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1 INDICATIONS AND USAGE SYNJARDY SYNJARDY is a combination of empagliflozin, a sodium-glucose co-transporter 2 (SGLT2) inhibitor and metformin hydrochloride (HCl) immediate-release, a biguanide, indicated as an adjunct to diet and exercise to improve glycemic control in adults and pediatric patients aged 10 years and older with type 2 diabetes mellitus. SYNJARDY XR SYNJARDY XR is a combination of empagliflozin, a SGLT2 inhibitor and metformin HCl extended-release, a biguanide, indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus . Empagliflozin Empagliflozin, when used as a component of SYNJARDY or SYNJARDY XR, is indicated in adults with type 2 diabetes mellitus to reduce the risk of: Cardiovascular (CV) death in adults with established CV disease. ( 1 ) CV death and hospitalization for heart failure in adults with heart failure. ( 1 ) Sustained decline in eGFR, end-stage kidney disease, CV death, and hospitalization in adults with chronic kidney disease at risk of progression. ( 1 ) Limitations of Use : Not recommended for use to improve glycemic control in patients with type 1 diabetes mellitus. It may increase the risk of diabetic ketoacidosis in these patients. ( 1 ) Because of the metformin HCl component, the use of SYNJARDY or SYNJARDY XR is limited to patients with type 2 diabetes mellitus for all indications. ( 1 ) Empagliflozin, when used as a component of SYNJARDY or SYNJARDY XR, is not recommended for the treatment of chronic kidney disease in patients with polycystic kidney disease or patients requiring or with a recent history of intravenous immunosuppressive therapy or greater than 45 mg of prednisone or equivalent for kidney disease. Empagliflozin is not expected to be effective in these populations. ( 1 ) SYNJARDY SYNJARDY is a combination of empagliflozin and metformin hydrochloride (HCl) immediate-release indicated as an adjunct to diet and exercise to improve glycemic control in adults and pediatric patients aged 10 years and older with type 2 diabetes mellitus . SYNJARDY XR SYNJARDY XR is a combination of empagliflozin and metformin HCl extended-release indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus . Empagliflozin Empagliflozin, when used as a component of SYNJARDY or SYNJARDY XR, is indicated in adults with type 2 diabetes mellitus to reduce the risk of: • Cardiovascular (CV) death in adults with established CV disease. • CV death and hospitalization for heart failure in adults with heart failure. • Sustained decline in eGFR, end-stage kidney disease, CV death, and hospitalization in adults with chronic kidney disease at risk of progression. Limitations of Use • SYNJARDY and SYNJARDY XR are not recommended for use to improve glycemic control in patients with type 1 diabetes mellitus. It may increase the risk of diabetic ketoacidosis in these patients [see Warnings and Precautions (5.2) ] . • Because of the metformin HCl component, the use of SYNJARDY or SYNJARDY XR is limited to patients with type 2 diabetes mellitus for all indications.

e glycemic control in patients with type 1 diabetes mellitus. It may increase the risk of diabetic ketoacidosis in these patients [see Warnings and Precautions (5.2) ] . • Because of the metformin HCl component, the use of SYNJARDY or SYNJARDY XR is limited to patients with type 2 diabetes mellitus for all indications. • Empagliflozin, when used as a component of SYNJARDY or SYNJARDY XR, is not recommended for the treatment of chronic kidney disease in patients with polycystic kidney disease or patients requiring or with a recent history of intravenous immunosuppressive therapy or greater than 45 mg of prednisone or equivalent for kidney disease [see Clinical Studies (14.5) ] . Empagliflozin is not expected to be effective in these populations.

tyleCode="Lrule Rrule">Male genital mycotic infections^d</td><td styleCode="Rrule">0.4</td><td styleCode="Rrule">3.1</td><td styleCode="Rrule">1.6</td></tr><tr><td styleCode="Lrule Rrule">Nausea</td><td styleCode="Rrule">1.4</td><td styleCode="Rrule">2.3</td><td styleCode="Rrule">1.1</td></tr></tbody></table> <table width="95%" ID="table3"><caption>Table 3 Incidence of Overall^a and Severe^b Hypoglycemic Events in Placebo-Controlled Clinical Trials for Glycemic Control in Adults with Type 2 Diabetes Mellitus^c</caption><col width="31%" align="left" valign="top"/><col width="20%" align="center" valign="top"/><col width="24%" align="center" valign="top"/><col width="25%" align="center" valign="top"/><tfoot><tr><td colspan="4" align="left" valign="top">^aOverall hypoglycemic events: plasma or capillary glucose of less than or equal to 70 mg/dL</td></tr><tr><td colspan="4" align="left" valign="top">^bSevere hypoglycemic events: requiring assistance regardless of blood glucose</td></tr><tr><td colspan="4" align="left" valign="top">^cTreated set (patients who had received at least one dosage of trial drug)</td></tr><tr><td colspan="4" align="left" valign="top">^dInsulin dosage could not be adjusted during the initial 18-week treatment period</td></tr></tfoot><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="bold">Monotherapy (24 weeks)</content></td><td styleCode="Rrule"><content styleCode="bold">Placebo (n=229)</content></td><td styleCode="Rrule"><content styleCode="bold">Empagliflozin 10 mg (n=224)</content></td><td styleCode="Rrule"><content styleCode="bold">Empagliflozin 25 mg (n=223)</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Overall (%)</td><td styleCode="Rrule">0.4</td><td styleCode="Rrule">0.4</td><td styleCode="Rrule">0.4</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Severe (%)</td><td styleCode="Rrule">0</td><td styleCode="Rrule">0</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="bold">In Combination with Metformin HCl (24 weeks)</content></td><td styleCode="Rrule"><content styleCode="bold">Placebo + Metformin HCl (n=206)</content></td><td styleCode="Rrule"><content styleCode="bold">Empagliflozin 10 mg + Metformin HCl (n=217)</content></td><td styleCode="Rrule"><content styleCode="bold">Empagliflozin 25 mg + Metformin HCl (n=214)</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Overall (%)</td><td styleCode="Rrule">0.5</td><td styleCode="Rrule">1.8</td><td styleCode="Rrule">1.4</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Severe (%)</td><td styleCode="Rrule">0</td><td styleCode="Rrule">0</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="bold">In Combination with Metformin HCl + Sulfonylurea (24 weeks)</content></td><td styleCode="Rrule"><content styleCode="bold">Placebo (n=225)</content></td><td styleCode="Rrule"><content styleCode="bold">Empagliflozin 10 mg + Metformin HCl + Sulfonylurea (n=224)</content></td><td styleCode="Rrule"><content styleCode="bold">Empagliflozin 25 mg + Metformin HCl + Sulfonylurea (n=217)</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Overall (%)</td><td styleCode="Rrule">8.4</td><td styleCode="Rrule">16.1</td><td styleCode="Rrule">11.5</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Severe (%)</td><td styleCode="Rrule">0</td><td styleCode="Rrule">0</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="bold">In Combination with Pioglitazone +/- Metformin HCl (24 weeks)</content></td><td styleCode="Rrule"><content styleCode="bol

