CENTER FOR DRUG EVALUATION AND
`
`RESEARCH
`
`'
`
`APPLICA TION NUMBER:
`22-044
`
`MEDICAL REVIEW! S!
`
`

`

`CLINICAL REVIEW
`
`Application Type
`Submission Number
`Submission Code
`
`NDA
`22—044
`3
`
`‘
`
`~
`
`Letter Date
`
`Stamp Date
`PDUFA Goal Date
`
`Reviewer Name
`
`.
`Through:
`Review Completion Date
`
`2006-05-3 l
`2006-05-3 1
`2007-03-3 l
`
`Ilan Irony
`Mary Parks
`2007-03 -05
`
`Established Name:
`
`(Proposed) Trade Name
`Therapeutic Class:
`Applicant .
`
`Sitagliptin / metformin fixed-dose combination
`Janumet
`
`Dipeptidyl peptidase IV inhibitor / biguanide
`Merck and Company, Inc.
`
`Priority Designation
`
`S
`
`Formulation
`
`Dosing Regimen
`Indication
`
`Intended Population
`
`Oral Tablet
`
`50 mg / 500 mg and 50 mg /1000 mg twice daily
`Improve glycemic control
`Adult patients with Type 2 diabetes mellitus
`
`

`

`Clinical Review
`
`Ilan Irony, M.D.
`NDA 22044, Submission 000
`Janumet TM (Sitagliptin / metformin fixed-dose combination)
`
`
`
`1
`
`EXECUTIVE SUMMARY................................................................................................................................5
`
`,
`
`Table of Contents
`
`1.1
`1.2
`
`1.3
`
`1.2.1
`1.2.2
`1.2.3
`1.2.4
`
`1.3.1
`1.3.2
`1.3.3
`
`1.3.4
`1.3.5
`1.3 .6
`
`RECOMMENDATION ON REGULATORY ACTION .......................................................................................... 5
`
`RECOMMENDATION ON POSTMARKETING ACTIONS
`
`Risk Management Activity .................................................’................................................................... 6
`Required Phase 4 Commitments ............................................................................................................6
`
`
`Other Phase 4 Requests..................................
`Recommended Trade Name ...................................................................................................................6
`SUMMARY OF CLINICAL FINDINGS ..............................................................................._...............................6
`Brief Overview of Clinical Program ............................
`‘
`
`
`
`
`Dosing Regimen and Administration...........................................................................
`Drug~Drug Interactions ........................
`
`Special Populations ...........................
`
`INTRODUCTION AND BACKGROUND...
`
`
`PRODUCT INFORMATION ........................................................................................................................... 13
`Product description ................................................................................................................... 13
`
`Established name and proposed trade name ......
`
`Chemical class ...................................................
`
`Pharmacologic class ....................................................................
`Proposed indications, dosing regimens and age groups ...................................................... 15
`
`CURRENTLY AVAILABLE TREATMENT FOR INDICATIONS ................................................................ 15
`AVAILABILITY OF PROPOSED ACTIVE INGREDIENT IN THE UNITED STATES ...................
`IMPORTANT ISSUES WITH PHARMACOLOGICALLY RELATED PRODUCTS ........................
`PRESUBMISSION REGULATORY ACTIVITY ....................................................................................
`OTHER RELEVANT BACKGROUND INFORMATION ...................................................................................... 17
`
`2
`
`2.1
`
`2.1.1
`2.1.2
`2.1.3
`2.1.4
`2.1.5
`2.2
`2.3
`2.4
`2.5
`2.6
`
`
`
`3
`
`4
`
`5
`
`6
`
`SIGNIFICANT FINDINGS FROM OTHER REVIEW DISCIPLINES .................................................... 19
`
`CMC (AND PRODUCT MICROBIOLOGY, IF APPLICABLE) ........................................................................... 19
`ANIMAL PHARMACOLOGY/TOXICOLOGY .................................................................................................. 20
`
`DATA SOURCES, REVIEW STRATEGY, AND DATA INTEGRITY.....................................................22
`
`SOURCES OF CLINICAL DATA ....................................................................................................................22
`TABLES OF CLINICAL STUDIES ...................
`
`REVIEW STRATEGY ....................................
`DATA QUALITY AND INTEGRITY .................................
`
`COMPLIANCE WITH GOOD CLINICAL PRACTICES ................
`.
`.
`FINANCIAL DISCLOSURES ................................................................. ......................................................... 27
`
`3.1
`3.2
`
`4.1
`4.2
`4.3
`4.4
`4.5
`4.6
`
`CLINICAL PHARMACOLOGY ...................................................................................................................28
`
`5.1
`5.2
`5.3
`
`PHARMACOKINETICS .................................................................................................................................29
`PHARMACODYNAMICS ............................................................................................................................... 34
`EXPOSURE-RESPONSE RELATIONSHIPS .....................................................................................................36
`
`.
`
`INTEGRATED REVIEW OF EFFICACY
`
`.......................................37
`
`6.1
`
`INDICATION ..................37
`6.1.1 Methods ...............................................................................................................................................37
`6.1.2
`General Discussion of Endpoints ......................................................................................................... 38
`6.1.3
`Study Design........................................................................................................................................ 38
`6.1.4
`Efficacy Findings ................................................................................................................................. 41
`
`

