CENTER FOR DRUG EVALUATION AND
`RESEARCH
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`APPLICATION NUMBER:
`202343Orig1s000
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`MEDICAL REVIEW(S)
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`DEPARTMENT OF HEALTH & HUMAN SERVICES
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`Public Health Service
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`NDA
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`Drug Product
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`Company
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`Division Director’s Memo
`
`Food and Drug Administration
`Silver Spring, MD 20993-002
`
`202-343
`
`Sitagliptin-Simvastatin Fixed-Dosed Combination Tablets
`
`Merck
`
`December 6, 2010
`
`October 7, 2011
`
`Date of Submission
`
`PDUFA Goal Date
`
`
`
`This NDA is for the fixed-dose combination (FDC) of sitagliptin and simvastatin. Both of these drug
`products are approved for use as described in the clinical reviews of Drs. Pratt and Irony. The pivotal
`studies supporting approval were bioequivalence studies to determine if the pharmacokinetics of the
`individual components in the FDC differed from when they are individually co-administered. These
`studies have been reviewed by Drs. Chung and Vaidyanathan and the Office of Clinical Pharmacology
`has recommended approval. The FDC will be available in the following sitagliptin/simvastatin dosage
`strengths: 100 mg/10 mg, 100 mg/20 mg, and 100 mg/40 mg. I concur with the medical and clinical
`pharmacology reviewers that this application can be approved and my memo will only note selected
`issues in the NDA which need to be highlighted.
`
`Dosage Strengths
`Sitagliptin is available in 25, 50, and 100 mg strengths. The 50 mg dose is recommended for patients
`with moderate renal impairment and the 25 mg dose is recommended for patients with severe renal
`impairment or with endstage renal disease. Simvastatin is available in 5, 10, 20, 40 and 80 mg strengths.
`Drug utilization data for both drug products revealed minimal use of the lowest dosage strengths;
`therefore, the company was not required to develop a FDC containing sitagliptin 25 mg and simvastatin 5
`mg. However, extensive discussions were held with the company regarding the availability of dosage
`strengths of sitagliptin 50 mg and simvastatin 80 mg.
`
`For sitagliptin 50 mg, it was felt that the population of patients with T2DM and moderate renal
`impairment was not an insignificant number. Not making available a FDC with sitagliptin 50 mg might
`result in such patients taking a higher dose than recommended. Labeling against its use was not
`appropriate given the sizeable patient population. The company proposed to develop and manufacture a
`FDC containing sitagliptin 50 mg and requested submission of data to support approval of
`sitagliptin/simvastatin 50/10, 50/20, and 50/40 as an efficacy supplement after approval of the FDC
`tablets containing sitagliptin 100 mg. This was deemed acceptable as the applicant provided a letter
`committing to submit this supplement to FDA by November 30, 2011, which did not signify an
`unreasonable delay to market. In the meanwhile, the label will include a “Limitations of Use” stating that
`patients with moderate and severe renal impairment should not take the FDC product due to unavailability
`of the 50 and 25-mg dosage strengths of sitagliptin.
`
`Prior to submission of this efficacy supplement, the Division was evaluating data from the SEARCH trial
`and assessing the risk of muscle toxicity associated with simvastatin 80 mg. Plans were underway to
`restrict the use of this dose to only those patients who were already on simvastatin 80 mg and tolerating
`
`Reference ID: 3025739
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`

