<?xml version="1.0" encoding="UTF-8"?><section ID="ID_33301ddc-9acf-49f6-bbab-dd94f9a64243">
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<code code="34090-1" codeSystem="2.16.840.1.113883.6.1" displayName="CLINICAL PHARMACOLOGY SECTION"/>
<title>12 CLINICAL PHARMACOLOGY </title>
<effectiveTime value="20241113"/>
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<code code="43679-0" codeSystem="2.16.840.1.113883.6.1" displayName="MECHANISM OF ACTION SECTION"/>
<title>12.1 Mechanism of Action </title>
<text>
<paragraph>
<content styleCode="italics">Dapagliflozin </content>
</paragraph>
<paragraph>Sodium-glucose cotransporter 2 (SGLT2), expressed in the proximal renal tubules, is responsible for the majority of the reabsorption of filtered glucose from the tubular lumen. Dapagliflozin is an inhibitor of SGLT2. By inhibiting SGLT2, dapagliflozin reduces reabsorption of filtered glucose and thereby promotes urinary glucose excretion. </paragraph>
<paragraph>
<content styleCode="italics">Saxagliptin </content>
</paragraph>
<paragraph>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 DPP-4 enzyme within minutes. GLP-1 also lowers glucagon secretion from pancreatic alpha cells, reducing hepatic glucose production. In patients with type 2 diabetes mellitus, concentrations of GLP-1 are reduced but the insulin response to GLP-1 is preserved. Saxagliptin is a competitive DPP-4 inhibitor that slows the inactivation of the incretin hormones, thereby increasing their bloodstream concentrations and reducing fasting and postprandial glucose concentrations in a glucose-dependent manner in patients with type 2 diabetes mellitus.</paragraph>
</text>
<effectiveTime value="20241113"/>
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<component>
<section ID="ID_11c6fc8e-3b98-49ea-8abf-01af850675b5">
<id root="58f0b05a-23c9-438e-b28d-eefd558a7fea"/>
<code code="43681-6" codeSystem="2.16.840.1.113883.6.1" displayName="PHARMACODYNAMICS SECTION"/>
<title>12.2 Pharmacodynamics </title>
<text>
<paragraph>
<content styleCode="italics">Dapagliflozin</content>
</paragraph>
<paragraph>Increases in the amount of glucose excreted in the urine were observed in healthy subjects and in patients with type 2 diabetes mellitus following the administration of dapagliflozin. Dapagliflozin dose of 5 or 10 mg per day in patients with type 2 diabetes mellitus for 12 weeks resulted in excretion of approximately 70 grams of glucose in the urine per day at Week 12. A near maximum glucose excretion was observed at the dapagliflozin daily dose of 20 mg. This urinary glucose excretion with dapagliflozin also results in increases in urinary volume <content styleCode="italics">[see </content>
<content styleCode="italics">
<linkHtml href="#ID_0f2b8bdc-51c8-4670-a642-fac6259fc95c">ADVERSE REACTIONS (6.1)</linkHtml>
</content>
<content styleCode="italics">]</content>. After discontinuation of dapagliflozin, on average, the elevation in urinary glucose excretion approaches baseline by about 3 days from discontinuation for the 10 mg dose.</paragraph>
<paragraph>
<content styleCode="bold">Figure 1: Scatter Plot and Fitted Line of Change from Baseline in 24-Hour Urinary Glucose Amount versus Dapagliflozin Dose in Healthy Subjects and Subjects with Type 2 Diabetes Mellitus (T2DM) (Semi-Log Plot)</content>
</paragraph>
<renderMultiMedia ID="id340673460" referencedObject="e048d1b0-6e61-494a-a562-f2493daf49f5"/>
<paragraph>
<content styleCode="italics">Saxagliptin </content>
</paragraph>
<paragraph>In patients with type 2 diabetes mellitus, administration of saxagliptin inhibits DPP-4 enzyme activity for a 24-hour period. After an oral glucose load or a meal, this DPP-4 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.</paragraph>
<paragraph>
<content styleCode="underline">Cardiac Electrophysiology</content>
</paragraph>
<paragraph>
<content styleCode="italics">Dapagliflozin</content>
</paragraph>
<paragraph>Dapagliflozin was not associated with clinically meaningful prolongation of QTc interval at daily doses up to 150 mg (15-times the recommended maximum dose) in a study of healthy subjects. In addition, no clinically meaningful effect on QTc interval was observed following single doses of up to 500 mg (50-times the recommended maximum daily dose) of dapagliflozin in healthy subjects.</paragraph>
<paragraph>
<content styleCode="italics">Saxagliptin </content>
</paragraph>
<paragraph>In a randomized, double-blind, placebo-controlled, 4-way crossover, active comparator study using moxifloxacin in 40 healthy subjects, saxagliptin was not associated with clinically meaningful prolongation of the QTc interval or heart rate at daily doses up to 40 mg (8-times the recommended maximum daily dose).</paragraph>
</text>
<effectiveTime value="20241113"/>
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<observationMedia ID="e048d1b0-6e61-494a-a562-f2493daf49f5">
<text>Figure 1</text>
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<reference value="Figure1Qtern.jpg"/>
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</section>
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<section ID="ID_cfd1b2e3-a800-4402-820d-440000179c8c">
<id root="ebca725c-8bad-4151-a3c4-84f53daf61bf"/>
<code code="43682-4" codeSystem="2.16.840.1.113883.6.1" displayName="PHARMACOKINETICS SECTION"/>
