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

`

`
`
`
`
`
`
`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`PUBLIC HEALTH SERVICE
`FOOD AND DRUG ADMINISTRATION
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`
`PHARMACOLOGY/TOXICOLOGY NDA REVIEW AND EVALUATION
`
`Application Number:
`Supporting Document/s:
`Applicant’s Letter Date
`CDER Stamp Date:
`Product:
`Indication:
`Applicant:
`Review Division:
`
`Reviewer:
`Supervisor/Team Leader:
`Division Director:
`Project Manager:
`
`202270
`SDN 1
`23 Sept 2010
`23 Sept 2010
`Sitagliptin/Metformin XR FDC (MK-0431A XR)
`Type 2 Diabetes Mellitus
`Merck
`Division of Metabolism and Endocrinology Products
`(HFD-510)
`Patricia Brundage, Ph.D.
`Todd Bourcier, Ph.D.
`Mary Parks, M.D.
`Raymond Chiang
`
`
`Disclaimer
`
`Except as specifically identified, all data and information discussed below and necessary for
`approval of NDA 202270 are owned by Merck or are data for which Merck has obtained a
`written right of reference. Any information or data necessary for approval of NDA 202270 that
`Merck does not own or have a written right to reference constitutes one of the following: (1)
`published literature, or (2) a prior FDA finding of safety or effectiveness for a listed drug, as
`described in the drug’s approved labeling. Any data or information described or referenced
`below from a previously approved application that Merck does not own (or from FDA reviews or
`summaries of a previously approved application) is for descriptive purposes only and is not
`relied upon for approval of NDA 202270.
`.
`
`Reference ID: 2950282
`
`1
`
`

`

`NDA 202270
`
`
`
`
`Patricia Brundage
`
`1
`
`TABLE OF CONTENTS
`EXECUTIVE SUMMARY ......................................................................................................3
`INTRODUCTION................................................................................................................3
`1.1
`1.2
`BRIEF DISCUSSION OF NONCLINICAL FINDINGS ................................................................3
`1.3
`RECOMMENDATIONS .......................................................................................................4
`2 DRUG INFORMATION .........................................................................................................5
`
`3
`
`4
`
`5
`
`STUDIES SUBMITTED.......................................................................................................10
`
`PHARMACOLOGY.............................................................................................................10
`
`PHARMACOKINETICS/ADME/TOXICOKINETICS ...........................................................11
`
`6 GENERAL TOXICOLOGY..................................................................................................12
`
`7 GENETIC TOXICOLOGY ...................................................................................................12
`7.1
`IN VITRO REVERSE MUTATION ASSAY IN BACTERIAL CELLS (AMES)................................13
`7.2
`IN VITRO CHROMOSOMAL ABERRATION ASSAYS IN MAMMALIAN CELLS ...........................16
`8 CARCINOGENICITY ..........................................................................................................20
`
`9 REPRODUCTIVE AND DEVELOPMENTAL TOXICOLOGY.............................................21
`
`SPECIAL TOXICOLOGY STUDIES ...............................................................................22
`
`INTEGRATED SUMMARY AND SAFETY EVALUATION.............................................26
`
`REFERENCES................................................................................................................27
`
`10
`
`11
`
`12
`
`
`Reference ID: 2950282
`
`2
`
`