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`the drug without evidence of muscle symptoms. The Division did not feel that it would be appropriate to
`consider approval of a FDC that would include the simvastatin 80 mg dose strength as it might further
`encourage the inappropriate use of this dose. especially as a new initiation only for the purpose of
`convenience dosing.
`“M"
`
`The applicant acknowledged the Division’s position on
`the matter and did not pursue marketing of the simvastatin 80 mg dosage strength; however,
`bioequivalence data including the sita/simva 10/80 fixed-dose combination tablet were accepted for
`review with biowaiver consideration for the lower dosage strengths intended for marketing.
`
`Statins and Diabetes
`
`Recently, two published meta-analyses of several randomized statin trials revealed an increased risk of
`developing diabetes associated with statin use, notably atorvastatin, rosuvastatin. and sirnvastatin.1’2 This
`was also observed by FDA in its review of rosuvastatin’s JUPITER trial and such an association has been
`included in rosuvastatin’s label (Warnings and Precautions and Adverse Reactions).
`
`The significance of this finding, particularly with a FDC to be used in the diabetic population was
`considered As summarized by the authors of one meta-analysis, the risk of developing diabetes in
`absolute terms was low in comparison to the benefits of statins in lowering a patient’s risk for future
`cardiovascular events. Reassuring for simvastatin is that analyses of large outcomes trial did not exclude
`the benefits of CV risk reduction from patients vw'th T2DM. However, labeling to describe this
`observation is appropriate such that healthcare providers and patients are aware of the potential for
`worsening glycemic control and adjust diabetic medications accordingly.
`
`The applicant has proposed to conduct a randomized, double-blind. active-controlled trial to study the
`effect of the FDC versus sitagliptin on glycemic control in T2DM patients on background metfomiin
`therapy as a postmarketing trial to prospectively evaluate the effects of simvastatin on glycemic control.
`This is an important trial that will inform prescribers and patients on the risk and benefits of this FDC
`product and will therefore be a required trial under FDAAA.
`
`Labeling
`The applicant is proposing that the FDC be indicated in patients for whom treatment with both sitagliptin
`and simvastatin is appropriate. Although FDA reviews and the applicant’s rationale for development of
`this product suggest a benefit with convenience dosing. the label should not include language which may
`be promotional to this effect. The applicant has not provided any data to support an assertion that the
`administration of one pill instead of two improves compliance or leads to better clinical outcomes.
`Although not a consideration in the approval process, one could argue from a health economics standpoint
`that a new FDC product might cost more than co—administration of the individual components. especially
`given that simvastatin is available as a generic. More importantly. the ‘convenience’ of the FDC should
`not encourage prescribing practice that runs contrary to the safe use of the individual components. To this
`end, the recent labeling changes recommended for simvastatin must be incorporated into the FDC label
`prior to approval.
`
`(5) (4)
`
`l Sattar N et al. Statins and risk of incident diabetes: a collaborative meta-analysis of randomised statin trials. The
`Lancet. 2010: 375:735-742.
`
`2 Rajpathak S et a1. Statin therapy and risk of developing type 2 diabetes: a meta-analysis. Diabetes Care. 2009;
`32: 1924-1929.
`
`Reference ID: 3025739
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`

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` the
` Although this labeling request was made to the
`changes are important to the safe use of any drug product containing simvastatin and therefore the FDC of
`sitagliptin and simvastatin should include these changes prior to approval.
`
`Recommendations
`Pending agreed-upon labeling, this application can be approved.
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`
`
`
`Reference ID: 3025739
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`3
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`(b) (4)
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`(b) (4)
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`

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`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`MARY H PARKS
`10/06/2011
`Division Director's memo
`
`Reference ID: 3025739
`
`

`

`CLINICAL REVIEW
`
`Application Type NDA
`Application Number(s) 202-343
`Priority or Standard Standard
`
`Submit Date(s) 12-6-10
`Received Date(s) 12-7-10
`PDUFA Goal Date 10-7-11
`Division / Office DMEP/ODEII/OND
`
`Reviewer Name(s) Valerie S. W. Pratt, M.D.
`Review Completion Date 09-01-11
`
`Established Name Sitagliptin/simvastatin FDC
`(Proposed) Trade Name
`
`Therapeutic Class DPP-4 inhibitor/Statin
`Applicant Merck
`
`Formulation(s) 100/10, 100/20, & 100/40 mg
`tablets
`Dosing Regimen Once daily
`Indication(s) Diabetes/hyperlipidemia
`Intended Population(s) Adult diabetics with
`hyperlipidemia
`
`
`
`Template Version: March 6, 2009
`
`Reference ID: 3009841
`
`(b) (4)
`
`