<title>12.3 Pharmacokinetics </title>
<text>
<paragraph>Overall, the pharmacokinetics of dapagliflozin and saxagliptin were not affected in a clinically relevant manner when administered as QTERN. </paragraph>
<paragraph>
<content styleCode="italics">Saxagliptin </content>
</paragraph>
<paragraph>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 C<sub>max</sub> 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 ng•h/mL and 214 ng•h/mL, respectively. The corresponding plasma C<sub>max</sub> values were 24 ng/mL and 47 ng/mL, respectively. The average variability (%CV) for AUC and C<sub>max</sub> for both saxagliptin and its active metabolite was less than 25%.</paragraph>
<paragraph>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.</paragraph>
<paragraph>
<content styleCode="underline">Absorption</content>
</paragraph>
<paragraph>
<content styleCode="italics">Dapagliflozin </content>
</paragraph>
<paragraph>Following oral administration of dapagliflozin, the maximum plasma concentration (C<sub>max</sub>) is usually attained within 2 hours under fasting state. The C<sub>max</sub> and AUC values increase dose proportionally with increase in dapagliflozin dose in the therapeutic dose range. The absolute oral bioavailability of dapagliflozin following the administration of a 10 mg dose is 78%. Administration of dapagliflozin with a high-fat meal decreases its C<sub>max</sub> by up to 50% and prolongs T<sub>max</sub> by approximately 1 hour but does not alter AUC as compared with the fasted state. </paragraph>
<paragraph>
<content styleCode="italics">Saxagliptin </content>
</paragraph>
<paragraph>The median time to maximum concentration (T<sub>max</sub>) 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 T<sub>max</sub> 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.</paragraph>
<paragraph>
<content styleCode="underline">Distribution</content>
</paragraph>
<paragraph>
<content styleCode="italics">Dapagliflozin </content>
</paragraph>
<paragraph>Dapagliflozin is approximately 91% protein bound. Protein binding is not altered in patients with renal or hepatic impairment.</paragraph>
<paragraph>
<content styleCode="italics">Saxagliptin </content>
</paragraph>
<paragraph>The <content styleCode="italics">in vitro</content> 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.</paragraph>
<paragraph>
<content styleCode="underline">Metabolism</content>
</paragraph>
<paragraph>
<content styleCode="italics">Dapagliflozin </content>
</paragraph>
<paragraph>The metabolism of dapagliflozin is primarily mediated by UGT1A9; CYP-mediated metabolism is a minor clearance pathway in humans. Dapagliflozin is extensively metabolized, primarily to yield dapagliflozin 3-O-glucuronide, which is an inactive metabolite. Dapagliflozin 3-O-glucuronide accounted for 61% of a 50 mg [<sup>14</sup>C]-dapagliflozin dose and is the predominant drug-related component in human plasma.</paragraph>
<paragraph>
<content styleCode="italics">Saxagliptin </content>
</paragraph>
<paragraph>The metabolism of saxagliptin is primarily mediated by cytochrome P450 3A4/5 (CYP3A4/5). The major metabolite of saxagliptin is also a DPP-4 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 <content styleCode="italics">[see </content>
<content styleCode="italics">
<linkHtml href="#ID_94d8f76e-f651-4f97-b6d2-f01505e0d77d">DRUG INTERACTIONS (7)</linkHtml>
</content>
<content styleCode="italics">]</content>.</paragraph>
<paragraph>
<content styleCode="underline">Elimination</content>
</paragraph>
<paragraph>
<content styleCode="italics">Dapagliflozin </content>
</paragraph>
<paragraph>Dapagliflozin and related metabolites are primarily eliminated via the renal pathway. Following a single 50 mg dose of [<sup>14</sup>C]-dapagliflozin, 75% and 21% total radioactivity is excreted in urine and feces, respectively. In urine, less than 2% of the dose is excreted as parent drug. In feces, approximately 15% of the dose is excreted as parent drug. The mean plasma terminal half-life (t<sub>1/2</sub>) for dapagliflozin is approximately 12.9 hours following a single oral dose of dapagliflozin 10 mg.</paragraph>
<paragraph>
<content styleCode="italics">Saxagliptin </content>
</paragraph>
<paragraph>Saxagliptin is eliminated by both renal and hepatic pathways. Following a single 50 mg dose of [<sup>14</sup>C]-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 (~230 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 saxagliptin 5 mg to healthy subjects, the mean plasma terminal half-life (t<sub>1/2</sub>) for saxagliptin and its active metabolite was 2.5 and 3.1 hours, respectively.</paragraph>
<paragraph>
<content styleCode="underline">Specific Populations</content>
</paragraph>
<paragraph>
<content styleCode="italics">
<content styleCode="underline">Effects of Age, Gender, Race and Body Weight on Pharmacokinetics</content>
</content>
</paragraph>
<paragraph>Based on a population pharmacokinetic analysis, age, gender, race, and body weight do not have a clinically meaningful effect on the pharmacokinetics of saxagliptin and dapagliflozin.</paragraph>
<paragraph>
<content styleCode="italics">
<content styleCode="underline">Renal Impairment</content>
</content>
</paragraph>
<paragraph>
<content styleCode="italics">Dapagliflozin</content>
