ADVERSE REACTIONS SECTION.


6 ADVERSE REACTIONS. The following important adverse reactionsare described below and elsewhere in the labeling:Hypotension [see Warnings and Precautions (5.1)] Ketoacidosis [see Warnings and Precautions (5.2)] Acute Kidney Injury and Impairment in Renal Function [see Warnings and Precautions (5.3)] Urosepsis and Pyelonephritis [see Warnings and Precautions(5.4)] Hypoglycemia with Concomitant Use with Insulin and InsulinSecretagogues [see Warnings and Precautions (5.5)] Genital Mycotic Infections [see Warnings and Precautions(5.6)] Hypersensitivity Reactions [see Warnings and Precautions(5.7)] Increased Low-Density Lipoprotein Cholesterol (LDL-C) [see Warnings and Precautions (5.8)] Hypotension [see Warnings and Precautions (5.1)] Ketoacidosis [see Warnings and Precautions (5.2)] Acute Kidney Injury and Impairment in Renal Function [see Warnings and Precautions (5.3)] Urosepsis and Pyelonephritis [see Warnings and Precautions(5.4)] Hypoglycemia with Concomitant Use with Insulin and InsulinSecretagogues [see Warnings and Precautions (5.5)] Genital Mycotic Infections [see Warnings and Precautions(5.6)] Hypersensitivity Reactions [see Warnings and Precautions(5.7)] Increased Low-Density Lipoprotein Cholesterol (LDL-C) [see Warnings and Precautions (5.8)] The most common adverse reactions associated with JARDIANCE (5% or greater incidence) were urinary tract infections and femalegenital mycotic infections (6.1)To report SUSPECTED ADVERSE REACTIONS,contact Boehringer Ingelheim Pharmaceuticals, Inc. at 1-800-542-6257or 1-800-459-9906 TTY, 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 femalegenital mycotic infections (6.1). 6.1 Clinical Trials Experience. Because clinical trials are conductedunder widely varying conditions, adverse reaction rates observed inthe clinical trials of drug cannot be directly compared to ratesin the clinical trials of another drug and may not reflect the ratesobserved in practice.Pool of Placebo-Controlled Trials evaluating JARDIANCE10 and 25 mg Thedata in Table are derived from pool of four 24-week placebo-controlledtrials and 18-week data from placebo-controlled trial with insulin. JARDIANCE was used as monotherapy in one trial and as add-on therapyin four trials [see Clinical Studies (14)].These data reflect exposure of 1976 patients to JARDIANCE with amean exposure duration of approximately 23 weeks. Patients receivedplacebo (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% wereolder than 75 years of age. More than half (55%) of the populationwas male; 46% were White, 50% were Asian, and 3% were Black or AfricanAmerican. At baseline, 57% of the population had diabetes more than5 years and had mean hemoglobin A1c (HbA1c) of 8%. Establishedmicrovascular complications of diabetes at baseline included diabeticnephropathy (7%), retinopathy (8%), or neuropathy (16%). Baselinerenal function was normal or mildly impaired in 91% of patients andmoderately impaired in 9% of patients (mean eGFR 86.8 mL/min/1.73m2).Table shows common adverse reactions (excludinghypoglycemia) associated with the use of JARDIANCE. The adverse reactionswere not present at baseline, occurred more commonly on JARDIANCEthan on placebo and occurred in greater than or equal to 2% of patientstreated with JARDIANCE 10 mg or JARDIANCE 25 mg.Table Adverse Reactions Reported in >=2% of Patients Treatedwith JARDIANCE and Greater than Placebo in Pooled Placebo-ControlledClinical Studies of JARDIANCE Monotherapy or Combination TherapyaPredefined adverse eventgrouping, including, but not limited to, urinary tract infection,asymptomatic bacteriuria, cystitisbFemale genital mycoticinfections include the following adverse reactions: vulvovaginal mycoticinfection, vaginal infection, vulvitis, vulvovaginal candidiasis,genital infection, genital candidiasis, genital infection fungal,genitourinary tract infection, vulvovaginitis, cervicitis, urogenitalinfection fungal, vaginitis bacterial. Percentages calculated withthe number of female subjects in each group as denominator: placebo(N=481), JARDIANCE 10 mg (N=443), JARDIANCE 25 mg (N=420).cPredefined adverse eventgrouping, including, but not limited to, polyuria, pollakiuria, andnocturiadMale genital mycotic infectionsinclude the following adverse reactions: balanoposthitis, balanitis,genital infections fungal, genitourinary tract infection, balanitiscandida, scrotal abscess, penile infection. Percentages calculatedwith the number of male subjects in each group as denominator: placebo(N=514), JARDIANCE 10 mg (N=556), JARDIANCE 25 mg (N=557). Number (%) of PatientsPlaceboN=995JARDIANCE10 mgN=999JARDIANCE25 mgN=977Urinary tract infectiona 7.6%9.3%7.6%Female genital mycotic infectionsb 1.5%5.4%6.4%Upper respiratory tract infection3.8%3.1%4.0%Increased urinationc 1.0%3.4%3.2%Dyslipidemia3.4%3.9%2.9%Arthralgia2.2%2.4%2.3%Male genital mycotic infectionsd 0.4%3.1%1.6%Nausea1.4%2.3%1.1%Thirst (including polydipsia)was reported in 0%, 1.7%, and 1.5% for placebo, JARDIANCE 10 mg, andJARDIANCE 25 mg, respectively.Volume Depletion JARDIANCE causes an osmotic diuresis, which may lead to intravascularvolume contraction and adverse reactions related to volume depletion. In the pool of five placebo-controlled clinical trials, adverse reactionsrelated 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 JARDIANCE25 mg, respectively. JARDIANCE may increase the risk of hypotensionin patients at risk for volume contraction [see Warnings andPrecautions (5.1) and Use in SpecificPopulations (8.5, 8.6)]. Increased Urination In the pool of five placebo-controlled clinical trials, adversereactions of increased urination (e.g., polyuria, pollakiuria, andnocturia) occurred more frequently on JARDIANCE than on placebo (seeTable 1). Specifically, nocturia was reported by 0.4%, 0.3%, and0.8% of patients treated with placebo, JARDIANCE 10 mg, and JARDIANCE25 mg, respectively.Acute Impairment in Renal Function Treatment with JARDIANCE was associated with increases in serumcreatinine and decreases in eGFR (see Table 2). Patients with moderaterenal impairment at baseline had larger mean changes [seeWarnings and Precautions (5.3) andUse in Specific Populations (8.5, 8.6)].In long-term cardiovascular outcome trial,the acute impairment in renal function was observed to reverse aftertreatment discontinuation suggesting acute hemodynamic changes playa role in the renal function changes observed with empagliflozin. Table Changes from Baseline in Serum Creatinine and eGFRa in the Pool of Four 24-week Placebo-Controlled Studiesand Renal Impairment StudyaObserved cases on treatment.bSubset of patients from renal impairmentstudy with eGFR 30 to less than 60 mL/min/1.73 m2cApproximately weeks afterend of treatment. Pool of 24-Week Placebo-Controlled StudiesPlaceboJARDIANCE10 mgJARDIANCE25 mgBaseline MeanN825830822Creatinine (mg/dL)0.840.850.85eGFR (mL/min/1.73m2)87.387.187.8Week 12 ChangeN771797783Creatinine (mg/dL)0.00 0.020.01eGFR (mL/min/1.73m2)-0.3-1.3-1.4Week 24 ChangeN708769754Creatinine (mg/dL)0.000.010.01eGFR (mL/min/1.73m2)-0.3-0.6-1.4 Moderate Renal Impairmentb Placebo JARDIANCE25 mgBaseline MeanN187--187Creatinine (mg/dL)1.49--1.46eGFR (mL/min/1.73m2)44.3--45.4Week 12 ChangeN176--179Creatinine (mg/dL)0.01--0.12eGFR (mL/min/1.73m2)0.1---3.8Week 24 ChangeN170--171Creatinine (mg/dL)0.01--0.10eGFR (mL/min/1.73m2)0.2---3.2Week 52 ChangeN164--162Creatinine (mg/dL)0.02--0.11eGFR (mL/min/1.73m2)-0.3---2.8Post-treatment Changec N98--103Creatinine (mg/dL)0.03--0.02eGFR (mL/min/1.73m2)0.16--1.48Hypoglycemia The incidence of hypoglycemiaby study is shown in Table 3. The incidence of hypoglycemia increasedwhen JARDIANCE was administered with insulin or sulfonylurea [see Warnings and Precautions (5.5)].Table Incidence of Overalla andSevereb Hypoglycemic Events in Placebo-ControlledClinical Studiesc aOverall hypoglycemic events:plasma or capillary glucose of less than or equal to 70 mg/dLbSevere hypoglycemic events: requiringassistance regardless of blood glucosecTreated set (patients who had received at least one dose of studydrug)dInsulin dose could notbe adjusted during the initial 18 week treatment periodMonotherapy(24 weeks)Placebo(n=229)JARDIANCE10 mg(n=224)JARDIANCE25 mg(n=223)Overall (%)0.4%0.4%0.4%Severe (%)0%0%0%In Combination withMetformin(24 weeks)Placebo+ Metformin (n=206)JARDIANCE10 mg Metformin(n=217)JARDIANCE25 mg Metformin(n=214)Overall (%)0.5%1.8%1.4%Severe (%)0%0%0%In Combination withMetformin Sulfonylurea(24 weeks)Placebo(n=225)JARDIANCE10 mg Metformin Sulfonylurea(n=224)JARDIANCE25 mg Metformin Sulfonylurea(n=217)Overall (%)8.4%16.1%11.5%Severe (%)0%0%0%In Combination withPioglitazone +/- Metformin(24 weeks)Placebo(n=165)JARDIANCE10 mg Pioglitazone +/- Metformin(n=165)JARDIANCE25 mg Pioglitazone +/- Metformin(n=168)Overall (%)1.8%1.2%2.4%Severe (%)0%0%0%In Combination with BasalInsulin +/- Metformin(18 weeksd)Placebo(n=170)JARDIANCE10 mg(n=169)JARDIANCE25 mg(n=155)Overall (%)20.6%19.5%28.4%Severe (%)0%0%1.3%In Combination with MDIInsulin +/-Metformin (18 weeksd)Placebo(n=188)JARDIANCE 10 mg(n=186)JARDIANCE 25 mg(n=189)Overall (%)37.2%39.8%41.3%Severe (%)0.5%0.5%0.5%Genital MycoticInfections In the poolof five placebo-controlled clinical trials, the incidence of genitalmycotic 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. Discontinuationfrom study due to genital infection occurred in 0% of placebo-treatedpatients and 0.2% of patients treated with either JARDIANCE 10 or25 mg.Genital mycoticinfections occurred more frequently in female than male patients (seeTable 1).Phimosisoccurred more frequently in male patients treated with JARDIANCE 10mg (less than 0.1%) and JARDIANCE 25 mg (0.1%) than placebo (0%).Urinary Tract Infections In the pool of five placebo-controlledclinical trials, the incidence of urinary tract infections (e.g.,urinary tract infection, asymptomatic bacteriuria, and cystitis) wasincreased in patients treated with JARDIANCE compared to placebo (seeTable 1). Patients with history of chronic or recurrent urinarytract infections were more likely to experience urinary tract infection. The rate of treatment discontinuation due to urinary tract infectionswas 0.1%, 0.2%, and 0.1% for placebo, JARDIANCE 10 mg, and JARDIANCE25 mg, respectively.Urinary tract infections occurred more frequently in female patients. The incidence of urinary tract infections in female patients randomizedto placebo, JARDIANCE 10 mg, and JARDIANCE 25 mg was 16.6%, 18.4%,and 17.0%, respectively. The incidence of urinary tract infectionsin male patients randomized to placebo, JARDIANCE 10 mg, and JARDIANCE25 mg was 3.2%, 3.6%, and 4.1%, respectively [see Warningsand Precautions (5.4) and Use in SpecificPopulations (8.5)].Laboratory TestsIncrease in Low-Density Lipoprotein Cholesterol(LDL-C) Dose-relatedincreases in low-density lipoprotein cholesterol (LDL-C) were observedin patients treated with JARDIANCE. LDL-C increased by 2.3%, 4.6%,and 6.5% in patients treated with placebo, JARDIANCE 10 mg, and JARDIANCE25 mg, respectively [see Warnings and Precautions (5.8)]. The range of mean baselineLDL-C levels was 90.3 to 90.6 mg/dL across treatment groups.Increase in Hematocrit In pool of four placebo-controlledstudies, median hematocrit decreased by 1.3% in placebo and increasedby 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 hematocritsinitially within the reference range had values above the upper limitof the reference range with placebo, JARDIANCE 10 mg, and JARDIANCE25 mg, respectively.. 6.2 Postmarketing Experience. Additional adverse reactionshave been identified during postapproval use of JARDIANCE. Becausethese reactions are reported voluntarily from population of uncertainsize, it is generally not possible to reliably estimate their frequencyor establish causal relationship to drug exposure.Ketoacidosis [see Warnings and Precautions (5.2)] Urosepsis and pyelonephritis [see Warnings and Precautions(5.4)] Angioedema [see Warnings and Precautions (5.7)] Skin reactions (e.g., rash, urticaria). Ketoacidosis [see Warnings and Precautions (5.2)] Urosepsis and pyelonephritis [see Warnings and Precautions(5.4)] Angioedema [see Warnings and Precautions (5.7)] Skin reactions (e.g., rash, urticaria).

