CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`208271Orig1s000
`
`MEDICAL REVIEW(S)
`
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`
`
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`
`
`
`

`

`CLINICAL REVIEW
`
`Application Type NDA
`Application Number(s)
`208,271
`Priority or Standard Standard
`
`6/19/2015
`Submit Date(s)
`6/19/2015
`Received Date(s)
`4/19/2016
`Original PDUFA Goal Date
`7/19/2016
`Amended PDUFA Date
`Division / Office Division of Gastroenterology and
`Inborn Errors Products/ Office of
`Drug Evaluation III
`
`Reviewer Name(s) Dina J. Zand M.D.
`Review Completion Date
`June 2, 2016
`
`Established Name Methylnaltrexone bromide
`(Proposed) Trade Name Relistor®
`Therapeutic Class Peripherally acting mu-opioid
`receptor antagonist (PAMORA)
`Applicant Salix Pharmaceuticals, Inc
`
`Formulation(s) Oral Tablet
`Dosing Regimen
`3 tablets once daily (450 mg/day)
`Indication(s) Opioid-induced constipation in
`adult patients with chronic non-
`cancer pain
`≥18 years of age
`
`Intended Population(s)
`
`Template Version: March 6, 2009
`
`Reference ID: 3940594
`
`1
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`

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`Clinical Review
`Dina Zand, MD
`NDA 208,271
`Methylnaltrexone Bromide (MNTX)
`
`2
`
`Table of Contents
`1 RECOMMENDATIONS/RISK BENEFIT ASSESSMENT..........................................9
`1.1 Recommendation on Regulatory Action ..............................................................9
`1.2 Risk Benefit Assessment .....................................................................................9
`1.3 Recommendations for Postmarket Risk Evaluation and Mitigation Strategies ..13
`1.4 Recommendations for Postmarket Requirements and Commitments...............15
`INTRODUCTION AND REGULATORY BACKGROUND .......................................15
`2.1 Product Information ...........................................................................................17
`2.2 Tables of Currently Available Treatments for Proposed Indications..................18
`2.3 Availability of Proposed Active Ingredient in the United States .........................18
`2.4
`Important Safety Issues with Consideration to Related Drugs ..........................19
`2.5 Summary of Presubmission Regulatory Activity Related to Submission ...........19
`2.6 Other Relevant Background Information ...........................................................24
`3 ETHICS AND GOOD CLINICAL PRACTICES........................................................24
`3.1 Submission Quality and Integrity .......................................................................24
`3.2 Compliance with Good Clinical Practices ..........................................................25
`3.3 Financial Disclosures.........................................................................................27
`4 SIGNIFICANT EFFICACY/SAFETY ISSUES RELATED TO OTHER REVIEW
`DISCIPLINES...........................................................................................................28
`4.1 Chemistry Manufacturing and Controls .............................................................28
`4.2 Clinical Microbiology ..........................................................................................29
`4.3 Preclinical Pharmacology/Toxicology ................................................................30
`4.4 Clinical Pharmacology .......................................................................................31
`4.4.1 Mechanism of Action...................................................................................31
`4.4.2 Pharmacodynamics.....................................................................................32
`4.4.3 Pharmacokinetics........................................................................................32
`5 SOURCES OF CLINICAL DATA.............................................................................35
`5.1 Tables of Studies/Clinical Trials.........................................................................36
`5.2 Review Strategy.................................................................................................37
`5.3 Discussion of Individual Studies/Clinical Trials..................................................38
`6 REVIEW OF EFFICACY ..........................................................................................56
`Efficacy Summary .......................................................................................................56
`6.1
`Indication ...........................................................................................................57
`6.1.1 Methods.......................................................................................................57
`6.1.2 Demographics .............................................................................................58
`6.1.3 Subject Disposition......................................................................................61
