CENTER FOR DRUG EVALUATION AND
`
`RESEARCH
`
`APPLICA TION NUMBER:
`
`22-044
`
`CLINICAL PHARMACOLOGY AND
`
`BIOPHARMACEUTICS REVIEW(S)
`
`

`

`Oflz‘ce of Clinical Pharmacology and Biopharmaceutics
`
`
`
`OCP Division (l, H, “LIV, V)
`
`DCP ll
`
`Medical Division
`OCPB Reviewer
`
`eam Leader053a --J
`
`Xiaoxion_ Jim Wei
`Hae-Youn Ahn
`
`
`
`
`
`
`
`
`
`New Dru A : :lication Filin and Review Form
`General information About the Submission
`NDA Number
`Brand Name
`Janumet TM
`Generic Name
`
`Sitagliptin
`phosphate/Metformin
`hydrochloride fixed-dose
`combination
`Anti-diabetic
`
`T $2 Diabetes
`tablets
`
`100 m [1500-2000 ; da
`
`Dru_ Class
`Indication s
`
`Dosa_e Form
`Dosin_ Re_imen
`Route of Administration
`
`Priori Classification
`
`
`
`
`05-31-2006
`Date of Submission
`Estimated Due Date of OCPB Review March 2, 2007
`Division Due Date
`March 2, 2007
`PDUFA Due Date
`
`March 30, 200;]
`Clin. I’harm. and Bio harm. Information
`
`“X" if included
`Number of
`Number of
`Critical Comments If any
`studies
`at filing
`reviewed
`
`STUDY TYPE
`
`Table of Contents present and sufficient to
`locate re orts, tables, data, etc.
`Tabular Listin_ otAll Human Studies
`
`Labelin_
`
`Reference Bioanalytical and Analytical
`Methods
`
`L Clinical Pharmacolo_
`Mass balance:
`lsoz me characterization:
`Blood/ ulasma ratio:
`
`Plasma orotein bindin_:
`Pharmacokinetics e.., Phase
`Health Volunteers-
`
`-
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`Patients-
`
`sin _le dose:
`multi . 1e dose:
`
`sin _1e dose:
`multi ule dose:
`
`Dose ro nortionali
`
`-
`
`fastin. Inon-fastin; sin_le dose:
`fastin ; / non-fastin ; multi . le dose:
`Dru_-dru_ interaction studies -
`dru_:
`In«vivo effects on rima
`dru_:
`ln-vivo effects of urima
`ln-vitro:
`
`Sub I ulation studies -
`
`
`
`ethnici
`
`:
`
`ender:
`ediatrics:
`
`eriatrics:
`' renal imain'nent:
`
`KNDA22—044NDA22-044-Janumet-Sitagliptain-Metformin—filing.doc
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` Filabilit 'and QBR- comments
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`Primary reviewer Signature and Date
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`Secondary reviewer Signature and Date
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`This Way
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`KNDA22—044NDA22—044-Janumei-Sitagiiptain-Metformin-filing.doc
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`