`

`Clinical Review
`
`Ilan Irony, M.D.
`NDA 22044, Submission 000
`
`Janumet TM (Sitagliptin / metformin fixed-dose combination)
`6.1.5
`Clinical Microbiology ....................................................................................................45
`6.1.6
`Efficacy Conclusions ........................................................................................................................... 46
`
`7
`
`INTEGRATED REVIEW OF SAFETY ....................................................................................................... 46
`
`7.1
`
`7.2
`
`METHODS AND FINDINGS .......................................................................................................................... 46
`
`Deaths ................................................................................................. 46
`7.1.1
`
`Other Serious Adverse Events ...........................................................................48
`7.1.2
`
`
`Dropouts and Other Significant Adverse Events ............................................. 52
`7.1.3
`
`
`Other Search Strategies ..................................................................................... 61
`7.1.4
`Common Adverse Events ..................................................................................... 61
`7.1.5
`
`Less Common Adverse Events ........................................................................................66
`7.1.6
`
`Laboratory Findings .................................................66
`7.1.7
`Vital Signs ..........................................................................................................................'................. 75
`7.1.8
`Electrocardiograms (ECGS) ................................................................................................................. 78
`7.1.9
`Immunogenicity ._............v............................................. 82
`7. 1. 10
`
`Human Carcinogenicity .................................................................................................................. 83
`7.1.11
`Special Safety Studies ..................................................................................................................... 83
`7.1.12
`Withdrawal Phenomena and/or Abuse Potential ...................................................................... 83
`7.1.13
`
`Human Reproduction and Pregnancy Data ..................................................................................... 84
`7.1.14
`Assessment of Effect on Growth .............................................._....................................................... 84
`7.1.15
`
`Overdose Experience ............................................. 84
`7.1.16
`Postmarketing Experience............................................................................................................... 85
`7.1.17
`ADEQUACY OF PATIENT EXPOSURE AND SAFETY ASSESSMENTS .............................................................. 85
`Description of Primary Clinical Data Sources (Populations Exposed and Extent of Exposure) Used to
`7.2.1
`Evaluate Safety .................................................................................................................................................. 85
`7.2.2
`Description of Secondary Clinical Data Sources Used to Evaluate Safety .......................................... 89
`
`Adequacy of Overall Clinical Experience ................................................................................ 89
`7.2.3
`Adequacy of Special Animal and/or In Vitro Testing ..................................................................... 89
`7.2.4
`
`Adequacy of Routine Clinical Testing .......................................................................................... 90
`7.2.5
`Adequacy of Metabolic, Clearance, and Interaction Workup .......‘‘. ......................................................90
`7.2.6
`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 ............................................90
`
`Assessment of Quality and Completeness of Data .............................................................'.......... 90
`7.2.8
`7.2.9
`Additional Submissions, Including Safety Update .............................................................................. 90
`SUMMARY OF SELECTED DRUG~RELATED ADVERSE EVENTS, IMPORTANT LIMITATIONS OF DATA, AND
`7.3
`CONCLUSIONS ......................................................................................................................................................... 91
`GENERAL METHODOLOGY .............................................................................. 92
`7.4
`
`
`Pooling Data Across Studies to Estimate and Compare Incidence .................................... 92
`
`Explorations for Predictive Factors .................................................................................... 92
`CausalityDeterrnInatIon ............ 94
`
`7.4.1
`7.4.2
`7.4.3
`
`8
`
`ADDITIONAL CLINICAL ISSUES94
`
`8.1
`8.2
`8.3
`8.4
`8.5
`8.6
`8.7
`8.8
`
`DOSING REGIMEN AND ADMINISTRATION ..............................................................................................1.94
`DRUG-DRUG INTERACTIONS .....................................................................................................................94
`
`-
`SPECIAL POPULATIONS ......................................
`..........................95
`PEDIATRICS ............................................................................................................................................... 96
`ADVISORY COMMITTEE MEETING .............................................................................................................96
`
`LITERATURE REVIEW ..................................................................................................................... 97
`POSTMARKETTNG RISK MANAGEMENT PLAN ............................................................................................ 97
`OTHER RELEVANT MATERIALS ................................................................................................. ................ 98
`
`9
`
`OVERALLASSESSMENT..............................................98
`
`9. 1
`9.2
`9.3
`
`CONCLUSIONS ........................................................................................................................................... 98
`RECOMMENDATION ON REGULATORY ACTION .........................................................................................99
`RECOMMENDATION ON POSTMARKETING ACTIONS ..................................................................................99
`
`

