CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`202270Orig1s000
`
`
`OTHER REVIEW(S)
`
`
`
`
`

`

`PMR/PMC Development Template
`
`
`This template should be completed by the PMR/PMC Development Coordinator and included for each
`PMR/PMC in the Action Package.
`
`
`NDA #/Product Name:
`
`
`PMR/PMC Description:
`
`202270/JANUMET XR (sitagliptin/metformin hydrochloride extended-
`release)
`Deferred randomized and controlled pediatric study under Pediatric Research
`Equity Act (PREA) to evaluate the pharmacokinetics of JANUMET XR
`(sitagliptin/metformin hydrochloride extended-release) in pediatric patients
`ages 10 to 17 years (inclusive).
`
` 06/01/2012
` 12/01/2013
` 06/01/2014
`
`
`
`
`PMR/PMC Schedule Milestones: Final Protocol Submission:
`
`Study/Trial Completion:
`
`Final Report Submission:
`
`Other:
`
`
`1. During application review, explain why this issue is appropriate for a PMR/PMC instead of a
`pre-approval requirement. Check type below and describe.
` Unmet need
` Life-threatening condition
` Long-term data needed
` Only feasible to conduct post-approval
` Prior clinical experience indicates safety
` Small subpopulation affected
` Theoretical concern
` Other
`
`
`
`JANUMET XR is ready for approval for use in adults; however, the pediatric studies have not been
`completed.
`
`
`2. Describe the particular review issue and the goal of the study/clinical trial. If the study/clinical trial is
`a FDAAA PMR, describe the risk. If the FDAAA PMR is created post-approval, describe the “new
`safety information.”
`
`Deferred pediatric study required under PREA to assess the pharmacokinetics of JANUMET XR
`(sitagliptin/metformin hydrochloride extended-release) in pediatric patients ages 10 to 17 years
`(inclusive) with type 2 diabetes,
`
`
`
`PMR/PMC Development Template
`
`Last Updated 1/26/2012
`
`Page 1 of 3
`
`Reference ID: 3078032
`
`(b) (4)
`
`

`

`
`
`3. If the study/clinical trial is a PMR, check the applicable regulation.
`If not a PMR, skip to 4.
`- Which regulation?
` Accelerated Approval (subpart H/E)
` Animal Efficacy Rule
` Pediatric Research Equity Act
` FDAAA required safety study/clinical trial
`- If the PMR is a FDAAA safety study/clinical trial, does it: (check all that apply)
` Assess a known serious risk related to the use of the drug?
` Assess signals of serious risk related to the use of the drug?
` Identify an unexpected serious risk when available data indicate the potential for a serious
`risk?
`
`- If the PMR is a FDAAA safety study/clinical trial, will it be conducted as:
` Analysis of spontaneous postmarketing adverse events?
`Do not select the above study/clinical trial type if: such an analysis will not be sufficient to
`assess or identify a serious risk
`
`
`
` Analysis using pharmacovigilance system?
`Do not select the above study/clinical trial type if: the new pharmacovigilance system that the
`FDA is required to establish under section 505(k)(3) has not yet been established and is thus
`not sufficient to assess this known serious risk, or has been established but is nevertheless not
`sufficient to assess or identify a serious risk
`
` Study: all other investigations, such as investigations in humans that are not clinical trials as
`defined below (e.g., observational epidemiologic studies), animal studies, and laboratory
`experiments?
`Do not select the above study type if: a study will not be sufficient to identify or assess a
`serious risk
`
`
`
`
`
` Clinical trial: any prospective investigation in which the sponsor or investigator determines
`the method of assigning investigational product or other interventions to one or more human
`subjects?
`4. What type of study or clinical trial is required or agreed upon (describe and check type below)? If the
`study or trial will be performed in a subpopulation, list here.
`A pharmacokinetic study of JANUMET XR in pediatric patients 10 through 17 years of age
`(inclusive) with type 2 diabetes mellitus.
`
`
`Required
` Observational pharmacoepidemiologic study
` Registry studies
` Primary safety study or clinical trial
` Pharmacogenetic or pharmacogenomic study or clinical trial if required to further assess safety
` Thorough Q-T clinical trial
` Nonclinical (animal) safety study (e.g., carcinogenicity, reproductive toxicology)
`
`PMR/PMC Development Template
`
`Last Updated 1/26/2012
`
`Page 2 of 3
`
`Reference ID: 3078032
`
`