`

`Briefing In Content:
`
`Merck submitted this NDA for seeking approval of fixed dose combination drug products of Sitagliptin and
`. Metformin. Sitagliptin phosphate (MK-0431) is a potent and selective dipeptidyl peptidase-4 (DPP-4)
`inhibitor developed by Merck & Co., Inc. for the treatment of type 2 diabetes mellitus, which is
`currently with the Agency for review under NDA21-995. Metformin hydrochloride is an approved anti-
`hyperglycemic agent widely used for the treatment of type 2 diabetes mellitus. TIE: sponsor has
`developed an immediate release product containing a fixed dose of sitagliptin phosphate and multiple
`dose levels of metformin hydrochloride for the treatment of patients with type 2 diabetes who are not
`adequately controlled with either agent alone or patients already being treated with the combination of
`sitagliptin and metformin. Two dose strengths of a film-coated fixed-dose Combination (FDC) tablet
`have been developed for the US. market: sitagliptin/metformin 50/500 mg/mg and 50/ 1000 mg/mg.
`
`To support this combo drug product, the sponsor submitted three new PK studies, two of which are BE studies,
`and one of which is PD study. All three studies were conducted in healthy subjects:
`
`1) Study P38 (BE with test formulations)
`
`A 2-Part, Open-Label, Randomized, 3—Period Crossover Study to Evaluate the Pharmacokinetic Profiles of MK-
`0431 and Metformin After Oral Administration of Single Doses of MK-043 l/Metforrnin Fixed~Dose
`Combination Tablet Probe Formulations or Coadministration of MK-0431 With Metforrnin as Individual
`
`' Tablets to Healthy Adult Subjects
`
`2) Study P48 (BE with commercial formulations)
`
`An Open-Label, Randomized, Two—Part, Two-Period Crossover Study to Demonstrate the Definitive
`Bioequivalence After Administration of the Final Market Image (FMI) of the MK-043l/Metformin 50/500 mg
`and 50/1000 mg Fixed-Dose Combination (FDC) Tablet and Concomitant Administration of 50-mg Doses of
`MK-043l and 500- or 1000-mg Doses of Metforrnin as Individual Tablets to Healthy Adult Subjects
`
`3) Study P50 (PD study)
`
`This is a randomized, placebo-controlled, double-blind, doublevdummy, four-period crossover study to assess
`the effects of concomitant administration of sitagliptin and metforrnin alone and in combination on post-meal
`incretin hormone concentrations in healthy adult subjects. The objectives are to determine the effect of
`concomitant administration of sitagliptin and metforrnin on post-meal plasma incretin hormone concentrations ‘(e.g.,
`active and inactive and/or total glucagon-like peptide-l [GLP-1] and gastric inhibitory peptide [GIP] concentrations,
`the ratio of active to total GLP-1 and GIP concentrations) in healthy adult subjects. This study is to assess the effects
`of sitagliptin and metforrnin on post-meal incretin hormone (active and total GLP-1 and GIP) concentrations after
`concomitant administration of sitagliptin and metformin and after administration of sitagliptin alone, metforrnin alone
`and placebo in healthy adult subjects. In each 2-day treatment period, subjects were randomized to receive either
`sitagliptin alone (active sitagliptin and placebo to metformin), metforrnin alone (placebo to sitagliptin and active
`metformin), concomitant administration of sitagliptin, and metformin or placebo (concomitant administration of
`placebo to sitagliptin and placebo to metformin) according to a computer-generated allocation schedule (see treatment
`schedule below). Each subject received all treatments and there was a minimum of a 7-day washout interval between
`the last dose of study drug in one treatment period and the first dose of study drug in subsequent treatment periods.
`
`KNDA22v044NDA22-044-Janumet-Sitagliptain-Metforminvfiling.doc
`
`3
`
`

`

`The Sponsor cited many supportive studies in NDA21-995 including drug interactiOn studies between
`sitagliptin and metformin.
`
`The sponsor has developed dissolution specification for this combo drug product: no less than ..—— dissolved in
`20 min.
`
`Appears This Way
`On Original
`
`KNDA22—044NDA22-044—Janumet-Sitagiiptain-Metformin-filing.doc
`
`4
`
`

`

`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`Xiao—xiong Wei
`7/17/2006 01:47:50 PM
`BIOPHARMACEUTICS
`
`Hae—Young Ahn
`7/17/2006 02:20:33 PM
`BIOPHARMACEUTICS
`
`

`

`.
`CLINICAL PHARMACOLOGY REVIEW
`_%
`
`NDA: 22-044
`
`Brand Name
`
`Generic Name
`
`Submission Date(s): 5/31/06
`
`Janumet
`
`Sitagliptin Phosphate and Metformifi‘ Hydrochloride
`Fixed Dose Tablets
`
`Reviewer
`
`Jaya bharathi Vaidyanathan, Ph.D.
`
`Team Leader (Acting)
`
`Jim Wei, Ph.D.
`
`OCP Division
`
`DCP-2
`
`0ND Division
`
`‘
`
`‘
`
`Division of Metabolic and Endocrine Products
`
`Sponsor
`
`Submission Type
`
`Formulation; Strength(s)
`
`Merck
`
`505 (b) (2)
`
`1000 mg
`50 mg/
`500 mg;
`50 mg/
`Sitagliptin/metformin Oral tablets administered
`
`_
`
`BID
`
`Indication
`Treatment of Type 2 Diabetes Mellitus
`
`
`Table of Contents
`
`I. Executive Summary ................................................................................................... 2
`A.
`Recommendation ................................................................................................. 2
`B.
`Phase IV Commitments....................................................................................... 2
`C.
`Summary of Clinical Pharmacology & Biopharmaceutics Findings.............. 3
`II. QBR .......................................-...........................................................................‘........... 3
`A.
`General Attributes........................................-....................................................... 3
`B.
`General Clinical Pharmacology ......................................................................... 6
`C.
`Intrinsic Factors ................................................................................................... 9
`D.
`Extrinsic Factors .................................................................................................. 9
`E.
`General Biopharmaceutics................................................................................ 10
`F.
`Analytical ............................................................................................................ 14
`III. Labeling Comments .........................’........................................................................ 15
`IV. Appendix ......................................................’............................................................. 16
`A.
`Proposed Labeling ............................................................................................. 15
`B.
`Individual Study synopsis ................................................................................. 36
`C. OCP Filing Memo ............................................................................................... 50
`
`