`6.1.4 Analysis of Primary Endpoint(s) ..................................................................67
`6.1.5 Analysis of Secondary Endpoints(s)............................................................68
`
`Reference ID: 3940594
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`Clinical Review
`Dina Zand, MD
`NDA 208,271
`Methylnaltrexone Bromide (MNTX)
`
`6.1.7 Subgroup Analyses .....................................................................................75
`6.1.8 Analysis of Clinical Information Relevant to Dosing Recommendations.....83
`6.1.9 Discussion of Persistence of Efficacy and/or Tolerance Effects .................84
`6.1.10 Additional Efficacy Issues/Analyses............................................................86
`7 REVIEW OF SAFETY..............................................................................................88
`Safety Summary..........................................................................................................88
`7.1 Methods .............................................................................................................89
`7.1.1 Studies/Clinical Trials Used to Evaluate Safety ..........................................90
`7.1.2 Categorization of Adverse Events...............................................................92
`7.1.3 Pooling of Data Across Studies/Clinical Trials to Estimate and Compare
`Incidence.....................................................................................................94
`7.2 Adequacy of Safety Assessments .....................................................................95
`7.2.1 Overall Exposure at Appropriate Doses/Durations and Demographics of
`Target Populations ......................................................................................95
`7.2.2 Explorations for Dose Response.................................................................98
`7.2.3 Special Animal and/or In Vitro Testing ......................................................102
`7.2.4 Routine Clinical Testing.............................................................................102
`7.2.5 Metabolic, Clearance, and Interaction Workup .........................................102
`7.2.6 Evaluation for Potential Adverse Events for Similar Drugs in Drug Class.103
`7.3 Major Safety Results........................................................................................105
`7.3.1 Deaths.......................................................................................................105
`7.3.2 Nonfatal Serious Adverse Events..............................................................105
`7.3.3 Dropouts and/or Discontinuations .............................................................109
`7.3.4 Significant Adverse Events........................................................................114
`7.3.5 Submission Specific Primary Safety Concerns .........................................115
`7.4 Supportive Safety Results ...............................................................................119
`7.4.2
`Laboratory Findings...................................................................................122
`7.4.3 Vital Signs .................................................................................................123
`7.4.4 Electrocardiograms (ECGs) ......................................................................124
`7.4.5 Special Safety Studies/Clinical Trials........................................................124
`7.4.6
`Immunogenicity .........................................................................................124
`7.5 Other Safety Explorations................................................................................125
`7.5.1 Dose Dependency for Adverse Events .....................................................125
`7.5.2 Time Dependency for Adverse Events......................................................128
`7.5.3 Drug-Demographic Interactions ................................................................130
`7.5.4 Drug-Disease Interactions.........................................................................133
`7.5.5 Drug-Drug Interactions..............................................................................134
`7.6
`Additional Safety Evaluations....................................................................135
`7.6.1 Human Carcinogenicity .............................................................................135
`7.6.2 Human Reproduction and Pregnancy Data...............................................136
`7.6.3 Pediatrics and Assessment of Effects on Growth .....................................136
`7.6.4 Overdose, Drug Abuse Potential, Withdrawal and Rebound ....................137
`7.7 Additional Submissions / Safety Issues ...........................................................137
`
`Reference ID: 3940594
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`Clinical Review
`Dina Zand, MD
`NDA 208,271
`Methylnaltrexone Bromide (MNTX)
`
`8 POSTMARKET EXPERIENCE..............................................................................137
