CENTER FOR DRUG EVALUATION AND
`
`RESEARCH
`
`APPLICA TION NUMBER:
`
`2 2 -3 0 1
`
`MEDICAL REVIEWg S!
`
`

`

`CLINICAL REVIEW
`
`Application Type
`Submission Number
`
`NDA
`
`22-301
`
`Submission Code
`
`N000
`
`Letter Date
`
`Stamp Date
`Safety Update Date
`PDUFA Goal Date
`
`December 21, 2007
`December 31, (2007
`April 25, 2008
`October 31, 2008
`
`Reviewer Name
`
`Aisha Peterson, MD, MPH, MBA
`
`Review Completion Date
`
`October 29, 2008
`
`Established Name
`
`mesalamine
`
`Trade Name
`
`Therapeutic Class
`Applicant
`
`Apriso
`Locally acting aminosalicylate
`Salix Pharmaceuticals, Inc.
`
`Priority Designation
`
`S .
`
`Formulation
`Dosing Regimen
`
`Indication
`
`Intended, Population
`
`0.375 g delayed—release capsules
`1.5 g (four 0.375g capsules)
`once daily
`-
`Maintenance of remission of
`
`-
`Ulcerative Colitis (UC)
`Adults ages 18 years and older
`currently in remission from UC
`
`

`

`Clinical Review
`.Aisha E. Peterson, MD, MPH, MBA
`NDA 22-301
`
`Apriso (mesalamine)
`
`1
`
`EXECUTIVE SUMMARY ........
`
`...............
`
`..................................................................................................5
`
`Table of Contents
`
`2
`
`3
`
`4
`
`5
`
`1.1
`1.2
`
`RECOMMENDATION ON REGULATORY ACTION ..................i ........................................................................ 5
`RECOMMENDATION ON POSTMARKETING ACTIONS .................................................................................... 5
`
`Risk Management Activity .................................................................................................................... _5
`1.2.1
`Required Phase 4 Commitments ............................................................................................................5
`1.2.2
`1.2.3 - Other Phase 4 Requests .......................................................................................................................... 5
`SUMMARY OF CLINICAL FINDINGS .............................................. ................................................................ 5
`
`13
`
`Brief Overview of Clinical Program ...................................................................................................... 5
`1.3.1
`Efficacy ...................................................................................
`1.3.2
`Safety ........................................
`1.3.3
`Dosing Regimen and Administration ......................................
`1.3.4
`Drug-Drug Interactions ...........................................................
`1.3.5
`Special Populations ................................................................................................................................ 8
`1 .3.6
`INTRODUCTION AND BACKGROUND .................................................................................................... 10
`
`
`
`2.1
`2.2
`2.3
`2.4
`2.5
`2.6
`
`PRODUCT INFORMATION ........................................................................................................................... 10
`‘ CURRENTLY AVAILABLE TREATMENT FOR INDICATION ............................................................................ 1 l
`AVAILABILITY OF PROPOSED ACTIVE INGREDIENT IN THE UNITED STATES ..‘. ........................................... 1 l
`IMPORTANT ISSUES WITH PHARMACOLOGICALLY RELATED PRODUCTS ............................................... 1 1
`PRESUBMISSION REGULATORY ACTIVITY .................................................................................................. 1 1
`OTHER RELEVANT BACKGROUND INFORMATION ...................................................................................... 12
`
`SIGNIFICANT FINDINGS FROM OTHER REVIEW DISCIPLINES .....
`
`
`
`....13
`
`3 .1
`3 .2
`
`13
`CMC (AND PRODUCT MICROBIOLOGY, IF APPLICABLE) ............................
`ANIMAL PHARMACOLOGY/TOXICOLOGY .................................................................................................. 13
`
`DATA SOURCES, REVIEW STRATEGY, AND DATA INTEGRITY ..................................................... 13
`SOURCES OF CLINICAL DATA .................................................................................................................... 13
`. TABLES OF CLINICAL STUDIES ..........................................
`
`REVIEW STRATEGY ...........................................................
`.......................................................................
`DATA QUALITY AND INTEGRITY
`
`COMPLIANCE WITH GOOD CLINICAL PRACTICES ......................................................
`FINANCIAL DISCLOSURES .......................................................................................................................... 16
`
`4.1
`4.2
`4.3
`
`4.4
`4.5
`4.6
`
`5. 1
`5.2
`5.3
`
`6.1
`
`CLINICAL PHARMACOLOGY ................................................................................................................... 16
`
`PHARMACOKINETICS ..................................................................................................................’............... 17
`PHARMACODYNAMICS ............................................................................................................................... 17
`EXPOSURE-RESPONSE RELATIONSHIPS ..................................................................................................... 17
`
`INTEGRATED REVIEW OF EFFICACY ...........................
`
`
`
`INDICATION .........................
`6.1.1 Methods .....................................................................................
`
`General Discussion of Endpoints ...............................................
`6.1.2
`
`Study Design ........................................................................................................................................20
`6.1.3
`Efi'Icacy Findings .................................................................................................................................21
`6.1.4
`
`Clinical Microbiology....
`....................................................................................................25
`6.1.5
`Efficacy Conclusions26
`6.1.6
`INTEGRATED REVIEW OF SAFETY ...................................................................
`................26
`
`7.1
`
`7.1.1
`
`METHODS AND FINDINGS ....................................._. ....................................................................................26
`Deaths ..........................................
`
`