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.


13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Carcinogenesis Carcinogenesis was evaluatedin 2-year studies conducted in CD-1 mice and Wistar rats. Empagliflozindid 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 maximumclinical dose of 25 mg). In male rats, hemangiomas of the mesentericlymph node were increased significantly at 700 mg/kg/day or approximately42 times the exposure from 25 mg clinical dose. Empagliflozin didnot 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 clinicaldose). Renal tubule adenomas and carcinomas were observed in malemice at 1000 mg/kg/day, which is approximately 45 times the exposureof the maximum clinical dose of 25 mg. These tumors may be associatedwith metabolic pathway predominantly present in the male mouse kidney.Mutagenesis Empagliflozin was not mutagenicor clastogenic with or without metabolic activation in the in vitro Ames bacterial mutagenicity assay, the in vitro L5178Y tk+/- mouse lymphomacell assay, and an in vivo micronucleus assay inrats.Impairmentof Fertility Empagliflozinhad no effects on mating, fertility or early embryonic developmentin 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.


12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Sodium-glucose co-transporter (SGLT2)is the predominant transporter responsible for reabsorption of glucosefrom the glomerular filtrate back into the circulation. Empagliflozinis an inhibitor of SGLT2. By inhibiting SGLT2, empagliflozin reducesrenal reabsorption of filtered glucose and lowers the renal thresholdfor glucose, and thereby increases urinary glucose excretion.. 12.2 Pharmacodynamics. Urinary Glucose Excretion In patients with type diabetes,urinary glucose excretion increased immediately following dose ofJARDIANCE and was maintained at the end of 4-week treatment periodaveraging at approximately 64 grams per day with 10 mg empagliflozinand 78 grams per day with 25 mg JARDIANCE once daily [seeClinical Studies (14)]. Urinary Volume In 5-day study, mean 24-hoururine volume increase from baseline was 341 mL on Day and 135 mLon Day of empagliflozin 25 mg once daily treatment.Cardiac ElectrophysiologyIn randomized, placebo-controlled, active-comparator,crossover study, 30 healthy subjects were administered single oraldose of JARDIANCE 25 mg, JARDIANCE 200 mg (8 times the maximum dose),moxifloxacin, and placebo. No increase in QTc was observed with either25 mg or 200 mg empagliflozin.. 12.3 Pharmacokinetics. AbsorptionThepharmacokinetics of empagliflozin has been characterized in healthyvolunteers and patients with type diabetes and no clinically relevantdifferences were noted between the two populations. After oral administration,peak plasma concentrations of empagliflozin were reached at 1.5 hourspost-dose. Thereafter, plasma concentrations declined in biphasicmanner with rapid distribution phase and relatively slow terminalphase. The steady state mean plasma AUC and Cmax were 1870 nmol.h/L and 259 nmol/L, respectively, with 10 mg empagliflozinonce daily treatment, and 4740 nmol.h/L and 687 nmol/L, respectively,with 25 mg empagliflozin once daily treatment. Systemic exposureof empagliflozin increased in dose-proportional manner in the therapeuticdose range. The single-dose and steady-state pharmacokinetic parametersof empagliflozin were similar, suggesting linear pharmacokineticswith respect to time.Administration of 25 mg empagliflozin after intake of high-fatand high-calorie meal resulted in slightly lower exposure; AUC decreasedby approximately 16% and Cmax decreased byapproximately 37%, compared to fasted condition. The observed effectof food on empagliflozin pharmacokinetics was not considered clinicallyrelevant and empagliflozin may be administered with or without food.DistributionThe apparent steady-state volume of distribution wasestimated to be 73.8 based on population pharmacokinetic analysis. Following administration of an oral [14C]-empagliflozin solution to healthy subjects, the red blood cellpartitioning was approximately 36.8% and plasma protein binding was86.2%. MetabolismNo major metabolites of empagliflozin were detected inhuman plasma and the most abundant metabolites were three glucuronideconjugates (2-O-, 3-O-, and 6-O-glucuronide). Systemic exposure ofeach metabolite was less than 10% of total drug-related material. In vitro studies suggested that the primary route of metabolismof empagliflozin in humans is glucuronidation by the uridine 5-diphospho-glucuronosyltransferasesUGT2B7, UGT1A3, UGT1A8, and UGT1A9.EliminationTheapparent terminal elimination half-life of empagliflozin was estimatedto be 12.4 and apparent oral clearance was 10.6 L/h based on thepopulation pharmacokinetic analysis. Following once-daily dosing,up to 22% accumulation, with respect to plasma AUC, was observed atsteady-state, which was consistent with empagliflozin half-life. Following 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 recoveredin feces was unchanged parent drug and approximately half of drug-relatedradioactivity excreted in urine was unchanged parent drug.Specific PopulationsRenal ImpairmentInpatients with mild (eGFR: 60 to less than 90 mL/min/1.73 m2), moderate (eGFR: 30 to less than 60 mL/min/1.73m2), and severe (eGFR: less than 30 mL/min/1.73m2) renal impairment and subjects withkidney failure/end stage renal disease (ESRD) patients, AUC of empagliflozinincreased by approximately 18%, 20%, 66%, and 48%, respectively, comparedto subjects with normal renal function. Peak plasma levels of empagliflozinwere similar in subjects with moderate renal impairment and kidneyfailure/ESRD compared to patients with normal renal function. Peakplasma levels of empagliflozin were roughly 20% higher in subjectswith mild and severe renal impairment as compared to subjects withnormal renal function. Population pharmacokinetic analysis showedthat the apparent oral clearance of empagliflozin decreased, witha 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 subjects with mild, moderate, and severe hepatic impairmentaccording to the Child-Pugh classification, AUC of empagliflozin increasedby approximately 23%, 47%, and 75%, and Cmax increased by approximately 4%, 23%, and 48%, respectively, comparedto subjects with normal hepatic function.Effects of Age, Body Mass Index,Gender, and RaceBased on the population PKanalysis, age, body mass index (BMI), gender and race (Asians versusprimarily Whites) do not have clinically meaningful effect on pharmacokineticsof empagliflozin [see Use in Specific Populations (8.5)].PediatricStudies characterizing the pharmacokinetics of empagliflozin inpediatric patients have not been performed.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 metabolismof empagliflozin in humans is glucuronidation by the uridine 5-diphospho-glucuronosyltransferasesUGT1A3, UGT1A8, UGT1A9, and UGT2B7. Empagliflozin does not inhibitUGT1A1, UGT1A3, UGT1A8, UGT1A9, or UGT2B7. Therefore, no effect ofempagliflozin is anticipated on concomitantly administered drugs thatare substrates of the major CYP450 isoforms or UGT1A1, UGT1A3, UGT1A8,UGT1A9, or UGT2B7. The effect of UGT induction (e.g., induction byrifampicin or any other UGT enzyme inducer) on empagliflozin exposurehas not been evaluated.Empagliflozin is substrate for P-glycoprotein (P-gp) and breastcancer resistance protein (BCRP), but it does not inhibit these effluxtransporters at therapeutic doses. Based on in vitro studies, empagliflozin is considered unlikely to cause interactionswith drugs that are P-gp substrates. Empagliflozin is substrateof the human uptake transporters OAT3, OATP1B1, and OATP1B3, but notOAT1 and OCT2. Empagliflozin does not inhibit any of these human uptaketransporters at clinically relevant plasma concentrations and, therefore,no effect of empagliflozin is anticipated on concomitantly administereddrugs that are substrates of these uptake transporters.In vivo Assessment of Drug InteractionsNo dose adjustmentof JARDIANCE is recommended when coadministered with commonly prescribedmedicinal products based on results of the described pharmacokineticstudies. Empagliflozin pharmacokinetics were similar with and withoutcoadministration of metformin, glimepiride, pioglitazone, sitagliptin,linagliptin, warfarin, verapamil, ramipril, and simvastatin in healthyvolunteers and with or without coadministration of hydrochlorothiazideand torsemide in patients with type diabetes (see Figure 1). Theobserved increases in overall exposure (AUC) of empagliflozin followingcoadministration with gemfibrozil, rifampicin, or probenecid are notclinically relevant. In subjects with normal renal function, coadministrationof empagliflozin with probenecid resulted in 30% decrease in thefraction of empagliflozin excreted in urine without any effect on24-hour urinary glucose excretion. The relevance of this observationto patients with renal impairment is unknown.Figure Effect of Various Medicationson the Pharmacokinetics of Empagliflozin as Displayed as 90% ConfidenceInterval 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, oncedaily; dempagliflozin, 10 mg, single doseEmpagliflozin had no clinicallyrelevant effect on the pharmacokinetics of metformin, glimepiride,pioglitazone, sitagliptin, linagliptin, warfarin, digoxin, ramipril,simvastatin, hydrochlorothiazide, torsemide, and oral contraceptiveswhen coadministered in healthy volunteers (see Figure 2).Figure Effect of Empagliflozinon the Pharmacokinetics of Various Medications 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,once daily; cempagliflozin, 25 mg, singledose; dadministered as simvastatin; eadministered as warfarin racemic mixture; fadministered as Microgynon(R); gadministered as ramipril. figure-1. figure-2.

CLINICAL STUDIES SECTION.


