Clinical Review
`Ilan Irony, MD.
`NDA 22044, Submission 000
`Janumet TM (Sitagliptin / metformin fixed-dose combination)
`Study P036
`
`In general, trends toward shorter QTc intervals were observed for subjects in the active treatment
`groups compared with those in the placebo group, with no clinically meaningful differences in
`QTc intervals between the treatment groups for subjects in either the Randomized Cohort or the
`OLC. In three subjects (all continuing in the study), QTc intervals >500 msecgvere observed
`following randomization (Table 55). One subject (in the sitagliptin monotherapy group) had a
`QTc interval of 5 19 msec on Day 106, compared with 497 msec at baseline. This subject had
`pre-randomization ECG abnormalities, including left bundle branch block (reported as an AB)
`and left atrial enlargement. Another subject (in the sitagliptin 50/metformin 1000 mg bid
`coadministration group) had a QTc interval of507 msec at Week 24, compared with 417 msec at
`baseline. This subject had a pre—randomization ECG abnormality of right bundle branch block
`and a medical history of hypertension. The third subject (also in the sitagliptin 50/metf0rmin
`1000 mg bid, coadministration group) had a QTc interval of 501 msec at Week 24 compared with
`440 msec at baseline. This subject had a medical history of arrhythmia and non-Specific ST-T
`changes. The subject’s repeat QTc interval on Day 174 was 455 msec while the patient continued
`taking study drug.
`‘
`
`Appears This Way
`On Original
`
`81
`
`

`

`Sita 100 m_ d
`Met 500 mg bid
`Met 1000 mg bid
`Sita 50 mg bid + Met 500 mg bid
`Sita 50 in bid + Met 1000 m_ bid
`Placebo
`.
`Sita 50 mg bid + Met 1000 mg bid OLC
`Sita 100 mg qd
`Met 500 mg bid
`Met 1000 mg bid
`Sita 50 mg bid + Met 500 mg bid
`Sim 50 mg bid + Met 1000 mg bid
`.
`Placebo
`Sita 50 mg bid + Met 1000 mg bid OLC
`Sim 100 m, -d
`Met 500 mg bid
`Met 1000 mg bid
`.
`.
`.
`Sita 50 mg bid + Met 500 mg bid
`Sim 50 mg bid + Met 1000 mg bid
`Placebo
`
`Clinical Review
`
`llan Irony, M.D.
`NDA 22044, Submission 000
`Janumet TM (Sitagliptin / metformin fixed-dose combination)
`Table 55. Subjects exceeding pre—deflned limits of change in QTc from baseline in Study P036
`.
`.
`Predefined le'ts 0f
`Change
`
`Treatment
`
`n/N (%)
`
`ECG parameter
`
`%.Difference
`
`with Placebo %
`
`95% C1
`
`
`
`
`
`.
`
`1,150 0.7)
`0/159 (00) .1.
`0/152 (0.0)
`0/168 (0.0) a
`2/162 1.2
`0/137 0.0
`0/ 99 (0.0)
`101145 (6.9)
`7/158 (4.4)
`13/147 (8.8)
`11/164 (6.7)
`10/155 (6.5)
`16/131 (12.2)
`8/ 99 (8.1)
`5/145 3.4)
`1/158 (0.6)
`2/147 (1.4)
`5/164 (3.0)
`5/155 (3.2)
`5/131 (3.8)
`3/ 99 (3.0)
`mm (0.0)
`Sita [00 mg Id
`' 0/153 (00)
`Met 500 mg bid
`0/147 (0.0)
`Met 1000 mg bid
`1/164 (0.6)
`Sita 50 mg bid + Met 500 mg bid
`2/155 (1.3)
`Sita 50 mg bid + Met 1000 mg bid
`Placebo __
`Sita 50 mg bid + Met 1000 mg bid OLC__
`mm
`. One value with an __-m_
`
`
`(.30 .....
`m... .0. ——.E-
`
`males and femaleS.
`
`resrvcctively) __.-—
`
`
`—_—
`
`Adapted from the applicant’s Table 1485, reference p036v1
`
`.— N
`
`5.3 (—12.7, 1.7)
`-711 (.149, .1.4)
`-3.4(—11.o, 3.9')
`—5.5 (-12.8, 1.2)
`-5.8(-13.1, 1.0)
`
`—3.2 (41.0, 0.4)
`-25 (—7.4, 1.6)
`-0.8 (—S.9, 37)
`-0.6 (—5.7, 4.1)
`
`'
`
`.
`
`
`2 30 msec
` -04 (-5.6, 4.5
`
`One value > 500 msec
`
`One value with increase
`
`One value with an
`increase 2 30 msec and
`
`> enders ecific ULN
`
`(£0 and 4p50 msec for
`
`
`males and females,
`reSPectively)
`
`
`QTc
`
`(milliseconds)
`
`
`
`
`
`
`
`
`One value with an
`increase 2 60 msec
`
`
`
` Sita 50 mg bid + Met 1000 mg bid OLC
`
`
`
`
`7. 1.9. 3.3 Marked outliers and dropoutsfor ECG abnormalities
`
`There were no marked outliers or dropouts in either Study P024 or P036 due to ECG
`abnormalities.
`
`g 7.1.9.4 Additional analyses and explorations
`
`7.1.10 Immunogenicity
`
`Sitagliptin, being a small molecule, is unlikely to generate an immune response. On the other
`hand, sitagliptin exerts its metabolic effect by inhibition of DPP4, which is identical to CD26, a
`
`82
`
`