</paragraph>
<paragraph>At steady state (20 mg once daily dapagliflozin for 7 days), patients with type 2 diabetes mellitus with mild, moderate, or severe renal impairment (as determined by eGFR) had geometric mean systemic exposures of dapagliflozin that were 45%, 100%, and 200% higher, respectively, as compared to patients with type 2 diabetes mellitus with normal renal function. Higher systemic exposure of dapagliflozin in patients with type 2 diabetes mellitus with renal impairment did not result in a correspondingly higher 24-hour urinary glucose excretion. The steady-state 24-hour urinary glucose excretion in patients with type 2 diabetes mellitus and mild, moderate, and severe renal impairment was 42%, 80%, and 90% lower, respectively, than in patients with type 2 diabetes mellitus with normal renal function. The impact of hemodialysis on dapagliflozin exposure is not known <content styleCode="italics">[see </content>
<content styleCode="italics">
<linkHtml href="#ID_cfd1b2e3-a800-4402-820d-440000179c8c">DOSAGE AND ADMINISTRATION (2.3)</linkHtml>
</content>
<content styleCode="italics">, </content>
<content styleCode="italics">
<linkHtml href="#ID_f1527d2c-4532-4b12-955d-1c22c1b63e06">WARNINGS AND PRECAUTIONS (5.4)</linkHtml>
</content>
<content styleCode="italics"> and </content>
<content styleCode="italics">
<linkHtml href="#ID_7d49aa9f-89ce-4e9a-a934-d4444b154226">USE IN SPECIFIC POPULATIONS (8.6)</linkHtml>
</content>
<content styleCode="italics">]</content>.</paragraph>
<paragraph>
<content styleCode="italics">Saxagliptin</content>
</paragraph>
<paragraph>A single-dose, open-label study was conducted to evaluate the pharmacokinetics of saxagliptin (10 mg dose) in subjects with varying degrees of chronic renal impairment compared to subjects with normal renal function. The 10 mg dosage is not an approved dosage. The degree of renal impairment did not affect C<sub>max</sub> of saxagliptin or its metabolite. In subjects with moderate renal impairment (eGFR 30 to less than 45 mL/min/1.73 m<sup>2</sup>), severe renal impairment (eGFR 15 to less than 30 mL/min/1.73 m<sup>2</sup>) and ESRD patient on hemodialysis, the AUC values of saxagliptin or its active metabolite were >2-fold higher than AUC values in subjects with normal renal function. QTERN is contraindicated in patients with an eGFR <45 mL/min/1.73 m<sup>2</sup>.</paragraph>
<paragraph>
<content styleCode="italics">
<content styleCode="underline">Hepatic Impairment</content>
</content>
</paragraph>
<paragraph>
<content styleCode="italics">Dapagliflozin</content>
</paragraph>
<paragraph>In subjects with mild and moderate hepatic impairment (Child-Pugh classes A and B), mean C<sub>max</sub> and AUC of dapagliflozin were up to 12% and 36% higher, respectively, as compared to healthy matched control subjects following single-dose administration of 10 mg dapagliflozin. These differences were not considered to be clinically meaningful. In patients with severe hepatic impairment (Child-Pugh class C), mean C<sub>max</sub> and AUC of dapagliflozin were up to 40% and 67% higher, respectively, as compared to healthy matched controls <content styleCode="italics">[see </content>
<content styleCode="italics">
<linkHtml href="#ID_565a39f4-403f-4a83-9db4-bba7d347dc9b">USE IN SPECIFIC POPULATIONS (8.7)</linkHtml>
</content>
<content styleCode="italics">]</content>.</paragraph>
<paragraph>
<content styleCode="italics">Saxagliptin</content>
</paragraph>
<paragraph>In subjects with hepatic impairment (Child-Pugh classes A, B, and C), mean C<sub>max</sub> 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 10 mg dosage is not an approved dosage. The corresponding C<sub>max</sub> 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.</paragraph>
<paragraph>
<content styleCode="italics">
<content styleCode="underline">Pediatric</content>
</content>
</paragraph>
<paragraph>Pharmacokinetics of QTERN in the pediatric population has not been studied. </paragraph>
<paragraph>
<content styleCode="underline">Drug Interactions</content>
</paragraph>
<paragraph>
<content styleCode="italics">
<content styleCode="underline">Saxagliptin and Dapagliflozin</content>
</content>
</paragraph>
<paragraph>The lack of pharmacokinetic interaction between dapagliflozin and saxagliptin was demonstrated in a drug-drug interaction study between dapagliflozin and saxagliptin.</paragraph>
<paragraph>
<content styleCode="italics">
<content styleCode="underline">Dapagliflozin</content>
</content>
</paragraph>
<paragraph>
<content styleCode="italics">In Vitro Assessment of Drug Interactions</content>
</paragraph>
<paragraph>The metabolism of dapagliflozin is primarily via glucuronide conjugation mediated by UDP glucuronosyltransferase 1A9 (UGT1A9). </paragraph>
<paragraph>In <content styleCode="italics">in vitro</content> studies, dapagliflozin and dapagliflozin 3-O-glucuronide neither inhibited CYP 1A2, 2C9, 2C19, 2D6, or 3A4, nor induced CYP 1A2, 2B6, or 3A4. Dapagliflozin is a weak substrate of the P-glycoprotein (P‑gp) active transporter, and dapagliflozin 3-O-glucuronide is a substrate for the OAT3 active transporter. Dapagliflozin or dapagliflozin 3-O-glucuronide did not meaningfully inhibit P‑gp, OCT2, OAT1, or OAT3 active transporters. Overall, dapagliflozin is unlikely to affect the pharmacokinetics of concurrently administered medications that are P‑gp, OCT2, OAT1, or OAT3 substrates.</paragraph>