14 CLINICAL STUDIES. 14.1 Glycemic Control. JARDIANCE has been studied asmonotherapy and in combination with metformin, sulfonylurea, pioglitazone,linagliptin, and insulin. JARDIANCE has also been studied in patientswith type diabetes with mild or moderate renal impairment.In patients with type diabetes,treatment with JARDIANCE reduced hemoglobin A1c (HbA1c), comparedto placebo. The reduction in HbA1c for JARDIANCE compared with placebowas observed across subgroups including gender, race, geographic region,baseline BMI and duration of disease.MonotherapyAtotal of 986 patients with type diabetes participated in double-blind,placebo-controlled study to evaluate the efficacy and safety of JARDIANCEmonotherapy.Treatment-naivepatients with inadequately controlled type diabetes entered an open-labelplacebo run-in for weeks. At the end of the run-in period, patientswho remained inadequately controlled and had an HbA1c between and10% were randomized to placebo, JARDIANCE 10 mg, JARDIANCE 25 mg,or reference comparator. At Week 24, treatment with JARDIANCE 10mg or 25 mg daily provided statistically significant reductions inHbA1c (p-value <0.0001), fasting plasma glucose (FPG), and bodyweight compared with placebo (see Table and Figure 3).Table Results at Week 24 From Placebo-Controlled MonotherapyStudy of JARDIANCEaModified intent to treatpopulation. Last observation on study (LOCF) was used to impute missingdata at Week 24. At Week 24, 9.4%, 9.4%, and 30.7% was imputed forpatients randomized to JARDIANCE 10 mg, JARDIANCE 25 mg, and placebo,respectively.bANCOVA derivedp-value <0.0001 (HbA1c: ANCOVA model includes baseline HbA1c, treatment,renal function, and region. Body weight and FPG: same model usedas for HbA1c but additionally including baseline body weight/baselineFPG, respectively.)cFPG (mg/dL);for JARDIANCE 10 mg, n=223, for JARDIANCE 25 mg, n=223, and for placebo,n=226 JARDIANCE10 mgN=224JARDIANCE25 mgN=224PlaceboN=228HbA1c (%)a Baseline (mean)7.97.97.9 Change from baseline (adjusted mean)-0.7-0.80.1 Difference from placebo (adjustedmean) (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 (adjustedmean) (95% CI)-31 (-37, -26)-36 (-42, -31)--Body Weight Baseline (mean) in kg787878 change from baseline (adjustedmean)-2.8-3.2-0.4 Difference from placebo (adjustedmean) (95% CI)-2.5b (-3.1, -1.9)-2.8b (-3.4, -2.2)--Figure AdjustedMean HbA1c Change at Each Time Point (Completers) and at Week 24 (mITTPopulation) LOCFAt Week 24, the systolic blood pressurewas statistically significantly reduced compared to placebo by -2.6mmHg (placebo-adjusted, p-value=0.0231) in patients randomized to10 mg of JARDIANCE and by -3.4 mmHg (placebo-corrected, p-value=0.0028)in patients randomized to 25 mg of JARDIANCE.Add-On Combination Therapy withMetforminA total of 637 patients with type 2diabetes participated in double-blind, placebo-controlled studyto evaluate the efficacy and safety of JARDIANCE in combination withmetformin.Patientswith type diabetes inadequately controlled on at least 1500 mg ofmetformin per day entered an open-label week placebo run-in. Atthe end of the run-in period, patients who remained inadequately controlledand had an HbA1c between and 10% were randomized to placebo, JARDIANCE10 mg, or JARDIANCE 25 mg.At Week 24, treatment with JARDIANCE 10mg or 25 mg daily provided statistically significant reductions inHbA1c (p-value <0.0001), FPG, and body weight compared with placebo(see Table 5).Table Results at Week 24 From Placebo-Controlled Studyfor JARDIANCE used in Combination with MetforminaModified intent to treatpopulation. Last observation on study (LOCF) was used to impute missingdata at Week 24. At Week 24, 9.7%, 14.1%, and 24.6% was imputed forpatients 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 butadditionally 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=207 JARDIANCE10 mg MetforminN=217JARDIANCE25 mg MetforminN=213Placebo MetforminN=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 (adjustedmean)-2.5-2.9-0.5 Difference from placebo (adjustedmean) (95% CI)-2.0b (-2.6, -1.4)-2.5b (-3.1, -1.9)--At Week 24, the systolicblood pressure was statistically significantly reduced compared toplacebo by -4.1 mmHg (placebo-corrected, p-value <0.0001) for JARDIANCE10 mg and -4.8 mmHg (placebo-corrected, p-value <0.0001) for JARDIANCE25 mg.InitialCombination Therapy with MetforminA total of1364 patients with type diabetes participated in double-blind,randomized, active-controlled study to evaluate the efficacy and safetyof JARDIANCE in combination with metformin as initial therapy comparedto the corresponding individual components.Treatment-naive patients with inadequatelycontrolled type diabetes entered an open-label placebo run-in for2 weeks. At the end of the run-in period, patients who remained inadequatelycontrolled and had an HbA1c between and 10.5% were randomized toone of active-treatment arms: JARDIANCE 10 mg or 25 mg; metformin1000 mg, or 2000 mg; JARDIANCE 10 mg in combination with 1000 mg or2000 mg metformin; or JARDIANCE 25 mg in combination with 1000 mgor 2000 mg metformin.At Week 24, initial therapy of JARDIANCE in combination with metforminprovided statistically significant reductions in HbA1c (p-value <0.01)compared to the individual components (see Table 6).Table Glycemic Parameters at 24 Weeks in Study ComparingJARDIANCE and Metformin to the Individual Components as Initial TherapyaMetformin total dailydose, administered in two equally divided doses per day.bp-value <=0.0062 (modified intent totreat population [observed case] MMRM model included treatment, renalfunction, region, visit, visit by treatment interaction, and baselineHbA1c). cp-value <=0.0056 (modifiedintent to treat population [observed case] MMRM model included treatment,renal function, region, visit, visit by treatment interaction, andbaseline HbA1c). JARDIANCE10 mg +Metformin1000 mga N=161JARDIANCE10 mg +Metformin2000 mga N=167JARDIANCE25 mg +Metformin1000 mga N=165JARDIANCE25 mg +Metformin2000 mga N=169JARDIANCE10 mgN=169JARDIANCE25 mgN=163Metformin1000 mga N=167Metformin2000 mga N=162HbA1c (%) Baseline (mean)8.78.78.88.78.68.98.78.6Change from baseline (adjustedmean)-2.0-2.1-1.9-2.1-1.4-1.4-1.2-1.8Comparison vs JARDIANCE (adjustedmean) (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 (adjustedmean) (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 CombinationTherapy with Metformin and SulfonylureaA totalof 666 patients with type diabetes participated in double-blind,placebo-controlled study to evaluate the efficacy and safety of JARDIANCEin combination with metformin plus sulfonylurea.Patients with inadequately controlled type2 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 between7% and 10% were randomized to placebo, JARDIANCE 10 mg, or JARDIANCE25 mg.Treatment withJARDIANCE 10 mg or 25 mg daily provided statistically significantreductions in HbA1c (p-value <0.0001), FPG, and body weight comparedwith placebo (see Table 7).Table Results at Week 24 from Placebo-Controlled Studyfor JARDIANCE in Combination with Metformin and SulfonylureaaModified intent to treatpopulation. Last observation on study (LOCF) was used to impute missingdata at Week 24. At Week 24, 17.8%, 16.7%, and 25.3% was imputedfor 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 usedas for HbA1c but additionally including baseline body weight/baselineFPG, respectively.)cFPG (mg/dL);for JARDIANCE 10 mg, n=225, for JARDIANCE 25 mg, n=215, for placebo,n=224 JARDIANCE10 mg Metformin+ SUN=225JARDIANCE 25 mg Metformin+ SUN=216Placebo+ Metformin SUN=225HbA1c (%)a Baseline (mean)8.18.18.2 Change from baseline (adjusted mean)-0.8-0.8-0.2 Difference from placebo (adjustedmean) (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 (adjustedmean)-29-29--Body Weight Baseline mean in kg777876 change from baseline (adjustedmean)-2.9-3.2-0.5 Difference from placebo (adjustedmean) (95% CI)-2.4b (-3.0, -1.8)-2.7b (-3.3, -2.1)--In Combinationwith Linagliptin as Add-On to Metformin Therapy total of 686 patients with type diabetes participated in adouble-blind, active-controlled study to evaluate the efficacy andsafety of JARDIANCE 10 mg or 25 mg in combination with linagliptin5 mg compared to the individual components. Patients with type diabetes inadequatelycontrolled on at least 1500 mg of metformin per day entered single-blindplacebo run-in period for weeks. At the end of the run-in period,patients who remained inadequately controlled and had an HbA1c between7 and 10.5% were randomized 1:1:1:1:1 to one of active-treatmentarms of JARDIANCE 10 mg or 25 mg, linagliptin mg, or linagliptin5 mg in combination with 10 mg or 25 mg JARDIANCE as fixed dosecombination tablet.At Week 24, JARDIANCE 10 mg or 25 mg used in combination with linagliptin5 mg provided statistically significant improvement in HbA1c (p-value<0.0001) and FPG (p-value <0.001) compared to the individualcomponents in patients who had been inadequately controlled on metformin. Treatment with JARDIANCE/linagliptin 25 mg/5 mg or JARDIANCE/linagliptin10 mg/5 mg daily also resulted in statistically significant reductionin body weight compared to linagliptin mg (p-value <0.0001). There was no statistically significant difference in body weight comparedto JARDIANCE alone.Active-Controlled Study versus Glimepiride in Combinationwith MetforminThe efficacy of JARDIANCE was evaluatedin double-blind, glimepiride-controlled, study in 1545 patientswith type diabetes with insufficient glycemic control despite metformintherapy.Patientswith inadequate glycemic control and an HbA1c between 7% and 10% aftera 2-week run-in period were randomized to glimepiride or JARDIANCE25 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 JARDIANCE25 mg and glimepiride excluded the pre-specified non-inferiority marginof 0.3%. The mean daily dose of glimepiride was 2.7 mg and the maximalapproved dose in the United States is mg per day. Table Results at Week 52 from an Active-Controlled StudyComparing JARDIANCE to Glimepiride as Add-On Therapy in Patients InadequatelyControlled on MetforminaModified intent to treatpopulation. Last observation on study (LOCF) was used to impute datamissing 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 additionallyincluding baseline body weight/baseline FPG, respectively.) dFPG (mg/dL); for JARDIANCE 25 mg, n=764,for placebo, n=779 JARDIANCE25 mg MetforminN=765Glimepiride+ MetforminN=780HbA1c (%)a Baseline (mean)7.97.9 Change from baseline (adjusted mean)-0.7-0.7 Difference from glimepiride (adjustedmean) (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 (adjustedmean)-11--Body Weight Baseline mean in kg82.583 change from baseline (adjustedmean)-3.92.0 Difference from glimepiride (adjustedmean) (95% CI)-5.9c (-6.3, -5.5)--Figure Adjustedmean HbA1c Change at Each Time Point (Completers) and at Week 52 (mITTPopulation) LOCFAt Week 52, the adjusted mean change frombaseline in systolic blood pressure was -3.6 mmHg, compared to 2.2mmHg for glimepiride. The differences between treatment groups forsystolic blood pressure was statistically significant (p-value <0.0001).At Week 104, the adjusted meanchange 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%), excludingthe pre-specified non-inferiority margin of 0.3%. The mean dailydose of glimepiride was 2.7 mg and the maximal approved dose in theUnited States is mg per day. The Week 104 analysis included datawith and without concomitant glycemic rescue medication, as well asoff-treatment data. Missing data for patients not providing any informationat the visit were imputed based on the observed off-treatment data. In this multiple imputation analysis, 13.9% of the data were imputedfor JARDIANCE 25 mg and 12.9% for glimepiride.At Week 104, JARDIANCE 25 mg daily resultedin statistically significant difference in change from baselinefor body weight compared to glimepiride (-3.1 kg for JARDIANCE 25mg vs. +1.3 kg for glimepiride; ANCOVA-LOCF, p-value <0.0001).Add-On Combination Therapywith Pioglitazone with or without MetforminAtotal of 498 patients with type diabetes participated in double-blind,placebo-controlled study to evaluate the efficacy and safety of JARDIANCEin combination with pioglitazone, with or without metformin. Patients with inadequately controlledtype diabetes on metformin at dose of at least 1500 mg per dayand pioglitazone at dose of at least 30 mg per day were placed intoan open-label placebo run-in for weeks. Patients with inadequateglycemic control and an HbA1c between 7% and 10% after the run-inperiod were randomized to placebo, JARDIANCE 10 mg, or JARDIANCE 25mg.Treatment withJARDIANCE 10 mg or 25 mg daily resulted in statistically significantreductions in HbA1c (p-value <0.0001), FPG, and body weight comparedwith placebo (see Table 9).Table Results of Placebo-Controlled Study for JARDIANCEin Combination Therapy with PioglitazoneaModified intent to treatpopulation. Last observation on study (LOCF) was used to impute missingdata at Week 24. At Week 24, 10.9%, 8.3%, and 20.6% was imputed forpatients 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 asfor HbA1c but additionally including baseline body weight/baselineFPG, respectively.) cFPG (mg/dL);for JARDIANCE 10 mg, n=163 JARDIANCE 10 mg +PioglitazoneN=165JARDIANCE 25 mg +PioglitazoneN=168Placebo PioglitazoneN=165HbA1c (%)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 (adjustedmean)-2.0-1.80.6 Difference from placebo (adjustedmean) (95% CI)-2.6b (-3.4, -1.8)-2.4b (-3.2, -1.6)--Add-On Combinationwith Insulin with or without Metformin and/or SulfonylureasA total of 494 patients with type diabetes inadequatelycontrolled on insulin, or insulin in combination with oral drugs participatedin double-blind, placebo-controlled study to evaluate the efficacyof JARDIANCE as add-on therapy to insulin over 78 weeks.Patients entered 2-week placeborun-in period on basal insulin (e.g., insulin glargine, insulin detemir,or NPH insulin) with or without metformin and/or sulfonylurea backgroundtherapy. Following the run-in period, patients with inadequate glycemiccontrol were randomized to the addition of JARDIANCE 10 mg, JARDIANCE25 mg, or placebo. Patients were maintained on stable dose of insulinprior to enrollment, during the run-in period, and during the first18 weeks of treatment. For the remaining 60 weeks, insulin couldbe adjusted. The mean total daily insulin dose at baseline for JARDIANCE10 mg, 25 mg, and placebo was 45 IU, 48 IU, and 48 IU, respectively.JARDIANCE used in combinationwith insulin (with or without metformin and/or sulfonylurea) providedstatistically significant reductions in HbA1c and FPG compared toplacebo after both 18 and 78 weeks of treatment (see Table 10). JARDIANCE10 mg or 25 mg daily also resulted in statistically significantlygreater percent body weight reduction compared to placebo.Table 10 Results at Week 18 and 78 for Placebo-ControlledStudy for JARDIANCE in Combination with InsulinaModified intent to treatpopulation. Last observation on study (LOCF) was used to impute missingdata at Week 18 and 78. At Week 18, 21.3%, 30.3%, and 21.8% was imputedfor patients randomized to JARDIANCE 10 mg, JARDIANCE 25 mg, and placebo,respectively. At Week 78, 32.5%, 38.1% and 42.4% was imputed forpatients 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: MMRMmodel includes baseline body weight, baseline HbA1c, treatment, region,visit and visit by treatment interaction. cp-value=0.0049 dp-value=0.0052 ep-value=0.0463 18 weeks(no insulin adjustment)78 weeks(adjustable insulin dose after18 weeks) JARDIANCE10 mg +InsulinN=169JARDIANCE25 mg +InsulinN=155Placebo InsulinN=170JARDIANCE10 mg +InsulinN=169JARDIANCE25 mg +InsulinN=155Placebo InsulinN=170HbA1c (%)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 (adjustedmean) (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 (adjustedmean) (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 (adjustedmean)-1.8-1.4-0.1-2.4-2.40.7 Difference from placebo (adjustedmean) (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 Combinationwith MDI Insulin with or without MetforminA totalof 563 patients with type diabetes inadequately controlled on multipledaily injections (MDI) of insulin (total daily dose >60 IU), aloneor in combination with metformin, participated in double-blind,placebo-controlled study to evaluate the efficacy of JARDIANCE asadd-on therapy to MDI insulin over 18 weeks.Patients entered 2-week placebo run-inperiod on MDI insulin with or without metformin background therapy. Following the run-in period, patients with inadequate glycemic controlwere randomized to the addition of JARDIANCE 10 mg, JARDIANCE 25 mg,or placebo. Patients were maintained on stable dose of insulinprior to enrollment, during the run-in period, and during the first18 weeks of treatment. The mean total daily insulin dose at baselinefor JARDIANCE 10 mg, JARDIANCE 25 mg, and placebo was 88.6 IU, 90.4IU, and 89.9 IU, respectively.JARDIANCE 10 mg or 25 mg daily used in combinationwith MDI insulin (with or without metformin) provided statisticallysignificant reductions in HbA1c compared to placebo after 18 weeksof treatment (see Table 11).Table 11 Results at Week 18 for Placebo-Controlled Studyfor JARDIANCE in Combination with Insulin and with or without MetforminaModified intent to treatpopulation. Last observation on study (LOCF) was used to impute missingdata at Week 18. At Week 18, 23.7%, 22.8% and 23.4% was imputed forpatients 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). JARDIANCE 10 mg Insulin +/- MetforminN=186JARDIANCE 25 mg Insulin +/- MetforminN=189Placebo Insulin +/- MetforminN=188HbA1c (%)a Baseline (mean)8.48.38.3 Change from baseline (adjustedmean)-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 periodwith treatment for up to 52 weeks, insulin could be adjusted to achievedefined glucose target levels. The change from baseline in HbA1cwas maintained from 18 to 52 weeks with both JARDIANCE 10 mg and 25mg. After 52 weeks, JARDIANCE 10 mg or 25 mg daily resulted in statisticallygreater percent body weight reduction compared to placebo (p-value<0.0001). The mean change in body weight from baseline was -1.95kg for JARDIANCE 10 mg, and -2.04 kg for JARDIANCE 25 mg.Renal ImpairmentA total of 738 patients with type diabetes and baselineeGFR less than 90 mL/min/1.73 m2 participatedin randomized, double-blind, placebo-controlled, parallel-groupto evaluate the efficacy and safety of JARDIANCE in patients withtype diabetes and renal impairment. The trial population comprisedof 290 patients with mild renal impairment (eGFR 60 to less than 90mL/min/1.73 m2), 374 patients with moderaterenal impairment (eGFR 30 to less than 60 mL/min/1.73 m2), and 74 with severe renal impairment (eGFR lessthan 30 mL/min/1.73 m2). total of 194patients with moderate renal impairment had baseline eGFR of 30to less than 45 mL/min/1.73 m2 and 180patients baseline eGFR of 45 to less than 60 mL/min/1.73 m2. At Week 24, JARDIANCE 25 mg provided statistically significant reductionin HbA1c relative to placebo in patients with mild to moderate renalimpairment (see Table 12). statistically significant reductionrelative to placebo was also observed with JARDIANCE 25 mg in patientswith 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 patientswith mild [-0.5 (95% CI: -0.7, -0.3)] renal impairment.The glucose lowering efficacyof JARDIANCE 25 mg decreased with decreasing level of renal functionin the mild to moderate range. Least square mean Hb1Ac changes at24 weeks were -0.6%, -0.5%, and -0.2% for those with baseline eGFRof 60 to less than 90 mL/min/1.73 m2, 45to less than 60 mL/min/1.73 m2, and 30to 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 weekswere 0.1%, -0.1%, and 0.2% for patients with baseline eGFR of 60to less than 90 mL/min/1.73 m2, 45 to lessthan 60 mL/min/1.73 m2, and 30 to lessthan 45 mL/min/1.73 m2, respectively.Table 12 Results at Week 24 (LOCF) of Placebo-ControlledStudy for JARDIANCE in Patients with Type Diabetes and Renal Impairmentap-value <0.0001 (HbA1c:ANCOVA model includes baseline HbA1c, treatment, renal function, andbackground medication)beGFR30 to less than 90 mL/min/1.73 m2- Modifiedintent to treat population. Last observation on study (LOCF) was usedto impute missing data at Week 24. At Week 24, 24.6% and 26.2% wasimputed for patients randomized to JARDIANCE 25 mg and placebo, respectively. Mild andModerate Impairmentb JARDIANCE25 mgHbA1c Number of patients n=284 Comparison vs placebo(adjusted mean) (95% CI)-0.5a (-0.6, -0.4)For patients with severerenal impairment, the analyses of changes in HbA1c and FPG showedno discernible treatment effect of JARDIANCE 25 mg compared to placebo [see Dosage and Administration (2.2) and Use in Specific Populations (8.6)].. Figure 3. Figure 4. 14.2 Cardiovascular Outcomes in Patients with Type Diabetes Mellitusand Atherosclerotic Cardiovascular Disease. The effect of JARDIANCE on cardiovascularrisk in adult patients with type diabetes and established, stable,atherosclerotic cardiovascular disease was evaluated in the EMPA-REGOUTCOME study, multicenter, multi-national, randomized, double-blindparallel group trial. The study compared the risk of experiencinga major adverse cardiovascular event (MACE) between JARDIANCE andplacebo when these were added to and used concomitantly with standardof care treatments for diabetes and atherosclerotic cardiovasculardisease. Coadministered antidiabetic medications were to be kept stablefor the first 12 weeks of the trial. Thereafter, antidiabetic andatherosclerotic therapies could be adjusted, at the discretion ofinvestigators, to ensure participants were treated according to thestandard care for these diseases. total of 7020 patients were treated (JARDIANCE10 mg 2345; JARDIANCE 25 mg 2342; placebo 2333) and followedfor median of 3.1 years. Approximately 72% of the study populationwas Caucasian, 22% was Asian, and 5% was Black. The mean age was63 years and approximately 72% were male.All patients in the study had inadequatelycontrolled type diabetes mellitus at baseline (HbA1c greater thanor equal to 7%). The mean HbA1c at baseline was 8.1% and 57% of participantshad had diabetes for more than 10 years. Approximately 31%, 22% and20% reported past history of neuropathy, retinopathy and nephropathyto investigators respectively and the mean eGFR was 74 mL/min/1.73m2. At baseline, patients were treatedwith one (~30%) or more (~70%) antidiabetic medications includingmetformin (74%), insulin (48%), and sulfonylurea (43%).All patients had establishedatherosclerotic cardiovascular disease at baseline including one (82%)or more (18%) of the following; documented history of coronary arterydisease (76%), stroke (23%) or peripheral artery disease (21%). Atbaseline, the mean systolic blood pressure was 136 mmHg, the meandiastolic blood pressure was 76 mmHg, the mean LDL was 86 mg/dL, themean HDL was 44 mg/dL, and the mean urinary albumin to creatinineratio (UACR) was 175 mg/g. At baseline, approximately 81% of patientswere 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 occurrenceof Major Adverse Cardiac Event (MACE). major adverse cardiacevent was defined as occurrence of either cardiovascular death ora nonfatal myocardial infarction (MI) or nonfatal stroke. The statisticalanalysis plan had pre-specified that the 10 and 25 mg doses wouldbe combined. Cox proportional hazards model was used to test fornon-inferiority against the pre-specified risk margin of 1.3 for thehazard ratio of MACE and superiority on MACE if non-inferiority wasdemonstrated. Type-1 error was controlled across multiples tests usinga hierarchical testing strategy.JARDIANCE significantly reduced the riskof first occurrence of primary composite endpoint of cardiovasculardeath, non-fatal myocardial infarction, or non-fatal stroke (HR: 0.86;95% CI 0.74, 0.99). The treatment effect was due to significantreduction in the risk of cardiovascular death in subjects randomizedto empagliflozin (HR: 0.62; 95% CI 0.49, 0.77), with no change inthe risk of non-fatal myocardial infarction or non-fatal stroke (seeTable 13 and Figure and 6). Results for the 10 mg and 25 mg empagliflozindoses were consistent with results for the combined dose groups.Table 13 Treatment Effect for the Primary Composite Endpoint,and its Componentsa aTreated set (patientswho had received at least one dose of study drug)bp-value for superiority (2-sided) 0.04 cTotal number of events PlaceboN=2333JARDIANCEN=4687Hazardratio vs placebo(95% CI) Composite ofcardiovascular death, non-fatal myocardial infarction, non-fatalstroke (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) The efficacy of JARDIANCE on cardiovasculardeath was generally consistent across major demographic and diseasesubgroups. Vitalstatus was obtained for 99.2% of subjects in the trial. total of463 deaths were recorded during the EMPA-REG OUTCOME trial. Mostof these deaths were categorized as cardiovascular deaths. The non-cardiovasculardeaths were only small proportion of deaths, and were balanced betweenthe treatment groups (2.1% in patients treated with JARDIANCE, and2.4% of patients treated with placebo).. Figure 5. Figure 6.