`

`Continuation of Question 4
`
`
` Nonclinical study (laboratory resistance, receptor affinity, quality study related to safety)
` Pharmacokinetic studies or clinical trials
` Drug interaction or bioavailability studies or clinical trials
` Dosing trials
` Additional data or analysis required for a previously submitted or expected study/clinical trial
`(provide explanation)
`
` Meta-analysis or pooled analysis of previous studies/clinical trials
` Immunogenicity as a marker of safety
` Other (provide explanation)
`Subpopulation: Pediatric patients ages 10 to 17 years (inclusive) with type 2 diabetes mellitus
`
`Agreed upon:
` Quality study without a safety endpoint (e.g., manufacturing, stability)
` Pharmacoepidemiologic study not related to safe drug use (e.g., natural history of disease,
`background rates of adverse events)
` Clinical trials primarily designed to further define efficacy (e.g., in another condition,
`different disease severity, or subgroup) that are NOT required under Subpart H/E
` Dose-response study or clinical trial performed for effectiveness
` Nonclinical study, not safety-related (specify)
`
` Other
`
`
`
`
`
`5. Is the PMR/PMC clear, feasible, and appropriate?
` Does the study/clinical trial meet criteria for PMRs or PMCs?
` Are the objectives clear from the description of the PMR/PMC?
` Has the applicant adequately justified the choice of schedule milestone dates?
` Has the applicant had sufficient time to review the PMRs/PMCs, ask questions, determine
`feasibility, and contribute to the development process?
`
`
`PMR/PMC Development Coordinator:
` This PMR/PMC has been reviewed for clarity and consistency, and is necessary to further refine
`the safety, efficacy, or optimal use of a drug, or to ensure consistency and reliability of drug
`quality.
`
`
`_______________________________________
`(signature line for BLAs)
`
`PMR/PMC Development Template
`
`Last Updated 1/26/2012
`
`Page 3 of 3
`
`Reference ID: 3078032
`
`

`

`PMR/PMC Development Template
`
`This template should be completed by the PMR/PMC Development Coordinator and included for each
`PMR/PMC in the Action Package.
`
`NDA #lProduct Name:
`
`202270/JANUMET XR (sitagliptin/metformin hydrochloride extended-
`release)
`
`PMR/PMC Description:
`
`PMR/PMC Schedule Milestones: Final Protocol Submission:
`
`Study/1"rial Completion:
`Final Report Submission:
`Other:
`
`06/01/2012
`
`09/01/2016
`03/01/2017
`
`1. During application review, explain why this issue is appropriate for a PMR/PMC instead of a
`pre-approval requirement. Check type below and describe.
`
`El Unmet need
`I:I Life-threatening condition
`El Long-term data needed
`[I Only feasible to conduct post-approval
`I:I Prior clinical experience indicates safety
`I:I Small subpopulation affected
`I] Theoretical concern
`IX Other
`
`JANUMET XR is ready for approval for use in adults; however, the pediatric studies have not been
`
`completed
`
`2. Describe the particular review issue and the goal of the study/clinical trial. Ifthe study/clinical trial is
`a FDAAA PMR, describe the risk. Ifthe FDAAA PMR is created post-approval, describe the “new
`safety information.”
`
`Deferred pediatric study required under PREA in pediatric patients ages 10 to 17 years (inclusive)
`with type 2 diabetes. The goal of the trial is to establish the safety and efficacy of JANUMET XR in
`
`this subpopulation.
`
`PMR/PMC Development Template
`
`Last Updated 1/26/2012
`
`Page 1 of 3
`
`Reference ID: 3078032
`
`