<paragraph>
<content styleCode="italics">Effects of Other Drugs on Dapagliflozin</content>
</paragraph>
<paragraph>Table 4 shows the effect of coadministered drugs on the pharmacokinetics of dapagliflozin.</paragraph>
<table styleCode="Noautorules" width="100%">
<caption>Table 4: Effects of Coadministered Drugs on Dapagliflozin Systemic Exposure</caption>
<col width="57%"/>
<col width="18%"/>
<col width="16%"/>
<col width="9%"/>
<tbody>
<tr>
<td align="center" rowspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="bottom">
<paragraph>
<content styleCode="bold">Coadministered Drug <br/>(Dose Regimen)</content>
<footnote ID="_Ref515918817">Single dose unless otherwise noted.</footnote>
</paragraph>
</td>
<td align="center" rowspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="bottom">
<paragraph>
<content styleCode="bold">Dapagliflozin<br/>(Dose Regimen)</content>
<footnoteRef IDREF="_Ref515918817"/>
</paragraph>
</td>
<td align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<paragraph>
<content styleCode="bold">Dapagliflozin</content>
</paragraph>
</td>
</tr>
<tr>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>
<content styleCode="bold">Change</content>
<footnote ID="_Ref515919384">Percent change (with/without coadministered drug and no change=0%); ↑ and ↓ indicate the exposure increase and decrease, respectively.</footnote>
<content styleCode="bold"> in AUC</content>
<footnote ID="_Ref515919466">AUC=AUC(INF) for drugs given as single dose and AUC=AUC(TAU) for drugs given in multiple doses.</footnote>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>
<content styleCode="bold">Change</content>
<footnoteRef IDREF="_Ref515919384"/>
<content styleCode="bold"> in C<sub>max</sub>
</content>
</paragraph>
</td>
</tr>
<tr>
<td colspan="4" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>
<content styleCode="bold">Oral Antidiabetic Agents</content>
</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph> Metformin (1000 mg)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>20 mg</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>↓1%</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>↓7%</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph> Pioglitazone (45 mg)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>50 mg</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>0%</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>↑9%</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph> Sitagliptin (100 mg)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>20 mg</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>↑8%</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>↓4%</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph> Glimepiride (4 mg)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>20 mg</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>↓1%</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>↑1%</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph> Voglibose (0.2 mg three times daily)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>10 mg</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>↑1%</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>↑4%</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph> Saxagliptin (5 mg single dose)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>10 mg (single dose)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>↓2%</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>↓6%</paragraph>
</td>
</tr>
<tr>
<td colspan="4" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>
<content styleCode="bold">Other Medications</content>
</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph> Hydrochlorothiazide (25 mg)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>50 mg</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>↑7%</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>↓1%</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph> Bumetanide (1 mg)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>10 mg once daily for 7 days</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>↑5%</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>↑8%</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph> Valsartan (320 mg)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>20 mg</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>↑2%</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>↓12%</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph> Simvastatin (40 mg)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>20 mg</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>↓1%</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>↓2%</paragraph>
</td>
</tr>
<tr>
<td colspan="4" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>
<content styleCode="bold">Anti‑infective Agent</content>
</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph> Rifampin (600 mg once daily for 6 days)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>10 mg</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>↓22%</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>↓7%</paragraph>
</td>
</tr>
<tr>
<td colspan="4" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>
