ADVERSE REACTIONS SECTION.


6ADVERSE REACTIONS. The following important adverse reactions are described below and elsewhere in the labeling:Ketoacidosis [see Warnings and Precautions (5.1)] Volume Depletion [see Warnings and Precautions (5.2)] Urosepsis and Pyelonephritis [see Warnings and Precautions (5.3)] Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues [see Warnings and Precautions (5.4)] Necrotizing Fasciitis of the Perineum (Fourniers Gangrene) [see Warnings and Precautions (5.5)] Genital Mycotic Infections [see Warnings and Precautions (5.6)] Hypersensitivity Reactions [see Warnings and Precautions (5.7)] Ketoacidosis [see Warnings and Precautions (5.1)] Volume Depletion [see Warnings and Precautions (5.2)] Urosepsis and Pyelonephritis [see Warnings and Precautions (5.3)] Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues [see Warnings and Precautions (5.4)] Necrotizing Fasciitis of the Perineum (Fourniers Gangrene) [see Warnings and Precautions (5.5)] Genital Mycotic Infections [see Warnings and Precautions (5.6)] Hypersensitivity Reactions [see Warnings and Precautions (5.7)] The most common adverse reactions associated with JARDIANCE (5% or greater incidence) were urinary tract infections and female genital mycotic infections (6.1)To report SUSPECTED ADVERSE REACTIONS, contact Boehringer Ingelheim Pharmaceuticals, Inc. at 1-800-542-6257 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.. The most common adverse reactions associated with JARDIANCE (5% or greater incidence) were urinary tract infections and female genital mycotic infections (6.1). 6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.. Pool of Placebo-Controlled Trials evaluating JARDIANCE 10 and 25 mgThe data in Table are derived from pool of four 24-week placebo-controlled trials and 18-week data from placebo-controlled trial with insulin. JARDIANCE was used as monotherapy in one trial and as add-on therapy in four trials [see Clinical Studies (14)].These data reflect exposure of 1976 patients to JARDIANCE with mean exposure duration of approximately 23 weeks. Patients received placebo (N=995), JARDIANCE 10 mg (N=999), or JARDIANCE 25 mg (N=977) once daily. The mean age of the population was 56 years and 3% were older than 75 years of age. More than half (55%) of the population was male; 46% were White, 50% were Asian, and 3% were Black or African American. At baseline, 57% of the population had diabetes more than years and had mean hemoglobin A1c (HbA1c) of 8%. Established microvascular complications of diabetes at baseline included diabetic nephropathy (7%), retinopathy (8%), or neuropathy (16%). Baseline renal function was normal or mildly impaired in 91% of patients and moderately impaired in 9% of patients (mean eGFR 86.8 mL/min/1.73 m2).Table shows common adverse reactions (excluding hypoglycemia) associated with the use of JARDIANCE. The adverse reactions were not present at baseline, occurred more commonly on JARDIANCE than on placebo and occurred in greater than or equal to 2% of patients treated with JARDIANCE 10 mg or JARDIANCE 25 mg.Table 1Adverse Reactions Reported in >=2% of Patients Treated with JARDIANCE and Greater than Placebo in Pooled Placebo-Controlled Clinical Studies of JARDIANCE Monotherapy or Combination TherapyAdverse ReactionsPlacebo (%)N=995JARDIANCE 10 mg (%)N=999JARDIANCE 25 mg (%)N=977aPredefined adverse event grouping, including, but not limited to, urinary tract infection, asymptomatic bacteriuria, cystitis bFemale genital mycotic infections include the following adverse reactions: vulvovaginal mycotic infection, vaginal infection, vulvitis, vulvovaginal candidiasis, genital infection, genital candidiasis, genital infection fungal, genitourinary tract infection, vulvovaginitis, cervicitis, urogenital infection fungal, vaginitis bacterial. Percentages calculated with the number of female subjects in each group as denominator: placebo (N=481), JARDIANCE 10 mg (N=443), JARDIANCE 25 mg (N=420). cPredefined adverse event grouping, including, but not limited to, polyuria, pollakiuria, and nocturia dMale genital mycotic infections include the following adverse reactions: balanoposthitis, balanitis, genital infections fungal, genitourinary tract infection, balanitis candida, scrotal abscess, penile infection. Percentages calculated with the number of male subjects in each group as denominator: placebo (N=514), JARDIANCE 10 mg (N=556), JARDIANCE 25 mg (N=557).Urinary tract infectiona 7.69.37.6Female genital mycotic infectionsb 1.55.46.4Upper respiratory tract infection3.83.14.0Increased urinationc 1.03.43.2Dyslipidemia3.43.92.9Arthralgia2.22.42.3Male genital mycotic infectionsd 0.43.11.6Nausea1.42.31.1Thirst (including polydipsia) was reported in 0%, 1.7%, and 1.5% for placebo, JARDIANCE 10 mg, and JARDIANCE 25 mg, respectively.. Volume DepletionJARDIANCE causes an osmotic diuresis, which may lead to intravascular volume contraction and adverse reactions related to volume depletion. In the pool of five placebo-controlled clinical trials, adverse reactions related to volume depletion (e.g., blood pressure (ambulatory) decreased, blood pressure systolic decreased, dehydration, hypotension, hypovolemia, orthostatic hypotension, and syncope) were reported by 0.3%, 0.5%, and 0.3% of patients treated with placebo, JARDIANCE 10 mg, and JARDIANCE 25 mg, respectively. JARDIANCE may increase the risk of hypotension in patients at risk for volume contraction [see Use in Specific Populations (8.5, 8.6)]. Increased UrinationIn the pool of five placebo-controlled clinical trials, adverse reactions of increased urination (e.g., polyuria, pollakiuria, and nocturia) occurred more frequently on JARDIANCE than on placebo (see Table 1). Specifically, nocturia was reported by 0.4%, 0.3%, and 0.8% of patients treated with placebo, JARDIANCE 10 mg, and JARDIANCE 25 mg, respectively.. HypoglycemiaThe incidence of hypoglycemia by study is shown in Table 2. The incidence of hypoglycemia increased when JARDIANCE was administered with insulin or sulfonylurea.Table 2Incidence of Overalla and Severeb Hypoglycemic Events in Placebo-Controlled Clinical Studiesc aOverall hypoglycemic events: plasma or capillary glucose of less than or equal to 70 mg/dL bSevere hypoglycemic events: requiring assistance regardless of blood glucose cTreated set (patients who had received at least one dose of study drug) dInsulin dose could not be adjusted during the initial 18 week treatment periodMonotherapy (24 weeks)Placebo (n=229)JARDIANCE 10 mg (n=224)JARDIANCE 25 mg (n=223)Overall (%)0.40.40.4Severe (%)000In Combination with Metformin (24 weeks)Placebo Metformin (n=206)JARDIANCE 10 mg Metformin (n=217)JARDIANCE 25 mg Metformin (n=214)Overall (%)0.51.81.4Severe (%)000In Combination with Metformin Sulfonylurea (24 weeks)Placebo (n=225)JARDIANCE 10 mg Metformin Sulfonylurea (n=224)JARDIANCE 25 mg Metformin Sulfonylurea (n=217)Overall (%)8.416.111.5Severe (%)000In Combination with Pioglitazone +/- Metformin (24 weeks)Placebo (n=165)JARDIANCE 10 mg Pioglitazone +/- Metformin (n=165)JARDIANCE 25 mg Pioglitazone +/- Metformin (n=168)Overall (%)1.81.22.4Severe (%)000In Combination with Basal Insulin +/- Metformin (18 weeksd)Placebo (n=170)JARDIANCE 10 mg (n=169)JARDIANCE 25 mg (n=155)Overall (%)20.619.528.4Severe (%)001.3In Combination with MDI Insulin +/-Metformin (18 weeksd)Placebo (n=188)JARDIANCE 10 mg (n=186)JARDIANCE 25 mg (n=189)Overall (%)37.239.841.3Severe (%)0.50.50.5. Genital Mycotic InfectionsIn the pool of five placebo-controlled clinical trials, the incidence of genital mycotic infections (e.g., vaginal mycotic infection, vaginal infection, genital infection fungal, vulvovaginal candidiasis, and vulvitis) was increased in patients treated with JARDIANCE compared to placebo, occurring in 0.9%, 4.1%, and 3.7% of patients randomized to placebo, JARDIANCE 10 mg, and JARDIANCE 25 mg, respectively. Discontinuation from study due to genital infection occurred in 0% of placebo-treated patients and 0.2% of patients treated with either JARDIANCE 10 or 25 mg.Genital mycotic infections occurred more frequently in female than male patients (see Table 1).Phimosis occurred more frequently in male patients treated with JARDIANCE 10 mg (less than 0.1%) and JARDIANCE 25 mg (0.1%) than placebo (0%).. Urinary Tract InfectionsIn the pool of five placebo-controlled clinical trials, the incidence of urinary tract infections (e.g., urinary tract infection, asymptomatic bacteriuria, and cystitis) was increased in patients treated with JARDIANCE compared to placebo (see Table 1). Patients with history of chronic or recurrent urinary tract infections were more likely to experience urinary tract infection. The rate of treatment discontinuation due to urinary tract infections was 0.1%, 0.2%, and 0.1% for placebo, JARDIANCE 10 mg, and JARDIANCE 25 mg, respectively.Urinary tract infections occurred more frequently in female patients. The incidence of urinary tract infections in female patients randomized to placebo, JARDIANCE 10 mg, and JARDIANCE 25 mg was 16.6%, 18.4%, and 17.0%, respectively. The incidence of urinary tract infections in male patients randomized to placebo, JARDIANCE 10 mg, and JARDIANCE 25 mg was 3.2%, 3.6%, and 4.1%, respectively [see Use in Specific Populations (8.5)].. Laboratory Tests. Increases in Serum Creatinine and Decreases in eGFRInitiation of JARDIANCE causes an increase in serum creatinine and decrease in eGFR within weeks of starting therapy and then these changes stabilize. In study of patients with moderate renal impairment, larger mean changes were observed. In long-term cardiovascular outcomes trial, the increase in serum creatinine and decrease in eGFR generally did not exceed 0.1 mg/dL and -9.0 mL/min/1.73 m2, respectively, at Week 4, and reversed after treatment discontinuation, suggesting acute hemodynamic changes may play role in the renal function changes observed with JARDIANCE.. Increase in Low-Density Lipoprotein Cholesterol (LDL-C)Dose-related increases in low-density lipoprotein cholesterol (LDL-C) were observed in patients treated with JARDIANCE. LDL-C increased by 2.3%, 4.6%, and 6.5% in patients treated with placebo, JARDIANCE 10 mg, and JARDIANCE 25 mg, respectively. The range of mean baseline LDL-C levels was 90.3 to 90.6 mg/dL across treatment groups.. Increase in HematocritIn pool of four placebo-controlled studies, median hematocrit decreased by 1.3% in placebo and increased by 2.8% in JARDIANCE 10 mg and 2.8% in JARDIANCE 25 mg treated patients. At the end of treatment, 0.6%, 2.7%, and 3.5% of patients with hematocrits initially within the reference range had values above the upper limit of the reference range with placebo, JARDIANCE 10 mg, and JARDIANCE 25 mg, respectively.. 6.2 Postmarketing Experience. Additional adverse reactions have been identified during postapproval use of JARDIANCE. Because these reactions are reported voluntarily from population of uncertain size, it is generally not possible to reliably estimate their frequency or establish causal relationship to drug exposure.KetoacidosisUrosepsis and PyelonephritisNecrotizing Fasciitis of the Perineum (Fourniers gangrene)AngioedemaAcute Kidney InjurySkin Reactions (e.g., rash, urticaria). Ketoacidosis. Urosepsis and Pyelonephritis. Necrotizing Fasciitis of the Perineum (Fourniers gangrene). Angioedema. Acute Kidney Injury. Skin Reactions (e.g., rash, urticaria).

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.


13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. CarcinogenesisCarcinogenesis was evaluated in 2-year studies conducted in CD-1 mice and Wistar rats. Empagliflozin did not increase the incidence of tumors in female rats dosed at 100, 300, or 700 mg/kg/day (up to 72 times the exposure from the maximum clinical dose of 25 mg). In male rats, hemangiomas of the mesenteric lymph node were increased significantly at 700 mg/kg/day or approximately 42 times the exposure from 25 mg clinical dose. Empagliflozin did not increase the incidence of tumors in female mice dosed at 100, 300, or 1000 mg/kg/day (up to 62 times the exposure from 25 mg clinical dose). Renal tubule adenomas and carcinomas were observed in male mice at 1000 mg/kg/day, which is approximately 45 times the exposure of the maximum clinical dose of 25 mg. These tumors may be associated with metabolic pathway predominantly present in the male mouse kidney.. MutagenesisEmpagliflozin was not mutagenic or clastogenic with or without metabolic activation in the in vitro Ames bacterial mutagenicity assay, the in vitro L5178Y tk+/- mouse lymphoma cell assay, and an in vivo micronucleus assay in rats.. Impairment of FertilityEmpagliflozin had no effects on mating, fertility or early embryonic development in treated male or female rats up to the high dose of 700 mg/kg/day (approximately 155 times the 25 mg clinical dose in males and females, respectively).

CLINICAL PHARMACOLOGY SECTION.


12CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Sodium-glucose co-transporter (SGLT2) is the predominant transporter responsible for reabsorption of glucose from the glomerular filtrate back into the circulation. Empagliflozin is an inhibitor of SGLT2. By inhibiting SGLT2, empagliflozin reduces renal reabsorption of filtered glucose and lowers the renal threshold for glucose, and thereby increases urinary glucose excretion.. 12.2 Pharmacodynamics. Urinary Glucose ExcretionIn patients with type diabetes, urinary glucose excretion increased immediately following dose of empagliflozin and was maintained at the end of 4-week treatment period averaging at approximately 64 grams per day with 10 mg empagliflozin and 78 grams per day with 25 mg empagliflozin once daily [see Clinical Studies (14)]. Data from single oral doses of empagliflozin in healthy subjects indicate that, on average, the elevation in urinary glucose excretion approaches baseline by about days for the 10 mg and 25 mg doses.. Urinary VolumeIn 5-day study, mean 24-hour urine volume increase from baseline was 341 mL on Day and 135 mL on Day of empagliflozin 25 mg once daily treatment.. Cardiac ElectrophysiologyIn randomized, placebo-controlled, active-comparator, crossover study, 30 healthy subjects were administered single oral dose of empagliflozin 25 mg, empagliflozin 200 mg (8 times the maximum dose), moxifloxacin, and placebo. No increase in QTc was observed with either 25 mg or 200 mg empagliflozin.. 12.3 Pharmacokinetics. AbsorptionThe pharmacokinetics of empagliflozin has been characterized in healthy volunteers and patients with type diabetes and no clinically relevant differences were noted between the two populations. After oral administration, peak plasma concentrations of empagliflozin were reached at 1.5 hours post-dose. Thereafter, plasma concentrations declined in biphasic manner with rapid distribution phase and relatively slow terminal phase. The steady-state mean plasma AUC and Cmax were 1870 nmolh/L and 259 nmol/L, respectively, with 10 mg empagliflozin once daily treatment, and 4740 nmolh/L and 687 nmol/L, respectively, with 25 mg empagliflozin once daily treatment. Systemic exposure of empagliflozin increased in dose-proportional manner in the therapeutic dose range. The single-dose and steady-state pharmacokinetic parameters of empagliflozin were similar, suggesting linear pharmacokinetics with respect to time.Administration of 25 mg empagliflozin after intake of high-fat and high-calorie meal resulted in slightly lower exposure; AUC decreased by approximately 16% and Cmax decreased by approximately 37%, compared to fasted condition. The observed effect of food on empagliflozin pharmacokinetics was not considered clinically relevant and empagliflozin may be administered with or without food.. DistributionThe apparent steady-state volume of distribution was estimated to be 73.8 based on population pharmacokinetic analysis. Following administration of an oral [14C]-empagliflozin solution to healthy subjects, the red blood cell partitioning was approximately 36.8% and plasma protein binding was 86.2%.. EliminationThe apparent terminal elimination half-life of empagliflozin was estimated to be 12.4 and apparent oral clearance was 10.6 L/h based on the population pharmacokinetic analysis. Following once-daily dosing, up to 22% accumulation, with respect to plasma AUC, was observed at steady-state, which was consistent with empagliflozin half-life.. MetabolismNo major metabolites of empagliflozin were detected in human plasma and the most abundant metabolites were three glucuronide conjugates (2-O-, 3-O-, and 6-O-glucuronide). Systemic exposure of each metabolite was less than 10% of total drug-related material. In vitro studies suggested that the primary route of metabolism of empagliflozin in humans is glucuronidation by the uridine 5-diphospho-glucuronosyltransferases UGT2B7, UGT1A3, UGT1A8, and UGT1A9.. ExcretionFollowing administration of an oral [14C]-empagliflozin solution to healthy subjects, approximately 95.6% of the drug-related radioactivity was eliminated in feces (41.2%) or urine (54.4%). The majority of drug-related radioactivity recovered in feces was unchanged parent drug and approximately half of drug-related radioactivity excreted in urine was unchanged parent drug.. Specific Populations. Renal ImpairmentIn patients with mild (eGFR: 60 to less than 90 mL/min/1.73 m2), moderate (eGFR: 30 to less than 60 mL/min/1.73 m2), and severe (eGFR: less than 30 mL/min/1.73 m2) renal impairment and patients with kidney failure/end stage renal disease (ESRD), AUC of empagliflozin increased by approximately 18%, 20%, 66%, and 48%, respectively, compared to subjects with normal renal function. Peak plasma levels of empagliflozin were similar in patients with moderate renal impairment and kidney failure/ESRD compared to subjects with normal renal function. Peak plasma levels of empagliflozin were roughly 20% higher in patients with mild and severe renal impairment as compared to subjects with normal renal function. Population pharmacokinetic analysis showed that the apparent oral clearance of empagliflozin decreased, with decrease in eGFR leading to an increase in drug exposure. However, the fraction of empagliflozin that was excreted unchanged in urine, and urinary glucose excretion, declined with decrease in eGFR.. Hepatic ImpairmentIn 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 Cmax increased by approximately 4%, 23%, and 48%, respectively, compared to subjects with normal hepatic function.. Effects of Age, Body Mass Index, Gender, and RaceBased on the population PK analysis, age, body mass index (BMI), gender and race (Asians versus primarily Whites) do not have clinically meaningful effect on pharmacokinetics of empagliflozin [see Use in Specific Populations (8.5)].. Drug Interactions. In vitro Assessment of Drug InteractionsEmpagliflozin 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 5-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 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 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 InteractionsEmpagliflozin pharmacokinetics were similar with and without coadministration of metformin, 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 diabetes (see Figure 1). In subjects with normal renal function, coadministration of empagliflozin with probenecid resulted in 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 1Effect of Various Medications on the Pharmacokinetics of Empagliflozin as Displayed as 90% Confidence Interval of Geometric Mean AUC and Cmax Ratios [reference lines indicate 100% (80% 125%)]aempagliflozin, 50 mg, once daily; bempagliflozin, 25 mg, single dose; cempagliflozin, 25 mg, once daily; dempagliflozin, 10 mg, single doseEmpagliflozin 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).Figure 2Effect of Empagliflozin on the Pharmacokinetics of Various Medications as Displayed as 90% Confidence Interval of Geometric Mean AUC andCmax Ratios [reference lines indicate 100% (80% 125%)]aempagliflozin, 50 mg, once daily; bempagliflozin, 25 mg, once daily; cempagliflozin, 25 mg, single dose; dadministered as simvastatin; eadministered as warfarin racemic mixture; fadministered as Microgynon(R); gadministered as ramipril. Figure 1. Figure 2.

CLINICAL STUDIES SECTION.