`

`NDA 202270
`
`Patricia Brundage
`
`1
`
`Executive Summary
`
`1 .1
`
`Introduction
`
`This is a 505(b)(2) application for the fixed dose combination (FDC) drug product of sitagliptin
`phosphate and extended release (XR) formulation of metformin hydrochloride (MK-0431A XR)
`for the treatment of patients with type 2 diabetes mellitus (T2DM). Both sitagliptin and metformin
`are approved oral antihyperglycemic agents. This 505(b)(2) application relies in part on the
`Agency’s findings of the safety and efficacy as reflected in the approved product labels for
`Janumet® (sitagliptin/metformin IR FDC; Merck; NDA 22—044) and Glumetza® (metformin XR;
`Depomed Inc; NDA 21-748). Because the sponsor is the primary NDA holder for sitagliptin, all
`nonclinical information for this component of the FDC was available for review. Chemical
`characterization of metformin did not identify differences from the referenced product that
`required additional toxicological evaluation. No nonclinical studies with the FDC of sitagliptin
`and metformin XR (MK-0431A XR) were conducted in support of this 505(b)(2) application.
`
`1.2
`
`Brief Discussion of Nonclinical Findings
`
`No nonclinical studies with the FDC drug product of sitagliptin and metformin XR
`(MK-0431A XR) were performed. The potential toxicity of sitagliptin co-administered with
`metformin was previously evaluated in 3-month toxicology studies in the dog under
`NDA 22-044.
`
`Information on the genotoxicity, carcinogenicity, and reproductive toxicity described in the
`reference listed drug labels of Janumet® (sitagliptin/metformin IR FDC) and Glumetza®
`(metformin XR) support the chronic administration of MK—0431A XR. Pregnancy Category ‘B' is
`recommended for the FDC drug product given that both sitagliptin and metformin are labeled as
`Pregnancy Category ‘B’.
`
`M" degradate of sitagliptin identified in MK—0431A XR at the
`To qualify an
`"m which exceeds the qualification threshold (ICH QBB(R2)), the sponsor
`proposed limit of
`conducted a 3-month toxicity study in rats and two in vitro genotoxicity studies (microbial
`mutagenesis assay and chromosomal aberration assay). Microbial mutagenesis and in vitro
`chromosomal aberration assays using
`«no batch of sitagliptin containing
`"m degradation products were negative
`“9‘" degradation product. A 3-month rat
`“"“’ limit for the
`supporting a
`toxicity study, in which rats were administered a 60 mg/kg (360 mg/mz) dose of sitagliptin with
`and without the two
`"N" degradation products
`M"
`(we) showed that the hydrolysis degradates had no
`toxicological effect. Given that the expected level of degrade at mo (0.19 mg/m2) associated
`with the MHRD of sitagliptin (100 mg; 62 mg/m2) is approximately 6-fold less than the level
`assessed in the 3-month toxicity study in rats, the
`“9‘" degradate is not
`expected to cause a toxicological effect in humans. Collectively, the findings of the 3—month
`toxicity study in rats and two negative in vitro genotoxicity studies (microbial mutagenesis assay
`and chromosomal aberration assay) support the
`m4) limit for
`"M degradation
`product of sitagliptin.
`
`Reference ID: 2950282
`
`

`

`NDA 202270
`
`Patricia Brundage
`
`1 .3
`
`Recommendations
`
`1.3.1
`
`Approvability
`
`Pharmacology and Toxicology recommends the approval of MK—0431A XR for the proposed
`indication in adults.
`
`1.3.2 Additional Non Clinical Recommendations
`
`No additional nonclinical studies are required.
`
`1.3.3
`
`Labeling
`
`For this 505(b)(2) application for which the sponsor did not conduct a nonclinical
`development/animal toxicology program with FDC, the language used in the label should be
`identical to the referenced drug labels of Janumet° (sitagliptin/metfonnin IR FDC) for sitagliptin
`and Glumetza® (metformin XR) for metfonnin XR. In the proposed labeling, the sections relative
`to the pharmacology/toxicology of sitagliptin and metformin are identical to the current Janumet0
`label. The sections of the proposed label discussing the phannacologyltoxicology of metformin
`were replaced with the information in the Glumetzao (metformin XR) label. Changes/additions to
`the proposed label are underlined.
`
`8.1
`
`Pregnancy
`
`Metformin h drochlon'de
`
` e ormIn was not teratogenic in rats and rabbits at doses up to 600 mg/kglday,
`
`which represent 3 and 6 times the maximum recommended human daily dose of 2000 mg
`based on body surface area comparison for rats and rabbits, respectively. However,
`because animal reproduction studies are not always predictive of human response,
`Metforrnin HCl should not be used during pregnancy unless clearly needed.
`
`13
`
`NONCLINICAL TOXICOLOGY
`
`13.1
`
`Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`Metformin hydrochloride
`
`
`
`Reference ID: 2950282
`
`