<content styleCode="bold">Nonsteroidal Anti‑inflammatory Agent</content>
</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Botrule Lrule Toprule " valign="top">
<paragraph> Mefenamic Acid (loading dose of 500 mg followed by 14 doses<br/> of 250 mg every 6 hours)</paragraph>
</td>
<td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<paragraph>10 mg</paragraph>
</td>
<td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<paragraph>↑51%</paragraph>
</td>
<td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<paragraph>↑13%</paragraph>
</td>
</tr>
</tbody>
</table>
<paragraph>
<content styleCode="italics">Effects of Dapagliflozin on Other Drugs</content>
</paragraph>
<paragraph>Table 5 shows the effect of dapagliflozin on other coadministered drugs. Dapagliflozin did not meaningfully affect the pharmacokinetics of the coadministered drugs.</paragraph>
<table width="100%">
<caption>Table 5: Effects of Dapagliflozin on the Systemic Exposures of Coadministered Drugs</caption>
<col width="40%"/>
<col width="26%"/>
<col width="17%"/>
<col width="18%"/>
<thead>
<tr>
<th align="center" rowspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="bottom">
<content styleCode="bold">Coadministered Drug <br/>(Dose Regimen)</content>
<footnote ID="_Ref515920112">Single dose unless otherwise noted.</footnote>
</th>
<th align="center" rowspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="bottom">
<content styleCode="bold">Dapagliflozin<br/>(Dose Regimen)</content>
<footnoteRef IDREF="_Ref515920112"/>
</th>
<th align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<content styleCode="bold">Coadministered Drug </content>
</th>
</tr>
<tr>
<th align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<content styleCode="bold">Change</content>
<footnote ID="_Ref447895386">Percent change (with/without coadministered drug and no change=0%); ↑ and ↓ indicate the exposure increase and decrease, respectively.</footnote>
<content styleCode="bold"> in AUC</content>
<footnote ID="_Ref447895394">AUC=AUC(INF) for drugs given as single dose and AUC=AUC(TAU) for drugs given in multiple doses.</footnote>
</th>
<th align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<content styleCode="bold">Change</content>
<footnoteRef IDREF="_Ref447895386"/>
<content styleCode="bold"> in C<sub>max</sub>
</content>
</th>
</tr>
</thead>
<tbody>
<tr>
<td colspan="4" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>
<content styleCode="bold">Oral Antidiabetic Agents</content>
</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph> Metformin (1000 mg)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>20 mg</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>0%</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>↓5%</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph> Pioglitazone (45 mg)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>50 mg</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>0%</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>↓7%</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph> Sitagliptin (100 mg)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>20 mg</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>↑1%</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>↓11%</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph> Glimepiride (4 mg)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>20 mg</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>↑13%</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>↑4%</paragraph>
</td>
</tr>
<tr>
<td colspan="4" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>
<content styleCode="bold">Other Medications</content>
</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph> Hydrochlorothiazide (25 mg)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>50 mg</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>↓1%</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>↓5%</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph> Bumetanide (1 mg)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>10 mg once daily <br/>for 7 days</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>↑13%</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>↑13%</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph> Valsartan (320 mg)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>20 mg</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>↑5%</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>↓6%</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph> Simvastatin (40 mg)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>20 mg</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>↑19%</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>↓6%</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph> Digoxin (0.25 mg)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>20 mg loading dose then 10 mg once daily for 7 days</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>0%</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>↓1%</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Botrule Lrule Toprule " valign="middle">
<paragraph> Warfarin (25 mg)</paragraph>
<paragraph> S‑warfarin <br/> R‑warfarin</paragraph>
</td>