<table width="90%" ID="table4"><caption>Table 4 Clinically Relevant Interactions with SYNJARDY or SYNJARDY XR</caption><col width="25%" align="left" valign="top"/><col width="75%" align="left" valign="top"/><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="2"><content styleCode="bold">Carbonic Anhydrase Inhibitors</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="italics">Clinical Impact</content></td><td styleCode="Rrule">Topiramate or other carbonic anhydrase inhibitors (e.g., zonisamide, acetazolamide or dichlorphenamide) frequently causes a decrease in serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis. Concomitant use of these drugs with SYNJARDY or SYNJARDY XR may increase the risk of lactic acidosis.</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="italics">Intervention</content></td><td styleCode="Rrule">Consider more frequent monitoring of these patients.</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="2"><content styleCode="bold">Drugs that Reduce Metformin Clearance</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="italics">Clinical Impact</content></td><td styleCode="Rrule">Concomitant use of drugs that interfere with common renal tubular transport systems involved in the renal elimination of metformin (e.g., organic cationic transporter-2 [OCT2] / multidrug and toxin extrusion [MATE] inhibitors such as ranolazine, vandetanib, dolutegravir, and cimetidine) could increase systemic exposure to metformin and may increase the risk for lactic acidosis <content styleCode="italics">[see <linkHtml href="#S12.3">Clinical Pharmacology (12.3)</linkHtml>]</content>.</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="italics">Intervention</content></td><td styleCode="Rrule">Consider the benefits and risks of concomitant use.</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="2"><content styleCode="bold">Alcohol</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="italics">Clinical Impact</content></td><td styleCode="Rrule">Alcohol is known to potentiate the effect of metformin on lactate metabolism.</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="italics">Intervention</content></td><td styleCode="Rrule">Warn patients against excessive alcohol intake while receiving SYNJARDY or SYNJARDY XR.</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="2"><content styleCode="bold">Diuretics</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="italics">Clinical Impact</content></td><td styleCode="Rrule">Coadministration of empagliflozin with diuretics resulted in increased urine volume and frequency of voids, which might enhance the potential for volume depletion.</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="italics">Intervention</content></td><td styleCode="Rrule">Before initiating SYNJARDY or SYNJARDY XR, assess volume status and renal function. In patients with volume depletion, correct this condition before initiating SYNJARDY or SYNJARDY XR.

pharmacokinetic studies of metformin have been conducted in patients with hepatic impairment. Drug Interaction Studies Pharmacokinetic drug interaction studies with SYNJARDY or SYNJARDY XR have not been performed; however, such studies have been conducted with the individual components empagliflozin and metformin HCl. Empagliflozin In vitro Assessment of Drug Interactions: Empagliflozin does not inhibit, inactivate, or induce CYP450 isoforms. In vitro data suggest that the primary route of metabolism of empagliflozin in humans is glucuronidation by the uridine 5ʹ-diphospho-glucuronosyltransferases UGT1A3, UGT1A8, UGT1A9, and UGT2B7. Empagliflozin does not inhibit UGT1A1, UGT1A3, UGT1A8, UGT1A9, or UGT2B7. Therefore, no effect of empagliflozin is anticipated on concomitantly administered drugs that are substrates of the major CYP450 isoforms or UGT1A1, UGT1A3, UGT1A8, UGT1A9, or UGT2B7. The effect of UGT induction (e.g., induction by rifampicin or any other UGT enzyme inducer) on empagliflozin exposure has not been evaluated. Empagliflozin is a substrate for P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), but it does not inhibit these efflux transporters at therapeutic doses. Based on in vitro studies, empagliflozin is considered unlikely to cause interactions with drugs that are P-gp substrates. Empagliflozin is a substrate of the human uptake transporters OAT3, OATP1B1, and OATP1B3, but not OAT1 and OCT2. Empagliflozin does not inhibit any of these human uptake transporters at clinically relevant plasma concentrations and, therefore, no effect of empagliflozin is anticipated on concomitantly administered drugs that are substrates of these uptake transporters. In vivo Assessment of Drug Interactions: Empagliflozin pharmacokinetics were similar with and without coadministration of metformin HCl, glimepiride, pioglitazone, sitagliptin, linagliptin, warfarin, verapamil, ramipril, and simvastatin in healthy volunteers and with or without coadministration of hydrochlorothiazide and torsemide in patients with type 2 diabetes mellitus (see Figure 1 ). In subjects with normal renal function, coadministration of empagliflozin with probenecid resulted in a 30% decrease in the fraction of empagliflozin excreted in urine without any effect on 24-hour urinary glucose excretion. The relevance of this observation to patients with renal impairment is unknown. Figure 1 Effect of Various Medications on the Pharmacokinetics of Empagliflozin as Displayed as 90% Confidence Interval of Geometric Mean AUC and C max Ratios [reference lines indicate 100% (80% - 125%)] a empagliflozin, 50 mg, once daily; b empagliflozin, 25 mg, single dose; c empagliflozin, 25 mg, once daily; d empagliflozin, 10 mg, single dose Empagliflozin had no clinically relevant effect on the pharmacokinetics of metformin, glimepiride, pioglitazone, sitagliptin, linagliptin, warfarin, digoxin, ramipril, simvastatin, hydrochlorothiazide, torsemide, and oral contraceptives when coadministered in healthy volunteers (see Figure 2 ).

