ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following important adverse reactions are described below and elsewhere in the labeling:Pancreatitis [see Warnings and Precautions (5.1)] Ketoacidosis [see Warnings and Precautions (5.2)] Volume Depletion [see Warnings and Precautions (5.3)] Urosepsis and Pyelonephritis [see Warnings and Precautions (5.4)] Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues [see Warnings and Precautions (5.5)] Necrotizing Fasciitis of the Perineum (Fourniers Gangrene) [see Warnings and Precautions (5.6)] Genital Mycotic Infections [see Warnings and Precautions (5.7)] Hypersensitivity Reactions [see Warnings and Precautions (5.8)] Severe and Disabling Arthralgia [see Warnings and Precautions (5.9)] Bullous Pemphigoid [see Warnings and Precautions (5.10)] Heart Failure [see Warnings and Precautions (5.11)] Pancreatitis [see Warnings and Precautions (5.1)] Ketoacidosis [see Warnings and Precautions (5.2)] Volume Depletion [see Warnings and Precautions (5.3)] Urosepsis and Pyelonephritis [see Warnings and Precautions (5.4)] Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues [see Warnings and Precautions (5.5)] Necrotizing Fasciitis of the Perineum (Fourniers Gangrene) [see Warnings and Precautions (5.6)] Genital Mycotic Infections [see Warnings and Precautions (5.7)] Hypersensitivity Reactions [see Warnings and Precautions (5.8)] Severe and Disabling Arthralgia [see Warnings and Precautions (5.9)] Bullous Pemphigoid [see Warnings and Precautions (5.10)] Heart Failure [see Warnings and Precautions (5.11)] The most common adverse reactions associated with GLYXAMBI (a 5% or greater incidence) were urinary tract infections, nasopharyngitis, and upper respiratory tract infections (6.1)To report SUSPECTED ADVERSE REACTIONS, contact Boehringer Ingelheim Pharmaceuticals, Inc. at 1-800-542-6257, or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.. The most common adverse reactions associated with GLYXAMBI (a 5% or greater incidence) were urinary tract infections, nasopharyngitis, and upper respiratory tract infections (6.1). 6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.. Empagliflozin and LinagliptinThe safety of concomitantly administered empagliflozin (daily dose 10 mg or 25 mg) and linagliptin (daily dose mg) has been evaluated in total of 1363 patients with type diabetes treated for up to 52 weeks in active-controlled clinical trials. The most common adverse reactions with concomitant administration of empagliflozin and linagliptin based on pooled analyses of these studies are shown in Table 1.Table Adverse Reactions Reported in >=5% of Patients Treated with Empagliflozin and LinagliptinAdverse ReactionsGLYXAMBI (%) 10 mg/5 mg n=272GLYXAMBI (%) 25 mg/5 mg n=273aPredefined adverse event grouping, including, but not limited to, urinary tract infection, asymptomatic bacteriuria, cystitisUrinary tract infectiona 12.511.4Nasopharyngitis5.96.6Upper respiratory tract infection7.07.0. EmpagliflozinAdverse reactions that occurred in >=2% of patients receiving empagliflozin and more commonly than in patients given placebo included (10 mg, 25 mg, and placebo): urinary tract infection (9.3%, 7.6%, and 7.6%), female genital mycotic infections (5.4%, 6.4%, and 1.5%), upper respiratory tract infection (3.1%, 4.0%, and 3.8%), increased urination (3.4%, 3.2%, and 1.0%), dyslipidemia (3.9%, 2.9%, and 3.4%), arthralgia (2.4%, 2.3%, and 2.2%), male genital mycotic infections (3.1%, 1.6%, and 0.4%), and nausea (2.3%, 1.1%, and 1.4%).Thirst (including polydipsia) was reported in 0%, 1.7%, and 1.5% for placebo, empagliflozin 10 mg, and empagliflozin 25 mg, respectively.Empagliflozin causes an osmotic diuresis, which may lead to intravascular volume contraction and adverse reactions related to volume depletion. Events related to volume depletion (hypotension and syncope) were reported in patients (1.1%) treated with GLYXAMBI plus metformin.. LinagliptinAdverse reactions reported in >=2% of patients treated with linagliptin mg and more commonly than in patients treated with placebo included: nasopharyngitis (7.0% and 6.1%), diarrhea (3.3% and 3.0%), and cough (2.1% and 1.4%).Other adverse reactions reported in clinical studies with treatment of linagliptin monotherapy were hypersensitivity (e.g., urticaria, angioedema, localized skin exfoliation, or bronchial hyperreactivity) and myalgia.In the clinical trial program, pancreatitis was reported in 15.2 cases per 10,000 patient year exposure while being treated with linagliptin compared with 3.7 cases per 10,000 patient year exposure while being treated with comparator (placebo and active comparator, sulfonylurea). Three additional cases of pancreatitis were reported following the last administered dose of linagliptin.. HypoglycemiaTable summarizes the reports of hypoglycemia with empagliflozin and linagliptin over treatment period of 52 weeks.Table Incidence of Overalla and Severeb Hypoglycemic Adverse ReactionsAdd-on to Metformin (52 weeks)GLYXAMBI (%) 10 mg/5 mg (n=136)GLYXAMBI (%) 25 mg/5 mg (n=137)aOverall hypoglycemic events: plasma or capillary glucose of less than or equal to 70 mg/dL or requiring assistancebSevere hypoglycemic events: requiring assistance regardless of blood glucoseOverall2.23.6Severe00. Laboratory Tests. Empagliflozin and LinagliptinChanges in laboratory findings in patients treated with the combination of empagliflozin and linagliptin included increases in cholesterol and hematocrit compared to baseline.. Empagliflozin. Increases in Serum Creatinine and Decreases in eGFR: Initiation of empagliflozin causes an increase in serum creatinine and decrease in eGFR within weeks of starting therapy and then these changes stabilize. In study of patients with moderate renal impairment, larger mean changes were observed. In long-term cardiovascular outcomes trial, the increase in serum creatinine and decrease in eGFR generally did not exceed 0.1 mg/dL and -9.0 mL/min/1.73 m2, respectively, at Week 4, and reversed after treatment discontinuation, suggesting acute hemodynamic changes may play role in the renal function changes observed with empagliflozin.. Increase in Low-Density Lipoprotein Cholesterol (LDL-C): Dose-related increases in low-density lipoprotein cholesterol (LDL-C) were observed in patients treated with empagliflozin. LDL-C increased by 2.3%, 4.6%, and 6.5% in patients treated with placebo, empagliflozin 10 mg, and empagliflozin 25 mg, respectively. The range of mean baseline LDL-C levels was 90.3 to 90.6 mg/dL across treatment groups.. Increase in Hematocrit: Median hematocrit decreased by 1.3% in placebo and increased by 2.8% in empagliflozin 10 mg and 2.8% in empagliflozin 25 mg treated patients. At the end of treatment, 0.6%, 2.7%, and 3.5% of patients with hematocrits initially within the reference range had values above the upper limit of the reference range with placebo, empagliflozin 10 mg, and empagliflozin 25 mg, respectively.. Linagliptin. Increase in Uric Acid: Changes in laboratory values that occurred more frequently in the linagliptin group and >=1% more than in the placebo group were increases in uric acid (1.3% in the placebo group, 2.7% in the linagliptin group).. Increase in Lipase: In placebo-controlled clinical trial with linagliptin in type diabetes mellitus patients with micro- or macroalbuminuria, mean increase of 30% in lipase concentrations from baseline to 24 weeks was observed in the linagliptin arm compared to mean decrease of 2% in the placebo arm. Lipase levels above times upper limit of normal were seen in 8.2% compared to 1.7% patients in the linagliptin and placebo arms, respectively.. Increase in Amylase: In cardiovascular safety study comparing linagliptin versus glimepiride in patients with type diabetes mellitus, amylase levels above times upper limit of normal were seen in 1.0% compared to 0.5% of patients in the linagliptin and glimepiride arms, respectively.The clinical significance of elevations in lipase and amylase with linagliptin is unknown in the absence of other signs and symptoms of pancreatitis.. 6.2 Postmarketing Experience. Additional adverse reactions have been identified during postapproval use of linagliptin and empagliflozin. Because these reactions are reported voluntarily from population of uncertain size, it is generally not possible to reliably estimate their frequency or establish causal relationship to drug exposure.Acute Pancreatitis, including Fatal Pancreatitis [see Indications and Usage (1)] KetoacidosisUrosepsis and PyelonephritisNecrotizing Fasciitis of the Perineum (Fourniers gangrene)Hypersensitivity Reactions including Anaphylaxis, Angioedema, and Exfoliative Skin ConditionsSevere and Disabling ArthralgiaBullous PemphigoidAcute Kidney InjurySkin Reactions (e.g., rash, urticaria)Mouth Ulceration, StomatitisRhabdomyolysis. Acute Pancreatitis, including Fatal Pancreatitis [see Indications and Usage (1)] Ketoacidosis. Urosepsis and Pyelonephritis. Necrotizing Fasciitis of the Perineum (Fourniers gangrene). Hypersensitivity Reactions including Anaphylaxis, Angioedema, and Exfoliative Skin Conditions. Severe and Disabling Arthralgia. Bullous Pemphigoid. Acute Kidney Injury. Skin Reactions (e.g., rash, urticaria). Mouth Ulceration, Stomatitis. Rhabdomyolysis.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. GLYXAMBINo carcinogenicity, mutagenicity, or impairment of fertility studies have been conducted with the combination of empagliflozin and linagliptin. General toxicity studies in rats up to 13 weeks were performed with the combined components. These studies indicated that no additive toxicity is caused by the combination of empagliflozin and linagliptin.. EmpagliflozinCarcinogenesis was evaluated in 2-year studies conducted in CD-1 mice and Wistar rats. Empagliflozin did not increase the incidence of tumors in female rats dosed at 100, 300, or 700 mg/kg/day (up to 72 times the exposure from the maximum clinical dose of 25 mg). In male rats, hemangiomas of the mesenteric lymph node were increased significantly at 700 mg/kg/day or approximately 42 times the exposure from 25 mg clinical dose. Empagliflozin did not increase the incidence of tumors in female mice dosed at 100, 300, or 1000 mg/kg/day (up to 62 times the exposure from 25 mg clinical dose). Renal tubule adenomas and carcinomas were observed in male mice at 1000 mg/kg/day, which is approximately 45 times the exposure of the maximum clinical dose of 25 mg. These tumors may be associated with metabolic pathway predominantly present in the male mouse kidney.Empagliflozin was not mutagenic or clastogenic with or without metabolic activation in the in vitro Ames bacterial mutagenicity assay, the in vitro L5178Y tk+/- mouse lymphoma cell assay, and an in vivo micronucleus assay in rats.Empagliflozin had no effects on mating, fertility or early embryonic development in treated male or female rats up to the high dose of 700 mg/kg/day (approximately 155 times the 25 mg clinical dose in males and females, respectively).. LinagliptinLinagliptin did not increase the incidence of tumors in male and female rats in 2-year study at doses of 6, 18, and 60 mg/kg. The highest dose of 60 mg/kg is approximately 418 times the clinical dose of mg/day based on AUC exposure. Linagliptin did not increase the incidence of tumors in mice in 2-year study at doses up to 80 mg/kg (males) and 25 mg/kg (females), or approximately 35- and 270-times the clinical dose based on AUC exposure. Higher doses of linagliptin in female mice (80 mg/kg) increased the incidence of lymphoma at approximately 215-times the clinical dose based on AUC exposure.Linagliptin was not mutagenic or clastogenic with or without metabolic activation in the Ames bacterial mutagenicity assay, chromosomal aberration test in human lymphocytes, and an in vivo micronucleus assay.In fertility studies in rats, linagliptin had no adverse effects on early embryonic development, mating, fertility, or bearing live young up to the highest dose of 240 mg/kg (approximately 943-times the clinical dose based on AUC exposure).