`

`I
`
`Executive Summary
`
`Merck has developed fixed-dose combination (FDC) tablets containing sitagliptin and
`metforrnin.
`
`The efficacy and safety of the concomitant use of sitagliptin and metforrnin has
`previously been evaluated in controlled clinical
`trials (NDA 21—995). Concomitant
`administration of the separate commercial sitagliptin and metforrnin tablets in adult
`patients with type 2 diabetes was approved by the FDA in October 16, 2006 as a part of'
`the original marketing approval of sitagliptin.
`
`Sitagliptin is approved for once-daily administration at doses of 100 mg. Metforrnin is
`available in 500, 850, and 1000 mg tablets and is approved for individualized treatment
`up to a maximum daily dose of 2550 mg in adults. Typically metformin is administered
`twice per day with meals.
`
`To aid in the approval of this application the sponsor has submitted one pivotal
`bioequivalence study (048) and one pharmacodynamic study (058). There were no
`clinical studies done with the to-be marketed combination product and the bioequivalence
`study was designed to bridge the proposed combination tablets to the clinical safety and
`efficacy database supporting the use of sitagliptin in combination with metformin-
`existing under the approved NDA.
`
`A
`
`Recommendation
`
`The Office of Clinical Pharmacology/Division of Clinical Pharamcology—Z (OCP/DCP-Z)
`has reviewed the information provided in the NDA 22-044'for Janumet tablets and finds
`it acceptable. Recommendations and labeling comments should be sent to the sponsor as
`appropriate.
`
`at
`
`Clinical Pharmacology briefing was held on 2/21/07 and the attendees were Drs. Chandra
`Sahajwalla, Suresh Doddapaneni, Ilan Irony, Jim Wei, Jayabharathi Vaidyanathan, Sally
`Choe, Leena Aljuburi and Qi Liu.
`
`B
`
`Phase 4 Commitments
`
`None.
`
`Appears This Way
`On Original
`
`

`

`C
`
`Summafl of Clinical Pharmacology Findings
`
`The summary of the results from the PK and PD studies are provided below.
`
`Bioequivalence: The results of the study demonstrated that the final market image (FMI)
`sitagliptin/metformin 50/500 and 50/1000 mg FDC tablets are bioequivalent
`to
`concomitant administration of corresponding doses of sitagliptin and metformin as
`individual
`tablets. The 90% confidence interval
`for
`the geometric mean ratios
`(FDC/concomitant administration) for the AUCinf and Cmax for both sitagliptin and
`metformin fell within the'bioequivalence limits of 80—125% for both strengths studied.
`Demonstration of bioequivalence thus bridges the safety and efficacy data from the
`clinical studies using co-administration of sitagliptin and metformin to the FDC tablets.
`
`Pharm'acodynamics: The 4 hour post-meal mean active glucagon like peptide-l (GLP-l)
`concentrations were increased significantly afier concomitant administration of sitagliptin
`and metformin compared with administration of sitagliptin alone. The ratio of active to
`total GLP—l concentrations increased after administration of sitagliptin alone. On the
`other hand, glucose dependent insulinotropic peptide (GIP) concentrations were similar
`following concomitant administration of sitagliptin and metforminversus sitagliptin
`alone.
`
`The known mechanism of action of metformin is as follows: Decreases hepatic glucose
`production, decreases intestinal absorption of glucose and improves insulin sensitivity by
`increasing peripheral glucose uptake and utilization. The results of the PD study indicates
`that metformin alone caused an increase in circulating levels of both active and total
`GLP-I to a similar extent (about 80%). Therefore, metformin may potentially increase
`the efficacy of sitagliptin due to at least partially the inhibition of GLP—1 metabolism.
`
`Drug Interaction: Co—administration of multiple twice-daily doses of sitaglitpin with
`metformin, an organic cation transporter (OCT) substrate, did not meaningfiilly alter the
`pharmacokinetics of metformin in patients with type 2 diabetes. Therefore, sitagliptin is
`not an inhibitor of OCT-mediated transport. Also co-administration of multiple doses of
`metformin with sitagliptin did not alter the pharmacokinetics of sitagliptin in type 2
`diabetic patients (From NDA 21-995).
`
`II
`
`A
`
`Question Based Review
`
`General Attributes
`
`What are the highlights of the chemistry and physico—chemical properties of
`Janumet?
`
`tablets contain 2 oral antihyperglycemic drugs used in type 2 diabetes:
`Janumet
`Sitagliptin phosphate and metformin hydrochloride.
`
`