`

`NDA 202270
`
`Patricia Brundage
`
`(5) (4)
`
`Long-term carcinogeniciy studies have been performed in Sprague Dawley rats at
`doses of 1501 300I and 450 mg/kg/day in males and 150l 450l 900l and 1200 mg/kg/day in
`females. These doses are approximately 2, 4, and 8 times in males, and 3, 7, 12, and
`16 times in females of the maximum recommended human daily dose of 2000 mg based
`on bod surface area com arisons. No evidence of carcino enic' with metformin was
`
`found in either male or female rats. A carcinogenicig study was also @rformed in Tg.AC
`transgenic mice at doses up to 2000 mg applied dermally. No evidence of carcinogenicity
`was observed in male or female mice.
`Genotoxici
`assessments in the Ames test
`
`ene mutation test mouse I m homa
`
`vivo mouse
`(human lymphocfles) and in
`test
`chromosomal aberrations
`cells),
`micronucleus tests were negative. Fertilig of male or female rats was not affected by
`metformin when administered at dose up to 600 mg/kg/dayl which is approximately 3
`times the maximum recommended human daily dose based on body surface area
`comparisons.
`
`2
`
`Drug Information
`
`2.1
`
`Drug
`
`CAS Registry Number
`
`Sitagliptin Phosphate: 654671-77-9
`
`Metformin HCI: 1115-70-4
`
`Code Name
`
`Sitagliptin Phosphate: MK-0431, L-000224715
`
`Metformin HCI: MK—9378, L—000282095
`
`Chemical Name
`
`Sitagliptin Phosphate:
`-
`7-[(3R)«3-amino—1-oxo-4-(2,4,5-trifluorophenyl)butyl]-5,6,7,8- tetrahydro-[3-
`(trifluoromethy|)-1,2,4-triazolo[4,3-a]pyrazine phosphate (1:1) monohydrate
`
`Metformin HCI:
`
`- N,N-dimethylimidodicarbonimidic diamide hydrochloride
`-
`1,1-dimethylbiguanide hydrochloride
`I N,N-dimethylbiguanide hydrochloride
`- N’-dimethylguanylguanidine hydrochloride
`
`Molecular Formula/Molecular Weight
`
`Sitagliptin Phosphate: C16H15F5N5O - H304P - H20/523.32
`
`Metformin HCI: C4H11N5 - HCl/165.63
`
`Reference ID: 2950282
`
`

`

`NDA 202270
`
`Structure or Biochemical Description
`Sitagliptin Phosphate:
`
`
`
`Patricia Brundage
`
`Metformin:
`
`
`
`
`
`
`Pharmacologic Class
`Sitagliptin is dipeptidyl peptidase 4 inhibitor (DPP4 inhibitor); an antihyperglycemic
`agent.
`Metformin is an antihyperglycemic agent.
`
`2.2
`
`Relevant NDAs and DMFs
`NDA 21-995 (Januvia®, sitagliptin phosphate)
`NDA 22-044 (Janumet™; sitagliptin phosphate and metformin HCl IR)
`NDA 21-748 (Glumetza™; metformin HCl XR)
`DMF
` (Type II;
` metformin)
`Drug Formulation
`2.3
`MK-0431A XR tablets contains 64.25 mg or 128.5 mg of sitagliptin phosphate (50 mg or 100 mg
`free base equivalent) and 500 mg or 1000 mg of extended-release metformin HCl
`(metformin XR). Three tablet strengths of the FDC drug product have been developed for
`registration:
`
`
`• Sitagliptin/metformin XR 50 mg/500 mg (to be given as 2 tablets once daily)
`• Sitagliptin/metformin XR 50 mg/1000 mg (to be given as 2 tablets once daily)
`• Sitagliptin/metformin XR 100 mg/1000 mg (to be given as 1 tablet once daily)
`
`
`MK-0431A XR tablets can be separated into three main components:
`• A
` core that provides an extended release profile of
`metformin HCl
`• A sitagliptin active coating over the
`sitagliptin
`• A polymeric film coating over the active
`
`
` core designed to provide immediate release of
`
`
`
`
`
`Reference ID: 2950282
`
`6
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`NDA 202270
`
`Patricia Brundage
`
`
`
`Sitagliptin is formulated as the monohydrate phosphat
`, which was extensively
`ro ram.
`characterized durin the Januvia0 develo ment
`
`
`Metfonnin HCI will be purchased as a oompendial grade material (conforming to the USP and/or
`
`Ph. Eur.) fiomunder Type II DMF. No modifications to the chemical or
`
`e rug su stance are required for the formulation and the material is
`
`physical prope Ies o
`used as supplied.
`
`Drug Product Unit Composition (Sponsor’s Table)
`
`
`
`mg Sitagliptin Phosphate/mg
`Metfonnin H drochloride
`
`Core Tablet
`Metf
`'
`'
`
`loride
`
`USP-NF, Ph. Eur.
`USP-NF, Ph. Eur.
`USP-NF, Ph. Eur.
`USP-NF, Pb. Eur.
`W10
`USP-NF, Ph. Eur.
`Wslafline Cellulose
`USP-NF, Ph. Eur.
`Silicon Dioxide, Colloidal
`USP-NF, Ph. Eur.
`Sodium St
`lFumarate
`Core Tablet Weight —
`API Film Cong
`Sitagliptin PhosphateT
`Propyl Gallat
`
`USP-NF, Ph. Eur.
`
`
`
`Hypromellosee‘ USP-NF, Ph. Eur.
`
`Polyethylene Glycol
`
`USP-NF, Ph. Eur.
`USP-NF
`USP-NF, Ph. Eur.
`
`USP-NF, Ph. Eur.
`
`USP-NF, Ph. Eur.
`
`2.4
`
`Comments on Novel Excipients
`
`All exci
`
`ients are com endial
`
`rade with the exce tion of the
`
`
`
`
`hydroxypropyl
`formulations are mixtures of excipients
`
`ce u ose, an
`Ianlum dioxide) covered by USP-NF, Ph. Eur. an or
`. Acceptance of the
`coating mixtures will be based on the supplier’s certificates of analysis and in-house testing of
`characteristics and a suitable identification test.
`
`The
`
`
`Reference ID: 2950282
`
`