`

`Clinical Review
`
`Ilan Irony, M.D.
`NDA 22044, Submission 000
`
`Janumet TM (Sitagliptin / metformin fixed-dose combination)
`9.3.1
`Risk Management Activity .................................................................................................................. 99
`9.3.2
`Required Phase 4 Commitments ..................
`
`9.3.3
`Other Phase 4 Requests .............................
`LABELING REVIEW .................................
`COMMENTS TO APPLICANT...................................
`
`10 APPENDICES ...............................
`.
`................................
`
`
`9.4
`9.5
`
`
`
`10.1
`10.2
`
`REVIEW OF INDIVIDUAL STUDY REPORTS ...............................................
`LINE—BY-LINE LABELING REVIEW ..................................................................,..........................-............... l 02
`
`REFERENCES ........................................................................................................................................................ 1 05
`
`Appears This Way:
`On Original
`
`

`

`Clinical Review
`
`Ilan Irony, MD.
`NDA 22044, Submission 000
`Janumet TM (Sitagliptin / metformin fixed-dose combination)
`
`1 EXECUTIVE SUMMARY
`
`This document is the Medical Officer’s Clinical Review of sitagliptin phosphate in a fixed-dose
`combination with metformin hydrochloride. Sitagliptin is a member of a new class of anti-
`diabetic agents, known as dipeptidyl peptidase inhibitors type IV. The indication sought is the
`treatment of patients with type 2 diabetes mellitus who do not achieve adequate glycemic control
`with either agent alone or for patients already being treated with the combination of sitagliptin
`and metformin.
`,
`Type 2 diabetes mellitus (T2DM) is a very prevalent condition characterized by abnormal
`metabolism and disposal of glucose. T2DM carries significant morbidity and mortality
`associated with both acute and chronic compliCations. Although several classes of drugs are
`available in the treatment of T2DM, many patients remain persistently hyperglycemic.
`Sitagliptin phosphate is a new molecular entity and part of a new class of drug products, called ’
`dipeptidyl peptidase IV (DPP4) inhibitors. Metforrnin hydrochloride has been widely prescribed
`for T2DM, with effects primarily on glucose production in liver and on insulin resistance. The
`New Drug Application reviewed in this document describes the clinical findings of the
`coadministration of sitagliptin and metformin during the development of sitagliptin (reviewed
`under NDA 21995) and the demonstration of bioequivalence between the sitagliptin / metformin
`fixed—dose combination (FDC) and the coadministration of sitagliptin and metformin.
`Coadministration of sitagliptin and metformin was studied in 1569 subjects with an average
`exposure of 255 days, across 3 different studies. Studies P015 (a Phase 2, 4-week, parallel group,
`randomized study) and P020 (a 24-week, randomized, placebo-controlled study, followed by an
`80-week active—controlled study) have been reviewed in the sitagliptin NDA submission 21995
`Data from the Open Label Cohort in Study P036 were submitted to this NDA. Additional data
`from Study P024 and the Randomized Cohorts of Study P036 were submitted with the 4-Month
`Safety Update Report for this application.
`
`1.1 Recommendation on Regulatory Action
`
`The clinical studies investigating the safety and efficacy of the coadministrationrof sitagliptin
`and metformin were reviewed under NDA 21995 and were deemed adequate to support approval
`of sitagliptin in the treatment of type 2 diabetics with inadequate glycemic control despite
`treatment with metformin. The approval of the sitagliptin / metformin FDC for second-line
`treatment (i.e., for patients already on metformin or on sitagliptinwho need additional glucose
`lowering, or for patients already treated with sitagliptin and metformin coadministered) is mainly
`contingent on the demonstration of bioequivalence between the coadministered and the
`combined components of the combination.
`Study P048 has provided the necessary evidence of the bioequivalence, and therefore this
`reviewer recommends approval of sitagliptin / metformin FDC for the second-line indications
`proposed.
`
`