<td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<paragraph>20 mg loading dose then 10 mg once daily for 7 days</paragraph>
</td>
<td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<paragraph>↑3%<br/>↑6%</paragraph>
</td>
<td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<paragraph>↑7%<br/>↑8%</paragraph>
</td>
</tr>
</tbody>
</table>
<paragraph>
<content styleCode="italics">
<content styleCode="underline">Saxagliptin </content>
</content>
</paragraph>
<paragraph>
<content styleCode="italics">In Vitro Assessment of Drug Interactions</content>
</paragraph>
<paragraph>The metabolism of saxagliptin is primarily mediated by CYP3A4/5. </paragraph>
<paragraph>In <content styleCode="italics">in vitro</content> studies, saxagliptin and its active metabolite did not inhibit CYP1A2, 2A6, 2B6, 2C9, 2C19, 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. </paragraph>
<paragraph>
<content styleCode="italics">Effects of Other Drugs on Saxagliptin and its Active Metabolite, 5-hydroxy Saxagliptin</content>
</paragraph>
<table width="100%">
<caption>Table 6: Effect of Coadministered Drugs on Systemic Exposures of Saxagliptin and its Active Metabolite, 5-hydroxy Saxagliptin</caption>
<col width="18%"/>
<col width="18%"/>
<col width="16%"/>
<col width="23%"/>
<col width="11%"/>
<col width="15%"/>
<thead>
<tr>
<th align="center" rowspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="bottom">
<content styleCode="bold">Coadministered Drug</content>
</th>
<th align="center" rowspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="bottom">
<content styleCode="bold">Dosage of <br/>Coadministered Drug</content>
<footnote ID="_Ref447893313">Single dose unless otherwise noted.</footnote>
</th>
<th align="center" rowspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="bottom">
<content styleCode="bold">Dosage of Saxagliptin</content>
<footnoteRef IDREF="_Ref447893313"/>
</th>
<th align="center" colspan="3" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<content styleCode="bold">Saxagliptin</content>
</th>
</tr>
<tr>
<th align="left" styleCode="Rrule Lrule Toprule Botrule " valign="top"/>
<th align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<content styleCode="bold">Change</content>
<footnote ID="_Ref500136806">Percent change (with/without coadministered drug and no change=0%); ↑ and ↓ indicate the exposure increase and decrease, respectively.</footnote>
<content styleCode="bold"> in AUC</content>
<footnote ID="_Ref447893338">AUC=AUC(INF) for drugs given as single dose and AUC=AUC(TAU) for drugs given in multiple doses.</footnote>
</th>
<th align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<content styleCode="bold">Change</content>
<footnoteRef IDREF="_Ref500136806"/>
<content styleCode="bold"> in C<sub>max</sub>
</content>
</th>
</tr>
</thead>
<tbody>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>Metformin</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>1000 mg</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>100 mg</paragraph>
</td>
<td styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>saxagliptin<br/>5‑hydroxy saxagliptin</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>↓2%<br/>↓1%</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>↓21%<br/>↓12%</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>Glyburide</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>5 mg</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>10 mg</paragraph>
</td>
<td styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>saxagliptin<br/>5‑hydroxy saxagliptin</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>↓2%<br/>ND</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>↑8%<br/>ND</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>Pioglitazone<footnote ID="_Ref447893553">Results exclude one subject.</footnote>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>45 mg QD for 10 days</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>10 mg QD<br/>for 5 days</paragraph>
</td>
<td styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>saxagliptin<br/>5‑hydroxy saxagliptin</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>↑11%<br/>ND</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>↑11%<br/>ND</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>Dapagliflozin</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>10 mg single dose</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>5 mg single dose</paragraph>
</td>
<td styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>saxagliptin</paragraph>
<paragraph>5-hydroxy saxagliptin</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>↓1%</paragraph>
<paragraph>↑9%</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>↓7%</paragraph>
<paragraph>↑6%</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>Digoxin</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>0.25 mg q6h first day followed by q12h second day followed by QD for 5 days</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>10 mg QD<br/>for 7 days</paragraph>
</td>
<td styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>saxagliptin<br/>5‑hydroxy saxagliptin</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>↑5%<br/>↑6%</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>↓1%<br/>↑2%</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>Simvastatin</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>40 mg QD for 8 days</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>10 mg QD<br/>for 4 days</paragraph>
