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

`

`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`PUBLIC HEALTH SERVICE
`FOOD AND DRUG ADMINISTRATION
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`PHARMACOLOGY/TOXICOLOGY NDA/BLA REVIEW AND EVALUATION
`
`Application number:
`Supporting document/s:
`Applicant’s letter date:
`CDER stamp date:
`Product:
`
`Indication:
`
`Applicant:
`Review Division:
`Reviewer:
`Supervisor:
`Division Director:
`Project Manager:
`
`205103
`046
`March 14, 2016
`March 14, 2016
`PA8140 and PA32540 (Yosprala®,
`Aspirin/Omeprazole) Tablets
`For use in the secondary prevention of cardio-
`and cerebrovascular events in patients at risk of
`developing aspirin-associated gastric ulcers
`POZEN, Inc.
`DGIEP
`Tamal Chakraborti, PhD
`Sushanta Chakder, PhD
`Donna Griebel, MD
`Brian Strongin, RPh, MBA
`
`Reference ID: 3968483
`
`1
`
`

`

`NDA # 205103 SDN 046
`
`Reviewer: Tamal Chakraborti, PhD
`
`TABLE OF CONTENTS
`
`EXECUTIVE SUMMARY..................................................................................................3
`INTRODUCTION ................................................................................................................3
`BRIEF DISCUSSION OF NONCLINICAL FINDINGS ..................................................................3
`RECOMMENDATIONS ........................................................................................................3
`STUDIES SUBMITTED ....................................................................................................3
`STUDIES REVIEWED.........................................................................................................3
`STUDIES NOT REVIEWED .................................................................................................4
`PREVIOUS REVIEWS REFERENCED ...................................................................................4
`INTEGRATED SUMMARY AND EVALUATION............................................................13
`
`Reference ID: 3968483
`
`2
`
`

`

`NDA # 205103 SDN 046
`
`Reviewer: Tamal Chakraborti, PhD
`
`Executive Summary
`
`Introduction
`Yosprala (Aspirin/Omeprazole) delayed-release tablets, 81 mg/40 mg (PA 8140) and
`325 mg/40 mg (PA 32540) was originally submitted on March 25, 2013, as a 505(b)(2)
`application indicated for patients who require aspirin for secondary prevention of
`cardiovascular and cerebrovascular events and who are at risk of developing aspirin
`associated gastric ulcers. On April 25, 2014, a Complete Response (CR) letter was
`issued. The CR deficiencies included the following items: 1) Manufacturing facility
`inspection deficiencies and 2) Labeling deficiencies. On June 30, 2014, the Applicant
`submitted a resubmission (SDN 036) responding to the above CR letter. On December
`16, 2014, a second CR letter was issued as the manufacturing facility deficiencies were
`not fully resolved along with the other deficiencies, which included the following:
`
`1. Manufacturing facility inspection deficiencies
`2. Labeling deficiencies
`3. A safety update
`4. Re-review of the proposed tradename, Yosprala
`
`On March 14, 2016, the Applicant submitted a Class 2 resubmission (SDN 046) in
`response to the above December 16, 2014 CR letter.
`
`Brief Discussion of Nonclinical Findings
`The Applicant did not submit any nonclinical study report in this resubmission. Please
`refer to previous pharmacology reviews of NDA 205103 dated December 13, 2013 and
`November 21, 2014 for nonclinical information.
`Recommendations
`
`Approvability
`From a nonclinical perspective, this NDA resubmission is recommended for approval.
`Additional Non Clinical Recommendations
`None
`
`Studies Submitted
`The Applicant did not submit any nonclinical study report in this resubmission.
`Studies Reviewed
`N/A
`
`Reference ID: 3968483
`
`3
`
`

`

`NDA # 205103 SDN 046
`
`Reviewer: Tamal Chakraborti, PhD
`
`Studies Not Reviewed
`N/A
`Previous Reviews Referenced
` Pharmacology review of NDA 205103 dated December 13, 2013 by Tamal
`Chakraborti, PhD
` Pharmacology review of NDA 205103 dated November 21, 2014 by Tamal
`Chakraborti, PhD
`
`Labeling
`
`The nonclinical sections of the proposed draft labeling of Yosprala® conforms to the
`content and format of labeling for human prescription drug and biological products
`under 21CFR201.57. However, the following revisions are recommended.
`
`8.1
`
`Pregnancy
`
`Applicant’s Version:
`
`Reference ID: 3968483
`
`4
`
`(b) (4)
`
`1 Page of Draft Labeling has been Withheld in Full as B4 (CCI/TS) immediately following this page
`
`