`

`Clinical Review
`Valerie S. W. Pratt, M.D.
`NDA 202-343
` / sitagliptin + simvastatin FDC
`
`
`
`Table of Contents
`
`2
`
`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 . 12
`1.4 Recommendations for Postmarket Requirements and Commitments .............. 13
`INTRODUCTION AND REGULATORY BACKGROUND ...................................... 13
`2.1 Product Information .......................................................................................... 13
`2.2 Tables of Currently Available Treatments for Proposed Indications ................. 15
`2.3 Availability of Proposed Active Ingredient in the United States ........................ 16
`2.4
`Important Safety Issues With Consideration to Related Drugs......................... 17
`2.5 Summary of Presubmission Regulatory Activity Related to Submission .......... 17
`2.6 Other Relevant Background Information .......................................................... 19
`3 ETHICS AND GOOD CLINICAL PRACTICES....................................................... 20
`3.1 Submission Quality and Integrity ...................................................................... 20
`3.2 Compliance with Good Clinical Practices ......................................................... 20
`3.3 Financial Disclosures........................................................................................ 20
`4 SIGNIFICANT EFFICACY/SAFETY ISSUES RELATED TO OTHER REVIEW
`DISCIPLINES ......................................................................................................... 21
`4.1 Chemistry Manufacturing and Controls ............................................................ 21
`4.2 Clinical Microbiology......................................................................................... 22
`4.3 Preclinical Pharmacology/Toxicology ............................................................... 22
`4.4 Clinical Pharmacology...................................................................................... 22
`4.4.1 Mechanism of Action.................................................................................. 24
`4.4.2 Pharmacodynamics.................................................................................... 24
`4.4.3 Pharmacokinetics....................................................................................... 24
`5 SOURCES OF CLINICAL DATA............................................................................ 25
`5.1 Tables of Studies/Clinical Trials ....................................................................... 26
`5.2 Review Strategy ............................................................................................... 30
`5.3 Discussion of Individual Studies/Clinical Trials................................................. 30
`6 REVIEW OF EFFICACY......................................................................................... 30
`Efficacy Summary...................................................................................................... 30
`6.1
`Indication .......................................................................................................... 31
`6.1.1 Methods ..................................................................................................... 32
`6.1.2 Demographics............................................................................................ 32
`6.1.3 Subject Disposition..................................................................................... 32
`6.1.4 Analysis of Primary Endpoint(s) ................................................................. 32
`6.1.5 Analysis of Secondary Endpoints(s) .......................................................... 40
`
`Reference ID: 3009841
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`2
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`(b) (4)
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`

