CENTER FOR DRUG EVALUATION AND RESEARCH
`
`
`
`
`
`
`APPLICATION NUMBER:
`22511Orig1s000
`
`
`CLINICAL PHARMACOLOGY AND
`BIOPHARMACEUTICS REVIEW(S)
`
`
`
`
`
`

`

`Office of New Drugs Quality Assessment
`BIOPHARMACEUTICS REVIEW - ADDENDUM
`
`NDA#:
`
`Submission Date:
`
`Brand Name:
`Generic Name:
`Formulation:
`
`
`
`
`
`
`
`
`
`
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`
`
`22-511/N-000
`03/04/10 (Amendment 0009) and
`04/23/10 (Amendment 0014)
`Vimovo
`Naproxen/Esomeprazole
` Naproxen Delayed release (DR)/Esomeprazole
`(Eso) magnesium immediate release (IR) fixed dose
`combination (FDC) tablets
`500/20 mg and 375/20 mg
`Pozen
`Amendment to NDA
`Tien-Mien Chen, Ph.D.
`
`
`
`
`
`
`Strength:
`
`
`Sponsor:
`
`
`Type of submission:
`Reviewer:
`
`
`SUBMISSION
`Reference is made to NDA 22-511 for VIMOVO (naproxen/esomeprazole) 375 mg/20
`mg and 500 mg/20 mg Tablets submitted on June 30, 2009, and to the Biopharmaceutics
`review comments sent to the applicant on April 19, 2010. Reference is also made to the
`teleconferences held between the applicant and FDA on
`1). Feb. 24, 2010, in which the phase 4 commitment on dissolution methodology for
`VIMOVO Tablets was discussed, and
`2). April 21, 2010, in which the dissolution specifications for VIMOVO Tablets on an
`interim basis (within one year post approval) were discussed.
`
`ADDENDUM
`The main objective of this Addendum to the previous Biopharmaceutics Review (in
`DARRTS dated March 8, 2010) for NDA 22-511 is to document the dissolution
`specifications that were agreed on with the applicant in the teleconference held on April
`21, 2010. Based on this agreement the following dissolution method and specifications
`will be used on an interim basis for one year for VIMOVO Tablets, 375 mg/20 mg and
`500 mg/20 mg.
`
`
`Acid Stage:
`Naproxen only
`Acid stage testing determines the acid resistance of the enteric-coated naproxen core tablet.
`
`Dissolution Method
`USP Apparatus 2 (with sinkers) at 75 rpm
`Medium: 475 mL of 0.1 M HCl at 37°C
`
`Dissolution Specification:
`NMT
`at 2 hours (Meets USP Requirements)
`
`
`
`
`
`1
`
`(b) (4)
`
`

`

`Buffer Stage:
`Esomeprazole and Naproxen
`(Using a second set of tablets)
`
`
`
`Dissolution Method
`USP Apparatus 2 (with sinkers) at 75 rpm
`Medium: 900 mL of 0.05 M phosphate buffer pH 7.4 at 37°C
`
`Dissolution Specifications:
`Q=
` at 60 minutes for Naproxen
`Q=
` at 60 minutes for Esomeprazole
`
`
`
`
`
`
`
`_____04/24/10, 04/26/10___
`
`Date
`
`_____04/24/10, 04/26/10___
`
`Date
`
`
`Regarding the final dissolution methodology for VIMOVO Tablets, the applicant
`previous Phase 4 commitment (submitted on March 4, 2010, Sequence #0009) to develop
`a method to test the naproxen component continuously (i.e. acid then buffer testing on the
`same set of tablets), remains unaffected. Additionally, the applicant agreed to generate
`dissolution profile data on multiple batches for both components and submit after one
`year a proposal for the final dissolution specifications based on the generated data.
`
`
`
`
`
`________________________________
`Tien-Mien Chen, Ph.D.
`
`Reviewer
`ONDQA Biopharmaceutics
`
`
`
`________________________________
`Patrick Marroum, Ph.D.
`
`ONDQA Biopharmaceutics
`
`
`
`
`
`CC:
`
`
`
`NDA
`Patrick Marroum, Angelica Dorantes, Tien-Mien Chen
`
`
`
`2
`
`(b) (4)
`
`(b) (4)
`
`

`

`Application
`Type/Number
`--------------------
`NDA-22511
`
`Submission
`Type/Number
`--------------------
`ORIG-1
`
`Submitter Name
`
`Product Name
`
`--------------------
`POZEN INC
`
`------------------------------------------
`PN 400
`NAPROXEN/ESOMEPRAZOLE
`MAGNESIUM
`
`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`TIEN MIEN CHEN
`04/28/2010
`
`PATRICK J MARROUM
`04/28/2010
`
`