(4) and Warnings and Precautions (5.1) ] . Patients with Hepatic Impairment SYNJARDY or SYNJARDY XR: Studies characterizing the pharmacokinetics of empagliflozin and metformin after administration of SYNJARDY or SYNJARDY XR in hepatically impaired patients have not been performed [see Warnings and Precautions (5.1) ] . Empagliflozin: In adult patients with mild, moderate, and severe hepatic impairment according to the Child-Pugh classification, AUC of empagliflozin increased by approximately 23%, 47%, and 75%, and C max increased by approximately 4%, 23%, and 48%, respectively, compared to subjects with normal hepatic function. Metformin HCl: No pharmacokinetic studies of metformin have been conducted in patients with hepatic impairment. Drug Interaction Studies Pharmacokinetic drug interaction studies with SYNJARDY or SYNJARDY XR have not been performed; however, such studies have been conducted with the individual components empagliflozin and metformin HCl. Empagliflozin In vitro Assessment of Drug Interactions: Empagliflozin does not inhibit, inactivate, or induce CYP450 isoforms. In vitro data suggest that the primary route of metabolism of empagliflozin in humans is glucuronidation by the uridine 5ʹ-diphospho-glucuronosyltransferases UGT1A3, UGT1A8, UGT1A9, and UGT2B7. Empagliflozin does not inhibit UGT1A1, UGT1A3, UGT1A8, UGT1A9, or UGT2B7. Therefore, no effect of empagliflozin is anticipated on concomitantly administered drugs that are substrates of the major CYP450 isoforms or UGT1A1, UGT1A3, UGT1A8, UGT1A9, or UGT2B7. The effect of UGT induction (e.g., induction by rifampicin or any other UGT enzyme inducer) on empagliflozin exposure has not been evaluated. Empagliflozin is a substrate for P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), but it does not inhibit these efflux transporters at therapeutic doses. Based on in vitro studies, empagliflozin is considered unlikely to cause interactions with drugs that are P-gp substrates. Empagliflozin is a substrate of the human uptake transporters OAT3, OATP1B1, and OATP1B3, but not OAT1 and OCT2. Empagliflozin does not inhibit any of these human uptake transporters at clinically relevant plasma concentrations and, therefore, no effect of empagliflozin is anticipated on concomitantly administered drugs that are substrates of these uptake transporters. In vivo Assessment of Drug Interactions: Empagliflozin pharmacokinetics were similar with and without coadministration of metformin HCl, glimepiride, pioglitazone, sitagliptin, linagliptin, warfarin, verapamil, ramipril, and simvastatin in healthy volunteers and with or without coadministration of hydrochlorothiazide and torsemide in patients with type 2 diabetes mellitus (see Figure 1 ). In subjects with normal renal function, coadministration of empagliflozin with probenecid resulted in a 30% decrease in the fraction of empagliflozin excreted in urine without any effect on 24-hour urinary glucose excretion. The relevance of this observation to patients with renal impairment is unknown. Figure 1 Effect of Various Medications on the Pharmacokinetics of Empagliflozin as Displayed as 90% Confidence Interval of Geometric Mean AUC and C max Ratios [reference lines indicate 100% (80% - 125%)] a empagliflozin, 50 mg, once daily; b empagliflozin, 25 mg, single dose; c empagliflozin, 25 mg, once daily; d empagliflozin, 10 mg, single dose Empagliflozin had no clinically relevant effect on the pharmacokinetics of metformin, glimepiride, pioglitazone, sitagliptin, linagliptin, warfarin, digoxin, ramipril, simvastatin, hydrochlorothiazide, torsemide, and oral contraceptives when coadministered in healthy volunteers (see Figure 2 ).