`

`7—[(3R)-3—amino-l-oxo-4-(2,4,5—
`is described chemically as
`Sitagliptin phosphate
`trifluorophenyl)butyl]—5,6,7,8-tetrahydro-3-(trifluoromethyl)—1,2,4—triazolo[4,3-
`is
`a]pyrazine
`phosphate
`(1:1)
`monohydrate.
`The
`empirical
`formula
`C(6H15F5N50'H3PO4°H20 and the molecular weight is 523.32 and is a white to off—white,
`crystalline, non-hygroscopic powder.
`
`Metformin hydrochloride (N,N -dimethylimidodicarbonimidic diamide. hydrochloride)
`(Figure l) is not chemically Or pharmacologically related to any other classes of oral
`antihyperglycemic agents. Metformin hydrochloride is a white crystalline powder with a
`molecular formula of C4H1 1N5°HCl and a molecular weight of 165.62.
`
`Figure 1: Chemical structure of Sitagliptin (top) and metformin (bottom).
`
`- H20
`
`- H3P04
`
`CH3
`l
`
`/
`
`H3C
`
`3
`\H/ \H/
`
`NH
`
`NH
`
`NH
`
`2
`
`- HCl
`
`What is the proposed mechanism (s) of action and therapeutic indication?
`
`Janumet combines two antihyperglycemic agents with different mechanisms of action to
`improve glycemic control
`in patients with type 2 diabetes: Sitagliptin phosphate, a
`dipeptidyl peptidase-4 (DPP-4) inhibitor and metformin hydrochloride, a member of the
`biguanide class.
`I
`
`Sitagliptin is an orally active DPP-4 inhibitor and a member of a new class of drugs
`intended to treat type 2 diabetes. DPP-4 inhibitors act by enhancing the levels of active
`incretin hormones. These hormones include glucagon-like peptide-l
`(GLP-1) and
`glucose-dependent insulinotropic peptide (GIP) which are released by the intestine in
`response to meal and are part of endogenous system involved in maintaining glucose
`homeostasis.
`'
`
`Metformin hydrochloride is a biguanide antihyperglycemic agent, which improves
`glucose tolerance in patients with type 2 diabetes, lowering both basal and postprandial
`plasma glucose. Metformin decreases hepatic glucose production, decreases intestinal
`absorption of glucose and improves insulin sensitivity by increasing peripheral glucose
`uptake and utilization.
`
`