CONTRAINDICATIONS SECTION.


4 CONTRAINDICATIONS. History of serious hypersensitivity reactionto empagliflozin or any of the excipients in JARDIANCE [seeWarnings and Precautions (5.7)].Severe renal impairment, end-stage renal disease, or dialysis [see Use in Specific Populations (8.6)].. History of serious hypersensitivity reactionto empagliflozin or any of the excipients in JARDIANCE [seeWarnings and Precautions (5.7)].. Severe renal impairment, end-stage renal disease, or dialysis [see Use in Specific Populations (8.6)].. History of serious hypersensitivity reaction to empagliflozinor any of the excipients in JARDIANCE (4)Severe renal impairment, end-stage renal disease, or dialysis(4). History of serious hypersensitivity reaction to empagliflozinor any of the excipients in JARDIANCE (4). Severe renal impairment, end-stage renal disease, or dialysis(4).

DESCRIPTION SECTION.


11 DESCRIPTION. JARDIANCE tablets contain empagliflozin,an orally-active inhibitor of the sodium-glucose co-transporter 2(SGLT2).The chemicalname of empagliflozin is D-Glucitol,1,5-anhydro-1-C-[4-chloro-3-[[4-[[(3S)-tetrahydro-3-furanyl]oxy]phenyl]methyl]phenyl]-,(1S).Its molecularformula is C23H27ClO7 and the molecular weight is 450.91. The structuralformula is:Empagliflozin is white to yellowish, non-hygroscopicpowder. It is very slightly soluble in water, sparingly soluble inmethanol, slightly soluble in ethanol and acetonitrile; soluble in50% acetonitrile/water; and practically insoluble in toluene.Each film-coated tablet of JARDIANCEcontains 10 mg or 25 mg of empagliflozin (free base) and the followinginactive ingredients: lactose monohydrate, microcrystalline cellulose,hydroxypropyl cellulose, croscarmellose sodium, colloidal silicondioxide and magnesium stearate. In addition, the film coating containsthe following inactive ingredients: hypromellose, titanium dioxide,talc, polyethylene glycol, and yellow ferric oxide.. Empagliflozin structure.

DOSAGE & ADMINISTRATION SECTION.


2 DOSAGE AND ADMINISTRATION. The recommended dose of JARDIANCE is 10 mg once daily, takenin the morning, with or without food (2.1)Dose may be increased to 25 mg once daily (2.1)Assess renal function before initiating JARDIANCE. Do notinitiate JARDIANCE if eGFR is below 45 mL/min/1.73 m2 (2.2)Discontinue JARDIANCE if eGFR falls persistently below 45 mL/min/1.73 m2 (2.2). The recommended dose of JARDIANCE is 10 mg once daily, takenin the morning, with or without food (2.1). Dose may be increased to 25 mg once daily (2.1). Assess renal function before initiating JARDIANCE. Do notinitiate JARDIANCE if eGFR is below 45 mL/min/1.73 m2 (2.2). Discontinue JARDIANCE if eGFR falls persistently below 45 mL/min/1.73 m2 (2.2). 2.1 Recommended Dosage. The recommended dose of JARDIANCEis 10 mg once daily in the morning, taken with or without food. Inpatients tolerating JARDIANCE, the dose may be increased to 25 mg [see Clinical Studies (14)].In patients withvolume depletion, correcting this condition prior to initiation ofJARDIANCE is recommended [see Warnings and Precautions (5.1), Use in Specific Populations (8.5) and Patient Counseling Information(17)]. 2.2 Patients with RenalImpairment. Assessment of renal function is recommended prior to initiation ofJARDIANCE and periodically thereafter.JARDIANCE should not be initiated in patientswith an eGFR less than 45 mL/min/1.73 m2.No dose adjustmentis needed in patients with an eGFR greater than or equal to 45 mL/min/1.73m2.JARDIANCE should be discontinued if eGFRis persistently less than 45 mL/min/1.73 m2 [see Warnings and Precautions (5.1, 5.3) and Use in SpecificPopulations (8.6)].