a Placebo-Controlled Trial for Empagliflozin in Combination with Metformin HCl and/or Insulin or as Monotherapy in Pediatric Patients Aged 10 to 17 Years with Type 2 Diabetes Mellitus a Empagliflozin 10 mg and 25 mg Placebo a Modified intent-to-treat set (All randomized and treated patients with baseline measurement). b Multiple imputations using placebo wash-out approach with 500 iterations for missing data. Imputed for HbA1c (empagliflozin N=5 (9.6%), placebo N=3 (5.7%)), for FPG (empagliflozin N=4 (8.3%), placebo N=2 (3.8%)). c Least-Square Mean from Analysis of Covariance (ANCOVA) adjusted for baseline value and baseline age stratum (< 15 years vs 15 to < 18 years). d Not evaluated for statistical significance, not part of sequential testing procedure. e p-value=0.0116 (two-sided) HbA1c (%) b Number of patients n=52 n=53 Baseline (mean) 8.0 8.1 Change from baseline c -0.2 0.7 Difference from placebo c (95% CI) -0.8 e (-1.5, -0.2) -- FPG (mg/dL) b,d Number of patients n=48 n=52 Baseline (mean) 154 159 Change from baseline c -19 17 Difference from placebo c (95% CI) -36 (-60.7, -10.7) -- Glycemic Control Trial of Metformin HCl Immediate-Release in Pediatric Patients Aged 10 to 16 Years with Type 2 Diabetes Mellitus: A double-blind, placebo-controlled trial was conducted in pediatric patients aged 10 to 16 years with type 2 diabetes mellitus (mean FPG 182.2 mg/dL), where patients were treated with metformin HCl immediate-release tablets (up to 2,000 mg/day) for up to 16 weeks (mean duration of treatment 11 weeks). The results are displayed in Table 12. Table 12 Mean Change in Fasting Plasma Glucose at Week 16 Comparing Metformin HCl vs. Placebo in Pediatric Patients a with Type 2 Diabetes Mellitus Metformin HCl Placebo p-value FPG (mg/dL) (n=37) (n=36) a Pediatric patients mean age 13.8 years (range 10-16 years) Baseline 162.4 192.3 Change at FINAL VISIT -42.9 21.4 <0.001 Mean baseline body weight was 205 lbs and 189 lbs in the metformin HCl immediate-release and placebo arms, respectively. Mean change in body weight from baseline to week 16 was -3.3 lbs and -2.0 lbs in the metformin HCl and placebo arms, respectively. 14.3 Empagliflozin CV Outcome Trial in Adult Patients with Type 2 Diabetes Mellitus and Atherosclerotic CV Disease EMPA-REG OUTCOME was a multicenter, multinational, randomized, double-blind parallel group trial that compared the risk of experiencing a major adverse CV event (MACE) between empagliflozin and placebo when these were added to and used concomitantly with standard of care treatments for diabetes mellitus and atherosclerotic CV disease. Concomitant antidiabetic medications were kept stable for the first 12 weeks of the trial. Thereafter, antidiabetic and atherosclerotic therapies could be adjusted, at the discretion of investigators, to ensure participants were treated according to the standard care for these diseases. A total of 7,020 patients were treated (empagliflozin 10 mg = 2,345; empagliflozin 25 mg = 2,342; placebo = 2,333) and followed for a median of 3.1 years. Approximately 72% of the trial population was White, 22% was Asian, and 5% was Black or African American. The mean age was 63 years and approximately 72% were male. All patients in the trial had inadequately controlled type 2 diabetes mellitus at baseline (HbA1c greater than or equal to 7%). The mean HbA1c at baseline was 8.1% and 57% of participants had diabetes mellitus for more than 10 years. Approximately 31%, 22% and 20% reported a past history of neuropathy, retinopathy and nephropathy to investigators, respectively and the mean eGFR was 74 mL/min/1.73 m 2 . At baseline, patients were treated with one (~30%) or more (~70%) antidiabetic medications including metformin HCl (74%), insulin (48%), and sulfonylurea (43%).

HbA1c &lt;7%</td><td styleCode="Rrule">96 (63%)</td><td styleCode="Rrule">112 (70%)</td><td styleCode="Rrule">91 (57%)</td><td styleCode="Rrule">111 (68%)</td><td styleCode="Rrule">69 (43%)</td><td styleCode="Rrule">51 (32%)</td><td styleCode="Rrule">63 (38%)</td><td styleCode="Rrule">92 (58%)</td></tr></tbody></table> <table width="85%" ID="table9"><caption>Table 9 Results at Week 24 from a Placebo-Controlled Trial for Empagliflozin in Combination with Metformin HCl and Sulfonylurea</caption><col width="40%" align="left" valign="middle"/><col width="20%" align="center" valign="middle"/><col width="20%" align="center" valign="middle"/><col width="20%" align="center" valign="middle"/><thead><tr><th styleCode="Lrule Rrule"/><th styleCode="Rrule">Empagliflozin 10 mg N=225</th><th styleCode="Rrule">Empagliflozin 25 mg N=216</th><th styleCode="Rrule" valign="top">Placebo N=225</th></tr></thead><tfoot><tr><td colspan="4" align="left" valign="top">^aModified intent-to-treat population. Last observation on trial (LOCF) was used to impute missing data at Week 24. At Week 24, 17.8%, 16.7%, and 25.3% was imputed for patients randomized to empagliflozin 10 mg, empagliflozin 25 mg, and placebo, respectively.</td></tr><tr><td colspan="4" align="left" valign="top">^bANCOVA p-value &lt;0.0001 (HbA1c: ANCOVA model includes baseline HbA1c, treatment, renal function, and region.

de="Botrule"><td styleCode="Lrule Rrule"> Change from baseline^c</td><td styleCode="Rrule">-19</td><td styleCode="Rrule">17</td></tr><tr><td styleCode="Lrule Rrule"> Difference from placebo^c (95% CI)</td><td styleCode="Rrule">-36 (-60.7, -10.7)</td><td styleCode="Rrule">--</td></tr></tbody></table> <table width="85%"><caption>Table 12 Mean Change in Fasting Plasma Glucose at Week 16 Comparing Metformin HCl vs. Placebo in Pediatric Patients^a with Type 2 Diabetes Mellitus</caption><col width="25%" align="left" valign="middle"/><col width="25%" align="left" valign="middle"/><col width="25%" align="left" valign="middle"/><col width="25%" align="left" valign="middle"/><thead><tr styleCode="Botrule"><th styleCode="Lrule Rrule"/><th styleCode="Rrule">Metformin HCl</th><th styleCode="Rrule">Placebo</th><th styleCode="Rrule">p-value</th></tr><tr><th styleCode="Lrule Rrule">FPG (mg/dL)</th><th styleCode="Rrule">(n=37)</th><th styleCode="Rrule">(n=36)</th><th styleCode="Rrule"/></tr></thead><tfoot><tr><td align="left" valign="top" colspan="4">^a Pediatric patients mean age 13.8 years (range 10-16 years)</td></tr></tfoot><tbody><tr><td styleCode="Lrule Rrule">Baseline</td><td styleCode="Rrule">162.4</td><td styleCode="Rrule">192.3</td><td styleCode="Rrule"/></tr><tr><td styleCode="Lrule Rrule">Change at FINAL VISIT</td><td styleCode="Rrule">-42.9</td><td styleCode="Rrule">21.4</td><td styleCode="Rrule">&lt;0.001</td></tr></tbody></table>