`

`3.
`
`If the study/clinical trial is a PMR, check the applicable regulation.
`Ifnot a PMR, skip to 4.
`
`— Which regulation?
`El Accelerated Approval (subpart HIE)
`I:I Animal Efficacy Rule
`E Pediatric Research Equity Act
`I:I FDAAA required safety study/clinical trial
`
`—
`
`—
`
`If the PMR is a FDAAA safety study/clinical trial, does it: (check all that apply)
`[I Assess a known serious risk related to the use of the drug?
`El Assess signals of serious risk related to the use of the drug?
`El Identify an unexpected serious risk when available data indicate the potential for a serious
`risk?
`
`If the PMR is a FDAAA safety study/clinical trial, will it be conducted as:
`[I Analysis of spontaneous p_ost1narketing adverse events?
`Do not select the above study/clinical trial type if such an analysis will not be sufficient to
`assess or identify a serious risk
`
`El Analysis using pharmacovigflance system?
`Do not select the above study/clinical trial type if: the new pharmacovigilance system that the
`FDA is required to establish under section 505(k)(3) has not yet been established and is thus
`not sufficient to assess this known serious risk, or has been established but is nevertheless not
`sufficient to assess or identify a serious risk
`
`I] Study: all other investigations, such as investigations in humans that are not clinical trials as
`defined below (e.g., observational epidemiologic studies), animal studies, and laboratory
`experiments?
`Do not select the above study type if: a study will not be sufficient to identify or assess a
`serious risk
`
`El Clinical trial: any prospective investigation in which the sponsor or investigator determines
`the method of assigning investigational product or other interventions to one or more human
`subjects?
`
`4. What type of study or clinical trial is required or agreed upon (describe and check type below)? If the
`study or trial will be performed in a subpopulation, list here.
`
`randomized, double-blind lacebo-controlled trial to evaluate the efficacy and safety of
`
`JANUMETXRvs.metforminm inpediatric patientswhoare
`
`inadequately controlled on diet an exercise. As part 0
`
`s stu y, you must evaluate whether
`
`.ediatric atients can safel swallow JANUMET XR over the course of the trial.
`
`Required
`
`I:I Observational pharmacoepidemiologic study
`El Registry studies
`El Primary safety study or clinical nial
`I:I Pharmacogenetic or pharmacogenomic study or clinical trial ifrequired to further assess safety
`I] Thorough Q—T clinical trial
`
`PMR/PMC Development Template
`
`Last Updated 1/26/2012
`
`Page 2 of 3
`
`Reference ID: 3078032
`
`

`

` Nonclinical (animal) safety study (e.g., carcinogenicity, reproductive toxicology)
`Continuation of Question 4
`
`
` Nonclinical study (laboratory resistance, receptor affinity, quality study related to safety)
` Pharmacokinetic studies or clinical trials
` Drug interaction or bioavailability studies or clinical trials
` Dosing trials
` Additional data or analysis required for a previously submitted or expected study/clinical trial
`(provide explanation)
`
` Meta-analysis or pooled analysis of previous studies/clinical trials
` Immunogenicity as a marker of safety
` Other (provide explanation)
`Subpopulation: Pediatric patients ages 10 to 17 years (inclusive) with type 2 diabetes mellitus
`
`Agreed upon:
` Quality study without a safety endpoint (e.g., manufacturing, stability)
` Pharmacoepidemiologic study not related to safe drug use (e.g., natural history of disease,
`background rates of adverse events)
` Clinical trials primarily designed to further define efficacy (e.g., in another condition,
`different disease severity, or subgroup) that are NOT required under Subpart H/E
` Dose-response study or clinical trial performed for effectiveness
` Nonclinical study, not safety-related (specify)
`
` Other
`
`
`
`
`
`5. Is the PMR/PMC clear, feasible, and appropriate?
` Does the study/clinical trial meet criteria for PMRs or PMCs?
` Are the objectives clear from the description of the PMR/PMC?
` Has the applicant adequately justified the choice of schedule milestone dates?
` Has the applicant had sufficient time to review the PMRs/PMCs, ask questions, determine
`feasibility, and contribute to the development process?
`
`
`PMR/PMC Development Coordinator:
` This PMR/PMC has been reviewed for clarity and consistency, and is necessary to further refine
`the safety, efficacy, or optimal use of a drug, or to ensure consistency and reliability of drug
`quality.
`
`
`_______________________________________
`(signature line for BLAs)
`
`PMR/PMC Development Template
`
`Last Updated 1/26/2012
`
`Page 3 of 3
`
`Reference ID: 3078032
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`AMY G EGAN
`01/26/2012
`
`Reference ID: 3078032
`
`