DOSAGE FORMS & STRENGTHS SECTION.


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

DRUG INTERACTIONS SECTION.


7 DRUGINTERACTIONS. 7.1 Diuretics. Coadministration of empagliflozinwith diuretics resulted in increased urine volume and frequency ofvoids, which might enhance the potential for volume depletion [see Warnings and Precautions (5.1)].. 7.2 Insulin or InsulinSecretagogues. Coadministration of empagliflozin with insulin or insulin secretagoguesincreases the risk for hypoglycemia [see Warnings and Precautions(5.5)]. 7.3 Positive Urine GlucoseTest. Monitoringglycemic control with urine glucose tests is not recommended in patientstaking SGLT2 inhibitors as SGLT2 inhibitors increase urinary glucoseexcretion and will lead to positive urine glucose tests. Use alternativemethods to monitor glycemic control.. 7.4 Interference with1,5-anhydroglucitol (1,5-AG) Assay. Monitoring glycemic control with 1,5-AGassay is not recommended as measurements of 1,5-AG are unreliablein assessing glycemic control in patients taking SGLT2 inhibitors. Use alternative methods to monitor glycemic control.

GERIATRIC USE SECTION.


8.5 Geriatric Use. No JARDIANCE dosage change is recommendedbased on age [see Dosage and Administration (2)]. In studies assessing the efficacyof empagliflozin in improving glycemic control in patients with type2 diabetes, total of 2721 (32%) patients treated with empagliflozinwere 65 years of age and older, and 491 (6%) were 75 years of ageand older. JARDIANCE is expected to have diminished glycemic efficacyin elderly patients with renal impairment [see Use in SpecificPopulations (8.6)]. Therisk of volume depletion-related adverse reactions increased in patientswho 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 infectionsincreased 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(5.1) and Adverse Reactions (6.1)].

HOW SUPPLIED SECTION.


16 HOWSUPPLIED/STORAGE AND HANDLING. JARDIANCE tablets are available in 10 mg and 25 mg strengths as follows:10 mg tablets: pale yellow, round, biconvex and bevel-edged, film-coated tabletsdebossed with S 10 on one side and the Boehringer Ingelheim companysymbol on the other side.Bottles of 30 (NDC 0597-0152-30)Bottles of 90 (NDC 0597-0152-90)Cartons containing 3blister cards of 10 tablets each (3 10) (NDC 0597-0152-37), institutionalpack.25 mg tablets: pale yellow, oval, biconvex film-coated tablets, debossed with S25 on one side and the Boehringer Ingelheim company symbol on theother side.Bottles of 30 (NDC 0597-0153-30)Bottles of 90 (NDC 0597-0153-90)Cartons containing 3blister cards of 10 tablets each (3 10) (NDC 0597-0153-37), institutionalpack.Dispense in awell-closed container as defined in the USP.StorageStore at 25C (77F); excursions permitted to 15-30C (59-86F) [see USP Controlled Room Temperature].

INDICATIONS & USAGE SECTION.


1 INDICATIONS AND USAGE. JARDIANCE is indicated: as an adjunct to diet and exercise to improve glycemic controlin adults with type diabetes mellitus,to reduce the risk of cardiovascular death in adult patientswith type diabetes mellitus and established cardiovascular disease.Limitations ofUseJARDIANCE is not recommended for patientswith type diabetes or for the treatment of diabetic ketoacidosis. as an adjunct to diet and exercise to improve glycemic controlin adults with type diabetes mellitus,. to reduce the risk of cardiovascular death in adult patientswith type diabetes mellitus and established cardiovascular disease.. JARDIANCE is sodium-glucose co-transporter2 (SGLT2) inhibitor indicated:as an adjunct to diet and exercise to improve glycemic controlin adults with type diabetes mellitus,to reduce the risk of cardiovascular death in adult patientswith type diabetes mellitus and established cardiovascular disease.(1)Limitations of Use: Not for the treatment of type diabetes mellitus or diabetic ketoacidosis(1) as an adjunct to diet and exercise to improve glycemic controlin adults with type diabetes mellitus,. to reduce the risk of cardiovascular death in adult patientswith type diabetes mellitus and established cardiovascular disease.(1).

INFORMATION FOR PATIENTS SECTION.


17 PATIENT COUNSELING INFORMATION. Advise the patient to read the FDA-approvedpatient labeling (Patient Information).InstructionsInstruct patients to read the Patient Information before startingJARDIANCE therapy and to reread it each time the prescription is renewed.Instruct patients to inform their doctor or pharmacist if they developany unusual symptom, or if any known symptom persists or worsens.Inform patients of the potentialrisks and benefits of JARDIANCE and of alternative modes of therapy.Also inform patients about the importance of adherence to dietaryinstructions, regular physical activity, periodic blood glucose monitoringand HbA1c testing, recognition and management of hypoglycemia andhyperglycemia, and assessment for diabetes complications. Advisepatients to seek medical advice promptly during periods of stresssuch as fever, trauma, infection, or surgery, as medication requirementsmay change.Instructpatients to take JARDIANCE only as prescribed. If dose is missed,it should be taken as soon as the patient remembers. Advise patientsnot to double their next dose.Inform patients that the most common adversereactions associated with the use of JARDIANCE are urinary tract infectionsand mycotic genital infections.Advise pregnant women, and females of reproductivepotential of the potential risk to fetus with treatment with JARDIANCE [see Use in Specific Populations (8.1)]. Instruct females of reproductive potential to reportpregnancies to their physicians as soon as possible.Advise women that breastfeeding is not recommendedduring treatment with JARDIANCE [see Use in Specific Populations(8.2)]. HypotensionInform patients that hypotension may occur with JARDIANCE and advisethem to contact their healthcare provider if they experience suchsymptoms [see Warnings and Precautions (5.1)]. Inform patients that dehydration may increasethe risk for hypotension, and to have adequate fluid intake.KetoacidosisInform patients that ketoacidosis is serious life-threateningcondition. Cases of ketoacidosis have been reported during use ofJARDIANCE. Instruct patients to check ketones (when possible) if symptomsconsistent with ketoacidosis occur even if blood glucose is not elevated.If symptoms of ketoacidosis (including nausea, vomiting, abdominalpain, tiredness, and labored breathing) occur, instruct patients todiscontinue JARDIANCE and seek medical advice immediately [see Warnings and Precautions (5.2)].Acute Kidney InjuryInform patients that acutekidney injury has been reported during use of JARDIANCE. Advise patientsto seek medical advice immediately if they have reduced oral intake(such as due to acute illness or fasting) or increased fluid losses(such as due to vomiting, diarrhea, or excessive heat exposure), asit may be appropriate to temporarily discontinue JARDIANCE use inthose settings [see Warnings and Precautions (5.3)]. Serious Urinary Tract InfectionsInform patients of the potential for urinary tract infections,which may be serious. Provide them with information on the symptomsof urinary tract infections. Advise them to seek medical advice ifsuch symptoms occur [see Warnings and Precautions (5.4)].Genital Mycotic Infectionsin Females (e.g., Vulvovaginitis)Inform femalepatients that vaginal yeast infections may occur and provide themwith 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 uncircumcisedmales and patients with chronic and recurrent infections. Providethem with information on the signs and symptoms of balanitis and balanoposthitis(rash or redness of the glans or foreskin of the penis). Advise themof treatment options and when to seek medical advice [seeWarnings and Precautions (5.6)].HypersensitivityReactionsInform patients that serious hypersensitivityreactions, such as urticaria and angioedema, have been reported withJARDIANCE. Advise patients to report immediately any skin reactionor angioedema, and to discontinue drug until they have consulted prescribingphysician [see Warnings and Precautions (5.7)].Laboratory TestsInform patients that renal function should be assessed prior toinitiation of JARDIANCE and monitored periodically thereafter.Inform patients that elevatedglucose in urinalysis is expected when taking JARDIANCE.Inform patients that responseto all diabetic therapies should be monitored by periodic measurementsof blood glucose and HbA1c levels, with goal of decreasing theselevels toward the normal range. Hemoglobin A1c monitoring is especiallyuseful for evaluating long-term glycemic control.

MECHANISM OF ACTION SECTION.


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

NONCLINICAL TOXICOLOGY SECTION.


13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Carcinogenesis Carcinogenesis was evaluatedin 2-year studies conducted in CD-1 mice and Wistar rats. Empagliflozindid 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 maximumclinical dose of 25 mg). In male rats, hemangiomas of the mesentericlymph node were increased significantly at 700 mg/kg/day or approximately42 times the exposure from 25 mg clinical dose. Empagliflozin didnot 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 clinicaldose). Renal tubule adenomas and carcinomas were observed in malemice at 1000 mg/kg/day, which is approximately 45 times the exposureof the maximum clinical dose of 25 mg. These tumors may be associatedwith metabolic pathway predominantly present in the male mouse kidney.Mutagenesis Empagliflozin was not mutagenicor clastogenic with or without metabolic activation in the in vitro Ames bacterial mutagenicity assay, the in vitro L5178Y tk+/- mouse lymphomacell assay, and an in vivo micronucleus assay inrats.Impairmentof Fertility Empagliflozinhad no effects on mating, fertility or early embryonic developmentin 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.


10 OVERDOSAGE. In the event of an overdose with JARDIANCE, contact the Poison ControlCenter. Employ the usual supportive measures (e.g., remove unabsorbedmaterial from the gastrointestinal tract, employ clinical monitoring,and institute supportive treatment) as dictated by the patients clinicalstatus. Removal of empagliflozin by hemodialysis has not been studied.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.


PRINCIPAL DISPLAY PANEL 25 mg. NDC 71610-177 Empagliflozin (Jardiance) 25 mg Rx Only Bottle Label 25 mg.

PEDIATRIC USE SECTION.


8.4 Pediatric Use. The safety and effectiveness of JARDIANCE in pediatric patientsunder 18 years of age have not been established.

PHARMACODYNULLMICS SECTION.


12.2 Pharmacodynamics. Urinary Glucose Excretion In patients with type diabetes,urinary glucose excretion increased immediately following dose ofJARDIANCE and was maintained at the end of 4-week treatment periodaveraging at approximately 64 grams per day with 10 mg empagliflozinand 78 grams per day with 25 mg JARDIANCE once daily [seeClinical Studies (14)]. Urinary Volume In 5-day study, mean 24-hoururine volume increase from baseline was 341 mL on Day and 135 mLon Day of empagliflozin 25 mg once daily treatment.Cardiac ElectrophysiologyIn randomized, placebo-controlled, active-comparator,crossover study, 30 healthy subjects were administered single oraldose of JARDIANCE 25 mg, JARDIANCE 200 mg (8 times the maximum dose),moxifloxacin, and placebo. No increase in QTc was observed with either25 mg or 200 mg empagliflozin.

PHARMACOKINETICS SECTION.