body><tr><td styleCode="Lrule Rrule">Baseline</td><td styleCode="Rrule">162.4</td><td styleCode="Rrule">192.3</td><td styleCode="Rrule"/></tr><tr><td styleCode="Lrule Rrule">Change at FINAL VISIT</td><td styleCode="Rrule">-42.9</td><td styleCode="Rrule">21.4</td><td styleCode="Rrule">&lt;0.001</td></tr></tbody></table> <table width="85%" ID="table13"><caption>Table 13 Treatment Effect for the Primary Composite Endpoint and its Components^a</caption><col width="40%" align="left" valign="middle"/><col width="18%" align="center" valign="middle"/><col width="20%" align="center" valign="middle"/><col width="22%" align="center" valign="middle"/><thead><tr><th styleCode="Lrule Rrule"/><th styleCode="Rrule">Placebo N=2,333</th><th styleCode="Rrule">Empagliflozin N=4,687</th><th styleCode="Rrule">Hazard ratio vs placebo (95% CI)</th></tr></thead><tfoot><tr><td align="left" valign="top" colspan="4">^aTreated set (patients who had received at least one dose of trial drug)</td></tr><tr><td align="left" valign="top" colspan="4">^bp-value for superiority (2-sided) 0.04</td></tr><tr><td align="left" valign="top" colspan="4">^cTotal number of events</td></tr></tfoot><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Composite of CV death, non-fatal myocardial infarction, non-fatal stroke (time to first occurrence)^b</td><td styleCode="Rrule">282 (12.1%)</td><td styleCode="Rrule">490 (10.5%)</td><td styleCode="Rrule">0.86 (0.74, 0.99)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Non-fatal myocardial infarction^c</td><td styleCode="Rrule">121 (5.2%)</td><td styleCode="Rrule">213 (4.5%)</td><td styleCode="Rrule">0.87 (0.70, 1.09)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Non-fatal stroke^c</td><td styleCode="Rrule">60 (2.6%)</td><td styleCode="Rrule">150 (3.2%)</td><td styleCode="Rrule">1.24 (0.92, 1.67)</td></tr><tr><td styleCode="Lrule Rrule">CV death^c</td><td styleCode="Rrule">137 (5.9%)</td><td styleCode="Rrule">172 (3.7%)</td><td styleCode="Rrule">0.62 (0.49, 0.77)</td></tr></tbody></table>

Distributed by: Boehringer Ingelheim Pharmaceuticals, Inc. Ridgefield, CT 06877 USA Licensed from: Boehringer Ingelheim International GmbH, Ingelheim, Germany SYNJARDY is a registered trademark of and used under license from Boehringer Ingelheim International GmbH. Boehringer Ingelheim Pharmaceuticals, Inc. either owns or uses the Jardiance ® , EMPA-REG OUTCOME ® , EMPEROR-Reduced ® , EMPEROR-Preserved ® , and EMPA-KIDNEY ® trademarks under license. The other brands listed are trademarks of their respective owners and are not trademarks of Boehringer Ingelheim Pharmaceuticals, Inc. Copyright © 2026 Boehringer Ingelheim International GmbH ALL RIGHTS RESERVED COL12574FA072026 SPL8978L

<table width="100%"><col width="3%" align="left" valign="top"/><col width="3%" align="left" valign="top"/><col width="23%" align="left" valign="top"/><col width="24%" align="left" valign="top"/><col width="23%" align="left" valign="top"/><col width="24%" align="left" valign="top"/><tfoot><tr><td colspan="5" align="left" valign="top">This Medication Guide has been approved by the U.S. Food and Drug Administration.</td><td align="right" valign="top"> Revised: January 2026</td></tr></tfoot><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="6" align="center"><content styleCode="bold">MEDICATION GUIDE SYNJARDY^&#xAE; (sin-JAR-dee) (empagliflozin and metformin hydrochloride tablets), for oral use and SYNJARDY^&#xAE; XR (sin-JAR-dee XR) (empagliflozin and metformin hydrochloride extended-release tablets), for oral use</content></td></tr><tr><td styleCode="Lrule Rrule" colspan="6"><content styleCode="bold" ID="whatis">What is the most important information I should know about SYNJARDY or SYNJARDY XR? </content> SYNJARDY or SYNJARDY XR can cause serious side effects, including:<list><item><content styleCode="bold">Lactic Acidosis. Metformin hydrochloride (HCl), one of the medicines in SYNJARDY and SYNJARDY XR, can cause a rare but serious condition called lactic acidosis (a build-up of lactic acid in the blood) that can cause death. Lactic acidosis is a medical emergency and must be treated in a hospital. Stop taking SYNJARDY or SYNJARDY XR and call your healthcare provider right away or go to the nearest hospital emergency room if you get any of the following symptoms of lactic acidosis:</content></item></list></td></tr><tr><td styleCode="Lrule" colspan="2"/><td colspan="2"><list listType="unordered" styleCode="circle"><item>feel very weak and tired</item><item>have unusual (not normal) muscle pain</item><item>have trouble breathing</item><item>have unexplained stomach or intestinal problems with nausea and vomiting, or diarrhea</item></list></td><td styleCode="Rrule" colspan="2"><list listType="unordered" styleCode="circle"><item>have unusual sleepiness or sleep longer than usual</item><item>feel cold, especially in your arms and legs</item><item>feel dizzy or lightheaded</item><item>have a slow or irregular heartbeat</item></list></td></tr><tr><td styleCode="Lrule"/><td styleCode="Rrule" colspan="5" align="left"><content styleCode="bold">You have a higher chance of getting lactic acidosis with SYNJARDY or SYNJARDY XR if you:</content><list><item>have moderate to severe kidney problems.</item><item>have liver problems.</item><item>drink a lot of alcohol (very often or short-term &quot;binge&quot; drinking).</item><item>get dehydrated (lose a large amount of body fluids). This can happen if you are sick with a fever, vomiting, or diarrhea. Dehydration can also happen when you sweat a lot with activity or exercise and do not drink enough fluids.</item><item>have certain x-ray tests with injectable dyes or contrast agents.</item><item>have surgery or other procedure for which you need to restrict the amount of food and liquid you eat and drink.</item><item>have congestive heart failure.</item><item>have a heart attack, severe infection, or stroke.</item><item>are 65 years of age or older.</item></list>Tell your healthcare provider if you have any of the problems in the list above. Tell your healthcare provider that you are taking SYNJARDY or SYNJARDY XR before you have surgery or x-ray tests.