`

`OFFICE OF CLINICAL PHARMACOLOGY REVIEW
`
`
`
`
`
`NDA: 22511
`Brand Name
`Generic Name
`Reviewers
`Team Leader
`OCP Division
`OND Division
`Sponsor
`Submission Type; Code
`Formulation; Strength(s)
`
`Indication
`
`Dosing Regiment
`
`Submission Date(s): 06/30/2009
`Vimovo®
`Naproxen / Esomeprazole Magnesium
`PeiFan Bai, Ph.D., Dilara Jappar, Ph.D.
`Sue-Chih Lee, Ph.D.
`Division of Clinical Pharmacology 3
`Division of Gastroenterology Products
`POZEN Inc
`NDA 505 (b) (2), Original
`Tablets; EC naproxen 375 mg/IR esomeprazole 20mg;
`EC naproxen 500 mg/IR esomeprazole 20 mg
`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.
`One tablet, twice daily
`
`
`
`
`Table of Contents
`
`Table of Contents ............................................................................................................................ 1
`1 Executive Summary ................................................................................................................. 2
`1.1
`Recommendation .............................................................................................................. 2
`1.2
`Phase IV Commitments .................................................................................................... 2
`1.3
`Regulatory Background .................................................................................................... 2
`1.4
`Summary of Important Clinical Pharmacology and Biopharmaceutics Findings............. 2
`2 Question Based Review ........................................................................................................... 3
`2.1
`General Attributes............................................................................................................. 3
`2.2
`General Clinical Pharmacology ........................................................................................ 5
`2.3
`Extrinsic Factors ............................................................................................................. 43
`2.4
`General Biopharmaceutics.............................................................................................. 43
`2.5
`Analytical Section........................................................................................................... 45
`3 Detailed Labeling Recommendations .................................................................................... 46
`4 Appendices............................................................................................................................. 53
`4.1
`Individual Study Review................................................................................................. 53
`4.2
`Cover sheet and OCP Filing/Review Form................................................................... 119
`
`
`
`
`
`
`
`
`1
`
`

`

`1 Executive Summary
`1.1 Recommendation
`The application is acceptable from the clinical pharmacology perspective provided the labeling
`comments are adequately addressed by the sponsor.
`
`
`
`1.2 Phase IV Commitments
`As a part of PREA requirement, the sponsor should conduct PK studies in pediatric population, 2-
`17 years of age.
`
`
`1.3 Regulatory Background
`Vimovo® has an immediate release (IR) esomeprazole magnesium layer and an enteric coated
`(EC) naproxen core. Being a 505 b(2) application, this NDA references two FDA-approved
`products as listed below.
`
`
`Name of Drug
`EC Naprosyn
`Nexium Capsules
`
`NDA #
`020067
`021153
`
`Sponsor
`Roche
`AstraZeneca
`
`Strength
`375 mg and 500 mg
`20 mg and 40 mg
`
`Approved Year
`1994
`2001
`
`
`Currently, EC-NAPROSYN® (naproxen delayed-release tablets) is available as enteric coated
`tablets containing 375 mg of naproxen or 500 mg of naproxen for oral administration. Nexium®
`(esomeprazole magnesium) is available as delayed-release capsules and delayed-released oral
`suspension. For the indication of risk reduction of NSAID-associated gastric ulcer, both 20 mg
`and 40 mg are approved for once daily for up to 6 months The Nexium® formulation used for
`comparison in this NDA submission is 20 mg delayed-release capsules.
`
`NOTE: In this review, Vimovo and PN 400 will be used inter-exchangeably.
`1.4 Summary of Important Clinical Pharmacology and Biopharmaceutics
`Findings
`
`Dose selection:
`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’s rationales for clinically study the 20 mg bid dose
`for esomeprazole are 1) after 2 weeks of bid dosing, esomeprazole 20 mg resulted in a higher
`percentage of subjects with no visible GI lesions (40% of subjects with Lanza Score of 0) as
`compared to 10 mg or 30 mg of esomeprazole, and 2) 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%).
`
`Bioequivalence with respect to naproxen and relative bioavailability of esomeprazole:
`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,
`
`
`
`
`
`2
`
`
`
`
`
`
`
`