`

`NDA 202270
`
`Patricia Brundage
`
`,
`(m4)
`S - onsor 5 Table
`
`
`
`Film-Coatinv lnvredicnts
`
`
`USP-NF, P11. Eur.
`Hypromellosel
`USP-NF. P11. Eur.
`USP—NF, Ph. Eur.
`21 CFR 82.51, 21 CFR 82.102 and E132
`
`(b) (9
` Hydroxyprupyl Cellulose
`
`Titanium Dioxide
`FD&C Blue #2flndiuo Carmine Aluminum Lake
`
`,
`(5X4)
`[Sponsor 5 Table)
`Film-Coatin Inmdicnts
`Hypromellose
`0)
`Hydroxypropyl Cellulose
`Titanium Dioxide
`FD&C Blue #2llndi o Camtine Alun‘iinun‘i Lake
`
`USP—NF. Ph. Eur.
`USP-NF. Ph. Eur.
`USP-NF. Ph. Eur.
`'21 CPR 82.51. '21 CPR 82.102 and E132
`
`
`USP—NF
`
`(19(4)
`
`S . onsor’s Table
`
`Hypromellose
`Hydroxypropyl Cellulose
`Titanium Dioxide
`FD&C Blue #Zi‘lndigo Cannine Aluminum Lake
`Iron Oxide Yellow
`
`USP-NF, P11. Eur.
`USP—NF. Pl]. Eur.
`USP-NF, P11. Eur.
`21 CFR 82.51. 21 CFR 82.102, and E132
`
`“M"
`The maximum daily intake of the compendial excipient hypromellose
`"M" in the sitagliptin coating, would be up to
`“M" which is greater than the level of
`hypromellose
`am in approved drug products
`M" However, there is no
`toxicological concern regarding this excipient that would necessitate reducing the level.
`
`2.5
`
`Comments on Impurities/Degradants of Concern
`
`Impurities
`(m4) and sitagliptin-related impurities are within the
`All metformin-related impurities (DMF
`ICH Q3A identification and qualification thresholds.
`
`Sitagliptin Impurities (Sponsor’s Tabbée)
`
`Degradants
`Acceptance criteria were established for individual and total degradates in MK—0431A XR tablets
`in accordance with the ICH Q3B(R2) and are based on potential contributions from the drug
`substances, manufacture of drug product, and any increase during formal stability studies (FSS)
`or product characterization studies (PCS) of the drug product. All the release and shelf-life
`criteria are supported by release and stability data for 9 F88 batches (up to 52 weeks).
`
`am (release and shelf-life) for single unspecified metformin degradates in
`The limit of
`MK—0431A XR tablets meets the ICH Q3B(R2) reporting threshold based on the maximum daily
`clinical dose of metformin (2000 mg/day).
`
`(m4)
`The proposed release and shelf-life limit for single unspecified sitagliptin degradates is
`which meets the ICH Q3B(R2) identification threshold based on the maximum daily clinical dose
`of sitagliptin (100 mg/day).
`“"0 studies identified a sitagliptin
`("mdegradation
`
`Reference ID: 2950282
`
`