12.3 Pharmacokinetics. AbsorptionThepharmacokinetics of empagliflozin has been characterized in healthyvolunteers and patients with type diabetes and no clinically relevantdifferences were noted between the two populations. After oral administration,peak plasma concentrations of empagliflozin were reached at 1.5 hourspost-dose. Thereafter, plasma concentrations declined in biphasicmanner with rapid distribution phase and relatively slow terminalphase. The steady state mean plasma AUC and Cmax were 1870 nmol.h/L and 259 nmol/L, respectively, with 10 mg empagliflozinonce daily treatment, and 4740 nmol.h/L and 687 nmol/L, respectively,with 25 mg empagliflozin once daily treatment. Systemic exposureof empagliflozin increased in dose-proportional manner in the therapeuticdose range. The single-dose and steady-state pharmacokinetic parametersof empagliflozin were similar, suggesting linear pharmacokineticswith respect to time.Administration of 25 mg empagliflozin after intake of high-fatand high-calorie meal resulted in slightly lower exposure; AUC decreasedby approximately 16% and Cmax decreased byapproximately 37%, compared to fasted condition. The observed effectof food on empagliflozin pharmacokinetics was not considered clinicallyrelevant and empagliflozin may be administered with or without food.DistributionThe apparent steady-state volume of distribution wasestimated to be 73.8 based on population pharmacokinetic analysis. Following administration of an oral [14C]-empagliflozin solution to healthy subjects, the red blood cellpartitioning was approximately 36.8% and plasma protein binding was86.2%. MetabolismNo major metabolites of empagliflozin were detected inhuman plasma and the most abundant metabolites were three glucuronideconjugates (2-O-, 3-O-, and 6-O-glucuronide). Systemic exposure ofeach metabolite was less than 10% of total drug-related material. In vitro studies suggested that the primary route of metabolismof empagliflozin in humans is glucuronidation by the uridine 5-diphospho-glucuronosyltransferasesUGT2B7, UGT1A3, UGT1A8, and UGT1A9.EliminationTheapparent terminal elimination half-life of empagliflozin was estimatedto be 12.4 and apparent oral clearance was 10.6 L/h based on thepopulation pharmacokinetic analysis. Following once-daily dosing,up to 22% accumulation, with respect to plasma AUC, was observed atsteady-state, which was consistent with empagliflozin half-life. Following 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 recoveredin feces was unchanged parent drug and approximately half of drug-relatedradioactivity excreted in urine was unchanged parent drug.Specific PopulationsRenal ImpairmentInpatients with mild (eGFR: 60 to less than 90 mL/min/1.73 m2), moderate (eGFR: 30 to less than 60 mL/min/1.73m2), and severe (eGFR: less than 30 mL/min/1.73m2) renal impairment and subjects withkidney failure/end stage renal disease (ESRD) patients, AUC of empagliflozinincreased by approximately 18%, 20%, 66%, and 48%, respectively, comparedto subjects with normal renal function. Peak plasma levels of empagliflozinwere similar in subjects with moderate renal impairment and kidneyfailure/ESRD compared to patients with normal renal function. Peakplasma levels of empagliflozin were roughly 20% higher in subjectswith mild and severe renal impairment as compared to subjects withnormal renal function. Population pharmacokinetic analysis showedthat the apparent oral clearance of empagliflozin decreased, witha 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 subjects with mild, moderate, and severe hepatic impairmentaccording to the Child-Pugh classification, AUC of empagliflozin increasedby approximately 23%, 47%, and 75%, and Cmax increased by approximately 4%, 23%, and 48%, respectively, comparedto subjects with normal hepatic function.Effects of Age, Body Mass Index,Gender, and RaceBased on the population PKanalysis, age, body mass index (BMI), gender and race (Asians versusprimarily Whites) do not have clinically meaningful effect on pharmacokineticsof empagliflozin [see Use in Specific Populations (8.5)].PediatricStudies characterizing the pharmacokinetics of empagliflozin inpediatric patients have not been performed.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 metabolismof empagliflozin in humans is glucuronidation by the uridine 5-diphospho-glucuronosyltransferasesUGT1A3, UGT1A8, UGT1A9, and UGT2B7. Empagliflozin does not inhibitUGT1A1, UGT1A3, UGT1A8, UGT1A9, or UGT2B7. Therefore, no effect ofempagliflozin is anticipated on concomitantly administered drugs thatare substrates of the major CYP450 isoforms or UGT1A1, UGT1A3, UGT1A8,UGT1A9, or UGT2B7. The effect of UGT induction (e.g., induction byrifampicin or any other UGT enzyme inducer) on empagliflozin exposurehas not been evaluated.Empagliflozin is substrate for P-glycoprotein (P-gp) and breastcancer resistance protein (BCRP), but it does not inhibit these effluxtransporters at therapeutic doses. Based on in vitro studies, empagliflozin is considered unlikely to cause interactionswith drugs that are P-gp substrates. Empagliflozin is substrateof the human uptake transporters OAT3, OATP1B1, and OATP1B3, but notOAT1 and OCT2. Empagliflozin does not inhibit any of these human uptaketransporters at clinically relevant plasma concentrations and, therefore,no effect of empagliflozin is anticipated on concomitantly administereddrugs that are substrates of these uptake transporters.In vivo Assessment of Drug InteractionsNo dose adjustmentof JARDIANCE is recommended when coadministered with commonly prescribedmedicinal products based on results of the described pharmacokineticstudies. Empagliflozin pharmacokinetics were similar with and withoutcoadministration of metformin, glimepiride, pioglitazone, sitagliptin,linagliptin, warfarin, verapamil, ramipril, and simvastatin in healthyvolunteers and with or without coadministration of hydrochlorothiazideand torsemide in patients with type diabetes (see Figure 1). Theobserved increases in overall exposure (AUC) of empagliflozin followingcoadministration with gemfibrozil, rifampicin, or probenecid are notclinically relevant. In subjects with normal renal function, coadministrationof empagliflozin with probenecid resulted in 30% decrease in thefraction of empagliflozin excreted in urine without any effect on24-hour urinary glucose excretion. The relevance of this observationto patients with renal impairment is unknown.Figure Effect of Various Medicationson the Pharmacokinetics of Empagliflozin as Displayed as 90% ConfidenceInterval 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, oncedaily; dempagliflozin, 10 mg, single doseEmpagliflozin had no clinicallyrelevant effect on the pharmacokinetics of metformin, glimepiride,pioglitazone, sitagliptin, linagliptin, warfarin, digoxin, ramipril,simvastatin, hydrochlorothiazide, torsemide, and oral contraceptiveswhen coadministered in healthy volunteers (see Figure 2).Figure Effect of Empagliflozinon the Pharmacokinetics of Various Medications 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,once daily; cempagliflozin, 25 mg, singledose; 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 showingadverse renal effects, JARDIANCE is not recommended during the secondand third trimesters of pregnancy.Limited data available with JARDIANCE inpregnant women are not sufficient to determine drug-associated riskfor major birth defects and miscarriage. There are risks to the motherand fetus associated with poorly controlled diabetes in pregnancy [see Clinical Considerations].In animal studies, adverse renal changes were observed inrats when empagliflozin was administered during period of renaldevelopment corresponding to the late second and third trimestersof human pregnancy. Doses approximately 13-times the maximum clinicaldose caused renal pelvic and tubule dilatations that were reversible.Empagliflozin was not teratogenic in rats and rabbits up to 300 mg/kg/day,which approximates 48-times and 128-times, respectively, the maximumclinical dose of 25 mg when administered during organogenesis [see Data].The estimatedbackground risk of major birth defects is 6-10% in women with pre-gestationaldiabetes with HbA1c >7 and has been reported to be as high as 20-25%in women with HbA1c >10. The estimated background risk of miscarriagefor the indicated population is unknown. In the U.S. general population,the estimated background risk of major birth defects and miscarriagein clinically recognized pregnancies is 2-4% and 15-20%, respectively.Clinical ConsiderationsDisease-associated maternal and/or embryo/fetalrisk: Poorly controlled diabetes in pregnancy increases thematernal risk for diabetic ketoacidosis, pre-eclampsia, spontaneousabortions, preterm delivery, stillbirth, and delivery complications.Poorly controlled diabetes increases the fetal risk for major birthdefects, stillbirth, and macrosomia related morbidity.DataAnimal 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 causedincreased kidney weights and renal tubular and pelvic dilatation at100 mg/kg/day, which approximates 13-times the maximum clinical doseof 25 mg, based on AUC. These findings were not observed after a13 week drug-free recovery period. These outcomes occurred with drugexposure during periods of renal development in rats that correspondto the late second and third trimester of human renal development. In embryo-fetal developmentstudies in rats and rabbits, empagliflozin was administered for intervalscoinciding with the first trimester period of organogenesis in humans.Doses up to 300 mg/kg/day, which approximates 48-times (rats) and128-times (rabbits) the maximum clinical dose of 25 mg (based on AUC),did not result in adverse developmental effects. In rats, at higherdoses of empagliflozin causing maternal toxicity, malformations oflimb bones increased in fetuses at 700 mg/kg/day or 154-times the25 mg maximum clinical dose. Empagliflozin crosses the placenta andreaches fetal tissues in rats. In the rabbit, higher doses of empagliflozinresulted in maternal and fetal toxicity at 700 mg/kg/day, or 139-timesthe 25 mg maximum clinical dose.In pre- and postnatal development studiesin pregnant rats, empagliflozin was administered from gestation day6 through to lactation day 20 (weaning) at up to 100 mg/kg/day (approximately16 times the 25 mg maximum clinical dose) without maternal toxicity. Reduced body weight was observed in the offspring at greater thanor equal to 30 mg/kg/day (approximately times the 25 mg maximumclinical dose).

RECENT MAJOR CHANGES SECTION.


Contraindications (4)12/2017Warnings and Precautions (5)12/2017.

SPL PATIENT PACKAGE INSERT SECTION.