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. GLYXAMBIGLYXAMBI contains: empagliflozin, sodium-glucose co-transporter (SGLT2) inhibitor, and linagliptin, dipeptidyl peptidase-4 (DPP-4) inhibitor.. EmpagliflozinSodium-glucose co-transporter (SGLT2) is the predominant transporter responsible for reabsorption of glucose from the glomerular filtrate back into the circulation. Empagliflozin is an inhibitor of SGLT2. By inhibiting SGLT2, empagliflozin reduces renal reabsorption of filtered glucose and lowers the renal threshold for glucose, and thereby increases urinary glucose excretion.. LinagliptinLinagliptin is an inhibitor of DPP-4, an enzyme that degrades the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). Thus, linagliptin increases the concentrations of active incretin hormones, stimulating the release of insulin in glucose-dependent manner and decreasing the levels of glucagon in the circulation. Both incretin hormones are involved in the physiological regulation of glucose homeostasis. Incretin hormones are secreted at low basal level throughout the day and levels rise immediately after meal intake. GLP-1 and GIP increase insulin biosynthesis and secretion from pancreatic beta cells in the presence of normal and elevated blood glucose levels. Furthermore, GLP-1 also reduces glucagon secretion from pancreatic alpha cells, resulting in reduction in hepatic glucose output.. 12.2 Pharmacodynamics. Empagliflozin. Urinary Glucose ExcretionIn patients with type diabetes, urinary glucose excretion increased immediately following dose of empagliflozin and was maintained at the end of 4-week treatment period averaging at approximately 64 grams per day with 10 mg empagliflozin and 78 grams per day with 25 mg empagliflozin once daily. Data from single oral doses of empagliflozin in healthy subjects indicate that, on average, the elevation in urinary glucose excretion approaches baseline by about days for the 10 mg and 25 mg doses.. Urinary VolumeIn 5-day study, mean 24-hour urine volume increase from baseline was 341 mL on Day and 135 mL on Day of empagliflozin 25 mg once daily treatment.. Cardiac ElectrophysiologyIn randomized, placebo-controlled, active-comparator, crossover study, 30 healthy subjects were administered single oral dose of empagliflozin 25 mg, empagliflozin 200 mg (8 times the maximum recommended dose), moxifloxacin, and placebo. No increase in QTc was observed with either 25 mg or 200 mg empagliflozin.. LinagliptinLinagliptin binds to DPP-4 in reversible manner and increases the concentrations of incretin hormones. Linagliptin glucose-dependently increases insulin secretion and lowers glucagon secretion, thus resulting in better regulation of the glucose homeostasis. Linagliptin binds selectively to DPP-4 and selectively inhibits DPP-4, but not DPP-8 or DPP-9 activity in vitro at concentrations approximating therapeutic exposures.. Cardiac ElectrophysiologyIn randomized, placebo-controlled, active-comparator, 4-way crossover study, 36 healthy subjects were administered single oral dose of linagliptin mg, linagliptin 100 mg (20 times the recommended dose), moxifloxacin, and placebo. No increase in QTc was observed with either the recommended dose of mg or the 100-mg dose. At the 100-mg dose, peak linagliptin plasma concentrations were approximately 38-fold higher than the peak concentrations following 5-mg dose.. 12.3 Pharmacokinetics. GLYXAMBIAdministration of the fixed-dose combination with food resulted in no change in overall exposure of empagliflozin or linagliptin; however, the peak exposure was decreased 39% and 32% for empagliflozin and linagliptin, respectively. These changes are not likely to be clinically significant.. Absorption. EmpagliflozinThe pharmacokinetics of empagliflozin has been characterized in healthy volunteers and patients with type diabetes and no clinically relevant differences were noted between the two populations. After oral administration, peak plasma concentrations of empagliflozin were reached at 1.5 hours post-dose. Thereafter, plasma concentrations declined in biphasic manner with rapid distribution phase and relatively slow terminal phase. The steady-state mean plasma AUC and Cmax were 1870 nmolh/L and 259 nmol/L, respectively, with 10 mg empagliflozin once daily treatment, and 4740 nmolh/L and 687 nmol/L, respectively, with 25 mg empagliflozin once daily treatment. Systemic exposure of empagliflozin increased in dose-proportional manner in the therapeutic dose range. The single-dose and steady-state pharmacokinetic parameters of empagliflozin were similar, suggesting linear pharmacokinetics with respect to time.Administration of 25 mg empagliflozin after intake of high-fat and high-calorie meal resulted in slightly lower exposure; AUC decreased by approximately 16% and Cmax decreased by approximately 37%, compared to fasted condition. The observed effect of food on empagliflozin pharmacokinetics was not considered clinically relevant and empagliflozin may be administered with or without food.. LinagliptinThe absolute bioavailability of linagliptin is approximately 30%. High-fat meal reduced Cmax by 15% and increased AUC by 4%; this effect is not clinically relevant. Linagliptin may be administered with or without food.. Distribution. EmpagliflozinThe apparent steady-state volume of distribution was estimated to be 73.8 based on population pharmacokinetic analysis. Following administration of an oral [14C]-empagliflozin solution to healthy subjects, the red blood cell partitioning was approximately 36.8% and plasma protein binding was 86.2%.. LinagliptinThe mean apparent volume of distribution at steady-state following single intravenous dose of linagliptin mg to healthy subjects is approximately 1110 L, indicating that linagliptin extensively distributes to the tissues. Plasma protein binding of linagliptin is concentration-dependent, decreasing from about 99% at nmol/L to 75% to 89% at >=30 nmol/L, reflecting saturation of binding to DPP-4 with increasing concentration of linagliptin. At high concentrations, where DPP-4 is fully saturated, 70% to 80% of linagliptin remains bound to plasma proteins and 20% to 30% is unbound in plasma. Plasma binding is not altered in patients with renal or hepatic impairment.. Elimination. Empagliflozin: The apparent terminal elimination half-life of empagliflozin was estimated to be 12.4 and apparent oral clearance was 10.6 L/h based on the population pharmacokinetic analysis. Following once-daily dosing, up to 22% accumulation, with respect to plasma AUC, was observed at steady-state, which was consistent with empagliflozin half-life. Linagliptin: Linagliptin has terminal half-life of about 200 hours at steady-state, though the accumulation half-life is about 11 hours. Renal clearance at steady-state was approximately 70 mL/min.. Metabolism. Empagliflozin: No major metabolites of empagliflozin were detected in human plasma and the most abundant metabolites were three glucuronide conjugates (2-O-, 3-O-, and 6-O-glucuronide). Systemic exposure of each metabolite was less than 10% of total drug-related material. In vitro studies suggested that the primary route of metabolism of empagliflozin in humans is glucuronidation by the uridine 5-diphospho-glucuronosyltransferases UGT2B7, UGT1A3, UGT1A8, and UGT1A9.. Linagliptin: Following oral administration, the majority (about 90%) of linagliptin is excreted unchanged, indicating that metabolism represents minor elimination pathway. small fraction of absorbed linagliptin is metabolized to pharmacologically inactive metabolite, which shows steady-state exposure of 13.3% relative to linagliptin.. Excretion. Empagliflozin: 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 recovered in feces was unchanged parent drug and approximately half of drug-related radioactivity excreted in urine was unchanged parent drug.. Linagliptin: Following administration of an oral [14C]-linagliptin dose to healthy subjects, approximately 85% of the administered radioactivity was eliminated via the enterohepatic system (80%) or urine (5%) within days of dosing.. Specific Populations. Renal Impairment. GLYXAMBI: Studies characterizing the pharmacokinetics of empagliflozin and linagliptin after administration of GLYXAMBI in renally impaired patients have not been performed.. Empagliflozin: In patients with mild (eGFR: 60 to less than 90 mL/min/1.73 m2), moderate (eGFR: 30 to less than 60 mL/min/1.73 m2), and severe (eGFR: less than 30 mL/min/1.73 m2) renal impairment and patients with kidney failure/end stage renal disease (ESRD), AUC of empagliflozin increased by approximately 18%, 20%, 66%, and 48%, respectively, compared to subjects with normal renal function. Peak plasma levels of empagliflozin were similar in patients with moderate renal impairment and kidney failure/ESRD compared to subjects with normal renal function. Peak plasma levels of empagliflozin were roughly 20% higher in patients with mild and severe renal impairment as compared to subjects with normal renal function. Population pharmacokinetic analysis showed that the apparent oral clearance of empagliflozin decreased, with decrease in eGFR leading to an increase in drug exposure. However, the fraction of empagliflozin that was excreted unchanged in urine, and urinary glucose excretion, declined with decrease in eGFR.. Linagliptin: An open-label pharmacokinetic study evaluated the pharmacokinetics of linagliptin mg in male and female patients with varying degrees of chronic renal impairment. The study included healthy subjects with normal renal function (creatinine clearance [CrCl] >=80 mL/min), patients with mild renal impairment (CrCl 50 to <80 mL/min), patients with moderate renal impairment (CrCl 30 to <50 mL/min), 10 patients with type diabetes and severe renal impairment (CrCl <30 mL/min), and 11 patients with type diabetes and normal renal function. Creatinine clearance was measured by 24-hour urinary creatinine clearance measurements or estimated from serum creatinine based on the Cockcroft-Gault formula.Under steady-state conditions, linagliptin exposure in patients with mild renal impairment was comparable to healthy subjects.In patients with moderate renal impairment under steady-state conditions, mean exposure of linagliptin increased (AUC,ss by 71% and Cmax by 46%) compared with healthy subjects. This increase was not associated with prolonged accumulation half-life, terminal half-life, or an increased accumulation factor. Renal excretion of linagliptin was below 5% of the administered dose and was not affected by decreased renal function. Patients with type diabetes and severe renal impairment showed steady-state exposure approximately 40% higher than that of patients with type diabetes and normal renal function (increase in AUC,ss by 42% and Cmax by 35%). For both type diabetes groups, renal excretion was below 7% of the administered dose.These findings were further supported by the results of population pharmacokinetic analyses.. Hepatic Impairment. GLYXAMBI: Studies characterizing the pharmacokinetics of empagliflozin and linagliptin after administration of GLYXAMBI in hepatically impaired patients have not been performed.. Empagliflozin: In patients with mild, moderate, and severe hepatic impairment according to the Child-Pugh classification, AUC of empagliflozin increased by approximately 23%, 47%, and 75% and Cmax increased by approximately 4%, 23%, and 48%, respectively, compared to subjects with normal hepatic function.. Linagliptin: In patients with mild hepatic impairment (Child-Pugh class A) steady-state exposure (AUC,ss) of linagliptin was approximately 25% lower and Cmax,ss was approximately 36% lower than in healthy subjects. In patients with moderate hepatic impairment (Child-Pugh class B), AUCss of linagliptin was about 14% lower and Cmax,ss was approximately 8% lower than in healthy subjects. Patients with severe hepatic impairment (Child-Pugh class C) had comparable exposure of linagliptin in terms of AUC0-24 and approximately 23% lower Cmax compared with healthy subjects. Reductions in the pharmacokinetic parameters seen in patients with hepatic impairment did not result in reductions in DPP-4 inhibition.. Effects of Age, Body Mass Index, Gender, and Race. Empagliflozin: Based on the population PK analysis, age, body mass index (BMI), gender and race (Asians versus primarily Whites) do not have clinically meaningful effect on pharmacokinetics of empagliflozin [see Use in Specific Populations (8.5)].. Linagliptin: Based on the population PK analysis, age, body mass index (BMI), gender and race do not have clinically meaningful effect on pharmacokinetics of linagliptin [see Use in Specific Populations (8.5)].. Drug InteractionsPharmacokinetic drug interaction studies with GLYXAMBI have not been performed; however, such studies have been conducted with the individual components of GLYXAMBI (empagliflozin and linagliptin).. Empagliflozin. In vitro Assessment of Drug InteractionsEmpagliflozin does not inhibit, inactivate, or induce CYP450 isoforms. In vitro data suggest that the primary route of metabolism of empagliflozin in humans is glucuronidation by the uridine 5-diphospho-glucuronosyltransferases UGT1A3, UGT1A8, UGT1A9 and UGT2B7. Empagliflozin does not inhibit UGT1A1, UGT1A3, UGT1A8, UGT1A9, or UGT2B7. Therefore, no effect of empagliflozin is anticipated on concomitantly administered drugs that are substrates of the major CYP450 isoforms or UGT1A1, UGT1A3, UGT1A8, UGT1A9, or UGT2B7. The effect of UGT induction (e.g., induction by rifampicin or any other UGT enzyme inducer) on empagliflozin exposure has not been evaluated.Empagliflozin is substrate for P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), but it does not inhibit these efflux transporters at therapeutic doses. Based on in vitro studies, empagliflozin is considered unlikely to cause interactions with drugs that are P-gp substrates. Empagliflozin is substrate of the human uptake transporters OAT3, OATP1B1, and OATP1B3, but not OAT1 and OCT2. Empagliflozin does not inhibit any of these human uptake transporters at clinically relevant plasma concentrations and, therefore, no effect of empagliflozin is anticipated on concomitantly administered drugs that are substrates of these uptake transporters.. In vivo Assessment of Drug InteractionsEmpagliflozin pharmacokinetics were similar with and without coadministration of metformin, glimepiride, pioglitazone, sitagliptin, linagliptin, warfarin, verapamil, ramipril, and simvastatin in healthy volunteers and with or without coadministration of hydrochlorothiazide and torsemide in patients with type diabetes (see Figure 1). In subjects with normal renal function, coadministration of empagliflozin with probenecid resulted in 30% decrease in the fraction of empagliflozin excreted in urine without any effect on 24-hour urinary glucose excretion. The relevance of this observation to patients with renal impairment is unknown.Figure Effect of Various Medications on the Pharmacokinetics of Empagliflozin as Displayed as 90% Confidence Interval of Geometric Mean AUC and Cmax Ratios [reference lines indicate 100% (80% 125%)]aempagliflozin, 50 mg, once daily; bempagliflozin, 25 mg, single dose; cempagliflozin, 25 mg, once daily; dempagliflozin, 10 mg, single doseEmpagliflozin had no clinically relevant effect on the pharmacokinetics of metformin, glimepiride, pioglitazone, sitagliptin, linagliptin, warfarin, digoxin, ramipril, simvastatin, hydrochlorothiazide, torsemide, and oral contraceptives when coadministered in healthy volunteers (see Figure 2). Figure Effect of Empagliflozin on 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, single dose; dadministered as simvastatin; eadministered as warfarin racemic mixture; fadministered as Microgynon(R); gadministered as ramipril. Figure 1. Figure 2. Linagliptin. In vitro Assessment of Drug InteractionsLinagliptin is weak to moderate inhibitor of CYP isozyme CYP3A4, but does not inhibit other CYP isozymes and is not an inducer of CYP isozymes, including CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, and 4A11.Linagliptin is P-glycoprotein (P-gp) substrate, and inhibits P-gp mediated transport of digoxin at high concentrations. Based on these results and in vivo drug interaction studies, linagliptin is considered unlikely to cause interactions with other P-gp substrates at therapeutic concentrations.. In vivo Assessment of Drug InteractionsStrong inducers of CYP3A4 or P-gp (e.g., rifampin) decrease exposure to linagliptin to subtherapeutic and likely ineffective concentrations [see Drug Interactions (7)]. In vivo studies indicated evidence of low propensity for causing drug interactions with substrates of CYP3A4, CYP2C9, CYP2C8, P-gp and organic cationic transporter (OCT).Table 4Effect of Coadministered Drugs on Systemic Exposure of LinagliptinCoadministered DrugDosing of Coadministered Druga Dosing of Linagliptina Geometric Mean Ratio (ratio with/without coadministered drug) No effect 1.0AUCd Cmax aMultiple dose (steady-state) unless otherwise notedbFor information regarding clinical recommendations [see Drug Interactions (7)].cSingle dosedAUC AUC(0 to 24 hours) for single dose treatments and AUC AUC(TAU) for multiple-dose treatmentsQD once dailyBID twice dailyTID three times dailyMetformin 850 mg TID10 mg QD1.201.03Glyburide 1.75 mgc mg QD1.021.01Pioglitazone45 mg QD10 mg QD1.131.07Ritonavir200 mg BID5 mgc 2.012.96Rifampinb 600 mg QD5 mg QD0.60 0.56Table 5Effect of Linagliptin on Systemic Exposure of Coadministered DrugsCoadministered DrugDosing of Coadministered Druga Dosing of Linagliptina Geometric Mean Ratio (ratio with/without coadministered drug) No effect 1.0AUCc Cmax aMultiple dose (steady-state) unless otherwise notedbSingle dosecAUC AUC(INF) for single dose treatments and AUC AUC(TAU) for multiple dose treatmentsdAUC=AUC(0-168) and Cmax Emax for pharmacodynamic end pointsINR International Normalized RatioPT Prothrombin TimeQD once dailyTID three times dailyMetformin850 mg TID10 mg QDmetformin1.010.89Glyburide 1.75 mgb mg QDglyburide0.860.86Pioglitazone45 mg QD10 mg QDpioglitazone0.940.86metabolite M-III0.980.96metabolite M-IV1.041.05Digoxin0.25 mg QD5 mg QDdigoxin1.020.94Simvastatin40 mg QD10 mg QDsimvastatin 1.341.10simvastatin acid1.331.21Warfarin10 mgb mg QDR-warfarin0.991.00S-warfarin1.031.01INR0.93d 1.04d PT1.03d 1.15d Ethinylestradiol and levonorgestrelethinylestradiol 0.03 mg and levonorgestrel 0.150 mg QD5 mg QDethinylestradiol1.011.08levonorgestrel1.091.13.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. GLYXAMBI Glycemic Control Studies Add-on Combination Therapy with MetforminA total of 686 patients with type diabetes participated in double-blind, active-controlled study to evaluate the efficacy and safety of empagliflozin 10 mg or 25 mg in combination with linagliptin mg compared to the individual components.Patients with type diabetes inadequately controlled on at least 1500 mg of metformin per day entered single-blind placebo run-in period for weeks. At the end of the run-in period, patients who remained inadequately controlled and had an HbA1c between 7% and 10.5% were randomized 1:1:1:1:1 to one of active-treatment arms of empagliflozin 10 mg or 25 mg, linagliptin mg, or linagliptin mg in combination with 10 mg or 25 mg empagliflozin as fixed dose combination tablet.At Week 24, empagliflozin 10 mg or 25 mg used in combination with linagliptin mg provided statistically significant improvement in HbA1c (p-value <0.0001) and FPG (p-value <0.001) compared to the individual components in patients who had been inadequately controlled on metformin (see Table 6, Figure 3). Treatment with GLYXAMBI 25 mg/5 mg or GLYXAMBI 10 mg/5 mg daily also resulted in statistically significant reduction in body weight compared to linagliptin mg (p-value <0.0001). There was no statistically significant difference compared to empagliflozin alone.Table 6Glycemic Parameters at 24 Weeks in Study Comparing GLYXAMBI to the Individual Components as Add-on Therapy in Patients Inadequately Controlled on MetforminGLYXAMBI 10 mg/5 mgGLYXAMBI 25 mg/5 mgEmpagliflozin 10 mgEmpagliflozin 25 mgLinagliptin mgaFull analysis population (observed case) using MMRM. MMRM model included treatment, renal function, region, visit, visit by treatment interaction, and baseline HbA1c.bPatients with HbA1c above 7% at baseline: GLYXAMBI 25 mg/5 mg, n=123; GLYXAMBI 10 mg/5 mg, n=128; empagliflozin 25 mg, n=132; empagliflozin 10 mg, n=125; linagliptin mg, n=119. Non-completers were considered failures (NCF).cFull analysis population using last observation carried forward. ANCOVA model included treatment, renal function, region, baseline weight, and baseline HbA1c.dp<0.001 for FPG; p<0.0001 for HbA1c and body weightHbA1c (%) Number of patientsn=135n=133n=137n=139n=128 Baseline (mean)8.07.98.08.08.0 Change from baseline (adjusted mean)-1.1-1.2-0.7-0.6-0.7 Comparison vs empagliflozin 25 mg or 10 mg (adjusted mean) (95% CI)a -0.4 (-0.6, -0.2)d -0.6 (-0.7, -0.4)d ------ Comparison vs linagliptin mg (adjusted mean) (95% CI)a -0.4 (-0.6, -0.2)d -0.5 (-0.7, -0.3)d ------ Patients [n (%)] achieving HbA1c <7%b 74 (58)76 (62)35 (28)43 (33)43 (36)FPG (mg/dL) Number of patientsn=133n=131n=136n=137n=125 Baseline (mean)157155162160156 Change from baseline (adjusted mean)-33-36-21-21-13 Comparison vs empagliflozin 25 mg or 10 mg (adjusted mean) (95% CI)a -12 (-18, -5)d -15 (-22, -9)d ------ Comparison vs linagliptin mg (adjusted mean) (95% CI)a -20 (-27, -13)d -23 (-29, -16)d ------Body Weight Number of patientsn=135n=134n=137n=140n=128 Baseline (mean) in kg8785868885 change from baseline (adjusted mean)-3.1-3.4-3.0-3.5-0.7 Comparison vs empagliflozin 25 mg or 10 mg (adjusted mean) (95% CI)c 0.0 (-0.9, 0.8)0.1 (-0.8, 0.9)------ Comparison vs linagliptin mg (adjusted mean) (95% CI)c -2.4 (-3.3, -1.5)d -2.7 (-3.6, -1.8)d ------Figure 3Adjusted Mean HbA1c Change at Each Time Point (Completers) and at Week 24 (mITT population). Figure 3. Empagliflozin Cardiovascular Outcome Study in Patients with Type Diabetes Mellitus and Atherosclerotic Cardiovascular DiseaseEmpagliflozin is indicated to reduce the risk of cardiovascular death in adults with type diabetes mellitus and established cardiovascular disease. The effect of empagliflozin on cardiovascular risk in adult patients with type diabetes and established, stable, atherosclerotic cardiovascular disease is presented below.The EMPA-REG OUTCOME study, multicenter, multi-national, randomized, double-blind parallel group trial compared the risk of experiencing major adverse cardiovascular event (MACE) between empagliflozin and placebo when these were added to and used concomitantly with standard of care treatments for diabetes and atherosclerotic cardiovascular disease. Coadministered antidiabetic medications were to be kept stable for the first 12 weeks of the trial. Thereafter, antidiabetic and atherosclerotic therapies could be adjusted, at the discretion of investigators, to ensure participants were treated according to the standard care for these diseases.A total of 7020 patients were treated (empagliflozin 10 mg 2345; empagliflozin 25 mg 2342; placebo 2333) and followed for median of 3.1 years. Approximately 72% of the study population was Caucasian, 22% was Asian, and 5% was Black. The mean age was 63 years and approximately 72% were male.All patients in the study had inadequately controlled type diabetes mellitus at baseline (HbA1c greater than or equal to 7%). The mean HbA1c at baseline was 8.1% and 57% of participants had diabetes for more than 10 years. Approximately 31%, 22% and 20% reported past history of neuropathy, retinopathy and nephropathy to investigators respectively and the mean eGFR was 74 mL/min/1.73 m2. At baseline, patients were treated with one (~30%) or more (~70%) antidiabetic medications including metformin (74%), insulin (48%), sulfonylurea (43%) and dipeptidyl peptidase-4 inhibitor (11%).All patients had established atherosclerotic cardiovascular disease at baseline including one (82%) or more (18%) of the following: documented history of coronary artery disease (76%), stroke (23%) or peripheral artery disease (21%). At baseline, the mean systolic blood pressure was 136 mmHg, the mean diastolic blood pressure was 76 mmHg, the mean LDL was 86 mg/dL, the mean HDL was 44 mg/dL, and the mean urinary albumin to creatinine ratio (UACR) was 175 mg/g. At baseline, approximately 81% of patients were treated with renin angiotensin system inhibitors, 65% with beta-blockers, 43% with diuretics, 77% with statins, and 86% with antiplatelet agents (mostly aspirin).The primary endpoint in EMPA-REG OUTCOME was the time to first occurrence of Major Adverse Cardiac Event (MACE). major adverse cardiac event was defined as occurrence of either cardiovascular death or non-fatal myocardial infarction (MI) or non-fatal stroke. The statistical analysis plan had pre-specified that the 10 and 25 mg doses would be combined. Cox proportional hazards model was used to test for non-inferiority against the pre-specified risk margin of 1.3 for the hazard ratio of MACE and superiority on MACE if non-inferiority was demonstrated. Type-1 error was controlled across multiples tests using hierarchical testing strategy.Empagliflozin significantly reduced the risk of first occurrence of primary composite endpoint of cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke (HR: 0.86; 95% CI: 0.74, 0.99). The treatment effect was due to significant reduction in the risk of cardiovascular death in subjects randomized to empagliflozin (HR: 0.62; 95% CI: 0.49, 0.77), with no change in the risk of non-fatal myocardial infarction or non-fatal stroke (see Table and Figures and 5). Results for the 10 mg and 25 mg empagliflozin doses were consistent with results for the combined dose groups.Table 7Treatment Effect for the Primary Composite Endpoint, and its Componentsa Placebo N=2333Empagliflozin N=4687Hazard ratio vs placebo (95% CI)aTreated set (patients who had received at least one dose of study drug)bp-value for superiority (2-sided) 0.04cTotal number of eventsComposite of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke (time to first occurrence)b 282 (12.1%)490 (10.5%)0.86 (0.74, 0.99)Non-fatal myocardial infarctionc 121 (5.2%)213 (4.5%)0.87 (0.70, 1.09)Non-fatal strokec 60 (2.6%)150 (3.2%)1.24 (0.92, 1.67)Cardiovascular deathc 137 (5.9%)172 (3.7%)0.62 (0.49, 0.77)Figure 4Estimated Cumulative Incidence of First MACEFigure 5Estimated Cumulative Incidence of Cardiovascular DeathThe efficacy of empagliflozin on cardiovascular death was generally consistent across major demographic and disease subgroups.Vital status was obtained for 99.2% of subjects in the trial. total of 463 deaths were recorded during the EMPA-REG OUTCOME trial. Most of these deaths were categorized as cardiovascular deaths. The non-cardiovascular deaths were only small proportion of deaths, and were balanced between the treatment groups (2.1% in patients treated with empagliflozin, and 2.4% of patients treated with placebo).. Figure 4. Figure 5. Linagliptin Cardiovascular Safety Trials. CARMELINAThe cardiovascular risk of linagliptin was evaluated in CARMELINA, multi-national, multi-center, placebo-controlled, double-blind, parallel group trial comparing linagliptin (N=3494) to placebo (N=3485) in adult patients with type diabetes mellitus and history of established macrovascular and/or renal disease. The trial compared the risk of major adverse cardiovascular events (MACE) between linagliptin and placebo when these were added to standard of care treatments for diabetes and other cardiovascular risk factors. The trial was event driven, the median duration of follow-up was 2.2 years and vital status was obtained for 99.7% of patients.Patients were eligible to enter the trial if they were adults with type diabetes, with HbA1c of 6.5% to 10%, and had either albuminuria and previous macrovascular disease (39% of enrolled population), or evidence of impaired renal function by eGFR and Urinary Albumin Creatinine Ratio (UACR) criteria (42% of enrolled population), or both (18% of enrolled population).At baseline the mean age was 66 years and the population was 63% male, 80% Caucasian, 9% Asian, and 6% Black. Mean HbA1c was 8.0% and mean duration of type diabetes mellitus was 15 years. The trial population included 17% patients >=75 years of age and 62% patients with renal impairment defined as eGFR <60 mL/min/1.73 m2. The mean eGFR was 55 mL/min/1.73 m2 and 27% of patients had mild renal impairment (eGFR 60 to 90 mL/min/1.73 m2), 47% of patients had moderate renal impairment (eGFR 30 to <60 mL/min/1.73 m2) and 15% of patients had severe renal impairment (eGFR <30 mL/min/1.73 m2). Patients were taking at least one antidiabetic drug (97%), and the most common were insulin and analogues (57%), metformin (54%) and sulfonylurea (32%). Patients were also taking antihypertensives (96%), lipid lowering drugs (76%) with 72% on statin, and aspirin (62%).The primary endpoint, MACE, was the time to first occurrence of one of three composite outcomes which included cardiovascular death, non-fatal myocardial infarction or non-fatal stroke. The study was designed as non-inferiority trial with pre-specified risk margin of 1.3 for the hazard ratio of MACE. total of 434 patients on linagliptin and 420 patients on placebo experienced MACE. The incidence rate of MACE in both treatment arms: 56.3 MACE per 1000 patient-years on placebo vs. 57.7 MACE per 1000 patient-years on linagliptin. The estimated hazard ratio for MACE associated with linagliptin relative to placebo was 1.02 with 95% confidence interval of (0.89, 1.17). The upper bound of this confidence interval, 1.17, excluded the risk margin of 1.3.. CAROLINAThe cardiovascular risk of linagliptin was evaluated in CAROLINA, multi-center, multi-national, randomized, double-blind parallel group trial comparing linagliptin (N=3023) to glimepiride (N=3010) in adult patients with type diabetes mellitus and history of established cardiovascular disease and/or multiple cardiovascular risk factors. The trial compared the risk of major adverse cardiovascular events (MACE) between linagliptin and glimepiride when these were added to standard of care treatments for diabetes and other cardiovascular risk factors. The trial was event driven, the median duration of follow-up was 6.23 years and vital status was obtained for 99.3% of patients.Patients were eligible to enter the trial if they were adults with type diabetes with insufficient glycemic control (defined as HbA1c of 6.5% to 8.5% or 6.5% to 7.5% depending on treatment-naive, on monotherapy or on combination therapy), and were defined to be at high cardiovascular risk with previous vascular disease, evidence of vascular related end-organ damage, age >=70 years, and/or two cardiovascular risk factors (duration of diabetes >10 years, systolic blood pressure >140 mmHg, current smoker, LDL cholesterol >=135 mg/dL).At baseline the mean age was 64 years and the population was 60% male, 73% Caucasian, 18% Asian, and 5% Black. The mean HbA1c was 7.15% and mean duration of type diabetes was 7.6 years. The trial population included 34% patients >=70 years of age and 19% patients with renal impairment defined as eGFR <60 mL/min/1.73 m2. The mean eGFR was 77 mL/min/1.73 m2. Patients were taking at least one antidiabetic drug (91%) and the most common were metformin (83%) and sulfonylurea (28%). Patients were also taking antihypertensives (89%), lipid lowering drugs (70%) with 65% on statin, and aspirin (47%).The primary endpoint, MACE, was the time to first occurrence of one of three composite outcomes which included cardiovascular death, non-fatal myocardial infarction or non-fatal stroke. The study was designed as non-inferiority trial with pre-specified risk margin of 1.3 for the hazard ratio of MACE. total of 356 patients on linagliptin and 362 patients on glimepiride experienced MACE. The incidence rate of MACE in both treatment arms: 20.7 MACE per 1000 patient-years on linagliptin vs. 21.2 MACE per 1000 patient-years on glimepiride. The estimated hazard ratio for MACE associated with linagliptin relative to glimepiride was 0.98 with 95% confidence interval of (0.84, 1.14). The upper bound of this confidence interval, 1.14, excluded the risk margin of 1.3.