`

`Clinical Review
`
`Aisha E. Peterson, MD, MPH, MBA
`NDA 22-30]
`
`Apriso (mesalamine)
`
`7.1.2
`7.1.3
`7.1.4
`7.1.5
`7.1.6
`7.1.7
`7.1.8
`7.1.9
`7.1.10
`7.1.11
`7.1.12
`7.1.13
`7.1.14
`7.1.15
`
`7.2
`
`Other Serious Adverse Events ........................... i .................................................................................27
`Dropouts and Other Significant Adverse Events ......
`
`Other Search Strategies ..........
`
`Common Adverse Events .........................................
`Less Common Adverse Events .................................................................................................43
`
`
`Laboratory Findings .............................................................................................................................43
`Vital Signs ...........................................................................................................................................46
`Electrocardiograms (ECGs) .....................................,............................................................. 48
`
`
`Immunogenicity...................
`............................................ 48
`
`
`............................................................................................48
`Human Carcinogenicity
`Special Safety Studies ..................................................................................................................... 48
`Withdrawal Phenomena and/or Abuse Potential ......................................................................48
`
`Human Reproduction and Pregnancy Data ..................................................................................... 48
`Assessment of Effect on Growth ..................................................................................................... 49
`
`Overdose Experience ........................................................................................................... 49
`7.1.16
`Postmarketing Experience ............................................................................................................... 50
`7.1.17
`ADEQUACY OF PATIENT EXPOSURE AND SAFETY ASSESSMENTS .............................................................. 51
`Description of Primary Clinical Data Sources (Populations Exposed and Extent of Exposure) Used to
`7.2.1
`Evaluate Safety .................................................................................................................................................. 5]
`7.2.2
`Description of Secondary Clinical Data Sources Used to Evaluate Safety ..........................................55
`7.2.3
`Adequacy of Overall Clinical Experience ........................................................................................... 60
`7.2.4
`Adequacy of Special Animal and/or In Vitro Testing ....................................................... ................... 60
`7.2.5
`Adequacy of Routine Clinical Testing ................................................................................................. 60
`7.2.6
`Adequacy of Metabolic, Clearance, and Interaction Workup .............................................................. 60
`7.2.7
`Adequacy of Evaluation for Potential Adverse Events for Any New Drug and Particularly for Drugs
`in the Class Represented by the New Drug; Recommendations for Further Study ............................................ 60
`7.2.8
`Assessment of Quality and Completeness of Data .............................................................................. 60
`7.2.9
`Additional Submissions, Including Safety Update .............................................................................. 61
`SUMMARY OF SELECTED DRUG-RELATED ADVERSE EVENTS, IMPORTANT LIMITATIONS OF DATA, AND
`7.3
`CONCLUSIONS ......................................................................................................................................................... 61
`7.4
`GENERAL METHODOLOGY .............
`
`7.4.1
`7.4.2
`7.4.3
`
`Pooling Data Across Studies to Estimate and Compare Incidence ................................
`Explorations for Predictive Factors ...............................................................................
`Causality Determination ...................................................................................................................... 63
`
`
`
`8
`
`ADDITIONAL CLINICAL ISSUES ...................-........................................................................................... 64
`
`8.1
`3.2
`8.3
`8.4
`8.5
`8.6
`8.7
`8.8
`
`DOSING REGIMEN AND ADMINISTRATION ................................................................................................. 64
`DRUG-DRUG INTERACTIONS
`............................................................................. . .................. 64
`
`SPECIAL POPULATIONS .................. .
`........... 64
`PEDIATRICS ........................................
`-
`........... 65
`
`ADVISORY COMMITTEE MEETING ............................................................................................................. 65
`LITERATURE REVIEW .............................................................................................'................................... 65
`
`POSTMARKETING RISK MANAGEMENT PLAN .......................................... 65
`OTHER RELEVANT MATERIALS ................................................................................................................. 65
`
`9
`
`OVERALL ASSESSMENT............................................................................................................................. 66
`
`9.1 CONCLUSIONS........................................................................... 66
`9.2
`RECOMMENDATION ON REGULATORY ACTION ............................
`
`RECOMMENDATION ON POSTMARKETING ACTIONS .................................................................................. 68
`9.3
`Risk Management Activity .................................................................................................................. 68
`Required Phase 4 Commitments .......................................................................................................... 68
`Other Phase 4 Requests ........................................................................................................................ 68
`LABELING REVIEW .................................................................................................................................... 68
`COMMENTS T0 APPLICANT........................................................................................................................ 69
`
`9.3 .1
`9.3.2
`9.3.3
`
`9.4
`9.5
`
`