r blood pressure, including diuretics (water pills)</item><item>are on a low sodium (salt) diet</item><item>have kidney problems</item><item>are 65 years of age or older</item></list>Talk to your healthcare provider about what you can do to prevent dehydration including how much fluid you should drink on a daily basis. Call your healthcare provider right away if you reduce the amount of food or liquid you drink, for example if you are sick or you cannot eat, or start to lose liquids from your body, for example from vomiting, diarrhea or being in the sun too long.</item></list></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="6"><content styleCode="bold">What is SYNJARDY or SYNJARDY XR?</content><list listType="unordered" styleCode="disc"><item>SYNJARDY is a prescription medicine that contains 2 diabetes medicines, empagliflozin (JARDIANCE) and metformin HCl immediate-release.</item><item>SYNJARDY XR is a prescription medicine that contains 2 diabetes medicines, empagliflozin (JARDIANCE) and metformin HCl extended-release.</item><item>SYNJARDY can be used along with diet and exercise to improve blood sugar (glucose) in adults and children who are 10 years of age and older with type 2 diabetes.</item><item>SYNJARDY XR can be used along with diet and exercise to improve blood sugar (glucose) in adults with type 2 diabetes.</item><item>One of the medicines in SYNJARDY and SYNJARDY XR, empagliflozin (JARDIANCE), can also be used in adults with type 2 diabetes:<list listType="unordered" styleCode="circle"><item>who have known cardiovascular disease to reduce the risk of cardiovascular death.</item><item>who have heart failure (when the heart cannot pump enough blood to the rest of your body) to reduce the risk of cardiovascular death and hospitalization for heart failure.</item><item>to reduce the risk of further worsening of kidney disease, end-stage kidney disease (ESKD), death due to cardiovascular disease, and hospitalization in adults with chronic kidney disease.</item></list></item><item>SYNJARDY or SYNJARDY XR is not for use to lower blood sugar (glucose) in people with type 1 diabetes. It may increase their risk of diabetic ketoacidosis (increased ketones in blood or urine).</item><item>SYNJARDY or SYNJARDY XR is only for use in people with type 2 diabetes, because it contains the prescription medicine metformin HCl.</item><item>One of the medicines in SYNJARDY or SYNJARDY XR, empagliflozin (JARDIANCE), is not for people with polycystic kidney disease, or who are taking or have recently received certain types of immunosuppressive therapy to treat kidney disease. Empagliflozin (JARDIANCE) is not expected to work if you have these conditions.</item><item>It is not known if SYNJARDY is safe and effective in children under 10 years of age.</item><item>It is not known if SYNJARDY XR is safe and effective in children.</item></list></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="6"><content styleCode="bold" ID="who">Who should not take SYNJARDY or SYNJARDY XR? Do not take SYNJARDY or SYNJARDY XR if you:</content><list><item>have severe kidney problems.</item><item>have a condition called metabolic acidosis or diabetic ketoacidosis (increased ketones in the blood or urine).</item><item>are allergic to empagliflozin (JARDIANCE), metformin HCl, or any of the ingredients in SYNJARDY or SYNJARDY XR. See the end of this Medication Guide for a complete list of ingredients in SYNJARDY and SYNJARDY XR.

cy room right away.</item><item>When taking SYNJARDY or SYNJARDY XR, you may have sugar in your urine, which will show up on a urine test.</item><item>When your body is under some types of stress, such as fever, trauma (such as a car accident), infection, or surgery, the amount of diabetes medicine you need may change. Tell your healthcare provider right away if you have any of these conditions and follow your healthcare provider&apos;s instructions.</item><item>Your healthcare provider may do certain blood tests before you start SYNJARDY or SYNJARDY XR and during your treatment as needed.</item></list></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="6"><content styleCode="bold">What should I avoid while taking SYNJARDY or SYNJARDY XR?</content> Avoid drinking alcohol very often, or drinking a lot of alcohol in a short period of time (&quot;binge&quot; drinking). It can increase your chances of getting serious side effects.</td></tr><tr><td styleCode="Lrule Rrule" colspan="6"><content styleCode="bold" ID="whatare">What are the possible side effects of SYNJARDY or SYNJARDY XR? SYNJARDY or SYNJARDY XR may cause serious side effects, including:</content><list><item>See <content styleCode="bold">&quot;<linkHtml href="#whatis">What is the most important information I should know about SYNJARDY or SYNJARDY XR?</linkHtml>&quot;</content></item><item><content styleCode="bold">Genital and urinary tract infections.</content> Empagliflozin, one of the medicines in SYNJARDY and SYNJARDY XR, can cause serious infections in your genital area or urinary tract that could require hospitalization. <content styleCode="bold">A rare but serious bacterial infection called necrotizing fasciitis can cause damage to the tissue under the skin in the area between and around the anus and genitals (perineum).</content> This infection may require hospitalization, multiple surgeries, and could lead to death.