`

`PN 400 was bioequivalent to EC NAPROSYN ®. We concluded that 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.
`
`Drug-drug intreractions, pharmacokinetics, and pharmacodynamic characteristics:
`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.
`
`Mean % time pH>4 following Vimovo increased with esomeprazole dose with 41%, 71%, and
`77%, for 10 mg, 20mg, and 30 mg, respectively.
`
`
`Food Effect
`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 III clinical trials as patients were instructed to take
`Vimovo 30-60 min before breakfast or dinner.
`
`
`
`
`
`
`
`
` 2
`
` Question Based Review
`2.1 General Attributes
`
`2.1.1 What are the highlights of Vimovo® (PN 400 tablet) formulation?
`Vimovo® (PN 400 tablet) is an oral fixed dose combination product (tablet) containing 375
`mg or 500 mg naproxen in the enteric coated core (delayed release) surrounded by 20 mg
`esomeprazole (22.3 mg magnesium trihydate) in the immediate-release film coat.
`
`2.1.2 What is the proposed indication of Vimovo® ?
`PN 400 tablet is indicated 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.
`
`
`2.1.3 What are the proposed mechanisms of actions of Vimovo?
`Vimovo is a combination drug product of naproxen and esomeprazole.
`
`
`
`
`
`
`3
`
`
`
`
`
`

`

`Naproxen is a nonsteroidal anti-inflammatory drug (NSAID) that inhibits cyclo-oxygenase
`(COX) enzyme activity which reduces prostaglandin synthesis resulting in anti-inflammatory,
`analgesic and anti-pyretic activity.
`
`Esomeprazole is a proton pump inhibitor (PPI) that suppresses gastric acid secretion via
`specific inhibition of the H+, K+-ATPase enzyme (proton pump) located in the secretory
`membrane of the gastric parietal cell. Esomeprazole does not exhibit anticholinergic or H2
`histamine antagonistic properties. In
`the acidic compartment of
`the parietal cell,
`esomeprazole is protonated and converted into a pharmacologically active inhibitor that react
`with luminally accessible cysteines of H+, K+-ATPase to form a disulfide bond, thus
`irreversibly inhibiting H+, K+-ATPase activity. Since PPIs block the final common pathway
`of acid production in the stomach, they inhibit both basal and stimulated gastric acid
`secretion. According to the sponsor, esomeprazole was selected as the PPI of choice because
`of its superior acid inhibiting properties compared to other marketed PPIs and its proven
`efficacy in risk reduction of NSAID-associated gastric ulcers.
`
`2.1.4 What are the proposed dosage and route of administration?
`The combination product Vimovo® is available as EC naproxen 375 mg/ IR esomeprazole 20
`mg tablet and EC naproxen 500 mg/ IR esomeprazole 20 mg tablet. The proposed route of
`administration for all the indications sought approval is oral; the proposed daily dosing
`regimen is one tablet twice daily. Use the lowest effective dose. Not recommended in
`moderate/severe renal insufficiency or in severe hepatic insufficiency. Consider dose
`reduction in mild/moderate hepatic insufficiency.
`
`
`2.1.5 What is the sponsor’s dose selection rationale?
`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’s rationales for choosing the 20 mg bid dose
`are 1) After 2 weeks of bid dosing, PN 400 containing an esomeprazole dose of 20 mg
`resulted in a higher percentage of subjects with no visible GI lesions (40% of subjects with
`Lanza Score of 0) compared to PN 400 formulations containing 10 mg or 30 mg of
`esomeprazole or naproxen alone (range 5.3-15%); 2) After 9 days of bid dosing, PN 400
`containing esomeprazole 20 mg treatment resulted in a greater percent time with intragastric
`pH > 4.0 (71.4% time with gastric pH > 4.0) than PN 400 containing esomeprazole 10 mg
`(40.6%).
`
`2.1.6 What is the regulatory background?
`
`This NDA is a 505 b(2) application with two reference-listed products shown below.
`
`Reference listed drug(s)
`Name of Drug
`EC Naprosyn
`Nexium Capsules
`
`NDA #
`020067
`021153
`
`
`
`
`
`
`
`4
`
`Sponsor
`Roche
`AstraZeneca
`
`Strength
`375 mg and 500 mg
`20 mg
`
`Approved Year
`1994
`2001
`
`
`
`
`
`
`
`