</td>
<td styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>saxagliptin<br/>5‑hydroxy saxagliptin</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>↑12%<br/>↑2%</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>↑21%<br/>↑8%</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>Diltiazem</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>360 mg LA QD for 9 days</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>10 mg</paragraph>
</td>
<td styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>saxagliptin<br/>5‑hydroxy saxagliptin</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>↑109%<br/>↓34%</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>↑63%<br/>↓43%</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>Rifampin<footnote ID="_Ref447893570">The plasma dipeptidyl peptidase-4 (DPP-4) activity inhibition over a 24-hour dose interval was not affected by rifampin.</footnote>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>600 mg QD for 6 days</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>5 mg</paragraph>
</td>
<td styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>saxagliptin<br/>5‑hydroxy saxagliptin</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>↓76%<br/>↑3%</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>↓53%<br/>↑39%</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>Omeprazole</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>40 mg QD for 5 days</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>10 mg</paragraph>
</td>
<td styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>saxagliptin<br/>5‑hydroxy saxagliptin</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>↑13%<br/>ND</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>↓2%<br/>ND</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>Aluminum hydroxide + magnesium hydroxide + simethicone</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>aluminum hydroxide:<br/> 2400 mg<br/> magnesium hydroxide: 2400 mg simethicone:<br/>240 mg</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>10 mg</paragraph>
</td>
<td styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>saxagliptin<br/>5‑hydroxy saxagliptin</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>↓3%<br/>ND</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>↓26%<br/>ND</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>Famotidine</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>40 mg</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>10 mg</paragraph>
</td>
<td styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>saxagliptin<br/>5‑hydroxy saxagliptin</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>↑3%<br/>ND</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>↑14%<br/>ND</paragraph>
</td>
</tr>
<tr>
<td colspan="6" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>
<content styleCode="bold">Saxagliptin coadministered with strong CYP3A4/5 inhibitors </content>
<content styleCode="italics">[see </content>
<content styleCode="italics">
<linkHtml href="#ID_94d8f76e-f651-4f97-b6d2-f01505e0d77d">DRUG INTERACTIONS (7)</linkHtml>
</content>
<content styleCode="italics"> and </content>
<content styleCode="italics">
<linkHtml href="#ID_d7329473-9f27-467c-a364-4374dd2c92a0">DOSAGE AND ADMINISTRATION (2.4)</linkHtml>
</content>
<content styleCode="italics">]</content>:</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>Ketoconazole</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>200 mg BID for 9 days</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>100 mg</paragraph>
</td>
<td styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>saxagliptin<br/>5‑hydroxy saxagliptin</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>↑145%<br/>↓88%</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>↑62%<br/>↓95%</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>Ketoconazole</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>200 mg BID for 7 days</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>20 mg</paragraph>
</td>
<td styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>saxagliptin<br/>5‑hydroxy saxagliptin</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>↑267%<br/>ND</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>↑144%<br/>ND</paragraph>
</td>
</tr>
<tr>
<td colspan="6" valign="top">
<paragraph>ND=not determined; QD=once daily; q6h=every 6 hours; q12h=every 12 hours; BID=twice daily; LA=long acting.</paragraph>
</td>
</tr>
</tbody>
</table>
<paragraph>
<content styleCode="italics">Effects of Saxagliptin on Other Drugs </content>
</paragraph>
<table width="100%">
<caption>Table 7: Effect of Saxagliptin on Systemic Exposures of Coadministered Drugs</caption>
<col width="19%"/>
<col width="19%"/>
<col width="16%"/>
<col width="20%"/>
<col width="12%"/>
<col width="13%"/>
<thead>
<tr>
<th align="left" rowspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="bottom">
<content styleCode="bold">Coadministered Drug</content>
</th>
<th align="left" rowspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="bottom">
<content styleCode="bold">Dosage of<br/>Coadministered Drug</content>