`

`Clinical Review
`Valerie S. W. Pratt, M.D.
`NDA 202-343
`/ sitagliptin + simvastatin FDC
`
`
`
`6.1.6 Other Endpoints ......................................................................................... 40
`6.1.7 Subpopulations .......................................................................................... 40
`6.1.8 Analysis of Clinical Information Relevant to Dosing Recommendations .... 40
`6.1.9 Discussion of Persistence of Efficacy and/or Tolerance Effects................. 40
`6.1.10 Additional Efficacy Issues/Analyses........................................................... 40
`7 REVIEW OF SAFETY............................................................................................. 40
`Safety Summary ........................................................................................................ 40
`7.1 Methods............................................................................................................ 43
`7.1.1 Studies/Clinical Trials Used to Evaluate Safety ......................................... 43
`7.1.2 Categorization of Adverse Events.............................................................. 44
`7.1.3 Pooling of Data Across Studies/Clinical Trials to Estimate and Compare
`Incidence.................................................................................................... 44
`7.2 Adequacy of Safety Assessments .................................................................... 44
`7.2.1 Overall Exposure at Appropriate Doses/Durations and Demographics of
`Target Populations..................................................................................... 45
`7.2.2 Explorations for Dose Response................................................................ 47
`7.2.3 Special Animal and/or In Vitro Testing ....................................................... 47
`7.2.4 Routine Clinical Testing ............................................................................. 47
`7.2.5 Metabolic, Clearance, and Interaction Workup .......................................... 47
`7.2.6 Evaluation for Potential Adverse Events for Similar Drugs in Drug Class .. 48
`7.3 Major Safety Results ........................................................................................ 48
`7.3.1 Deaths........................................................................................................ 48
`7.3.2 Nonfatal Serious Adverse Events .............................................................. 49
`7.3.3 Dropouts and/or Discontinuations .............................................................. 53
`7.3.4 Significant Adverse Events ........................................................................ 54
`7.3.5 Submission Specific Primary Safety Concerns .......................................... 69
`7.4 Supportive Safety Results ................................................................................ 69
`7.4.1 Common Adverse Events .......................................................................... 69
`7.4.2 Laboratory Findings ................................................................................... 74
`7.4.3 Vital Signs .................................................................................................. 81
`7.4.4 Electrocardiograms (ECGs) ....................................................................... 82
`7.4.5 Special Safety Studies/Clinical Trials......................................................... 82
`7.4.6
`Immunogenicity.......................................................................................... 83
`7.5 Other Safety Explorations................................................................................. 83
`7.5.1 Dose Dependency for Adverse Events ...................................................... 83
`7.5.2 Time Dependency for Adverse Events....................................................... 84
`7.5.3 Drug-Demographic Interactions ................................................................. 84
`7.5.4 Drug-Disease Interactions.......................................................................... 86
`7.5.5 Drug-Drug Interactions............................................................................... 86
`7.6 Additional Safety Evaluations ........................................................................... 86
`7.6.1 Human Carcinogenicity.............................................................................. 87
`7.6.2 Human Reproduction and Pregnancy Data................................................ 87
`7.6.3 Pediatrics and Assessment of Effects on Growth ...................................... 87
`
`Reference ID: 3009841
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`

`

`Clinical Review
`Valerie S. W. Pratt, M.D.
`NDA 202-343
` / sitagliptin + simvastatin FDC
`
`
`
`7.6.4 Overdose, Drug Abuse Potential, Withdrawal and Rebound...................... 88
`7.7 Additional Submissions / Safety Issues............................................................ 88
`8 POSTMARKET EXPERIENCE............................................................................... 89
`
`9 APPENDICES ........................................................................................................ 92
`9.1 Literature Review/References .......................................................................... 92
`9.2 Labeling Recommendations ............................................................................. 92
`9.3 Advisory Committee Meeting............................................................................ 92
`
`
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`Reference ID: 3009841
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`4
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`(b) (4)
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`