`

`_ Janumet is indicated as an adjunct to diet and exercise to improve glycemic control in
`patients with type 2 diabetes who are already treated with a combination of sitagliptin and
`metformin or whose diabetes is not adequately controlled with either agent alone.
`
`What is the proposed dose and dosage form?
`
`Janumet is available as immediate release tablets. Based on package insErt “The dosage
`of antihyperglycemic therapy with Janumet should be individualized on the basis of the
`patient’s current
`regimen, effectiveness, and tolerability while not exceeding the
`maximum recommended daily dose of 100 mg sitagliptin and 2000 mg metformin.
`
`A
`
`Janumet should generally be given twice daily with meals, with gradual dose escalation,
`to reduce the gastrointestinal (GI) side effects due to metformin.
`
`Dosing Recommendations
`
`The starting dose of Janumet should be based on the patient’s current regimen.
`Janumet should be given twice daily with meals. The following doses are available:
`50 mg sitagliptin/500 mg metformin hydrochloride
`50 mg sitagliptin/ 1000 mg metformin hydrochloride
`
`For patients inadequately controlled on metformin monotherapy
`For patients not adequately controlled on metformin alone, the usual starting dose of
`Janumet should be equal to 100 mg total daily dose (50 mg twice daily) of sitagliptin plus
`the dose of metformin already being taken.
`For patients inadequately controlled on sitagliptin monotherapy
`For patients not adequately controlled on sitagliptin alone, the usual starting dose of
`Janumet is 50mg sitagliptin/500 mg metformin hydrochloride twice daily. Patients may
`be titrated up to 50 mg sitagliptin/1000 mg metformin hydrochloride twice daily. Patients
`taking sitagliptin monotherapy dose-adjusted » for renal
`insufficiency should not be
`switched to Janumet.
`
`For patients switching from sitagliptin co-administer-ed with metformin
`For patients switching from sitagliptin co-administrated with metformin, Janumet may be
`initiated at the dose of sitagliptinand metformin already being taken.
`No studies have been performed specifically examining the safety and efficacy of
`Janumet
`in patients previously treated with other oral antihyperglycemic agents and
`switched to Janumet. Any change in‘therapy of type 2 diabetes should be undertaken with
`care and appropriate monitoring 'as changes in glycemic control can occur.”
`
`

`

`B
`
`I General Clinical Pharmacology
`
`What are the design features of the clinical pharmacology and clinical studies used
`to support dosing or claims?
`‘
`
`No clinical studies with the drug product were performed in support of this submission.
`Consistent with the requirements for a 505 (b) (2) application, the clinical pharmacology
`studies were performed to demonstrate the bioequivalence of the combined drug product
`to the commercially available reference products.
`'
`
`Two doses of the sitaglitpin/metformin fixed dose tablet (50 mg/SOO mg and 50 mg/ 1000
`mg) were evaluated in bioequivalence study. The doses selected for the fixed dose
`combination tablets were based on the sitagliptin Phase II dose—ranging studies (P010 and
`P014). Study P014 evaluated sitagliptin 100 mg per day administered as a twice—daily
`dose (50 mg bid) or a once-daily dose (100 mg qd) and results indicated that both
`provided similar tolerability and reduction in glycemic endpoints. A Phase II add—on to
`metformin study (P015) was conducted in parallel to the dose-ranging study and results
`indicate that dosing of 50 mg bid or 100 mg qd sitagliptin resulted in similar overall drug
`exposures and comparable efficacy and safety of sitagliptin when administered as 50 mg
`bid or 100 mg qd in combination with metformin.
`
`4 PK studies were included in the clinical development program for the FDC tablets (2
`BE studies, one PD study and one DDI study). A pilot BE study was conducted with
`probe formulations (P038) and data from this study was used to develop the final market
`image (FMI) sitagliptin/metformin FDC tablets. A pivotal BE study (P048) was
`conducted in order to demonstrate bioequivalence between the FMI tablets and co-
`administration of corresponding doses of sitagliptin and metformin as individual tablets
`and therefore used to bridge the clinical safety and efficacy data for co-administration of
`sitagliptin and metformin to the FDC tablets.
`
`Study P050 was conducted to explore the complementary mechanisms of action of
`sitagliptin and metformin by determining the effect of administration of sitagliptin alone
`and metformin alone or in combination on active GLP-1 and GIP levels and glucose
`concentrations.
`
`Study P012 was a drug interaction study between sitagliptin and metformin in type?
`diabetic patients (also submitted with original NDA 21-995 for Januvia).
`
`What is the pharmacodynamic effect resulting from concomitant administration of
`sitagliptin and metformin?
`
`In order to assess whether concomitant administration of metformin and sitagliptin
`resulted in enhanced post meal active GLP—l and/or GIP concentrations compared with
`administration of sitagliptin alone, metformin alone or placebo, a randomized, placebo-
`controlled, double-blind, double~dummy, 4-period crossover study was conducted in
`
`