`

`Clinical Review
`
`Aisha E. Peterson, MD, MPH, MBA
`NDA 22-301
`
`Apriso (mesalamine)
`
`10 APPENDICES............................................................. 70
`
`10.1
`10.1.1
`10.1.2
`10.1.3
`
`STUDY PROTOCOL MPUC3003 ........................................................................................................... 70
`, Protocol Summary................................................... ....70
`Inclusion Criteria
`71
`Exclusion Criteria .................................................................. 71
`
`
`
`Primary Efficacy Endpoint ................................................................................................... 71
`10.1.4
`
`Secondary Efficacy Endpoints ........................................................................................................ 72
`10.1.5
`Treatment ........................................................................................................................................ 73
`10.1.6
`' Monitoring ...................................... 73
`10.1.7
`
`Control Procedures ................................................................. 75
`10. 1 .8
`
`Safety evaluation ......................................................... '...
`....77
`10.1.9
`Protocol Amendments ............................................................ 77
`10. 1 .10
`Statistical Methods ................................................................. 78
`10.1.1 1
`Study Results .................................................................................................................................. 78
`10.1.12
`10.2
`STUDY PROTOCOL MPUC3004 .................................................................................. . ........................ 92
`Protocol Summary..................................................................................................... 92
`10.2. 1
`
`
`
`Inclusion Criteria .................................................................................................. 93
`10.2.2
`Exclusion Criteria ........................................................................................................... 93
`10.2.3
`
`10.2.4
`Primary Efficacy Endpoint...............................
`................................................................ 93
`
`Secondary Efficacy Endpoints ............................................................................................. 94
`10.2.5
`
`Treatment ........................................................................................................................................ 95
`10.2 .6
`
`
`
`
`
`10.2.7
`.. Monitoring ...................................................................................................................................... 95
`10.2.8
`....................................................................................................... 97
`Control Procedures...
`
`
`10.2.9
`Safety evaluation ..................................................................................................................... 99
`
`10.2.10
`Protocol Amendments ...................................................................................................... 99
`
`
`10.2.1 1
`Statistical Methods ......................................................................................................... 100
`
`10.2.12
`Study Results ..................................................................................................................... 100
`
`10.3
`STUDY PROTOCOL MPUC3005 ......................................................................................................... 1 13
`10.3.1
`Protocol Summary......................................................................................................................... 113
`
`Inclusion Criteria ...................................................................................................................... 114
`10.3.2
`10.3.3
`Exclusion Criteria ......................................................................................................................... 114