`

`NDA 202270
`
`Patricia Brundage
`
`path. The proposed shelf-life limit for the identified
`
`
`(anticipated level at the proposed the two-year prolu! eprryi; He rale of
`degradant is
`
`degradate formation is dependent on relative humidity at 25°C. NH),
`
`
`on
`in a
`degradant” exceeds the qualification limit. The lack o oxn
`toxicity
`
`0 negative in vitro genotoxicity studies (microbial muta enesis assa and
`an
`study in ra
`
`chromosomal aberration assay) using a sitagliptin batch containing
`
`egr a on
`
`
`*degradation products supports th- Iimit for th
`
`pro u
`
`.
`
`No significant increase in the level of any degradates has been observed in FSS out to
`52 weeks at the proposed storage condition of 25°C.
`
`
`
`M—cttormin Any Unspecified: Max.
`
`Acce ance Criteria
`
`Total chmdates: Max.
`
`R_elcase:
`
`AnyUnspecified. Max.
`
`Total Degradatcs: Max
`
`mcgmdatc: Max.
`Any Unspecified: Max.
`Total De radatcs: Max.
`
`chradates
`release and shelf-life
`
`Sitagliptin chradates
`
`(release and shelf-life)
`
`ATTRIBUTES
`
`|
`
`DCImdntes (351's) - Simgliptin
`
`Inspecified Degradate
`oml Degmdates
`Degradates (is) - Metformin
`ingle Unspecified Degradate
`oml D'; dates
`
`Test Methods
`
`Assay, Degradalc & Identity by
`
`HPDC
`Sec. 3.2.P.5.2.2-0431a-xrtablct
`
`Assay, chradatc & identity by
`
`HPDC
`
`Sec. 3 .2.P.5.2. l-0431a—xrtablct
`
`TIME Weeks
`
`2.6
`
`Proposed Clinical Population and Dosing Regimen
`
`The proposed dosing regimen is sitagliptin/metformin XR 50 mgl500 mg and 50 mgl1000 mg
`administered as two tablets once daily and sitagliptin/metformin XR 100 mgl1000 mg
`administered as one tablet once daily.
`
`Reference ID: 2950282
`
`

`

`
`
`Patricia Brundage
`
`NDA 202270
`
`Regulatory Background
`2.7
`Sitagliptin (25, 50, and 100 mg tablets) was approved in 2006 as an oral antihyperglycemic in
`patients with T2DM (Januvia®; NDA 21-955) with a recommended dose of 100 mg/daily. In
`2007, a FDC of sitagliptin and metformin IR (50 mg sitagliptin/500 mg metformin and 50 mg
`sitagliptin/1000 mg metformin tablets) was approved (Janumet®; NDA 22-044) for glycemic
`control in T2DM patients. Janumet® is administered twice daily with a maximum recommended
`daily dose of 100 mg sitagliptin and 2000 mg metformin.
`
`Metformin (IR formulation) was first approved in the United States in 1994 (Glucophage®;
`NDA 20-357) as an oral antihyperglycemic in patients with type 2 diabetes mellitus. The
`maximum recommended daily dose is 2550 mg in adults. Several extended release
`formulations were also approved:
`
`
`• 2000/2002: extended release tablet containing 500 mg or 750 mg metformin
`(Glucophage XR®, NDA 21-202).
`• 2004: extended release tablet containing 500 mg or 1000 mg metformin (Fortamet®,
`NDA 21-574)
`• 2005: extended release tablet containing 500 mg or 1000 mg metformin (Glumetza®;
`NDA 21-748)
`Studies Submitted
`
`3
`
`Studies Reviewed
`3.1
`This is a 505(b)(2) submission. The sponsor is referencing the Agency’s previous findings of
`safety and efficacy for the reference listed drugs of Janumet® (sitagliptin/metformin IR) and
`Glumetza ® (metformin XR; NDA 21-748) to support the nonclinical safety of MK-0431A XR
`(sitagliptin/metformin XR FDC). The sponsor conducted the following studies to qualify two
`degradates of sitagliptin:
`
`
`
`• Microbial Mutagenesis Assay (TT #09-8168)
`• Assay for Chromosomal Aberrations In Vitro, in Chinese Hamster Ovary Cells
`(TT #09-8623)
`• Three-Month Oral Toxicity Study in Rats (TT #09-1239)
`3.2
`Studies Not Reviewed
`None.
`Previous Reviews Referenced
`3.3
`Nonclinical data supporting the safety the co-administration of are reviewed under NDA 22-044
`by Dr. Todd Bourcier.
`4
`Pharmacology
`No nonclinical pharmacology studies were conducted for this 505(b)(2) submission for
`MK-0431A XR. The nonclinical pharmacology of sitagliptin and metformin (IR and XR),
`individually, were previously established. Information pertaining to sitagliptin and metformin is
`derived from the approved Janumet® (sitagliptin/metformin IR FDC) and Glumetza®
`(metformin XR) labels.
`
`
`Reference ID: 2950282
`
`10
`
`(b) (4)
`
`