`

`Currently, EC-NAPROSYN® (naproxen delayed-release tablets) is available as enteric
`coated tablets containing 375 mg of naproxen or 500 mg of naproxen for oral
`administration. Nexium® (esomeprazole magnesium) is available as delayed-release
`capsules and delayed-released oral suspension. The Nexium® formulation used for
`comparison in this NDA submission is 20 mg delayed-release capsules.
`
`The clinical efficacy of Vimovo in treating osteoarthritis, rheumatoid arthritis, and ankylosing
`spondyliti was established in part through the demonstration of bioequivalence of naproxen
`component to enteric-coated naproxen, Naprosyn®. The sponsor conducted 3 studies (PN400-
`102, PN400-114, and PN400-105) to demonstrate bioequivalence on the naproxen component
`in Vimovo tablets with EC-Naprosyn. Per our request during the End-of-Phase II meeting on
`17 July 2007, the sponsor conducted a relative bioavailability study for the esomeprazole
`component.
`
`2.2 General Clinical Pharmacology
`
`2.2.1 What are the design features of clinical pharmacology and clinical studies used to
`support the dosing and efficacy claim?
`The naproxen dose strengths in PN400, 375 mg and 500 mg, correspond to those approved for
`Naprosyn®. Bioequivalence of naproxen in Vimovo (PN 400) as compared to Naprosyn® was
`evaluated in 3 separate phase I studies.
`
`Bioequivalence of naproxen component of PN 400 at 375 mg was evaluated in an open-label,
`randomized, single oral dose, two-way crossover study with 30 healthy volunteers (PN 400-
`105), in which PK and relative BA of naproxen was compared from a single oral dose of PN
`400 (naproxen 375 mg/ esomeprazole 20 mg) and a single oral dose of EC-ECNAPROSYN®
`375 mg. The result of this study supported the bioequivalence of PN 400 with EC-
`NAPROSYN in terms of naproxen component at 375 mg dose.
`
`The bioequivalence of naproxen at 500 mg was evaluated in 2 studies.
`Study PN400-102 was the first bioequivalence study at 500 mg naproxen dose, which was a
`randomized, open-label, three-way crossover study in 36 subjects at a single center in the
`United States. The washout period was at least 8 days. The primary objective was to assess
`and compare the pharmacokinetics and relative bioavailability of a single oral dose of
`naproxen 500 mg administered in three formulations (PN 400, the naproxen component of PN
`400, and EC-NAPROSYN®) in healthy volunteers. The study design is considered
`acceptable.
`
`The second bioequivalence study at 500 mg naproxen dose was a randomized, open-label,
`single oral dose, 4-way crossover study where 37 healthy subjects completed the study with 3
`formulations (PN 400 (delayed-release naproxen 500 mg /immediate-release esomeprazole 20
`mg), EC naproxen 500 mg tablet (EC Naprosyn®) plus EC esomeprazole 20 mg capsule
`(Nexium®), and the EC naproxen 500 mg tablet (EC Naprosyn®) alone).
`
`The effect of food and timing of food intake on bioavailability of naproxen and esomeprazole
`from PN 400 was evaluated in phase I, open-label, randomized, single-dose, 4-way crossover
`study in 21 healthy volunteers utilizing the standard high-fat breakfast.
`
`
`
`
`
`
`5
`
`
`
`
`
`
`
`
`
`

`

`Study PN400-101 was a Phase 1, randomized, investigator-blinded, open-label, parallel-group,
`active controlled study conducted in a single center in 80 healthy volunteers. EC Naprosyn®
`500 mg tablets were the comparator. The primary objective was to evaluate the risk of
`naproxen associated gastroduodenal injury of three PN 400 dose combinations, as determined
`by combined gastric and duodenal Grade 3 or 4 lesions
`One secondary objective was to assess the pharmacokinetics of esomeprazole on Day 1 and
`Day 14 in each of the PN 400 treatment groups, and the pharmacokinetics of naproxen on Day
`1 and Day 14 in all treatment groups. The study design is considered acceptable.
`
`Study PN400-104 was a randomized, open-label, 4-way crossover, single-center study in 28
`healthy adults comparing the effect on intragastric pH of three esomeprazole dose levels
`formulated in PN 400 with a treatment of non-EC naproxen plus EC esomeprazole. Hereafter,
`the non-EC naproxen of the control treatment is referred to as naproxen. The objective was to
`compare the pharmacodynamic (PD) measurements of intragastric pH (percent time
`intragastric pH > 4.0) on Day 9 of three PN 400 dose levels following twice-daily (bid)
`administration versus a combination of EC naproxen taken bid and EC esomeprazole taken
`once daily. The study consisted of four 9-day treatment periods. The first, second and third
`treatment periods were followed by a washout period of 12 days. Considering a plasma half-
`life of 1.5 hrs for esomeprazole, a plasma half-life of 12-17 hrs for naproxen, and a regular and
`constant turnover of H+/K+ ATPases, which in humans have a half-life of 2–3 days, the
`washout period of 12 days is considered acceptable.
`
`
`The efficacy and safety of PN 400 in reduction of gastric ulcer occurrence was evaluated in 2
`pivotal 6-month, Phase III, double blind, parallel group, randomized, active controlled, multi-
`center study where subjects took either PN400 (500 mg naproxen/20 mg esomeprazole) tablet
`BID or EC naproxen 500 mg tablet BID on a daily basis.
`
`Long term safety of PN 400 was evaluated in a 12-month, phase III, open –label, multi-center
`study.
`
`2.2.2 What was the clinical endpoint in the Phase 3 trials?
`
`The pivotal efficacy and safety studies had following endpoints:
`
`The primary endpoint:
`• The cumulative proportion of subjects developing endoscopically visualized gastric
`ulcers (GU) through 6 months of treatment with PN 400 tablets relative to the EC
`naproxen control. Endoscopies were conducted at baseline and at 1, 3 and 6 months of
`treatment.
`
`The key secondary endpoints:
`• Pre-specified NSAID-associated UGI AEs and/or duodenal ulcers,
`• Discontinuation from study due to NSAID-associated UGI AEs or to duodenal ulcers
`• The overall incidence of duodenal ulcers diagnosed endoscopically throughout the 6
`months of study treatment.
`
`
`
`
`
`6
`
`
`
`
`
`
`
`
`
`
`
`
`