`

`Clinical Review
`
`-
`Ilan Irony, M.D.
`NDA 22044, Submission 000
`
`Janumet TM (Sitagliptin / metformin fixed-dose combination)
`T lymphocyte surface glycoprotein. This fact prompted the applicant to be particularly vigilant to
`effects of sitagliptin on infections or otherimmune disorders1n the clinical studies No increased
`risk of infections or immune disorders has been observed
`
`7.1.1 1 Human Carcinogenicity
`
`The review of the sitagliptin clinical studies did not reveal an increase risk of neoplasia.
`Please see Dr. Bourcier’s toxicology review for a complete discussion of the applicant’s
`carcinogenicity program. Sitagliptin was found to increase risk of hepatic neoplasia in rat
`toxicity studies, when exposed to a dose of 500 mg/kg/day, corresponding to 250 times the
`human dose and a 58-fold greater exposure than that achieved with the maximum recommended
`human dose. This dose was associated with hepatotoxicityin those animal studies. In addition,
`no evidence of genotoxicity or mutagenicity with sitagliptin was found and no trend to cause
`tumors was evident in mice studies with the MTD of 500 mg/kg/day f0r~2 years.
`From metformin labeling: “Long-tenn carcinogenicity studies have been performed in rats
`(dosing duration of 104 weeks) and mice (dosing duration of 91 weeks) at doses up to and
`including 900 mg/kg/day and 1500 mg/kg/day, respectively. These doses are both approximately
`four times the maximum recommended human daily dose of 2000 mg based on body surface
`area comparisons. No evidence of carcinogenicity with metformin was found in either. male or
`female mice. Similarly, there was no tumorigenic potential observed with metformin in male
`rats. There was, however, an increased incidence of benign stromal uterine polyps in female rats
`treated with 900 mg/kg/day.”
`
`7.1.12 Special Safety Studies
`
`As discussed in Section 7.1.9.2 in this review document, the applicant has conducted a clinical
`study to assess effects of sitagliptin on the QTc interval in healthy vol'unteersxThat study did not
`demonstrate prolongation of the QTc interval that would merit concerns for arrhythmias or
`Torsades.
`‘
`Sitagliptin is the first representative of a new class of antidiabetic medications, first approved for
`marketing in the US only recently (October 16, 2006). Therefore, most of the experience with
`sitagliptin that has been reviewed comes from clinical studies reported in the present application,
`as well as those reported under 'NDA 21995. No special safety studies have been performed.
`
`7.1.13 Withdrawal Phenomena and/or Abuse Potential
`
`Based on the 2-week post study telephone contact and based on the direct follow up of subjects
`who had sitagliptin discontinued or held during the clinical studies, there is no indication of
`withdrawal or rebound symptoms.
`The potential for abuse was not investigated1n the sitagliptin development. No effect on the
`Central Nervous System was detected to suggest an abuse potential. Unlike Exenatide, whichIS a
`GLPl analog that was Shown to cause weight loss, sitagliptin has not demonstrated capacity to
`decrease weight, and therefore use (or abuse) for weight loss is not anticipated. There were no
`CNS ABS to suggest impairment of mental ability or ability to drive or operate machinery.
`
`83
`
`