`

`
`FROM:
`
`
`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`
`MEMORANDUM
`
`
`PUBLIC HEALTH SERVICE
`
`
`
`
`
`FOOD AND DRUG ADMINISTRATION
`
`
`
`
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`
`
`
`___________________________________________________________
`
`DATE:
`July 15, 2011
`
`TO:
`Mary Parks, Director,
`Division of Metabolism and Endocrinology Products
`Office of Drug Evaluation
`Gopa Biswas, Ph.D.
`Bioequivalence Branch
`Division of Bioequivalence and GLP Compliance
`Office of Scientific Investigations
`
`THROUGH: Martin K. Yau, Ph.D.
`Acting Team Leader – Bioequivalence Branch
`Division of Bioequivalence and GLP Compliance
`Office of Scientific Investigations
`
`SUBJECT: Review of
` response dated July 11,
`2011: Addendum to EIR review covering NDA 202-
`270, JANUMET XR (Sitagliptin/ Metformin
`Hydrochloride XR) Tablets 50/ 500 mg, 50/ 1000 mg
`and 100/ 1000 mg, sponsored by Merck Sharp &
`Dohme Corp.
`
`At the request of the Division of Metabolism and
`Endocrinology
`Products
`(DMEP),
`the
`Division
`of
`Bioequivalence and GLP Compliance (DBGC) conducted
`inspections of clinical and analytical portions of the
`following bioequivalence study:
`
`Study #: 147
`
`Study Title: “An open-label, randomized, 5-period
`crossover study to demonstrate bioequivalence
`between the final market image (FMI)
`sitagliptin/ metformin XR 50 mg/ 500 mg and
`100 mg/ 1000 mg fixed-dose combination (FDC)
`tablets and co-administration of
`corresponding doses of sitagliptin and
`GLUMETZA®
` as individual tablets in healthy
`adult, human subjects”
`
`
`
`
`Reference ID: 2974564
`
`(b) (4)
`
`

`

`Page 2 — NDA 202—270 JANUMET XR (Sitagliptin/ Metformin
`Hydrochloride XR) Tablets 50/ 500 mg, 50/ 1000 mg and 100/
`1000 mg
`
`DBGC’s review submitted on July 1, 2011 evaluated the Form
`FDA—483 items issued at the analytical site, —
`—)- There were no
`significant findings after inspection of the clinical
`portion at Covance, Dallas, TX (April 11-21, 2011). An
`electronic response to the Form FDA—483 was received from
`_ on July 11, 2011 (Attachment 1). This addendum
`provides DBGC’s evaluation of— response to the
`483 items that needed to be resolved prior to accepting the
`bioanalytical study data for review.
`The evaluation is as
`follows:
`
`
`
`Reference ID: 2974564
`
`

`

`Page 3 — NDA 202—270 JANUMET XR (Sitagliptin/ Metformin
`Hydrochloride XR) Tablets 50/ 500 mg, 50/ 1000 mg and 100/
`1000 mg
`
`
`
`Conclusion:
`
`DBGC has evaluated and found that_ has provided
`adequate response to the Form FDA-483.
`DBGC recommends that
`the review division should ask the sponsor to repeat the
`bioequivalence determination using the new reintegrated data
`and re-evaluate the study outcomes.
`
`After you have reviewed this transmittal memo, please
`append it to the original NDA submission.
`
`Gopa Biswas, Ph.D.
`Bioequivalence Branch, DBGC, OSI
`
`Reference ID: 2974564
`
`

`

`Page 4 – NDA 202-270 JANUMET XR (Sitagliptin/ Metformin
`Hydrochloride XR) Tablets 50/ 500 mg, 50/ 1000 mg and 100/
`1000 mg
`
`Final Classification:
`NAI – Covance Clinical Research Unit Inc., Dallas, TX
`FEI: 3007024261
`VAI –
`
`
`FEI: Not Available
`
`
`
`cc:
`OSI/Ball
`OSI/DBGC/Salewski/Viswanathan/Dejernett
`OSI/DBGC/BB/Mada/Biswas/Yau/Haidar
`OCP/DCP2/Lee/Choe
`ODE2/DMEP/Parks/Chiang
`HFR-SW150/Fleming/Osei
`HFR-SW350/Kuchenthal
`Draft: GB 07/13/2011
`Edit: MKY 07/14/2011, 07/15/2011
`DSI: 6134; O:\Bioequiv\EIRCover\202270.mer.jan.addendum.doc
`FACTS: 1255786
`
`
`
`
`Reference ID: 2974564
`
`(b) (4)
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`GOPA BISWAS
`07/15/2011
`
`MARTIN K YAU
`07/15/2011
`
`Reference ID: 2974564
`
`