`10.3.4
`Efficacy Analyses ..........'............................................................................................................... 1 15
`10.3.5
`SafetyAnalyses ................................................................ 115
`10.3.6
`Treatment ...................................................................................................................................... 115
`10.3.7
`Monitoring .................................................................................................................................... 1 15
`10.3.8
`Control Procedures ............................................................................................................. 1 16
`10.3.9
`Safety Evaluation ............................................................................................................... 117
`10.3. 10
`Protocol Amendments .......................................................... 1 l8
`10.3.11
`‘ Statistical Methods ................................................................
`Study Results ...........................'.......................................................................’.......................... 118
`10.3.12
`
`Adverse Events .................................................................................................................................... 121
`LIST AND DESCRIPTION OF INVESTIGATORS ............................................................................................ 127
`10.4
`10.4.1
`MPUC3003 Clinical Investigators ................................................................................................ 128
`10.4.2
`Study MPUC3004 Clinical Investigators.........................................:............................................ 133
`Study MPUC3005 Clinical Investigatbrs ....................................................................... 137
`10.4.3
`
`LINE-BY-LINE LABELING REVIEW ..................................................................................... 143
`10.5
`
`REFERENCES ............................................................................................. 144
`
`
`
`
`
`‘
`
`11
`
`

`

`Clinical Review
`
`Aisha E. Peterson, MD, MPH, MBA
`NDA 22-301
`Apriso (mesalamine)
`
`1 EXECUTIVE SUMMARY
`
`1.1 Recommendation on Regulatory Action
`
`This reviewer recommends that Apriso, encapsulated mesalamine granules (eMG), be approved
`for the maintenance of remission of ulcerative colitis in patients 18 years of age and older.
`Treatment duration in the prospective, placebo-controlled trials was 6 months.
`
`1.2 Recommendation on Postmarketing Actions
`
`1.2.1 Risk Management Activity
`
`There is no applicable activity related to risk management for this New Drug Application
`(NDA).
`
`1.2.2 Required Phase 4 Commitments
`
`Safety and effectiveness have not been established in pediatric patients. The Applicant is
`required to perform clinical studies to evaluate the safety and effectiveness of mesalmine ,
`granules in the pediatric population. Specifically, the Applicant hasagreed to conduct studies to
`evaluate the safety and effectiveness of at least two dosing regimens in patients in remission of
`ulcerative colitis who are five years of age or older. Studies in those ages birth to less than five
`years have been waived.
`
`The Applicant agreed to submit the final study report by June 1, 2013.
`
`1.2.3 Other Phase 4 Requests
`
`There are no additional Phase 4 requests.
`
`1.3 Summary of Clinical Findings
`
`1.3.1 Brief Overview of Clinical Program
`
`Two pivotal, Phase 3 studies were submitted by Salix Pharmaceuticals, Inc. to evaluate the
`clinical efficacy and safety of eMG (encapsulated mesalamine granules) for the maintenance of
`remission of ulcerative colitis (UC) in patients ages 18 years and over for consecutive therapy up
`to six months. In addition, a single open-label long-term extension study, MPUC3005, was
`submitted as part of this NDA submission.
`
`

