CENTER FOR DRUG EVALUATION AND RESEARCH
`
`
`
`
`
`APPLICATION NUMBER:
`22511Orig1s000
`
`
`CROSS DISCIPLINE TEAM LEADER REVIEW
`
`
`
`
`
`

`

`Cross-Discipline Team Leader Review
`
`April 22, 2010
`
`Ruyi He, MD
`Acting Deputy Director/Medical Team Leader
`Division of Gastroenterology Products/ODE III
`
`Cross-Discipline Team Leader Review
`22-511
`POZEN Inc
`June 30, 2009
`April 30, 2010
`
`VIMOVO (naproxen/esomeprazole magnesium) Tablets.
`• 375 mg enteric coated naproxen and 20 mg
`esomeprazole (as magnesium trihydrate) Tablet, or
`• 500 mg enteric coated naproxen and 20 mg
`esomeprazole (as magnesium trihydrate) Tablet.
`VIMOVO is indicated for the relief of signs and symptoms
`of osteoarthritis, rheumatoid arthritis and ankylosing
`spondylitis in patients at risk of developing NSAID-
`associated gastric ulcers.
`NDA 22-511 VIMOVO (naproxen/esomeprazole
`magnesium) Tablets be approved for the indication of the
`relief of signs and symptoms of osteoarthritis, rheumatoid
`arthritis and ankylosing spondylitis and risk reduction of
`developing gastric ulcers in patients at risk of developing
`NSAID-associated gastric ulcers.
`
`NDA 22511 CDTL Review
`Ruyi He, MD
`
`
`Date
`
`From
`
`Subject
`NDA
`Applicant
`Date of Submission
`PDUFA Goal Date
`
`Proprietary Name /
`Established (USAN) names
`Dosage forms / Strength
`
`Proposed Indication(s)
`
`Recommended:
`
`
`
`
`
`1. Introduction
`
`
`PN 400 (VIMOVO) is a fixed dose combination tablet containing 375 mg or 500 mg naproxen
`in the core and 20 mg esomeprazole in the film coat. Esomeprazole is immediately released
`from the film coat, whereas the release of naproxen from the enteric coated core is delayed as
`it is dependent on elevated pH. Oral administration of PN 400 Tablets on a twice daily
`regimen is intended for the treatment of the signs and symptoms of osteoarthritis, rheumatoid
`arthritis and ankylosing spondylitis in patients at risk for developing NSAID-associated
`gastric ulcers.
`
`
`Page 1 of 16
`
`1
`
`

`

`NDA 22511 CDTL Review
`Ruyi He, MD
`
`Like other non-steroidal anti-inflammatory drugs (NSAIDs), naproxen inhibits
`cyclooxygenase enzyme activity. This inhibition reduces prostaglandin synthesis and
`leukocyte activation resulting in anti-inflammatory, and analgesic activity.
`
`Esomeprazole is a gastric proton pump inhibitor (PPI) that inhibits the final common pathway
`of acid production in the stomach and thus inhibit both basal and stimulated gastric acid
`secretion.
`
`NSAIDs remain the primary therapy for the management of signs and symptoms of chronic
`inflammatory conditions such as osteoarthritis. However, chronic NSAID therapy is associated
`with a substantial risk of upper gastrointestinal (UGI) ulcerations and ulcer complications,
`such as bleeding and perforations. The cumulative incidence of gastroduodenal ulcers with
`conventional NSAID use has been reported to be as high as 25-30% at 3 months and 45% at 6
`months, while that of placebo is 3-7%. Important risk factors for UGI ulcers in NSAID users
`are advancing age, a history of UGI ulcer or bleeding, and concomitant aspirin use. Up to 4%
`of NSAID users experience serious UGI adverse events, such as bleeding, perforation or
`obstruction. Ulcer formation and complications associated with having an ulcer may also be
`asymptomatic. In fact, up to 80% of those who develop an ulcer complication have no warning
`signs or symptoms.
`
`In clinical practice, the use of PPIs to inhibit gastric acid secretion has been shown to mitigate
`the risk from daily NSAID use by significantly reducing the development of gastric ulcers.
`
`As such, the sponsor developed a combination product to increase compliance with the 2-drug
`regimen with every dose since it combines both agents into a single tablet. Tablets are
`formulated to immediately release esomeprazole followed by release of naproxen after
`dissolution of the enteric coat at pH above 5.0.
`
`
`2. Background
`
`
`The development program to support this 505(b)2 application for PN 400 Tablets was
`discussed and agreed with the Agency. EC-Naprosyn is approved for the indications of
`Rheumatoid Arthritis, Osteoarthritis and Ankylosing Spondylitis at both 500 mg and 375 mg
`doses for twice daily administration. Esomeprazole is approved for risk reduction of NSAID-
`associated gastric ulcer 20 mg or 40 mg once daily for up to 6 months.
`
`The sponsor conducted 2 controlled pivotal efficacy and safety studies, PN400-301 and
`PN400-302, to demonstrate a reduction in gastric ulcer formation in subjects who took PN 400
`Tablets bid compared with those who took EC naproxen 500 mg bid on a daily basis for 6
`months. Those 2 trials are evaluated by the division of gastroenterology products (DGP).
`
`The sponsor also conducted two controlled studies (PN400-307 and PN400-309) to compare
`PN 400 Tablets with celecoxib in the management of signs and symptoms of osteoarthritis of
`the knee. These 2 trials are evaluated by the Division of Analgesics, Anesthetics, and
`Rheumatology Products (DAARP).
`
`Page 2 of 16
`
`2
`
`