`

`FOOD AND DRUG ADMINISTRATION
`Center for Drug Evaluation and Research
`Division of Drug Marketing, Advertising, and Communications
`****Pre-decisional Agency Information****
`Memorandum
`
`
`July 14, 2011
`
`Raymond Chiang, Regulatory Project Manager, DMEP
`
`Samuel Skariah, Regulatory Review Officer, DDMAC
`
`Date:
`
`
`To:
`
`
`
`From:
`
`
`CC:
`
`
`
`
`
`
`Subject:
`
`
`
`Lisa Hubbard, Professional Group Leader, DDMAC
`Shefali Doshi, DTC Group Leader, DDMAC
`Kendra Jones, Regulatory Review Officer
`
`
`NDA 202270/S-023/S-024
`
`DDMAC labeling comments for JANUMET® XR (sitagliptin and metformin
`HCl extended-release) tablets
`
`
`
`
`
`General Comments
`
`In response to DMEP’s October 26, 2010 consult request, DDMAC has reviewed the
`proposed carton and container labels for JANUMET® XR (sitagliptin and metformin HCl
`extended-release) tablets.
`
`DDMAC’s comments on the proposed carton and container labels are based on the draft
`proposed versions of the carton and container labels submitted by Merck and Co. Inc. on
`July 1, and July 11, 2011, located in the EDR.
`
`DDMAC has reviewed the proposed carton and container labels and we have no
`comments at this time.
`
`Thank you for the opportunity to comment on these proposed materials.
`
`If you have any questions on the PI, please contact Samuel Skariah at 301. 796. 2774 or
`Sam.Skariah@fda.hhs.gov.
`
`
`
`Reference ID: 2973713
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`SAMUEL M SKARIAH
`07/14/2011
`
`Reference ID: 2973713
`
`

`

`
`
`Department of Health and Human Services
`Public Health Service
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Office of Surveillance and Epidemiology
`Office of Medication Error Prevention and Risk Management
`
`Label and Labeling Review
`
`
`July 11, 2011
`Date:
`Richard A. Abate, RPh, MS, Safety Evaluator
`Reviewer:
`Division of Medication Error Prevention and Analysis
`
`Lubna Merchant, MS, PharmD, Team Leader
`Team Leader:
`Division of Medication Error Prevention and Analysis
`
`Kellie Taylor, PharmD, MPH, Associate Director
`Associate Director:
`Division of Medication Error Prevention and Analysis
`
`Drug Name and Strengths: Janumet XR (Sitagliptin and Metformin HCl Extended-
`release) Tablets, 50 mg/500 mg, 50 mg/1000 mg, and
`100 mg/1000 mg tablets
`Application Type/Number: NDA 202270
`Applicant:
`Merck, Sharpe and Dohme
`OSE RCM #:
`2010-2299-1
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 2972133
`
`

`

`
`
`1
`INTRODUCTION
`This memo summarizes DMEPA’s evaluation of the revised proposed container labels
`and carton labeling for Janumet XR (Sitagliptin and Metformin HCL Extended-release)
`Tablets. The revisions were made based on comments provided by DMEPA in OSE
`review # 2010-2299 dated June 15, 2011 and comments from DDMAC.
`2 MATERIALS REVIEWED
`DMEPA reviewed the revisions to the proposed container labels and carton labeling
`submitted July 1, 2011 and July 11, 2011. We also evaluated our recommendations made
`in OSE review # 2010-2299 to determine whether the revisions address DMEPA’s
`concerns from a medication error perspective.
`3 CONCLUSIONS AND RECOMMENDATIONS
`DMEPA finds the revised container labels and carton labeling for Janumet XR in
`NDA 202270 acceptable. We have no additional comments at this time.
`If you have further questions or need clarification, please contact OSE project manager,
`Rita Tossa, at 301-796-4053.
`4 REFERENCES
`OSE review #2010-2299, Label and Labeling Review Janumet XR; Abate, R, June 15, 2011.
`
`
`
`
`
`Reference ID: 2972133
`
`1
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`RICHARD A ABATE
`07/11/2011
`
`LUBNA A MERCHANT
`07/11/2011
`
`KELLIE A TAYLOR
`07/13/2011
`
`Reference ID: 2972133
`
`

