents treated with omeprazole at 13.8 to 138
`mg/kg/day (about 3.4 to 34 times the human doses on a body surface area basis).
`
`Juvenile Animal Study
`
`A 28-day toxicity study with a 14-day recovery phase was conducted in juvenile rats
`with esomeprazole magnesium at oral doses of 70 to 280 mg/kg/day (about 17 to 67
`times a daily oral human dose of 40 mg on a body surface area basis). An increase in
`the number of deaths at the high dose of 280 mg/kg/day was observed when juvenile
`rats were administered esomeprazole magnesium from postnatal day 7 through
`postnatal day 35. In addition, doses equal to or greater than 140 mg/kg/day (about 34
`times a daily oral human dose of 40 mg on a body surface area basis), produced
`treatment-related decreases in body weight (approximately 14%) and body weight
`gain, decreases in femur weight and femur length, and affected overall growth.
`Comparable findings described above have also been observed in this study with
`another esomeprazole salt, esomeprazole strontium, at equimolar doses of
`esomeprazole.
`
`4.3
`
`Final Recommendation
`
`An Approval Action is the final recommendation by the Nonclinical Pharmacology/
`Toxicology discipline provided the labeling revisions described above are made.
`
`Reference ID: 3985627
`
`14
`
`

`

`CDTL Review 0 NDA 205103 0 Yosprala (Aspirin and Omeprazole) o Aralez Pharmaceuticals
`
`5. Clinical Pharmacology/Biopharmaceutics
`
`5.1
`
`Issues
`
`The Clinical Pharmacology Reviewer referred to previous clinical pharmacology reviews
`from the first and second review cycles. The Clinical Pharmacology Reviewer noted that a
`full clinical pharmacology review was conducted during the first review cycle and the
`application was acceptable from a clinical pharmacology perspective. The Clinical
`Pharmacology Reviewer further noted that there was not a new clinical pharmacology study
`in the second cycle NDA submission.
`
`The Clinical Pharmacology Reviewer summarized the Clinical Pharmacology findings
`pertinent to the current submission as follows:
`
`Aspirin Supplier Comparison:
`In this submission, the sponsor changed API aspirin srgglier source from
`to
`(also referred to as
`(b) (4)
`In addition, aspirin from this new supplier
`
`).
`
`(b) (4)
`
`(b) (4)
`
`(5) (4)
`
`BA/BE study:
`(I'm was
`Aspirin components of PA8140 and PA32540 from the new supplier
`bioequivalent to that of previous supplier
`one based on two separate BE studies
`(PA8140-104 and PA32540-119) that had used partial reference-replicate3-way study
`design with a reference-scaled average BE approach.
`
`081 inspection:
`An inspection for bioequivalence (BE) studies PA8140-104 and PA32540-119 for
`both clinical site and bioanalyti