14CLINICAL STUDIES Glycemic ControlJARDIANCE has been studied as monotherapy and in combination with metformin, sulfonylurea, pioglitazone, linagliptin, and insulin. JARDIANCE has also been studied in patients with type diabetes with mild or moderate renal impairment.In patients with type diabetes, treatment with JARDIANCE reduced hemoglobin A1c (HbA1c), compared to placebo. The reduction in HbA1c for JARDIANCE compared with placebo was observed across subgroups including gender, race, geographic region, baseline BMI and duration of disease.. MonotherapyA total of 986 patients with type diabetes participated in double-blind, placebo-controlled study to evaluate the efficacy and safety of JARDIANCE monotherapy.Treatment-naive patients with inadequately controlled type diabetes entered an open-label placebo run-in for weeks. At the end of the run-in period, patients who remained inadequately controlled and had an HbA1c between and 10% were randomized to placebo, JARDIANCE 10 mg, JARDIANCE 25 mg, or reference comparator.At Week 24, treatment with JARDIANCE 10 mg or 25 mg daily provided statistically significant reductions in HbA1c (p-value <0.0001), fasting plasma glucose (FPG), and body weight compared with placebo (see Table and Figure 3).Table 4Results at Week 24 From Placebo-Controlled Monotherapy Study of JARDIANCEJARDIANCE 10 mg N=224JARDIANCE 25 mg N=224Placebo N=228aModified intent to treat population. Last observation on study (LOCF) was used to impute missing data at Week 24. At Week 24, 9.4%, 9.4%, and 30.7% was imputed for patients randomized to JARDIANCE 10 mg, JARDIANCE 25 mg, and placebo, respectively. bANCOVA derived p-value <0.0001 (HbA1c: ANCOVA model includes baseline HbA1c, treatment, renal function, and region. Body weight and FPG: same model used as for HbA1c but additionally including baseline body weight/baseline FPG, respectively.) cFPG (mg/dL); for JARDIANCE 10 mg, n=223, for JARDIANCE 25 mg, n=223, and for placebo, n=226HbA1c (%)a Baseline (mean)7.97.97.9 Change from baseline (adjusted mean)-0.7-0.80.1 Difference from placebo (adjusted mean) (97.5% CI)-0.7b (-0.9, -0.6)-0.9b (-1.0, -0.7)-- Patients [n (%)] achieving HbA1c <7%72 (35%)88 (44%)25 (12%)FPG (mg/dL)c Baseline (mean)153153155 Change from baseline (adjusted mean)-19-2512 Difference from placebo (adjusted mean) (95% CI)-31 (-37, -26)-36 (-42, -31)--Body Weight Baseline (mean) in kg787878 change from baseline (adjusted mean)-2.8-3.2-0.4 Difference from placebo (adjusted mean) (95% CI)-2.5b (-3.1, -1.9)-2.8b (-3.4, -2.2)--Figure 3Adjusted Mean HbA1c Change at Each Time Point (Completers) and at Week 24 (mITT Population) LOCFAt Week 24, the systolic blood pressure was statistically significantly reduced compared to placebo by -2.6 mmHg (placebo-adjusted, p-value=0.0231) in patients randomized to 10 mg of JARDIANCE and by -3.4 mmHg (placebo-corrected, p-value=0.0028) in patients randomized to 25 mg of JARDIANCE.. Figure 3. Add-On Combination Therapy with MetforminA total of 637 patients with type diabetes participated in double-blind, placebo-controlled study to evaluate the efficacy and safety of JARDIANCE in combination with metformin.Patients with type diabetes inadequately controlled on at least 1500 mg of metformin per day entered an open-label week placebo run-in. At the end of the run-in period, patients who remained inadequately controlled and had an HbA1c between and 10% were randomized to placebo, JARDIANCE 10 mg, or JARDIANCE 25 mg.At Week 24, treatment with JARDIANCE 10 mg or 25 mg daily provided statistically significant reductions in HbA1c (p-value <0.0001), FPG, and body weight compared with placebo (see Table 5).Table 5Results at Week 24 From Placebo-Controlled Study for JARDIANCE used in Combination with MetforminJARDIANCE 10 mg Metformin N=217JARDIANCE 25 mg Metformin N=213Placebo Metformin N=207aModified intent to treat population. Last observation on study (LOCF) was used to impute missing data at Week 24. At Week 24, 9.7%, 14.1%, and 24.6% was imputed for patients randomized to JARDIANCE 10 mg, JARDIANCE 25 mg, and placebo, respectively. bANCOVA p-value <0.0001 (HbA1c: ANCOVA model includes baseline HbA1c, treatment, renal function, and region. Body weight and FPG: same model used as for HbA1c but additionally including baseline body weight/baseline FPG, respectively.) cFPG (mg/dL); for JARDIANCE 10 mg, n=216, for JARDIANCE 25 mg, n=213, and for placebo, n=207HbA1c (%)a Baseline (mean)7.97.97.9 Change from baseline (adjusted mean)-0.7-0.8-0.1 Difference from placebo metformin (adjusted mean) (95% CI)-0.6b (-0.7, -0.4)-0.6b (-0.8, -0.5)-- Patients [n (%)] achieving HbA1c <7%75 (38%)74 (39%)23 (13%)FPG (mg/dL)c Baseline (mean)155149156 Change from baseline (adjusted mean)-20-226 Difference from placebo metformin (adjusted mean)-26-29--Body Weight Baseline mean in kg828280 change from baseline (adjusted mean)-2.5-2.9-0.5 Difference from placebo (adjusted mean) (95% CI)-2.0b (-2.6, -1.4)-2.5b (-3.1, -1.9)--At Week 24, the systolic blood pressure was statistically significantly reduced compared to placebo by -4.1 mmHg (placebo-corrected, p-value <0.0001) for JARDIANCE 10 mg and -4.8 mmHg (placebo-corrected, p-value <0.0001) for JARDIANCE 25 mg.. Initial Combination Therapy with MetforminA total of 1364 patients with type diabetes participated in double-blind, randomized, active-controlled study to evaluate the efficacy and safety of JARDIANCE in combination with metformin as initial therapy compared to the corresponding individual components.Treatment-naive patients with inadequately controlled type diabetes entered an open-label placebo run-in for weeks. At the end of the run-in period, patients who remained inadequately controlled and had an HbA1c between and 10.5% were randomized to one of active-treatment arms: JARDIANCE 10 mg or 25 mg; metformin 1000 mg, or 2000 mg; JARDIANCE 10 mg in combination with 1000 mg or 2000 mg metformin; or JARDIANCE 25 mg in combination with 1000 mg or 2000 mg metformin.At Week 24, initial therapy of JARDIANCE in combination with metformin provided statistically significant reductions in HbA1c (p-value <0.01) compared to the individual components (see Table 6).Table 6Glycemic Parameters at 24 Weeks in Study Comparing JARDIANCE and Metformin to the Individual Components as Initial TherapyJARDIANCE 10 mg Metformin 1000 mga N=161JARDIANCE 10 mg Metformin 2000 mga N=167JARDIANCE 25 mg Metformin 1000 mga N=165JARDIANCE 25 mg Metformin 2000 mga N=169JARDIANCE 10 mg N=169JARDIANCE 25 mg N=163Metformin 1000 mga N=167Metformin 2000 mga N=162aMetformin total daily dose, administered in two equally divided doses per day. bp-value <=0.0062 (modified intent to treat population [observed case] MMRM model included treatment, renal function, region, visit, visit by treatment interaction, and baseline HbA1c). cp-value <=0.0056 (modified intent to treat population [observed case] MMRM model included treatment, renal function, region, visit, visit by treatment interaction, and baseline HbA1c).HbA1c (%)Baseline (mean)8.78.78.88.78.68.98.78.6Change from baseline (adjusted mean)-2.0-2.1-1.9-2.1-1.4-1.4-1.2-1.8Comparison vs JARDIANCE (adjusted mean) (95% CI)-0.6b (-0.9, -0.4)-0.7b (-1.0, -0.5)-0.6c (-0.8, -0.3)-0.7c (-1.0, -0.5)--------Comparison vs metformin (adjusted mean) (95% CI)-0.8b (-1.0, -0.6)-0.3b (-0.6, -0.1)-0.8c (-1.0, -0.5)-0.3c (-0.6, -0.1)--------. Add-On Combination Therapy with Metformin and SulfonylureaA total of 666 patients with type diabetes participated in double-blind, placebo-controlled study to evaluate the efficacy and safety of JARDIANCE in combination with metformin plus sulfonylurea.Patients with inadequately controlled type diabetes on at least 1500 mg per day of metformin and on sulfonylurea, entered 2 week open-label placebo run-in. At the end of the run-in, patients who remained inadequately controlled and had an HbA1c between 7% and 10% were randomized to placebo, JARDIANCE 10 mg, or JARDIANCE 25 mg.Treatment with JARDIANCE 10 mg or 25 mg daily provided statistically significant reductions in HbA1c (p-value <0.0001), FPG, and body weight compared with placebo (see Table 7).Table 7Results at Week 24 from Placebo-Controlled Study for JARDIANCE in Combination with Metformin and SulfonylureaJARDIANCE 10 mg Metformin SU N=225JARDIANCE 25 mg Metformin SU N=216Placebo Metformin SU N=225aModified intent to treat population. Last observation on study (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 JARDIANCE 10 mg, JARDIANCE 25 mg, and placebo, respectively. bANCOVA p-value <0.0001 (HbA1c: ANCOVA model includes baseline HbA1c, treatment, renal function, and region. Body weight and FPG: same model used as for HbA1c but additionally including baseline body weight/baseline FPG, respectively.) cFPG (mg/dL); for JARDIANCE 10 mg, n=225, for JARDIANCE 25 mg, n=215, for placebo, n=224HbA1c (%)a Baseline (mean)8.18.18.2 Change from baseline (adjusted mean)-0.8-0.8-0.2 Difference from placebo (adjusted mean) (95% CI)-0.6b (-0.8, -0.5)-0.6b (-0.7, -0.4)-- Patients [n (%)] achieving HbA1c <7%55 (26%)65 (32%)20 (9%)FPG (mg/dL)c Baseline (mean)151156152 Change from baseline (adjusted mean)-23-236 Difference from placebo (adjusted mean)-29-29--Body Weight Baseline mean in kg777876 change from baseline (adjusted mean)-2.9-3.2-0.5 Difference from placebo (adjusted mean) (95% CI)-2.4b (-3.0, -1.8)-2.7b (-3.3, -2.1)--. In Combination with Linagliptin as Add-On to Metformin TherapyA total of 686 patients with type diabetes participated in double-blind, active-controlled study to evaluate the efficacy and safety of JARDIANCE 10 mg or 25 mg in combination with linagliptin mg compared to the individual components.Patients with type diabetes inadequately controlled on at least 1500 mg of metformin per day entered single-blind placebo run-in period for weeks. At the end of the run-in period, patients who remained inadequately controlled and had an HbA1c between and 10.5% were randomized 1:1:1:1:1 to one of active-treatment arms of JARDIANCE 10 mg or 25 mg, linagliptin mg, or linagliptin mg in combination with 10 mg or 25 mg JARDIANCE as fixed dose combination tablet.At Week 24, JARDIANCE 10 mg or 25 mg used in combination with linagliptin mg provided statistically significant improvement in HbA1c (p-value <0.0001) and FPG (p-value <0.001) compared to the individual components in patients who had been inadequately controlled on metformin. Treatment with JARDIANCE/linagliptin 25 mg/5 mg or JARDIANCE/linagliptin 10 mg/5 mg daily also resulted in statistically significant reduction in body weight compared to linagliptin mg (p-value <0.0001). There was no statistically significant difference in body weight compared to JARDIANCE alone.. Active-Controlled Study versus Glimepiride in Combination with MetforminThe efficacy of JARDIANCE was evaluated in double-blind, glimepiride-controlled, study in 1545 patients with type diabetes with insufficient glycemic control despite metformin therapy.Patients with inadequate glycemic control and an HbA1c between 7% and 10% after 2-week run-in period were randomized to glimepiride or JARDIANCE 25 mg.At Week 52, JARDIANCE 25 mg and glimepiride lowered HbA1c and FPG (see Table 8, Figure 4). The difference in observed effect size between JARDIANCE 25 mg and glimepiride excluded the pre-specified non-inferiority margin of 0.3%. The mean daily dose of glimepiride was 2.7 mg and the maximal approved dose in the United States is mg per day.Table 8Results at Week 52 from an Active-Controlled Study Comparing JARDIANCE to Glimepiride as Add-On Therapy in Patients Inadequately Controlled on MetforminJARDIANCE 25 mg Metformin N=765Glimepiride Metformin N=780aModified intent to treat population. Last observation on study (LOCF) was used to impute data missing at Week 52. At Week 52, data was imputed for 15.3% and 21.9% of patients randomized to JARDIANCE 25 mg and glimepiride, respectively. bNon-inferior, ANCOVA model p-value <0.0001 (HbA1c: ANCOVA model includes baseline HbA1c, treatment, renal function, and region) cANCOVA p-value <0.0001 (Body weight and FPG: same model used as for HbA1c but additionally including baseline body weight/baseline FPG, respectively.) dFPG (mg/dL); for JARDIANCE 25 mg, n=764, for glimepiride, n=779HbA1c (%)a Baseline (mean)7.97.9 Change from baseline (adjusted mean)-0.7-0.7 Difference from glimepiride (adjusted mean) (97.5% CI)-0.07b (-0.15, 0.01)--FPG (mg/dL)d Baseline (mean)150150 Change from baseline (adjusted mean)-19-9 Difference from glimepiride (adjusted mean)-11--Body Weight Baseline mean in kg82.583 change from baseline (adjusted mean)-3.92.0 Difference from glimepiride (adjusted mean) (95% CI)-5.9c (-6.3, -5.5)--Figure 4Adjusted mean HbA1c Change at Each Time Point (Completers) and at Week 52 (mITT Population) LOCFAt Week 52, the adjusted mean change from baseline in systolic blood pressure was -3.6 mmHg, compared to 2.2 mmHg for glimepiride. The differences between treatment groups for systolic blood pressure was statistically significant (p-value <0.0001).At Week 104, the adjusted mean change from baseline in HbA1c was -0.75% for JARDIANCE 25 mg and -0.66% for glimepiride. The adjusted mean treatment difference was -0.09% with 97.5% confidence interval of (-0.32%, 0.15%), excluding the pre-specified non-inferiority margin of 0.3%. The mean daily dose of glimepiride was 2.7 mg and the maximal approved dose in the United States is mg per day. The Week 104 analysis included data with and without concomitant glycemic rescue medication, as well as off-treatment data. Missing data for patients not providing any information at the visit were imputed based on the observed off-treatment data. In this multiple imputation analysis, 13.9% of the data were imputed for JARDIANCE 25 mg and 12.9% for glimepiride.At Week 104, JARDIANCE 25 mg daily resulted in statistically significant difference in change from baseline for body weight compared to glimepiride (-3.1 kg for JARDIANCE 25 mg vs. +1.3 kg for glimepiride; ANCOVA-LOCF, p-value <0.0001).. Figure 4. Add-On Combination Therapy with Pioglitazone with or without MetforminA total of 498 patients with type diabetes participated in double-blind, placebo-controlled study to evaluate the efficacy and safety of JARDIANCE in combination with pioglitazone, with or without metformin.Patients with inadequately controlled type diabetes on metformin at dose of at least 1500 mg per day and pioglitazone at dose of at least 30 mg per day were placed into an open-label placebo run-in for weeks. Patients with inadequate glycemic control and an HbA1c between 7% and 10% after the run-in period were randomized to placebo, JARDIANCE 10 mg, or JARDIANCE 25 mg.Treatment with JARDIANCE 10 mg or 25 mg daily resulted in statistically significant reductions in HbA1c (p-value <0.0001), FPG, and body weight compared with placebo (see Table 9).Table 9Results of Placebo-Controlled Study for JARDIANCE in Combination Therapy with PioglitazoneJARDIANCE 10 mg Pioglitazone N=165JARDIANCE 25 mg Pioglitazone N=168Placebo Pioglitazone N=165aModified intent to treat population. Last observation on study (LOCF) was used to impute missing data at Week 24. At Week 24, 10.9%, 8.3%, and 20.6% was imputed for patients randomized to JARDIANCE 10 mg, JARDIANCE 25 mg, and placebo, respectively. bANCOVA p-value <0.0001 (HbA1c: ANCOVA model includes baseline HbA1c, treatment, renal function, and background medication. Body weight and FPG: same model used as for HbA1c but additionally including baseline body weight/baseline FPG, respectively.) cFPG (mg/dL); for JARDIANCE 10 mg, n=163HbA1c (%)a Baseline (mean)8.18.18.2 Change from baseline (adjusted mean)-0.6-0.7-0.1 Difference from placebo pioglitazone (adjusted mean) (95% CI)-0.5b (-0.7, -0.3)-0.6b (-0.8, -0.4)-- Patients [n (%)] achieving HbA1c <7%36 (24%)48 (30%)12 (8%)FPG (mg/dL)c Baseline (mean)152152152 Change from baseline (adjusted mean)-17-227 Difference from placebo pioglitazone (adjusted mean) (97.5% CI)-23b (-31.8, -15.2)-28b (-36.7, -20.2)--Body Weight Baseline mean in kg787978 change from baseline (adjusted mean)-2.0-1.80.6 Difference from placebo (adjusted mean) (95% CI)-2.6b (-3.4, -1.8)-2.4b (-3.2, -1.6)--. Add-On Combination with Insulin with or without Metformin and/or SulfonylureasA total of 494 patients with type diabetes inadequately controlled on insulin, or insulin in combination with oral drugs participated in double-blind, placebo-controlled study to evaluate the efficacy of JARDIANCE as add-on therapy to insulin over 78 weeks.Patients entered 2-week placebo run-in period on basal insulin (e.g., insulin glargine, insulin detemir, or NPH insulin) with or without metformin and/or sulfonylurea background therapy. Following the run-in period, patients with inadequate glycemic control were randomized to the addition of JARDIANCE 10 mg, JARDIANCE 25 mg, or placebo. Patients were maintained on stable dose of insulin prior to enrollment, during the run-in period, and during the first 18 weeks of treatment. For the remaining 60 weeks, insulin could be adjusted. The mean total daily insulin dose at baseline for JARDIANCE 10 mg, 25 mg, and placebo was 45 IU, 48 IU, and 48 IU, respectively.JARDIANCE used in combination with insulin (with or without metformin and/or sulfonylurea) provided statistically significant reductions in HbA1c and FPG compared to placebo after both 18 and 78 weeks of treatment (see Table 10). JARDIANCE 10 mg or 25 mg daily also resulted in statistically significantly greater percent body weight reduction compared to placebo.Table 10Results at Week 18 and 78 for Placebo-Controlled Study for JARDIANCE in Combination with Insulin18 weeks (no insulin adjustment)78 weeks (adjustable insulin dose after 18 weeks)JARDIANCE 10 mg Insulin N=169JARDIANCE 25 mg Insulin N=155Placebo Insulin N=170JARDIANCE 10 mg Insulin N=169JARDIANCE 25 mg Insulin N=155Placebo Insulin N=170aModified intent to treat population. Last observation on study (LOCF) was used to impute missing data at Week 18 and 78. At Week 18, 21.3%, 30.3%, and 21.8% was imputed for patients randomized to JARDIANCE 10 mg, JARDIANCE 25 mg, and placebo, respectively. At Week 78, 32.5%, 38.1% and 42.4% was imputed for patients randomized to JARDIANCE 10 mg, JARDIANCE 25 mg, and placebo, respectively. bANCOVA p-value <0.0001 (HbA1c: ANCOVA model includes baseline HbA1c, treatment, and region; FPG: MMRM model includes baseline FPG, baseline HbA1c, treatment, region, visit and visit by treatment interaction. Body weight: MMRM model includes baseline body weight, baseline HbA1c, treatment, region, visit and visit by treatment interaction. cp-value=0.0049 dp-value=0.0052 ep-value=0.0463HbA1c (%)a Baseline (mean)8.38.38.28.38.38.2 Change from baseline (adjusted mean)-0.6-0.70-0.4-0.60.1 Difference from placebo (adjusted mean) (97.5% CI)-0.6b (-0.8, -0.4)-0.7b (-0.9, -0.5)---0.5b (-0.7, -0.3)-0.7b (-0.9, -0.5)-- Patients (%) achieving HbA1c <7%18.019.55.512.017.56.7FPG (mg/dL) Baseline (mean)138146142138146142 Change from baseline (adjusted mean, SE)-17.9 (3.2)-19.1 (3.3)10.4 (3.1)-10.1 (3.2)-15.2 (3.4)2.8 (3.2) Difference from placebo (adjusted mean) (95% CI)-28.2b (-37.0, -19.5)-29.5b (-38.4, -20.6)---12.9c (-21.9, 3.9)-17.9b (-27.0, -8.8)--Body Weight Baseline mean in kg929590929590 change from baseline (adjusted mean)-1.8-1.4-0.1-2.4-2.40.7 Difference from placebo (adjusted mean) (95% CI)-1.7d (-3.0, -0.5)-1.3e (-2.5, -0.0)---3.0b (-4.4, -1.7)-3.0b (-4.4, -1.6)--. Add-on Combination with MDI Insulin with or without MetforminA total of 563 patients with type diabetes inadequately controlled on multiple daily injections (MDI) of insulin (total daily dose >60 IU), alone or in combination with metformin, participated in double-blind, placebo-controlled study to evaluate the efficacy of JARDIANCE as add-on therapy to MDI insulin over 18 weeks.Patients entered 2-week placebo run-in period on MDI insulin with or without metformin background therapy. Following the run-in period, patients with inadequate glycemic control were randomized to the addition of JARDIANCE 10 mg, JARDIANCE 25 mg, or placebo. Patients were maintained on stable dose of insulin prior to enrollment, during the run-in period, and during the first 18 weeks of treatment. The mean total daily insulin dose at baseline for JARDIANCE 10 mg, JARDIANCE 25 mg, and placebo was 88.6 IU, 90.4 IU, and 89.9 IU, respectively.JARDIANCE 10 mg or 25 mg daily used in combination with MDI insulin (with or without metformin) provided statistically significant reductions in HbA1c compared to placebo after 18 weeks of treatment (see Table 11).Table 11Results at Week 18 for Placebo-Controlled Study for JARDIANCE in Combination with Insulin and with or without MetforminJARDIANCE 10 mg Insulin +/- Metformin N=186JARDIANCE 25 mg Insulin +/- Metformin N=189Placebo Insulin +/- Metformin N=188aModified intent to treat population. Last observation on study (LOCF) was used to impute missing data at Week 18. At Week 18, 23.7%, 22.8% and 23.4% was imputed for patients randomized to JARDIANCE 10 mg, JARDIANCE 25 mg, and placebo, respectively. bANCOVA p-value <0.0001 (HbA1c: ANCOVA model includes baseline HbA1c, treatment, renal function, geographical region, and background medication).HbA1c (%)a Baseline (mean)8.48.38.3 Change from baseline (adjusted mean)-0.9-1.0-0.5 Difference from placebo (adjusted mean) (95% CI)-0.4b (-0.6, -0.3)-0.5b (-0.7, -0.4)--During an extension period with treatment for up to 52 weeks, insulin could be adjusted to achieve defined glucose target levels. The change from baseline in HbA1c was maintained from 18 to 52 weeks with both JARDIANCE 10 mg and 25 mg. After 52 weeks, JARDIANCE 10 mg or 25 mg daily resulted in statistically greater percent body weight reduction compared to placebo (p-value <0.0001). The mean change in body weight from baseline was -1.95 kg for JARDIANCE 10 mg, and -2.04 kg for JARDIANCE 25 mg.. Renal ImpairmentA total of 738 patients with type diabetes and baseline eGFR less than 90 mL/min/1.73 m2 participated in randomized, double-blind, placebo-controlled, parallel-group to evaluate the efficacy and safety of JARDIANCE in patients with type diabetes and renal impairment. The trial population comprised of 290 patients with mild renal impairment (eGFR 60 to less than 90 mL/min/1.73 m2), 374 patients with moderate renal impairment (eGFR 30 to less than 60 mL/min/1.73 m2), and 74 with severe renal impairment (eGFR less than 30 mL/min/1.73 m2). total of 194 patients with moderate renal impairment had baseline eGFR of 30 to less than 45 mL/min/1.73 m2 and 180 patients baseline eGFR of 45 to less than 60 mL/min/1.73 m2.At Week 24, JARDIANCE 25 mg provided statistically significant reduction in HbA1c relative to placebo in patients with mild to moderate renal impairment (see Table 12). statistically significant reduction relative to placebo was also observed with JARDIANCE 25 mg in patients with either mild [-0.7 (95% CI: -0.9, -0.5)] or moderate [-0.4 (95% CI: -0.6, -0.3)] renal impairment and with JARDIANCE 10 mg in patients with mild [-0.5 (95% CI: -0.7, -0.3)] renal impairment.The glucose lowering efficacy of JARDIANCE 25 mg decreased with decreasing level of renal function in the mild to moderate range. Least square mean Hb1Ac changes at 24 weeks were -0.6%, -0.5%, and -0.2% for those with baseline eGFR of 60 to less than 90 mL/min/1.73 m2, 45 to less than 60 mL/min/1.73 m2, and 30 to less than 45 mL/min/1.73 m2, respectively [see Dosage and Administration (2) and Use in Specific Populations (8.6)]. For placebo, least square mean HbA1c changes at 24 weeks were 0.1%, -0.1%, and 0.2% for patients with baseline eGFR of 60 to less than 90 mL/min/1.73 m2, 45 to less than 60 mL/min/1.73 m2, and 30 to less than 45 mL/min/1.73 m2, respectively.Table 12Results at Week 24 (LOCF) of Placebo-Controlled Study for JARDIANCE in Patients with Type Diabetes and Renal ImpairmentMild and Moderate Impairmentb JARDIANCE 25 mgap-value <0.0001 (HbA1c: ANCOVA model includes baseline HbA1c, treatment, renal function, and background medication) beGFR 30 to less than 90 mL/min/1.73 m2- Modified intent to treat population. Last observation on study (LOCF) was used to impute missing data at Week 24. At Week 24, 24.6% and 26.2% was imputed for patients randomized to JARDIANCE 25 mg and placebo, respectively.HbA1c Number of patientsn=284 Comparison vs placebo (adjusted mean) (95% CI)-0.5a (-0.6, -0.4)For patients with severe renal impairment, the analyses of changes in HbA1c and FPG showed no discernible treatment effect of JARDIANCE 25 mg compared to placebo [see Indications and Usage (1), Dosage and Administration (2.3) and Use in Specific Populations (8.6)].. Cardiovascular Outcomes in Patients with Type Diabetes Mellitus and Atherosclerotic Cardiovascular DiseaseThe effect of JARDIANCE on cardiovascular risk in adult patients with type diabetes and established, stable, atherosclerotic cardiovascular disease was evaluated in the EMPA-REG OUTCOME study, multicenter, multi-national, randomized, double-blind parallel group trial. The study compared the risk of experiencing major adverse cardiovascular event (MACE) between JARDIANCE and placebo when these were added to and used concomitantly with standard of care treatments for diabetes and atherosclerotic cardiovascular disease. Coadministered antidiabetic medications were to be 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 7020 patients were treated (JARDIANCE 10 mg 2345; JARDIANCE 25 mg 2342; placebo 2333) and followed for median of 3.1 years. Approximately 72% of the study population was Caucasian, 22% was Asian, and 5% was Black. The mean age was 63 years and approximately 72% were male.All patients in the study had inadequately controlled type 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 for more than 10 years. Approximately 31%, 22% and 20% reported past history of neuropathy, retinopathy and nephropathy to investigators respectively and the mean eGFR was 74 mL/min/1.73 m2. At baseline, patients were treated with one (~30%) or more (~70%) antidiabetic medications including metformin (74%), insulin (48%), and sulfonylurea (43%).All patients had established atherosclerotic cardiovascular disease at baseline including one (82%) or more (18%) of the following: documented history of coronary artery disease (76%), stroke (23%) or peripheral artery disease (21%). At baseline, the mean systolic blood pressure was 136 mmHg, the mean diastolic blood pressure was 76 mmHg, the mean LDL was 86 mg/dL, the mean HDL was 44 mg/dL, and the mean urinary albumin to creatinine ratio (UACR) was 175 mg/g. At baseline, approximately 81% of patients were treated with renin angiotensin system inhibitors, 65% with beta-blockers, 43% with diuretics, 77% with statins, and 86% with antiplatelet agents (mostly aspirin).The primary endpoint in EMPA-REG OUTCOME was the time to first occurrence of Major Adverse Cardiac Event (MACE). major adverse cardiac event was defined as occurrence of either cardiovascular death or non-fatal myocardial infarction (MI) or non-fatal stroke. The statistical analysis plan had pre-specified that the 10 and 25 mg doses would be combined. Cox proportional hazards model was used to test for non-inferiority against the pre-specified risk margin of 1.3 for the hazard ratio of MACE and superiority on MACE if non-inferiority was demonstrated. Type-1 error was controlled across multiples tests using hierarchical testing strategy.JARDIANCE significantly reduced the risk of first occurrence of primary composite endpoint of cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke (HR: 0.86; 95% CI: 0.74, 0.99). The treatment effect was due to significant reduction in the risk of cardiovascular death in subjects randomized to empagliflozin (HR: 0.62; 95% CI: 0.49, 0.77), with no change in the risk of non-fatal myocardial infarction or non-fatal stroke (see Table 13 and Figures and 6). Results for the 10 mg and 25 mg empagliflozin doses were consistent with results for the combined dose groups.Table 13Treatment Effect for the Primary Composite Endpoint, and its Componentsa Placebo N=2333JARDIANCE N=4687Hazard ratio vs placebo (95% CI)aTreated set (patients who had received at least one dose of study drug) bp-value for superiority (2-sided) 0.04 cTotal number of eventsComposite of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke (time to first occurrence)b 282 (12.1%)490 (10.5%)0.86 (0.74, 0.99)Non-fatal myocardial infarctionc 121 (5.2%)213 (4.5%)0.87 (0.70, 1.09)Non-fatal strokec 60 (2.6%)150 (3.2%)1.24 (0.92, 1.67)Cardiovascular deathc 137 (5.9%)172 (3.7%)0.62 (0.49, 0.77)Figure 5Estimated Cumulative Incidence of First MACEFigure 6Estimated Cumulative Incidence of Cardiovascular DeathThe efficacy of JARDIANCE on cardiovascular death was generally consistent across major demographic and disease subgroups.Vital status was obtained for 99.2% of subjects in the trial. total of 463 deaths were recorded during the EMPA-REG OUTCOME trial. Most of these deaths were categorized as cardiovascular deaths. The non-cardiovascular deaths were only small proportion of deaths, and were balanced between the treatment groups (2.1% in patients treated with JARDIANCE, and 2.4% of patients treated with placebo).. Figure 5. Figure 6.