`

`Clinical Review
`
`Aisha E. Peterson, MD, MPH, MBA
`NDA 22-301
`
`Apriso (mesalamine)
`
`1.3.2 Efficacy
`
`Two pivotal Phase 3 studies were submitted by the Applicant to provide data for the efficacy
`review in support of the maintenance of remission of ulcerative colitis indication being sought.
`These studies—~MPUC3003 and MPUC3004-~were randomized, double-blind, placebo-
`controlled, parallel group, multi-center studies conducted in Russia and the United States. Both
`studies used identical inclusion and exclusion criteria, efficacy endpoints, and study schedules.
`The only difference between the two studies was the total number of patients randomized—305
`in MPUC3003 and 257 in MPUC3 004. Both studies randomized patients in a 2:1 ratio
`(eMGzplacebo). The distribution of demographic and baseline disease characteristics were
`similar across treatment groups.
`
`The primary efficacy endpoint for both studies was the number and proportion of patients who
`remained relapse-free at Month 6/End of Study (EOS). Relapse (or treatment failure) was
`defined as a rectal bleeding score of 1 or more AND a mucosal appearance score of 2 or more as
`described in the revised Sutherland Disease Activity Index (see Section 6 for a detailed
`description of this index). In addition, patients who experienced symptoms of a UC flare or
`restarted medications used to treat UC were counted as relapses. In the original protocol,
`patients who prematurely discontinued a study for any reason were counted as relapses.
`However, in a late-stage protocol amendment, premature diScontinuations were only counted as
`relapses if they discontinued for an adverse event related to UC. Efficacy was analyzed using
`the intent-to-treat (ITT) population, all randomized patients who received at least one dose of the
`study drug.
`
`In study MPUC3003, 305 patients were randomized and received at least one dose of study
`medication (209 eMG: 96 placebo). At Month 6/EOS, 78.9% of eMG subjects and 58.3% of
`' placebo subjects remained relapse-free (p<0.001). If(we analyze the primary efficacy results
`using the original definition of relapse (i.e., all premature withdrawals counted as relapses), at
`Month6/EOS, 68.4% of eMG patients and 51.0% of placebo patients remained relapse-free
`(p<0.001). Both results are highly statistically significant.
`
`In study MPUC3004, 257 patients were randomized and received at least one dose of study
`medication (164 eMG, 93 placebo). At Month 6/EOS, 79.9% of eMG patients remained relapse~
`free, compared with 67.7% of placebo patients (p=0.029). If we analyze the primary efficacy
`results using the original definition of relapse, at Month 6/EOS, 71.3% of eMG patients and
`59.1% of placebo patients remained relapse free (p=0.046).
`
`For both studies, analysis of the primary endpoint was repeated controlling for gender, age group
`(<65, 265), race (White, non-White), and baseline disease severity category (0, 21). The results
`remained statistically significant. For subgroup analysis, studies MPUC3003 and MPUC3004
`were combined. Subgroup analysis by baseline disease category showed a statistically
`significant difference (eMG over placebo) in both baseline disease categories, both genders, and
`. both countries. However, statistically significant differences (eMG over placebo) were only seen
`in the <65 age group and the White race grOup. The numbers of patients the Z65 age group and
`the white race group were very small.
`
`