`

`NDA 22511 CDTL Review
`Ruyi He, MD
`
`
`In addition, the 12-month open-label safety study PN400-304 provides the long-term safety of
`PN 400 Tablets in subjects at risk of developing NSAID-associated gastrointestinal ulcers and
`provided safety and tolerability data.
`
`
`3. CMC
`
`
`PN 400 Tablets have been designed as a single combination tablet of two distinct formulations,
`an inner enteric coated (delayed release) component of naproxen containing either 375 mg or
`500 mg of naproxen and an outer immediate release film coat of esomeprazole containing 20
`mg of esomeprazole (present as 22.3 mg of esomeprazole magnesium trihydrate). The tablet is
`designed to release the active ingredients in a coordinated, yet independent fashion.
`
`The tablet consists of a naproxen core tablet that is coated with
`
`
`
`
`
` PN 400 Tablets use conventional pharmaceutical ingredients and
`manufacturing processes that are well established for use in solid oral dosage forms.
`
` A
`
` 24 months shelf-life is proposed for PN 400 Tablets 500mg/20 mg and 375 mg/20 mg
`stored at controlled room temperature, 25°C (77°F) excursions 15°C to 30°C (59°F to 86°F),
`in the proposed commercial container closure system.
`
`
`
`
`
`
`
`
`
`The dissolution data submitted are acceptable based on Dr. Tien-Mien Chen’s evaluation;
`however, the currently proposed dissolution methodology by the sponsor for Vimovo tablets
`can only be used on an interim basis. As a Phase 4 commitment, the sponsor agreed to submit
`additional dissolution testing/data on the naproxen of Vimovo tablets for review. See Dr. Tien-
`Mien Chen’s review for details.
`
`Based on Dr. Rajiv Agarwal’s review (CMC reviewer), this NDA has provided sufficient
`CMC information to assure the identity, strength, purity, and quality of the drug product. The
`final “Acceptable” recommendation from the Office of Compliance is received on 24-MAR-
`2010. The labeling information on immediate container and carton labels is adequate. This
`NDA is recommended for APPROVAL form the CMC perspective.
`
`
`4. Nonclinical Pharmacology/Toxicology
`
`
`This NDA is submitted under section 505(b) (2) and is supported by reference to the Agency’s
`previous findings of safety and publicly available information on the toxicology of naproxen
`and esomeprazole (including omeprazole) to meet the nonclinical assessment requirements as
`part of the PN 400 new drug application.
`
`Page 3 of 16
`
`3
`
`(b) (4)
`
`(b) (4)
`
`