CLINICAL TRIALS EXPERIENCE SECTION.

6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.. Empagliflozin and LinagliptinThe safety of concomitantly administered empagliflozin (daily dose 10 mg or 25 mg) and linagliptin (daily dose mg) has been evaluated in total of 1363 patients with type diabetes treated for up to 52 weeks in active-controlled clinical trials. The most common adverse reactions with concomitant administration of empagliflozin and linagliptin based on pooled analyses of these studies are shown in Table 1.Table Adverse Reactions Reported in >=5% of Patients Treated with Empagliflozin and LinagliptinAdverse ReactionsGLYXAMBI (%) 10 mg/5 mg n=272GLYXAMBI (%) 25 mg/5 mg n=273aPredefined adverse event grouping, including, but not limited to, urinary tract infection, asymptomatic bacteriuria, cystitisUrinary tract infectiona 12.511.4Nasopharyngitis5.96.6Upper respiratory tract infection7.07.0. EmpagliflozinAdverse reactions that occurred in >=2% of patients receiving empagliflozin and more commonly than in patients given placebo included (10 mg, 25 mg, and placebo): urinary tract infection (9.3%, 7.6%, and 7.6%), female genital mycotic infections (5.4%, 6.4%, and 1.5%), upper respiratory tract infection (3.1%, 4.0%, and 3.8%), increased urination (3.4%, 3.2%, and 1.0%), dyslipidemia (3.9%, 2.9%, and 3.4%), arthralgia (2.4%, 2.3%, and 2.2%), male genital mycotic infections (3.1%, 1.6%, and 0.4%), and nausea (2.3%, 1.1%, and 1.4%).Thirst (including polydipsia) was reported in 0%, 1.7%, and 1.5% for placebo, empagliflozin 10 mg, and empagliflozin 25 mg, respectively.Empagliflozin causes an osmotic diuresis, which may lead to intravascular volume contraction and adverse reactions related to volume depletion. Events related to volume depletion (hypotension and syncope) were reported in patients (1.1%) treated with GLYXAMBI plus metformin.. LinagliptinAdverse reactions reported in >=2% of patients treated with linagliptin mg and more commonly than in patients treated with placebo included: nasopharyngitis (7.0% and 6.1%), diarrhea (3.3% and 3.0%), and cough (2.1% and 1.4%).Other adverse reactions reported in clinical studies with treatment of linagliptin monotherapy were hypersensitivity (e.g., urticaria, angioedema, localized skin exfoliation, or bronchial hyperreactivity) and myalgia.In the clinical trial program, pancreatitis was reported in 15.2 cases per 10,000 patient year exposure while being treated with linagliptin compared with 3.7 cases per 10,000 patient year exposure while being treated with comparator (placebo and active comparator, sulfonylurea). Three additional cases of pancreatitis were reported following the last administered dose of linagliptin.. HypoglycemiaTable summarizes the reports of hypoglycemia with empagliflozin and linagliptin over treatment period of 52 weeks.Table Incidence of Overalla and Severeb Hypoglycemic Adverse ReactionsAdd-on to Metformin (52 weeks)GLYXAMBI (%) 10 mg/5 mg (n=136)GLYXAMBI (%) 25 mg/5 mg (n=137)aOverall hypoglycemic events: plasma or capillary glucose of less than or equal to 70 mg/dL or requiring assistancebSevere hypoglycemic events: requiring assistance regardless of blood glucoseOverall2.23.6Severe00. Laboratory Tests. Empagliflozin and LinagliptinChanges in laboratory findings in patients treated with the combination of empagliflozin and linagliptin included increases in cholesterol and hematocrit compared to baseline.. Empagliflozin. Increases in Serum Creatinine and Decreases in eGFR: Initiation of empagliflozin causes an increase in serum creatinine and decrease in eGFR within weeks of starting therapy and then these changes stabilize. In study of patients with moderate renal impairment, larger mean changes were observed. In long-term cardiovascular outcomes trial, the increase in serum creatinine and decrease in eGFR generally did not exceed 0.1 mg/dL and -9.0 mL/min/1.73 m2, respectively, at Week 4, and reversed after treatment discontinuation, suggesting acute hemodynamic changes may play role in the renal function changes observed with empagliflozin.. Increase in Low-Density Lipoprotein Cholesterol (LDL-C): Dose-related increases in low-density lipoprotein cholesterol (LDL-C) were observed in patients treated with empagliflozin. LDL-C increased by 2.3%, 4.6%, and 6.5% in patients treated with placebo, empagliflozin 10 mg, and empagliflozin 25 mg, respectively. The range of mean baseline LDL-C levels was 90.3 to 90.6 mg/dL across treatment groups.. Increase in Hematocrit: Median hematocrit decreased by 1.3% in placebo and increased by 2.8% in empagliflozin 10 mg and 2.8% in empagliflozin 25 mg treated patients. At the end of treatment, 0.6%, 2.7%, and 3.5% of patients with hematocrits initially within the reference range had values above the upper limit of the reference range with placebo, empagliflozin 10 mg, and empagliflozin 25 mg, respectively.. Linagliptin. Increase in Uric Acid: Changes in laboratory values that occurred more frequently in the linagliptin group and >=1% more than in the placebo group were increases in uric acid (1.3% in the placebo group, 2.7% in the linagliptin group).. Increase in Lipase: In placebo-controlled clinical trial with linagliptin in type diabetes mellitus patients with micro- or macroalbuminuria, mean increase of 30% in lipase concentrations from baseline to 24 weeks was observed in the linagliptin arm compared to mean decrease of 2% in the placebo arm. Lipase levels above times upper limit of normal were seen in 8.2% compared to 1.7% patients in the linagliptin and placebo arms, respectively.. Increase in Amylase: In cardiovascular safety study comparing linagliptin versus glimepiride in patients with type diabetes mellitus, amylase levels above times upper limit of normal were seen in 1.0% compared to 0.5% of patients in the linagliptin and glimepiride arms, respectively.The clinical significance of elevations in lipase and amylase with linagliptin is unknown in the absence of other signs and symptoms of pancreatitis.