CONTRAINDICATIONS SECTION.


4CONTRAINDICATIONS. Hypersensitivity to empagliflozin or any of the excipients in JARDIANCE, reactions such as angioedema have occurred [see Warnings and Precautions (5.7)].Patients on dialysis [see Use in Specific Populations (8.6)].. Hypersensitivity to empagliflozin or any of the excipients in JARDIANCE, reactions such as angioedema have occurred [see Warnings and Precautions (5.7)].. Patients on dialysis [see Use in Specific Populations (8.6)].. Hypersensitivity to empagliflozin or any of the excipients in JARDIANCE (4)Patients on dialysis (4). Hypersensitivity to empagliflozin or any of the excipients in JARDIANCE (4). Patients on dialysis (4).

DESCRIPTION SECTION.


11DESCRIPTION. JARDIANCE tablets for oral use contain empagliflozin, an inhibitor of the sodium-glucose co-transporter (SGLT2).The chemical name of empagliflozin is D-Glucitol,1,5-anhydro-1-C-[4-chloro-3-[[4-[[(3S)-tetrahydro-3-furanyl]oxy]phenyl]methyl]phenyl]-, (1S).Its molecular formula is C23H27ClO7 and the molecular weight is 450.91. The structural formula is:Empagliflozin is white to yellowish, non-hygroscopic powder. It is very slightly soluble in water, sparingly soluble in methanol, slightly soluble in ethanol and acetonitrile, soluble in 50% acetonitrile/water, and practically insoluble in toluene.Each film-coated tablet of JARDIANCE contains 10 mg or 25 mg of empagliflozin (free base) and the following inactive ingredients: lactose monohydrate, microcrystalline cellulose, hydroxypropyl cellulose, croscarmellose sodium, colloidal silicon dioxide and magnesium stearate. In addition, the film coating contains the following inactive ingredients: hypromellose, titanium dioxide, talc, polyethylene glycol, and yellow ferric oxide.. Chemical Structure.

DOSAGE & ADMINISTRATION SECTION.


2DOSAGE AND ADMINISTRATION. Assess renal function before initiating JARDIANCE and as clinically indicated (2.1)The recommended dose of JARDIANCE is 10 mg once daily, taken in the morning, with or without food (2.2)Dose may be increased to 25 mg once daily (2.2). Assess renal function before initiating JARDIANCE and as clinically indicated (2.1). The recommended dose of JARDIANCE is 10 mg once daily, taken in the morning, with or without food (2.2). Dose may be increased to 25 mg once daily (2.2). 2.1 Prior to Initiation of JARDIANCE. Assess renal function before initiating JARDIANCE and as clinically indicated [see Warnings and Precautions (5.2)].In patients with volume depletion, correct this condition before initiating JARDIANCE [see Warnings and Precautions (5.2), Use in Specific Populations (8.5, 8.6)]. Assess renal function before initiating JARDIANCE and as clinically indicated [see Warnings and Precautions (5.2)].. In patients with volume depletion, correct this condition before initiating JARDIANCE [see Warnings and Precautions (5.2), Use in Specific Populations (8.5, 8.6)]. 2.2 Recommended Dosage. The recommended dose of JARDIANCE is 10 mg once daily in the morning, taken with or without food. In patients tolerating JARDIANCE, the dose may be increased to 25 mg for additional glycemic control.. 2.3 Dosage Recommendations in Patients with Renal Impairment. JARDIANCE is not recommended for use in patients with an eGFR less than 30 mL/min/1.73 m2 and contraindicated in patients on dialysis [see Indications and Usage (1), Contraindications (4), Warnings and Precautions (5.2) and Use in Specific Populations (8.6)].

DOSAGE FORMS & STRENGTHS SECTION.


3DOSAGE FORMS AND STRENGTHS. JARDIANCE tablets available as:10 mg pale yellow, round, biconvex and bevel-edged, film-coated tablets debossed with S 10 on one side and the Boehringer Ingelheim company symbol on the other side.25 mg pale yellow, oval, biconvex, film-coated tablets debossed with S 25 on one side and the Boehringer Ingelheim company symbol on the other side.. 10 mg pale yellow, round, biconvex and bevel-edged, film-coated tablets debossed with S 10 on one side and the Boehringer Ingelheim company symbol on the other side.. 25 mg pale yellow, oval, biconvex, film-coated tablets debossed with S 25 on one side and the Boehringer Ingelheim company symbol on the other side.. Tablets: 10 mg, 25 mg (3).

DRUG INTERACTIONS SECTION.