`

`NDA 22511 CDTL Review
`Ruyi He, MD
`
`
`There are no nonclinical study reports in this NDA except a PK study on determination of
`urinary and plasma metabolite profiles following 4 days oral administration of buffered- and
`unbuffered-omeprazole to female Sprague Dawley rats. In addition, the sponsor provided
`published studies to support the safety of the drug from a nonclinical standpoint.
`
`Pharmacologic, pharmacokinetic and toxicological properties of individual components of PN
`400 (naproxen and esomeprazole, including omeprazole) are well-established. From a
`nonclinical standpoint, approval of the NDA application is recommended. Please see Dr.
`Charles Wu’s review dated March 17, 2010 for detail.
`
`5. Clinical Pharmacology/Biopharmaceutics
`
`
`The 10, 20 and 30 mg bid dose for esomeprazole were tested. After 9 days of bid dosing,
`esomeprazole 20 mg resulted in a greater percent time with intragastric pH > 4.0 than
`esomeprazole 10 mg (71.4% vs 40.6%). Mean % time pH>4 following Vimovo increased with
`esomeprazole dose with 41%, 71%, and 77%, for 10 mg, 20mg, and 30 mg, respectively. The
`20 mg dose for esomeprazole is reasonable.
`
`At 375 mg dose of naproxen, PN 400 was bioequivalent to EC-NAPROSYN. At 500 mg dose
`of naproxen, the first bioequivalence study with less frequent sampling failed to demonstrate
`bioequivalence (BE) for Cmax. With more frequent sampling in a second bioequivalence
`study, PN 400 was bioequivalent to EC NAPROSYN. Based on Dr. Bai and Dr. Jappar’s
`Clinical Pharmacology review, Vimovo is bioequivalent to EC-NAPROSYN. At 20 mg,
`average esomeprazole AUC following Vimovo was approximately 50% of that following
`Nexium, indicating that immediate release of esomeprazole without protection against gastric
`acidic degradation resulted in significantly lower esomeprazole exposure.
`
`Co-administration of naproxen and esomeprazole in PN 400 did not alter the PK profile of
`either drug regardless of esomeprazole formulation (IR or EC), suggesting the absence of
`pharmacokinetic drug-drug interaction between naproxen and esomeprazole. The afternoon
`dose had lower esomeprazole AUC and Cmax than the morning dose. AUC and
`Cmax following multiple doses were higher than following single dose. Esomeprazole
`component of PN 400 has very high inter- and intra-individual variability regardless of single
`dose or multiple dose administration.
`
`High-fat meal significantly reduced esomeprazole bioavailability by 50% and delayed
`naproxen absorption by 10 hr from Vimovo. When Vimovo was administered 30 min or 60
`min prior to food intake, food had less effect on esomaprozole and naproxen absorption. This
`observed food effect was taken into consideration in Phase 3 clinical trials as patients were
`instructed to take Vimovo 30-60 min before breakfast or dinner.
`
`From the clinical pharmacology perspective, the application is acceptable provided the
`labeling comments are adequately addressed by the sponsor. Please see Dr. Bai and Dr.
`Jappar’s Clinical Pharmacology review dated April 7, 2010 for details.
`
`Page 4 of 16
`
`4
`
`

`

`NDA 22511 CDTL Review
`Ruyi He, MD
`6. Clinical Microbiology
`N/A
`
`
`
`7. Clinical/Statistical- Efficacy
`
`
`Studies PN400-307 and PN400-309 in the management of signs and symptoms of
`osteoarthritis of the knee
`
`The sponsor conducted two controlled studies (PN400-307 and PN400-309) to compare PN
`400 Tablets with celecoxib in the management of signs and symptoms of osteoarthritis of the
`knee. These 2 trials are evaluated by the Division of Analgesics, Anesthetics, and Rheumatology
`Products (DAARP).
`
`DAARP was consulted on the study design of the two pivotal trials (Studies 307 and 309) and
`attended EOP2 meeting on June 10, 2008 and Pre-NDA meetings on March 23, 2009. The
`following main issues were discussed and conveyed to the Sponsor:
`
`Primary endpoint must be the change from baseline to the end of treatment (12 weeks) in
`WOMAC Pain, WOMAC Function and Patient Global Assessment.
`Handling dropouts: a conservative imputation method for dropouts should be used as most of
`the dropouts are nonrandom.
`Pediatric studies
`
`
`Substantial evidence of analgesic efficacy of PN400 will be based on bioequivalence to EC-
`Naprosyn. The Studies 307 and 309 are intended to demonstrate comparability of PN-400 to
`celecoxib and is not possible to establish an "acceptable" non-inferiority margin at that time.
`
`The sponsor submitted three bioequivalence studies (Studies 102, 114 and 105) to establish
`bioequivalence of naproxen in PN400 tablets vs. EC-Naprosyn that were evaluated by clinical
`biopharmacology team (see reviews by Dr. Dilara Jappar and Dr. Jane Bai).
`
`Based on the evaluation by Dr. Dilara Jappar and Dr. Jane Bai, PN400 is bioequivalent to EC-
`Naprosyn. Therefore, analgesic efficacy of PN400 is established based on bioequivalence to
`EC-Naprosyn.
`
`Study 307 and Study 309 were designed identically as 12-week, multi-center, randomized,
`double-blind, placebo-controlled, active-controlled, non-inferiority (NI) studies. A total of 619
`(Study 307) and 615 (Study 309) patients with the knee OA were enrolled from 75-82 study
`sites in the US and were randomized into three groups with a ratio of 2:2:1 (PN400:celecoxib:
`placebo). The planned enrollment for each study was 570 patients with a study power of 90%
`based on the proposed NI margin of 10 mm difference (2-sided 95% CI) in three co-primary
`endpoints between PN400 and celecoxib. The subjects were treated with PN400 tablets (500
`mg naproxen/20 mg esomeprazole) bid, celecoxib capsules 200 mg qd or placebo for 12
`weeks.
`
`
`
`
`Page 5 of 16
`
`5
`
`(b) (4)
`
`