`

`NDA # 205103 SDN 046
`
`Reviewer: Tamal Chakraborti, PhD
`
`0:) (4)
`
`Aspirin
`
`Aspirin produced a spectrum of developmental anomalies when administered to \Vistar rats as
`single. large doses (500-625 mgr-leg) 0n gestational day (GD) 9. 10. or 11. These doses (500 to
`625 nigfkg) in rats are about 15 to 19 times the maximum recommended human dose ofaspirin
`(325 mgs'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 I
`contrast to the rat. aspirin was not developmentally toxic in rabbits.
`/
`
`ll
`
`Evaluation: The Applicant’s proposed version appears to be acceptable. However, the
`aspirin data was moved before omeprazole data in order to be consistent with Sections
`13.1 and 13.2 of the label.
`
`Recommended Version:
`
`Animal Data
`
`Asgin‘n: Aspirin produced a spectrum of developmental anomalies when administered
`to Wistar rats as single, large doses (500-625 mglkg) on gestational day (GD) 9, 10, or
`11. These doses (500 to 625 mglkg) 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.
`
`OmeQrazole: Reproductive studies conducted with omeprazole in rats at oral doses up
`to 138 mglkg/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 mglkg/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 mglkg/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.
`
`Reference ID: 3968483
`
`

`

`NDA # 205103 SDN 046
`
`Reviewer: Tamal Chakraborti, PhD
`
`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.
`
`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
`
`Reference ID: 3968483
`
`7
`
`

`

`NDA # 205103 SDN 046
`
`Reviewer: Tamal Chakraborti, PhD
`
`Applicant’s Version:
`
`In a juvenile rat toxicity study. esomedgrgzole was administered with both magnesium and
`strontium salts at oral doses about
`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 .N'onclinical Toxicology (13.2)].
`
`Evaluation: The Applicant’s proposed version appears to be acceptable. However,
`multiples of human exposure values were corrected in appropriate places.
`
`Recommended Version:
`
`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)].
`
`1 3
`
`NONCLIICAL TOXICOLOGY
`
`Applicant’s Version:
`
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`Studies to evaluate the potential effects of YOSPRALA on carcinogenicity, mutagenicity, or
`impainnent 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 mgrkg-“day (about 0.35 to gtimes 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 carcinoids seldom occur in the untreated rat.
`In
`
`Reference ID: 3968483
`
`

`

`NDA # 205103 SDN 046
`
`Reviewer: Tamal Chakraborti, PhD
`
`In one of these
`addition. EC L cell hyperplasia was present in all treated groups of both sexes.
`studies, female rats were treated with 13.8 mg omeprazolew'kglday (about (m4) 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 EC L 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- veek
`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 mgrkga‘day (about 0.1 to 3.2
`times the human dose of 40 mg/day. based on body surface area). 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 inglkg/day (about «9(4)
`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 rin'o human lymphocyte chromosomal
`aberration assay.
`in one of two in viva mouse micronucleus tests. and in an in viva bone
`marrow cell chromosomal aberration assay. Omeprazole was negative in the in vitro Ames
`Salmonella [uphimurium assay. an in \‘in'o mouse lymphoma cell forward mutation assay and
`an in wig): rat liver DNA damage assay. Omeprazole at oral doses up to 138.0 mgikg/day
`(about
`(4) 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.
`
`Omeprazole was positive for clastogenic effects in an in rin'o htunan lymphocyte chromosomal
`aberration assay.
`in one of two in rim mouse micronucleus tests. and in an in vivo bone
`marrow cell chromosomal aberration assay. Omeprazole was negative in the in virro Ames
`test, an in vitro mouse lymphoma cell forward mutation assay. and an in viva rat liver DNA
`damage assay.
`
`.
`(I!)
`Omeprazole at oral doses up to 138.0 mgrkgfday (about
`(Otimes the human dose of 40 mg per
`day. based on body surface area) was found to have no effect on fertility and reproductive
`performance.
`
`Evaluation: 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.
`
`Reference ID: 3968483
`
`

`

`NDA # 205103 SDN 046
`
`Reviewer: Tamal Chakraborti, PhD
`
`Recommended Version:
`
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`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 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
`
`Reference ID: 3968483
`
`10
`
`

`

`NDA # 205103 SDN 046
`
`Reviewer: Tamal Chakraborti, PhD
`
`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
`
`Applicant’s Version:
`
`Reference ID: 3968483
`
`11
`
`