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. Patients on dialysis [see Use in Specific Populations (8.6)]. Hypersensitivity to empagliflozin, linagliptin, or any of the excipients in GLYXAMBI, reactions such as anaphylaxis, angioedema, exfoliative skin conditions, urticaria, or bronchial hyperreactivity have occurred [see Warnings and Precautions (5.8) and Adverse Reactions (6)].. Patients on dialysis [see Use in Specific Populations (8.6)]. Hypersensitivity to empagliflozin, linagliptin, or any of the excipients in GLYXAMBI, reactions such as anaphylaxis, angioedema, exfoliative skin conditions, urticaria, or bronchial hyperreactivity have occurred [see Warnings and Precautions (5.8) and Adverse Reactions (6)].. Patients on dialysis (4) Hypersensitivity to empagliflozin, linagliptin, or any of the excipients in GLYXAMBI (4, 5.8). Patients on dialysis (4). Hypersensitivity to empagliflozin, linagliptin, or any of the excipients in GLYXAMBI (4, 5.8).

DESCRIPTION SECTION.

11 DESCRIPTION. GLYXAMBI tablets for oral use contain: empagliflozin and linagliptin.. EmpagliflozinEmpagliflozin is an inhibitor of the sodium-glucose co-transporter (SGLT2).The chemical name of empagliflozin is D-Glucitol,1,5-anhydro-1-C-[4-chloro-3-[[4-[[(3S)-tetrahydro-3-furanyl]oxy]phenyl]methyl]phenyl]-, (1S).The molecular formula is C23H27ClO7 and the molecular weight is 450.91. The structural formula is:Empagliflozin is white to yellowish, non-hygroscopic powder. It is very slightly soluble in water, sparingly soluble in methanol, slightly soluble in ethanol and acetonitrile, soluble in 50% acetonitrile/water, and practically insoluble in toluene.. Chemical Structure. LinagliptinLinagliptin is an inhibitor of the dipeptidyl peptidase-4 (DPP-4) enzyme.The chemical name of linagliptin is 1H-Purine-2,6-dione, 8-[(3R)-3-amino-1-piperidinyl]-7-(2-butyn-1-yl)-3,7-dihydro-3-methyl-1-[(4-methyl-2-quinazolinyl)methyl]-The molecular formula is C25H28N8O2 and the molecular weight is 472.54. The structural formula is:Linagliptin is white to yellowish, not or only slightly hygroscopic solid substance. It is very slightly soluble in water. Linagliptin is soluble in methanol, sparingly soluble in ethanol, very slightly soluble in isopropanol, and very slightly soluble in acetone.. Chemical Structure. GLYXAMBIGLYXAMBI tablets are available in two dosage strengths containing 10 mg or 25 mg empagliflozin in combination with mg linagliptin. The inactive ingredients of GLYXAMBI are the following: Tablet Core: mannitol, pregelatinized starch, corn starch, copovidone, crospovidone, talc and magnesium stearate. Coating: hypromellose, mannitol, talc, titanium dioxide, polyethylene glycol and ferric oxide, yellow (10 mg/5 mg) or ferric oxide, red (25 mg/5 mg).

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. Assess renal function before initiating and as clinically indicated (2.1) The recommended dose of GLYXAMBI is 10 mg empagliflozin and mg linagliptin once daily, taken in the morning, with or without food (2.2) Dose may be increased to 25 mg empagliflozin and mg linagliptin once daily (2.2). Assess renal function before initiating and as clinically indicated (2.1) The recommended dose of GLYXAMBI is 10 mg empagliflozin and mg linagliptin once daily, taken in the morning, with or without food (2.2). Dose may be increased to 25 mg empagliflozin and mg linagliptin once daily (2.2). 2.1 Prior to Initiation of GLYXAMBI. Assess renal function before initiating GLYXAMBI and as clinically indicated [see Warnings and Precautions (5.3)].In patients with volume depletion, correct this condition before initiating GLYXAMBI [see Warnings and Precautions (5.3) and Use in Specific Populations (8.5, 8.6)].. Assess renal function before initiating GLYXAMBI and as clinically indicated [see Warnings and Precautions (5.3)].. In patients with volume depletion, correct this condition before initiating GLYXAMBI [see Warnings and Precautions (5.3) and Use in Specific Populations (8.5, 8.6)].. 2.2 Recommended Dosage. The recommended dose of GLYXAMBI is 10 mg empagliflozin/5 mg linagliptin once daily in the morning, taken with or without food. GLYXAMBI may be increased to 25 mg empagliflozin/5 mg linagliptin once daily for additional glycemic control.. 2.3 Dosage Recommendations in Patients with Renal Impairment. GLYXAMBI is not recommended for use in patients with an eGFR less than 30 mL/min/1.73 m2 and contraindicated in patients on dialysis [see Indications and Usage (1), Contraindications (4), Warnings and Precautions (5.3) and Use in Specific Populations (8.6)].

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. GLYXAMBI tablets are combination of empagliflozin and linagliptin available as:10 mg empagliflozin/5 mg linagliptin are pale yellow, arc triangular, flat-faced, bevel-edged, film-coated tablets. One side is debossed with the Boehringer Ingelheim company symbol; the other side is debossed with 10/5.25 mg empagliflozin/5 mg linagliptin are pale pink, arc triangular, flat-faced, bevel-edged, film-coated tablets. One side is debossed with the Boehringer Ingelheim company symbol; the other side is debossed with 25/5.. 10 mg empagliflozin/5 mg linagliptin are pale yellow, arc triangular, flat-faced, bevel-edged, film-coated tablets. One side is debossed with the Boehringer Ingelheim company symbol; the other side is debossed with 10/5.. 25 mg empagliflozin/5 mg linagliptin are pale pink, arc triangular, flat-faced, bevel-edged, film-coated tablets. One side is debossed with the Boehringer Ingelheim company symbol; the other side is debossed with 25/5.. Tablets:10 mg empagliflozin/5 mg linagliptin25 mg empagliflozin/5 mg linagliptin (3).

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. Table 3Clinically Relevant Interactions with GLYXAMBIDiureticsClinical ImpactCoadministration of empagliflozin with diuretics resulted in increased urine volume and frequency of voids, which might enhance the potential for volume depletion.InterventionBefore initiating GLYXAMBI, assess volume status and renal function. In patients with volume depletion, correct this condition before initiating GLYXAMBI. Monitor for signs and symptoms of volume depletion, and renal function after initiating therapy.Insulin or Insulin SecretagoguesClinical ImpactEmpagliflozin or linagliptin in combination with an insulin secretagogue (e.g., sulfonylurea) or insulin was associated with higher rate of hypoglycemia compared with placebo in clinical trial.InterventionCoadministration of GLYXAMBI with an insulin secretagogue (e.g., sulfonylurea) or insulin may require lower doses of the insulin secretagogue or insulin to reduce the risk of hypoglycemia.Positive Urine Glucose TestClinical ImpactSGLT2 inhibitors increase urinary glucose excretion and will lead to positive urine glucose tests.InterventionMonitoring glycemic control with urine glucose tests is not recommended in patients taking SGLT2 inhibitors. Use alternative methods to monitor glycemic control.Interference with 1,5-anhydroglucitol (1,5-AG) AssayClinical ImpactMeasurements of 1,5-AG are unreliable in assessing glycemic control in patients taking SGLT2 inhibitors. InterventionMonitoring glycemic control with 1,5-AG assay is not recommended. Use alternative methods to monitor glycemic control.Inducers of P-glycoprotein or CYP3A4 EnzymesClinical ImpactRifampin decreased linagliptin exposure, suggesting that the efficacy of linagliptin may be reduced when administered in combination with strong P-gp or CYP3A4 inducer. InterventionUse of alternative treatments is strongly recommended when linagliptin is to be administered with strong P-gp or CYP3A4 inducer.

GERIATRIC USE SECTION.

8.5 Geriatric Use. GLYXAMBIEmpagliflozin is associated with osmotic diuresis, which could affect hydration status of patients age 75 years and older [see Warnings and Precautions (5.3)].. EmpagliflozinIn empagliflozin type diabetes studies, 2721 empagliflozin-treated patients were 65 years of age and older and 491 patients were 75 years of age and older. In these studies, volume depletion-related adverse reactions occurred in 2.1%, 2.3%, and 4.4% of patients 75 years of age and older in the placebo, empagliflozin 10 mg, and empagliflozin 25 mg once daily groups, respectively; and urinary tract infections occurred in 10.5%, 15.7%, and 15.1% of patients 75 years of age and older in the placebo, empagliflozin 10 mg, and empagliflozin 25 mg once daily groups, respectively.. LinagliptinIn linagliptin studies, 1085 linagliptin-treated patients were 65 years of age and older and 131 patients were 75 years of age and older. In these linagliptin studies, no overall differences in safety or effectiveness of linagliptin were observed between geriatric patients and younger adult patients.

HEPATIC IMPAIRMENT SUBSECTION.

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

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. GLYXAMBI (empagliflozin and linagliptin) tablets are available as follows:10 mg/5 mg tablets: pale yellow, arc triangular, flat-faced, bevel-edged, film-coated tablets. One side is debossed with the Boehringer Ingelheim company symbol; the other side is debossed with 10/5.Bottles of 30 (NDC 0597-0182-30) Bottles of 90 (NDC 0597-0182-90)Cartons containing blister cards of 10 tablets each (3 10) (NDC 0597-0182-39), institutional pack.25 mg/5 mg tablets: pale pink, arc triangular, flat-faced, bevel-edged, film-coated tablets. One side is debossed with the Boehringer Ingelheim company symbol; the other side is debossed with 25/5.Bottles of 30 (NDC 0597-0164-30) Bottles of 90 (NDC 0597-0164-90) Cartons containing blister cards of 10 tablets each (3 10) (NDC 0597-0164-39), institutional pack.If repackaging is required, dispense in tight container as defined in USP.. StorageStore at 20C to 25C (68F to 77F); excursions permitted to 15C to 30C (59F to 86F) [see USP Controlled Room Temperature].

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. GLYXAMBI is combination of empagliflozin and linagliptin indicated as an adjunct to diet and exercise to improve glycemic control in adults with type diabetes mellitus. Empagliflozin is indicated to reduce the risk of cardiovascular death in adults with type diabetes mellitus and established cardiovascular disease [see Clinical Studies (14)].. GLYXAMBI is combination of empagliflozin, sodium-glucose co-transporter (SGLT2) inhibitor and linagliptin, dipeptidyl peptidase-4 (DPP-4) inhibitor, indicated as an adjunct to diet and exercise to improve glycemic control in adults with type diabetes mellitus.Empagliflozin is indicated to reduce the risk of cardiovascular death in adults with type diabetes mellitus and established cardiovascular disease. (1)Limitations of Use Not recommended in patients with type diabetes mellitus. It may increase the risk of diabetic ketoacidosis in these patients (1) Has not been studied in patients with history of pancreatitis (1) Not recommended for use to improve glycemic control in adults with type diabetes mellitus with an eGFR less than 30 mL/min/1.73 m2 (1). Not recommended in patients with type diabetes mellitus. It may increase the risk of diabetic ketoacidosis in these patients (1). Has not been studied in patients with history of pancreatitis (1). Not recommended for use to improve glycemic control in adults with type diabetes mellitus with an eGFR less than 30 mL/min/1.73 m2 (1). Limitations of UseGLYXAMBI is not recommended in patients with type diabetes mellitus. It may increase the risk of diabetic ketoacidosis in these patients [see Warnings and Precautions (5.2)].GLYXAMBI has not been studied in patients with history of pancreatitis. It is unknown whether patients with history of pancreatitis are at an increased risk for the development of pancreatitis while using GLYXAMBI [see Warnings and Precautions (5.1)]. GLYXAMBI is not recommended for use to improve glycemic control in adults with type diabetes mellitus with an eGFR less than 30 mL/min/1.73 m2. GLYXAMBI is likely to be ineffective in this setting based upon its mechanism of action.

