CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`202270Orig1s000
`
`SUMMARY REVIEW
`
`
`
`
`

`

`Cross Discipline Team Leader Review
`
`Cross-Discipline Team Leader Review
`
`
`Date
`January 27, 2012
`From
`H lton V. Joffe, M.D., M.M.Sc.
`m_ Cross-Disci line Team Leader Review
`NDA/BLA #
`NDA 202270
`
`Su u vlement#
`
`Date of Submission
`
`PDUFA Goal Date
`
`Au lst 3, 2011
`
`Feb
`
`.
`
`3, 2012
`
`
`
`Proprietary Name /
`Established
`S 1
`
`names
`
`Janumet XR (sitagliptin/metfonnin extended-release fixed-
`dose combination tablet
`
`Dosa _e forms / Stren_ 11
`
`50/500 111 , 50/ 1000 m , 100/1000 m- tablets
`
`Proposed Indication(s)
`
`Recommended:
`
`As an adjunct to diet and exercise to improve glycemic
`control in adults with type 2 diabetes mellitus when
`treatment with both sitagliptin and metfonnin extended-
`release is appropriate
`A roval,1'endin a eement on lube/in
`
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`Cross Discipline Team Leader Review
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`
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`Cross Discipline Team Leader Review Template
`1. Introduction
`
`
`Janumet XR is a fixed-dose combination (FDC) tablet that contains two anti-diabetic
`medications: sitagliptin and an extended-release formulation of metformin. This is a 505(b)(1)
`application because Merck is the sponsor for sitagliptin (Januvia), a dipeptidyl-peptidase 4
`inhibitor approved by FDA in 2006, and has a full right of reference to Glumetza, an extended-
`release metformin approved by FDA in 2005.
`
`Janumet XR is dosed once daily and will be available in the following strengths (shown as
`sitagliptin/metformin extended-release): 50 mg/500 mg, 50 mg/1000 mg, and 100 mg/1000
`mg.
`2. Background
`
`
`This is the second review cycle for Janumet XR. We issued a Complete Response letter on
`July 22, 2011. Our letter noted FDA Form 483 deficiencies identified during the pre-approval
`inspection of the Puerto Rico manufacturing facility that needed to be satisfactorily resolved
`before the application could be approved. In addition, we requested an updated study report for
`the pivotal bioequivalence study (see Section 5 for more details).
`
`Please see reviews from the first cycle for further details, including Dr. Ilan Irony’s Cross-
`Discipline Team Leader memorandum.
`3. CMC
`
`
`The Office of Compliance issued an overall “acceptable” recommendation on January 25,
`2012, for the manufacturing facilities for Janumet XR. Therefore, the FDA Form 483
`deficiencies identified in our Complete Response letter have been adequately addressed.
`Chemistry/Manufacturing/Controls (CMC) recommends approval.
`4. Nonclinical Pharmacology/Toxicology
`
`
`This resubmission does not contain new nonclinical pharmacology/toxicology data.
`
`
`5. Clinical Pharmacology/Biopharmaceutics
`
`
`The pivotal bioequivalence Study (147) was reviewed during the first cycle and showed
`bioequivalence between Janumet XR and the co-administered individual components
`(sitagliptin and Glumetza). However,
` the site that analyzed the blood samples for
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`Cross Discipline Team Leader Review
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`this study, had to rerun some of its analyses in response to concerns raised by the Office of
`Scientific Investigation. These new analyses changed some of the underlying data. Therefore,
`OSI requested confirmation that the FDC and individual components are still bioequivalent
`when these updated data are used in the pharmacokinetic analyses. This deficiency was
`included in the Complete Response letter and has now been adequately addressed, as shown
`below.
`
`Study 147 compared the administration of Janumet XR to the co-administration of sitagliptin
`and Glumetza. This study also compared the administration of two 50/500 mg FDC tablets to
`the administration of one 100/1000 mg FDC tablet. Using the updated
` data, the
`90% confidence intervals for the geometric mean ratios all still fall within the bioequivalence
`criteria of 80%-125%, as shown in Table 1. Therefore, the updated
` data do not
`change the prior conclusion regarding bioequivalence between Janumet XR and the co-
`administered components. Please see the review by Dr. Jee Eun Lee for additional details.
`
`
`Table 1. Pharmacokinetic analyses - geometric means with 90% confidence intervals
`Revised analyses using updated data
`(adapted from Tables 1 and 2 in Dr. Lee’s review)
`FDC 50/500 mg vs.