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`Clinical Review
`Valerie S. W. Pratt, M.D.
`NDA 202-343
`/ sitagliptin + simvastatin FDC
`
`
`
`Table of Tables
`
`Table 1. Timeline for the development of sitagliptin/simvastatin FDC tablets containing
`50 mg sitagliptin............................................................................................. 15
`Table 2. Clinical pharmacology studies........................................................................ 23
`Table 3. Bioequivalence study results.......................................................................... 25
`Table 4. Studies included in the pooled analysis for safety by exposure to sitagliptin
`and statins, including controlled portions and excluding data after initiation of
`glycemic rescue therapy. ............................................................................... 26
`Table 5. HPS: Change from baseline in HbA1c in a random sample of T2DM subjects
`at the end of follow up in HPS........................................................................ 33
`Table 6. HPS: Number (%) of T2DM subjects on AHA at baseline and change in AHA
`at final follow up visit...................................................................................... 34
`Table 7. MK-0733-P187: Change from baseline in HbA1c in T2DM subjects at week 24
`....................................................................................................................... 34
`Table 8. Analysis of change from baseline in HbA1c by simvastatin/statin use (FAS
`unless specified) ............................................................................................ 35
`Table 9. Submission timeline of studies included in SCS............................................. 44
`Table 10. Exposure to sitagliptin and simvastatin in controlled portion of pooled studies,
`excluding data after initiation of glycemic rescue........................................... 45
`Table 11. Exposure to sitagliptin and simvastatin in controlled portion of pooled studies,
`excluding data after initiation of glycemic rescue........................................... 45
`Table 12. Exposure to sitagliptin and any statin in controlled portion of pooled studies,
`excluding data after initiation of glycemic rescue........................................... 45
`Table 13. Summary of simvastatin and any statin use in controlled portions of pooled
`studies, excluding data after initiation of glycemic rescue.............................. 46
`Table 14. Demographics of controlled portions of pooled studies, excluding data after
`initiation of glycemic rescue therapy .............................................................. 46
`Table 15. Deaths in the controlled portions of pooled studies, including data after the
`initiation of glycemic rescue ........................................................................... 49
`Table 16. Nonfatal SAEs in the simvastatin population in controlled portions of pooled
`studies, excluding data after initiation of glycemic rescue.............................. 50
`Table 17. Nonfatal SAEs in the all statins population in the controlled portions of pooled
`studies, excluding data after initiation of glycemic rescue.............................. 52
`Table 18. Subjects with adverse events which resulted in discontinuation in controlled
`portions of pooled studies, excluding data after initiation of glycemic rescue 53
`Table 19. Subjects with muscle events in controlled portions of pooled studies,
`excluding data after initiation of glycemic rescue........................................... 54
`Table 20. Summary of subjects with blood CPK increased by statin and sitagliptin use,
`excluding data after initiation of glycemic rescue........................................... 55
`Table 21. CPK values for subjects with blood CPK (mIU/ml) increased, excluding data
`after initiation of glycemic rescue................................................................... 57
`
`Reference ID: 3009841
`
`5
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`(b) (4)
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`

`

`Clinical Review
`Valerie S. W. Pratt, M.D.
`NDA 202-343
` / sitagliptin + simvastatin FDC
`
`
`Table 22. Subjects with serum ALT and/or AST elevated consecutively ≥3x ULN in
`controlled portions of pooled studies, excluding data after the initiation of
`glycemic rescue ............................................................................................. 60
`Table 23. ALT and AST values for subjects with ALT and/or AST elevations
`consistently ≥3x ULN, excluding data after initiation of glycemic rescue ....... 62
`Table 24. Postmarketing AEs for sitagliptin and concomitant statin (through March 31,
`2010).............................................................................................................. 66
`Table 25. Subjects discontinued due to renal impairment-related AEs in the simvastatin
`and all statins populations, excluding data after initiation of glycemic rescue
`(n, %) ............................................................................................................. 68
`Table 26. Postmarketing reports for sitagliptin used concomitantly with selected statins
`(through March 31, 2010) .............................................................................. 69
`Table 27. Subjects with one or more AEs in the controlled portions of pooled studies,
`excluding data after initiation of glycemic rescue........................................... 69
`Table 28. Exposure-adjusted incidence rate of subjects with one or more adverse
`events occurring with simvastatin or all statin use in controlled portions of
`pooled studies, excluding data after initiation of glycemic rescue.................. 70
`Table 29. Subjects with AEs by system organ class in the controlled portion of pooled
`studies, excluding data after initiation of glycemic rescue (Simvastatin and all
`statins analyses) ............................................................................................ 70
`Table 30. Subjects with musculoskeletal and connective tissue disorders occurring with
`simvastatin or all statins use (Incidence ≥2% in one or more treatment groups)
`in controlled portions of pooled studies, excluding data after initiation of
`glycemic rescue ............................................................................................. 73
`Table 31. Subjects with musculoskeletal and connective tissue events occurring with
`simvastatin in controlled portions of pooled studies, excluding data after
`initiation of glycemic rescue ........................................................................... 73
`Table 32. Time grid of chemistry panel for individual studies in the SCS..................... 75
`Table 33. Change from baseline in chemistry values at week 104/106 in controlled
`portions of pooled studies, excluding data after initiation of glycemic rescue
`(Simvastatin [sitagliptin n=106, non-exposed n=76] and all statins [sitagliptin
`n=252, non-exposed n=178] safety populations) ........................................... 76
`Table 34. Change from baseline in creatinine kinase at weeks 52/54 and 78/82 in
`controlled portions of pooled studies (010, 014, 021, 023, 049, 061), excluding
`data after initiation of glycemic rescue (Simvastatin and all statins safety
`populations) ................................................................................................... 76
`Table 35. Change from baseline in hematology values at week 104/106 in controlled
`portions of pooled studies, excluding data after initiation of glycemic rescue
`(Simvastatin and all statins safety populations) ............................................. 77
`Table 36. Subjects meeting PDLC in controlled portions of pooled studies, excluding
`data after initiation of glycemic rescue (Simvastatin population).................... 78
`Table 37. Change from baseline to week 104/106 in blood pressure and heart rate in
`controlled portions of pooled studies, excluding data after initiation of glycemic
`rescue ............................................................................................................ 81
`
`Reference ID: 3009841
`
`6
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`(b) (4)
`
`