`

`2.2.3 What are the PK characteristics of PN 400 and its individual components
`following single oral dose?
`
`All of the following pharmacokinetic parameters were determined using non-compartmental
`analysis from the plasma concentration vs. time profile.
`
`Naproxen PK at 375 mg in healthy subjects:
`
`In PN 400-105, 30 healthy volunteers received single dose of either PN 400 (375 mg
`naproxen/ 20 mg esomeprazole) or EC- NAPROSYN® 375 mg in a crossover study design
`following an overnight fasting of at least 10 hr. No food was allowed for at least 4 hours post-
`dose.
`
`Summary of Naproxen Pharmacokinetic Parameters at 375 mg by Treatment:
`AUC0-t
`AUC0-inf
`Cmax
`(µg/mL) Tmax (hr)
`(hr*µg/mL)
`(hr*µg/mL)
`57.9
`4.73
`
`t½ (hr)
`
`977
`
`1060
`
`19.8
`
`17
`
`56.9
`
`21
`
`36
`
`5.02
`
`84
`
`15
`
`1003
`
`15
`
`17
`
`1084
`
`17
`
`14
`
`19.3
`
`15
`
`Treatment
`
`Statistics
`
`A
`PN 400 375 mg
`(N = 30)
`
`Mean
`
`% CV
`
`Mean
`
`B
`EC-
`NAPROSYN®
`375 mg (N = 30) % CV
`
`
`
`
`
`
`
`
`
`
`Naproxen PK at 500 mg in healthy subjects:
`
`In study PN 400-114, the sponsor evaluated the naproxen pharmacokinetic profile following a
`single oral dose administration of either PN 400 (500 mg naproxen/ 20 mg esomeprazole) or
`EC-NAPROSYN 500 mg tablet + EC-Esomeprazole 20 mg capsule (NEXIUM) or EC-
`NAPROSYN 500 mg tablet alone to healthy volunteers following overnight fasting of at least
`10 hrs. No food was allowed for at least 4 additional hours after the dose administration.
`
`Summary of Naproxen Pharmacokinetic Parameters at 500 mg by Treatment:
`Cmax
`Tmax
`Tlag
`AUC0-t
`AUC0-inf
`Treatment
`Statistics
`(µg/mL)
`(hr)
`(hr)
`(hr*µg/mL)
`(hr*µg/mL)
`66.9
`6.15
`1.98
`1226
`1326
`22
`58
`53
`15
`17
`74.3
`4.95
`1.22
`1263
`1374
`
`A
`PN 400 (N = 38)
`
`22
`
`75.3
`
`96
`
`4.99
`
`88
`
`1.69
`
`15
`
`1266
`
`17
`
`1375
`
`69
`85
`20
`%CV
`PN 400 (500 mg naproxen/ 20 mg esomeprazole)
`EC-NAPROSYN 500 mg tablet + EC-Esomeprazole 20 mg capsule (NEXIUM)
`
`EC-NAPROSYN 500 mg tablet
`
`15
`
`16
`
`Mean
`%CV
`Mean
`B
`EC Naproxen
`+EC Eso (N = 39) %CV
`Mean
`C
`EC Naproxen
`(N = 39)
`Treatment A:
`Treatment B:
`Treatment C:
`
`
`t½
`(hr)
`18.9
`14
`19.6
`
`14
`
`19.4
`
`11
`
`
`
`
`
`
`
`7
`
`