`

`Clinical Review
`
`Ilan Irony, MD.
`NDA 22044, Submission 000
`Janumet TM (Sitagliptin / metformin fixed-dose combination)
`‘ 7.1.14 Human Reproduction and Pregnancy Data
`
`,
`Sitagliptin
`The sitagliptin development did not provide evidence of effects on reproduction and pregnancy.
`Preclinical development and reproductive toxicity studies indicate that sitagliptin does not affect
`fertility in female or male rats at the limit dose of 1000 mg/kg/day but does slightly increase the
`incidence of rib abnormalities at this dose with a NOEL for developmental toxicity in rats of 250
`mg/kg/day. There was no effect on fetal development in rabbits at 125 mg/kg/day. Sitagliptin is
`classified as a Pregnancy Category B drug.
`Sitagliptin is secreted in the milk of lactating rats. It is not known whether sitagliptin is secreted
`in human milk. Therefore it should not be used by a woman who is nursing. Please see Dr.
`Bourcier’s review for a complete discussion on the effects of sitagliptin on reproduction in
`1.
`animal studies.
`
`Metformin
`
`Metforrnin is a Pregnancy Category B drug. There are no adequate and well-controlled studies in
`pregnant women with metformin. Metformin was not teratogenic in rats and rabbits at doses up
`to 600 mg/kg/day. This represents an exposure of about two and six times the maximum
`recommended human daily dose of 2000 mg based on body surface area comparisons for rats
`and rabbits, respectively. Determination of fetal concentrations demonstrated a partial placental
`barrier to metformin.
`.
`
`Studies in lactating rats show that metformin is excreted into milk and reaches levels comparable
`to those in plasma. Similar studies have not been conducted in nursing mothers.
`
`7.1.15 Assessment of Effect on Growth
`
`The youngest subjects enrolled in the Phase 3 studies were 18 years old, and therefore no effect
`of sitagliptin on linear growth can be inferred from these studies.
`Diprotin A, another DPP4 inhibitor, was shown to inhibit the degradation of human growth
`hormone releasing hormone GRH (1-44)-NH2 to GRH (344)-NH2 in in-vitro experiments. 2
`Metforrnin has been used widely in adolescents with T2DM and with insulin resistance
`associated with polycystic ovaries, and has not been shown to have direct effects on linear
`growth.
`
`7.1.16 Overdose Experience
`
`No overdose in excess of 400 mg occurred during the Phase 2 or Phase 3 studies with sitagliptin
`under NDA 21995. In Phase 1 studies, single doses of 800 mg or 10-day dosing with 600 mg
`daily of sitagliptin have been well tolerated in healthy volunteers. There has been more _
`substantive experience with a dose of9200 mg daily, in healthy obese middle age volunteers
`during Phase 1 studies as well as in diabetics during Phase 3 studies, without dose-dependent
`events related to safety or tolerability.
`
`2 Frohman LA, Downs TR et al. Dipeptidylpeptidase IV and trypsin—like enzymatic degradation of human growth
`hormone-releasing hormone in plasma. J Clin Invest. 1989 May; 83(5): 1533—1540
`
`84
`
`

`

`Clinical Review
`
`
`
`Ilan Irony, MD.
`NDA 22044, Submis'sion 000
`Janumet TM (Sitagliptin / metformin fixed-dose combination)
`Sitagliptin has a wide therapeutic margin; thus, the potential for toxicity as a result of Overdose is
`limited. Since single doses up to 800 mg have been well-tolerated in Phase 1 studies, hence
`accidental exposure to doses of up to 800 mg are unlikely to result in clinical sequelae. There is
`no clinical experience with doses above 800 mg.
`'
`In the event of an overdose, the applicant proposes to employ usual supportiVe measures,
`e.g., remove unabsorbed material from the gastrointestinal tract, employ clinical monitoring
`(including obtaining an electrocardiogram), and institute supportive therapy ifTequired.
`Sitagliptin is modestly dialyzable. In clinical studies, approximately 13.5% of the dose was
`removed over a 3 to 4 hour hemodialysis session. Prolonged hemodialysis may be considered if
`clinically appropriate. It is not known if sitagliptin is dialyzable by peritoneal, dialysis.
`
`7. 1. 17 Postmarketing Experience
`
`There has been little postmarketing experience with the use of sitagliptin reported and reviewed.
`No safety signals from the postmarketing experience are apparent that have not been detected in
`the original sitagliptin development controlled studies.
`
`7.2 Adequacy of Patient Exposure and Safety Assessments
`
`7.2.1 Description of Primary Clinical Data Sources (Populations Exposed and
`Extent of Exposure) Used to Evaluate Safety
`
`A total of 2930 subjects have participated in the Phase 2 and Phase 3 studies in which sitagliptin
`100 mg daily (either as 100 mg qd or 50 mg bid) and metformin (2 15.00 mg/day in P015, P020,
`P024) were coadministered. In these studies 1569 subjects have been exposed to coadministered
`sitagliptin and metformin for between HQ 404 days with a mean duration of exposure of 254.8
`days (approximately 36 weeks).
`
`Appears This Way
`On Original
`
`85
`
`