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise the patient to read the FDA-approved patient labeling (Medication Guide).. PancreatitisInform patients that acute pancreatitis has been reported during use of linagliptin. Inform patients that persistent severe abdominal pain, sometimes radiating to the back, which may or may not be accompanied by vomiting, is the hallmark symptom of acute pancreatitis. Instruct patients to discontinue GLYXAMBI promptly and contact their physician if persistent severe abdominal pain occurs [see Warnings and Precautions (5.1)].. KetoacidosisInform patients that ketoacidosis is serious life-threatening condition and that cases of ketoacidosis have been reported during use of empagliflozin, sometimes associated with illness or surgery among other risk factors. Instruct patients to check ketones (when possible) if symptoms consistent with ketoacidosis occur even if blood glucose is not elevated. If symptoms of ketoacidosis (including nausea, vomiting, abdominal pain, tiredness, and labored breathing) occur, instruct patients to discontinue GLYXAMBI and seek medical attention immediately [see Warnings and Precautions (5.2)].. Volume DepletionInform patients that symptomatic hypotension may occur with GLYXAMBI and advise them to contact their healthcare provider if they experience such symptoms [see Warnings and Precautions (5.3)]. Inform patients that dehydration may increase the risk for hypotension, and to maintain adequate fluid intake.. Serious Urinary Tract InfectionsInform patients of the potential for urinary tract infections, which may be serious. Provide them with information on the symptoms of urinary tract infections. Advise them to seek medical advice if such symptoms occur [see Warnings and Precautions (5.4)].. HypoglycemiaInform patients that the incidence of hypoglycemia is increased when GLYXAMBI is used in combination with an sulfonylurea or insulin, and that lower dose of the sulfonylurea or insulin may be required to reduce the risk of hypoglycemia [see Warnings and Precautions (5.5)].. Necrotizing Fasciitis of the Perineum (Fourniers Gangrene)Inform patients that necrotizing infections of the perineum (Fourniers gangrene) have occurred with empagliflozin, component of GLYXAMBI. Counsel patients to promptly seek medical attention if they develop pain or tenderness, redness, or swelling of the genitals or the area from the genitals back to the rectum, along with fever above 100.4F or malaise [see Warnings and Precautions (5.6)]. Genital Mycotic Infections in Females (e.g., Vulvovaginitis)Inform female patients that vaginal yeast infections may occur and provide them with information on the signs and symptoms of vaginal yeast infections. Advise them of treatment options and when to seek medical advice [see Warnings and Precautions (5.7)].. Genital Mycotic Infections in Males (e.g., Balanitis or Balanoposthitis)Inform male patients that yeast infection of penis (e.g., balanitis or balanoposthitis) may occur, especially in uncircumcised males and patients with chronic and recurrent infections. Provide them with information on the signs and symptoms of balanitis and balanoposthitis (rash or redness of the glans or foreskin of the penis). Advise them of treatment options and when to seek medical advice [see Warnings and Precautions (5.7)].. Hypersensitivity ReactionsInform patients that serious allergic reactions, such as anaphylaxis, angioedema, and exfoliative skin conditions, have been reported during postmarketing use of linagliptin or empagliflozin, components of GLYXAMBI. If symptoms of allergic reactions (such as rash, skin flaking or peeling, urticaria, swelling of the skin, or swelling of the face, lips, tongue, and throat that may cause difficulty in breathing or swallowing) occur, patients must stop taking GLYXAMBI and seek medical advice promptly [see Warnings and Precautions (5.8)].. Severe and Disabling ArthralgiaInform patients that severe and disabling joint pain may occur with this class of drugs. The time to onset of symptoms can range from one day to years. Instruct patients to seek medical advice if severe joint pain occurs [see Warnings and Precautions (5.9)].. Bullous PemphigoidInform patients that bullous pemphigoid has been reported during use of linagliptin. Instruct patients to seek medical advice if blisters or erosions occur [see Warnings and Precautions (5.10)]. Heart FailureInform patients of the signs and symptoms of heart failure. Before initiating GLYXAMBI, patients should be asked about history of heart failure or other risk factors for heart failure including moderate to severe renal impairment. Instruct patients to contact their healthcare provider as soon as possible if they experience symptoms of heart failure, including increasing shortness of breath, rapid increase in weight or swelling of the feet [see Warnings and Precautions (5.11)].. Laboratory TestsInform patients that elevated glucose in urinalysis is expected when taking GLYXAMBI.. PregnancyAdvise pregnant patients, and patients of reproductive potential, of the potential risk to fetus with treatment with GLYXAMBI [see Use in Specific Populations (8.1)]. Instruct patients to report pregnancies to their physicians as soon as possible.. LactationAdvise patients that breastfeeding is not recommended during treatment with GLYXAMBI [see Use in Specific Populations (8.2)]. Missed DoseInstruct patients to take GLYXAMBI only as prescribed. If dose is missed, it should be taken as soon as the patient remembers. Advise patients not to double their next dose.

LACTATION SECTION.

8.2 Lactation. Risk SummaryThere is no information regarding the presence of GLYXAMBI, or its individual components in human milk, the effects on the breastfed infant, or the effects on milk production. Empagliflozin and linagliptin are present in rat milk (see Data). Since human kidney maturation occurs in utero and during the first years of life when lactational exposure may occur, there may be risk to the developing human kidney.Because of the potential for serious adverse reactions in breastfed infant, including the potential for empagliflozin to affect postnatal renal development, advise patients that use of GLYXAMBI is not recommended while breastfeeding. DataEmpagliflozin was present at low level in rat fetal tissues after single oral dose to the dams at gestation day 18. In rat milk, the mean milk to plasma ratio ranged from 0.634 to 5, and was greater than one from to 24 hours post-dose. The mean maximal milk to plasma ratio of occurred at hours post-dose, suggesting accumulation of empagliflozin in the milk. Juvenile rats directly exposed to empagliflozin showed risk to the developing kidney (renal pelvic and tubular dilatations) during maturation.

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action. GLYXAMBIGLYXAMBI contains: empagliflozin, sodium-glucose co-transporter (SGLT2) inhibitor, and linagliptin, dipeptidyl peptidase-4 (DPP-4) inhibitor.. EmpagliflozinSodium-glucose co-transporter (SGLT2) is the predominant transporter responsible for reabsorption of glucose from the glomerular filtrate back into the circulation. Empagliflozin is an inhibitor of SGLT2. By inhibiting SGLT2, empagliflozin reduces renal reabsorption of filtered glucose and lowers the renal threshold for glucose, and thereby increases urinary glucose excretion.. LinagliptinLinagliptin is an inhibitor of DPP-4, an enzyme that degrades the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). Thus, linagliptin increases the concentrations of active incretin hormones, stimulating the release of insulin in glucose-dependent manner and decreasing the levels of glucagon in the circulation. Both incretin hormones are involved in the physiological regulation of glucose homeostasis. Incretin hormones are secreted at low basal level throughout the day and levels rise immediately after meal intake. GLP-1 and GIP increase insulin biosynthesis and secretion from pancreatic beta cells in the presence of normal and elevated blood glucose levels. Furthermore, GLP-1 also reduces glucagon secretion from pancreatic alpha cells, resulting in reduction in hepatic glucose output.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. GLYXAMBINo carcinogenicity, mutagenicity, or impairment of fertility studies have been conducted with the combination of empagliflozin and linagliptin. General toxicity studies in rats up to 13 weeks were performed with the combined components. These studies indicated that no additive toxicity is caused by the combination of empagliflozin and linagliptin.. EmpagliflozinCarcinogenesis was evaluated in 2-year studies conducted in CD-1 mice and Wistar rats. Empagliflozin did not increase the incidence of tumors in female rats dosed at 100, 300, or 700 mg/kg/day (up to 72 times the exposure from the maximum clinical dose of 25 mg). In male rats, hemangiomas of the mesenteric lymph node were increased significantly at 700 mg/kg/day or approximately 42 times the exposure from 25 mg clinical dose. Empagliflozin did not increase the incidence of tumors in female mice dosed at 100, 300, or 1000 mg/kg/day (up to 62 times the exposure from 25 mg clinical dose). Renal tubule adenomas and carcinomas were observed in male mice at 1000 mg/kg/day, which is approximately 45 times the exposure of the maximum clinical dose of 25 mg. These tumors may be associated with metabolic pathway predominantly present in the male mouse kidney.Empagliflozin was not mutagenic or clastogenic with or without metabolic activation in the in vitro Ames bacterial mutagenicity assay, the in vitro L5178Y tk+/- mouse lymphoma cell assay, and an in vivo micronucleus assay in rats.Empagliflozin had no effects on mating, fertility or early embryonic development in treated male or female rats up to the high dose of 700 mg/kg/day (approximately 155 times the 25 mg clinical dose in males and females, respectively).. LinagliptinLinagliptin did not increase the incidence of tumors in male and female rats in 2-year study at doses of 6, 18, and 60 mg/kg. The highest dose of 60 mg/kg is approximately 418 times the clinical dose of mg/day based on AUC exposure. Linagliptin did not increase the incidence of tumors in mice in 2-year study at doses up to 80 mg/kg (males) and 25 mg/kg (females), or approximately 35- and 270-times the clinical dose based on AUC exposure. Higher doses of linagliptin in female mice (80 mg/kg) increased the incidence of lymphoma at approximately 215-times the clinical dose based on AUC exposure.Linagliptin was not mutagenic or clastogenic with or without metabolic activation in the Ames bacterial mutagenicity assay, chromosomal aberration test in human lymphocytes, and an in vivo micronucleus assay.In fertility studies in rats, linagliptin had no adverse effects on early embryonic development, mating, fertility, or bearing live young up to the highest dose of 240 mg/kg (approximately 943-times the clinical dose based on AUC exposure).

OVERDOSAGE SECTION.

10 OVERDOSAGE. In the event of an overdose with GLYXAMBI, contact the Poison Control Center. Removal of empagliflozin by hemodialysis has not been studied, and removal of linagliptin by hemodialysis or peritoneal dialysis is unlikely.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PRINCIPAL DISPLAY PANEL 10 mg/5 mg Bottle Label. NDC 0597-0182-90Glyxambi(R) (empagliflozin andlinagliptin tablets)10 mg/5 mgDISPENSE WITH ACCOMPANYING MEDICATION GUIDE90 tabletsRx onlyBoehringerIngelheimLilly. PRINCIPAL DISPLAY PANEL 10 mg/5 mg Bottle Label.

PEDIATRIC USE SECTION.