`

`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`M E M O R A N D U M
`PUBLIC HEALTH SERVICE
`
`FOOD AND DRUG ADMINISTRATION
`
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`____________________________________________________________________________
`
`DATE:
`
`TO:
`
`
`
`FROM:
`
`June 30, 2011
`
`Mary Parks, M.D.
`Director, Division of Metabolism and Endocrinology
`Products
`Office of Drug Evaluation
`
`Sripal R. Mada, Ph.D.
`Bioequivalence Branch
` Division of Bioequivalence and GLP Compliance
` Office of Scientific Investigations
`
`
`THROUGH: Martin K. Yau, Ph.D.
`Acting Team Leader – Bioequivalence Branch
` Division of Bioequivalence and GLP Compliance
` Office of Scientific Investigations
`
`SUBJECT: Review of EIR Covering NDA 202-270, JANUMET XR
`(Sitagliptin / Metformin Hydrochloride XR) Tablets
`50 / 500 mg, 50 / 1000 mg, 100 / 1000 mg, from Merck
`Sharp & Dohme Corp.
`
`
`
`
`At the request of the Division of Metabolism and Endocrinology
`Products (DMEP), the Division of Bioequivalence and GLP
`Compliance (DBGC) conducted inspections of clinical and
`analytical portions of the following study:
`
`Study: 147: “An open-label, randomized, 5-period crossover study
`to demonstrate bioequivalence between the final
`market image (FMI) sitagliptin / metformin XR 50 mg /
`500 mg and 100 mg / 1000 mg fixed-dose combination
`(FDC) tablets and co-administration of corresponding
`doses of sitagliptin and GLUMETZA® as individual
`tablets in healthy adult, human subjects”
`
`
`
`CLINICAL SITE INSPECTION:
`
`The inspection of clinical portion was conducted at Covance
`Clinical Research Unit Inc., Dallas, TX. Following the
`inspection (April 11-21, 2011), No Form FDA-483 was issued.
`
`
`
`
`Reference ID: 2968440
`
`

`

`JANUMET XR (Sitagliptin / Metformin HCl XR)
`Page 2 - NDA 202-270,
`Tablets 50 / 500 mg, 50 / 1000 mg, 100 / 1000 mg
`
`ANALYTICAL SITE INSPECTION:
`
`The inspection of analytical portion was conducted at —
`
`— Following the inspection a—
`- Form FDA-483 was issued (Attachment SRM1) .
`
`
`
`Our evaluation of the Form FDA-483 observations follows:
`
`Reference ID: 2968440
`
`

`

`Page 3 - NDA 202-270,
`Tablets 50
`
`JANUMET XR (Sitagliptin / Metformin HCl XR)
`
`
`
`Conclusions:
`
`Following the inspection, DBGC recommends the following:
`
`- _ should provide— data for
`MK-0431 and metformin usin
`
`(see Form FDA—483,
`
`item 2).
`
`- _ should provide— data for
`MK-0431 (see Form FDA-483,
`item 4).
`
`° ——
`
`—soo Form FDA-483.
`item 5).
`
`The clinical data and other analytical data are acceptable for
`your review.
`
`Please note that DBGC has not yet received the written response
`to the Form FDA-483 from— DBGC will update DMEP if our
`review of the response upon receipt results in a change of our
`recommendation.
`
`After you have reviewed this transmittal memo, please append it
`to the original NDA submission.
`
`Reference ID: 2968440
`
`

`

`Page 4 - NDA 202-270, JANUMET XR (Sitagliptin / Metformin HCl XR)
`Tablets 50 / 500 mg, 50 / 1000 mg, 100 / 1000 mg
`
`
`Sripal R. Mada, Ph.D.
`Bioequivalence Branch, DBGC, OSI
`
`
`Final Classification:
`
`NAI – Covance Clinical Research Unit Inc., Dallas, TX
`FEI: 3007024261
`
`VAI –
`
`
`FEI: Not Available
`
`cc:
`OSI/Ball
`OSI/DBGC/Salewski/Dejernett
`OSI/DBGC/BB/Mada/Yau/Haidar
`OCP/DCP2/Lee/Choe
`ODE2/DMEP/Parks/Chiang
`HFR-SW150/Fleming/Osei
`HFR-SW350/Kuchenthal
`Draft: SRM 06/27/2011
`Edit: MKY 06/28/2011, 06/30/2011
`DSI: 6134; O:\Bioequiv\EIRCover\202270.mer.jan.doc
`FACTS: 1255786
`
`
`
`
`
`Reference ID: 2968440
`
`(b) (4)
`
`2 Pages have been Withheld in
`Full as b4 (CCI/TS)
`immediately following this
`page
`
`