`

`Clinical Review
`
`[lan Irony, M.D.
`NDA. 22044, Submission 000
`
`Janumet TM (Sitagliptin / metformin fixed-dose combination)
`Table 56. Overall exposure to the coadministration of sitagliptin and metformin
`
`
`
`
`
`Study and dose
`
`<14
`Da 5
`y
`
`
` Number of
`214 to
`242 to
`<42
`<84
`Days on
`Days
`Days
`
`
`
`
`
`—--nnnnnnn-- 28.3.
`Minn-“nun“:-
`
`—-—-——--——nnm
`“alumna-“—
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`ANY DOSE.(h‘g'.‘er‘d°SC
`coadmmistratlon)
`
`Sitagliptin 100 mg +
`Metformin 2000 mg
`5
`4
`12
`152
`14 to 184
`156.4
`‘
`
`P036 OLC
`
`—-nnl-n—nnn———
`_I------Ilflllllll
`
`Total of all Studies
`-
`
`—-—-————--—mm
`
`\
`Adapted from the applicant’s Table 2.7.4: 5, Reference Summary of Clinical Safety in the 4—Month Safety Update Report
`'
`
`moosssnagupun
`
`s
`
`14
`
`22
`
`n n—---1m4o4 297.4
`
`
`P036 Randomized cohorts
`‘
`ANY DOSE.(‘°"".e"d°S°
`5
`5
`7
`155
`1 to 202
`152.4
`coadmmlstration)
`Sitagliptin 100 mg
`+Metf0rmin 1000 mg
`
`158
`
`3 to 192
`
`153.1
`
`5
`
`3
`
`7
`
`5
`
`2
`
`182
`
`1 to 189
`
`158.2
`
`»
`
`The exposure is adequate for assessment of the safety of coadministration of sitagliptin and
`' metformin, at doses that are being proposed for the FDC. In addition, experience with sitagliptin
`from other studies (not listed above) adding to approximately 2000 subjects has been reviewed
`under NDA 21995, and the experience with the use of metformin spans over 20 years in the US,
`being prescribed for millions of people worldwide.
`
`7.2.1.1 Study type and design/patient enumeration
`
`Table 57 is a comprehensive list of the clinical safety and efficacy studies conducted in the
`development of sitagliptin / metformin FDC. These studies are described in the new drug
`application.
`I
`
`86
`
`

`

`Clinical Review
`
`Ilan Irony, MD.
`NDA 22044, Submission 000
`
`Janumet TM (Sitagliptin / metformin fixed—dose combination)
`Table 57. Listing of studies contributing data to support the safety of sitagliptin / metformin FDC
`Stud Poulation
`Stud Goal
`-
`
`
`
`—----__
`
`
`P015 “n 38-71
`Combination with metfonnin: safety /
`DB, R, PC, crossover study with 50 mg bid (or PBO, random sequence) and
`efiicac
`metfonnin X 4 weeks er - riod
`
`
`
`X 24 weeks with extension
`
` DB: double-blind; R: randomized; PC: nlacebo-controlled; AC: active—controlled; MC: multicenter; PBO: '
`
`
`Phase 3, MC, DB, AC (versus glipizide), X 104 wks on metformin 2 1500 mg
`randomized-1:1 to sita_-litin 100 m_ or _liizide 5- 20 m -d
`Phase 3, MC, DB, Factorial, R to 1 of 6 Woups: sita 100 qd, metformin 500
`bid, metformin 1000 bid, sita 50 /met 500 bid, sita 50/ met 1000 bid, or placebo
`
`7.2.1.2 Demographics
`
`,
`
`.
`
`Table 58 and Table 59 show the demographic characteristics (age, gender and race) of subjects
`who participated in Studies P024 and P036.
`’
`
`Table 58. Demographic.characteristics of subjects in Study P024, by treatment group
`
`
`_— an
`
`
`
` 588
`
`_
`
`584
`
`1172
`
`_
`
`.
`
`
`
`
`
`
`
`
`
`
`
`Z}.0% 6‘M.5 § 5m
`Glipizide
`A
`
`Race
`
`'
`
`m toex Au: .‘lIv
`358 (61.3)
`
`Nu:N A4:.5"lV
`226 (38.7)
`
`694 (59.2)
`
`478 (40.8)
`
`.
`
`N(%> —. N(%)
`41m»
`m)
`
`
`
`am)
`76(6.5)
`
`
`
`49am
`9905.4)
`
`
`
`
`
`87
`
`