`

`Clinical Review
`
`[lan Irony, MD.
`NDA 22044, Submission 000
`
`Janumet TM (Sitagliptin / metformin fixed—dose combination)
`1.2» Recommendation on Postmarketing Actions
`
`1.2.1 Risk Management Activity
`
`Although the studies supporting this application have enrolled subjects in a wide range of
`demographic characteristics (age and race), subjects younger than 18 years of age and pregnant
`or lactating women have been excluded. The studies enrolled subjects that, in addition to their
`TZDM, had a variety of co-morbid conditions; however, subjects with congestive heart failure
`requiring medications, liver cirrhosis, and renal dysfunction have been appropriately excluded, as
`these constitute contraindications to the use of metformin.
`There are no new identified risks forwthe sitagliptin / metformin FDC that have not been
`identified for. each of its components.
`_
`The applicant has proposed standard operating procedures for pharmacovigilance. In ongoing
`and future clinical studies, the applicant will continue to include routine surveillance for
`laboratory findings that were more frequently observed among sitagliptin-treated subjects, such
`as decreased alkaline phosphatase, increased uric acid, creatinine and neutrophil counts.
`Exposure to sitagliptin / metformin FDC during pregnancy will be monitored by routine
`pharmacovigilance and by establishment of a pregnancy registry, similar as described in the
`sitagliptin NDA. There is no or little potential for abuse or unintended use of this product. Unlike
`exenatide, a recently approved glucagon-like peptide-l analogue which has produced significant
`amount of weight loss in patients with T2DM, sitagliptin was not found to exert a meaningfiJl
`weight loss in clinical studies, and is unlikely to be abused for this end.
`No risk minimization plan is being proposed in this application.
`
`1.2.2 Required Phase 4 Commitments
`
`The applicant has a Phase 4 commitment to study the effects of sitagliptin in the pediatric
`population. Since this study will not be completed by the time the review of the current
`application of sitagliptin / metformin FDC is due, the commitment to comply with the'Pediatric
`Research Equity Act is deferred at this time".
`
`1.2.3 Other Phase 4 Requests
`
`Not applicable
`
`1.2.4 Recommended Trade Name
`
`Janumet is the proposed Trade Name. DMETS/OSE/CDER was consulted regarding the trade
`name, and the consultation reportis pending at this time.
`
`1.3 Summary of Clinical Findings
`
`