This Patient Information has been approvedby the U.S. Food and Drug Administration. Revised: December 2017PATIENT INFORMATIONJARDIANCE(R) (jar DEE ans)(empagliflozin)TabletsWhat is themost important information should know about JARDIANCEJARDIANCE can cause serious side effects, including:Dehydration. JARDIANCE can cause some peopleto have dehydration (the loss of body water and salt). Dehydrationmay cause you to feel dizzy, faint, light-headed, or weak, especiallywhen you stand up (orthostatic hypotension). You may be at higher risk of dehydration if you:have low blood pressuretake medicines to lower your blood pressure, including diuretics(water pills)are on low sodium (salt) diethave kidney problemsare 65 years of age or older Vaginal yeast infection. Women who take JARDIANCEmay get vaginal yeast infections. Symptoms of vaginal yeast infectioninclude:vaginal odorwhite or yellowish vaginal discharge (discharge may be lumpyor look like cottage cheese)vaginal itching Yeast infection of the penis (balanitis or balanoposthitis). Men who take JARDIANCE may get yeast infection of the skin aroundthe penis. Certain men who are not circumcised may have swelling ofthe penis that makes it difficult to pull back the skin around thetip 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 penis Talk to your doctor about what to do if you get symptoms ofa yeast infection of the vagina or penis. Your doctor may suggestyou use an over-the-counter antifungal medicine. Talk to your doctorright away if you use an over-the-counter antifungal medication andyour symptoms do not go away.What is JARDIANCEJARDIANCE is prescription medicine used: along with diet and exercise to lower blood sugar in adultswith type diabetes.to reduce the risk of cardiovascular death in adults withtype diabetes who have known cardiovascular disease. JARDIANCE is not for people with type diabetes.JARDIANCE is not for people with diabetic ketoacidosis (increasedketones in the blood or urine).It is not known if JARDIANCE is safe and effective in childrenunder 18 years of age.Who shouldnot take JARDIANCEDo not take JARDIANCE if you:are allergic to empagliflozin or any of the ingredientsin JARDIANCE. See the end of this leaflet for list of ingredientsin JARDIANCE.have severe kidney problems or are on dialysisWhat shouldI tell my doctor before using JARDIANCEBefore you take JARDIANCE, tell your doctor if you:have kidney problemshave liver problemshave history of urinary tract infections or problems withurinationare going to have surgeryare eating less due to illness, surgery, or change inyour diethave or have had problems with your pancreas, includingpancreatitis or surgery on your pancreasdrink alcohol very often, or drink lot of alcohol in theshort term (binge drinking)have any other medical conditionsare pregnant or plan to become pregnant. JARDIANCE may harmyour unborn baby. If you become pregnant while taking JARDIANCE, tellyour doctor as soon as possible. Talk with your doctor about the bestway to control your blood sugar while you are pregnant.are breastfeeding or plan to breastfeed. JARDIANCE may passinto your breast milk and may harm your baby. Talk with your doctorabout 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 affectthe way other medicines work, and other medicines may affect how JARDIANCEworks. Especially tell your doctor if you take:diuretics (water pills)insulin or other medicines that can lower your blood sugar Ask your doctor or pharmacist for list of these medicinesif you are not sure if your medicine is listed above.How shouldI take JARDIANCETake JARDIANCE exactly as your doctor tells you to takeit.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. Ifyou do not remember until it is time for your next dose, skip themissed dose and go back to your regular schedule. Do not take twodoses of JARDIANCE at the same time. Talk with your doctor if youhave questions about missed dose.Your doctor may tell you to take JARDIANCE along with otherdiabetes medicines. Low blood sugar can happen more often when JARDIANCEis taken with certain other diabetes medicines. See What arethe possible side effects of JARDIANCE If you take too much JARDIANCE, call your doctor or go tothe nearest hospital emergency room right away.When your body is under some types of stress, such as fever,trauma (such as car accident), infection, or surgery, the amountof diabetes medicine that you need may change. Tell your doctor rightaway if you have any of these conditions and follow your doctorsinstructions.Check your blood sugar as your doctor tells you to.Stay on your prescribed diet and exercise program whiletaking JARDIANCE.Talk to your doctor about how to prevent, recognize andmanage low blood sugar (hypoglycemia), high blood sugar (hyperglycemia),and complications of diabetes.Your doctor will check your diabetes with regular bloodtests, including your blood sugar levels and your hemoglobin HbA1c.When taking JARDIANCE, you may have sugar in your urine,which will show up on urine test.What are the possibleside effects of JARDIANCEJARDIANCE may cause serious side effects, including:See What is the most important information shouldknow about JARDIANCEKetoacidosis (increased ketones in your blood or urine). Ketoacidosis has happened in people who have type diabetesor type diabetes, during treatment with JARDIANCE. Ketoacidosisis serious condition, which may need to be treated in hospital.Ketoacidosis may lead to death. Ketoacidosis can happen withJARDIANCE even if your blood sugar is less than 250 mg/dL. Stop taking JARDIANCE and call your doctor right away if you getany of the following symptoms: nauseavomitingstomach-area (abdominal) paintirednesstrouble breathing If you get any ofthese symptoms during treatment with JARDIANCE, if possible, checkfor ketones in your urine, even if your bloodsugar is less than 250 mg/dL.Serious urinary tract infections. Seriousurinary tract infections that may lead to hospitalization have happenedin people who are taking JARDIANCE. Tell your doctor if you have anysigns or symptoms of urinary tract infection such as burning feelingwhen passing urine, need to urinate often, the need to urinate rightaway, pain in the lower part of your stomach (pelvis), or blood inthe urine. Sometimes people also may have fever, back pain, nauseaor vomiting.Low blood sugar (hypoglycemia). If you takeJARDIANCE with another medicine that can cause low blood sugar, suchas sulfonylurea or insulin, your risk of getting low blood sugaris higher. The dose of your sulfonylurea medicine or insulin may needto be lowered while you take JARDIANCE. Signs and symptoms of lowblood sugar may include: headachedrowsinessweaknessirritabilityhungerfast heartbeatconfusionshaking or feeling jitterydizzinesssweating Kidney problems. Sudden kidney injury hashappened to people taking JARDIANCE. Talk to your doctor right awayif you: reduce the amount of food or liquid you drink for example,if you are sick or cannot eat orstart to lose liquids from your body for example, from vomiting,diarrhea or being in the sun too long Allergic (hypersensitivity) reactions. Seriousallergic reactions have happened in people who are taking JARDIANCE.Symptoms may includeswelling of your face, lips, throat and other areas of yourskindifficulty with swallowing or breathing.raised, red areas on your skin (hives) If you have any of these symptoms, stop takingJARDIANCE and call your doctor right away or go to the nearest hospitalemergency room.Increased fats in your blood (cholesterol) These are not all the possible side effects of JARDIANCE.For more information, ask your doctor or pharmacist.Callyour doctor for medical advice about side effects. You may reportside effects to FDA at 1-800-FDA-1088.How shouldI store JARDIANCEStore JARDIANCE at room temperature68F to 77F (20C to 25C).General informationabout the safe and effective use of JARDIANCE.Medicinesare sometimes prescribed for purposes other than those listed in PatientInformation. Do not use JARDIANCE for condition for which it isnot prescribed. Do not give JARDIANCE to other people, even if theyhave the same symptoms you have. It may harm them.ThisPatient Information summarizes the most important information aboutJARDIANCE. If you would like more information, talk with your doctor.You can ask your pharmacist or doctor for information about JARDIANCEthat is written for health professionals.Formore information about JARDIANCE, go to www.jardiance.com, scan the code below, or call Boehringer Ingelheim Pharmaceuticals,Inc. at 1-800-542-6257 or (TTY) 1-800-459-9906.What are theingredients in JARDIANCEActive Ingredient: empagliflozin Inactive Ingredients: lactosemonohydrate, 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 yellowferric oxide.Distributed by:Boehringer Ingelheim Pharmaceuticals, Inc.; Ridgefield, CT 06877 USAMarketed by: Boehringer Ingelheim Pharmaceuticals, Inc.; Ridgefield,CT 06877 USA and Eli Lilly and Company, Indianapolis, IN 46285 USALicensed from: Boehringer Ingelheim International GmbH, Ingelheim,Germany Boehringer Ingelheim Pharmaceuticals,Inc. either owns or uses the Jardiance(R) and EMPA-REG OUTCOME(R) trademarks underlicense.The other trademarks referenced are owned by thirdparties not affiliated with Boehringer Ingelheim Pharmaceuticals,Inc. Copyright (C) 2017 Boehringer IngelheimInternational GmbHALL RIGHTS RESERVED IT5728RL112017. Dehydration. JARDIANCE can cause some peopleto have dehydration (the loss of body water and salt). Dehydrationmay cause you to feel dizzy, faint, light-headed, or weak, especiallywhen you stand up (orthostatic hypotension). You may be at higher risk of dehydration if you:have low blood pressuretake medicines to lower your blood pressure, including diuretics(water pills)are on low sodium (salt) diethave kidney problemsare 65 years of age or older have low blood pressure. 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. Vaginal yeast infection. Women who take JARDIANCEmay get vaginal yeast infections. Symptoms of vaginal yeast infectioninclude:vaginal odorwhite or yellowish vaginal discharge (discharge may be lumpyor look like cottage cheese)vaginal itching vaginal odor. white or yellowish vaginal discharge (discharge may be lumpyor look like cottage cheese). vaginal itching. Yeast infection of the penis (balanitis or balanoposthitis). Men who take JARDIANCE may get yeast infection of the skin aroundthe penis. Certain men who are not circumcised may have swelling ofthe penis that makes it difficult to pull back the skin around thetip 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 penis redness, itching, or swelling of the penis. rash of the penis. foul smelling discharge from the penis. pain in the skin around penis. JARDIANCE is prescription medicine used: along with diet and exercise to lower blood sugar in adultswith type diabetes.to reduce the risk of cardiovascular death in adults withtype diabetes who have known cardiovascular disease. along with diet and exercise to lower blood sugar in adultswith type diabetes.. to reduce the risk of cardiovascular death in adults withtype diabetes who have known cardiovascular disease.. JARDIANCE is not for people with type diabetes.. JARDIANCE is not for people with diabetic ketoacidosis (increasedketones in the blood or urine).. It is not known if JARDIANCE is safe and effective in childrenunder 18 years of age.. are allergic to empagliflozin or any of the ingredientsin JARDIANCE. See the end of this leaflet for list of ingredientsin JARDIANCE.. have severe kidney problems or are on dialysis. have kidney problems. have liver problems. have history of urinary tract infections or problems withurination. are going to have surgery. are eating less due to illness, surgery, or change inyour diet. have or have had problems with your pancreas, includingpancreatitis or surgery on your pancreas. drink alcohol very often, or drink lot of alcohol in theshort term (binge drinking). have any other medical conditions. are pregnant or plan to become pregnant. JARDIANCE may harmyour unborn baby. If you become pregnant while taking JARDIANCE, tellyour doctor as soon as possible. Talk with your doctor about the bestway to control your blood sugar while you are pregnant.. are breastfeeding or plan to breastfeed. JARDIANCE may passinto your breast milk and may harm your baby. Talk with your doctorabout 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 takeit.. 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. Ifyou do not remember until it is time for your next dose, skip themissed dose and go back to your regular schedule. Do not take twodoses of JARDIANCE at the same time. Talk with your doctor if youhave questions about missed dose.. Your doctor may tell you to take JARDIANCE along with otherdiabetes medicines. Low blood sugar can happen more often when JARDIANCEis taken with certain other diabetes medicines. See What arethe possible side effects of JARDIANCE If you take too much JARDIANCE, call your doctor or go tothe nearest hospital emergency room right away.. When your body is under some types of stress, such as fever,trauma (such as car accident), infection, or surgery, the amountof diabetes medicine that you need may change. Tell your doctor rightaway if you have any of these conditions and follow your doctorsinstructions.. Check your blood sugar as your doctor tells you to.. Stay on your prescribed diet and exercise program whiletaking JARDIANCE.. Talk to your doctor about how to prevent, recognize andmanage low blood sugar (hypoglycemia), high blood sugar (hyperglycemia),and complications of diabetes.. Your doctor will check your diabetes with regular bloodtests, including your blood sugar levels and your hemoglobin HbA1c.. When taking JARDIANCE, you may have sugar in your urine,which will show up on urine test.. See What is the most important information shouldknow about JARDIANCE. Ketoacidosis (increased ketones in your blood or urine). Ketoacidosis has happened in people who have type diabetesor type diabetes, during treatment with JARDIANCE. Ketoacidosisis serious condition, which may need to be treated in hospital.Ketoacidosis may lead to death. Ketoacidosis can happen withJARDIANCE even if your blood sugar is less than 250 mg/dL. Stop taking JARDIANCE and call your doctor right away if you getany of the following symptoms:. nausea. vomiting. stomach-area (abdominal) pain. tiredness. trouble breathing. Serious urinary tract infections. Seriousurinary tract infections that may lead to hospitalization have happenedin people who are taking JARDIANCE. Tell your doctor if you have anysigns or symptoms of urinary tract infection such as burning feelingwhen passing urine, need to urinate often, the need to urinate rightaway, pain in the lower part of your stomach (pelvis), or blood inthe urine. Sometimes people also may have fever, back pain, nauseaor vomiting.. Low blood sugar (hypoglycemia). If you takeJARDIANCE with another medicine that can cause low blood sugar, suchas sulfonylurea or insulin, your risk of getting low blood sugaris higher. The dose of your sulfonylurea medicine or insulin may needto be lowered while you take JARDIANCE. Signs and symptoms of lowblood sugar may include:. headache. drowsiness. weakness. irritability. hunger. fast heartbeat. confusion. shaking or feeling jittery. dizziness. sweating. Kidney problems. Sudden kidney injury hashappened to people taking JARDIANCE. Talk to your doctor right awayif you: reduce the amount of food or liquid you drink for example,if you are sick or cannot eat orstart to lose liquids from your body for example, from vomiting,diarrhea or being in the sun too long 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. Allergic (hypersensitivity) reactions. Seriousallergic reactions have happened in people who are taking JARDIANCE.Symptoms may includeswelling of your face, lips, throat and other areas of yourskindifficulty with swallowing or breathing.raised, red areas on your skin (hives) If you have any of these symptoms, stop takingJARDIANCE and call your doctor right away or go to the nearest hospitalemergency room.. swelling of your face, lips, throat and other areas of yourskin. difficulty with swallowing or breathing.. raised, red areas on your skin (hives). Increased fats in your blood (cholesterol). qr-code.

SPL UNCLASSIFIED SECTION.


2.1 Recommended Dosage. The recommended dose of JARDIANCEis 10 mg once daily in the morning, taken with or without food. Inpatients tolerating JARDIANCE, the dose may be increased to 25 mg [see Clinical Studies (14)].In patients withvolume depletion, correcting this condition prior to initiation ofJARDIANCE is recommended [see Warnings and Precautions (5.1), Use in Specific Populations (8.5) and Patient Counseling Information(17)].

USE IN SPECIFIC POPULATIONS SECTION.