`

`
`
`
`
`
`
`
`Clinical Review
`
`Ilan Irony, M.D.
`NDA 22044, Submission 000
`
`Janumet TM (Sitagliptin / metformin fixed-dose combination)
`.
`Table 59. Demographic characteristics of subjects in Study P036, by treatment group
`
`
`Age (years)
`
`Treatment Group
`
`'
`
`N
`
`Mean
`
`Metrommsoomgmd
`182 "“—
`~
`Metronnmwoomgbid
`Sita 50 mg + Met 500 bid —_——-m-
`smommooobw
`182 ——_-z-
`Placebo
`176
`24.0 to 78.0
`54.0
`—-m-—_
`All Randomized
`1091
`53.5
`20.0 to 78.0
`'
`54.0
`_“—_
`53.0
`52.6
`_
`26.0 to 75.0
`
`Sita 50 + Met 1000 bid OLC
`
`117
`
`Gender
`
`‘
`
`Metformin 1000 mg bid
`Sita 50 + Met 500 mg bid
`Sita 50+Met 1000 bid
`Placebo
`All Randomized
`Sita 50 + Met 1000 bid OLC
`Race
`
`82 (45.1)
`105 (55.3)
`77 (42.3)
`93 52.3
`539 49.4)
`67 (57.3)
`
`100 (54.9)
`85 (44.7)
`105 (57.7)
`83 47.2)
`552 50.6)
`50 (42.7)
`
`182
`
`1091
`117
`
`
`
`
`
`
`
`
`
`.
`
`
`
`_——————
`
`——————-fi-
`
`_-——_—m
`44m 9m)
`54062)
`
`Similar to the conclusions fromthe review of NDA 21995, the group of African Americans'has
`been underrepresented as compared to the proportion of Type 2 diabetics in the United States
`Population who are African American.
`
`7.2.1.3 Extent of exposure (dose/duration)
`
`Only the dose of sitagliptin of 100 mg (either administered as a single dose or as 50 mg bid)
`coadministered with metformin at doses of either 500 mg bid or 1000 mg bid have been studied
`in this development program. Table 56 provides the overall exposure to these drugs in the studies
`described in this application.
`
`88
`
`

`

`Clinical Review
`
`Ilan Irony, M.D.
`NDA 22044, Submission 000
`
`Janumet TM (Sitagliptin / metformin fixed-dose combination)
`
`7.2.2 Description of Secondary Clinical Data Sources Used tovaaluate Safety
`
`No secondary sources of clinical data were submitted for review. The clinical reviewer
`conducted a literature search for evidence of safety concerns with sitagliptin or other DPP4
`inhibitors.
`
`7.2.2.1 Other studies
`
`V
`
`‘
`
`There were no additional studies conducted with sitagliptin, other than the ones reported under
`this application. This clinical reviewer has enriched the review of sitagliptin by comparing the
`data from the clinical studies to the data obtained from clinical studies investigating safety of
`vildagliptin, a similar DPP4 inhibitor, used in combination with metformin.
`,7
`
`7.2.2.2 Postmarketing experience
`
`Sitagliptin has only recently been approved for marketing in the United States (October 16,
`2006). Sitagliptin is the first DPP4 inhibitor approved for the treatment of T2DM.
`
`7.2.2.3 _ Literature
`
`The applicant has provided relevant references to the review of sitagliptin / metformin FDC. The
`clinical reviewer has also searched the medical literature for additional references to address
`specificissues of review.
`
`7.2.3 Adequacy of Overall Clinical Experience
`
`The clinical experience with the coadministration of sitagliptin and metformin at doses that are
`part of the fixed-dose combinations, regarding extent and duration of exposure needed to assess
`safety is adequate, according to the ICH El guidance. ICH E1 mentions a total exposure of about
`1500 subjects, with 300—600 for 6 months and 100 for one year for products intended to treat
`chronic conditions. The Division of Metabolism and Endocrinology Products has traditionally
`requested more substantive safety experience in the development of products intended for the
`treatment of T2DM, for which the applicant generally complied with.
`The design of studies intended to demonstrate the safety of sitagliptin1n combination with
`metformin1s adequate
`The applicant appropriately excluded subjects with renal impairment, as thisIS a contraindication
`for the use of metformin. The applicant has proposed labeling where use of the product1n
`patients with chronic renal insufficiency is contraindicated.
`
`7.2.4 Adequacy of Special Animal and/or In Vitro Testing
`
`Please see Dr. Bourcier's toxicology review for details of the adequacy of preclinical testing of
`sitagliptin. In general, preclinical testing for sitagliptin was adequate, and an important toxicity
`study in monkeys is still ongoing at the time of this review.
`
`89
`
`