`

`Clinical Review
`llan Irony, MD.
`NDA 22044, Submission 000
`
`Janumet TM (Sitagliptin / metformin fixed-dose combination)
`The data supporting the efficacy of coadministration of Sitagliptin and metformin were described
`in detail in the Sitagliptin NDA. The doses of Sitagliptin and metformin in those clinical studies
`were similar to the doses proposed for the FDC. Briefly, the applicant initially conducted a
`placebo-controlled crossover Phase 2 study where subjects taking metformin where randomized
`to a sequence of Sitagliptin-placebo or placebo-Sitagliptin for treatment periods of 4 weeks
`duration (Study P015). The applicant subsequently conducted a randomized, placebo— and active-
`controlled Phase 3 study of the safety and efficacy of Sitagliptin when added to metformin (Study
`P020).
`In addition to these studies reported under NDA 21995, the applicant submitted in the current
`application additional data to further support the safety of the Sitagliptin in combination with
`metformin. These data comprise 117 subjects who had poor glycemic control at the time of
`screening and these subjects were assigned to the Open Label Cohort of Study P03 6, a factorial
`study currently ongoing. The 4-Month Safety Update Report included new data from 1172
`subjects participating in the Phase 3 glipizide-controlled non-inferiority Study P024, safety data
`from the randomized cohorts in Study P036 as well as updated reports received by the applicant
`through its established Worldwide Adverse Event System (WAES).
`
`1.3.1 Brief Overview of Clinical Program
`
`The clinical program described in this application was conducted in order to support the use of
`Sitagliptin and metformin in fixed-dose combinations in the treatment of patients with T2DM.
`Sitagliptin is a newly approved dipeptidyl peptidase 4 inhibitor (the first member in this class)
`and metformin is a biguanide with long established safety and efficacy. The doses proposed for
`treatment are Sitagliptin 50 mg / metformin 500 mg and Sitagliptin 50 mg / metformin 1000 mg
`to be used orally twice daily.
`Both components of this fixed-dose combination product have been approved for the treatment
`of T2DM. For this application, FDA had requested the applicant to:
`0
`Provide demonstration of the bioequivalence between the coadministration of Sitagliptin and
`metformin and the fixed-dose combination and
`.
`Provide additional safety data on the coadministration of Sitagliptin and metformin, beyond
`the experience obtained in the Sitagliptin NDA.
`A total of 2930 subjects participated in Phase 2 and Phase 3 studies in which Sitagliptin 100 mg
`daily (either as 100 mg qdor 50 mg bid) and metformin at daily doses 2 1500 mg were
`coadministered. In these studies 1569 subjects have been exposed to coadministered Sitagliptin
`and metformin for periods of 1 to 404 days, with a mean duration of 255 days.
`
`7
`
`1.3.2 Efficacy
`
`The effect of Sitagliptin when administered to subjects with inadequate glycemic control while
`treated with metformin has been studied in the Phase 3, randomized, multicenter, parallel-group,
`placebo-controlled and active-controlled Study P020 and its extension. That study was reviewed
`under NDA 21995 as supportive of the indication of Sitagliptin as an add-on medication to
`metformin.
`
`The main characteristics of the study were:
`0
`Subjects needed to' be on stable metformin doses of at least 1500 mg daily and have
`
`

`

`Clinical Review
`
`llan Irony, M.D.
`NDA 22044, Submission 000
`
`Janumet TM (Sitagliptin / metformin fixed-dose combination)
`HbAlc between 7 and 10 % at randomization
`
`.
`
`701 subjects were randomized 2:1 favoring sitagliptin 100 mg qd versus placebo.
`o
`0 After assessment of'the primary endpoint at week 24 (Phase A), subjects randomized to
`placebo were switched to glipizide, and both groups continued in the extension study for
`80 weeks currently ongoing (Phase B).
`Table 1 summarizes the data on the primary endpoint: change in HbAlc from baseline to
`week 24 in the ITT population.
`
`Table 1. Change of HbAlc from baseline to week 24 in Study P020 (ITT population)
`
`Change from baseline
`—- Mean (SD)
`_-___— 95% CI for L8
`_-——-Il-Il__
`
`
`
`
`
`
`
`
`
`
`
`<0.001
`-o.7 (0.1)
`—0.7 (0.0)
`7.3 (1.0)
`8.0 (0.8)
`Sitagliptin 100 mg
`minimum-m.—
`—-—__——_
`Difference in LS means 95 %CI
`—0.65 -o.s,-o.5
`Sita_litin 100 m_ vs. Placebo
`
`C1=Confidence Interval; LS=Least S - uares; SD=Standard Deviation; SE=Standard Error.
`Adapted from the applicant’s Table 1 1-1, reference P020vl
`
`
`
`.
`
`
`
`After the initial 24 weeks of study, subjects on placebo were switched to treatment with
`.
`glipizide. Data from the first 30 weeks of the extension study were reported in the 4-month
`safety update report that was part of NDA 21995. Figure 1 shows the changes in HbAlc in the
`24 weeks of placebo—controlled study and the additional 30 weeks where subjects who had
`been randomized to placebo in Phase A were treated with glipizide during the ensuing 30
`weeks of the extension study (Phase B).
`‘
`
`Figure 1. LS Mean change from baseline in HbAlc (%) over time by treatment group (LS Mean :1: SE) in
`Study P020
`
`Phase}.
`
`v
`
`
`'-
`"
`
`' PhaseBl-
`
` LSMeanChange
`
`fromBaseline
`
`Week
`
`0 targets: :00 mgnoe mg
`0 PlaceiioIGlipizide
`Copied from the applicant’s Figure 2.73:2 in Reference 2.7.3 Summary of Clinical Efficacy
`
`