7DRUG INTERACTIONS. Table 3Clinically Relevant Interactions with JARDIANCEDiureticsClinical ImpactCoadministration of empagliflozin with diuretics resulted in increased urine volume and frequency of voids, which might enhance the potential for volume depletion.InterventionBefore initiating JARDIANCE, assess volume status and renal function. In patients with volume depletion, correct this condition before initiating JARDIANCE. Monitor for signs and symptoms of volume depletion, and renal function after initiating therapy.Insulin or Insulin SecretagoguesClinical ImpactThe risk of hypoglycemia is increased when JARDIANCE is used in combination with insulin secretagogues (e.g., sulfonylurea) or insulin.InterventionCoadministration of JARDIANCE with an insulin secretagogue (e.g., sulfonylurea) or insulin may require lower doses of the insulin secretagogue or insulin to reduce the risk of hypoglycemia.Positive Urine Glucose TestClinical ImpactSGLT2 inhibitors increase urinary glucose excretion and will lead to positive urine glucose tests.InterventionMonitoring glycemic control with urine glucose tests is not recommended in patients taking SGLT2 inhibitors. Use alternative methods to monitor glycemic control.Interference with 1,5-anhydroglucitol (1,5-AG) AssayClinical ImpactMeasurements of 1,5-AG are unreliable in assessing glycemic control in patients taking SGLT2 inhibitors.InterventionMonitoring glycemic control with 1,5-AG assay is not recommended. Use alternative methods to monitor glycemic control.

GERIATRIC USE SECTION.


8.5 Geriatric Use. In studies assessing the efficacy of empagliflozin in improving glycemic control in patients with type diabetes, total of 2721 (32%) patients treated with empagliflozin were 65 years of age and older, and 491 (6%) were 75 years of age and older. JARDIANCE is expected to have diminished glycemic efficacy in elderly patients with renal impairment [see Use in Specific Populations (8.6)]. The risk of volume depletion-related adverse reactions increased in patients who were 75 years of age and older to 2.1%, 2.3%, and 4.4% for placebo, JARDIANCE 10 mg, and JARDIANCE 25 mg. The risk of urinary tract infections increased in patients who were 75 years of age and older to 10.5%, 15.7%, and 15.1% in patients randomized to placebo, JARDIANCE 10 mg, and JARDIANCE 25 mg, respectively [see Warnings and Precautions (5.2) and Adverse Reactions (6.1)].

HEPATIC IMPAIRMENT SUBSECTION.


8.7 Hepatic Impairment. JARDIANCE may be used in patients with hepatic impairment [see Clinical Pharmacology (12.3)].

HOW SUPPLIED SECTION.


16HOW SUPPLIED/STORAGE AND HANDLING. JARDIANCE tablets are available as follows:10 mg tablets: pale yellow, round, biconvex and bevel-edged film-coated tablets debossed with S 10 on one side and the Boehringer Ingelheim company symbol on the other side. Bottles of 30 (NDC 0597-0152-30) Bottles of 90 (NDC 0597-0152-90) Cartons containing blister cards of 10 tablets each (3 10) (NDC 0597-0152-37), institutional pack.25 mg tablets: pale yellow, oval, biconvex film-coated tablets, debossed with S 25 on one side and the Boehringer Ingelheim company symbol on the other side. Bottles of 30 (NDC 0597-0153-30) Bottles of 90 (NDC 0597-0153-90) Cartons containing blister cards of 10 tablets each (3 10) (NDC 0597-0153-37), institutional pack.Dispense in well-closed container as defined in the USP.. StorageStore at 20C to 25C (68F to 77F); excursions permitted to 15C to 30C (59F to 86F) [see USP Controlled Room Temperature].

INDICATIONS & USAGE SECTION.


1INDICATIONS AND USAGE. JARDIANCE is indicated:as an adjunct to diet and exercise to improve glycemic control in adults with type diabetes mellitus,to reduce the risk of cardiovascular death in adult patients with type diabetes mellitus and established cardiovascular disease.. as an adjunct to diet and exercise to improve glycemic control in adults with type diabetes mellitus,. to reduce the risk of cardiovascular death in adult patients with type diabetes mellitus and established cardiovascular disease.. JARDIANCE is sodium-glucose co-transporter (SGLT2) inhibitor indicated:as an adjunct to diet and exercise to improve glycemic control in adults with type diabetes mellitus,to reduce the risk of cardiovascular death in adult patients with type diabetes mellitus and established cardiovascular disease. (1)Limitations of Use:Not recommended in patients with type diabetes mellitus. It may increase the risk of diabetic ketoacidosis in these patients (1)Not recommended for use to improve glycemic control in adults with type diabetes mellitus with an eGFR less than 30 mL/min/1.73 m2 (1). as an adjunct to diet and exercise to improve glycemic control in adults with type diabetes mellitus,. to reduce the risk of cardiovascular death in adult patients with type diabetes mellitus and established cardiovascular disease. (1). Not recommended in patients with type diabetes mellitus. It may increase the risk of diabetic ketoacidosis in these patients (1). Not recommended for use to improve glycemic control in adults with type diabetes mellitus with an eGFR less than 30 mL/min/1.73 m2 (1). Limitations of UseJARDIANCE is not recommended in patients with type diabetes mellitus. It may increase the risk of diabetic ketoacidosis in these patients [see Warnings and Precautions (5.1)].JARDIANCE is not recommended for use to improve glycemic control in adults with type diabetes mellitus with an eGFR less than 30 mL/min/1.73 m2. JARDIANCE is likely to be ineffective in this setting based upon its mechanism of action.

INFORMATION FOR PATIENTS SECTION.


17PATIENT COUNSELING INFORMATION. Advise the patient to read the FDA-approved patient labeling (Medication Guide).. KetoacidosisInform patients that ketoacidosis is serious life-threatening condition and that cases of ketoacidosis have been reported during use of JARDIANCE, sometimes associated with illness or surgery among other risk factors. Instruct patients to check ketones (when possible) if symptoms consistent with ketoacidosis occur even if blood glucose is not elevated. If symptoms of ketoacidosis (including nausea, vomiting, abdominal pain, tiredness, and labored breathing) occur, instruct patients to discontinue JARDIANCE and seek medical attention immediately [see Warnings and Precautions (5.1)].. Volume DepletionInform patients that symptomatic hypotension may occur with JARDIANCE and advise them to contact their healthcare provider if they experience such symptoms [see Warnings and Precautions (5.2)]. Inform patients that dehydration may increase the risk for hypotension, and to maintain adequate fluid intake.. Serious Urinary Tract InfectionsInform patients of the potential for urinary tract infections, which may be serious. Provide them with information on the symptoms of urinary tract infections. Advise them to seek medical advice if such symptoms occur [see Warnings and Precautions (5.3)].. HypoglycemiaInform patients that the incidence of hypoglycemia is increased when JARDIANCE is used in combination with insulin secretagogues (e.g., sulfonylurea) or insulin and that lower dose of the insulin secretagogue or insulin may be required to reduce the risk of hypoglycemia [see Warnings and Precautions (5.4)].. Necrotizing Fasciitis of the Perineum (Fourniers Gangrene)Inform patients that necrotizing infections of the perineum (Fourniers gangrene) have occurred with JARDIANCE. Counsel patients to promptly seek medical attention if they develop pain or tenderness, redness, or swelling of the genitals or the area from the genitals back to the rectum, along with fever above 100.4F or malaise [see Warnings and Precautions (5.5)].. Genital Mycotic Infections in Females (e.g., Vulvovaginitis)Inform female patients that vaginal yeast infections may occur and provide them with information on the signs and symptoms of vaginal yeast infections. Advise them of treatment options and when to seek medical advice [see Warnings and Precautions (5.6)].. Genital Mycotic Infections in Males (e.g., Balanitis or Balanoposthitis)Inform male patients that yeast infection of penis (e.g., balanitis or balanoposthitis) may occur, especially in uncircumcised males and patients with chronic and recurrent infections. Provide them with information on the signs and symptoms of balanitis and balanoposthitis (rash or redness of the glans or foreskin of the penis). Advise them of treatment options and when to seek medical advice [see Warnings and Precautions (5.6)].. Hypersensitivity ReactionsInform patients that serious hypersensitivity reactions, such as urticaria and angioedema, have been reported with JARDIANCE. Advise patients to report immediately any skin reaction or angioedema, and to discontinue drug until they have consulted prescribing physician [see Warnings and Precautions (5.7)].. Laboratory TestsInform patients that elevated glucose in urinalysis is expected when taking JARDIANCE.. PregnancyAdvise pregnant patients, and patients of reproductive potential, of the potential risk to fetus with treatment with JARDIANCE [see Use in Specific Populations (8.1)]. Instruct patients to report pregnancies to their physicians as soon as possible.. LactationAdvise patients that breastfeeding is not recommended during treatment with JARDIANCE [see Use in Specific Populations (8.2)]. Missed DoseInstruct patients to take JARDIANCE only as prescribed. If dose is missed, it should be taken as soon as the patient remembers. Advise patients not to double their next dose.

LACTATION SECTION.


8.2 Lactation. Risk SummaryThere is limited information regarding the presence of JARDIANCE in human milk, the effects of JARDIANCE on the breastfed infant or the effects on milk production. Empagliflozin is present in the milk of lactating rats [see Data]. Since human kidney maturation occurs in utero and during the first years of life when lactational exposure may occur, there may be risk to the developing human kidney.Because of the potential for serious adverse reactions in breastfed infant, including the potential for empagliflozin to affect postnatal renal development, advise patients that use of JARDIANCE is not recommended while breastfeeding.. DataEmpagliflozin was present at low level in rat fetal tissues after single oral dose to the dams at gestation day 18. In rat milk, the mean milk to plasma ratio ranged from 0.634 to 5, and was greater than one from to 24 hours post-dose. The mean maximal milk to plasma ratio of occurred at hours post-dose, suggesting accumulation of empagliflozin in the milk. Juvenile rats directly exposed to empagliflozin showed risk to the developing kidney (renal pelvic and tubular dilatations) during maturation.

MECHANISM OF ACTION SECTION.


12.1 Mechanism of Action. Sodium-glucose co-transporter (SGLT2) is the predominant transporter responsible for reabsorption of glucose from the glomerular filtrate back into the circulation. Empagliflozin is an inhibitor of SGLT2. By inhibiting SGLT2, empagliflozin reduces renal reabsorption of filtered glucose and lowers the renal threshold for glucose, and thereby increases urinary glucose excretion.

NONCLINICAL TOXICOLOGY SECTION.


13NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. CarcinogenesisCarcinogenesis was evaluated in 2-year studies conducted in CD-1 mice and Wistar rats. Empagliflozin did not increase the incidence of tumors in female rats dosed at 100, 300, or 700 mg/kg/day (up to 72 times the exposure from the maximum clinical dose of 25 mg). In male rats, hemangiomas of the mesenteric lymph node were increased significantly at 700 mg/kg/day or approximately 42 times the exposure from 25 mg clinical dose. Empagliflozin did not increase the incidence of tumors in female mice dosed at 100, 300, or 1000 mg/kg/day (up to 62 times the exposure from 25 mg clinical dose). Renal tubule adenomas and carcinomas were observed in male mice at 1000 mg/kg/day, which is approximately 45 times the exposure of the maximum clinical dose of 25 mg. These tumors may be associated with metabolic pathway predominantly present in the male mouse kidney.. MutagenesisEmpagliflozin was not mutagenic or clastogenic with or without metabolic activation in the in vitro Ames bacterial mutagenicity assay, the in vitro L5178Y tk+/- mouse lymphoma cell assay, and an in vivo micronucleus assay in rats.. Impairment of FertilityEmpagliflozin had no effects on mating, fertility or early embryonic development in treated male or female rats up to the high dose of 700 mg/kg/day (approximately 155 times the 25 mg clinical dose in males and females, respectively).

OVERDOSAGE SECTION.


10OVERDOSAGE. In the event of an overdose with JARDIANCE, contact the Poison Control Center. Removal of empagliflozin by hemodialysis has not been studied.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.


PRINCIPAL DISPLAY PANEL 10 mg Tablet Blister Pack Carton. NDC 0597-0152-37DISPENSE WITH ENCLOSED MEDICATION GUIDEJardiance(R) (empagliflozin tablets)10 mgThis unit dose package is not child-resistant. If dispensed for outpatient use, child-resistant container should be utilized.Rx only30 tablets3 blister cards. Each card contains 10 tablets.BoehringerIngelheimLilly. PRINCIPAL DISPLAY PANEL 10 mg Tablet Blister Pack Carton.

PEDIATRIC USE SECTION.


8.4 Pediatric Use. The safety and effectiveness of JARDIANCE have not been established in pediatric patients.

PHARMACODYNULLMICS SECTION.


12.2 Pharmacodynamics. Urinary Glucose ExcretionIn patients with type diabetes, urinary glucose excretion increased immediately following dose of empagliflozin and was maintained at the end of 4-week treatment period averaging at approximately 64 grams per day with 10 mg empagliflozin and 78 grams per day with 25 mg empagliflozin once daily [see Clinical Studies (14)]. Data from single oral doses of empagliflozin in healthy subjects indicate that, on average, the elevation in urinary glucose excretion approaches baseline by about days for the 10 mg and 25 mg doses.. Urinary VolumeIn 5-day study, mean 24-hour urine volume increase from baseline was 341 mL on Day and 135 mL on Day of empagliflozin 25 mg once daily treatment.. Cardiac ElectrophysiologyIn randomized, placebo-controlled, active-comparator, crossover study, 30 healthy subjects were administered single oral dose of empagliflozin 25 mg, empagliflozin 200 mg (8 times the maximum dose), moxifloxacin, and placebo. No increase in QTc was observed with either 25 mg or 200 mg empagliflozin.

PHARMACOKINETICS SECTION.