`

`Clinical Review
`
`Ilan Irony, MD.
`NDA 22044, Submission 000
`
`Janumet TM (Sitagliptin / metformin fixed-dose combination)
`7.2.5 Adequacy of Routine Clinical Testing
`
`The clinical testing performed routinely in the studies was adequate to elicit adverse events and
`other clinical, electrocardiographic and laboratory parameters that could represent a safety
`concern.
`
`7.2.6 Adequacy of Metabolic, Clearance, and Interaction Workup
`
`Please see Dr. Jaya Vaidyanathan’s Biopharmacology review for details on the adequacy of the
`sitagliptin PK evaluation program. The overall program is adequate to learn about the PK of
`sitagliptin and effects of meals and interactions with metformin (both1n terms of PK as well as
`PD). However, there13 no significant experience of the concomitant use of sitagliptin with
`insulin and insulin analogs, and a limited experience with oral insulin secretagogues. This15 an
`important issue because sitagliptin indirectly stimulatesendogenous insulin and although the risk
`of hypoglycemia13 small when used1n monotherapy or in combination with insulin sensitizing
`drugs, the risk of hypoglycemia with other insulin secretagogues (that do not stimulate insulin
`secretion in a glucose-dependent manner) is unknowu. This deficiency is currently being
`addressed as a post-marketing commitment, under the original sitagliptin approval.
`
`7.2.7 Adequacy of Evaluation for Potential Adverse Events for Any New
`Drug and Particularly for Drugs in the Class Represented by the New
`Drug; Recommendations for Further Study
`
`The applicant has adequately collected data on potential adverse events that could be resulting
`from exposure to any new drug / drug class. For this purpose the applicant has conducted a QT
`interval study. and studies in chronic renal insufficiency and chronic liver dysfunction, which
`were reviewed under NDA 21995. In addition, the applicant planned for and gathered
`information on AEs expected based on mechanism of action (such as hypoglycemia, for insulin
`secretagogues).
`
`7.2.8 Assessment of Quality and Completeness of Data
`
`The overall assessment of the application and study reports regarding the safety of sitagliptin in
`combination with metformin is that sufficient data to assess risk to benefit profile of sitagliptin
`have been provided. Data that are as c0mplete and of good quality are available for review, and
`the applicant provided in the study reports important analyses of the safety data.
`
`7.2.9 Additional Submissions, Including Safety Update
`
`Most of the review of safety data in this document is based on the 4-Month Safety Update
`Report, submitted tO'FDA on October 19, 2006. The original submission contained only data on
`the OLC of Study P036 (117 subjects followed for a mean 66 days on sitagliptin 100 mg and
`metformin >1500 mg qd) and data from Studies P015 and P020 which had been previously
`reviewed under NDA 21995. The 4-Month Safety Update Report contained data from 24 weeks
`
`90
`
`