`

`Clinical Review
`
`Aisha E. Peterson, MD, MPH, MBA
`NDA 22-30]
`
`Apriso (mesalamine)
`
`Seven secondary endpoints were defined a priori and tested using a hierarchical approach. In
`Study MPUC3003, only the first secondary endpoint, the number and proportion of patients in
`each level of change from baseline in rectal bleeding score at months 1, 3, and 6, was found to
`have a statistically significant difference between the eMG and placebo groups (p=0.008). In
`Study MPUCSOO4, a statistically significant difference between eMG and placebo groups was
`not found for any of the secondary endpoints. Once a secondary endpoint failed to reach
`statistical significance, further endpoints in the hierarchy were deemed exploratory (and not
`inferential) in nature.
`
`1.3.3 Safety
`
`'
`
`’
`
`The study drug, eMG, was evaluated in 557 unique patients whose UC was in remission in
`controlled and open-label studies in the US and Russia. Overall, adverse events in the eMG
`clinical development program were similar to those attributable to other mesalamine
`formulations. The majority of adverse events were related to the gastrointestinal system or were
`events common to the general population (i.e., headache, nasopharyngitis, and sinusitis).
`
`the RCT population and the All eMG
`Two populations were used for the safety analyses:
`population. These populations were taken from the larger safety population which included all
`patients who received at least one dose of the study drug (eMG or placebo) and provided at least
`one post—baseline safety assessment. The RCT population included all safety patients in studies
`MPUC3003 and MPUC3004. The All eMG population included all patients in MPUC3 003 and
`MPUC3004 who received eMG in addition to all patients from study MPUC3005, an open-label
`extension study.
`
`RCT Population
`In the RCT population, 59% of patients treated with eMG reported a treatment-emergent adverse
`event (TEAE), compared with 64% of placebo patients. Of these, the most commonly reported
`TEAEs were colitis ulcerative and headache (a known possible mesalmine adverse event) in both
`treatment groups. Eight patients (1.4%) reported a total of eight serious adverse events (SAES).
`Four SAES (1.1%) were reported in eMG patients, and 4 SAES (2.2%) were reported in placebo
`patients. Only One patient in this population withdrew from the study due to an SAE.
`
`All eMG Population
`In the All eMG population, 69% of patients experienced a TEAE. Of these, the most commonly
`reported were also ulcerative colitis and headache. Twenty-six patients reported a SAE. Of the
`22 SAES that occurred in Study MPUC3005, 10 patients withdrew due to the SAE. It should be
`noted that, Study MPUC3005 is on—going and the results included in this review are as of the 12-
`Day Safety Update clinical cut-off date of 14 January 2008.
`
`Four supportive studies using mesalamine formulations similar to eMG were submitted with
`NDA 22-301—SAG-2,'SAG-15, SAG-26, and SAG-27. The TEAES reported and their
`incidences were similar to those found in the primary studies—MPUC3003, MPUC3 004, and
`MPUC3005.
`
`

`

`Clinical Review
`Aisha E. Peterson, MD, MPH, MBA
`NDA 22-301
`
`Apriso (mesalamine)
`
`A query of the Adverse Events Reporting System (AERS) revealed several cases of mesalamine
`use associated with liver failure. These spontaneous case reports along with post-marketing data
`from other mesalamine products prompted a recommendatiOn that a liver impairment warning be
`added to mesalamine labeling.
`
`There were no deaths reported in any of the submitted primary or supportive studies.
`
`1.3.4 Dosing Regimen and Administration
`
`This reviewer recommends that the proposed dosage of eMG for the maintenance of remission
`from ulcerative colitis of 1.5 g once daily taken as four 0.375 g capsules orally be accepted.
`Treatment duration in the prospective, placebo—controlled trials was 6 months. .The use of eMG
`beyond six months has been studied in only one study, MPUC3005. Capsules of eMG can be
`taken without regard for the timing of food intake, but should not be co-administered with
`antacids.
`’
`
`1.3.5 Drug-Drug Interactions
`
`In an in vitro study using human liver microsomes, mesalamine and its metabolites were not
`shown to inhibit the major CYP enzymes CYP1A2, CYP2C9, CYPsC19, CYP2D6, and
`CYP3A4 (Study Report XT055039). There are no known drug interactions with mesalamine
`products.
`
`1.3 .6 Special Populations
`
`The safety and efficacy of eMG has not been established in the pediatric population. The
`Applicant requested a partial waiver of pediatric studies. The waiver included the age group of
`birth to less than five years of age. The Applicant reasons that studies are impossible or highly
`impractical because the pool of patients in this age group with ulcerative colitis eligible to take
`medication for maintenance of remission is too small. Given that pediatric ulcerative colitis has
`been designated an orphan indication and Colazal was granted a waiver for the age group birth to
`less than five years of age, the Applicant argues that their waiver request should also be granted.
`The Food and Drug Administration’s (FDA) Pediatric Review Committee (PeRC) granted the
`Applicant’s waiver for studies in patient’s less than five years of age.
`
`The Applicant also requested a deferral of pediatric studies for ages greater than five years and
`less than 18 years of age. The Applicant has committed to designing and implementing a safety,
`effectiveness, and pharmacokinetic study with mesalamine granules of at least two dosing
`regimens for in patients in remission of ulcerative colitis who are five years of age or older at
`study entry. The Applicant has agreed to submit a study protocol to the Agency by June 1, 2009
`and initiate the study by January 1, 2010. The Applicant has also agreed to submit the final
`study report for this study by June 1, 2013.
`
`