`

`Naproxen PK parameters at 500 mg were also evaluated in study PN 400-102 and PN 400-
`103. In study PN 400-102, AUC and half life of naproxen from PN 400 and commercially
`available EC-NAPROSYN 500 mg table were comparable to the result from study PN 400-
`114; However, due to difference in sampling frequency, Cmax and Tmax from study PN 400-102
`were slightly different from results of study PN 400-114. PK parameters of naproxen from PN
`400 from study PN 400-103 (food effect study) were comparable to the study result of PN
`400-114.
`
`Summary of Naproxen PK Parameters at 500 mg by different studies:
`Study
`Cmax
`Tmax
`Tlag
`AUC0-t
`Treatment
`(µg/mL)
`(hr)
`(hr)
`(hr*µg/mL)
`66.9
`6.15
`1.98
`1226
`22
`58
`53
`15
`75.3
`4.99
`1.69
`1266
`
`Statistics
`
`Mean
`%CV
`Mean
`
`%CV
`
`Mean
`
`%CV
`
`Mean
`
`%CV
`
`Mean
`
`%CV
`
`20
`
`57.6
`
`25
`
`66.6
`
`20
`
`62.4
`
`19
`
`85
`
`7.07
`
`69
`
`5.78
`
`79
`
`6.1
`
`55
`
`69
`
`
`
`
`
`
`
`
`
`2.00
`
`49
`
`15
`
`1178
`
`19
`
`1285
`
`19
`
`1135
`
`10
`
`PN 400-114
`PN 400
`
`PN 400-114
`EC Naproxen
`
`
`PN 400-102
`PN 400
`
`PN 400-102
`EC Naproxen
`
`
`PN 400-103
`(Food effect Study)
`
`AUC0-inf
`(hr*µg/mL)
`1326
`17
`1375
`
`16
`
`1290
`
`22
`
`1415
`
`23
`
`1220
`
`12
`
`t½
`(hr)
`18.9
`14
`19.4
`
`11
`
`19.3
`
`18
`
`20.2
`
`16
`
`18.8
`
`10
`
`
`
`Esomeprazole PK parameters in healthy subjects:
`
`Esomeprazole (20 mg) pharmacokinetics parameters were evaluated in several different
`studies.
`In study PN 400-114, the sponsor evaluated the esomeprazole pharmacokinetic profile
`following a single oral dose administration of either PN 400 (500 mg naproxen/ 20 mg
`esomeprazole) or EC-NAPROSYN 500 mg tablet + EC-Esomeprazole 20 mg capsule
`(NEXIUM) or EC-Esomeprazole capsule (Nexium®) alone to healthy volunteers following
`overnight fasting of at least 10 hrs and continued fasting for 4 additional hours after dosing.
`
`Summary of Esomeprazole (20 mg) Pharmacokinetic Parameters by treatment:
`Cmax
`Tmax
`Tlag
`AUC0-t
`AUC0-inf
`(ng/mL)
`(hr)
`(hr)
`(hr*ng/mL)
`(hr*ng/mL)
`425
`0.51
`0.03
`465
`467
`
`Treatment
`
`Statistics
`
`A
`PN 400
`(N = 38)
`B
`EC Naproxen +EC
`Eso (N = 39)
`
`Mean
`
`%CV
`
`Mean
`%CV
`
`81
`
`432
`48
`
`49
`
`2.50
`54
`
`234
`
`0.91
`134
`
`91
`
`801
`79
`
`91
`
`803
`79
`
`t½
`(hr)
`0.971
`
`45
`
`0.945
`49
`
`
`
`
`
`8
`
`
`
`
`
`
`
`