`

`NDA 202270
`
`Sitagliptin
`According to the approved label for Janumet® (sitagliptin/metformin IR):
`
`
`
`
`Patricia Brundage
`
`Sitagliptin is a DPP-4 inhibitor, which is believed to exert its actions in patients with
`type 2 diabetes by slowing the inactivation of incretin hormones. Concentrations of the
`active intact hormones are increased by sitagliptin, thereby increasing and prolonging
`the action of these hormones. Incretin hormones, including glucagon-like peptide-1
`(GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), are released by the
`intestine throughout the day, and levels are increased in response to a meal. These
`hormones are rapidly inactivated by the enzyme DPP-4. The incretins are part of an
`endogenous system involved in the physiologic regulation of glucose homeostasis.
`When blood glucose concentrations are normal or elevated, GLP-1 and GIP increase
`insulin synthesis and release from pancreatic beta cells by intracellular signaling
`pathways involving cyclic AMP. GLP-1 also lowers glucagon secretion from pancreatic
`alpha cells, leading to reduced hepatic glucose production. By increasing and prolonging
`active incretin levels, sitagliptin increases insulin release and decreases glucagon levels
`in the circulation in a glucose-dependent manner. Sitagliptin demonstrates selectivity for
`DPP-4 and does not inhibit DPP-8 or DPP-9 activity in vitro at concentrations
`approximating those from therapeutic doses.
`
`
`Sitagliptin inhibits plasma DPP-4 activity in a dose- and concentration-dependent manner. In
`vitro measurement of DPP-4 inhibition indicates that near-maximal glucose lowering activity is
`associated with inhibition of plasma DPP-4 activity of approximately ≥ 80% and enhancement of
`post-glucose challenge active GLP-1 concentrations of ≥ 2-fold.
`
`Metformin
`According to the approved label for Glumetza® (metformin XR):
`
`Metformin is an antihyperglycemic agent, which improves glucose tolerance in patients
`with type 2 diabetes, lowering both basal and postprandial plasma glucose. Its
`pharmacologic mechanisms of action are different from other classes of oral
`antihyperglycemic agents. Metformin decreases hepatic glucose production, decreases
`intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral
`glucose uptake and utilization. Unlike sulfonylureas, metformin does not produce
`hypoglycemia in either patients with type 2 diabetes or normal subjects (except in
`special circumstances) and does not cause hyperinsulinemia. With metformin therapy,
`insulin secretion remains unchanged while fasting insulin levels and day-long plasma
`insulin response may actually decrease.
`
`
`Metformin has also been reported to increase GLP-1 concentrations (Drucker et al., 2006;
`Godarzi et al., 2005; Holst et al., 2008; Migoya et al., 2010).
`
` 5
`
`Pharmacokinetics/ADME/Toxicokinetics
`
`No nonclinical pharmacokinetic/ADME/toxicokinetic studies were conducted with MK-0431A XR.
`The nonclinical ADME properties and pharmacokinetics (PK) of sitagliptin and metformin XR,
`individually, were previously established. Doses of each component of the FDC are consistent
`with the doses approved for each drug separately; therefore, exposure margins achieved in the
`nonclinical toxicology program for each component are applicable to the proposed FDC product.
`
`
`Reference ID: 2950282
`
`11
`
`

`

`
`
`Patricia Brundage
`
`NDA 202270
`
`In lieu of nonclinical PK studies, the sponsor conduced clinical pharmacology studies including
`four biopharmaceutics studies (P112, P163, P164 and P147) and two PK studies (P012 and
`P165) in support of this 505(b)(2) submission for MK-0431A XR. Results of these clinical studies
`were evaluated by FDA’s clinical pharmacology review team.
`
` 6
`
`General Toxicology
`
`No nonclinical toxicology studies were conducted with MK-0431A XR.
`
`Nonclinical studies with sitagliptin were conducted in mice (3 months), rats (up to 6 months),
`dogs (up to 1 year), rhesus and cynomolgus monkeys (up to 3 months) under NDA 21-955
`(Januvia®; sitagliptin), which is held by the sponsor of the proposed FDC product. The kidney
`(renal tubule degeneration and necrosis at ≥1500 mg/kg), liver (hepatocellular hypertrophy with
`↑ liver weight at ≥500 mg/kg; hepatocellular degeneration and necrosis at 2000 mg/kg), heart
`(myocardial degeneration and necrosis at ≥1500 mg/kg), teeth (1000 mg/kg), bone marrow
`(necrosis at 2000 mg/kg), and lymph nodes (2000 mg/kg) were identified as the target organs of
`toxicity in the rat. Some consistent neurological clinical signs (reduced activity, hunched
`posture, ataxia, tremor, and sporadic emesis) were present in all the dog studies at 50 mg/kg.
`Sitagliptin did not produce vascular/skin lesions in rhesus monkeys, as seen with some DPP4
`inhibitors, when administered at doses up to 100 mg/kg (~25X MRHD of 100 mg; based on
`AUC) for 3 months.
`
`The Glumetza® (metformin XR) label does not provide information regarding the nonclinical
`target organs of toxicity of metformin.
`
` A
`
` series of studies conducted by the sponsor in support of NDA 22-044 for the
`sitagliptin/metformin IR FDC (Janumet®) evaluated the potential toxicity of sitagliptin
`co-administered with metformin IR to dogs. The combination of sitagliptin (2-50 mg/kg) and
`metformin (50 mg/kg) in dogs resulted in more numerous and earlier deaths than observed with
`metformin alone. However, the combination of sitagliptin and a lower dose of metformin
`(20 mg/kg), which better approximates human exposure, resulted in no deaths and yielded no
`evidence of exacerbated toxicity. Although it was determined that the deaths at 50 mg/kg of
`metformin were due to metformin toxicity and not to the combination, the possibility of slight
`exacerbated toxicity with clinical high exposure to metformin (≥400 μM·h [AUC]) and clinical
`exposure to sitagliptin (≥10 μM·h [AUC]) could not be ruled out.
`7
`Genetic Toxicology
`No genetic toxicology studies were conducted with MK-0431A XR. The genotoxicity of sitagliptin
`and metformin, individually, were previously established in in vitro and in vivo genotoxicity
`studies. As summarized in the Janumet® (sitagliptin/metformin IR FDC) and Glumetza®
`(metformin XR) labels, neither drug product is genotoxic.
`
`According to the approved label for Janumet® (sitagliptin/metformin IR):
`Sitagliptin was not mutagenic or clastogenic with or without metabolic activation in the
`Ames bacterial mutagenicity assay, a Chinese hamster ovary (CHO) chromosome
`aberration assay, an in vitro cytogenetics assay in CHO, an in vitro rat hepatocyte DNA
`alkaline elution assay, and an in vivo micronucleus assay.
`
`
`
`Reference ID: 2950282
`
`12
`
`