12.3 Pharmacokinetics. AbsorptionThe pharmacokinetics of empagliflozin has been characterized in healthy volunteers and patients with type diabetes and no clinically relevant differences were noted between the two populations. After oral administration, peak plasma concentrations of empagliflozin were reached at 1.5 hours post-dose. Thereafter, plasma concentrations declined in biphasic manner with rapid distribution phase and relatively slow terminal phase. The steady-state mean plasma AUC and Cmax were 1870 nmolh/L and 259 nmol/L, respectively, with 10 mg empagliflozin once daily treatment, and 4740 nmolh/L and 687 nmol/L, respectively, with 25 mg empagliflozin once daily treatment. Systemic exposure of empagliflozin increased in dose-proportional manner in the therapeutic dose range. The single-dose and steady-state pharmacokinetic parameters of empagliflozin were similar, suggesting linear pharmacokinetics with respect to time.Administration of 25 mg empagliflozin after intake of high-fat and high-calorie meal resulted in slightly lower exposure; AUC decreased by approximately 16% and Cmax decreased by approximately 37%, compared to fasted condition. The observed effect of food on empagliflozin pharmacokinetics was not considered clinically relevant and empagliflozin may be administered with or without food.. DistributionThe apparent steady-state volume of distribution was estimated to be 73.8 based on population pharmacokinetic analysis. Following administration of an oral [14C]-empagliflozin solution to healthy subjects, the red blood cell partitioning was approximately 36.8% and plasma protein binding was 86.2%.. EliminationThe apparent terminal elimination half-life of empagliflozin was estimated to be 12.4 and apparent oral clearance was 10.6 L/h based on the population pharmacokinetic analysis. Following once-daily dosing, up to 22% accumulation, with respect to plasma AUC, was observed at steady-state, which was consistent with empagliflozin half-life.. MetabolismNo major metabolites of empagliflozin were detected in human plasma and the most abundant metabolites were three glucuronide conjugates (2-O-, 3-O-, and 6-O-glucuronide). Systemic exposure of each metabolite was less than 10% of total drug-related material. In vitro studies suggested that the primary route of metabolism of empagliflozin in humans is glucuronidation by the uridine 5-diphospho-glucuronosyltransferases UGT2B7, UGT1A3, UGT1A8, and UGT1A9.. ExcretionFollowing administration of an oral [14C]-empagliflozin solution to healthy subjects, approximately 95.6% of the drug-related radioactivity was eliminated in feces (41.2%) or urine (54.4%). The majority of drug-related radioactivity recovered in feces was unchanged parent drug and approximately half of drug-related radioactivity excreted in urine was unchanged parent drug.. Specific Populations. Renal ImpairmentIn patients with mild (eGFR: 60 to less than 90 mL/min/1.73 m2), moderate (eGFR: 30 to less than 60 mL/min/1.73 m2), and severe (eGFR: less than 30 mL/min/1.73 m2) renal impairment and patients with kidney failure/end stage renal disease (ESRD), AUC of empagliflozin increased by approximately 18%, 20%, 66%, and 48%, respectively, compared to subjects with normal renal function. Peak plasma levels of empagliflozin were similar in patients with moderate renal impairment and kidney failure/ESRD compared to subjects with normal renal function. Peak plasma levels of empagliflozin were roughly 20% higher in patients with mild and severe renal impairment as compared to subjects with normal renal function. Population pharmacokinetic analysis showed that the apparent oral clearance of empagliflozin decreased, with decrease in eGFR leading to an increase in drug exposure. However, the fraction of empagliflozin that was excreted unchanged in urine, and urinary glucose excretion, declined with decrease in eGFR.. Hepatic ImpairmentIn 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 Cmax increased by approximately 4%, 23%, and 48%, respectively, compared to subjects with normal hepatic function.. Effects of Age, Body Mass Index, Gender, and RaceBased on the population PK analysis, age, body mass index (BMI), gender and race (Asians versus primarily Whites) do not have clinically meaningful effect on pharmacokinetics of empagliflozin [see Use in Specific Populations (8.5)].. Drug Interactions. In vitro Assessment of Drug InteractionsEmpagliflozin 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 5-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 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 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 InteractionsEmpagliflozin pharmacokinetics were similar with and without coadministration of metformin, 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 diabetes (see Figure 1). In subjects with normal renal function, coadministration of empagliflozin with probenecid resulted in 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 1Effect of Various Medications on the Pharmacokinetics of Empagliflozin as Displayed as 90% Confidence Interval of Geometric Mean AUC and Cmax Ratios [reference lines indicate 100% (80% 125%)]aempagliflozin, 50 mg, once daily; bempagliflozin, 25 mg, single dose; cempagliflozin, 25 mg, once daily; dempagliflozin, 10 mg, single doseEmpagliflozin 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).Figure 2Effect of Empagliflozin on the Pharmacokinetics of Various Medications as Displayed as 90% Confidence Interval of Geometric Mean AUC andCmax Ratios [reference lines indicate 100% (80% 125%)]aempagliflozin, 50 mg, once daily; bempagliflozin, 25 mg, once daily; cempagliflozin, 25 mg, single dose; dadministered as simvastatin; eadministered as warfarin racemic mixture; fadministered as Microgynon(R); gadministered as ramipril. Figure 1. Figure 2.

PREGNULLNCY SECTION.


8.1 Pregnancy. Risk SummaryBased on animal data showing adverse renal effects, JARDIANCE is not recommended during the second and third trimesters of pregnancy.The limited available data with JARDIANCE in pregnant women are not sufficient to determine drug-associated risk for major birth defects and miscarriage. There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy [see Clinical Considerations].In animal studies, adverse renal changes were observed in rats when empagliflozin was administered during period of renal development corresponding to the late second and third trimesters of human pregnancy. Doses approximately 13-times the maximum clinical dose caused renal pelvic and tubule dilatations that were reversible. [see Data].The estimated background risk of major birth defects is 6% to 10% in women with pre-gestational diabetes with HbA1c >7 and has been reported to be as high as 20% to 25% in women with HbA1c >10. The estimated background risk of miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.. Clinical ConsiderationsDisease-associated maternal and/or embryo/fetal risk: Poorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, pre-eclampsia, spontaneous abortions, preterm delivery, and delivery complications. Poorly controlled diabetes increases the fetal risk for major birth defects, stillbirth, and macrosomia related morbidity.. Data. Animal DataEmpagliflozin dosed directly to juvenile rats from postnatal day (PND) 21 until PND 90 at doses of 1, 10, 30, and 100 mg/kg/day caused increased kidney weights and renal tubular and pelvic dilatation at 100 mg/kg/day, which approximates 13-times the maximum clinical dose of 25 mg, based on AUC. These findings were not observed after 13-week, drug-free recovery period. These outcomes occurred with drug exposure during periods of renal development in rats that correspond to the late second and third trimester of human renal development.In embryo-fetal development studies in rats and rabbits, empagliflozin was administered for intervals coinciding with the first trimester period of organogenesis in humans. Doses up to 300 mg/kg/day, which approximates 48-times (rats) and 128-times (rabbits) the maximum clinical dose of 25 mg (based on AUC), did not result in adverse developmental effects. In rats, at higher doses of empagliflozin causing maternal toxicity, malformations of limb bones increased in fetuses at 700 mg/kg/day or 154-times the 25 mg maximum clinical dose. Empagliflozin crosses the placenta and reaches fetal tissues in rats. In the rabbit, higher doses of empagliflozin resulted in maternal and fetal toxicity at 700 mg/kg/day, or 139-times the 25 mg maximum clinical dose.In pre- and postnatal development studies in pregnant rats, empagliflozin was administered from gestation day through to lactation day 20 (weaning) at up to 100 mg/kg/day (approximately 16-times the 25 mg maximum clinical dose) without maternal toxicity. Reduced body weight was observed in the offspring at greater than or equal to 30 mg/kg/day (approximately 4-times the 25 mg maximum clinical dose).

RECENT MAJOR CHANGES SECTION.


Indications and Usage (1)6/2021Dosage and Administration (2.1, 2.3)6/2021Contraindications (4)6/2021Warnings and Precautions (5.1, 5.2)6/2021Warnings and Precautions (5.9) Removed6/2021.

RENULLL IMPAIRMENT SUBSECTION.


8.6 Renal Impairment. The efficacy and safety of JARDIANCE for glycemic control were evaluated in study of patients with mild and moderate renal impairment (eGFR 30 to less than 90 mL/min/1.73 m2) [see Clinical Studies (14)]. In this study, 195 patients exposed to JARDIANCE had an eGFR between 60 and 90 mL/min/1.73 m2, 91 patients exposed to JARDIANCE had an eGFR between 45 and 60 mL/min/1.73 m2, and 97 patients exposed to JARDIANCE had an eGFR between 30 and 45 mL/min/1.73 m2. The glucose lowering benefit of JARDIANCE 25 mg decreased in patients with worsening renal function. The risks of renal impairment, volume depletion adverse reactions and urinary tract infection-related adverse reactions increased with worsening renal function [see Warnings and Precautions (5.2)].In large cardiovascular outcomes study, there were 1819 patients with eGFR below 60 mL/min/1.73 m2. The cardiovascular death findings in this subgroup were consistent with the overall findings [see Clinical Studies (14)]. The efficacy and safety studies with JARDIANCE did not enroll patients with ESRD, on dialysis or patients with an eGFR less than 30 mL/min/1.73 m2. JARDIANCE is contraindicated in patients on dialysis [see Indications and Usage (1) and Contraindications (4)].

SPL MEDGUIDE SECTION.