hospitalization. <content styleCode="bold">A rare but serious bacterial infection called necrotizing fasciitis can cause damage to the tissue under the skin in the area between and around the anus and genitals (perineum).</content> This infection may require hospitalization, multiple surgeries, and could lead to death. <content styleCode="bold">Seek medical attention immediately if you have a fever or you are feeling very weak, tired or uncomfortable (malaise), and you develop any of the following symptoms in the area between and around your anus and genitals:</content></item></list></td></tr><tr><td styleCode="Lrule"/><td colspan="2"><list listType="unordered" styleCode="circle"><item>pain or tenderness</item></list></td><td><list listType="unordered" styleCode="circle"><item>swelling</item></list></td><td styleCode="Rrule" colspan="2"><list listType="unordered" styleCode="circle"><item>redness of skin (erythema)</item></list></td></tr><tr><td styleCode="Lrule"/><td styleCode="Rrule" colspan="5">Also tell your healthcare provider if you have any of these signs or symptoms of urinary tract infections or yeast infections:</td></tr><tr><td styleCode="Lrule"/><td styleCode="Rrule" colspan="5"><list listType="unordered" styleCode="circle"><item><content styleCode="bold">Urinary tract infection:</content></item></list></td></tr><tr><td styleCode="Lrule" colspan="2"/><td styleCode="Rrule" colspan="4"><list listType="unordered" styleCode="square"><item>burning feeling when you urinate</item><item>need to urinate often or right away</item><item>pain in the lower part of your stomach (pelvis)</item><item>blood in your urine</item></list></td></tr><tr><td styleCode="Lrule" colspan="2"/><td styleCode="Rrule" colspan="4">You may also have a fever, back pain, nausea, or vomiting.</td></tr><tr><td styleCode="Lrule"/><td styleCode="Rrule" colspan="5"><list listType="unordered" styleCode="circle"><item><content styleCode="bold">Vaginal yeast infection:</content></item></list></td></tr><tr><td styleCode="Lrule" colspan="2"/><td styleCode="Rrule" colspan="4"><list listType="unordered" styleCode="square"><item>vaginal odor</item><item>white or yellowish vaginal discharge (may be lumpy or look like cottage cheese)</item><item>vaginal itching</item></list></td></tr><tr><td styleCode="Lrule"/><td styleCode="Rrule" colspan="5"><list listType="unordered" styleCode="circle"><item><content styleCode="bold">Yeast infection of the skin around the penis (balanitis or balanoposthitis):</content> If you are uncircumcised, swelling may make it difficult to pull back the skin around the tip of your penis. Other symptoms include:</item></list></td></tr><tr><td styleCode="Lrule" colspan="2"/><td colspan="2"><list listType="unordered" styleCode="square"><item>redness, itching, or swelling of the penis</item><item>bad smelling discharge from the penis</item></list></td><td styleCode="Rrule" colspan="2"><list listType="unordered" styleCode="square"><item>rash on the penis</item><item>pain in the skin around the penis</item></list></td></tr><tr><td styleCode="Lrule" colspan="2"/><td styleCode="Rrule" colspan="4">Talk to your healthcare provider about what to do if you get symptoms of a yeast infection. They may suggest you use an over-the-counter antifungal medicine. Contact your healthcare provider right away if your symptoms do not improve after using an over-the-counter antifungal medicine.</td></tr><tr><td styleCode="Lrule Rrule" colspan="6"><list listType="unordered" styleCode="disc"><item><content styleCode="bold">Low blood sugar (hypoglycemia).</content> In adults, if you take SYNJARDY or SYNJARDY XR with another medicine that can cause low blood sugar, such as a sulfonylurea or insulin, your risk of getting low blood sugar is higher.

Rrule" colspan="6"><list listType="unordered" styleCode="disc"><item><content styleCode="bold">Low blood sugar (hypoglycemia).</content> In adults, if you take SYNJARDY or SYNJARDY XR with another medicine that can cause low blood sugar, such as a sulfonylurea or insulin, your risk of getting low blood sugar is higher. In children 10 years of age and older, the risk for low blood sugar is higher with SYNJARDY even if you do not use another medicine that can also lower blood sugar. The dose of your sulfonylurea medicine or insulin may need to be lowered while you take SYNJARDY or SYNJARDY XR. Signs and symptoms of low blood sugar may include:</item></list></td></tr><tr><td styleCode="Lrule"/><td colspan="2"><list listType="unordered" styleCode="circle"><item>headache</item><item>drowsiness</item><item>weakness</item></list></td><td><list listType="unordered" styleCode="circle"><item>irritability</item><item>hunger</item><item>fast heartbeat</item></list></td><td><list listType="unordered" styleCode="circle"><item>confusion</item><item>shaking or feeling jittery</item></list></td><td styleCode="Rrule"><list listType="unordered" styleCode="circle"><item>dizziness</item><item>sweating</item></list></td></tr><tr><td styleCode="Lrule Rrule" colspan="6"><list><item><content styleCode="bold">Amputations. SGLT2 inhibitors may increase your risk of lower limb amputations.</content> You may be at a higher risk of lower limb amputation if you:<list styleCode="circle" listType="unordered"><item>have a history of amputation</item><item>have had blocked or narrowed blood vessels, usually in your leg</item><item>have had diabetic foot infection, ulcers or sores</item></list><content styleCode="bold">Call your healthcare provider right away if you have new pain or tenderness, any sores, ulcers, or infections in your leg or foot.</content> Talk to your healthcare provider about proper foot care.</item><item><content styleCode="bold">Serious allergic reactions.</content> If you have any symptoms of a serious allergic reaction, stop taking SYNJARDY or SYNJARDY XR and call your healthcare provider right away or go to the nearest hospital emergency room. See &quot;<content styleCode="bold"><linkHtml href="#who">Who should not take SYNJARDY or SYNJARDY XR?</linkHtml></content>&quot;.</item><item><content styleCode="bold">Low vitamin B₁₂ (vitamin B₁₂ deficiency).</content> Using metformin for long periods of time may cause a decrease in the amount of vitamin B₁₂ in your blood, especially if you have had low vitamin B₁₂ blood levels before. Your healthcare provider may do blood tests to check your vitamin B₁₂ levels.</item></list></td></tr><tr><td styleCode="Lrule Rrule" colspan="6"><content styleCode="bold">The most common side effects of SYNJARDY or SYNJARDY XR include:</content></td></tr><tr><td colspan="4" styleCode="Lrule"><list><item>low blood sugar</item><item>urinary tract infections</item><item>stuffy or runny nose and sore throat</item><item>yeast infections in females</item><item>diarrhea</item><item>nausea or vomiting</item></list></td><td styleCode="Rrule" colspan="2"><list><item>gas</item><item>stomach discomfort</item><item>indigestion</item><item>weakness</item><item>headache</item></list></td></tr><tr styleCode="Botrule"><td colspan="6" styleCode="Lrule Rrule">These are not all the possible side effects of SYNJARDY or SYNJARDY XR. For more information, ask your healthcare provider or pharmacist. Call your doctor for medical advice about side effects.