8.4 Pediatric Use. Safety and effectiveness of GLYXAMBI have not been established in pediatric patients.

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics. Empagliflozin. Urinary Glucose ExcretionIn patients with type diabetes, urinary glucose excretion increased immediately following dose of empagliflozin and was maintained at the end of 4-week treatment period averaging at approximately 64 grams per day with 10 mg empagliflozin and 78 grams per day with 25 mg empagliflozin once daily. Data from single oral doses of empagliflozin in healthy subjects indicate that, on average, the elevation in urinary glucose excretion approaches baseline by about days for the 10 mg and 25 mg doses.. Urinary VolumeIn 5-day study, mean 24-hour urine volume increase from baseline was 341 mL on Day and 135 mL on Day of empagliflozin 25 mg once daily treatment.. Cardiac ElectrophysiologyIn randomized, placebo-controlled, active-comparator, crossover study, 30 healthy subjects were administered single oral dose of empagliflozin 25 mg, empagliflozin 200 mg (8 times the maximum recommended dose), moxifloxacin, and placebo. No increase in QTc was observed with either 25 mg or 200 mg empagliflozin.. LinagliptinLinagliptin binds to DPP-4 in reversible manner and increases the concentrations of incretin hormones. Linagliptin glucose-dependently increases insulin secretion and lowers glucagon secretion, thus resulting in better regulation of the glucose homeostasis. Linagliptin binds selectively to DPP-4 and selectively inhibits DPP-4, but not DPP-8 or DPP-9 activity in vitro at concentrations approximating therapeutic exposures.. Cardiac ElectrophysiologyIn randomized, placebo-controlled, active-comparator, 4-way crossover study, 36 healthy subjects were administered single oral dose of linagliptin mg, linagliptin 100 mg (20 times the recommended dose), moxifloxacin, and placebo. No increase in QTc was observed with either the recommended dose of mg or the 100-mg dose. At the 100-mg dose, peak linagliptin plasma concentrations were approximately 38-fold higher than the peak concentrations following 5-mg dose.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. GLYXAMBIAdministration of the fixed-dose combination with food resulted in no change in overall exposure of empagliflozin or linagliptin; however, the peak exposure was decreased 39% and 32% for empagliflozin and linagliptin, respectively. These changes are not likely to be clinically significant.. Absorption. EmpagliflozinThe pharmacokinetics of empagliflozin has been characterized in healthy volunteers and patients with type diabetes and no clinically relevant differences were noted between the two populations. After oral administration, peak plasma concentrations of empagliflozin were reached at 1.5 hours post-dose. Thereafter, plasma concentrations declined in biphasic manner with rapid distribution phase and relatively slow terminal phase. The steady-state mean plasma AUC and Cmax were 1870 nmolh/L and 259 nmol/L, respectively, with 10 mg empagliflozin once daily treatment, and 4740 nmolh/L and 687 nmol/L, respectively, with 25 mg empagliflozin once daily treatment. Systemic exposure of empagliflozin increased in dose-proportional manner in the therapeutic dose range. The single-dose and steady-state pharmacokinetic parameters of empagliflozin were similar, suggesting linear pharmacokinetics with respect to time.Administration of 25 mg empagliflozin after intake of high-fat and high-calorie meal resulted in slightly lower exposure; AUC decreased by approximately 16% and Cmax decreased by approximately 37%, compared to fasted condition. The observed effect of food on empagliflozin pharmacokinetics was not considered clinically relevant and empagliflozin may be administered with or without food.. LinagliptinThe absolute bioavailability of linagliptin is approximately 30%. High-fat meal reduced Cmax by 15% and increased AUC by 4%; this effect is not clinically relevant. Linagliptin may be administered with or without food.. Distribution. EmpagliflozinThe apparent steady-state volume of distribution was estimated to be 73.8 based on population pharmacokinetic analysis. Following administration of an oral [14C]-empagliflozin solution to healthy subjects, the red blood cell partitioning was approximately 36.8% and plasma protein binding was 86.2%.. LinagliptinThe mean apparent volume of distribution at steady-state following single intravenous dose of linagliptin mg to healthy subjects is approximately 1110 L, indicating that linagliptin extensively distributes to the tissues. Plasma protein binding of linagliptin is concentration-dependent, decreasing from about 99% at nmol/L to 75% to 89% at >=30 nmol/L, reflecting saturation of binding to DPP-4 with increasing concentration of linagliptin. At high concentrations, where DPP-4 is fully saturated, 70% to 80% of linagliptin remains bound to plasma proteins and 20% to 30% is unbound in plasma. Plasma binding is not altered in patients with renal or hepatic impairment.. Elimination. Empagliflozin: The apparent terminal elimination half-life of empagliflozin was estimated to be 12.4 and apparent oral clearance was 10.6 L/h based on the population pharmacokinetic analysis. Following once-daily dosing, up to 22% accumulation, with respect to plasma AUC, was observed at steady-state, which was consistent with empagliflozin half-life. Linagliptin: Linagliptin has terminal half-life of about 200 hours at steady-state, though the accumulation half-life is about 11 hours. Renal clearance at steady-state was approximately 70 mL/min.. Metabolism. Empagliflozin: No major metabolites of empagliflozin were detected in human plasma and the most abundant metabolites were three glucuronide conjugates (2-O-, 3-O-, and 6-O-glucuronide). Systemic exposure of each metabolite was less than 10% of total drug-related material. In vitro studies suggested that the primary route of metabolism of empagliflozin in humans is glucuronidation by the uridine 5-diphospho-glucuronosyltransferases UGT2B7, UGT1A3, UGT1A8, and UGT1A9.. Linagliptin: Following oral administration, the majority (about 90%) of linagliptin is excreted unchanged, indicating that metabolism represents minor elimination pathway. small fraction of absorbed linagliptin is metabolized to pharmacologically inactive metabolite, which shows steady-state exposure of 13.3% relative to linagliptin.. Excretion. Empagliflozin: 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 recovered in feces was unchanged parent drug and approximately half of drug-related radioactivity excreted in urine was unchanged parent drug.. Linagliptin: Following administration of an oral [14C]-linagliptin dose to healthy subjects, approximately 85% of the administered radioactivity was eliminated via the enterohepatic system (80%) or urine (5%) within days of dosing.. Specific Populations. Renal Impairment. GLYXAMBI: Studies characterizing the pharmacokinetics of empagliflozin and linagliptin after administration of GLYXAMBI in renally impaired patients have not been performed.. Empagliflozin: In patients with mild (eGFR: 60 to less than 90 mL/min/1.73 m2), moderate (eGFR: 30 to less than 60 mL/min/1.73 m2), and severe (eGFR: less than 30 mL/min/1.73 m2) renal impairment and patients with kidney failure/end stage renal disease (ESRD), AUC of empagliflozin increased by approximately 18%, 20%, 66%, and 48%, respectively, compared to subjects with normal renal function. Peak plasma levels of empagliflozin were similar in patients with moderate renal impairment and kidney failure/ESRD compared to subjects with normal renal function. Peak plasma levels of empagliflozin were roughly 20% higher in patients with mild and severe renal impairment as compared to subjects with normal renal function. Population pharmacokinetic analysis showed that the apparent oral clearance of empagliflozin decreased, with decrease in eGFR leading to an increase in drug exposure. However, the fraction of empagliflozin that was excreted unchanged in urine, and urinary glucose excretion, declined with decrease in eGFR.. Linagliptin: An open-label pharmacokinetic study evaluated the pharmacokinetics of linagliptin mg in male and female patients with varying degrees of chronic renal impairment. The study included healthy subjects with normal renal function (creatinine clearance [CrCl] >=80 mL/min), patients with mild renal impairment (CrCl 50 to <80 mL/min), patients with moderate renal impairment (CrCl 30 to <50 mL/min), 10 patients with type diabetes and severe renal impairment (CrCl <30 mL/min), and 11 patients with type diabetes and normal renal function. Creatinine clearance was measured by 24-hour urinary creatinine clearance measurements or estimated from serum creatinine based on the Cockcroft-Gault formula.Under steady-state conditions, linagliptin exposure in patients with mild renal impairment was comparable to healthy subjects.In patients with moderate renal impairment under steady-state conditions, mean exposure of linagliptin increased (AUC,ss by 71% and Cmax by 46%) compared with healthy subjects. This increase was not associated with prolonged accumulation half-life, terminal half-life, or an increased accumulation factor. Renal excretion of linagliptin was below 5% of the administered dose and was not affected by decreased renal function. Patients with type diabetes and severe renal impairment showed steady-state exposure approximately 40% higher than that of patients with type diabetes and normal renal function (increase in AUC,ss by 42% and Cmax by 35%). For both type diabetes groups, renal excretion was below 7% of the administered dose.These findings were further supported by the results of population pharmacokinetic analyses.. Hepatic Impairment. GLYXAMBI: Studies characterizing the pharmacokinetics of empagliflozin and linagliptin after administration of GLYXAMBI in hepatically impaired patients have not been performed.. Empagliflozin: In patients with mild, moderate, and severe hepatic impairment according to the Child-Pugh classification, AUC of empagliflozin increased by approximately 23%, 47%, and 75% and Cmax increased by approximately 4%, 23%, and 48%, respectively, compared to subjects with normal hepatic function.. Linagliptin: In patients with mild hepatic impairment (Child-Pugh class A) steady-state exposure (AUC,ss) of linagliptin was approximately 25% lower and Cmax,ss was approximately 36% lower than in healthy subjects. In patients with moderate hepatic impairment (Child-Pugh class B), AUCss of linagliptin was about 14% lower and Cmax,ss was approximately 8% lower than in healthy subjects. Patients with severe hepatic impairment (Child-Pugh class C) had comparable exposure of linagliptin in terms of AUC0-24 and approximately 23% lower Cmax compared with healthy subjects. Reductions in the pharmacokinetic parameters seen in patients with hepatic impairment did not result in reductions in DPP-4 inhibition.. Effects of Age, Body Mass Index, Gender, and Race. Empagliflozin: Based on the population PK analysis, age, body mass index (BMI), gender and race (Asians versus primarily Whites) do not have clinically meaningful effect on pharmacokinetics of empagliflozin [see Use in Specific Populations (8.5)].. Linagliptin: Based on the population PK analysis, age, body mass index (BMI), gender and race do not have clinically meaningful effect on pharmacokinetics of linagliptin [see Use in Specific Populations (8.5)].. Drug InteractionsPharmacokinetic drug interaction studies with GLYXAMBI have not been performed; however, such studies have been conducted with the individual components of GLYXAMBI (empagliflozin and linagliptin).. Empagliflozin. In vitro Assessment of Drug InteractionsEmpagliflozin does not inhibit, inactivate, or induce CYP450 isoforms. In vitro data suggest that the primary route of metabolism of empagliflozin in humans is glucuronidation by the uridine 5-diphospho-glucuronosyltransferases UGT1A3, UGT1A8, UGT1A9 and UGT2B7. Empagliflozin does not inhibit UGT1A1, UGT1A3, UGT1A8, UGT1A9, or UGT2B7. Therefore, no effect of empagliflozin is anticipated on concomitantly administered drugs that are substrates of the major CYP450 isoforms or UGT1A1, UGT1A3, UGT1A8, UGT1A9, or UGT2B7. The effect of UGT induction (e.g., induction by rifampicin or any other UGT enzyme inducer) on empagliflozin exposure has not been evaluated.Empagliflozin is substrate for P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), but it does not inhibit these efflux transporters at therapeutic doses. Based on in vitro studies, empagliflozin is considered unlikely to cause interactions with drugs that are P-gp substrates. Empagliflozin is substrate of the human uptake transporters OAT3, OATP1B1, and OATP1B3, but not OAT1 and OCT2. Empagliflozin does not inhibit any of these human uptake transporters at clinically relevant plasma concentrations and, therefore, no effect of empagliflozin is anticipated on concomitantly administered drugs that are substrates of these uptake transporters.. In vivo Assessment of Drug InteractionsEmpagliflozin pharmacokinetics were similar with and without coadministration of metformin, glimepiride, pioglitazone, sitagliptin, linagliptin, warfarin, verapamil, ramipril, and simvastatin in healthy volunteers and with or without coadministration of hydrochlorothiazide and torsemide in patients with type diabetes (see Figure 1). In subjects with normal renal function, coadministration of empagliflozin with probenecid resulted in 30% decrease in the fraction of empagliflozin excreted in urine without any effect on 24-hour urinary glucose excretion. The relevance of this observation to patients with renal impairment is unknown.Figure Effect of Various Medications on the Pharmacokinetics of Empagliflozin as Displayed as 90% Confidence Interval of Geometric Mean AUC and Cmax Ratios [reference lines indicate 100% (80% 125%)]aempagliflozin, 50 mg, once daily; bempagliflozin, 25 mg, single dose; cempagliflozin, 25 mg, once daily; dempagliflozin, 10 mg, single doseEmpagliflozin had no clinically relevant effect on the pharmacokinetics of metformin, glimepiride, pioglitazone, sitagliptin, linagliptin, warfarin, digoxin, ramipril, simvastatin, hydrochlorothiazide, torsemide, and oral contraceptives when coadministered in healthy volunteers (see Figure 2). Figure Effect of Empagliflozin on 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, single dose; dadministered as simvastatin; eadministered as warfarin racemic mixture; fadministered as Microgynon(R); gadministered as ramipril. Figure 1. Figure 2. Linagliptin. In vitro Assessment of Drug InteractionsLinagliptin is weak to moderate inhibitor of CYP isozyme CYP3A4, but does not inhibit other CYP isozymes and is not an inducer of CYP isozymes, including CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, and 4A11.Linagliptin is P-glycoprotein (P-gp) substrate, and inhibits P-gp mediated transport of digoxin at high concentrations. Based on these results and in vivo drug interaction studies, linagliptin is considered unlikely to cause interactions with other P-gp substrates at therapeutic concentrations.. In vivo Assessment of Drug InteractionsStrong inducers of CYP3A4 or P-gp (e.g., rifampin) decrease exposure to linagliptin to subtherapeutic and likely ineffective concentrations [see Drug Interactions (7)]. In vivo studies indicated evidence of low propensity for causing drug interactions with substrates of CYP3A4, CYP2C9, CYP2C8, P-gp and organic cationic transporter (OCT).Table 4Effect of Coadministered Drugs on Systemic Exposure of LinagliptinCoadministered DrugDosing of Coadministered Druga Dosing of Linagliptina Geometric Mean Ratio (ratio with/without coadministered drug) No effect 1.0AUCd Cmax aMultiple dose (steady-state) unless otherwise notedbFor information regarding clinical recommendations [see Drug Interactions (7)].cSingle dosedAUC AUC(0 to 24 hours) for single dose treatments and AUC AUC(TAU) for multiple-dose treatmentsQD once dailyBID twice dailyTID three times dailyMetformin 850 mg TID10 mg QD1.201.03Glyburide 1.75 mgc mg QD1.021.01Pioglitazone45 mg QD10 mg QD1.131.07Ritonavir200 mg BID5 mgc 2.012.96Rifampinb 600 mg QD5 mg QD0.60 0.56Table 5Effect of Linagliptin on Systemic Exposure of Coadministered DrugsCoadministered DrugDosing of Coadministered Druga Dosing of Linagliptina Geometric Mean Ratio (ratio with/without coadministered drug) No effect 1.0AUCc Cmax aMultiple dose (steady-state) unless otherwise notedbSingle dosecAUC AUC(INF) for single dose treatments and AUC AUC(TAU) for multiple dose treatmentsdAUC=AUC(0-168) and Cmax Emax for pharmacodynamic end pointsINR International Normalized RatioPT Prothrombin TimeQD once dailyTID three times dailyMetformin850 mg TID10 mg QDmetformin1.010.89Glyburide 1.75 mgb mg QDglyburide0.860.86Pioglitazone45 mg QD10 mg QDpioglitazone0.940.86metabolite M-III0.980.96metabolite M-IV1.041.05Digoxin0.25 mg QD5 mg QDdigoxin1.020.94Simvastatin40 mg QD10 mg QDsimvastatin 1.341.10simvastatin acid1.331.21Warfarin10 mgb mg QDR-warfarin0.991.00S-warfarin1.031.01INR0.93d 1.04d PT1.03d 1.15d Ethinylestradiol and levonorgestrelethinylestradiol 0.03 mg and levonorgestrel 0.150 mg QD5 mg QDethinylestradiol1.011.08levonorgestrel1.091.13.

POSTMARKETING EXPERIENCE SECTION.

6.2 Postmarketing Experience. Additional adverse reactions have been identified during postapproval use of linagliptin and empagliflozin. Because these reactions are reported voluntarily from population of uncertain size, it is generally not possible to reliably estimate their frequency or establish causal relationship to drug exposure.Acute Pancreatitis, including Fatal Pancreatitis [see Indications and Usage (1)] KetoacidosisUrosepsis and PyelonephritisNecrotizing Fasciitis of the Perineum (Fourniers gangrene)Hypersensitivity Reactions including Anaphylaxis, Angioedema, and Exfoliative Skin ConditionsSevere and Disabling ArthralgiaBullous PemphigoidAcute Kidney InjurySkin Reactions (e.g., rash, urticaria)Mouth Ulceration, StomatitisRhabdomyolysis. Acute Pancreatitis, including Fatal Pancreatitis [see Indications and Usage (1)] Ketoacidosis. Urosepsis and Pyelonephritis. Necrotizing Fasciitis of the Perineum (Fourniers gangrene). Hypersensitivity Reactions including Anaphylaxis, Angioedema, and Exfoliative Skin Conditions. Severe and Disabling Arthralgia. Bullous Pemphigoid. Acute Kidney Injury. Skin Reactions (e.g., rash, urticaria). Mouth Ulceration, Stomatitis. Rhabdomyolysis.

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummaryBased on animal data showing adverse renal effects from empagliflozin, GLYXAMBI is not recommended during the second and third trimesters of pregnancy.The limited available data with GLYXAMBI, linagliptin, or empagliflozin in pregnant women are not sufficient to determine drug-associated risk for major birth defects and miscarriage. There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy (see Clinical Considerations). In animal studies, empagliflozin, component of GLYXAMBI, resulted in adverse renal changes in rats when administered during period of renal development corresponding to the late second and third trimesters of human pregnancy. Doses approximately 13-times the maximum clinical dose caused renal pelvic and tubule dilatations that were reversible. No adverse developmental effects were observed when the combination of linagliptin and empagliflozin was administered to pregnant rats (see Data). The estimated background risk of major birth defects is 6% to 10% in women with pre-gestational diabetes with HbA1c >7 and has been reported to be as high as 20% to 25% in women with HbA1c >10. The estimated background risk of miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.. Clinical Considerations. Disease-associated maternal and/or embryo/fetal risk: Poorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, pre-eclampsia, spontaneous abortions, preterm delivery, and delivery complications. Poorly controlled diabetes increases the fetal risk for major birth defects, stillbirth, and macrosomia related morbidity.. Data. Animal DataThe combined components administered during the period of organogenesis were not teratogenic in rats up to and including combined dose of 700 mg/kg/day empagliflozin and 140 mg/kg/day linagliptin, which is 253- and 353-times the clinical exposure. pre- and postnatal development study was not conducted with the combined components of GLYXAMBI.. Empagliflozin: Empagliflozin dosed directly to juvenile rats from postnatal day (PND) 21 until PND 90 at doses of 1, 10, 30, and 100 mg/kg/day caused increased kidney weights and renal tubular and pelvic dilatation at 100 mg/kg/day, which approximates 13-times the maximum clinical dose of 25 mg, based on AUC. These findings were not observed after 13-week, drug-free recovery period. These outcomes occurred with drug exposure during periods of renal development in rats that correspond to the late second and third trimester of human renal development.In embryo-fetal development studies in rats and rabbits, empagliflozin was administered for intervals coinciding with the first trimester period of organogenesis in humans. Doses up to 300 mg/kg/day, which approximates 48-times (rats) and 128-times (rabbits) the maximum clinical dose of 25 mg (based on AUC), did not result in adverse developmental effects. In rats, at higher doses of empagliflozin causing maternal toxicity, malformations of limb bones increased in fetuses at 700 mg/kg/day or 154-times the 25 mg maximum clinical dose. Empagliflozin crosses the placenta and reaches fetal tissues in rats. In the rabbit, higher doses of empagliflozin resulted in maternal and fetal toxicity at 700 mg/kg/day, or 139-times the 25 mg maximum clinical dose.In pre- and postnatal development studies in pregnant rats, empagliflozin was administered from gestation day through to lactation day 20 (weaning) at up to 100 mg/kg/day (approximately 16-times the 25 mg maximum clinical dose) without maternal toxicity. Reduced body weight was observed in the offspring at greater than or equal to 30 mg/kg/day (approximately 4-times the 25 mg maximum clinical dose).. Linagliptin: No adverse developmental outcome was observed when linagliptin was administered to pregnant Wistar Han rats and Himalayan rabbits during the period of organogenesis at doses up to 240 mg/kg/day and 150 mg/kg/day, respectively. These doses represent approximately 943-times (rats) and 1943-times (rabbits) the mg maximum clinical dose, based on exposure. No adverse functional, behavioral, or reproductive outcome was observed in offspring following administration of linagliptin to Wistar Han rats from gestation day to lactation day 21 at dose 49-times the maximum recommended human dose, based on exposure.Linagliptin crosses the placenta into the fetus following oral dosing in pregnant rats and rabbits.

RECENT MAJOR CHANGES SECTION.

Indications and Usage (1)6/2021Dosage and Administration (2.1, 2.3)6/2021Contraindications (4)6/2021Warnings and Precautions (5.2, 5.3)6/2021.

RENAL IMPAIRMENT SUBSECTION.

8.6 Renal Impairment. EmpagliflozinThe glucose lowering benefit of empagliflozin 25 mg decreased in patients with worsening renal function. The risks of renal impairment [see Warnings and Precautions (5.3)], volume depletion adverse reactions and urinary tract infection-related adverse reactions increased with worsening renal function.Efficacy and safety studies with empagliflozin did not enroll patients with ESRD on dialysis or patients with an eGFR less than 30 mL/min/1.73 m2. Empagliflozin is contraindicated in patients on dialysis [see Indications and Usage (1) and Contraindications (4)].

SPL MEDGUIDE SECTION.