This MEDICATION GUIDE has been approved by the U.S. Food and Drug Administration.Revised: June 2021 MEDICATION GUIDE JARDIANCE(R) (jar DEE ans) (empagliflozin tablets)for oral useWhat is the most important information should know about JARDIANCEJARDIANCE can cause serious side effects, including:Ketoacidosis (increased ketones in your blood or urine). Ketoacidosis has happened in people who have type diabetes or type diabetes, during treatment with JARDIANCE. Ketoacidosis has also happened in people with diabetes who were sick or who had surgery during treatment with JARDIANCE. Ketoacidosis is serious condition, which needs to be treated in hospital. Ketoacidosis may lead to death. Ketoacidosis can happen with JARDIANCE even if your blood sugar is less than 250 mg/dL. Stop taking JARDIANCE and call your doctor right away or go to the nearest hospital emergency room if you get any of the following symptoms:nauseavomitingstomach-area (abdominal) paintirednesstrouble breathingIf you get any of these symptoms during treatment with JARDIANCE, if possible, check for ketones in your urine, even if your blood sugar is less than 250 mg/dL.Dehydration. JARDIANCE can cause some people to become dehydrated (the loss of body water and salt). Dehydration may cause you to feel dizzy, faint, light-headed, or weak, especially when you stand up (orthostatic hypotension). There have been reports of sudden worsening of kidney function in people who are taking JARDIANCE. You may be at higher risk of dehydration if you: take medicines to lower your blood pressure, including diuretics (water pills)are on low sodium (salt) diethave kidney problemsare 65 years of age or older Talk to your doctor about what you can do to prevent dehydration including how much fluid you should drink on daily basis.Talk to your doctor right away if you reduce the amount of food or liquid you drink, for example if you are sick or cannot eat, or start to lose liquids from your body, for example from vomiting, diarrhea or being in the sun too long.What is JARDIANCEJARDIANCE is prescription medicine used: along with diet and exercise to lower blood sugar in adults with type diabetes.to reduce the risk of cardiovascular death in adults with type diabetes who have known cardiovascular disease. JARDIANCE is not for people with type diabetes. It may increase their risk of diabetic ketoacidosis (increased ketones in blood or urine).JARDIANCE is not for use to lower blood sugar in adults with type diabetes who have severe kidney problems, because it may not work.It is not known if JARDIANCE is safe and effective in children.Who should not take JARDIANCE Do not take JARDIANCE if you:are allergic to empagliflozin or any of the ingredients in JARDIANCE. See the end of this Medication Guide for complete list of ingredients in JARDIANCE. Symptoms of serious allergic reaction to JARDIANCE may include:swelling of your face, lips, throat and other areas of your skindifficulty with swallowing or breathingraised, red areas on your skin (hives)If you have any of these symptoms, stop taking JARDIANCE and call your doctor right away or go to the nearest hospital emergency room.are on dialysis.What should tell my doctor before taking JARDIANCE Before taking JARDIANCE, tell your doctor about all of your medical conditions, including if you:have kidney problems.have liver problems.have history of infection of the vagina or penis.have history of urinary tract infections or problems with urination.are going to have surgery. Your doctor may stop your JARDIANCE before you have surgery. Talk to your doctor if you are having surgery about when to stop taking JARDIANCE and when to start it again.are eating less, or there is change in your diet.have or have had problems with your pancreas, including pancreatitis or surgery on your pancreas.drink alcohol very often, or drink lot of alcohol in the short term (binge drinking).have type diabetes. JARDIANCE should not be used to treat people with type diabetes.are pregnant or plan to become pregnant. JARDIANCE may harm your unborn baby. If you become pregnant while taking JARDIANCE, tell your doctor as soon as possible. Talk with your doctor about the best way to control your blood sugar while you are pregnant.are breastfeeding or plan to breastfeed. JARDIANCE may pass into your breast milk and may harm your baby. Talk with your doctor about the best way to feed your baby if you are taking JARDIANCE. Do not breastfeed while taking JARDIANCE.Tell your doctor about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.JARDIANCE may affect the way other medicines work, and other medicines may affect how JARDIANCE works. Especially tell your doctor if you take: diuretics (water pills)insulin or other medicines that can lower your blood sugarKnow the medicines you take. Keep list of them to show your doctor and pharmacist when you get new medicine.How should take JARDIANCETake JARDIANCE exactly as your doctor tells you to take it.Take JARDIANCE by mouth time in the morning each day, with or without food.Your doctor may change your dose if needed.If you miss dose, take it as soon as you remember. If you do not remember until it is time for your next dose, skip the missed dose and go back to your regular schedule. Do not take two doses of JARDIANCE at the same time. Talk with your doctor if you have questions about missed dose.Your doctor may tell you to take JARDIANCE along with other diabetes medicines. Low blood sugar can happen more often when JARDIANCE is taken with certain other diabetes medicines. See What are the possible side effects of JARDIANCE If you take too much JARDIANCE, call your doctor or go to the nearest hospital emergency room right away.When taking JARDIANCE, you may have sugar in your urine, which will show up on urine test.Your doctor may do blood tests to check how well your kidneys are working before and during your treatment with JARDIANCE.What are the possible side effects of JARDIANCEJARDIANCE may cause serious side effects, including:See What is the most important information should know about JARDIANCESerious urinary tract infections. Serious urinary tract infections that may lead to hospitalization have happened in people who are taking JARDIANCE. Tell your doctor if you have any signs or symptoms of urinary tract infection such as burning feeling when passing urine, need to urinate often, the need to urinate right away, pain in the lower part of your stomach (pelvis), or blood in the urine. Sometimes people also may have fever, back pain, nausea or vomiting.Low blood sugar (hypoglycemia). If you take JARDIANCE with another medicine that can cause low blood sugar, such as sulfonylurea or insulin, your risk of getting low blood sugar is higher. The dose of your sulfonylurea medicine or insulin may need to be lowered while you take JARDIANCE. Signs and symptoms of low blood sugar may include:headachedrowsinessweaknessirritabilityhungerfast heartbeatconfusionshaking or feeling jitterydizzinesssweatingA rare but serious bacterial infection that causes damage to the tissue under the skin (necrotizing fasciitis) in the area between and around the anus and genitals (perineum). Necrotizing fasciitis of the perineum has happened in women and men who take JARDIANCE. Necrotizing fasciitis of the perineum may lead to hospitalization, may require multiple surgeries, and may lead to death. Seek medical attention immediately if you have 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: pain or tendernessswellingredness of skin (erythema)Vaginal yeast infection. Symptoms of vaginal yeast infection include: vaginal odorwhite or yellowish vaginal discharge (discharge may be lumpy or look like cottage cheese)vaginal itching Yeast infection of the penis (balanitis). Swelling of an uncircumcised penis may develop that makes it difficult to pull back the skin around the tip of the penis. Other symptoms of yeast infection of the penis include: redness, itching, or swelling of the penisrash of the penisfoul smelling discharge from the penispain in the skin around the penis Talk to your doctor about what to do if you get symptoms of yeast infection of the vagina or penis. Your doctor may suggest you use an over-the-counter antifungal medicine. Talk to your doctor right away if you use an over-the-counter antifungal medication and your symptoms do not go away.Allergic (hypersensitivity) reactions. Serious allergic reactions have happened in people who are taking JARDIANCE. Symptoms may include: swelling of your face, lips, throat and other areas of your skindifficulty with swallowing or breathing.raised, red areas on your skin (hives)If you have any of these symptoms, stop taking JARDIANCE and call your doctor right away or go to the nearest hospital emergency room.The most common side effects of JARDIANCE include:urinary tract infectionsyeast infections in femalesThese are not all the possible side effects of JARDIANCE. For more information, ask your doctor or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.How should store JARDIANCEStore JARDIANCE at room temperature between 68F to 77F (20C to 25C).Keep JARDIANCE and all medicines out of the reach of children.General information about the safe and effective use of JARDIANCE.Medicines are sometimes prescribed for purposes other than those listed in Medication Guide. Do not use JARDIANCE for condition for which it is not prescribed. Do not give JARDIANCE to other people, even if they have the same symptoms you have. It may harm them. You can ask your pharmacist or doctor for information about JARDIANCE that is written for health professionals.What are the ingredients in JARDIANCEActive Ingredient: empagliflozinInactive Ingredients: lactose monohydrate, microcrystalline cellulose, hydroxypropyl cellulose, croscarmellose sodium, colloidal silicon dioxide and magnesium stearate. In addition, the film coating contains the following inactive ingredients: hypromellose, titanium dioxide, talc, polyethylene glycol, and yellow ferric oxide.Distributed by: Boehringer Ingelheim Pharmaceuticals, Inc.; Ridgefield, CT 06877 USA Marketed by: Boehringer Ingelheim Pharmaceuticals, Inc.; Ridgefield, CT 06877 USA and Eli Lilly and Company, Indianapolis, IN 46285 USA JARDIANCE is registered trademark of and used under license from Boehringer Ingelheim International GmbH.Boehringer Ingelheim Pharmaceuticals, Inc. either owns or uses the EMPA-REG OUTCOME(R) trademark under license.The other brands listed are trademarks of their respective owners and are not trademarks of Boehringer Ingelheim Pharmaceuticals, Inc.Copyright (C) 2021 Boehringer Ingelheim International GmbH ALL RIGHTS RESERVEDCOL8914BF142021For more information about JARDIANCE, including current prescribing information and Medication Guide, go to www.jardiance.com, scan the code, or call Boehringer Ingelheim Pharmaceuticals, Inc. at 1-800-542-6257. Ketoacidosis (increased ketones in your blood or urine). Ketoacidosis has happened in people who have type diabetes or type diabetes, during treatment with JARDIANCE. Ketoacidosis has also happened in people with diabetes who were sick or who had surgery during treatment with JARDIANCE. Ketoacidosis is serious condition, which needs to be treated in hospital. Ketoacidosis may lead to death. Ketoacidosis can happen with JARDIANCE even if your blood sugar is less than 250 mg/dL. Stop taking JARDIANCE and call your doctor right away or go to the nearest hospital emergency room if you get any of the following symptoms:. nausea. vomiting. stomach-area (abdominal) pain. tiredness. trouble breathing. Dehydration. JARDIANCE can cause some people to become dehydrated (the loss of body water and salt). Dehydration may cause you to feel dizzy, faint, light-headed, or weak, especially when you stand up (orthostatic hypotension). There have been reports of sudden worsening of kidney function in people who are taking JARDIANCE. You may be at higher risk of dehydration if you: take medicines to lower your blood pressure, including diuretics (water pills)are on low sodium (salt) diethave kidney problemsare 65 years of age or older take medicines to lower your blood pressure, including diuretics (water pills). are on low sodium (salt) diet. have kidney problems. are 65 years of age or older. JARDIANCE is prescription medicine used: along with diet and exercise to lower blood sugar in adults with type diabetes.to reduce the risk of cardiovascular death in adults with type diabetes who have known cardiovascular disease. along with diet and exercise to lower blood sugar in adults with type diabetes.. to reduce the risk of cardiovascular death in adults with type diabetes who have known cardiovascular disease.. JARDIANCE is not for people with type diabetes. It may increase their risk of diabetic ketoacidosis (increased ketones in blood or urine).. JARDIANCE is not for use to lower blood sugar in adults with type diabetes who have severe kidney problems, because it may not work.. It is not known if JARDIANCE is safe and effective in children.. are allergic to empagliflozin or any of the ingredients in JARDIANCE. See the end of this Medication Guide for complete list of ingredients in JARDIANCE. Symptoms of serious allergic reaction to JARDIANCE may include:swelling of your face, lips, throat and other areas of your skindifficulty with swallowing or breathingraised, red areas on your skin (hives)If you have any of these symptoms, stop taking JARDIANCE and call your doctor right away or go to the nearest hospital emergency room.. swelling of your face, lips, throat and other areas of your skin. difficulty with swallowing or breathing. raised, red areas on your skin (hives). are on dialysis.. have kidney problems.. have liver problems.. have history of infection of the vagina or penis.. have history of urinary tract infections or problems with urination.. are going to have surgery. Your doctor may stop your JARDIANCE before you have surgery. Talk to your doctor if you are having surgery about when to stop taking JARDIANCE and when to start it again.. are eating less, or there is change in your diet.. have or have had problems with your pancreas, including pancreatitis or surgery on your pancreas.. drink alcohol very often, or drink lot of alcohol in the short term (binge drinking).. have type diabetes. JARDIANCE should not be used to treat people with type diabetes.. are pregnant or plan to become pregnant. JARDIANCE may harm your unborn baby. If you become pregnant while taking JARDIANCE, tell your doctor as soon as possible. Talk with your doctor about the best way to control your blood sugar while you are pregnant.. are breastfeeding or plan to breastfeed. JARDIANCE may pass into your breast milk and may harm your baby. Talk with your doctor about the best way to feed your baby if you are taking JARDIANCE. Do not breastfeed while taking JARDIANCE.. diuretics (water pills). insulin or other medicines that can lower your blood sugar. Take JARDIANCE exactly as your doctor tells you to take it.. Take JARDIANCE by mouth time in the morning each day, with or without food.. Your doctor may change your dose if needed.. If you miss dose, take it as soon as you remember. If you do not remember until it is time for your next dose, skip the missed dose and go back to your regular schedule. Do not take two doses of JARDIANCE at the same time. Talk with your doctor if you have questions about missed dose.. Your doctor may tell you to take JARDIANCE along with other diabetes medicines. Low blood sugar can happen more often when JARDIANCE is taken with certain other diabetes medicines. See What are the possible side effects of JARDIANCE If you take too much JARDIANCE, call your doctor or go to the nearest hospital emergency room right away.. When taking JARDIANCE, you may have sugar in your urine, which will show up on urine test.. Your doctor may do blood tests to check how well your kidneys are working before and during your treatment with JARDIANCE.. See What is the most important information should know about JARDIANCE. Low blood sugar (hypoglycemia). If you take JARDIANCE with another medicine that can cause low blood sugar, such as sulfonylurea or insulin, your risk of getting low blood sugar is higher. The dose of your sulfonylurea medicine or insulin may need to be lowered while you take JARDIANCE. Signs and symptoms of low blood sugar may include:. headache. drowsiness. weakness. irritability. hunger. fast heartbeat. confusion. shaking or feeling jittery. dizziness. sweating. rare but serious bacterial infection that causes damage to the tissue under the skin (necrotizing fasciitis) in the area between and around the anus and genitals (perineum). Necrotizing fasciitis of the perineum has happened in women and men who take JARDIANCE. Necrotizing fasciitis of the perineum may lead to hospitalization, may require multiple surgeries, and may lead to death. Seek medical attention immediately if you have 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: pain or tenderness. swelling. redness of skin (erythema). Vaginal yeast infection. Symptoms of vaginal yeast infection include: vaginal odorwhite or yellowish vaginal discharge (discharge may be lumpy or look like cottage cheese)vaginal itching vaginal odor. white or yellowish vaginal discharge (discharge may be lumpy or look like cottage cheese). vaginal itching. Yeast infection of the penis (balanitis). Swelling of an uncircumcised penis may develop that makes it difficult to pull back the skin around the tip of the penis. Other symptoms of yeast infection of the penis include: redness, itching, or swelling of the penisrash of the penisfoul smelling discharge from the penispain in the skin around the penis redness, itching, or swelling of the penis. rash of the penis. foul smelling discharge from the penis. pain in the skin around the penis. Allergic (hypersensitivity) reactions. Serious allergic reactions have happened in people who are taking JARDIANCE. Symptoms may include: swelling of your face, lips, throat and other areas of your skindifficulty with swallowing or breathing.raised, red areas on your skin (hives)If you have any of these symptoms, stop taking JARDIANCE and call your doctor right away or go to the nearest hospital emergency room.. swelling of your face, lips, throat and other areas of your skin. difficulty with swallowing or breathing.. raised, red areas on your skin (hives). urinary tract infections. yeast infections in females. Store JARDIANCE at room temperature between 68F to 77F (20C to 25C).. Keep JARDIANCE and all medicines out of the reach of children.. QR code.

SPL UNCLASSIFIED SECTION.


Limitations of UseJARDIANCE is not recommended in patients with type diabetes mellitus. It may increase the risk of diabetic ketoacidosis in these patients [see Warnings and Precautions (5.1)].JARDIANCE is not recommended for use to improve glycemic control in adults with type diabetes mellitus with an eGFR less than 30 mL/min/1.73 m2. JARDIANCE is likely to be ineffective in this setting based upon its mechanism of action.

STORAGE AND HANDLING SECTION.


StorageStore at 20C to 25C (68F to 77F); excursions permitted to 15C to 30C (59F to 86F) [see USP Controlled Room Temperature].

USE IN SPECIFIC POPULATIONS SECTION.