8 USE IN SPECIFIC POPULATIONS. Pregnancy: Advise females of the potentialrisk to fetus especially during the second and third trimesters(8.1)Lactation: JARDIANCE is not recommendedwhen breastfeeding (8.2)Geriatric patients: Higher incidence ofadverse reactions related to volume depletion and reduced renal function(5.1, 5.3, 8.5)Patients with renal impairment: Higherincidence of adverse reactions related to reduced renal function (2.2, 5.3, 8.6). Pregnancy: Advise females of the potentialrisk to fetus especially during the second and third trimesters(8.1). Lactation: JARDIANCE is not recommendedwhen breastfeeding (8.2). Geriatric patients: Higher incidence ofadverse reactions related to volume depletion and reduced renal function(5.1, 5.3, 8.5). Patients with renal impairment: Higherincidence of adverse reactions related to reduced renal function (2.2, 5.3, 8.6). 8.1 Pregnancy. Risk SummaryBased on animal data showingadverse renal effects, JARDIANCE is not recommended during the secondand third trimesters of pregnancy.Limited data available with JARDIANCE inpregnant women are not sufficient to determine drug-associated riskfor major birth defects and miscarriage. There are risks to the motherand fetus associated with poorly controlled diabetes in pregnancy [see Clinical Considerations].In animal studies, adverse renal changes were observed inrats when empagliflozin was administered during period of renaldevelopment corresponding to the late second and third trimestersof human pregnancy. Doses approximately 13-times the maximum clinicaldose caused renal pelvic and tubule dilatations that were reversible.Empagliflozin was not teratogenic in rats and rabbits up to 300 mg/kg/day,which approximates 48-times and 128-times, respectively, the maximumclinical dose of 25 mg when administered during organogenesis [see Data].The estimatedbackground risk of major birth defects is 6-10% in women with pre-gestationaldiabetes with HbA1c >7 and has been reported to be as high as 20-25%in women with HbA1c >10. The estimated background risk of miscarriagefor the indicated population is unknown. In the U.S. general population,the estimated background risk of major birth defects and miscarriagein clinically recognized pregnancies is 2-4% and 15-20%, respectively.Clinical ConsiderationsDisease-associated maternal and/or embryo/fetalrisk: Poorly controlled diabetes in pregnancy increases thematernal risk for diabetic ketoacidosis, pre-eclampsia, spontaneousabortions, preterm delivery, stillbirth, and delivery complications.Poorly controlled diabetes increases the fetal risk for major birthdefects, stillbirth, and macrosomia related morbidity.DataAnimal 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 causedincreased kidney weights and renal tubular and pelvic dilatation at100 mg/kg/day, which approximates 13-times the maximum clinical doseof 25 mg, based on AUC. These findings were not observed after a13 week drug-free recovery period. These outcomes occurred with drugexposure during periods of renal development in rats that correspondto the late second and third trimester of human renal development. In embryo-fetal developmentstudies in rats and rabbits, empagliflozin was administered for intervalscoinciding with the first trimester period of organogenesis in humans.Doses up to 300 mg/kg/day, which approximates 48-times (rats) and128-times (rabbits) the maximum clinical dose of 25 mg (based on AUC),did not result in adverse developmental effects. In rats, at higherdoses of empagliflozin causing maternal toxicity, malformations oflimb bones increased in fetuses at 700 mg/kg/day or 154-times the25 mg maximum clinical dose. Empagliflozin crosses the placenta andreaches fetal tissues in rats. In the rabbit, higher doses of empagliflozinresulted in maternal and fetal toxicity at 700 mg/kg/day, or 139-timesthe 25 mg maximum clinical dose.In pre- and postnatal development studiesin pregnant rats, empagliflozin was administered from gestation day6 through to lactation day 20 (weaning) at up to 100 mg/kg/day (approximately16 times the 25 mg maximum clinical dose) without maternal toxicity. Reduced body weight was observed in the offspring at greater thanor equal to 30 mg/kg/day (approximately times the 25 mg maximumclinical dose).. 8.2 Lactation. Risk SummaryThere is no informationregarding the presence of JARDIANCE in human milk, the effects ofJARDIANCE 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 mayoccur, there may be risk to the developing human kidney.Because of the potential forserious adverse reactions in breastfed infant, including the potentialfor empagliflozin to affect postnatal renal development, advise womenthat use of JARDIANCE is not recommended while breastfeeding.Data Empagliflozin was present at low levelin rat fetal tissues after single oral dose to the dams at gestationday 18. In rat milk, the mean milk to plasma ratio ranged from 0.634-5, and was greater than one from to 24 hours post-dose. The meanmaximal milk to plasma ratio of occurred at hours post-dose, suggestingaccumulation of empagliflozin in the milk. Juvenile rats directlyexposed to empagliflozin showed risk to the developing kidney (renalpelvic and tubular dilatations) during maturation.. 8.4 Pediatric Use. The safety and effectiveness of JARDIANCE in pediatric patientsunder 18 years of age have not been established.. 8.5 Geriatric Use. No JARDIANCE dosage change is recommendedbased on age [see Dosage and Administration (2)]. In studies assessing the efficacyof empagliflozin in improving glycemic control in patients with type2 diabetes, total of 2721 (32%) patients treated with empagliflozinwere 65 years of age and older, and 491 (6%) were 75 years of ageand older. JARDIANCE is expected to have diminished glycemic efficacyin elderly patients with renal impairment [see Use in SpecificPopulations (8.6)]. Therisk of volume depletion-related adverse reactions increased in patientswho 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 infectionsincreased 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(5.1) and Adverse Reactions (6.1)].. 8.6 Renal Impairment. The efficacy and safety of JARDIANCEwere evaluated in study of patients with mild and moderate renalimpairment [see Clinical Studies (14.1)]. In this study, 195 patients exposed to JARDIANCEhad an eGFR between 60 and 90 mL/min/1.73 m2, 91 patients exposed to JARDIANCE had an eGFR between 45 and 60mL/min/1.73 m2 and 97 patients exposedto JARDIANCE had an eGFR between 30 and 45 mL/min/1.73 m2. The glucose lowering benefit of JARDIANCE 25 mgdecreased in patients with worsening renal function. The risks ofrenal impairment [see Warnings and Precautions (5.3)], volume depletion adversereactions and urinary tract infection-related adverse reactions increasedwith worsening renal function.In large cardiovascular outcomes study,there were 1819 patients with eGFR below 60 mL/min/1.73 m2. The cardiovascular death findings in this subgroupwere consistent with the overall findings [see Clinical Studies(14.2)]. The efficacy and safety of JARDIANCE havenot been established in patients with severe renal impairment, withESRD, or receiving dialysis. JARDIANCE is not expected to be effectivein these patient populations [see Dosage and Administration(2.2), Contraindications (4) and Warnings and Precautions (5.1, 5.3)]. 8.7 Hepatic Impairment. JARDIANCE may be used in patientswith hepatic impairment [see Clinical Pharmacology (12.3)].

WARNINGS AND PRECAUTIONS SECTION.


5 WARNINGS AND PRECAUTIONS. Hypotension: Before initiating JARDIANCEassess and correct volume status in patients with renal impairment,the elderly, in patients with low systolic blood pressure, and inpatients on diuretics. Monitor for signs and symptoms during therapy.(5.1)Ketoacidosis: Assess patients who presentwith signs and symptoms of metabolic acidosis for ketoacidosis, regardlessof blood glucose level. If suspected, discontinue JARDIANCE, evaluateand treat promptly. Before initiating JARDIANCE, consider risk factorsfor ketoacidosis. Patients on JARDIANCE may require monitoring andtemporary discontinuation of therapy in clinical situations knownto predispose to ketoacidosis. (5.2)Acute kidney injury and impairment in renal function: Consider temporarily discontinuing in settings of reduced oral intakeor fluid losses. If acute kidney injury occurs, discontinue and promptlytreat. Monitor renal function during therapy. (5.3)Urosepsis and Pyelonephritis: Evaluatepatients for signs and symptoms of urinary tract infections and treatpromptly, if indicated (5.4)Hypoglycemia: Consider lowering the doseof insulin secretagogue or insulin to reduce the risk of hypoglycemiawhen initiating JARDIANCE (5.5)Genital mycotic infections: Monitor andtreat as appropriate (5.6)Hypersensitivity reactions: DiscontinueJARDIANCE, treat promptly, and monitor until signs and symptoms resolve(5.7)Increased LDL-C: Monitor and treat as appropriate(5.8). Hypotension: Before initiating JARDIANCEassess and correct volume status in patients with renal impairment,the elderly, in patients with low systolic blood pressure, and inpatients on diuretics. Monitor for signs and symptoms during therapy.(5.1). Ketoacidosis: Assess patients who presentwith signs and symptoms of metabolic acidosis for ketoacidosis, regardlessof blood glucose level. If suspected, discontinue JARDIANCE, evaluateand treat promptly. Before initiating JARDIANCE, consider risk factorsfor ketoacidosis. Patients on JARDIANCE may require monitoring andtemporary discontinuation of therapy in clinical situations knownto predispose to ketoacidosis. (5.2). Acute kidney injury and impairment in renal function: Consider temporarily discontinuing in settings of reduced oral intakeor fluid losses. If acute kidney injury occurs, discontinue and promptlytreat. Monitor renal function during therapy. (5.3). Urosepsis and Pyelonephritis: Evaluatepatients for signs and symptoms of urinary tract infections and treatpromptly, if indicated (5.4). Hypoglycemia: Consider lowering the doseof insulin secretagogue or insulin to reduce the risk of hypoglycemiawhen initiating JARDIANCE (5.5). Genital mycotic infections: Monitor andtreat as appropriate (5.6). Hypersensitivity reactions: DiscontinueJARDIANCE, treat promptly, and monitor until signs and symptoms resolve(5.7). Increased LDL-C: Monitor and treat as appropriate(5.8). 5.1 Hypotension. JARDIANCE causes intravascularvolume contraction. Symptomatic hypotension may occur after initiatingJARDIANCE [see Adverse Reactions (6.1)] particularly in patients with renal impairment,the elderly, in patients with low systolic blood pressure, and inpatients on diuretics. Before initiating JARDIANCE, assess for volumecontraction and correct volume status if indicated. Monitor for signsand symptoms of hypotension after initiating therapy and increasemonitoring in clinical situations where volume contraction is expected [see Use in Specific Populations (8.5)].. 5.2 Ketoacidosis. Reports of ketoacidosis, seriouslife-threatening condition requiring urgent hospitalization have beenidentified in postmarketing surveillance in patients with type andtype diabetes mellitus receiving sodium glucose co-transporter-2(SGLT2) inhibitors, including JARDIANCE. Fatal cases of ketoacidosishave been reported in patients taking JARDIANCE. JARDIANCE is notindicated for the treatment of patients with type diabetes mellitus [see Indications and Usage (1)].Patients treatedwith JARDIANCE who present with signs and symptoms consistent withsevere metabolic acidosis should be assessed for ketoacidosis regardlessof presenting blood glucose levels, as ketoacidosis associated withJARDIANCE may be present even if blood glucose levels are less than250 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 carbohydratereplacement.In manyof the postmarketing reports, and particularly in patients with type1 diabetes, the presence of ketoacidosis was not immediately recognizedand institution of treatment was delayed because presenting bloodglucose levels were below those typically expected for diabetic ketoacidosis(often less than 250 mg/dL). Signs and symptoms at presentation wereconsistent with dehydration and severe metabolic acidosis and includednausea, vomiting, abdominal pain, generalized malaise, and shortnessof breath. In some but not all cases, factors predisposing to ketoacidosissuch as insulin dose reduction, acute febrile illness, reduced caloricintake due to illness or surgery, pancreatic disorders suggestinginsulin deficiency (e.g., type diabetes, history of pancreatitisor pancreatic surgery), and alcohol abuse were identified.Before initiating JARDIANCE,consider factors in the patient history that may predispose to ketoacidosisincluding pancreatic insulin deficiency from any cause, caloric restriction,and alcohol abuse. In patients treated with JARDIANCE consider monitoringfor ketoacidosis and temporarily discontinuing JARDIANCE in clinicalsituations known to predispose to ketoacidosis (e.g., prolonged fastingdue to acute illness or surgery).. 5.3 Acute Kidney Injuryand Impairment in Renal Function. JARDIANCE causes intravascular volume contraction [see Warnings and Precautions (5.1)] and can cause renal impairment [see Adverse Reactions(6.1)]. There have been postmarketingreports of acute kidney injury, some requiring hospitalization anddialysis, in patients receiving SGLT2 inhibitors, including JARDIANCE;some reports involved patients younger than 65 years of age.Before initiating JARDIANCE,consider factors that may predispose patients to acute kidney injuryincluding hypovolemia, chronic renal insufficiency, congestive heartfailure and concomitant medications (diuretics, ACE inhibitors, ARBs,NSAIDs). Consider temporarily discontinuing JARDIANCE in any settingof reduced oral intake (such as acute illness or fasting) or fluidlosses (such as gastrointestinal illness or excessive heat exposure);monitor patients for signs and symptoms of acute kidney injury. Ifacute kidney injury occurs, discontinue JARDIANCE promptly and institutetreatment. JARDIANCEincreases serum creatinine and decreases eGFR. Patients with hypovolemiamay be more susceptible to these changes. Renal function abnormalitiescan occur after initiating JARDIANCE [see Adverse Reactions(6.1)]. Renal function shouldbe evaluated prior to initiation of JARDIANCE and monitored periodicallythereafter. More frequent renal function monitoring is recommendedin patients with an eGFR below 60 mL/min/1.73 m2. Use of JARDIANCE is not recommended when eGFR is persistently lessthan 45 mL/min/1.73 m2 and is contraindicatedin patients with an eGFR less than 30 mL/min/1.73 m2 [see Dosage and Administration (2.2), Contraindications (4)and Use in Specific Populations (8.6)].. 5.4 Urosepsis and Pyelonephritis. There have been postmarketingreports of serious urinary tract infections including urosepsis andpyelonephritis requiring hospitalization in patients receiving SGLT2inhibitors, including JARDIANCE. Treatment with SGLT2 inhibitors increasesthe risk for urinary tract infections. Evaluate patients for signsand symptoms of urinary tract infections and treat promptly, if indicated [see Adverse Reactions (6)].. 5.5 Hypoglycemia withConcomitant Use with Insulin and Insulin Secretagogues. Insulin and insulin secretagoguesare known to cause hypoglycemia. The risk of hypoglycemia is increasedwhen JARDIANCE is used in combination with insulin secretagogues (e.g.,sulfonylurea) or insulin [see Adverse Reactions (6.1)]. Therefore, lower doseof the insulin secretagogue or insulin may be required to reduce therisk of hypoglycemia when used in combination with JARDIANCE.. 5.6 Genital Mycotic Infections. JARDIANCE increases the riskfor genital mycotic infections [see Adverse Reactions (6.1)]. Patients with historyof chronic or recurrent genital mycotic infections were more likelyto develop genital mycotic infections. Monitor and treat as appropriate.. 5.7 HypersensitivityReactions. There have been postmarketing reports of serioushypersensitivity reactions, (e.g., angioedema) in patients treatedwith JARDIANCE. If hypersensitivity reaction occurs, discontinueJARDIANCE; treat promptly per standard of care, and monitor untilsigns and symptoms resolve. JARDIANCE is contraindicated in patientswith previous serious hypersensitivity reaction to empagliflozinor any of the excipients in JARDIANCE [see Contraindications(4)].. 5.8 Increased Low-Density Lipoprotein Cholesterol (LDL-C). Increases in LDL-C can occurwith JARDIANCE [see Adverse Reactions (6.1)]. Monitor and treat as appropriate.