<footnote ID="_Ref447894223">Single dose unless otherwise noted.</footnote>
</th>
<th align="left" rowspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="bottom">
<content styleCode="bold">Dosage of <br/>Saxagliptin</content>
<footnoteRef IDREF="_Ref447894223"/>
</th>
<th align="center" colspan="3" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<content styleCode="bold">Coadministered Drug</content>
</th>
</tr>
<tr>
<th align="left" styleCode="Rrule Lrule Toprule Botrule " valign="top"/>
<th align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<content styleCode="bold">Change</content>
<footnote ID="_Ref500137118">Percent change (with/without coadministered drug and no change=0%); ↑ and ↓ indicate the exposure increase and decrease, respectively.</footnote>
<content styleCode="bold"> in AUC</content>
<footnote ID="_Ref447894282">AUC=AUC(INF) for drugs given as single dose and AUC=AUC(TAU) for drugs given in multiple doses.</footnote>
</th>
<th align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<content styleCode="bold">Change</content>
<footnoteRef IDREF="_Ref500137118"/>
<content styleCode="bold">
<sup/>
<br/>in C<sub>max</sub>
</content>
</th>
</tr>
</thead>
<tbody>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>Metformin</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>1000 mg</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>100 mg</paragraph>
</td>
<td styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>metformin</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>↑20%</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>↑9%</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>Glyburide</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>5 mg</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>10 mg</paragraph>
</td>
<td styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>glyburide</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>↑6%</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>↑16%</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>Pioglitazone<footnote ID="_Ref447894294">Results include all subjects.</footnote>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>45 mg QD for 10 days</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>10 mg QD<br/>for 5 days</paragraph>
</td>
<td styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>pioglitazone<br/>hydroxy‑pioglitazone</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>↑8%<br/>ND</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>↑14%<br/>ND</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>Digoxin</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>0.25 mg q6h first day followed by q12h second day followed by QD for 5 days</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>10 mg QD<br/>for 7 days</paragraph>
</td>
<td styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>digoxin</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>↑6%</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>↑9%</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>Simvastatin</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>40 mg QD for 8 days</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>10 mg QD<br/>for 4 days</paragraph>
</td>
<td styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>simvastatin<br/>simvastatin acid</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>↑4%<br/>↑16%</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>↓12%<br/>0%</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>Diltiazem</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>360 mg LA QD for 9 days</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>10 mg</paragraph>
</td>
<td styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>diltiazem</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>↑10%</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>↑16%</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>Ketoconazole</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>200 mg BID for 9 days</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>100 mg</paragraph>
</td>
<td styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>ketoconazole</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>↓13%</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>↓16%</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>Ethinyl estradiol and Norgestimate</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>ethinyl estradiol 0.035 mg and norgestimate 0.250 mg for 21 days</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>5 mg QD for 21 days</paragraph>
</td>
<td styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>ethinyl estradiol <br/>norelgestromin<br/>norgestrel</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>↑7%<br/>↑10%<br/>↑13%</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>↓2%<br/>↑9%<br/>↑17%</paragraph>
</td>
</tr>
<tr>
<td colspan="6" valign="top">
<list listType="ordered">
<item>
<caption> </caption>ND=not determined; QD=once daily; q6h=every 6 hours; q12h=every 12 hours; BID=twice daily; LA=long acting.</item>
</list>
</td>
</tr>
</tbody>
</table>
</text>
<effectiveTime value="20241113"/>
</section>
</component>
</section>
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