`

`FOOD AND DRUG ADMINISTRATION
`
`Center for Drug Evaluation and Research
`Division of Drug Marketing, Advertising, and Communications
`
`****Pre—decisi0nal Agency Information****
`
`Memorandum
`
`Date:
`
`June 21, 2011
`
`To:
`
`From:
`
`CC:
`
`Raymond Chiang, Regulatory Project Manager,
`Division of Metabolism and Endocrinology Products (DMEP)
`
`Samuel Skariah, Regulatory Review Officer
`Kendra Jones, Regulatory Review Officer
`Division of Drug Marketing, Advertising, and Communications (DDMAC)
`
`Lisa Hubbard, Group Leader, DDMAC
`Shefali Doshi, Group Leader, DDMAC
`Mike Wade, Project Manager, DDMAC
`
`Subject:
`
`NDA 202270 Janumet XR (sitagliptinlmetformin XR FDC)
`
`DDMAC labeling review — carton/container labeling
`
`DDMAC has reviewed the proposed carton and container labeling for Janumet XR
`(sitagliptinlmetformin XR) originally consulted to DDMAC on October 26, 2010. DDMAC has
`based its review on the carton and container labels submitted by the applicant on September 24,
`2010, available in the EDR at:
`
`\\CDSESUB1\EVSPROD\NDA202270\202270 .enx
`
`We offer the following comments:
`
`General Comment
`
`0
`
`Professional Sample Cartons (all strengths)
`
`0
`
`.
`
`one
`
`Thank you for the opportunity to comment on these proposed materials.
`
`If you have any questions please contact Samuel Skariah at 301.796.2774 or
`Sam.Skariah@fda.hhs.gov or Kendra Jones at 301.796.3917 or Kendra.Jones@fda.hhs.gov
`
`Reference ID: 2963888
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`SAMUEL M SKARIAH
`06/21/2011
`
`KENDRA Y JONES
`06/21/2011
`
`Reference ID: 2963888
`
`

`

`Department of Health and Human Services
`Public Health Service
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Office of Surveillance and Epidemiology
`Office of Medication Error Prevention and Risk Management
`
`Label and Labeling Review
`
`Date:
`
`June 15, 2011
`
`
`
`Reviewer:
`
`Team Leader:
`
`
`
`Division Director
`
`Drug Name and Strength:
`
`Richard A. Abate, RPh, MS, Safety Evaluator
`Division of Medication Error Prevention and Analysis
`Lubna Merchant, MS, PharmD, Acting Team Leader
`Division of Medication Error Prevention and Analysis
`Carol Holquist, RPh, Director
`Division of Medication Error Prevention and Analysis
`Janumet XR (Sitagliptin and Metformin HCl Extended-
`release) Tablets, 50 mg/500 mg, 50 mg/1000 mg, and
`100 mg/1000 mg
`Application Type/Number: NDA 202270
`Applicant/sponsor:
`Merck, Sharpe and Dohme
`OSE RCM #:
`2010-2299
`
`
`
`
`Reference ID: 2961280
`
`