`FDC 100/1000 mg vs.
`Two FDC 50/500 mg vs.
`Co-administration
`Co-administration
`FDC 100/1000 mg
`
`Parameter
`
`1.00 (0.99, 1.02)
`1.01 (0.99, 1.02)
`0.96 (0.92, 1.01)
`
`Sitagliptin
`AUC0-inf
`AUC0-last
`Cmax
`Metformin
`1.07 (1.01, 1.13)
`AUC0-inf
`1.05 (1.00, 1.09)
`AUC0-last
`1.08 (1.03, 1.14)
`Cmax
`FDC=fixed dose combination
`
`
`
`1.01 (0.99, 1.03)
`1.01 (0.99, 1.02)
`1.00 (0.96, 1.05)
`
`0.96 (0.91, 1.01)
`0.97 (0.93, 1.02)
`1.14 (1.09, 1.19)
`
`1.00 (0.98, 1.02)
`1.00 (0.98, 1.02)
`0.96 (0.92, 1.00)
`
`1.03 (0.97, 1.08)
`1.01 (0.97, 1.06)
`1.01 (0.97, 1.06)
`
`6. Clinical Microbiology
`
`
`This resubmission does not contain new clinical microbiology data.
`
`
`7. Clinical/Statistical- Efficacy
`
`
`This resubmission does not contain new clinical data.
`8. Safety
`
`
`This resubmission does not contain new clinical data.
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`9. Advisory Committee Meeting
`
`
`This submission did not identify new efficacy or safety issues that rose to the level of needing
`input from an advisory panel. Therefore, this submission was not taken to advisory committee.
`
`
`Pediatrics
`10.
`
`
`This submission triggers new pediatric studies under the Pediatric Research and Equity Act
`(PREA). The pediatric plan had been addressed during the first review cycle. During the
`current review cycle, Merck provided updated timelines for the two pediatric studies, which
`are shown below. These timelines are acceptable.
`
`
`PMR 1802-1: A pharmacokinetic study of JANUMET XR in pediatric patients 10
`through 17 years of age (inclusive) with type 2 diabetes mellitus.
`
`Final Protocol Submission:
`Trial Completion:
`
`Final Report Submission:
`
`
`
`
`
`by June 1, 2012
`by December 1, 2013
`by June 1, 2014
`
`
`
`
`
`PMR 1802-2: A 54-week, randomized, double-blind placebo-controlled trial to evaluate
`the efficacy and safety of JANUMET XR vs. metformin in pediatric patients who are
`inadequately controlled on diet and exercise. You must also evaluate whether pediatric
`patients can safely swallow JANUMET XR over the course of the trial.
`
`Final Protocol Submission: by June 1, 2012
`Trial Completion:
`
`by September 1, 2016
`Final Report Submission:
`by March 1, 2017
`
`11.
`
`Other Relevant Regulatory Issues
`
`
`Tradename re-review: The Division of Medication Error Prevention and Analysis (DMEPA)
`completed its re-review of the Janumet XR tradename on November 2, 2011, and concluded
`that this tradename is acceptable. Please see the review by Richard Abate for details. DMEPA
`confirmed via an email, dated January 6, 2012, that another review of the tradename is not
`needed provided we approve this application by the action goal date of February 3, 2012.
`
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`Cross Discipline To- Leader Review
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`12.
`
`Labeflng
`
`Most of the language in the label and Medication Guide had been finalized during the first
`review cycle. During this review cycle, we have requested the following additional revisions to
`the label:
`
`
`
`Minor formatting issues
`
`1 3.
`
`Recommendations/Risk Benefit Assessment
`
`0 Recommended Regulatory Action
`
`APPROVAL, pending agreement on labeling.
`
`0 Risk Benefit Assessment
`
`There are no new considerations regarding the risk-benefit assessment.
`
`0 Recommendation for Postmarketing Risk Evaluation and Management Strategies
`
`There are no new safety findings from the submitted data that prompt the need for Risk
`Evaluation and Mitigation Strategies.
`
`0 Recommendation for other Postmarketing Requirements and Commitments
`
`There are no new safety findings from the submitted data fllat prompt the need for new
`postmarketing required trials. Two pediatric studies will be required under PREA (see Section
`1 0).
`
`0 Recommended Comments to Applicant
`
`None.
`
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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/
`----------------------------------------------------
`
`HYLTON V JOFFE
`01/27/2012
`
`MARY H PARKS
`01/27/2012
`
`Reference ID: 3078256
`
`