`

`D
`EC Esomeprazole
`(N = 39)
`Treatment A:
`Treatment B:
`Treatment D:
`
`Mean
`
`455
`
`2.43
`
`0.87
`
`806
`
`815
`
`47
`34
`40
`%CV
`PN 400 (500 mg naproxen/ 20 mg esomeprazole)
`EC-NAPROSYN 500 mg tablet + EC-Esomeprazole 20 mg capsule (NEXIUM)
`EC-Esomeprazole 20 mg capsule (Nexium®)
`
`78
`
`81
`
`0.936
`
`44
`
`The results of esomeprazole PK parameters from other studies (PN 400-103, 105, 111)
`following the administration of PN 400 were comparable with the results from study PN
`400-114 that they all had a very high PK variability.
`
`Summary of Esomeprazole (20 mg) Pharmacokinetic Parameters by different studies:
`Study
`Cmax
`Tmax
`AUC0-t
`AUC0-inf
`t½
`Treatment
`(ng/mL)
`(hr)
`(hr*ng/mL)
`(hr)
`(hr*ng/mL)
`425
`0.51
`465
`467
`0.971
`PN 400-114
`PN 400
`
`
`Statistics
`
`Mean
`
`%CV
`
`81
`
`49
`
`91
`
`91
`
`45
`
`PN 400-103
`PN 400
`
`PN 400-105
`PN 400
`
`PN 400-111
`PN 400
`
`
`Mean
`
`%CV
`
`Mean
`
`%CV
`
`Mean
`%CV
`
`464
`
`80
`
`424
`
`86
`
`383
`87
`
`0.57
`
`41
`
`0.52
`
`35
`
`
`
`
`576
`
`80
`
`566
`
`128
`
`383
`97
`
`579
`
`79
`
`569
`
`128
`
`385
`97
`
`1.06
`
`33
`
`1.04
`
`39
`
`0.99
`27
`
`2.2.4 What are the pharmacokinetics of esomeprazole and naproxen following one-day
`and multiple-day administrations?
`The primary objective of study PN400-101 was to evaluate the risk of naproxen associated
`gastroduodenal injury of three PN 400 dose levels. The secondary objective was to assess the
`pharmacokinetics of esomeprazole on Day 1 and Day 14 in each of the PN 400 treatment
`groups, and the pharmacokinetics of naproxen on Day 1 and Day 14 in all treatment groups.
`No food was allowed after midnight prior to the am dose on days 1 to 14. On Days 1 to 14 no
`food was allowed 2 hours prior to the PM dose. Each dose of study medication was
`administered 60 minutes prior to breakfast (for the AM dose) and 60 minutes prior to dinner
`(for the PM dose). From the clinical pharmacology perspective, our review will focus only on
`the pharmacokinetic and pharmacodynamic section. On Days 1 and 14, 24-hour blood
`samples were collected for PK assessments, beginning just prior to the morning dose of study
`medication, and continuing at the following times post-dosing: 10, 20, 30 and 45 minutes and
`1, 1.5, 2, 2.5, 3, 4, 6, 8, 10 (just prior to the afternoon dose), 10.17, 10.33, 10.5, 10.75, 11,
`11.5, 12, 12.5, 13, 14, 16, 18, 20 and 24 hours. The 24-hr blood samples following 14 days of
`administration were taken in the morning of day 15.
`
`
`
`
`
`9
`
`
`
`
`
`
`
`
`
`

`

`
`
`
`
`
`
`
`
`EC Naprosyn® 500 mg tablets (naproxen delayed release tablets) were manufactured by
`Roche Pharmaceuticals. Treatment began on the morning of Day 1 and continued through the
`evening of Day 14, for a total of 28 doses. Doses on each treatment day were given
`approximately 10 hours apart. Study drug was swallowed each time with 240 ml of water.
`
`Demographic characteristics of the groups
`
`
`
`The four treatment groups have similar demographic characteristics.
`
`Endoscopies were performed on Day -1 and Day 15. The same gastroenterologist performed
`all endoscopies and was blinded to the assigned treatment group for each subject. All areas of
`the gastric and duodenal bulb were examined and the numbers of hemorrhages, erosions, and
`ulcers in each location were recorded. Any ulcers were measured and the largest diameter
`recorded. An ulcer was defined as a mucosal break of at least 3 mm in diameter
`(measured by close application of open endoscopic biopsy forceps) with depth.
`
`
`
`
`
`
`
`
`10
`
`

`

`Lanza Scores - Day 15/End of Study – Stomach and Duodenum Combined – Per Protocol
`Population.
`
`
`
`Percent of Subjects with a Grade 3 and 4 Lanza Score on Day 15
`
`
`
`
`
`Treatment differences in the distribution of Lanza scores were statistically significant in each
`pair-wise comparison with EC naproxen.
`
`Esomeprazole pharmacokinetics
`
`Mean Plasma Esomeprazole Concentration vs. Time Curves for All PN 400 Treatments on
`Day 1 and Day 14
`
`
`
`
`
`11
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`