`

`Clinical Review
`
`Ilan Irony, M.D.
`NDA 22044, Submission 000
`
`Janumet TM (Sitagliptin / metformin fixed-dose combination)
`of Study P036 (all randomized cohorts as well as the OLC), 52 weeks ofdata1n Study P024 and
`an updated reporting of SAEs through Merck’s Worldwide Adverse Event Reporting System.
`
`_7.3 , Summary of Selected Drug-Related Adverse Events, Important Limitations
`a
`of Data, and Conclusions
`
`At each dose of metformin tested, the combination of sitagliptin and metformin was generally
`well tolerated and was comparable to either component of the combination when given alone.
`One general concern in the review of products to treat T2DM is the incidence of hypoglycemia.
`In addition, since sitagliptin in monotherapy has been noted to cause small increases in
`.gastrointestinal AES compared to placebo (specifically abdominal pain, nausea and diarrhea) and
`since metformin also is known to cause dose-dependent gastrointestinal AEsv (specifically
`abdominal pain, nausea, and diarrhea) the studies of the combination of sitagliptin and
`metformin were planned and powered to focus on this issue. The review of the sitagliptin NDA
`has also revealed some consistent laboratory findings, none of them raising specific clinical
`concerns except for a small mean increase in serum creatinine, particularly in subjects with mild
`to moderate renal failure. Because renal failure is a contraindication for the use of metformin,
`patients with such condition were appropriately excluded from Studies P024 and P036. Below
`the reviewer presents a brief summary of the findings addressing these concerns in the NDA
`22044.
`
`Hypoglycemia
`
`Table 32 shows a summary of the hypoglycemic events reported in Study P036, in terms of
`number of subjects reporting the AE and number of episodes occurring in each treatment cohort.
`Hypoglycemia occurred infrequently (11 subjects out of 1091 randomized and 2 subjects out of
`117 in the OLC), with symptoms being mild to moderate, none requiring medical assistance, and
`the majority of these not confirmed with concurrent fingerstick blood glucose.
`Table 33 shows the summary of hypoglycemic events in Study P024; as compared to the
`combination of metformin and glipizide, subjects randomized to metformin and sitagliptin had
`few events and milder events (4.9 % for sitagliptin / metformin combination versus 32 % for the
`glipizide/metformin combination).
`
`Gastrointestinal Events
`
`From Table 34, there is a metformin dose-proportional increase in nausea and diarrhea.
`Sitagliptin, on the other hand, tends to increase constipation. There were no clinically meaningful
`differences in the incidences of diarrhea, nausea and vomiting in the group receiving
`coadministered sitagliptin and metformin compared to the group receiving metformin alone,
`when properly comparing the groups according to the metformin dose (500 mg bid versus 1000
`mg bid) received. In summary, the gastrointestinal AEs were mostly driven by the metformin
`dose used.
`
`In Study P024, pre—specified gastrointestinal AEs'(abdominal pain, diarrhea, nausea and
`vomiting) occurred with similar rates among the sitagliptin-treated and the glipizide—treated
`subjects.
`
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`

`Clinical Review
`
`Ilan Irony, MD.
`NDA 22044, Submission 000
`Janumet TM (Sitagliptin / metformin fixed-dose combination)
`
`7.4 General Methodology
`
`.7-4-1 Pooling Data Across Studies to Estimate and Compare Incidence
`-‘
`
`7.4.1.1 I Pooled data vs. individual study data
`
`There were 2 new Phase 3 studies reported in this NDA (Studies P024 and P03 6). The studies
`had different goals and designs. However, when considering all subjects exposed to the
`combination of sitagliptin and metformin, the incidence of specific AEs, SAEs, and laboratory
`abnormalities remain low and generally well tolerated.
`
`7.4.1.2 Combining data
`
`Combining data from the 2 new studies reported in this NDA does not change the overall rates of
`these specific AEs (such as hypoglycemia or gastrointestinal events), and does not raise new
`concerns about particular clusters of ABS the applicant had considered of special interest at the
`time of submission‘of the sitagliptin NDA, such as infections, and neurologic and skeletal
`muscle-related AES). The new laboratory data reported in these 2 new studies have not raise any
`new concerns regarding the combination of sitagliptin and metformin. In particular, anemia was
`investigated in the separate studies and with the data combined, and no concerns emerged from
`the review.
`
`7.4.2 Explorations for Predictive Factors
`
`7.4.2.1 Explorations for dose dependency for adverse findings
`
`The only dose of sitagliptin proposed for marketing in the sitagliptin / metformin FDC is 100 mg
`daily dose, the same dose that has been extensively studied in the sitagliptin NDA. From Study
`P036, it is clear that gastrointestinal adverse findings are proportional to the dose of metformin,
`as there were more events of nausea, abdominal pain and diarrhea in the groups treated with
`sitagliptin 50 mg / metformin 1000 mg bid as compared to the group treated with sitagliptin 50
`mg / metformin 500 mg bid, in Similar proportions as occurred in the metformin 500 mg bid and
`1000 mg bid alone. NO other AEs had dose dependency.
`
`7.4.2.2 Explorations for time dependency for adverse findings
`
`There was no time dependency for adverse findings in the studies reviewed in this NDA.
`
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`