`

`NDA 22511 CDTL Review
`Ruyi He, MD
`
`The standard three co-primary endpoints for the OA indication were used: the mean change
`from baseline at Week 12 in WOMAC Pain, WOMAC Function and Patient Global
`Assessment. The secondary endpoints included common supportive efficacy variables for OA
`and variables for GI tolerability.
`
`The Applicant’s analyses of the primary endpoints for both noninferiority (PN400 vs.
`celecoxib) and superiority (PN400 and celecoxib vs. placebo) were consistent with the re-
`analyses performed by DAARP’s statistical reviewer. See both the medical review by Dr. Jin
`Chen and statistical review by Ms. Katherine Meaker for details.
`
`According to Dr. Chen, the upper bound of the 95% CI of the differences in three co-primary
`endpoints between PN400 and celecoxib were 4-5 mm, within the pre-specified NI margin of
`10 mm, based on the primary analysis, secondary analyses and sensitivity analyses in both
`studies. Also, the effect sizes of PN400 compared to placebo were similar to celecoxib (Table
`1 in Dr. Chen’s review).
`
`However, the pre-specified NI margin is considered to be inadequate as determined by both
`the clinical and statistical review teams in DAARP. The conclusion is based on the observed
`effect size of celecoxib over placebo from this study and the effect sizes were too small as
`compared with similar OA trials on the similar products. Dr. Chen pointed out in his review
`that the upper bound of the 95% CI of the observed effect sizes of celecoxib (vs. placebo) were
`only 0.28-1.75 mm less than the pre-specified NI margin (10 mm) for WOMAC pain and
`Function in both studies. Dr. Chen indicated that PN400 might be similar to placebo if a non-
`inferiority is established based on this NI margin. The non-inferiority of PN400 compared to
`celecoxib cannot be established as demonstrated by the re-analyses of non-inferiority
`performed by the statistical review team using a re-defined NI margin (see the statistical
`review for details).
`
`In both studies PN400 was statistically superior to placebo in all three co-primary endpoints in
`the primary analysis.
`
`In summary, I concurred with Dr. Chen and Ms. Katherine Meaker that PN400 is efficacious
`for the treatment of signs and symptoms of osteoarthritis of the knee based on superiority
`analyses comparing PN400 with placebo in both trials. Because the bioequivalence of PN400
`to the reference drug EC-Naprosyn (naproxen PK profile) is adequately established, the
`Applicant’s proposed indication “for the relief of signs and symptoms of osteoarthritis,
`rheumatoid arthritis and ankylosing spondyitis” and dosing regimen would be acceptable. The
`non-inferiority of PN400 (500/20 mg bid) compared to celecoxib (200 mg qd) cannot be
`established based on the totality of efficacy outcomes from both trials. The DAARP’s
`statistical review team re-defined the NI margin based on the observed effect size of celecoxib
`and concluded that PN400 was not noninferior to celecoxib in both studies.
`
`No new safety signals have been identified from either study, as compared to the reference
`drugs. Please see Dr. Chen’s review for detail clinical evaluation.
`
`
`
`Page 6 of 16
`
`6
`
`