`9 APPENDICES........................................................................................................142
`Source: Modified from Section 1.16.1 Module 1 Administrative Information NDA
`208271.............................................................................................................146
`4 NOVEMBER 2014 MEETING CLINICAL COMMENTS:...........................................147
`9.1
`Literature Review/References .........................................................................155
`9.2
`Labeling Recommendations ............................................................................155
`9.3 Advisory Committee Meeting...........................................................................155
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`Reference ID: 3940594
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`Clinical Review
`Dina Zand, MD
`NDA 208,271
`Methylnaltrexone Bromide (MNTX)
`
`Table of Tables
`
`Table 1: FDA Approved Prescription Drugs for use in Chronic OIC..............................18
`Table 2: Summary of Meeting Requests for IND 067452..............................................22
`Table 3: Clinical Site Inspections...................................................................................25
`Table 4: Components and Composition of Methylnaltrexone Bromide Tablets, 150 mg
`........................................................................................................................28
`Table 5: Components and Composition of Methylnaltrexone Bromide: Tablets 150 mg
`–
` and
` Formulations..............................29
`Table 6: Additional Pre-clinical Studies Completed to support NDA 208271 ................30
`Table 7: Summary of Clinical Trials Included in PK/PD, Bioavailability (BA) and
`Bioequivalence (BE) Analyses ........................................................................32
`Table 8: Single-Dose Pharmacokinetic Parameters for Oral Methylnaltrexone Bromide
`and Subcutaneous Methylnaltrexone Bromide ...............................................33
`Table 9: MNOC1111 comparison of Cmax and AUC in Phase 3 and TBM formulations
`of Oral Methylnaltrexone Bromide...................................................................34
`Table 10: Overview of Clinical Development Program Supporting Efficacy of MNTX
`Tablets for Chronic OIC ..................................................................................36
`Table 11: MNTX3201 Schedule of Assessments and Procedures................................45
`Table 12: MNTX3201 Schedule of Assessments and Procedures - continued.............46
`Table 13: Definition of Analysis Sets for MNTX3201.....................................................58
`Table 14: Demographic Characteristics (ITT) for Study MNTX3201 .............................59
`Table 15: Baseline Disease Characteristics (ITT Population) .......................................60
`Table 16: Analysis Populations by Treatment Groups Study MNTX3201 .....................61
`Table 17: Subject Disposition by Dosing Period (All subjects and PRN Subjects)........62
`Table 18: Study MNTX3201 Summary of the Incidence of Major Protocol Deviations by
`Category (Deviations Reported During the QD/PRN Phases) in Randomized
`Subjects ..........................................................................................................64
`Table 19: Statistical Concerns with Analysis of Study MNTX3201................................65
`Table 20: Percentage of Subjects using Laxatives during Study MNTX3201 (total
`subjects and %)...............................................................................................65
`Table 21: Episodes of Reported Laxative use by Concomitant Medication Dataset
`Variables .........................................................................................................66
`Table 22: Percentage of Dosing Days that Resulted in RFBMs within 4 hours of Dosing
`during Weeks 1-4 ............................................................................................68
`Table 23: First Key Secondary Endpoint (Responder Endpoint) - Defined as ≥ 3
`RFBM/week, with an increase of ≥ 1 RFBM/week over baseline, for ≥ 3 out of
`the first 4 weeks of the treatment period. (ITT Population) ............................69
`Table 24: Second Key Secondary Efficacy Endpoint: Change in Weekly Number of
`RFBMs from Baseline over the First 4 Weeks of Dosing in Study 3201 (ITT
`Population) ......................................................................................................70
`Table 25: Proportion (%) of Subjects Achieving at Least 3 RFBMs per Week (LOCF)
`during Weeks 1-4 of Study MNTX3201 (Exploratory Endpoint)......................72
`
`Reference ID: 3940594
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`(b) (4)
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`(b) (4)
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`

`Clinical Review
`Dina Zand, MD
`NDA 208,271
`Methylnaltrexone Bromide (MNTX)