`Clinical Review
`[lan Irony, MD.
`NDA 22044, Submission 000
`
`Janumet TM (Sitagliptin / metformin fixed-dose combination)
`7.4.2.3 Explorations for drug-demographic interactions
`
`There were similar rates of ABS and types of ABS across genders and racial groups among the
`different treatment groups. Also there were similar rates of ABS in different age categories,
`although it is worth emphasizing-here that metformin should be prescribed with caution to
`elderly patients (those older than 80 years) only after documentation of normal renal function.
`Even in those patients with normal renal fimction, the sitagliptin / metformin FDC label
`recommends apprOpriately yearly assessment of renal function.
`
`7.4.2.4 Explorations for drug-disease interactions
`
`A wide range of diseases and conditions affectng many organs and systems were’represented in
`the study population at baseline. There were no apparent interactions between treatmentand
`AEs. The most common conditions present at baseline were hypertension, hyperlipidemia,
`obesity, drug hypersensitivity and allergies, GERD, depression,jand back pain, and there appears
`to be no significant exacerbation of these conditions in any of the treatment groups. It is
`important to point out again that metformin is contraindicated in patients with renal dysfunction
`and other patients with conditions that put them at higher risk for lactic acidosis.
`
`7.4.2.5 Explorations for drug-drug interactions
`
`' Metformin and sitagliptin administered in combination have not been shown to exert effects on
`the individual pharrnacokinetic characteristics of each other.
`-
`Sitagliptin did not have clinically meaningful effects on the pharmacokinetics of the following:
`rosiglitazone, glyburide, simvastatin, warfarin or the ethinyl estradiol/norethindrone oral.
`contraceptive combination. Sitagliptin did not inhibit any of the CYP isozymes, and 100 mg
`doses of sitagliptin increased digoxin AUC by 11 % and Cmax by 18 %, without an effect on
`digoxin clearance.
`ln single-dose drug interactions studies of metformin, the following conclusions were obtained:
`0 With glyburide: metformin decreased glyburide AUC and Cmax, but glyburide did not
`changed metformin PK;
`0 With furosemide: furosemide increased metformin plasma and blood AUC by 15 % and Cmax
`by 22 %, while metformin decreased furosemide AUC by 12 % and Cmax by 31 %.
`0 With nifedipine: nifedipine increased plasma metformin AUC by 9% and Cmax by 20 %,
`while metformin had minimal effects on nifedipine PK.
`'
`- Cationic drugs: Cationic drugs (6g. amiloride, digoxin, morphine, procainamide, quinidine,
`quinine, ranitidine, triamterene, trimethoprim, or vancomycin) that are eliminated by renal
`tubular secretion theoretically have the potential for interaction with metformin by competing
`for common renal tubular transport systems. Such interaction between metformin and oral
`cimetidine has been observed in normal healthy volunteers in both single- and multiple-dose,
`metformin-cimetidine drug interaction studies, with a 60% increase in metformin Cmax and a
`-» ~—40% incre-a-seinmet-formin—AUQMet-fermin had~~noeffect~on eimetidinepharmacokinetics.
`Although such interactions remain theoretical (except for cimetidine), careful patient
`monitoring and dose adjustment of sitagliptin/metformin FDC and/or the interfering drug is
`recommended in patients who are taking cationic medications that are excreted via the
`proximal renal tubular secretory system.
`
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`

`

`Clinical Review
`
`Ilan Irony, MD.
`_
`NDA 22044, Submission 000
`Janumet TM (Sitagliptin / metformin fixed-dose combination)
`
`7.4.3 Causality Determination
`
`The group of ABS most likely to have been caused by the coadministration of sitagliptin and
`metformin is related to gastrointestinal effects, mainly abdominal pain, nausea and diarrhea. As
`seen in this review document, the incidence of these AEs was proportional to the dose of
`metformin administered, with rates similar to those found when patients are treated'with
`metformin alone.
`..
`
`8 ADDITIONAL CLINICAL ISSUES
`
`8.1 Dosing Regimen and Administration
`
`The Only dose of sitagliptin investigated in this NDA is the 100 mg daily dose. Because of the
`pharrnacokinetic characteristics of metformin, the dose of sitagliptin was divided in 2 doses (bid
`administration). The doses of metformin as part of the FDC tablet are the doses used by more
`than 93 % of the diabetic population who uses this medication in the US, namely 500 or 1000 mg
`bid. The studies reviewed under NDA 21995 (P015 and P020) and the new data under this
`application support the safety of coadministration of sitagliptin 50 mg with metformin at either
`500 or 1000 mg bid. Study P036 provides evidence of a dose—response in the metformin in
`reducing HbAlc in subjects treated with the combination of metformin and sitagliptin, with
`effect more prominent with each dose in combination compared to the same metformin dose
`alone.
`
`f’
`
`.1
`Daily doses of 50 mg and 25 mg of sitagliptin have been approved for use in- diabetic
`patients with moderate or with severe renal insufficiency, respectively. Since any degree of renal
`insufficiency constitutes a contraindication for the use of metformin, these lower sitagliptin
`doses cannot be part of fixed-dose combination tablets for patients with renal dysfunction.
`It is recommended that the starting dose of metformin be low,