`

`NDA # 205103 SDN 046
`
`Reviewer: Tamal Chakraborti, PhD
`
`Omeprazole
`Reproductive Toxicologr Studies
`Reproductive studies conducted with omeprazole in rats at oral doses up to 138 mg/kg/day
`(about (”whines the human dose on a body surface area basis) and in rabbits at doses up to 69
`nigfkg/day (aboutmmtimes 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 mgrkg’day (about
`(m4) 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 embryoffetal toxicity and postnatal developmental toxicity
`were observed in offspring resulting from parents treated with omeprazole at 13.8 to 138.0
`mgr'kg! day (about
`(m4) 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 iiigjlch’da}r (about 17 to guines 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 mgs’kgfiday 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 mglkg/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.
`
`Evaluation: The Applicant’s proposed version appears to be acceptable. However,
`multiples of human exposure values were corrected in appropriate places.
`
`Recommended Version:
`
`Aspirin
`
`The acute oral 50% lethal dose in rats is about 1.5 glkg and in mice 1.1 glkg. 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
`
`Reference ID: 3968483
`
`1 2
`
`

`

`NDA # 205103 SDN 046
`
`Reviewer: Tamal Chakraborti, PhD
`
`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.
`
`Integrated Summary and Evaluation
`This Class 2 resubmission is in response to the Complete Response (CR) letter dated
`December 16, 2014. The Applicant did not submit any nonclinical study report in this
`submission. There are no nonclinical issues. Please refer to previous pharmacology
`reviews of NDA 205103 dated December 13, 2013 and November 21, 2014 for
`nonclinical information. From a nonclinical perspective, this resubmission is
`recommended for approval.
`
`Reference ID: 3968483
`
`13
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`TAMAL K CHAKRABORTI
`08/05/2016
`
`SUSHANTA K CHAKDER
`08/05/2016
`
`Reference ID: 3968483
`
`

`

`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`PUBLIC HEALTH SERVICE
`FOOD AND DRUG ADMINISTRATION
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`PHARMACOLOGY/TOXICOLOGY NDA/BLA REVIEW AND EVALUATION
`
`Application number:
`Supporting document/s:
`Applicant’s letter date:
`CDER stamp date:
`Product:
`
`Indication:
`
`Applicant:
`Review Division:
`Reviewer:
`Supervisor:
`Division Director:
`Project Manager:
`
`205103
`036
`June 30, 2014
`June 30, 2014
`PA8140 and PA32540 (Yosprala®,
`Aspirin/Omeprazole) Tablets
`For use in the secondary prevention of cardio-
`and cerebrovascular events in patients at risk of
`developing aspirin-associated gastric ulcers
`POZEN, Inc.
`DGIEP
`Tamal Chakraborti, Ph.D.
`Sushanta Chakder, Ph.D.
`Donna Griebel, MD
`Stacy Barley, RN, M.S.N., M.H.A
`
`Reference ID: 3662463
`
`1
`
`

`

`NDA # 205103
`
`Reviewer: Tamal Chakraborti, Ph.D.
`
`TABLE OF CONTENTS
`
`1
`
`EXECUTIVE SUMMARY ......................................................................................... 3
`1.1
`INTRODUCTION.................................................................................................... 3
`1.2
`BRIEF DISCUSSION OF NONCLINICAL FINDINGS ...................................................... 3
`1.3
`RECOMMENDATIONS............................................................................................ 3
`INTEGRATED SUMMARY AND EVALUATION............................................................. 7
`
`Reference ID: 3662463
`
`2
`
`

`

`NDA # 205103
`
`Reviewer: Tamal Chakraborti, Ph.D.
`
`1
`
`Executive Summary
`
`Introduction
`1.1
`PA8140 and PA32540 are the code names for aspirin 81 mg/omeprazole 40 mg tablets
`and aspirin 325 mg/omeprazole 40 mg tablets, respectively. This Class 2 resubmission
`is in response to the Complete Response (CR) letter dated April 25, 2014 regarding
`facility inspections, labeling issues and safety update.
`1.2 Brief Discussion of Nonclinical Findings
`The Applicant did not submit any nonclinical study report in this submission. Please
`refer to pharmacology review of NDA 205103 dated December 13, 2013 for nonclinical
`information.
`1.3 Recommendations
`
`1.3.1 Approvability
`From a nonclinical perspective, this NDA resubmission is recommended for approval.
`1.3.2 Additional Non Clinical Recommendations
`None
`Labeling
`1.3.3
`The Applicant has accepted the nonclinical revisions that are contained in FDA’s
`version of the labeling attached to the CR letter dated April 25, 2014. The current draft
`labeling of Yosprala® conforms to the content and format of labeling for human
`prescription drug and biological products under 21CFR201.57.
`
`8.1 Pregnancy
`
`Applicant’s Version:
`
`Reference ID: 3662463
`
`3
`
`2 Page(s) of Draft Labeling have been Withheld in Full as b4 (CCI/TS) immediately following this page
`
`