MEDICATION GUIDE GLYXAMBI(R) (glik-SAM-bee) (empagliflozin and linagliptin tablets)for oral useThis Medication Guide has been approved by the U.S. Food and Drug Administration.Revised: June 2021 What is the most important information should know about GLYXAMBIGLYXAMBI can cause serious side effects, including:Inflammation of the pancreas (pancreatitis) which may be severe and lead to death. Certain medical problems make you more likely to get pancreatitis. Before you start taking GLYXAMBI, tell your doctor if you have ever had: inflammation of your pancreas (pancreatitis)a history of alcoholismstones in your gallbladder (gallstones)high blood triglyceride levelsStop taking GLYXAMBI and call your doctor right away if you have pain in your stomach area (abdomen) that is severe and will not go away. The pain may be felt going from your abdomen to your back. The pain may happen with or without vomiting. These may be symptoms of pancreatitis. Ketoacidosis (increased ketones in your blood or urine). Ketoacidosis has happened in people who have type diabetes or type diabetes, during treatment with empagliflozin, one of the medicines in GLYXAMBI. Ketoacidosis has also happened in people with diabetes who were sick or who had surgery during treatment with GLYXAMBI. Ketoacidosis is serious condition, which needs to be treated in hospital. Ketoacidosis may lead to death. Ketoacidosis can happen with GLYXAMBI even if your blood sugar is less than 250 mg/dL. Stop taking GLYXAMBI and call your doctor right away or go to the nearest hospital emergency room if you get any of the following symptoms: nauseavomitingstomach-area (abdominal) paintirednesstrouble breathingIf you get any of these symptoms during treatment with GLYXAMBI, if possible, check for ketones in your urine, even if your blood sugar is less than 250 mg/dL. Dehydration. GLYXAMBI can cause some people to become dehydrated (the loss of body water and salt). Dehydration may cause you to feel dizzy, faint, light-headed, or weak, especially when you stand up (orthostatic hypotension). There have been reports of sudden worsening of kidney function in people who are taking GLYXAMBI.You may be at higher risk of dehydration if you: are on low sodium (salt) diet are 65 years of age or oldertake medicines to lower your blood pressure, including diuretics (water pills)have kidney problemsTalk to your doctor about what you can do to prevent dehydration including how much fluid you should drink on daily basis.Talk to your doctor right away if you reduce the amount of food or liquid you drink, for example if you are sick or cannot eat, or start to lose liquids from your body, for example from vomiting, diarrhea or being in the sun too long.What is GLYXAMBIGLYXAMBI is prescription medicine that contains diabetes medicines, empagliflozin (JARDIANCE) and linagliptin (TRADJENTA). GLYXAMBI can be used: along with diet and exercise to lower blood sugar in adults with type diabetes,in adults with type diabetes who have known cardiovascular disease when empagliflozin (JARDIANCE), one of the medicines in GLYXAMBI, is needed to reduce the risk of cardiovascular death.GLYXAMBI is not for people with type diabetes. It may increase their risk of diabetic ketoacidosis (increased ketones in blood or urine).If you have had pancreatitis in the past, it is not known if you have higher chance of getting pancreatitis while you take GLYXAMBI.GLYXAMBI is not for use to lower blood sugar in adults with type diabetes who have severe kidney problems, because it may not work.It is not known if GLYXAMBI is safe and effective in children.Who should not take GLYXAMBIDo not take GLYXAMBI if you:are on dialysis.are allergic to linagliptin (TRADJENTA), empagliflozin (JARDIANCE) or any of the ingredients in GLYXAMBI. See the end of this Medication Guide for complete list of ingredients in GLYXAMBI. Symptoms of serious allergic reaction to GLYXAMBI may include:skin rash, itching, flaking or peelingraised red patches on your skin (hives)swelling of your face, lips, tongue and throat that may cause difficulty in breathing or swallowingdifficulty with swallowing or breathing If you have any of these symptoms, stop taking GLYXAMBI and call your doctor right away or go to the nearest hospital emergency room. What should tell my doctor before taking GLYXAMBIBefore taking GLYXAMBI, tell your doctor about all of your medical conditions, including if you:have kidney problems.have liver problems.have history of infection of the vagina or penis.have history of urinary tract infection or problems with urination.are going to have surgery. Your doctor may stop your GLYXAMBI before you have surgery. Talk to your doctor if you are having surgery about when to stop taking GLYXAMBI and when to start it again.are eating less, or there is change in your diet.have or have had problems with your pancreas, including pancreatitis or surgery on your pancreas.drink alcohol very often, or drink lot of alcohol in the short term (binge drinking).have type diabetes. GLYXAMBI should not be used to treat people with type diabetes.are pregnant or plan to become pregnant. GLYXAMBI may harm your unborn baby. If you become pregnant while taking GLYXAMBI, tell your doctor as soon as possible. Talk with your doctor about the best way to control your blood sugar while you are pregnant.are breastfeeding or plan to breastfeed. GLYXAMBI may pass into your breast milk and may harm your baby. Talk with your doctor about the best way to feed your baby if you are taking GLYXAMBI. Do not breastfeed while taking GLYXAMBI.Tell your doctor about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.GLYXAMBI may affect the way other medicines work, and other medicines may affect how GLYXAMBI works. Especially tell your doctor if you take: insulin or other medicines that can lower your blood sugardiuretics (water pills)rifampin (Rifadin, Rimactane, Rifater, Rifamate), an antibiotic that is used to treat tuberculosis Know the medicines you take. Keep list of them to show your doctor and pharmacist when you get new medicine.How should take GLYXAMBITake GLYXAMBI exactly as your doctor tells you to take it.Take GLYXAMBI time each day in the morning, with or without food.If you miss dose, take it as soon as you remember. If you do not remember until it is time for your next dose, skip the missed dose and go back to your regular schedule. Do not take two doses of GLYXAMBI at the same time.Your doctor may tell you to take GLYXAMBI along with other diabetes medicines. Low blood sugar can happen more often when GLYXAMBI is taken with certain other diabetes medicines. See What are the possible side effects of GLYXAMBI If you take too much GLYXAMBI, call your doctor or local poison control center or go to the nearest hospital emergency room right away.When taking GLYXAMBI, you may have sugar in your urine, which will show up on urine test.Your doctor may do blood tests to check how well your kidneys are working before and during your treatment with GLYXAMBI.What are the possible side effects of GLYXAMBIGLYXAMBI may cause serious side effects, including:See What is the most important information should know about GLYXAMBI Serious urinary tract infections. Serious urinary tract infections that may lead to hospitalization have happened in people who are taking empagliflozin, one of the medicines in GLYXAMBI. Tell your doctor if you have any signs or symptoms of urinary tract infection such as burning feeling when passing urine, need to urinate often, the need to urinate right away, pain in the lower part of your stomach (pelvis), or blood in the urine. Sometimes people also may have fever, back pain, nausea or vomiting.Low blood sugar (hypoglycemia). If you take GLYXAMBI with another medicine that can cause low blood sugar, such as sulfonylurea or insulin, your risk of getting low blood sugar is higher. The dose of your sulfonylurea medicine or insulin may need to be lowered while you take GLYXAMBI. Signs and symptoms of low blood sugar may include:headachedrowsinessweaknessirritabilityhungerfast heartbeatconfusionshaking or feeling jitterydizzinesssweatingA rare but serious bacterial infection that causes damage to the tissue under the skin (necrotizing fasciitis) in the area between and around the anus and genitals (perineum). Necrotizing fasciitis of the perineum has happened in women and men who take empagliflozin, one of the medicines in GLYXAMBI. Necrotizing fasciitis of the perineum may lead to hospitalization, may require multiple surgeries, and may lead to death. Seek medical attention immediately if you have fever or you are feeling very weak, tired or uncomfortable (malaise), and you develop any of the following symptoms in the area between and around your anus and genitals: pain or tendernessswellingredness of skin (erythema)Vaginal yeast infection. Symptoms of vaginal yeast infection include:vaginal odorvaginal itchingwhite or yellowish vaginal discharge (discharge may be lumpy or look like cottage cheese)Yeast infection of the penis (balanitis). Swelling of an uncircumcised penis may develop that makes it difficult to pull back the skin around the tip of the penis. Other symptoms of yeast infection of the penis include:redness, itching, or swelling of the penisfoul smelling discharge from the penisrash of the penispain in the skin around penisTalk to your doctor about what to do if you get symptoms of yeast infection of the vagina or penis. Your doctor may tell you to use an over-the-counter antifungal medicine. Talk to your doctor right away if you use an over-the-counter antifungal medicine and your symptoms do not go away. Allergic (hypersensitivity) reactions. Serious allergic reactions have happened in people who are taking GLYXAMBI. Symptoms may include:swelling of your face, lips, tongue, throat, and other areas on your skindifficulty with swallowing or breathingraised, red areas on your skin (hives)skin rash, itching, flaking, or peelingIf you have any of these symptoms, stop taking GLYXAMBI and call your doctor right away or go to the nearest hospital emergency room. Joint pain. Some people who take medicines called DPP-4 inhibitors, one of the medicines in GLYXAMBI, may develop joint pain that can be severe. Call your doctor if you have severe joint pain.Skin reaction. Some people who take medicines called DPP-4 inhibitors, one of the medicines in GLYXAMBI, may develop skin reaction called bullous pemphigoid that can require treatment in hospital. Tell your doctor right away if you develop blisters or the breakdown of the outer layer of your skin (erosion). Your doctor may tell you to stop taking GLYXAMBI.Heart failure. Heart failure means your heart does not pump blood well enough.Before you start taking GLYXAMBI, tell your doctor if you have ever had heart failure or have problems with your kidneys. Contact your doctor right away if you have any of the following symptoms:increasing shortness of breath or trouble breathing, especially when you lie downswelling or fluid retention, especially in the feet, ankles or legsan unusually fast increase in weightunusual tirednessThese may be symptoms of heart failure.The most common side effects of GLYXAMBI include:urinary tract infectionupper respiratory tract infectionstuffy or runny nose and sore throatTell your doctor if you have any side effect that bothers you or that does not go away.These are not all the possible side effects of GLYXAMBI. For more information, ask your doctor or pharmacist.Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.How should store GLYXAMBIStore GLYXAMBI at room temperature between 68F to 77F (20C to 25C).Keep GLYXAMBI and all medicines out of the reach of children.General information about the safe and effective use of GLYXAMBI.Medicines are sometimes prescribed for purposes other than those listed in Medication Guide. Do not use GLYXAMBI for condition for which it was not prescribed. Do not give GLYXAMBI to other people, even if they have the same symptoms that you have. It may harm them.You can ask your pharmacist or doctor for information about GLYXAMBI that is written for health professionals.What are the ingredients in GLYXAMBIActive ingredients: empagliflozin and linagliptin Inactive ingredients: mannitol, pregelatinized starch, corn starch, copovidone, crospovidone, talc and magnesium stearate. The film coating contains the following inactive ingredients: hypromellose, mannitol, talc, titanium dioxide, polyethylene glycol.10 mg/5 mg tablets also contain yellow ferric oxide.25 mg/5 mg tablets also contain red ferric 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 USAGLYXAMBI is registered trademark of and used under license from Boehringer Ingelheim International GmbH.Boehringer Ingelheim Pharmaceuticals, Inc. either owns or uses the Jardiance(R), Tradjenta(R), EMPA-REG OUTCOME(R), CARMELINA(R), and CAROLINA(R) trademarks under license.The other brands listed are trademarks of their respective owners and are not trademarks of Boehringer Ingelheim Pharmaceuticals, Inc.Copyright (C) 2021 Boehringer Ingelheim International GmbHALL RIGHTS RESERVEDCOL8994BF142021For more information about GLYXAMBI, including current prescribing information and Medication Guide, go to www.glyxambi.com, scan the code, or call Boehringer Ingelheim Pharmaceuticals, Inc. at 1-800-542-6257. Inflammation of the pancreas (pancreatitis) which may be severe and lead to death. Certain medical problems make you more likely to get pancreatitis. Before you start taking GLYXAMBI, tell your doctor if you have ever had: inflammation of your pancreas (pancreatitis). history of alcoholism. stones in your gallbladder (gallstones). high blood triglyceride levels. Ketoacidosis (increased ketones in your blood or urine). Ketoacidosis has happened in people who have type diabetes or type diabetes, during treatment with empagliflozin, one of the medicines in GLYXAMBI. Ketoacidosis has also happened in people with diabetes who were sick or who had surgery during treatment with GLYXAMBI. Ketoacidosis is serious condition, which needs to be treated in hospital. Ketoacidosis may lead to death. Ketoacidosis can happen with GLYXAMBI even if your blood sugar is less than 250 mg/dL. Stop taking GLYXAMBI and call your doctor right away or go to the nearest hospital emergency room if you get any of the following symptoms: nausea. vomiting. stomach-area (abdominal) pain. tiredness. trouble breathing. Dehydration. GLYXAMBI can cause some people to become dehydrated (the loss of body water and salt). Dehydration may cause you to feel dizzy, faint, light-headed, or weak, especially when you stand up (orthostatic hypotension). There have been reports of sudden worsening of kidney function in people who are taking GLYXAMBI.. are on low sodium (salt) diet are 65 years of age or older. take medicines to lower your blood pressure, including diuretics (water pills). have kidney problems. along with diet and exercise to lower blood sugar in adults with type diabetes,in adults with type diabetes who have known cardiovascular disease when empagliflozin (JARDIANCE), one of the medicines in GLYXAMBI, is needed to reduce the risk of cardiovascular death.. along with diet and exercise to lower blood sugar in adults with type diabetes,. in adults with type diabetes who have known cardiovascular disease when empagliflozin (JARDIANCE), one of the medicines in GLYXAMBI, is needed to reduce the risk of cardiovascular death.. GLYXAMBI is not for people with type diabetes. It may increase their risk of diabetic ketoacidosis (increased ketones in blood or urine).. If you have had pancreatitis in the past, it is not known if you have higher chance of getting pancreatitis while you take GLYXAMBI.. GLYXAMBI is not for use to lower blood sugar in adults with type diabetes who have severe kidney problems, because it may not work.. It is not known if GLYXAMBI is safe and effective in children.. are on dialysis.. are allergic to linagliptin (TRADJENTA), empagliflozin (JARDIANCE) or any of the ingredients in GLYXAMBI. See the end of this Medication Guide for complete list of ingredients in GLYXAMBI. Symptoms of serious allergic reaction to GLYXAMBI may include:skin rash, itching, flaking or peelingraised red patches on your skin (hives)swelling of your face, lips, tongue and throat that may cause difficulty in breathing or swallowingdifficulty with swallowing or breathing skin rash, itching, flaking or peeling. raised red patches on your skin (hives). swelling of your face, lips, tongue and throat that may cause difficulty in breathing or swallowing. difficulty with swallowing or breathing have kidney problems.. have liver problems.. have history of infection of the vagina or penis.. have history of urinary tract infection or problems with urination.. are going to have surgery. Your doctor may stop your GLYXAMBI before you have surgery. Talk to your doctor if you are having surgery about when to stop taking GLYXAMBI and when to start it again.. are eating less, or there is change in your diet.. have or have had problems with your pancreas, including pancreatitis or surgery on your pancreas.. drink alcohol very often, or drink lot of alcohol in the short term (binge drinking).. have type diabetes. GLYXAMBI should not be used to treat people with type diabetes.. are pregnant or plan to become pregnant. GLYXAMBI may harm your unborn baby. If you become pregnant while taking GLYXAMBI, tell your doctor as soon as possible. Talk with your doctor about the best way to control your blood sugar while you are pregnant.. are breastfeeding or plan to breastfeed. GLYXAMBI may pass into your breast milk and may harm your baby. Talk with your doctor about the best way to feed your baby if you are taking GLYXAMBI. Do not breastfeed while taking GLYXAMBI.. insulin or other medicines that can lower your blood sugar. diuretics (water pills). rifampin (Rifadin, Rimactane, Rifater, Rifamate), an antibiotic that is used to treat tuberculosis Take GLYXAMBI exactly as your doctor tells you to take it.. Take GLYXAMBI time each day in the morning, with or without food.. If you miss dose, take it as soon as you remember. If you do not remember until it is time for your next dose, skip the missed dose and go back to your regular schedule. Do not take two doses of GLYXAMBI at the same time.. Your doctor may tell you to take GLYXAMBI along with other diabetes medicines. Low blood sugar can happen more often when GLYXAMBI is taken with certain other diabetes medicines. See What are the possible side effects of GLYXAMBI If you take too much GLYXAMBI, call your doctor or local poison control center or go to the nearest hospital emergency room right away.. When taking GLYXAMBI, you may have sugar in your urine, which will show up on urine test.. Your doctor may do blood tests to check how well your kidneys are working before and during your treatment with GLYXAMBI.. See What is the most important information should know about GLYXAMBI Serious urinary tract infections. Serious urinary tract infections that may lead to hospitalization have happened in people who are taking empagliflozin, one of the medicines in GLYXAMBI. Tell your doctor if you have any signs or symptoms of urinary tract infection such as burning feeling when passing urine, need to urinate often, the need to urinate right away, pain in the lower part of your stomach (pelvis), or blood in the urine. Sometimes people also may have fever, back pain, nausea or vomiting.. Low blood sugar (hypoglycemia). If you take GLYXAMBI with another medicine that can cause low blood sugar, such as sulfonylurea or insulin, your risk of getting low blood sugar is higher. The dose of your sulfonylurea medicine or insulin may need to be lowered while you take GLYXAMBI. Signs and symptoms of low blood sugar may include:. headache. drowsiness. weakness. irritability. hunger. fast heartbeat. confusion. shaking or feeling jittery. dizziness. sweating. rare but serious bacterial infection that causes damage to the tissue under the skin (necrotizing fasciitis) in the area between and around the anus and genitals (perineum). Necrotizing fasciitis of the perineum has happened in women and men who take empagliflozin, one of the medicines in GLYXAMBI. Necrotizing fasciitis of the perineum may lead to hospitalization, may require multiple surgeries, and may lead to death. Seek medical attention immediately if you have fever or you are feeling very weak, tired or uncomfortable (malaise), and you develop any of the following symptoms in the area between and around your anus and genitals: pain or tenderness. swelling. redness of skin (erythema). Vaginal yeast infection. Symptoms of vaginal yeast infection include:. vaginal odor. vaginal itching. white or yellowish vaginal discharge (discharge may be lumpy or look like cottage cheese). Yeast infection of the penis (balanitis). Swelling of an uncircumcised penis may develop that makes it difficult to pull back the skin around the tip of the penis. Other symptoms of yeast infection of the penis include:. redness, itching, or swelling of the penis. foul smelling discharge from the penis. rash of the penis. pain in the skin around penis. Allergic (hypersensitivity) reactions. Serious allergic reactions have happened in people who are taking GLYXAMBI. Symptoms may include:swelling of your face, lips, tongue, throat, and other areas on your skindifficulty with swallowing or breathingraised, red areas on your skin (hives)skin rash, itching, flaking, or peelingIf you have any of these symptoms, stop taking GLYXAMBI and call your doctor right away or go to the nearest hospital emergency room. swelling of your face, lips, tongue, throat, and other areas on your skin. difficulty with swallowing or breathing. raised, red areas on your skin (hives). skin rash, itching, flaking, or peeling. Joint pain. Some people who take medicines called DPP-4 inhibitors, one of the medicines in GLYXAMBI, may develop joint pain that can be severe. Call your doctor if you have severe joint pain.. Skin reaction. Some people who take medicines called DPP-4 inhibitors, one of the medicines in GLYXAMBI, may develop skin reaction called bullous pemphigoid that can require treatment in hospital. Tell your doctor right away if you develop blisters or the breakdown of the outer layer of your skin (erosion). Your doctor may tell you to stop taking GLYXAMBI.. Heart failure. Heart failure means your heart does not pump blood well enough.Before you start taking GLYXAMBI, tell your doctor if you have ever had heart failure or have problems with your kidneys. Contact your doctor right away if you have any of the following symptoms:increasing shortness of breath or trouble breathing, especially when you lie downswelling or fluid retention, especially in the feet, ankles or legsan unusually fast increase in weightunusual tirednessThese may be symptoms of heart failure.. increasing shortness of breath or trouble breathing, especially when you lie down. swelling or fluid retention, especially in the feet, ankles or legs. an unusually fast increase in weight. unusual tiredness. urinary tract infection. upper respiratory tract infection. stuffy or runny nose and sore throat. Store GLYXAMBI at room temperature between 68F to 77F (20C to 25C).. Keep GLYXAMBI and all medicines out of the reach of children.. Image.