`

`NDA 202270
`
`Patricia Brundage
`
`According to the approved label for Glumetza® (metformin XR):
`
`Genotoxicity assessments in the Ames test, gene mutation test (mouse lymphoma cells),
`chromosomal aberrations test (human lymphocytes) and in vivo mouse micronucleus
`tests were negative.
`
`In support of this 505(b)(2) submission for MK-0431A XR, in vitro microbial mutagenesis and
`(”msitagliptin batch containing
`chromosomal aberration assays were conducted using a
`“"9 degradation products to qualify a
`am
`am in the drug product.
`degradation product of sitagliptin at the proposed limit 01
`
`7.1
`
`In Vitro Reverse Mutation Assay in Bacterial Cells (Ames)
`
`Microbial Mutagenesis Assay (TT #09-8168) - GLP
`
`09-8168
`Study No.:
`Study Report Location: EDR
`Conducting Laboratory and Merck Research Laboratories,
`Location: West Point, PA
`Date of Study Initiation:
`9 December 2009
`GLP Compliance: Yes
`QA Statement: Yes
`
`(5) (4)
`
`Drug, Lot #, and % Purity: MK-0431/sitagliptin (contains
`] degradates; artificially
`(m4). purity not
`degraded)
`applicable as material is artificially degraded
`
`Key Study Findings
`
`. A
`
`“9‘" batch of sitagliptin
`products was not mutagenic in the Ames test at concentrations
`
`(m4)
`
`up to 5000 ug/plate.
`
`Reference ID: 2950282
`
`1 3
`
`