`

`Clinical Review
`Valerie S. W. Pratt, M.D.
`NDA 202-343
`/ sitagliptin + simvastatin FDC
`
`
`Table 38. Adverse events by simvastatin dose (n, %, 95% CI) in controlled portions of
`pooled studies, excluding data after initiation of glycemic rescue.................. 83
`Table 39. Most common AEs by demographic group in pooled studies, excluding data
`after initiation of glycemic rescue (Simvastatin population)............................ 84
`Table 40. SOCs and AEs with greater incidence in the sitagliptin group and 95% CI
`around the between group difference excluding zero in the pooled database,
`excluding data after initiation of glycemic rescue (Simvastatin population).... 85
`Table 41. Summary of postmarketing AE reports for sitagliptin used concomitantly with
`simvastatin, atorvastatin, and rosuvastatin .................................................... 90
`
`
`
`Reference ID: 3009841
`
`7
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`(b) (4)
`
`

`

`Clinical Review
`Valerie S. W. Pratt, M.D.
`NDA 202-343
` / sitagliptin + simvastatin FDC
`
`
`
`Table of Figures
`
`Figure 1. Analysis of change from baseline in HbA1c (%) by simvastatin/statin use
`(Protocols 010 – 036)..................................................................................... 38
`Figure 2. Analysis of change from baseline in HbA1c (%) by simvastatin/statin use
`(Protocols 040 – 801)..................................................................................... 39
`
`
`
`Reference ID: 3009841
`
`8
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`(b) (4)
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`