8USE IN SPECIFIC POPULATIONS. Pregnancy: Advise females of the potential risk to fetus especially during the second and third trimesters (8.1)Lactation: JARDIANCE is not recommended when breastfeeding (8.2)Geriatric Patients: Higher incidence of adverse reactions related to volume depletion and reduced renal function (5.2, 8.5, 8.6)Renal Impairment: Higher incidence of adverse reactions related to reduced renal function (2.3, 5.2, 8.6). Pregnancy: Advise females of the potential risk to fetus especially during the second and third trimesters (8.1). Lactation: JARDIANCE is not recommended when breastfeeding (8.2). Geriatric Patients: Higher incidence of adverse reactions related to volume depletion and reduced renal function (5.2, 8.5, 8.6). Renal Impairment: Higher incidence of adverse reactions related to reduced renal function (2.3, 5.2, 8.6). 8.1 Pregnancy. Risk SummaryBased on animal data showing adverse renal effects, JARDIANCE is not recommended during the second and third trimesters of pregnancy.The limited available data with JARDIANCE in pregnant women are not sufficient to determine drug-associated risk for major birth defects and miscarriage. There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy [see Clinical Considerations].In animal studies, adverse renal changes were observed in rats when empagliflozin was administered during period of renal development corresponding to the late second and third trimesters of human pregnancy. Doses approximately 13-times the maximum clinical dose caused renal pelvic and tubule dilatations that were reversible. [see Data].The estimated background risk of major birth defects is 6% to 10% in women with pre-gestational diabetes with HbA1c >7 and has been reported to be as high as 20% to 25% in women with HbA1c >10. The estimated background risk of miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.. Clinical ConsiderationsDisease-associated maternal and/or embryo/fetal risk: Poorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, pre-eclampsia, spontaneous abortions, preterm delivery, and delivery complications. Poorly controlled diabetes increases the fetal risk for major birth defects, stillbirth, and macrosomia related morbidity.. Data. Animal DataEmpagliflozin dosed directly to juvenile rats from postnatal day (PND) 21 until PND 90 at doses of 1, 10, 30, and 100 mg/kg/day caused increased kidney weights and renal tubular and pelvic dilatation at 100 mg/kg/day, which approximates 13-times the maximum clinical dose of 25 mg, based on AUC. These findings were not observed after 13-week, drug-free recovery period. These outcomes occurred with drug exposure during periods of renal development in rats that correspond to the late second and third trimester of human renal development.In embryo-fetal development studies in rats and rabbits, empagliflozin was administered for intervals coinciding with the first trimester period of organogenesis in humans. Doses up to 300 mg/kg/day, which approximates 48-times (rats) and 128-times (rabbits) the maximum clinical dose of 25 mg (based on AUC), did not result in adverse developmental effects. In rats, at higher doses of empagliflozin causing maternal toxicity, malformations of limb bones increased in fetuses at 700 mg/kg/day or 154-times the 25 mg maximum clinical dose. Empagliflozin crosses the placenta and reaches fetal tissues in rats. In the rabbit, higher doses of empagliflozin resulted in maternal and fetal toxicity at 700 mg/kg/day, or 139-times the 25 mg maximum clinical dose.In pre- and postnatal development studies in pregnant rats, empagliflozin was administered from gestation day through to lactation day 20 (weaning) at up to 100 mg/kg/day (approximately 16-times the 25 mg maximum clinical dose) without maternal toxicity. Reduced body weight was observed in the offspring at greater than or equal to 30 mg/kg/day (approximately 4-times the 25 mg maximum clinical dose).. 8.2 Lactation. Risk SummaryThere is limited information regarding the presence of JARDIANCE in human milk, the effects of JARDIANCE on the breastfed infant or the effects on milk production. Empagliflozin is present in the milk of lactating rats [see Data]. Since human kidney maturation occurs in utero and during the first years of life when lactational exposure may occur, there may be risk to the developing human kidney.Because of the potential for serious adverse reactions in breastfed infant, including the potential for empagliflozin to affect postnatal renal development, advise patients that use of JARDIANCE is not recommended while breastfeeding.. DataEmpagliflozin was present at low level in rat fetal tissues after single oral dose to the dams at gestation day 18. In rat milk, the mean milk to plasma ratio ranged from 0.634 to 5, and was greater than one from to 24 hours post-dose. The mean maximal milk to plasma ratio of occurred at hours post-dose, suggesting accumulation of empagliflozin in the milk. Juvenile rats directly exposed to empagliflozin showed risk to the developing kidney (renal pelvic and tubular dilatations) during maturation.. 8.4 Pediatric Use. The safety and effectiveness of JARDIANCE have not been established in pediatric patients.. 8.5 Geriatric Use. In studies assessing the efficacy of empagliflozin in improving glycemic control in patients with type diabetes, total of 2721 (32%) patients treated with empagliflozin were 65 years of age and older, and 491 (6%) were 75 years of age and older. JARDIANCE is expected to have diminished glycemic efficacy in elderly patients with renal impairment [see Use in Specific Populations (8.6)]. The risk of volume depletion-related adverse reactions increased in patients who were 75 years of age and older to 2.1%, 2.3%, and 4.4% for placebo, JARDIANCE 10 mg, and JARDIANCE 25 mg. The risk of urinary tract infections increased in patients who were 75 years of age and older to 10.5%, 15.7%, and 15.1% in patients randomized to placebo, JARDIANCE 10 mg, and JARDIANCE 25 mg, respectively [see Warnings and Precautions (5.2) and Adverse Reactions (6.1)].. 8.6 Renal Impairment. The efficacy and safety of JARDIANCE for glycemic control were evaluated in study of patients with mild and moderate renal impairment (eGFR 30 to less than 90 mL/min/1.73 m2) [see Clinical Studies (14)]. In this study, 195 patients exposed to JARDIANCE had an eGFR between 60 and 90 mL/min/1.73 m2, 91 patients exposed to JARDIANCE had an eGFR between 45 and 60 mL/min/1.73 m2, and 97 patients exposed to JARDIANCE had an eGFR between 30 and 45 mL/min/1.73 m2. The glucose lowering benefit of JARDIANCE 25 mg decreased in patients with worsening renal function. The risks of renal impairment, volume depletion adverse reactions and urinary tract infection-related adverse reactions increased with worsening renal function [see Warnings and Precautions (5.2)].In large cardiovascular outcomes study, there were 1819 patients with eGFR below 60 mL/min/1.73 m2. The cardiovascular death findings in this subgroup were consistent with the overall findings [see Clinical Studies (14)]. The efficacy and safety studies with JARDIANCE did not enroll patients with ESRD, on dialysis or patients with an eGFR less than 30 mL/min/1.73 m2. JARDIANCE is contraindicated in patients on dialysis [see Indications and Usage (1) and Contraindications (4)]. 8.7 Hepatic Impairment. JARDIANCE may be used in patients with hepatic impairment [see Clinical Pharmacology (12.3)].

WARNINGS AND PRECAUTIONS SECTION.


5WARNINGS AND PRECAUTIONS. Ketoacidosis: Assess patients who present with signs and symptoms of metabolic acidosis for ketoacidosis, regardless of blood glucose level. If suspected, discontinue JARDIANCE, evaluate and treat promptly. Before initiating JARDIANCE, consider risk factors for ketoacidosis. Patients on JARDIANCE may require monitoring and temporary discontinuation of therapy in clinical situations known to predispose to ketoacidosis. (5.1)Volume Depletion: Before initiating JARDIANCE, assess volume status and renal function in patients with impaired renal function, elderly patients, or patients on loop diuretics. Monitor for signs and symptoms during therapy. (5.2, 6.1)Urosepsis and Pyelonephritis: Evaluate patients for signs and symptoms of urinary tract infections and treat promptly, if indicated (5.3)Hypoglycemia: Consider lowering the dose of insulin secretagogue or insulin to reduce the risk of hypoglycemia when initiating JARDIANCE (5.4)Necrotizing Fasciitis of the Perineum (Fourniers Gangrene): Serious, life-threatening cases have occurred in both females and males. Assess patients presenting with pain or tenderness, erythema, or swelling in the genital or perineal area, along with fever or malaise. If suspected, institute prompt treatment. (5.5)Genital Mycotic Infections: Monitor and treat as appropriate (5.6)Hypersensitivity Reactions: Serious hypersensitivity reactions (e.g., angioedema) have occurred with JARDIANCE. If hypersensitivity reactions occur, discontinue JARDIANCE, treat promptly, and monitor until signs and symptoms resolve. (5.7). Ketoacidosis: Assess patients who present with signs and symptoms of metabolic acidosis for ketoacidosis, regardless of blood glucose level. If suspected, discontinue JARDIANCE, evaluate and treat promptly. Before initiating JARDIANCE, consider risk factors for ketoacidosis. Patients on JARDIANCE may require monitoring and temporary discontinuation of therapy in clinical situations known to predispose to ketoacidosis. (5.1). Volume Depletion: Before initiating JARDIANCE, assess volume status and renal function in patients with impaired renal function, elderly patients, or patients on loop diuretics. Monitor for signs and symptoms during therapy. (5.2, 6.1). Urosepsis and Pyelonephritis: Evaluate patients for signs and symptoms of urinary tract infections and treat promptly, if indicated (5.3). Hypoglycemia: Consider lowering the dose of insulin secretagogue or insulin to reduce the risk of hypoglycemia when initiating JARDIANCE (5.4). Necrotizing Fasciitis of the Perineum (Fourniers Gangrene): Serious, life-threatening cases have occurred in both females and males. Assess patients presenting with pain or tenderness, erythema, or swelling in the genital or perineal area, along with fever or malaise. If suspected, institute prompt treatment. (5.5). Genital Mycotic Infections: Monitor and treat as appropriate (5.6). Hypersensitivity Reactions: Serious hypersensitivity reactions (e.g., angioedema) have occurred with JARDIANCE. If hypersensitivity reactions occur, discontinue JARDIANCE, treat promptly, and monitor until signs and symptoms resolve. (5.7). 5.1 Ketoacidosis. Reports of ketoacidosis, serious life-threatening condition requiring urgent hospitalization have been identified in clinical trials and postmarketing surveillance in patients with type and type diabetes mellitus receiving sodium glucose co-transporter-2 (SGLT2) inhibitors, including JARDIANCE. Fatal cases of ketoacidosis have been reported in patients taking JARDIANCE. In placebo-controlled trials of patients with type diabetes, the risk of ketoacidosis was increased in patients who received SGLT2 inhibitors compared to patients who received placebo. JARDIANCE is not indicated for the treatment of patients with type diabetes mellitus [see Indications and Usage (1)].Patients treated with JARDIANCE who present with signs and symptoms consistent with severe metabolic acidosis should be assessed for ketoacidosis regardless of presenting blood glucose levels, as ketoacidosis associated with JARDIANCE may be present even if blood glucose levels are less than 250 mg/dL. If ketoacidosis is suspected, JARDIANCE should be discontinued, patient should be evaluated, and prompt treatment should be instituted. Treatment of ketoacidosis may require insulin, fluid and carbohydrate replacement.In many of the postmarketing reports, and particularly in patients with type diabetes, the presence of ketoacidosis was not immediately recognized and institution of treatment was delayed because presenting blood glucose levels were below those typically expected for diabetic ketoacidosis (often less than 250 mg/dL). Signs and symptoms at presentation were consistent with dehydration and severe metabolic acidosis and included nausea, vomiting, abdominal pain, generalized malaise, and shortness of breath. In some but not all cases, factors predisposing to ketoacidosis such as insulin dose reduction, acute febrile illness, reduced caloric intake, surgery, pancreatic disorders suggesting insulin deficiency (e.g., type diabetes, history of pancreatitis or pancreatic surgery), and alcohol abuse were identified.Before initiating JARDIANCE, consider factors in the patient history that may predispose to ketoacidosis including pancreatic insulin deficiency from any cause, caloric restriction, and alcohol abuse.For patients who undergo scheduled surgery, consider temporarily discontinuing JARDIANCE for at least days prior to surgery [see Clinical Pharmacology (12.2, 12.3)].Consider monitoring for ketoacidosis and temporarily discontinuing JARDIANCE in other clinical situations known to predispose to ketoacidosis (e.g., prolonged fasting due to acute illness or post-surgery). Ensure risk factors for ketoacidosis are resolved prior to restarting JARDIANCE.Educate patients on the signs and symptoms of ketoacidosis and instruct patients to discontinue JARDIANCE and seek medical attention immediately if signs and symptoms occur.. 5.2 Volume Depletion. JARDIANCE can cause intravascular volume depletion which may sometimes manifest as symptomatic hypotension or acute transient changes in creatinine [see Adverse Reactions (6.1)]. There have been post-marketing reports of acute kidney injury, some requiring hospitalization and dialysis, in patients with type diabetes mellitus receiving SGLT2 inhibitors, including JARDIANCE. Patients with impaired renal function (eGFR less than 60 mL/min/1.73 m2), elderly patients, or patients on loop diuretics may be at increased risk for volume depletion or hypotension. Before initiating JARDIANCE in patients with one or more of these characteristics, assess volume status and renal function. In patients with volume depletion, correct this condition before initiating JARDIANCE. Monitor for signs and symptoms of volume depletion, and renal function after initiating therapy.. 5.3 Urosepsis and Pyelonephritis. There have been postmarketing reports of serious urinary tract infections including urosepsis and pyelonephritis requiring hospitalization in patients receiving SGLT2 inhibitors, including JARDIANCE. Treatment with SGLT2 inhibitors increases the risk for urinary tract infections. Evaluate patients for signs and symptoms of urinary tract infections and treat promptly, if indicated [see Adverse Reactions (6)].. 5.4 Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues. Insulin and insulin secretagogues are known to cause hypoglycemia. The risk of hypoglycemia is increased when JARDIANCE is used in combination with insulin secretagogues (e.g., sulfonylurea) or insulin [see Adverse Reactions (6.1)]. Therefore, lower dose of the insulin secretagogue or insulin may be required to reduce the risk of hypoglycemia when used in combination with JARDIANCE.. 5.5 Necrotizing Fasciitis of the Perineum (Fourniers Gangrene). Reports of necrotizing fasciitis of the perineum (Fourniers gangrene), rare but serious and life-threatening necrotizing infection requiring urgent surgical intervention, have been identified in postmarketing surveillance in patients with diabetes mellitus receiving SGLT2 inhibitors, including JARDIANCE. Cases have been reported in both females and males. Serious outcomes have included hospitalization, multiple surgeries, and death.Patients treated with JARDIANCE presenting with pain or tenderness, erythema, or swelling in the genital or perineal area, along with fever or malaise, should be assessed for necrotizing fasciitis. If suspected, start treatment immediately with broad-spectrum antibiotics and, if necessary, surgical debridement. Discontinue JARDIANCE, closely monitor blood glucose levels, and provide appropriate alternative therapy for glycemic control.. 5.6 Genital Mycotic Infections. JARDIANCE increases the risk for genital mycotic infections [see Adverse Reactions (6.1)]. Patients with history of chronic or recurrent genital mycotic infections were more likely to develop genital mycotic infections. Monitor and treat as appropriate.. 5.7 Hypersensitivity Reactions. There have been postmarketing reports of serious hypersensitivity reactions (e.g., angioedema) in patients treated with JARDIANCE. If hypersensitivity reaction occurs, discontinue JARDIANCE; treat promptly per standard of care, and monitor until signs and symptoms resolve. JARDIANCE is contraindicated in patients with hypersensitivity to empagliflozin or any of the excipients in JARDIANCE [see Contraindications (4)].