`

`healthy adult subjects The treatments shown below were administered following a
`overnight fast and with a minimum 7-day washout period.
`
`‘ Snagllpun aiohe '
`
`_ Day2: AM (Rambo(0.1901113 53231192111
`and-1000 m metiomm '
`
`De} 2: AM (9m to 190-mgsitagliptin”
`
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`'
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`mdpkceboto‘OOm mezfgnhin)
`PM(Placebo(a 500mg malformin)
`
`.
`
`In this study PK analysis was not done. On day 2 of each treatment, blood samples were
`collected for determination of active GLP-1 and GIP concentrations, plasma glucose
`concentrations. The primary endpoint was 4h post meal total GLP-l, ratio of active to
`total GLP-l. GIP concentrations after concomitant administration of sitagliptin and
`metformin with administration of sitagliptin alone, metformin alone and placebo. DPP—4
`inhibitory activity was not assayed.
`
`The total GLP-l plasma concentrations were determined at Day 2. The geometric means
`pre—dose (fasting) and post-meal total GLP—l concentrations (pM) are shown in Figure 2.
`The 4-h post-meal average GLP-l concentrations were significantly increased after
`concomitant administration of sitagliptin and metformin compared with administration of
`sitagliptin alone; while it was similar to that of administration of metformin alone. The 4—
`h post meal average total GLP—l concentrations were significantly decreased after
`administration of sitagliptin alone as compared to placebo and increased following
`administration after metformin (Figure 2).
`
`Appears This Way-
`On Original
`
`

`

`Figure 2: Total GLP—l concentrations versus time on'Day 2 after concomitant
`administration of sitagliptin and metformin and after administration of sitagliptin
`alone, metformin alone andplacebo in healthy adult subjects.
`50
`
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`levels were significantly increased after concomitant administration of
`Active GLP-l
`sitagliptin and metformin compared with administration of metformin alone or placebo.
`The 4-h GLP-l levels were also increased with sitagliptin alone and metformin alone as
`compared to placebo (Figure 3). Administration of metformin alone increases circulating
`concentrations of both active and total GLP—l
`to similar extent suggesting the effect of
`metformin is primarily due to increase in total GLP—l concentrations. Sitagliptin therefore
`appears to stabilize the active GLP-l since it increases the active form of GLP-1.
`
`\‘K
`
`Figure 3: Active GLP-l levels after concomitant administration of sitagliptin and
`metformin versus administration of sitagliptin alone, metformin alone and placebo
`.
`.
`..
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`in healthy adult subjects.-
`.
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`

`

`The ratio of active to total GLP-l concentrations after administration of sitagliptin alone
`is
`increased by 100%. On the other hand,
`total GIP concentrations
`following
`administration of both metformin and sitagliptin were similar to that when the drugs were
`given alone. While, active GIP concentrations increased after concomitant administration
`of sitagliptin and metformin as compared to metformin alone or placebo. The ratio of 4-h
`post meal average ratio of active to total GIP concentrations after concomitant
`administration of sitagliptin and metforrnin compared with sitagliptin alone were similar.
`The ratio increased slightly with concomitant therapy when compared to metforrnin alone
`or placebo.
`
`(Note: The GLP-l level at the-2 h time point on Day 2 (Figure 2 & 3) is much higher for
`the concomitant treatment group as compared to the individual drugs and placebo. This
`could be due to the fact that GLP-l levels may already have started to rise after Day 1
`dose of the 2 drugs.) ~
`.
`t
`
`Glucose concentrations pre-meal and at 2 h post meal (4 h post-dose) were similar
`between all active treatments and placebo in this study.
`
`This study indicates that metformin can increase GLP-l levels. The results of the current
`study suggest a complimentary and potentially additive effect of the combination therapy
`with sitagliptin and metformin however the glucose-lowering effects in patients with type
`2 diabetes with concomitant administration for longer duration is unknown.
`
`C
`
`Intrinsic Factors
`
`The effects of various intrinsic factors (e.g., hepatic, renal, gender, elderly) were provided
`in the original NDA for each drug.
`
`D
`
`Extrinsic Factors
`
`Is there any drug—drug interaction between sitagliptin and metformin?
`
`No.
`
`No drug interaction study was conducted with the fixed-dose combination tablet. Drug-
`drug interaction between sitagliptin and metformin was conducted under the original
`NDA submission for Januvia. (sitagliptin) and was referred to in this NDA. The
`conclusions from that study (P012) are as follows:
`
`Co-administration of multiple twice-daily doses of sitaglitpin with metformin, an OCT .
`substrate, did not meaningfully alter the pharmacokinetics of metforrnin in patients with
`type 2 diabetes. Therefore, sitagliptin is not an inhibitor of OCT-mediated transport. Also
`
`