`

`Clinical Review
`
`Aisha E. Peterson, MD, MPH, MBA
`NDA 22-301 '
`
`Apriso (mesalamine)
`
`In non—clinical studies with mesalamine, the kidney has been identified as the primary organ of
`toxicity. Therefore, it is recommended that all patients have an evaluation of renal function prior
`to initiation of mesalamine products and periodically while on therapy. Current mesalamine
`labeling states in the Warning and Precautions section that “Renal impairment, including
`minimal change nephropathy, acute and chronic interstitial nephritis, and, rarely, renal failure,
`has been reported...”
`
`Studies using eMG contained few patients with renal insufficiency, hepatic insufficiency, age
`>65 years, non-white race, or pregnant or nursing women. Despite the lack of non-White
`patients in the eMG studies, currently available information on the use of other mesalmine
`products in non-white patients does not suggest that eMG will have a different efficacy or safety
`profile in this group. Caution should be taken when prescribing eMG to the elderly as this group
`of patients is more likely to have concomitant renal and/or hepatic insufficiency. It is
`recommended that the drug product, eMG, be assigned to pregnancy category B and should,
`therefore, only be used by pregnant women if clearly needed. This recommendation is based on
`pre-clinical reproduction studies and is consistent with the labeling of other mesalamine
`products.
`
`

`

`Clinical Review
`Aisha E. Peterson, MD, MPH, MBA
`NDA 22-301
`
`Apriso (mesalamine)
`
`2 V
`
`INTRODUCTION AND BACKGROUND
`
`2.1 Product Information
`
`Trade Name:
`Generic Name:
`Code Name:
`
`Apriso
`Mesalamine (5-aminosalicylic acid; S—ASA)
`eMG
`
`Chemical Name:
`
`5-amino—2-hydroxybenzoic acid
`
`Structural formula:
`
`COOH
`
`OH
`
`HQN
`
`Therapeutic Class:
`Formulation:
`Proposed indication:
`
`Anti-inflammatory
`Encapsulated granules
`Maintenance of remission of UC
`
`Encapsulated mesalamine granules, formerly referred to as mesalamine pellets, are 1 mm
`granules of 5-ASA. The granules are contained in a hard gelatin capsule shell. The formulation .
`is designed to offer delayed release of mesalamine controlled by a L
`j coating which
`dissolves when exposed to pH 6, but resists dissolution in the stomach where the pH is lower. In
`addition, extended release is controlled by a E.
`J coating over the granules which
`unifome releases and distributes mesalamine in the lumen of the colon. This mesalamine
`formulation does not contain phthalates.
`
`m4)
`
`The exact mechanism of action of mesalamine is unknown, but it appears to act topically rather
`than systemically. Oral mesalamine formulations have been accepted as a first line treatment for
`the induction and maintenance of remission of ulcerative colitis for over 40 years.
`
`10
`
`