SPL UNCLASSIFIED SECTION.

Limitations of UseGLYXAMBI is not recommended in patients with type diabetes mellitus. It may increase the risk of diabetic ketoacidosis in these patients [see Warnings and Precautions (5.2)].GLYXAMBI has not been studied in patients with history of pancreatitis. It is unknown whether patients with history of pancreatitis are at an increased risk for the development of pancreatitis while using GLYXAMBI [see Warnings and Precautions (5.1)]. GLYXAMBI is not recommended for use to improve glycemic control in adults with type diabetes mellitus with an eGFR less than 30 mL/min/1.73 m2. GLYXAMBI is likely to be ineffective in this setting based upon its mechanism of action.

STORAGE AND HANDLING SECTION.

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

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Pregnancy: Advise females of the potential risk to fetus especially during the second and third trimesters (8.1)Lactation: GLYXAMBI is not recommended when breastfeeding (8.2)Pediatric Patients: Safety and effectiveness of GLYXAMBI in pediatric patients have not been established (8.4)Geriatric Patients: Higher incidence of adverse reactions related to volume depletion and reduced renal function (5.3, 8.5, 8.6)Renal Impairment: Higher incidence of adverse reactions related to reduced renal function (2.1, 5.3, 8.6). Pregnancy: Advise females of the potential risk to fetus especially during the second and third trimesters (8.1). Lactation: GLYXAMBI is not recommended when breastfeeding (8.2). Pediatric Patients: Safety and effectiveness of GLYXAMBI in pediatric patients have not been established (8.4). Geriatric Patients: Higher incidence of adverse reactions related to volume depletion and reduced renal function (5.3, 8.5, 8.6). Renal Impairment: Higher incidence of adverse reactions related to reduced renal function (2.1, 5.3, 8.6). 8.1 Pregnancy. Risk SummaryBased on animal data showing adverse renal effects from empagliflozin, GLYXAMBI is not recommended during the second and third trimesters of pregnancy.The limited available data with GLYXAMBI, linagliptin, or empagliflozin in pregnant women are not sufficient to determine drug-associated risk for major birth defects and miscarriage. There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy (see Clinical Considerations). In animal studies, empagliflozin, component of GLYXAMBI, resulted in adverse renal changes in rats when administered during period of renal development corresponding to the late second and third trimesters of human pregnancy. Doses approximately 13-times the maximum clinical dose caused renal pelvic and tubule dilatations that were reversible. No adverse developmental effects were observed when the combination of linagliptin and empagliflozin was administered to pregnant rats (see Data). The estimated background risk of major birth defects is 6% to 10% in women with pre-gestational diabetes with HbA1c >7 and has been reported to be as high as 20% to 25% in women with HbA1c >10. The estimated background risk of miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.. Clinical Considerations. Disease-associated maternal and/or embryo/fetal risk: Poorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, pre-eclampsia, spontaneous abortions, preterm delivery, and delivery complications. Poorly controlled diabetes increases the fetal risk for major birth defects, stillbirth, and macrosomia related morbidity.. Data. Animal DataThe combined components administered during the period of organogenesis were not teratogenic in rats up to and including combined dose of 700 mg/kg/day empagliflozin and 140 mg/kg/day linagliptin, which is 253- and 353-times the clinical exposure. pre- and postnatal development study was not conducted with the combined components of GLYXAMBI.. Empagliflozin: Empagliflozin dosed directly to juvenile rats from postnatal day (PND) 21 until PND 90 at doses of 1, 10, 30, and 100 mg/kg/day caused increased kidney weights and renal tubular and pelvic dilatation at 100 mg/kg/day, which approximates 13-times the maximum clinical dose of 25 mg, based on AUC. These findings were not observed after 13-week, drug-free recovery period. These outcomes occurred with drug exposure during periods of renal development in rats that correspond to the late second and third trimester of human renal development.In embryo-fetal development studies in rats and rabbits, empagliflozin was administered for intervals coinciding with the first trimester period of organogenesis in humans. Doses up to 300 mg/kg/day, which approximates 48-times (rats) and 128-times (rabbits) the maximum clinical dose of 25 mg (based on AUC), did not result in adverse developmental effects. In rats, at higher doses of empagliflozin causing maternal toxicity, malformations of limb bones increased in fetuses at 700 mg/kg/day or 154-times the 25 mg maximum clinical dose. Empagliflozin crosses the placenta and reaches fetal tissues in rats. In the rabbit, higher doses of empagliflozin resulted in maternal and fetal toxicity at 700 mg/kg/day, or 139-times the 25 mg maximum clinical dose.In pre- and postnatal development studies in pregnant rats, empagliflozin was administered from gestation day through to lactation day 20 (weaning) at up to 100 mg/kg/day (approximately 16-times the 25 mg maximum clinical dose) without maternal toxicity. Reduced body weight was observed in the offspring at greater than or equal to 30 mg/kg/day (approximately 4-times the 25 mg maximum clinical dose).. Linagliptin: No adverse developmental outcome was observed when linagliptin was administered to pregnant Wistar Han rats and Himalayan rabbits during the period of organogenesis at doses up to 240 mg/kg/day and 150 mg/kg/day, respectively. These doses represent approximately 943-times (rats) and 1943-times (rabbits) the mg maximum clinical dose, based on exposure. No adverse functional, behavioral, or reproductive outcome was observed in offspring following administration of linagliptin to Wistar Han rats from gestation day to lactation day 21 at dose 49-times the maximum recommended human dose, based on exposure.Linagliptin crosses the placenta into the fetus following oral dosing in pregnant rats and rabbits.. 8.2 Lactation. Risk SummaryThere is no information regarding the presence of GLYXAMBI, or its individual components in human milk, the effects on the breastfed infant, or the effects on milk production. Empagliflozin and linagliptin are present in rat milk (see Data). Since human kidney maturation occurs in utero and during the first years of life when lactational exposure may occur, there may be risk to the developing human kidney.Because of the potential for serious adverse reactions in breastfed infant, including the potential for empagliflozin to affect postnatal renal development, advise patients that use of GLYXAMBI is not recommended while breastfeeding. DataEmpagliflozin was present at low level in rat fetal tissues after single oral dose to the dams at gestation day 18. In rat milk, the mean milk to plasma ratio ranged from 0.634 to 5, and was greater than one from to 24 hours post-dose. The mean maximal milk to plasma ratio of occurred at hours post-dose, suggesting accumulation of empagliflozin in the milk. Juvenile rats directly exposed to empagliflozin showed risk to the developing kidney (renal pelvic and tubular dilatations) during maturation.. 8.4 Pediatric Use. Safety and effectiveness of GLYXAMBI have not been established in pediatric patients.. 8.5 Geriatric Use. GLYXAMBIEmpagliflozin is associated with osmotic diuresis, which could affect hydration status of patients age 75 years and older [see Warnings and Precautions (5.3)].. EmpagliflozinIn empagliflozin type diabetes studies, 2721 empagliflozin-treated patients were 65 years of age and older and 491 patients were 75 years of age and older. In these studies, volume depletion-related adverse reactions occurred in 2.1%, 2.3%, and 4.4% of patients 75 years of age and older in the placebo, empagliflozin 10 mg, and empagliflozin 25 mg once daily groups, respectively; and urinary tract infections occurred in 10.5%, 15.7%, and 15.1% of patients 75 years of age and older in the placebo, empagliflozin 10 mg, and empagliflozin 25 mg once daily groups, respectively.. LinagliptinIn linagliptin studies, 1085 linagliptin-treated patients were 65 years of age and older and 131 patients were 75 years of age and older. In these linagliptin studies, no overall differences in safety or effectiveness of linagliptin were observed between geriatric patients and younger adult patients.. 8.6 Renal Impairment. EmpagliflozinThe glucose lowering benefit of empagliflozin 25 mg decreased in patients with worsening renal function. The risks of renal impairment [see Warnings and Precautions (5.3)], volume depletion adverse reactions and urinary tract infection-related adverse reactions increased with worsening renal function.Efficacy and safety studies with empagliflozin did not enroll patients with ESRD on dialysis or patients with an eGFR less than 30 mL/min/1.73 m2. Empagliflozin is contraindicated in patients on dialysis [see Indications and Usage (1) and Contraindications (4)].. 8.7 Hepatic Impairment. GLYXAMBI may be used in patients with hepatic impairment [see Clinical Pharmacology (12.3)].

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Pancreatitis: There have been reports of acute pancreatitis, including fatal pancreatitis. If pancreatitis is suspected, promptly discontinue GLYXAMBI. (5.1)Ketoacidosis: Assess patients who present with signs and symptoms of metabolic acidosis for ketoacidosis, regardless of blood glucose level. If suspected, discontinue GLYXAMBI, evaluate and treat promptly. Before initiating GLYXAMBI, consider risk factors for ketoacidosis. Patients on GLYXAMBI may require monitoring and temporary discontinuation of therapy in clinical situations known to predispose to ketoacidosis. (5.2)Volume Depletion: Before initiating GLYXAMBI, assess volume status and renal function in patients with impaired renal function, elderly patients, or patients on loop diuretics. Monitor for signs and symptoms during therapy. (5.3, 6.1)Urosepsis and Pyelonephritis: Evaluate patients for signs and symptoms of urinary tract infections and treat promptly, if indicated (5.4)Hypoglycemia: Consider lowering the dose of insulin secretagogue or insulin to reduce the risk of hypoglycemia when initiating GLYXAMBI (5.5)Necrotizing Fasciitis of the Perineum (Fourniers Gangrene): Serious, life-threatening cases have occurred in both females and males. Assess patients presenting with pain or tenderness, erythema, or swelling in the genital or perineal area, along with fever or malaise. If suspected, institute prompt treatment. (5.6)Genital Mycotic Infections: Monitor and treat as appropriate (5.7)Hypersensitivity Reactions: Serious hypersensitivity reactions (e.g., anaphylaxis, angioedema, and exfoliative skin conditions) have occurred with empagliflozin and linagliptin. If hypersensitivity reactions occur, discontinue GLYXAMBI, treat promptly, and monitor until signs and symptoms resolve. (5.8)Arthralgia: Severe and disabling arthralgia has been reported in patients taking DPP-4 inhibitors. Consider as possible cause for severe joint pain and discontinue drug if appropriate. (5.9)Bullous Pemphigoid: There have been reports of bullous pemphigoid requiring hospitalization. Tell patients to report development of blisters or erosions. If bullous pemphigoid is suspected, discontinue GLYXAMBI. (5.10)Heart Failure: Heart failure has been observed with two other members of the DPP-4 inhibitor class. Consider risks and benefits of GLYXAMBI in patients who have known risk factors for heart failure. Monitor for signs and symptoms. (5.11). Pancreatitis: There have been reports of acute pancreatitis, including fatal pancreatitis. If pancreatitis is suspected, promptly discontinue GLYXAMBI. (5.1). