8
`
`USE IN SPECIFIC POPULATIONS
`
`8.1
`
`Pregnancy
`
`Pregnancy Category B
`
`There are no adequate and well-controlled studies in pregnant women. Because animal
`
`reproduction studies are not always predictive of human response, ONGLYZA,
`
`like other
`
`antidiabetic medications, should be used during pregnancy only if clearly needed.
`
`Saxagliptin was not teratogenic at any dose tested when administered to pregnant rats and rabbits
`
`during periods of organogenesis. Incomplete ossification of the pelvis, a form of developmental
`
`delay, occurred in rats at a dose of 240 mg/kg, or approximately 1503 and 66 times human
`
`exposure to saxagliptin and the active metabolite, respectively, at the maximum recommended
`
`human dose (MRHD) of 5 mg. Maternal toxicity and reduced fetal body weights were observed
`
`at 7986 and 328 times the human exposure at the MRHD for saxagliptin and the active
`
`metabolite, respectively. Minor skeletal variations in rabbits occurred at a maternally toxic dose
`
`of 200 mg/kg, or approximately 1432 and 992 times the MRHD. When administered to rats in
`
`combination with metformin, saxagliptin was not teratogenic nor embryolethal at exposures 21
`
`times the saxagliptin MRHD. Combination administration of metforrnin with a higher dose of
`
`saxagliptin (109 times the saxagliptin MRHD) was associated with craniorachischisis (a rare
`
`neural tube defect characterized by incomplete closure of the skull and spinal column) in two
`
`fetuses from a single dam. Metformin exposures in each combination were 4 times the human
`
`exposure of 2000 mg daily.
`
`Saxagliptin administered to female rats from gestation day 6 to lactation day 20 resulted in
`
`decreased body weights in male and female offspring only at maternally toxic doses (exposures
`
`21629 and 53 times saxagliptin and its active metabolite at the MRHD). No fiinctional or
`
`behavioral toxicity was observed in offspring of rats administered saxagliptin at any dose.
`
`Saxagliptin crosses the placenta into the "fetus following dosing in pregnant rats.
`
`8.3
`
`Nursing Mothers
`
`Saxagliptin is secreted in the milk of lactating rats at approximately a 1:1 ratio with plasma drug
`
`concentrations. It is not known whether saxagliptin is secreted in human milk. Because many
`
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`
`

`
`drugs are secreted in human milk, caution should be exercised when ONGLYZA is administered
`
`to a nursing woman.
`
`8.4
`
`Pediatric Use
`
`Safety and effectiveness of ONGLYZA in pediatric patients have not been established.
`
`8.5
`
`Geriatric Use
`
`In the six, double-blind, controlled clinical safety and efficacy trials of ONGLYZA, 634 (15.3%)
`
`of the 4148 randomized patients were 65 years and over, and 59 (1.4%) patients were 75 years
`
`and over. No overall differences in safety or effectiveness were observed between patients 265
`
`years old and the younger patients. While this clinical experience has not identified differences
`
`in responses between the elderly and younger patients, greater sensitivity of some older
`
`individuals cannot be ruled out.
`
`Saxagliptin and its active metabolite are eliminated in part by the kidney. Because elderly
`
`patients are more likely to have decreased renal function, care should be taken in dose selection
`
`in the elderly based on renal function.
`
`[See Dosage and Administration (2.2) and Clinical
`
`Pharmacology (12.3).]
`
`10
`
`OVERDOSAGE
`
`In a controlled clinical trial, once-daily, orally-administered ONGLYZA in healthy subjects at
`
`doses up to 400 mg daily for 2 weeks (80 times the MRHD) had no dose-related clinical adverse
`
`reactions and no clinically meaningful effect on QTc interval or heart rate.
`
`In the event of an overdose, appropriate supportive treatment should be initiated as dictated by
`
`the patient’s clinical status. Saxagliptin and its active metabolite are removed by hemodialysis
`
`(23% of dose over 4 hours).
`
`11
`
`DESCRIPTION
`
`Saxagliptin is an orally-active inhibitor of the DPP4 enzyme.
`
`Saxagliptin monohydrate
`is
`described
`chemically
`as
`(1S,3S,5S)-2-[(2S)—2-Amino-2-(3-
`hydroxytricyclo[3.3.1.13’7]dec—1-yl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile,
`
`monohydrate
`
`or
`
`(IS, 3S,5S)-2- [(2S)-2-Amino-2-(3 -hydroxyadamantan-1-yl)acetyl]-2-
`10
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`
`

`
`azabicyc1o[3.1.0]hexane-3-carbonitrile hydrate. The empirical formula is C1gH25N3O2oH2O and
`
`the molecular weight is 333.43. The structural formula is:
`
`HO
`
`HZN
`
`N
`
`. H20
`
`0
`
`CN
`
`Saxagliptin monohydrate is a white to light yellow or light brown, non-hygroscopic, crystalline
`
`powder. It is sparingly soluble in water at 24°C :1: 3°C, slightly soluble in ethyl acetate, and
`
`soluble in methanol, ethanol, isopropyl alcohol, acetonitrile, acetone, and polyethylene glycol
`
`400 (PEG 400).
`
`Each film-coated tablet of ONGLYZA for oral use contains either 2.79 mg saxagliptin
`
`hydrochloride (anhydrous) equivalent to 2.5 mg saxagliptin or 5.58 mg saxagliptin hydrochloride
`
`(anhydrous) equivalent
`
`to 5 mg saxagliptin and the following inactive ingredients:
`
`lactose
`
`monohydrate, microcrystalline cellulose, croscarmellose sodium, and magnesium stearate. In
`
`addition,
`
`the film coating contains the following inactive ingredients: polyvinyl alcohol,
`
`polyethylene glycol, titanium dioxide, talc, and iron oxides.
`
`12
`
`CLINICAL PHARMACOLOGY
`
`12.1
`
`Mechanism of Action
`
`Increased concentrations of the incretin hormones such as glucagon—like peptide-1 (GLP-1) and
`
`glucose-dependent insulinotropic polypeptide (GIP) are released into the bloodstream from the
`
`small intestine in response to meals. These hormones cause insulin release from the pancreatic
`
`beta cells in a glucose-dependent manner but are inactivated by the dipeptidyl peptidase-4
`
`(DPP4) enzyme within minutes. GLP-1 also lowers glucagon secretion from pancreatic alpha
`
`cells, reducing hepatic glucose production. In patients with type 2 diabetes, concentrations of
`
`GLP—1 are reduced but the insulin response to GLP-1 is preserved. Saxagliptin is a competitive
`
`DPP4 inhibitor that slows the inactivation of the incretin hormones, thereby increasing their
`
`11
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`
`

`
`bloodstream concentrations and reducing fasting and postprandial glucose concentrations in a
`
`glucose-dependent manner in patients with type 2 diabetes mellitus.
`
`12.2
`
`Pharmacodynamics
`
`In patients with type 2 diabetes mellitus, administration of ONGLYZA inhibits DPP4 enzyme
`
`activity for a 24-hour period. After an oral glucose load or a meal, this DPP4 inhibition resulted
`
`in a 2- to 3-fold increase in circulating levels of active GLP-1 and GIP, decreased glucagon
`
`concentrations, and increased glucose-dependent insulin secretion from pancreatic beta cells. The
`
`rise in insulin and decrease in glucagon were associated with lower
`
`fasting glucose
`
`concentrations and reduced glucose excursion following an oral glucose load or a meal.
`
`Cardiac Electrophysiology
`
`In a randomized, double-blind, placebo-controlled, 4-way crossover, active comparator study
`
`using moxifloxacin in 40 healthy subjects, ONGLYZA was not associated with clinically
`
`meaningful prolongation of the QTc interval or heart rate at daily doses up to 40 mg (8 times the
`
`MRHD).
`
`12.3
`
`Pharmacokinetics
`
`The pharmacokinetics of saxagliptin and its active metabolite, 5-hydroxy saxagliptin were
`
`similar in healthy subjects and in patients with type 2 diabetes mellitus. The Cmax and AUC
`
`values of saxagliptin and its active metabolite increased proportionally in the 2.5 to 400 mg dose
`
`range. Following a 5 mg single oral dose of saxagliptin to healthy subjects, the mean plasma
`
`AUC values for saxagliptin and its active metabolite were 78 ngoh/mL and 214 ngoh/mL,
`
`respectively. The corresponding plasma Cmax values were 24 ng/mL and 47 ng/mL, respectively.
`
`The average variability (%CV) for AUC and Cmax for both saxagliptin and its active metabolite
`
`was less than 25%.
`
`No appreciable accumulation of either saxagliptin or its active metabolite was observed with
`
`repeated once-daily dosing at any dose level. No dose- and time-dependence were observed in
`
`the clearance of saxagliptin and its active metabolite over 14 days of once-daily dosing with
`
`saxagliptin at doses ranging from 2.5 to 400 mg.
`
`12
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`
`

`
`IOIOOOCOQOOOCCCCOOQOOCUOOCOOOOOOOOOOOOOOQOOO
`
`Absorption
`
`The median time to maximum concentration (Tmax) following the 5 mg once daily dose was 2
`
`hours for saxagliptin and 4 hours for its active metabolite. Administration with a high-fat meal
`
`resulted in an increase in Tmax of saxagliptin by approximately 20 minutes as compared to fasted
`
`conditions. There was a 27% increase in the AUC of saxagliptin when given with a meal as
`
`compared to fasted conditions. ONGLYZA may be administered with or without food.
`
`Distribution
`
`The in vitro protein binding of saxagliptin and its active metabolite in human serum is negligible.
`
`Therefore, changes in blood protein levels in various disease states (e.g., renal or hepatic
`
`impairment) are not expected to alter the disposition of saxagliptin.
`
`ivletabolism
`
`The metabolism of saxagliptin is primarily mediated by cytochrome P450 3A4/5 (CYP3A4/5).
`
`The major metabolite of saxagliptin is also a DPP4 inhibitor, which is one-half as potent as
`
`saxagliptin. Therefore, strong CYP3A4/5 inhibitors and inducers will alter the pharmacokinetics
`
`of saxagliptin and its active metabolite. [See Drug Interactions (7).]
`
`Excretion
`
`Saxagliptin is eliminated by both renal and hepatic pathways. Following a single 50 mg dose of
`MC-saxagliptin, 24%, 36%, and 75% of the dose was excreted in the urine as saxagliptin, its
`
`active metabolite, and total radioactivity, respectively. The average renal clearance of saxagliptin
`
`(~23O mL/min) was greater than the average estimated glomerular filtration rate (~120 mL/min),
`
`suggesting some active renal excretion. A total of 22% of the administered radioactivity was
`
`recovered in feces representing the fraction of the saxagliptin dose excreted in bile and/or
`
`unabsorbed drug from the gastrointestinal tract. Following a single oral dose of ONGLYZA
`
`5 mg to healthy subjects, the mean plasma terminal half-life (t1/2) for saxagliptin and its active
`
`metabolite was 2.5 and 3.1 hours, respectively.
`
`13
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`
`

`
`D0000.COOOGOCCICOOQCOQ.QOOOOOOOOOOOOOOOOQOOO
`
`Specific Populations
`
`Renal Impairment
`
`A single-dose, open-label study was conducted to evaluate the phannacokinetics of saxagliptin
`
`(10 mg dose) in subjects with varying degrees of chronic renal impairment (N=8 per group)
`
`compared to subjects with normal renal function. The study included patients with renal
`
`impairment classified on the basis of creatinine clearance as mild (>50 to $80 mL/min),
`
`moderate (30 to $50 mL/min), and severe (<30 mL/min), as well as patients with end-stage renal
`
`disease on hemodialysis. Creatinine clearance was estimated from serum creatinine based on the_
`Cockcroft-Gault formula:
`
`CrCl = | 140 — age gyearsfl >< weight gkg} {X 0.85 for female patients}
`[72 X serum creatinine (mg/dL)]
`
`The degree of renal impairment did not affect the Cmax of saxagliptin or its active metabolite. In
`
`subjects with mild renal impairment, the AUC values of saxagliptin and its active metabolite
`
`were 20% and 70% higher, respectively,
`
`than AUC values in subjects with normal renal
`
`function. Because increases of this magnitude are not considered to be clinically relevant, dosage
`
`adjustment
`
`in patients with mild renal
`
`impairment
`
`is not recommended.
`
`In subjects with
`
`moderate or severe renal impairment, the AUC values of saxagliptin and its active metabolite
`
`were up to 2.1- and 4.5-fold higher, respectively, than AUC values in subjects with normal renal
`
`function. To achieve plasma exposures of saxagliptin and its active metabolite similar to thosein
`
`patients with normal renal function, the recommended dose is 2.5 mg once daily in patients with
`
`moderate and severe renal
`
`impairment, as well as in patients with end-stage renal disease
`
`requiring hemodialysis. Saxagliptin is removed by hemodialysis.
`
`Hepatic Impairment
`
`In subjects with hepatic impairment (Child-Pugh classes A, B, and C), mean Cmax and AUC of
`
`saxagliptin were up to 8% and 77% higher, respectively, compared to healthy matched controls
`
`following administration of a single 10 mg dose of saxagliptin. The corresponding Cmax and
`
`AUC of the active metabolite were up to 59% and 33% lower, respectively, compared to healthy
`
`matched controls. These differences are not considered to be clinically meaningful. No dosage
`
`adjustment is recommended for patients with hepatic impairment.
`
`14
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`
`

`
`OOOOOCOOCOOOOOQOGOOC0000OCOCQOCCOOOOCQ-COOOOO
`
`Body Mass Index
`
`No dosage adjustment
`
`is recommended based on body mass index (BMI) which was not
`
`identified as a significant covariate on the apparent clearance of saxagliptin or its active
`
`metabolite in the population pharmacokinetic analysis.
`
`Gender
`
`No dosage adjustment is recommended based on gender. There were no differences observed in
`
`saxagliptin pharmacokinetics between males and females. Compared to males, females had
`
`approximately 25% higher exposure values for the active metabolite than males, but
`
`this
`
`difference is unlikely to be of clinical relevance. Gender was not identified as a significant
`
`covariate on the apparent clearance of saxagliptin and its active metabolite in the population
`
`pharmacokinetic analysis.
`
`Geriatric
`
`No dosage adjustment is recommended based on age alone. Elderly subjects (65-80 years) had
`
`23% and 59% higher geometric mean Cmax and geometric mean AUC values, respectively, for
`
`saxagliptin than young subjects (18-40 years). Differences in active metabolite pharmacokinetics
`
`between elderly and young subjects generally reflected the differences observed in saxagliptin
`
`pharmacokinetics. The difference between the pharmacokinetics of saxagliptin and the active
`
`metabolite in young and elderly subjects is likely due to multiple factors including declining
`
`renal function and metabolic capacity with increasing age. Age was not identified as a significant
`
`covariate on the apparent clearance of saxagliptin and its active metabolite in the population
`
`pharmacokinetic analysis.
`
`Pediatric
`
`Studies characterizing the pharmacokinetics of saxagliptin in pediatric patients have not been
`
`performed.
`
`Race and Ethnicity
`
`No dosage adjustment is recommended based on race. The population pharmacokinetic analysis
`
`compared the pharmacokinetics of saxagliptin and its active metabolite in 309 Caucasian
`
`subjects with 105 non-Caucasian subjects (consisting of six racial groups). No significant
`
`15
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`
`

`
`IOIOOO000.0000QCOOQCOQOQOCOOQOOOOOOOQOOOOOOO
`
`difference in the pharmacokinetics of saxagliptin and its active metabolite were detected between
`
`these two populations.
`
`Drug-Drug Interactions
`
`In Vitro Assessment of Drug Interactions
`
`The metabolism of saxagliptin is primarily mediated by CYP3A4/5.
`
`In in vitro studies, saxagliptin and its active metabolite did not inhibit CYP1A2, 2A6, 2B6, 2C9,
`
`2Cl9, 2D6, 2E1, or 3A4, or induce CYP1A2, 2B6, 2C9, or 3A4. Therefore, saxagliptin is not
`
`expected to alter the metabolic clearance of coadministered drugs that are metabolized by these
`
`enzymes. Saxagliptin is a P-glycoprotein (P-gp) substrate but is not a significant inhibitor or
`inducer of P-gp.‘
`
`The in vitro protein binding of saxagliptin and its active metabolite in human serum is negligible.
`Thus, protein binding would not have a meaningful
`influence on the pharmacokinetics of
`
`saxagliptin or other drugs.
`
`In Vivo Assessment of Drug Interactions
`
`Effects of Saxagliptin on Other Drugs
`
`In studies conducted in healthy subjects, as described below, saxagliptin did not meaningfully
`
`alter the pharmacokinetics of metformin, glyburide, pioglitazone, digoxin, simvastatin, diltiazem,
`or ketoconazole.
`
`Metformins Coadministration of a single dose of saxagliptin (100 mg) and metformin (1000 mg),
`
`an hOCT-2 substrate, did not alter the pharmacokinetics of metformin in healthy subjects.
`
`Therefore, ONGLYZA is not an inhibitor of hOCT-2—mediated transport.
`
`Glyburide: Coadministration of a single dose of saxagliptin (10 mg) and glyburide (5 mg), a
`
`CYPZC9 substrate,
`
`increased the plasma Cmax of glyburide by 16%; however,
`
`the AUC of
`
`glyburide was unchanged. Therefore, ONGLYZA does not meaningfully inhibit CYP2C9-
`mediated metabolism.
`
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`
`

`
`IOOOOOOOQOOOOOCCOOOOOOCOOCOOOOOOCOOOOOOOOOOO
`
`Pioglitazones Coadministration of multiple once-daily doses of saxagliptin (10 mg) and
`pioglitazone (45 mg), a CYP2C8 substrate, increased the plasma Cmax of pioglitazone by 14%;
`
`however, the AUC of pioglitazone was unchanged.
`
`Digoxins Coadministration of multiple once-daily doses of saxagliptin (10 mg) and digoxin
`
`(0.25 mg), a P-gp substrate, did not alter
`
`the pharmacokinetics of digoxin. Therefore,
`
`ONGLYZA is not an inhibitor or inducer of P-gp-mediated transport.
`
`Simvastatin: Coadministration of multiple once-daily doses of saxagliptin (10 mg) and
`
`simvastatin (40 mg), a CYP3A4/5 substrate, did not alter the pharmacokinetics of simvastatin.
`
`Therefore, ONGLYZA is not an inhibitor or inducer of CYP3A4/5-mediated metabolism.
`
`Diltiazem: Coadministration of multiple once-daily doses of saxagliptin (10 mg) and diltiazem
`
`(360 mg long-acting formulation at steady state), a moderate inhibitor of CYP3A4/5, increased
`
`the plasma Cmax of diltiazem by 16%; however, the AUC of diltiazem was unchanged.
`
`Ketoconazole: Coadministration of a single dose of saxagliptin (100 mg) and multiple doses of
`
`ketoconazole (200 mg every 12 hours at steady state), a strong inhibitor of CYP3A4/5 and P-gp,
`
`decreased the plasma Cmax and AUC of ketoconazole by 16% and 13%, respectively.
`
`Effects of Other Drugs on Saxagligtin
`
`Metformin: Coadministration of a single dose of saxagliptin (100 mg) and metformin (1000 mg),
`
`an hOCT-2 substrate, decreased the Cmax of saxagliptin by 21%; however,
`
`the AUC was
`
`unchanged.
`
`Glyburide: Coadministration of a single dose of saxagliptin (10 mg) and glyburide (5 mg), a
`
`CYP2C9 substrate, increased the Cmax of saxagliptin by 8%; however, the AUC of saxagliptin
`
`was unchanged.
`
`Pioglitazones Coadministration of multiple once-daily doses of saxagliptin (10 mg) and
`
`pioglitazone (45 mg), a CYP2C8 (major) and CYP3A4 (minor) substrate, did not alter the
`
`pharmacokinetics of saxagliptin.
`
`Digoxin: Coadministration of multiple once-daily doses of saxagliptin (10 mg) and digoxin
`
`(0.25 mg), a P-gp substrate, did not alter the pharmacokinetics of saxagliptin.
`
`17
`
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`
`

`
`ICCOOOOOCOO-COCIOUOOCCIOOOCOOCIOCOOCCOOOO-COCO
`
`Simvastatin: Coadministration of multiple once-daily doses of saxagliptin (10 mg) and
`
`simvastatin (40 mg), a CYP3A4/5 substrate, increased the Cmax of saxagliptin by 21%; however,
`
`the AUC of saxagliptin was unchanged.
`
`Diltiazem: Coadministration of a single dose of saxagliptin (10 mg) and diltiazem (360 mg long-
`
`acting formulation at steady state), a moderate inhibitor of CYP3A4/5, increased the Cum of
`
`saxagliptin by 63% and the AUC by 2.1-fold. This was associated with a corresponding decrease
`in the Cmax and AUC of the active metabolite by 44% and 36%, respectively.
`
`Ketoconazoles Coadministration of a single dose of saxagliptin (100 mg) and ketoconazole
`
`(200 mg every 12 hours at steady state), a strong inhibitor of CYP3A4/5 and P-gp, increased the
`
`Cmax for saxagliptin by 62% and the AUC by 2.5-fold. This was associated with a corresponding
`
`decrease in the Cmax and AUC of the active metabolite by 95% and 91%, respectively.
`
`_
`
`In another study, coadministration of a single dose of saxagliptin (20 mg) and ketoconazole
`
`(200 mg every 12 hours at steady state), increased the Cmax and AUC of saxagliptin by 2.4-fold
`
`and 3.7-fold, respectively. This was associated with a corresponding decrease in the Cmax and
`
`AUC of the active metabolite by 96% and 90%, respectively.
`
`Rifampin: Coadministration of a single dose of saxagliptin (5 mg) and rifampin (600 mg QD at
`
`steady state) decreased the Cmax and AUC of saxagliptin by 53% and 76%, respectively, with a
`
`corresponding increase in Cmax (39%) but no significant change in the plasma AUC of the active
`
`metabolite.
`
`Omeprazole: Coadministration of multiple once-daily doses of saxagliptin ( 10 mg) and
`
`omeprazole (40 mg), a CYP2C19 (major) and CYP3A4 substrate, an inhibitor of CYP2C19, and
`
`an inducer of MRP-3, did not alter the pharmacokinetics of saxagliptin.
`
`Aluminum hydroxide + magnesium hydroxide + simethicone: Coadministration of a single dose
`
`of saxagliptin (10 mg) and a liquid containing aluminum hydroxide (2400 mg), magnesium
`
`hydroxide (2400 mg), and simethicone (240 mg) decreased the Cmax of saxagliptin by 26%;
`
`however, the AUC of saxagliptin was unchanged.
`
`Famotidine: Administration of a single dose of saxagliptin (10 mg) 3 hours after a single dose of
`
`famotidine (40 mg), an inhibitor of hOCT-l, hOCT-2, and hOCT-3,
`
`increased the Cmax of
`
`saxagliptin by 14%; however, the AUC of saxagliptin was unchanged.
`
`18
`
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`
`

`
`ICCCCQCCC.'OCCCC.UC...=CCCC.C..CC.C.CC.~C‘.COCC.
`
`13
`
`NONCLINICAL TOXICOLOGY
`
`13.1
`
`Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`Saxagliptin did not induce tumors in either mice (50, 250, and 600 mg/kg) or rats (25, 75, 150,
`
`and 300 mg/kg) at the highest doses evaluated. The highest doses evaluated in mice were
`
`equivalent to approximately 870 (males) and 1165 (females) times the human exposure at the
`
`MRHD of 5 mg/day. In rats, exposures were approximately 355 (males) and 2217 (females)
`times the MRHD.
`
`Saxagliptin was not mutagenic or clastogenic with or without metabolic activation in an in vitro
`
`Ames bacterial assay, an in vitro cytogenetics assay in primary human lymphocytes, an in vivo
`
`oral micronucleus assay in rats, an in vivo oral DNA repair study in rats, and an oral in vivo/in
`
`vitro cytogenetics study in rat peripheral blood lymphocytes. The active metabolite was not
`
`mutagenic in an in vitro Ames bacterial assay.
`
`In a rat fertility study, males were treated with oral gavage doses for 2 weeks prior to mating,
`
`during mating, and up to scheduled termination (approximately 4 weeks total) and females were
`
`treated with oral gavage doses for 2 weeks prior to mating through gestation day 7. No adverse
`
`effects on fertility were observed at exposures of approximately 603 (males) and 776 (females)
`
`times the MRHD. Higher doses that elicited maternal toxicity also increased fetal resorptions
`
`(approximately 2069 and 6138 times the MRHD). Additional effects on estrous cycling, fertility,
`
`ovulation, and implantation were observed at approximately 6138 times the MRHD.
`
`13.2
`
`Animal Toxicology
`
`Saxagliptin produced adverse skin changes in the extremities of cynomolgus monkeys (scabs
`
`and/or ulceration of tail, digits, scrotum, and/or nose). Skin lesions were reversible at 220 times
`
`the MRHD but in some cases were irreversible and necrotizing at higher exposures. Adverse skin
`
`changes were not observed at exposures similar to (1 to 3 times) the MRHD of 5 mg. Clinical
`
`correlates to skin lesions in monkeys have not been observed in human clinical
`
`trials of
`
`Saxagliptin.
`
`19
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`
`

`
`IUCOOQOOQOOO.OOOOOOCCCCQOCOOCIUC0000007000000
`
`14
`
`CLINICAL STUDIES
`
`ONGLYZA has been studied as monotherapy and in combination with metformin, glyburide,
`
`and thiazolidinedione (pioglitazone and rosiglitazone) therapy. ONGLYZA has not been studied
`
`in combination with insulin.