`

`1
`
`INTRODUCTION
`
`This review summarizes the Division of Medication Error Prevention and Analysis’
`GJMEPA’S) evaluation of the proposed container labels and carton and insert labeling for
`Janumet XR (Sitagliptin and Metformin HCl Extended-release) Tablets for NDA 202270
`for areas of vulnerability that could lead to medications errors. The review responds to a
`request from the Division of Metabolism and Endocrinology Products ODMEP) to review
`the container labels and carton labeling for this Application.
`
`1.1
`
`REGULATORY HISTORY
`
`Merck, the Applicant for this NDA, has standardized the label design for the container
`labels of their oral solid dosage forms. DMEPA reviewed and provided
`recommendations for the labels of the effected products included in a bundled
`supplement in OSE review # 2010-628 dated August 13, 2010 and 2010-628-1 dated
`April 11, 2011. Additionally, Janumet (Sitagliptin and Metformin HCl) tablets (NDA
`022044) was approved March 30, 2007. Janumet is currently marketed in 50 mg/500 mg
`and 50 mg/ 1000 mg strength presentations.
`
`1.2
`
`PRODUCT INFORMATION
`
`Janumet XR (Sitagliptin and Metformin HCl Extended—release) tablets are indicated as an
`adjunct to exercise and diet to improve glycemic control in adults with type 2 diabetes
`mellitus. Janumet XR is designed to release Sitagliptin immediately with Metformin HCl
`as an extended-release formulation is the core of the tablet. Janumet XR will be
`
`marketed as 50 mg/500 mg, 50 mg/1000 mg, and 100 mg/1000 mg tablets. Janumet XR
`is dosed as two tablets (50 mg/500 mg or 50 mg/1000 mg) or one tablet (100 mg/
`1000 mg) by mouth once daily, up to a maximum daily dose of 100 mg of Sitagliptin and
`2000 mg of Metformin.
`(m4)
`In addition, professional samples are proposed in a
`presentation of cartons containing two bottles of 14 tablets of either 50 mg/500 mg tablets
`or 50 mg/1000 mg Janumet XR and cartons containing two bottles of 7 tablets of 100
`mg/1000 mg Janumet XR. The product is stored at room temperature.
`
`2
`
`METHODS AND MATERIALS REVIEWED
`
`Using Failure Mode and Effects Analysis1 and postmarketing medication error data, the
`Division of Medication Error Prevention and Analysis (DIVIEPA) evaluated the
`following:
`
`0 Container Labels submitted September 24, 2010 (Appendix A)
`
`o Carton Labeling submitted September 24, 2010 (Appendix B)
`
`0
`
`Insert Labeling submitted May 27, 2011
`
`1 Institute for Healthcare Improvement (IHI). Failure Modes and Effects Analysis. Boston. 1111:2004.
`
`Reference ID: 2961280
`
`

`

`
`
`Additionally, since Janumet is currently marketed, DMEPA searched the FDA Adverse
`Event Reporting System (AERS) database to identify medication errors involving
`Janumet. DMEPA searched the Adverse Event Reporting System (AERS) database on
`March 29, 2011 using the following search terms: trade name “Janumet%”; verbatim
`terms “Janume%” and “Sitagliptin%,” selecting only those sitagliptin terms that also
`included metformin; and the MedDRA High Level Group Term (HLGT) “Medication
`Errors,” and High Level Terms (HLT) “Product Label Issues” and “Product Quality
`Issues NEC.” No time limit was set. The ISR numbers of the cases retrieved appear in
`Appendix C.
`The reports were manually reviewed to determine if a medication error occurred.
`Duplicate reports were combined into cases. The cases that described a medication error
`were categorized by type of error. We reviewed the cases within each category to
`identify factors that contributed to the medication errors. If a root cause was associated
`with the label or labeling of the product, the case was considered pertinent to this review.
`Reports excluded from the case series include those that did not describe a medication
`error, those in which Janumet was a concomitant medication not involved in the
`medication error, the medication error related to patient compliance with using
`medication including intentional overdose, or the report involved a product complaint.
`Following exclusions we evaluated a total of 13 cases relevant to this review. The
`medication errors are classified into the following medication error types:
`• Wrong Drug (n=4): These cases involve the confusion between Janumet and
`other marketed products. The cases were discussed in the review of the
`proprietary name Janumet XR, OSE review # 2011-1111.
`• Wrong Technique (n=4): These cases involve the patient splitting the tablets in
`half and taking one half tablet twice daily. However, the reasons for cutting the
`tablets could not be determined from the details provided in the case narrative.
`The patients in these cases experienced indigestion and diarrhea which was
`reported to have improved when the tablets were administered whole.
`• Extra Dose (n=3): These cases involve the patients taking Janumet more
`frequently than twice daily. One case noted the patient had developed pancreatitis
`after taking Janumet four times a day. However, the cause could not be
`determined. The remaining two cases were foreign and resulted from the
`prescribers instruct