`
`Table 26: Overall Responders with Durability for the Last Month – Proportion (%) of
`Subjects Responding to Study Drug for ≥9 of 12 Weeks Including ≥ 3 of the
`Final 4 Weeks of Treatment (ITT Population) .................................................74
`Table 27: Overall Responders-Proportion (%) of Subjects Responding to Study Drug
`for ≥9 of 12 Weeks of the treatment Period (ITT Population)..........................75
`Table 28: Key Secondary Efficacy Endpoint 1 (Responder Endpoint): Proportion (%) of
`subjects responding to study drug during weeks 1 to 4 by Gender Population:
`ITT...................................................................................................................79
`Table 29: Key Secondary Efficacy Endpoint 1 (Responder Endpoint) : Proportion (%)
`of subjects responding to study drug during weeks 1 to 4 by Age Group
`Population: ITT...............................................................................................80
`Table 30: Key Secondary Efficacy Endpoint 1 (Responder Endpoint) : Proportion (%)
`of subjects responding to study drug during weeks 1 to 4 by Race: ITT........81
`Table 31: Key Secondary Efficacy Endpoint 1 (Responder Endpoint): Proportion (%) of
`subjects responding to study drug during weeks 1 to 4 by Baseline Opioid
`morphine equivalent dose groups: ..................................................................82
`Table 32: Key Secondary Efficacy Endpoint 1 (Responder Endpoint) Proportion (%) of
`subjects responding to study drug during weeks 1 to 4 by Baseline primary
`pain condition using the Responder Endpoint.................................................83
`Table 33: Overall Responders with Durability for the Last Month- Proportion (%) of
`Subjects Responding to Study Drug for ≥9 of 12 weeks Inclusive of ≥3 of the
`Final 4 Weeks of Treatment (ITT Population) .................................................85
`Table 34: Analysis of Coprimary Endpoints (ITT Population)........................................86
`Table 35: Safety Populations and Definitions................................................................90
`Table 36: Description of the Phase 3 Study Primarily Reviewed in Safety Review.......90
`Table 37: Additional Studies used in Analysis for the Integrated Summary of Safety...91
`Table 38: Summary of Adverse Event Variables...........................................................93
`Table 39: AEDECOD Terms Re-assigned by Medical Officer.......................................94
`Table 40: Treatment Groups from Oral Methylnaltrexone bromide-only OIC pool ........95
`Table 41: Extent of Exposure: Oral Placebo-Controlled OIC Pool ...............................96
`Table 42: Extent of Exposure: Oral MNTX-only OIC Pool............................................97
`Table 43: Study Drug Exposure MNTX3201 .................................................................97
`Table 44: Overview of Adverse Events: Oral Placebo-Controlled OIC Pool ................99
`Table 45: Adverse reactions that occurred in ≥2% of subjects and more frequently in
`the MNTX Treatment Group Than the Placebo Group in SC MNTX 3356 and
`in Oral MNTX Study 3201 .............................................................................100
`Table 46: Comparison of the Applicant’s Recoded AEs (Study MNTX3356) and Medical
`Officer’s Recoded
` in 4 Week Double-
`Blind Portions of Studies MNTX and MNTX3201..........................................101
`Table 47: Serious Adverse Event Criteria ...................................................................106
`Table 48: Summary of SAEs for Study MNTX3201 for full 12 week duration .............107
`Table 49: Disposition of Subjects: Oral Placebo-controlled OIC Pool ........................110
`Table 50: Study MNTX3201 Subject Disposition by Dosing Period (All Subjects and
`PRN Subjects)...............................................................................................111
`
`Reference ID: 3940594
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`(b) (4)
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`

`

`Clinical Review
`Dina Zand, MD
`NDA 208,271
`Methylnaltrexone Bromide (MNTX)
`
`Table 51: Treatment-Emergent Adverse Events Leading to Study Discontinuation
`During 12 weeks of study (Randomized Subjects Population) .....................112
`Table 52: Medical Officer Review of the Most Commonly Reported AEs in Study
`MNOC1111 ...................................................................................................114
`Table 53: Cardiovascular Disorder AEs reported in the Oral Placebo-controlled OIC
`Pool (Recoded by Medical Officer) ...............................................................115
`Table 54: Summary of Adverse Events (Safety Population) of Study MNTX3201 ......120
`Table 55: Treatment-Emergent Adverse Events in Subjects Treated with MNTX or
`Placebo (Safety Population) in Study MNTX3201 over 4 weeks ..................121
`Table 56: Clinical Chemistry Parameters: Clinically Relevant Shifts from Baseline To