`

`Clinical Review
`
`Valerie S. W. Pratt, M.D.
`NDA 202—343
`“""I sitagliptin + simvastatin FDC
`
`1 Recommendations/Risk Benefit Assessment
`
`1.1 Recommendation on Regulatory Action
`
`| recommend approval of sitagliptinlsimvastatin fixed dose combination (FDC) new drug
`application (NDA) 202-343 for use in patients for whom treatment with both sitagliptin
`and simvastatin is appropriate.
`
`1.2 Risk Benefit Assessment
`
`Sitagliptin, a dipeptidyl peptidase 4 (DPP—4) inhibitor, has been approved for treatment
`of type 2 diabetes mellitus (T2DM) in the United States (US) since October 2006 under
`NDA 21-995. The recommended dose is 100 mg daily for subjects with normal renal
`function, 50 mg daily for subjects with moderate renal impairment, and 25 mg daily for
`subjects with severe and end stage renal disease (ESRD).
`
`Simvastatin, a hydroxymethyl glutaryl coenzyme A (HMG-CoA) reductase inhibitor
`(statin), was approved in December 1991 and currently has five cardiovascular (CV)
`indications.
`
`As T2DM patients are at high risk for macrovascular complications and compliance with
`medications decreases as the number of required medications increases, the applicant
`proposes sitagliptin/simvastatin FDC for use in patients for whom treatment with both
`sitagliptin and simvastatin is appropriate. Prior to submitting NDA 202-343,
`teleconferences were held with the applicant regarding the proposed doses of
`sitagliptin/simvastatin FDC and which doses were required for filing. On September 30,
`2010, the following agreements were made:
`0
`
`(b) (4)
`
`0 Submission of a NDA without the 50 mg sitagliptin dose for use in subjects with
`moderate renal insufficiency is both a review and safety issue.
`
`0
`
`If not contained in the original NDA, the development of the 50 mg sitagliptin
`doses may be a post-marketing requirement (PMR).
`
`Thus, the current NDA 202-343 proposes sitagliptin/simvastatin 100/10, 100/20, and
`100I40 mg FDC tablets, as previously agreed. The applicant is now developing 50/10,
`50/20, and 50/40 mg FDC doses and plans to submit a supplemental NDA (sNDA) for
`them by November 2011.
`
`Reference ID: 3009841
`
`

`

`Clinical Review
`Valerie S. W. Pratt, M.D.
`NDA 202-343
` sitagliptin + simvastatin FDC
`
`
`The registration of sitagliptin/simvastatin FDC is based on the demonstration of
`bioequivalence (BE) between the FDC tablets and co-administration of corresponding
`doses of sitagliptin and simvastatin. Although no phase 3 clinical studies were
`conducted with the sitagliptin/simvastatin FDC or with the co-administration of sitagliptin
`and simvastatin, seven clinical pharmacology studies support registration of the FDC.
`
`There are published reports of statins altering glycemic control.1,2 However, the
`applicant demonstrated that the risks of the concomitant administration of sitaglitpin and
`simvastatin do not outweigh its benefits. We will require a postmarketing clinical study
`to conclusively demonstrate the safety of this convenience product.
`• Using subgroup analyses, the applicant demonstrated that there was no clinically
`significant difference in the change in glycemic control (HbA1c) in T2DM subjects
`randomized to simvastatin compared to placebo in the simvastatin clinical
`development program.
`o Heart Protection Study (HPS): In a random sample of T2DM subjects,
`there was no significant difference (-0.03 ± 0.13) between treatment
`groups in the change in HbA1c.
`In study MK-0733-P187, there was no significant difference between the
`simvastatin 40 mg and placebo groups in the change in HbA1c at week 24
`(95% confidence interval [CI] -0.1, 0.4).
`• The HbA1c-lowering efficacy of sitagliptin versus comparator was analyzed in 19
`pooled sitagliptin clinical trials in the following subgroups: simvastatin users,
`statin users, and non-statin users. The results were generally similar between
`the groups, although few subjects were on simvastatin or any statin in some
`studies, which resulted in wide 95% CI intervals. (See section 6.1.4 Analysis of
`Primary Endpoint(s) for full details.)
`• Review of the change from baseline HbA1c in patients who initiated
`simvastatin/statin during the treatment period in the sitagliptin clinical
`development program did not suggest a clinically significant effect on the
`initiation of simvastatin or another statin on glycemic control.
`
`o
`
`
`As no phase 3 studies were conducted with the sitagliptin/simvastatin FDC, the
`applicant analyzed the safety of the FDC using sitagliptin and simvastatin co-
`administration data from the following 19 sitagliptin studies which were included in the
`Summary of Clinical Safety (SCS):
`• Phase 1 protocol 061
`• Phase 2 protocols 010 and 014
`• Phase 3 protocols 019, 020, 021, 023, 024, 035, 036, 040, 047, 049, 051, 052,
`053, 064, 079, and 801
`
`
`