`

`NDA 22511 CDTL Review
`Ruyi He, MD
`
`PN400-301 and PN400-302 for a reduction in gastric ulcer formation
`
`The sponsor conducted 2 controlled pivotal efficacy and safety studies, PN400-301 and
`PN400-302, to demonstrate a reduction in gastric ulcer formation in subjects who took PN 400
`Tablets bid compared with those who took EC naproxen 500 mg bid on a daily basis for 6
`months. Those 2 trials are evaluated by the division of gastroenterology products (DGP).
`
`Studies PN400-301 and PN400-302 were identical as 6 month, Phase 3, randomized, double-
`blind, parallel group, multicenter, outpatient studies at sites throughout the United States.
`Studies PN400-301 and PN400-302 each had 2 arms; the PN 400 and the EC naproxen.
`
`These studies enrolled subjects with risk factors for developing NSAID-associated gastric
`ulcer. Specifically, the inclusion required that subjects 18 years or older, but less than 50 years
`old must have had a documented, uncomplicated gastric or duodenal ulcer within 5 years of
`the study enrollment. Subjects 50 years or older did not require such a history but were not
`excluded if such a history existed.
`
`Efficacy endpoints in PN400-301 and PN400-302 were identical. The primary endpoint to
`support product approval was the cumulative proportion of subjects developing endoscopically
`visualized gastric ulcers (GU) through 6 months of treatment with PN 400 relative to the EC
`naproxen control. Endoscopies were conducted at baseline and at 1, 3 and 6 months of
`treatment; treatment emergent endoscopies were to be conducted in response to certain
`hemodynamic events and in response to dyspeptic symptoms. The definition of GU, both for
`the purposes of patient inclusion/exclusion and assessment of response, was a mucosal break ≥
`3mm in diameter with depth.
`
`The key secondary efficacy and tolerability endpoint assessments included:
`1. Pre-specified NSAID-associated UGI AEs
`2. Discontinuation from the study due to NSAID-associated UGI AEs
`3. Duodenal ulcers throughout 6 months of study treatment
`
`Both pivotal studies enrolled a majority of females (63- 69%) equally into both arms. The
`population was predominantly White (84- 90%), and had mean ages between 58 and 62 years.
`Approximately one quarter of the subjects in PN400-301 used low-dose aspirin (LDA)
`distributed equally between treatment groups, and there were equal histories of documented
`ulcer within the past 5 years. In PN400-302, slightly fewer subjects in the PN 400 group
`(21.9%) used LDA compared to subjects taking EC naproxen (24.3%).
`
` A
`
` significantly lower proportion of subjects who took PN 400 in both trials had gastric ulcers
`(GU) than subjects who used EC naproxen at 1 month, 3 months and at 6 months (p<0.001 at
`each time point, Table 1).
`
`
`
`
`
`
`Page 7 of 16
`
`7
`
`

`

`NDA 22511 CDTL Review
`Ruyi He, MD
`
`Table 1: Analysis of Cumulative Observed Incidence of Gastric Ulcers at 1, 3 and 6
`Months – ITT Population, PN400-301 and PN400-302
`
`
`Gastric ulcer
`n (%)
`
`Study 302
`PN 400
`EC naproxen
`N=210
`N=210
`% (95% CI)
`% (95% CI)
`
`
`54.3%
`71.9%
`(47.3 – 61.2%)
`(65.3 – 77.9%)
`(p< 0.001)
`
`
`
`1.0%
`5.7%
`(p= 0.007)
`
`
`
`4.8 %
`11.9%
`(2.3, 8.6%)
`(7.9, 17.1%)
`(p= 0.009)
`
`Study 301
`PN 400
`EC naproxen
`N=218
`N=216
`% (95% CI)
`% (95% CI)
`
`
`52.3%
`69.0%
`(45.4 – 59.1%)
`(62.4 – 75.1%)
`(p< 0.001)
`
`
`
`0.5%
`5.1%
`(p= 0.003)
`
`
`
`3.2 %
`12%
`(1.3 - 6.5%)
`(8.0 - 17%)
`(p< 0.001)
`
`
`NSAID Associated
`Upper GI AE and/or
`Duodenal Ulcers (DU)
`
`Incidence of DU at 6
`months
`
`Discontinuation due to
`NSAID Associated
`Upper GI AE or DU 6
`months
`
`Significantly fewer subjects in both trials who took PN 400 had a pre-specified NSAID-
`associated upper GI adverse event and/or duodenal ulcer than did those who took EC
`naproxen. Additionally, more subjects in both studies who took EC naproxen discontinued
`due to upper GI AE or DU compared to subjects who took PN 400; and subjects in both
`studies treated with EC naproxen had a higher incidence of duodenal ulcers, compared to those
`taking PN 400 (Table 2).
`
`
`Page 8 of 16
`
`8
`
`Study 302
`Study 301
`PN 400
`EC naproxen
`EC naproxen
`PN 400
`N=210
`N=210
`N=216
`N=218
`
`
`
`
`21 (10.0)
`4 (1.9)
`28 (13.0)
`3 (1.4)
`
`
`
`
`37 (17.6)
`10 (4.8)
`42 (19.4)
`4 (1.8)
`
`
`
`
`51 (24.3)
`15 (7.1)
`50 (23.1)
`9 (4.1)
` months
`P is <0.001 for both studies at 1 month, 3 months and at 6 months. P-value for ulcer occurrence is from a CMH
`test stratified by low-dose aspirin use, at randomization, as reported on the concomitant medications CRF page.
`
`Fewer subjects assigned to PN 400 developed GU throughout 6 months in PN400-301
`(4.1%) compared to those in PN400-302 (7.1%), while approximately the same percentage of
`those assigned to EC naproxen developed GU (23.1 % and 24.3%, respectively).
`
`PN 400 treatment also demonstrated improvements in the key secondary upper GI endpoints,
`including duodenal ulcer (Table 2).
`
`Table 2: Outcomes of Key Secondary Endpoints
`
`
`Key Secondary
`Endpoint
`
` month
`
` months
`
` 1
`
` 3
`
` 6
`
`