`the End of Treatment in ≥5% of Subjects in MNTX3201 Study Patients ......122
`Table 57: TEAEs Associated with Abnormal Laboratory Results in 1% of MNTX3201
`Study Patients ...............................................................................................123
`Table 58: Dose Dependency for Adverse Events in Oral Placebo-Controlled OIC pool
`......................................................................................................................126
`Table 59: Summary of Adverse Events – Study MNTX3201.......................................127
`Table 60: Related Treatment-Emergent Adverse Events by system Organ Class and
`Preferred Term: Oral Placebo-Controlled OIC Pool (3200A3-200-WW,
`3200A3-2201-US, 3200A3-2202-WW, MNTX3201, MNOC1111) ................128
`Table 61: TEAEs with Incidence ≥5% by Age: Oral Placebo-Controlled OIC Pool ....131
`Table 62: TEAEs with Incidence ≥5% by Gender: Oral Placebo-Controlled OIC Pool
`......................................................................................................................132
`Table 63: Concomitant Medications Taken by ≥15% of Subjects in any Treatment
`Group (Safety Population) for Study MNTX3201 ..........................................135
`Table 64: Labeling Revisions for Relistor® SC ...........................................................138
`Table 65: Overview of Relistor® SC Postmarketing Adverse Events (28 March 2008
`through 27 March 2015)................................................................................139
`Table 66: SAEs During Post-marketing use of Relistor...............................................140
`
`Reference ID: 3940594
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`Clinical Review
`Dina Zand, MD
`NDA 208,271
`Methylnaltrexone Bromide (MNTX)
`
`Table of Figures
`
`Figure 1: Structural formula: ..........................................................................................17
`Figure 2: MNTX3201 Study Design...............................................................................39
`Figure 3: Proportion of subjects responding (responder/nonresponder) to study drug
`over the entire 12-week treatment period .......................................................73
`Figure 4: Subgroup Analysis of Key Secondary Efficacy Endpoint #1: Proportion of
`Drug Responders (ITT Population) MNTX 3201 .............................................77
`Figure 5: (continued): Subgroup Analysis of Key Secondary Efficacy Endpoint #1:
`Proportion of Drug Responders (ITT Population) MNTX 3201 .....................78
`Figure 6: Proportion of Subjects with ≥ 3 Rescue-Free Bowel Movements per Week
`and an Increase of ≥1 Rescue-Free Bowel Movement from Baseline (ITT
`Population, LOCF Analysis) ............................................................................85
`Figure 7: Pairwise Correlations Among the Primary and Key Secondary Efficacy
`Endpoints During the QD and PRN Treatment Periods (ITT Population) .......87
`Figure 8: Categorical Changes in Hemodynamic Parameters at 1 Hour following the
`First Dose of Study Drug by Treatment Group (Safety Population) ..............124
`Figure 9: Time Dependency of Reported AEs in the Oral Placebo Controlled OIC
`Pooled Data ..................................................................................................129
`Figure 10: Time Dependency of Reported AEs in Study MNTX 3201........................130
`
`Reference ID: 3940594
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`Clinical Review
`Dina Zand, MD
`NDA 208,271
`Methylnaltrexone Bromide (MNTX)
`
`1 Recommendations/Risk Benefit Assessment
`
`1.1 Recommendation on Regulatory Action
`
`It is the opinion of this reviewer that methylnaltrexone bromide tablets 450 mg may be
`approved for marketing in the United States for the treatment of opioid-induced
`constipation (OIC) in adult patients with chronic, non-cancer pain. It is also the opinion
`of this reviewer that methylnaltrexone bromide 150 mg once daily may also be approved
`for patients with hepatic impairment (See Pharmacology Review) for the same
`indication. These recommendations are based on the Applicant’s demonstration of
`efficacy for their pre-specified primary endpoint at the proposed dose for marketing and
`the demonstration of statistical significance over placebo with the Applicant’s key
`secondary endpoint. While there were limitations to the data provided, the oral
`formulation of methylnaltrexone bromide may have slightly better tolerability, and there
`are benefits to the availability of an oral formulation for patients who may not be able to
`use the subcutaneous formulation.
`
`Because the duration of the double blind treatment phase in the pivotal phase 3 trial
`submitted for NDA 208271 was 4 weeks and the efficacy was not as robust as that
`demonstrated with subcutaneous methylnaltrexone bromide (Relistor® SC; NDA
`021964), this reviewer recommends the label should state that the durability of effect of
`Relistor® tablets has been established for 3 of 4 weeks.