`

`Clinical Review
`
`Ilan Irony, M.D.
`NDA 22044, Submission 000
`
`Janumet TM (Sitagliptin / metformin fixed-dose combination)
`The significant reduction in HbAlc, with favorable effects on fasting plasma glucose and on
`the 2-hour post-meal glucose (data not shown) served as the basis for approval of sitagliptin
`for the treatment of patients with TZDM whose glycemic control is inadequate on metformin
`therapy alone.
`p
`Two other studies investigating effects of sitagliptin in combination with metformin are
`currently ongoing.
`‘
`o
`‘ Study P036 is a randomized, placebo-controlled, factorial study investigating effects on
`glycemic control of the coadministration of sitagliptin and either low or high metformin
`doses against the effect of each component (sitagliptin, low or high dose metformin)
`separately. The primary endpoint is the change in LS mean HbAlc from baseline to week
`24.'The effect of the coadministration of sitagliptin and each dose of metformin on HbAlc
`was greater than the effect of each component alone, compared at the same doses of
`metformin (Figure 2). The mean Effect on HbAlc in the Open Label Cohort (not shown in
`the figure) was similar in magnitude as the effect shown for the coadministration of
`sitagliptin 50 mg bid and metformin 1000 mg bid.
`
`Figure 2. Changes in Least Square Mean HbAlc (%) among the Randomized Cohorts in Study P036
`
`train-Sesame
`
`LSMeanchange
`
`Week
`
`0 saw {so "gum. . Mal 5m mg mu
`1 5m; mm mm. . Mel moo nigh“?
`0 Mel sun my bid.
`1
`_El' Met mm mg!) m,
`0 MW -
`'5 ,
`".1 Ska H10 mg‘qit
`Copied from the applicant’s Figure l H, reference p036vl
`
`-
`
`Study P024 is an active-controlled, non-inferiority study comparing the glycemic effects
`of the addition of either sitagliptin 0r glipizide in subjects with inadequate glycemic
`control on metformin monotherapy. Only summary efficacy data related to the primary
`endpoint are being submitted in this NDA.
`
`

`

`Clinical Review
`Ilan Irony, M.D.
`NDA 22044, Submission 000
`Janumet TM (Sitagliptin / metformin fixed-dose combination)
`
`Table 2. Changes from baseline to week 52 in HbAlc in Study P024, in the per protocol population
`
`Mean (SD)
`
`'Week 24
`7
`6.8 (0.)
`
`7.5 (0.3)
`
`
`
`Treatment
`I
`
`
`Sitagliptin 100m
`(—07,—0.6)
`
`~07, ~06
`—--_—_
`
`Difference in LS means 95 % CI
`
`.
`~0.01 -0.09, 0.08
`
`D=Standard Deviation; SE=Standard Error.
`
`Adapted from the applicant’s Table ”—1, reference p024vl, in the 4-Month Safety Update Report
`
`Change from baseline
`LS Mean
`95% CI for LS
`Mean
`
`-O.6 (0.0)
`
`--o.7 (0.0)
`
`The same analysis in the ITT population (including 576 subjects on sitagliptin and 559 on
`glipizide, in addition to metformin) yielded similar results, with a difference in LS means for
`the change in HbAlc from baseline to week 52 of 0.04.
`
`1.3.3 Safety
`
`Sources‘of safety data on the coadministration of sitagliptin and metformin inthe NDA 22044
`that were submitted with the original application are listed below:
`0 The Phase 2 Study P015
`‘
`o The Phase 3 Study P020, including results of the placebo-controlled, 24—week period and the
`first 30 weeks of the ongoing 80-week Phase B
`'
`o The Phase 3 Study P036 Open-label Cohort Interim Safety Assessment.
`0
`In addition, the 4-Month Safety Update Report added safety information on the randomized
`cohorts of Study P036 and 52 weeks of data from Study P024.
`In these 4 combined studies, 1569 subjects received metformin at daily doses 2 1500 mg and
`sitagliptin at daily doses‘of 100 mg (either as 100 mg qd or 50 mg bid) fora mean period of
`36.4 weeks. The clinical safety assessments were based on review of ABS (including SAEs),
`laboratory abnormalities, electrocardiographic changes, and vital signs.
`
`0
`
`There are no new concerns regarding the safety of the coadministration of sitagliptin and
`metformin than those already noted in the review of the sitagliptin NDA and the known safety
`profile of metformin (for example, the rare risk of lactic acidosis under specified circumstances).
`
`1.3.4 Dosing Regimen and Administration
`
`The applicant proposes the use of sitagliptin / metformin FDC as a treatment of patients with
`TZDM who are not. adequately controlled on either metformin or sitagliptin alone or in patients
`already being treated with the combination of sitagliptin and metformin.
`The dose of sitagliptin / metformin FDC is mostly driven by the patient’s current antidiabetic
`treatment regimen, and is titrated based on the effeCtiveneSS in reaching glycemic goals and the
`tolerability of the metformin component. The sitagliptin dose that has been selected for
`marketing, as monotherapy or in combination with metformin or a PPAR 7 agonist, is 100 mg
`qd. The safety, pharmacokinetic and'pharmacodynamic profiles of a regimen of 100 mg qd are
`very similar to those seen with 50 mg bid, as reported under NDA 21995. For patients who are
`
`10
`
`