`

`NDA # 205103
`
`Reviewer: Tamal Chakraborti, Ph.D.
`
`
`
`Evaluation: The Applicant deleted the duplicated sentence “Animal reproduction
`studies with omeprazole....human dose of 40 mg") from the beginning of the fourth
`paragraph on page 16 of the draft label (Section 8.1 Pregnancy) in the revised version
`dated October 30, 2014. The above sentence was duplicated in the second paragraph
`of Section 8.1 of the label. The Applicant’s deletion of the above sentence and the
`proposed version is acceptable.
`
`Recommended Version: N/A
`
`Reference ID: 3662463
`
`

`

`NDA # 205103
`
`Reviewer: Tamal Chakraborti, Ph.D.
`
`Integrated Summary and Evaluation
`This Class 2 resubmission is in response to the Complete Response (CR) letter dated
`April 25, 2014 regarding facility inspections, labeling issues and safety update. The
`Applicant did not submit any nonclinical study report in this submission.
`
`The proposed labeling of Yosprala appears to conform to the specific requirements on
`content and format of relevant nonclinical sections of label for human prescription drugs
`under 21CFR 201.57. This resubmission is recommended for approval.
`
`Reference ID: 3662463
`
`7
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`TAMAL K CHAKRABORTI
`11/21/2014
`
`SUSHANTA K CHAKDER
`11/21/2014
`
`Reference ID: 3662463
`
`

`

`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`PUBLIC HEALTH SERVICE
`FOOD AND DRUG ADMINISTRATION
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`PHARMACOLOGY/TOXICOLOGY NDA/BLA REVIEW AND EVALUATION
`
`Application number:
`Supporting document/s:
`Applicant’s letter date:
`CDER stamp date:
`Product:
`
`Indication:
`
`Applicant:
`Review Division:
`Reviewer:
`Supervisor:
`Division Director:
`Project Manager:
`
`205103
`001
`March 25, 2013
`March 25, 2013
`PA8140 and PA32540 (Yosprala®,
`Aspirin/Omeprazole) Tablets
`For use in the secondary prevention of cardio-
`and cerebrovascular events in patients at risk of
`developing aspirin-associated gastric ulcers
`POZEN, Inc.
`DGIEP
`Tamal K. Chakraborti, Ph.D.
`Sushanta K. Chakder, Ph.D.
`Donna Griebel, MD
`Stacy Barley, RN, M.S.N., M.H.A
`
`Disclaimer
`
`Except as specifically identified, all data and information discussed below and
`necessary for approval of NDA 205103 are owned by POZEN, Inc. or are data for which
`POZEN, Inc. has obtained a written right of reference. Any information or data
`necessary for approval of NDA 205103 that POZEN, Inc. does not own or have a written
`right to reference constitutes one of the following: (1) published literature, or (2) a prior
`FDA finding of safety or effectiveness for a listed drug, as reflected in the drug’s
`approved labeling. Any data or information described or referenced below from reviews
`or publicly available summaries of a previously approved application is for descriptive
`purposes only and is not relied upon for approval of NDA 205103.
`
`Reference ID: 3421791
`
`1
`
`

`

`NDA # 205103
`
`Reviewer: Tamal K. Chakraborti, Ph.D.
`
`TABLE OF CONTENTS
`
`1
`
`3
`
`EXECUTIVE SUMMARY ......................................................................................... 3
`1.1
`INTRODUCTION.................................................................................................... 3
`1.2
`BRIEF DISCUSSION OF NONCLINICAL FINDINGS ...................................................... 3
`1.3
`RECOMMENDATIONS............................................................................................ 3
`2 DRUG INFORMATION .......................................................................................... 13
`2.1
`DRUG............................................................................................................... 13
`2.2
`RELEVANT INDS, NDAS, BLAS AND DMFS......................................................... 14
`2.3
`DRUG FORMULATION ......................................................................................... 14
`2.4
`COMMENTS ON NOVEL EXCIPIENTS..................................................................... 22
`2.5
`COMMENTS ON IMPURITIES/DEGRADANTS OF CONCERN ....................................... 24
`2.6
`PROPOSED CLINICAL POPULATION AND DOSING REGIMEN .................................... 30
`2.7
`REGULATORY BACKGROUND .............................................................................. 30
`STUDIES SUBMITTED.......................................................................................... 30
`3.1
`STUDIES REVIEWED........................................................................................... 30
`3.2
`STUDIES NOT REVIEWED ................................................................................... 30
`3.3
`PREVIOUS REVIEWS REFERENCED...................................................................... 30
`PHARMACOLOGY................................................................................................ 31
`4.1
`PRIMARY PHARMACOLOGY...............