`
`1.2 Risk Benefit Assessment
`
`Worldwide, opioid induced constipation is the most common adverse reaction
`associated with the use of opioids. A recent study estimated that 47% of patients with
`chronic opioid use reported associated constipation.1 As compared with other adverse
`reactions associated with opioid use, the associated constipation does not improve with
`time.2,3 Overall, OIC significantly affects patients’ quality of life, for example, by
`increasing the number of visits to health care providers and decreasing a patients’
`ability to work and performance at work.4
`
`1 Tujeta AK, Biskupiak J, Stoddard GJ et al. Opioid-induced bowel disorders and narcotic bowel
`syndrome in patients with chronic non-cancer pain. Neurogastroenterol Motil 2010;22:424-420
`2 Manchikanti L Helm S, Fellows B, Janata JW, Pampati V, Grider JS, Boswell MV, Opioid epidemic in the
`United
`States. Pain Physician. 2012 Jul;15(3 Suppl):ES9-38.
`3 Warner EA. Opioids for the Treatment of Chronic Noncancer Pain, Am J of Med 2012;125:1155-1161.
`4 Bell T, Annunziata K, Leslie JB. Opioid-induced constipation negatively impacts pain management,
`productivity, and health-related quality of life: findings from the National Health and Wellness Survey. J
`Opioid Manag 2009;5:137-44.
`
`Reference ID: 3940594
`
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`

`Clinical Review
`Dina Zand, MD
`NDA 208,271
`Methylnaltrexone Bromide (MNTX)
`
`Management of chronic OIC includes use of dietary fiber, increased fluid intake and
`physical activity. When these measures do not help, usually pharmacologic means are
`added including laxatives, stool softeners, and use of enemas. Opioid antagonists have
`been used for the treatment of OIC5 and currently there are three approved medications
`specifically indicated for the treatment of adults with OIC due to chronic, non-cancer
`pain: subcutaneous (SC) methylnaltrexone bromide (subsequently referred to as
`Relistor® SC) injection, naloxegol (Movantik®) oral tablets and lubiprostone (Amitiza®)
`oral tablets. As Relistor® SC is currently only approved as a subcutaneous (SC)
`injection, approval of methylnaltrexone bromide tablets would provide an alternative
`route of administration for patients currently receiving the SC injection, as well as an
`alternative to the currently approved oral products indicated for the treatment of OIC in
`adults with chronic non-cancer pain.
`
`Efficacy: A single Phase 3 clinical trial (MNTX3201) was conducted to evaluate the
`efficacy of oral methylnaltrexone bromide at 450 mg once daily for the treatment of OIC
`in adults. Data from this study, in conjunction with the methylnaltrexone SC clinical data
`and the pharmacokinetic (PK)/pharmacodynamic (PD) relationship of SC, intravenous
`and oral dosage forms of methylnaltrexone combined to support the efficacy of the oral
`methylnaltrexone bromide for the proposed indication.
`
`As noted in pre-NDA meetings (07March2012 and 04November2014), support for the
`approval of oral methylnaltrexone bromide would require the results of the pre-specified
`analyses supporting the proposed dose to first be statistically valid, allowing for
`evaluation of key secondary analyses of interest for purposes of ultimately approving
`and labeling the product. In addition, the results of these key analyses of clinical
`endpoints considered suitable for purposes of labeling would need to be robust (e.g.,
`analyses comparable to the analyses presented in subcutaneous methylnaltrexone
`product labeling for the indication of OIC in chronic pain.)
`
`The Phase 3 oral methylnaltrexone bromide clinical trial is the primary subject of the
`current review. Study MNTX3201 was a multicenter, randomized, double-blind,
`placebo-controlled, parallel-group study of oral methylnaltrexone for the treatment of
`OIC in 803 subjects with chronic, non-malignant pain. The pre-specified primary
`endpoint in this study was the percentage of dosing days that resulted in rescue free
`bowel movements (RFBMs) within 4 hours of dosing during weeks 1-4. This endpoint
`was not acceptable to the Division; however, the applicant proposed that approval be
`based on results of the first key secondary endpoint, also known as the responder
`endpoint. The responder endpoint was pre-specified as the proportion of subjects who
`responded to study drug during weeks 1-4, where a responder is defined as ≥3
`RFBM/week, with an increase of ≥1 RFBM/week over baseline, for ≥3 out of the first 4
`weeks of the treatment period.