tem><item>weakness</item><item>headache</item></list></td></tr><tr styleCode="Botrule"><td colspan="6" styleCode="Lrule Rrule">These are not all the possible side effects of SYNJARDY or SYNJARDY XR. For more information, ask your healthcare provider or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="6"><content styleCode="bold">How should I store SYNJARDY or SYNJARDY XR?</content><list><item>Store SYNJARDY or SYNJARDY XR at room temperature between 68&#xB0;F to 77&#xB0;F (20&#xB0;C to 25&#xB0;C).</item><item><content styleCode="bold">Keep SYNJARDY or SYNJARDY XR and all medicines out of the reach of children.</content></item></list></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="6"><content styleCode="bold">General information about the safe and effective use of SYNJARDY or SYNJARDY XR.</content> Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use SYNJARDY or SYNJARDY XR for a condition for which it was not prescribed. Do not give SYNJARDY or SYNJARDY XR to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about SYNJARDY or SYNJARDY XR that is written for health professionals.</td></tr><tr><td styleCode="Lrule Rrule" colspan="6"><content styleCode="bold">What are the ingredients in SYNJARDY?</content> <content styleCode="bold">Active Ingredients:</content> empagliflozin and metformin HCl <content styleCode="bold">Inactive Ingredients:</content> colloidal silicon dioxide, copovidone, corn starch, and magnesium stearate. In addition, the film coating contains the following inactive ingredients: hypromellose, polyethylene glycol 400, talc, and titanium dioxide. 5 mg/500 mg and 5 mg/1,000 mg tablets also contain ferric oxide yellow. 12.5 mg/500 mg and 12.5 mg/1,000 mg tablets also contain black ferrosoferric oxide and ferric oxide red. <content styleCode="bold">What are the ingredients in SYNJARDY XR?</content> <content styleCode="bold">Active Ingredients:</content> empagliflozin and metformin HCl <content styleCode="bold">Inactive Ingredients:</content> Tablet core contains: hypromellose, magnesium stearate, and polyethylene oxide. The film coatings and printing ink contain: carnauba wax, FD&amp;C blue#2/indigo carmine aluminum lake (12.5 mg/1,000 mg, 25 mg/1,000 mg), ferric oxide red (10 mg/1,000 mg), ferric oxide yellow (5 mg/1,000 mg, 10 mg/1,000 mg, 25 mg/1,000 mg), ferrosoferric oxide, hypromellose, isopropyl alcohol, polydextrose, polyethylene glycol, propylene glycol, purified water, talc, and titanium dioxide.</td></tr><tr><td styleCode="Lrule Rrule" colspan="6"><paragraph>Distributed by: Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT 06877 USA Licensed from: Boehringer Ingelheim International GmbH, Ingelheim, Germany SYNJARDY is a registered trademark of and used under license from Boehringer Ingelheim International GmbH. Boehringer Ingelheim Pharmaceuticals, Inc. either owns or uses the Jardiance^&#xAE;, EMPA-REG OUTCOME^&#xAE;, EMPEROR-Reduced^&#xAE;, EMPEROR-Preserved^&#xAE;, and EMPA-KIDNEY^&#xAE; trademarks under license. The other brands listed are trademarks of their respective owners and are not trademarks of Boehringer Ingelheim Pharmaceuticals, Inc.

nce^&#xAE;, EMPA-REG OUTCOME^&#xAE;, EMPEROR-Reduced^&#xAE;, EMPEROR-Preserved^&#xAE;, and EMPA-KIDNEY^&#xAE; trademarks under license. The other brands listed are trademarks of their respective owners and are not trademarks of Boehringer Ingelheim Pharmaceuticals, Inc. Copyright &#xA9; 2026 Boehringer Ingelheim International GmbH ALL RIGHTS RESERVED COL12574FA072026 For more information about SYNJARDY or SYNJARDY XR, including current prescribing information and Medication Guide, go to <content styleCode="bold">www.synjardy.com</content> or <content styleCode="bold">www.synjardyxr.com</content>, scan the code, or call Boehringer Ingelheim Pharmaceuticals, Inc. at 1-800-542-6257. <renderMultiMedia referencedObject="MM8"/></paragraph></td></tr></tbody></table>