`
`A total of 4148 patients with type 2 diabetes mellitus were randomized in six, double-blind,
`
`controlled clinical trials conducted to evaluate the safety and glycemic efficacy of ONGLYZA.
`
`A total of 3021 patients in these trials were treated with ONGLYZA. In these trials, the mean age
`
`was 54 years, and 71% of patients were Caucasian, 16% were Asian, 4% were black, and 9%
`
`were of other racial groups. An additional 423 patients, including 315 who received ONGLYZA,
`
`participated in a placebo-controlled, dose-ranging study of 6 to 12 weeks in duration.
`
`In these six, double-blind trials, ONGLYZA was evaluated at doses of 2.5 mg and 5 mg once
`
`daily. Three of these trials also evaluated a saxagliptin dose of 10 mg daily. The 10 mg daily
`
`dose of saxagliptin did not provide greater efficacy than the 5 mg daily dose. Treatment with
`
`ONGLYZA at all doses produced clinically relevant and statistically significant improvements in
`
`hemoglobin Alc (AIC), fasting plasma glucose (FPG), and 2-hour postprandial glucose (PPG)
`
`following a standard oral glucose tolerance test (OGTT), compared to control. Reductions in
`
`AlC were seen across subgroups including gender, age, race, and baseline BMI.
`
`ONGLYZA was not associated with significant changes from baseline in body weight or fasting
`
`serum lipids compared to placebo.
`
`14.1
`
`Monotherapy
`
`A total of 766 patients with type 2 diabetes inadequately controlled on diet and exercise (AlC
`
`27% to S10%) participated in two 24-week, double-blind, placebo-controlled trials evaluating
`
`the efficacy and safety of ONGLYZA monotherapy.
`
`In the first trial, following a 2-week single-blind diet, exercise, and placebo lead-in period, 401
`
`patients were randomized to 2.5 mg, 5 mg, or 10 mg of ONGLYZA or placebo. Patients who
`
`failed to meet specific glycemic goals during the study were treated with metformin rescue
`
`therapy, added on to placebo or ONGLYZA. Efficacy was evaluated at the last measurement
`
`prior to rescue therapy for patients needing rescue. Dose titration of ONGLYZA was not
`
`permitted.
`
`20
`
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`
`

`
`Treatment with ONGLYZA 2.5 mg and 5 mg daily provided significant improvements in AIC,
`
`FPG, and PPG compared to placebo (Table 3). The percentage of patients who discontinued for
`
`lack of glycemic control or who were rescued for meeting prespecified glycemic criteria was
`
`16% in the ONGLYZA 2.5 mg treatment group, 20% in_the ONGLYZA 5 mg treatment group,
`
`and 26% in the placebo group.
`
`Table 3:
`
`Glycemic Parameters at Week 24 in a Placebo-Controlled Study of
`ONGLYZA Monotherapy in Patients with Type 2 Diabetes*
`
`ONGLYZA
`
`ONGLYZA
`
`Efficacy Parameter
`
`
`
`N=95
`
`
`
`2.5 mg
`N=102
`
`5 mg
`N=l06
`
`
`
`
`
`
`
`
`
`
`
`
`
`>l<
`
`%:l73++'-F
`
`N=92
`N=103
`N=l00
`Hemolobin A1C %
`221 7.9
`
`Difference from placebo (adjusted meanl)
`
`-0.6:
`
`'
`
`-0.61
`
`Fastin Plasma Glucose m dL
`
`N=l0l
`
`N=l05
`
`change from baseline (adjusted mean*> n
`
`24% <22/92>
`N=92
`172
`+6
`
`N=71
`283
`
`Difference from placebo (adjusted meanl)
`95% Confidence Interval
`
`-61, —l6
`
`-59, -15
`
`
`
`Intent-to-treat population using last observation on study or last observation prior to metfonnin rescue therapy for
`patients needing rescue.
`Least squares mean adjusted for baseline value.
`p—value <0.000l compared to placebo
`
`p—value <0.05 compared to placebo
`Significance was not tested for the 2-hour PPG for the 2.5 mg dose of ONGLYZA.
`
`
`
`
`
`
`
`
`
`
`A second 24-week monotherapy trial was conducted to assess a r