`

`NDA 22511 CDTL Review
`Ruyi He, MD
`
`Analyses were performed on subgroups of patients who did and did not take low-dose aspirin,
`subgroups of age and in subgroups of subjects who entered the trial with and without a history
`of gastric ulcer. The factors known to increase the risk of GU with the use of naproxen are
`increasing age, use of low dose aspirin (LDA), and history of gastric ulcer within 5 years of
`the study. Table 3 summarizes the findings at 6 months in these pre-defined subpopulations on
`the combined dataset.
`
`Table 3: Cumulative Proportion of Patients with Gastric Ulcers at 6 Months by
`Risk Factors, Combined Studies PN400-301 and PN400-302
`
`Risk Factor
`
`Vimovo % GU (95%CI)
`N
`99 3.0 (0.6-8.6)
`
`329 6.4 (4.0-9.6)
`
`216 8.3 (5.0-12.9)
`
`212 2.8 (1.0-6.1)
`
`393 5.1 (3.1-7.8)
`
`21 4.8 (0.1-23.8)
`
`
`EC naproxen % GU
`N
`102 28.4 (19.9-38.2)
`
`324 22.2 (17.8-27.1)
`
`217 21.2 (16.0-27.2)
`
`209 26.3 (20.5-32.8)
`
`390 21.5 (17.6-26.0)
`
`27 55.6 (35.3-74.5)
`
`
`Used LDA
`
`Did not use LDA
`
`Age < 60 years
`
`Age ≥ 60 years
`
`Age ≥ 50 years/ no history of ulcer
`
`Age ≥ 50 years/ history of ulcer
`P < 0.001 between Vimovo and Naproxen groups for all risk factors listed.
`
`
`The effectiveness of PN 400 in the reduction in occurrence of gastric ulcers was not decreased
`when analyzed by the risk factors of age, or the concomitant use of low dose aspirin.
`
`The efficacy of PN 400 is also supported by significant improvement in the secondary
`endpoints of reduction of pre-specified NSAID-associated UGI adverse events, duodenal
`ulcers and discontinuations from therapy due to each of those endpoints. The improved
`tolerability profile of PN 400 was further demonstrated by the fact that a higher proportion of
`subjects in the combined analysis assigned to PN 400 (71.4%) completed 6 months of
`treatment without developing a gastric or duodenal ulcer than subjects assigned to EC
`naproxen (47.6%). Importantly, the reductions in rates of DU and pre-specified NSAID-
`associated UGI adverse events in those who took PN 400 were not impacted by age or
`concomitant use of LDA.
`
`In conclusion, Studies PN400-301 and PN400-302 demonstrated individually and when
`combined that the use of PN 400 results in a significantly lower proportion of subjects with
`NSAID-associated gastric or duodenal ulcers over 6 months of treatment. The effect was
`consistent through the six months of treatment.
`
`
`
`Page 9 of 16
`
`9
`
`