`

`co-administration of multiple doses of metforrnin with sitagliptin did not alter the
`pharmacokinetics of sitagliptin in type 2 diabetic patients Therefore sitagliptin and
`metformin do not have any effect on pharmacokinetics of each other (From Dr. Wei’3
`Clinical Pharmacology review of NDA 21 —,995 Januvia)
`
`E
`
`General .Biopharmaceutics
`
`What is the formulation of Janumet tablets?
`
`Two drug strengths were selected for the development, containing 50 mg of sitagliptin
`phosphate and either 500 mg or 1000 mg of metforrnin hydrochloride in an immediate-
`release oral tablet and supplied as a film coated tablet. The compositions for the two
`dosage forms are shown in Table 1.
`
`Table 1: Composition of Janumet tablets
`
`Core Tablet
`Snagiiptin Phosplmte
`(asmlodtmpmshatea_-
`Metfernn‘nflydtochiofide
`»
`'
`Mict'ccxvstalkue (3&1!me
`. _Poiymfip}urolidone.'( A )
`Sodiumfit931}!!th '
`
`_ Sodimimuyl Suifate
`
`'
`
`
` I}org-(table:
`.
`'
`‘
`f
`'
`. m
`.
`Active
`63‘2-5
`,
`..
`,
`i USP Phfiur. Acme.
`31000
`.NF. Phi Eur
`138?;Pb. Eur
`~ "NF.I’tiEar
`NF. PhiEiw
`
`
`
`-
`
`Core Tablet Weight
`Film Coating-Swami:
`
`M
`,
`
`
`l
`
`
`
`
`
`
`
`,
`.
`FflmGoatedTabiet
`'
`"'
`KVJ'4- f
`I
`a
`
`
`
`
`
`H
`
`$1.6
`
`Is the dissolution method appropriate for Janumet tablets?
`
`Please refer to Chemistry review for dissolution details.
`
`10
`
`

`

`Bioeguivalence Studv:
`
`Are the combination tablets of sitagliptin and metformin (50mg/500 mg and 50
`mg/1000 mg) bioequivalent
`to concomitant dosing of sitaglitpin 50mg and
`metformin- 500 mg or 1000 mg (50 mg + 500 mg; 50 mg + 1000 mg) commercial
`tablets in healthy subjects?
`
`Yés.
`
`two-period crossover study
`randomized,
`The BB study. (P048) was an open-label,
`conducted in two parts: Part
`I determined the bioequivalence of
`the FMI
`sitagliptin/metformin 50/500 mg FDC tablet and concomitant administration of
`corresponding doses of sitagliptin and metformin as individual
`tablets and Part II
`determined the bioequivalence of the FMI sitagliptin/metformin 50/1000 mg FDC tablet
`and concomitant administration of corresponding doses of sitagliptin and metformin (2 x
`500 mg) as individual tablets. Blood samples were collected up to 72 h post-dose for
`pharmacokinetic analysis (half-life for sitagliptin ~14 h and metformin~ 2—4 h), with 7-
`days washout between periods. Subjects (N =24; 8 males; 16 females) received all
`treatments after an overnight fast. The treatments were:
`
`Treatment C“
`
`_ -
`
`A single 504112 'dojs'éjefsi glip mend 3900.413 dose ofmetforme ..
`a SOO-mgggcneric, Ageless); as individualtablets; given
`.
`.
`,
`concomitant} .
`fl
`,
`‘
`;
`p
`:
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`A single doseoftlxe9FMI sitagliptinfmetfomfin soaooc‘mgxmg-mc -.
`tablet.
`;
`_
`-
`I,
`'
`.
`TMI-‘Final‘marketimage.
`
`7
`
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`
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`
`.
`
`.
`
`,
`
`Part I Results: (FMI sitagliptin/metformin 50/500 mg FDC tablets vs. concomitant
`administration)
`
`after
`sitagliptin and metformin plasma concentration-time profiles
`The mean
`administration of a single dose of the sitagliptin/metformin 50/500 mg FDC and
`concomitant administration of individual tablets are shown in Figure 4. As shown the
`profiles were superimposable.
`
`11
`
`

`

`Figure 4: Mean sitagliptin (top) and metformin (bottom) concentration-time profiles
`after administration of administratiOn of a single dose of the sitagliptin/metformin
`50/500 mg FDC and concomitant administration of individual tablets (50 mg + 500
`31g) ,
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`
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`Time-(hr)
`
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`Metformin’Eia'lsma‘ConcentrationingfmL)
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`V,
`The pharmacokinetic parameters for sitagliptin and metformin were also similar
`following the two treatments. The geometric mean rations (FDC tablet/concomitant
`administration) and corresponding 90% confidence interval for the AUCinf and Cmax of
`sitagliptin as well as metformin fell within the prespecified bounds of 80-125% indicating
`bioequivalence (Table 1). Additionally there were no difference observed in Tmax and
`apparent tl/2 for both components following administration of the two treatments.
`
`Appears This Way
`On Original
`
`12
`
`

`

`Table 1: Summary statistics of sitagliptin and metformin after administration of
`administration of a single dose of the sitagliptin/metformin 50/500 mg FDC and
`concomitant administration of individual tablets _(50 mg + 500 mg) (N= 24)
`
`
`
`Metformin
`
`
`
`
`Sitagliptin
`
`
`
`LS Mean LS
`Reference Mean
`Test
`
`Parameter
`
`
`
`
`
`
`
`Ratio
`(90%CI)
`
`LS Mean LS Mean Ratio (90%CI)
`Reference Test
`
`
`
`98.10 (96.48 —
`
`
`99.75)
`
`
`
`
`
`99.76(93.67—
`99.71 (93.71 —
`106.09) '
`
`106.24)
`
`
`
`7.261
`
`7.250
`
`99.85 (95.47—
`104.43)
`
`
`
`1180.178
`
`1177.330
`
`
`
`
`
`
`
`"AUCinf
`.
`
`4.085
`
`4.007
`
`414.73
`
`413.51'r
`
`Part II Results: (FMI sitagliptin/metformin 50/1000 mg FDC tablets vs. concomitant
`administration)
`
`The mean sitagliptin and metformin plasma concentration time profiles after
`administration of the two treatments are presented in Figure 5. As shown the profiles of
`both components following the two treatments are similar. The summary statistics are
`provided in Table 2. The 90% confidence interval for AUCinf and Cmax for both
`sitagliptin and metformin were within the 80-125% range. There were no differences
`observed in other PK parameters of sitagliptin and metformin between the two
`treatments.
`
`Figure 5: Mean sitagliptin (top) and metformin (bottom) concentration-time profiles
`after administration of administration of a single dose of the sitagliptin/metformin
`50/1000 mg FDC and concomitant administration of individual tablets (50 mg +
`1000 mg)
`§
`
`
`
`
`
`MK-0431PlasmaConcentrationmm aO
`
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`0
`
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`FDC tablet 50110007:
`
`.'
`
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`
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`
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`
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`
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`
`36 42 ‘48
`30
`Time(hr)‘
`
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`
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`
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`
`13
`
`

`

`
`
`
`
`
`
`MenorminPIééhaCohéentration(091001.)
`
`individual mums 50110007
`B Foo 1811;145:5011ng -.
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`n’mé.(hr)-
`
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`
`’:
`
`..
`
`Table 2: Summary statisticswof sitagliptin and metformin after administration of
`administration of a single dose of the sitagliptin/metformin 50/1000 mg FDC and
`concomitant administration of individual tablets (50 mg + 1000 mg) (N= 24)
`
`
`Parameter
`
`
`
`
`
`LS Mean LS
`Reference Mean
`Test
`
`4.053
`
`3.938
`
`423.29
`
`397.172
`
` Metformin
`Sitagliptin
`
`
`
`
`LS Mean LS Mean
`
`Ratio
`Reference Test
`
`(90%CI)
`
`
`
`
`
`
`
`11.869
`
`99.99 (93.55 —
`97.17 (95.00 —
`11.868
`
`
`
`106.87)
`99.39)
`
`
`
`
`
`1870.22
` 93.83 (87.51 —
`1848.044
`101.20
`(93.21
`
`— 109.88)
`
`100.61)
`
`
`
`
`
`Ratio (90%CI)
`
`3
`
`
`
`F
`
`Analytical
`
`Have the analytical methods been sufficiently validated?
`
`Sitagligtin .
`
`14
`
`

`

`Table: Mean accuracy and precision of sitagliptin plasma samples analysis _
`
`,
`
`V
`
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`
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