`
`5 Nelson AD and Camilleri M. Chronic opioid induced constipation in patients with nonmalignant pain:
`challenges and opportunities. Therap Adv Gastroenterol 2015;8:206-220
`
`Reference ID: 3940594
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`

`Clinical Review
`Dina Zand, MD
`NDA 208,271
`Methylnaltrexone Bromide (MNTX)
`
`The current standard for approvability for drugs intended to be used chronically in the
`management of OIC in adults with chronic, non-cancer pain (CNCP) includes two Phase
`3 studies of at least 12 weeks in duration. The recommended primary endpoint for such
`studies is the proportion of subjects who are weekly responders for at least 9 of the 12
`weeks, including 3 of the last 4 weeks of the 12-week study period, where a weekly
`responder is defined as ≥ 3 RFBMs/week for each week of the study, with an increase
`of ≥ 1 RFBM/week over baseline
`
`However, Relistor® SC was previously approved based on a Phase 3 study of only 4
`weeks in duration. For approval of oral methylnaltrexone bromide, NDA 208271 is
`relying on the comparability of the pharmacokinetic (PK)/pharmacodynamic (PD)
`relationship of subcutaneous (SC), intravenous (IV) and the oral dosage form and the
`clinical data from the Relistor® SC development program (NDA 021964), in addition to
`the oral clinical data from the Phase 3 MNTX3201 study. As such, the Division
`determined that the applicant’s 4 week primary analysis period was sufficient
`
`The development programs for Relistor® SC and methylnaltrexone bromide tablets
`were initiated and completed prior to the current standards for approvability for drugs
`intended to be used chronically in the management of OIC in adults with CNCP. These
`programs were short in duration, 4 weeks, for the double blind, placebo controlled
`portion of each study. The key responder endpoints for the Relistor® SC OIC Phase 3
`study and the oral methylnaltrexone bromide Study MNTX3201 were:
`
` Relistor® SC: Proportion of subjects who responded to study drug during
`Weeks 1 to 4, where a responder is defined as ≥ 3 RFBMs/week for each week
`of the 4 week study,
` Oral Tablets: proportion of subjects who responded to study drug during Weeks
`1 to 4, where a responder is defined as ≥ 3 RFBMs/week for 3 of the 4 weeks of
`the study with an increase of ≥ 1 RFBM/week over baseline.
`
`While these responder endpoints are slightly different, the Applicant did find substantial
`statistical significance at 450 mg for both the primary and Responder endpoints so that
`the totality of evidence does support that methylnaltrexone bromide tablets (450 mg) is
`effective in the treatment of OIC in adults with chronic, non-cancer pain.
`
`Safety: In the clinical development program, 1057 subjects with OIC and chronic, non-
`cancer pain were enrolled in a placebo-controlled clinical trial and received at least 1
`dose of methylnaltrexone bromide tablets. The most commonly reported AEs were
`complaints of abdominal pain, nausea and diarrhea.
`
`In the methylnaltrexone tablet development program one death of a patient receiving
`450 mg occurred and was interpreted as related to atherosclerotic disease and not
`study drug (Refer to section 7.3.1). The largest percentage of Serious Adverse Events
`
`Reference ID: 3940594
`
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`

`Clinical Review
`
`Dina Zand, MD
`
`NDA 208,271
`Methylnaltrexone Bromide (MNTX)
`
`(SAEs) was noted at >450 mg (7.7%) which was studied in phase 2 studies, in
`comparison to 5150 mg (1.8%), 300 mg (2.1%), 450 mg (2.1%) and placebo (2.3%).
`
`Overall, the incidence rates for adverse events (AEs) with 450 mg methylnaltrexone
`bromide tablets were similar to the labeled adverse events reported for Relistor® SC 12
`mg, with the exception of GI adverse events of abdominal pain, nausea, and diarrhea.
`The most commonly reported AEs for both oral and subcutaneous methylnaltrexone
`bromide w