`

`NDA 22511 CDTL Review
`Ruyi He, MD
`8. Safety
`
`
`The active ingredients in PN 400, naproxen and esomeprazole, have been commercially
`available in the US since 1976 and 2001, respectively and have been used together in clinical
`practice since 2004 when esomeprazole was first approved to reduce the gastric injury that can
`result from chronic use of NSAIDs. There are no known interactions between naproxen and
`esomeprazole that would indicate any novel adverse pharmacology, toxicology, physical or
`chemical interaction or tolerability issues as a result of their combination. Accordingly, no new
`non-clinical pharmacology, pharmacokinetic or toxicology studies have been conducted with
`PN 400.
`
`At least one dose of PN 400 was given to 1326 subjects in the Phase 1 and Phase 3 studies. Of
`these, 135 subjects took PN 400 for 12 months and 491 for six months. More than 360 doses
`were taken by 264 subjects and more than 180 doses were taken by 561 subjects.
`
`The Expanded Safety Population (ESP) included studies PN400-301, PN400-302, PN400-304,
`PN400-307, and PN400-309. The ESP examines only subjects who were assigned to the PN
`400 treatment group (N= 1157). The population was predominantly white (83%), female
`(67%) and had a mean age of 61 years. About 7% of subjects were greater than or equal to 75
`years of age and approximately 33.4% were ≥ 65 years.
`
`In the ESP, 88.5% of subjects reported taking NSAIDs for osteoarthritis, 4.7% for rheumatoid
`arthritis (RA), 0.4% for ankylosing spondylitis (AS) and 13% had other reasons for use of
`NSAIDs. Twenty five point seven percent (25.7%) used Low Dose Aspirin, 51.9% entered
`with a history of upper GI disorders and 56.4% entered with a history of cardiovascular
`disease.
`
`
`Common Treatment Emergent Adverse Events (TEAEs) in the Primary Safety
`Population
`
`More subjects who took EC naproxen reported related TEAEs (75.8%) compared to subjects
`who took PN 400 (53.5%). This difference was primarily due to reports of TEAEs in GI
`Disorders. The most common preferred term, erosive gastritis, was found in 38.0% of subjects
`taking EC naproxen and 19.4% of those taking PN 400. Subjects assigned to EC naproxen also
`had more dyspepsia, gastric ulcer, esophagitis, erosive duodenitis, GERD, duodenal ulcer, and
`erosive esophagitis than did subjects who took PN 400. The preferred term gastritis was the
`only related TEAE more frequently reported in subjects taking PN 400 (15%) than in subjects
`taking EC naproxen (12.2%).The only related TEAE in Cardiac Disorders was a single case of
`angina in a subject from the EC naproxen group.
`
`Deaths
`
`There were no deaths reported in any subject participating in any of the studies reported in this
`application.
`
`Page 10 of 16
`
`10
`
`

`

`NDA 22511 CDTL Review
`Ruyi He, MD
`
`
`
`Other Serious Adverse Events
`
`All 58 SAEs were reported by 53 subjects in the 6 Phase 3 studies. Overall, the frequency of
`SAEs was similar between PN 400 (2.7%) and EC naproxen (3.1%). When adjusted for
`exposure, the rate of SAEs was similar in the PN 400, EC naproxen and celecoxib groups. In
`the PN 400 group, there were 6.8 SAEs per 100 patient-years compared with 9.1 SAEs per 100
`patient-years in the EC naproxen group and 7.9 SAES per 100 patient-years in the celecoxib
`group.
`
`The most common SAEs were in Cardiac Disorders. The frequency of Cardiac Disorders was
`0.5% in the PN 400 group, 0.5% in the EC naproxen group and 0.2% in the celecoxib group.
`There were 4 reports of atrial fibrillation/flutter in subjects assigned to PN 400, 3 of which
`were SAEs. One subject entered the study with irregular rhythm that was later confirmed to be
`atrial fibrillation and a second subject developed atrial fibrillation approximately 3 weeks after
`stopping study drug. There were 2 cases of atrial fibrillation that occurred while the subjects
`were taking PN 400. However, none of the events were considered to be related to study drug
`by the Principal Investigator.
`
`Serious adverse events were next most commonly reported from the SOC of Infections and
`Infestations. There was a similar frequency of pneumonia in the PN 400 treatment group with
`2 cases (0.2%) compared to the EC naproxen group with 1 case (0.2%). There were no reports
`of pneumonia in the celecoxib group.
`
`
`Serious Adverse Events and Treatment Emergent Adverse Events Leading to
`Discontinuation
`
`More subjects discontinued from the EC naproxen group (40.6%) than from PN 400 (12.2%)
`and celecoxib (7.8%). This difference was due to discontinuation from GI Disorders including
`gastric ulcer, duodenal ulcer, and dyspepsia. More subjects assigned to PN 400 withdrew due
`to TEAEs from Investigations (0.9%) than did celecoxib (0.6%) or naproxen (none) or placebo
`(none) although no pattern was detected.
`
`Withdrawal from clinical studies due to TEAEs from Cardiac Disorders occurred in 0.4% and
`0.5% of subjects assigned to PN 400 and EC naproxen, respectively. The TEAE of
`hypertension, using the combined preferred terms of ‘hypertension’ and ‘blood pressure
`increase’, lead to the withdrawal of 4 subjects assigned to PN 400, 2 subjects assigned to EC
`naproxen, 3 subjects (in the celecoxib treatment group and 1 subject assigned to placebo.
`
`
`Laboratory Values in Studies in Patients
`
`More subjects shifted neutrophils from low or normal to high in the PN 400 treatment group
`(16.5%) than did celecoxib or placebo treatment groups (12.6% and 11.6%, respectively).
`
`Page 11 of 16
`
`11
`
`

`

`NDA 22511 CDTL Review
`Ruyi He, MD
`
`More subjects shifted eosinophils from low or normal to high in the PN 400 treatment group
`(18.1%) than did celecoxib or placebo treatment groups (10.3% and 7.1%, respectively)
`
`Over a period of 3-12 months, there were no increases in the mean for ALT, AST, alkaline
`phosphatase or bilirubin for PN 400 subjects. Group mean, median and shifts in ALT and
`AST, and in bilirubin, were similar and consistent between the active treatment groups.
`Elevations in transaminases greater than 3x ULN were noted in subjects in all treatment
`groups and were rare. Similar proportions of subjects in all treatment groups had elevation of
`transaminases to greater than 3X ULN. The observations with regards to the liver function
`tests performed in this program are consistent with the medical literature and the product labels
`for the individual components of PN 400.
`
`The laboratory findings in this application were consistent with the changes in laboratory tests
`described in the Approved Product Labeling of the components of PN 400. The clinical
`laboratory changes seen in the PN 400 treatments group are generally similar to the active
`comparators, EC naproxen and celecoxib, in the trials.
`
`
`Post Marketing Data
`
`PN 400 tablets are currently not approved for marketing in any country and therefore there are
`no post marketing data on the use of PN 400.
`
`The individual components of PN 400, esomeprazole and naproxen, have been marketed
`globally for a number of years and post-marketing adverse experience data are recorded in the
`individual prescribing information.
`
`The concurrent prescribing of esomeprazole and NSAIDs such as naproxen is supported by
`NEXIUM Approved Product Labeling. POZEN is relying on previous findings of safety and
`efficacy of naproxen in this 505(b)2 application. The proposed information to be included in
`the PN 400 prescribing information regarding adverse experiences should be derived from
`naproxen labeling and esomeprazole labeling.
`
`There are several published randomized controlled studies that address the safety and efficacy
`of esomeprazole when prescribed with NSAIDS including naproxen for the reduction in
`NSAID-associated gastric ulcer. However, specific safety information on esomeprazole and
`naproxen is not provided in these published studies.
`
`The cumulative reported (inclusive to 11 May 2009) medically confirmed, spontaneous case
`reports to AstraZeneca with esomeprazole specifically with concomitant naproxen was 67
`including 34 SAEs. The most common AE was pruritus (3 AE reports) and the most common
`SAE was hypersensitivity (2 SAE reports). Other reported AEs include arthritis, confusional
`state, gait disturbance, nausea; peripheral edema, decreased platelet count and decrease WBC
`count. There were no reports of liver function abnormalities or of liver disease.
`
`
`Page 12 of 16
`
`12
`
`

`

`NDA 22511 CDTL Review
`Ruyi He, MD
`
`In general the types of spontaneous adverse events reported are