`

`NDA 202270
`
`Methods
`
`
`
`Patricia Brundage
`
`Strains: TA100, TA1535, TA98, TA97a, and WP2urvrA
`pKM101
`Concentrations in Definitive Study: 100, 300, 1000, 3000, and 5000 µg/plate (with and
`without S9)
`Basis of Concentration Selection: Used doses up 5000 μg/plate (limit dose)
`Negative Control: Water, acidified with 1 mM HCl, pH ~4.0
`Positive Control: Salmonella strains and E. coli strain WP2 uvrA
`pKM101 (with and without S9): 2-aminoanthracene
`(2AA), 1 and 2 μg/plate with S9 and 2 and 5 μg/plate
`without S9
`Diagnostic mutagens (without S9): Sodium azide
`(0.75 μg/plate), 4-Nitroquinoline-N-oxide (4NQO;
`1 μg/plate); 2-Nitrofluorene (2NF; 1 μg/plate), and
`ICR-191, (1.5 μg/plate)
`S9 Mix: Liver from rats treated with phenobarbital and
`beta-naphthoflavone (MOLTOX, Inc.); 50 μL/plate,
`when appropriate
`Formulation/Vehicle: Acidified water
`Incubation & Sampling Time:
`Plates were incubated at 37oC for 48 hrs. Revertant
`colonies on the histidine or tryptophan deficient plates
`were counted and the supplemental plates examined
`for evidence of inhibition or contamination. Revertant
`colony counts on the test plates were averaged and
`compared with the appropriate control plate average.
`
`
`
`
`
`Judgment
`(cid:131) Positive: (1) a 2-fold or greater increase in number of revertant colonies, and (2) a
`dose-related increase in number of revertant colonies.
`Study Validity
`Dose selection for the plate incorporation assay was adequate based on the limit dose
`(i.e., 5000 μg/plate). All test article concentrations and concurrent negative and positive controls
`were carried out in triplicate plates. Four or more doses had no inhibition of bacterial lawn or
`revertant growth and there were at least 5 analyzable doses with and without S9. The dose
`formulations were within nominal concentrations. The negative and positive controls were within
`acceptable ranges, and the positive controls produced the expected responses.
`2-Aminoanthracene was the sole S9 positive control. The sponsor did not indicate that
`preliminary studies characterized the S9 with benzo[a]pyrene and 2-aminoanthracene were
`conducted.
`Results
`No precipitate was seen on the plates at any concentration tested. No inhibition of bacterial lawn
`or revertant growth was noted at any concentration tested. Artificially degraded MK-0431 and its
` degradation products did not produce 2-fold or greater
`increases in revertants relative to control. The positive control and diagnostic mutagens showed
`appropriate S9- and strain-dependent increases in revertants.
`
`
`Reference ID: 2950282
`
`14
`
`(b) (4)
`
`

`

`NDA 202270
`
`Microbial Mutagenesis Assay: Results with Artificially Degraded MK-0431 (Sponsor’s
`Table)
`
`Patricia Brundage
`
`
`
`
`Microbial Mutagenesis Assay: Results with Artificially Degraded MK-0431 (Sponsor’s
`Table)
`
`
`
`
`Microbial Mutagenesis Assay: Results with Positive Control Mutagens (Sponsor’s Table)
`
`
`
`
`
`
`
`Reference ID: 2950282
`
`15
`
`

`

`NDA 202270
`
`Microbial Mutagenesis Assay: Results with Positive Control Mutagens (Sponsor’s Table)
`
`Patricia Brundage
`
`
`
`
`7.2
`
`In Vitro Chromosomal Aberration Assays in Mammalian Cells
`
`Assay for Chromosomal Aberrations In Vitro, in Chinese Hamster Ovary Cells
`(TT #09-8623) - GLP
`
`
`
`Study No.:
`09-8623
`Study Report Location:
`EDR
`Conducting Laboratory and
`Merck Research Laboratories,
`Location:
`West Point, PA
`Date of Study Initiation:
`9 December 2009
`GLP Compliance:
`Yes
`QA Statement:
`Yes
`Drug, Lot #, and % Purity: MK-0431/sitagliptin (contains
`
` degradates; artificially
`degraded), L-000224715-013D00, purity not
`applicable as material is artificially degraded
`
`Key Study Findings
`(cid:131) A
`batch of sitagliptin with
`degradation products did not induce chromosomal aberrations in the absence or
`presence of S9 in CHO cells.
` degradation
`In the cultures treated for 20 hours without S9, sitagliptin and its
`products caused an increase in polyploidy metaphases at 0.9 and 1 mg/mL (12-14%),
`which exceeded the historical control range for polyploidy (0-7%).
`
`(cid:131)
`
`
`
`Reviewer’s Comments
`The increase in polyploidy prompted the sponsor to re-evaluate the 20-hour treatment of the
`original chromosomal aberration assay conducted with an
` batch of sitagliptin in 2002
`as there was no report of endoreduplication or polyploidy in the 20-hour cultures in the original
`in vitro chromosomal aberration assay report (NDA 21-995); the results of the re-evaluation
`were submitted under IND 103183 (SDN23). The re-evaluation of the 20-hour treatment cultures
`showed an increase in polyploidy metaphases (10%) at the highest sitagliptin concentration
`
`Reference ID: 2950282
`
`16
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`NDA 202270
`
`Patricia Brundage
`
`evaluated (1 mg/mL), which exceeded historical control data. Given that an increase in
`polyploidy metaphases was observed with the
`(”"9 batches, the increase
`was considered to be attributable to sitagliptin, not the
`"'"" degradates.
`
`Based on the absence of mutagenesis and clastogenesis, the increase in polyploidy associated
`with sitagliptin is not due to a direct interaction with DNA but to an unidentified indirect
`mechanism. There is no particular cause for concern regarding the in vivo genotoxicity of the
`drug given the negative mouse bone marrow micronucleus study using up to