`

`Clinical Review
`
`llan Irony, M.D.
`NDA 22044, Submission 000
`Janumet TM (Sitagliptin / metformin fixed-dose combination)
`
`nai've to treatment with metformin, the dose is usually titrated weekly from 500 mg qd or bid up
`to 1000 mg bid, in order to decrease gastrointestinal events that may lead to discontinuation due
`to poor tolerability.
`The proposed label proposes the following dosing recommendations:
`The starting dose of sitagliptin / metformin FDC should be based on the patient’s current
`regimen. Sitagliptin / metformin FDC should be given twicedaily with meals. The following
`doses are available: sitagliptin 50 mg / metformin hydrochloride 500 mg and Sltagliptin 50 mg/
`metformin hydrochloride 1000 mg.
`
`For patients inadequately controlled on metformin monotherapy
`For patients not adequately controlled on metformin alone, the usual starting dose of sitagliptin/
`metformin FDC should be equal to 100 mg total daily dose (50 mg twice daily) of sitagliptin plus
`the dose of metformin already being taken.
`
`For patients inadequately controlled on sitagliptin monotherapy
`For patients not adequately controlled on sitagliptin alone, the usual starting dose of sitagliptin /
`metformin F DC is sitagliptin 50 mg / metformin hydrochloride 500 mg twice daily. Patients may
`be titrated up to sitagliptin 50 mg / metformin hydrochloride 1000 mg twice daily. Patients
`taking sitagliptin monotherapy dose~adjusted for renal insufficiency should not be switched to
`sitagliptin / metformin FDC.
`
`For patients switching from sitagliptin coadministered with metformin
`For patients switching from sitagliptin coadministrated with metformin, sitagliptin / metformin
`FDC may be initiated at the dose of sitagliptin and metformin already being taken.
`
`The dose strengths of sitagliptin / metformin FDC do not include a combination of sitagliptin 50
`mg with metformin 850 mg. The applicant argued that more than ’ ’A) of prescriptions written
`for metformin in the United States are for either 500 mg or 1000 mg (source cited: IMS Health,
`NPA PlusTM from 9/2005 to 3/2006). The applicant states that no increased issues of safety or
`tolerability would be expected if a patient whose glycemic control is not adequate with
`metformin 850 mg bid were to switch to the sitagliptin 50 mg / metformin 1000 mg bid FDC,
`with the possibility that the small metformin dose1ncrease will fi1rther helpImprove glycemia.
`This reviewer agrees with the applicant’s assessment.
`
`1.3 .5 Drug-Drug Interactions
`
`Coadministration of multiple doses of sitagliptin (50 mg) and metformin (1000 mg) given twice
`daily did not meaningfully alter the pharmacokinetics of either sitagliptin or metformin in
`patients with type 2 diabetes.
`Pharmacokinetic drug interaction studies with sitagliptin / metformin FDC have not been
`performed; however, such studies have been conducted with the individual components of
`(sitagliptin phosphate and metformin hydrochloride).
`'
`Sitagliptin is well absorbed with an absolute bioavailability of 87 %, which does not change
`substantially when dosing follows a high fat meal. Sitagliptin is eliminated by the kidneys as
`unchanged drug, with minor metabolism mediated by CYP3A4. Sitagliptin is not an inducer of
`CYP3A4. The renal clearance is approximately 350 mL/min, suggesting that active tubular
`
`11
`
`

`

`Clinical Review
`
`llan Irony, MD.
`NDA 22044, Submission 000
`Janumet TM (Sitagliptin / metformin fixed~dose combination)
`secretion is involved in the renal elimination of sitagliptin, possibly by the organic anionic
`transport