`

`
`
`
`
`
`
`
`
`
`
`
`
`
`Plasma esomeprazole concentrations after the PM dose were similar to those after the AM
`dose on Day 1, but on Day 14 esomeprazole concentrations after the PM dose were lower than
`those after the AM dose for each treatment. In addition, the mean/median concentrations of
`esomeprazole were higher on Day 14 than on Day 1, especially after the AM dose. Though
`esomeprazole has a short half life, its am and pm exposures on day 14 were consistently higher
`than the respective exposures on day 1, for each PN400 formulation.
`
`
`
`Mean (CV%) of Esomeprazole Pharmacokinetic Parameters by Study Day and Dose
`Time for Treatment A (PN 400/E30)
`Cmax
`(ng/mL)
`
`Day, dose, N
`
`Tmax (hr)
`
`Day 1, am
`N=20
`Day 1, pm
`N=20
`Day 14, am
`N=20
`Day 14, pm
`N=20
`
`435 (90)
`
`457 (120)
`
`1804 (26)
`
`949 (60)
`
`0.63 (33)
`
`0.68 (58)
`
`0.56 (40)
`
`1.00 (57)
`
`AUC0-10,am or
`AUC0-14,pm
`(hr*ng/mL)
`594 (83)
`
`767 (119)
`
`4161 (32)
`
`2800 (48)
`
`AUC0-24
`(hr*ng/mL)
`
`T1/2 (hrs)
`
`--
`
`1361 (99)
`
`--
`
`6961 (36)
`
`0.94 (25)
`
`1.06 (29)
`
`1.52 (18)
`
`1.68 (22)
`
`Mean half life (CV%) values of esomeprazole for Day 1 am, Day 1 pm, Day 14 am, and Day
`14 pm, respectively, were 0.94 hr (25%), 1.06 (29%), 1.52 (18%) , and 1.68 (22%). On day
`14, the pm dose showed lower esomeprazole exposure than the am dose. AUC0-24 represents
`AUC from time zero (time of AM dosing) to 24 hours after the AM dose.
`
`Mean (CV%) of Esomeprazole Pharmacokinetic Parameters by Study Day and Dose
`Time for Treatment B (PN 400/E20)
`Cmax
`(ng/mL)
`
`AUC0-10,am or
`AUC0-14,pm
`(hr*ng/mL)
`
`AUC0-24
`(hr*ng/mL)
`
`T1/2 (hrs)
`
`Day, dose, N
`
`Tmax (hr)
`
`
`
`
`
`12
`
`

`

`Day 1, am
`N=20
`Day 1, pm
`N=20
`Day 14, am
`N=19
`Day 14, pm
`N=19
`
`339 (84)
`
`246 (116)
`
`1034 (35)
`
`468 (81)
`
`0.52 (34)
`
`0.60 (58)
`
`0.53 (44)
`
`1.10 (84)
`
`398 (88)
`
`384 (145)
`
`1874 (50)
`
`1120 (73)
`
`--
`
`781 (109)
`
`--
`
`2994 (57)
`
`0.89 (26)
`
`1.06 (33)
`
`1.24 (35)
`
`1.48 (36)
`
`Mean half life (CV%) values of esomeprazole for Day 1 am, Day 1 pm, Day 14 am, and Day
`14 pm, respectively, were 0.89 hr (26%), 1.06 (33%), 1.24 (35%) , and 1.48 (36%). On day 1
`and day 14 each, the pm dose showed lower esomeprazole exposure than the am dose.
`
`Mean (CV%) of Esomeprazole Pharmacokinetic Parameters by Study Day and Dose Time for
`Treatment C (PN 400/E10)
`Cmax
`(ng/mL)
`
`Day, dose, N
`
`Tmax (hr)
`
`Day 1, am
`N=20
`Day 1, pm
`N=20
`Day 14, am
`N=19
`Day 14, pm
`N=19
`
`164 (86)
`
`159 (139)
`
`319 (59)
`
`155 (91)
`
`0.43 (38)
`
`0.55 (82)
`
`0.53 (57)
`
`0.75 (65)
`
`AUC0-10,am or
`AUC0-14,pm
`(hr*ng/mL)
`234 (153)
`
`AUC0-24
`(hr*ng/mL)
`
`--
`
`180 (163)
`
`414 (154)
`
`535 (93)
`
`--
`
`346 (118)
`
`881 (103)
`
`T1/2 (hrs)
`
`0.87 (45)
`
`0.96 (47)
`
`1.03 (39)
`
`1.24 (52)
`
`
`
`
`
`
`
`
`
`
`
`
`Mean half life (CV%) values of esomeprazole for Day 1 am, Day 1 pm, Day 14 am, and Day
`14 pm, respectively, were 0.87 hr (45%), 0.96 (47%), 1.03 (39%) , and 1.24 (52%).
`On day 1 and day 14 each, the pm dose showed lower esomeprazole exposure than the am
`dose.
`
`Reviewer’s Comments: On Day 1, the AUC and Cmax of esomeprazole increased
`approximately proportionally with dose with high variability. The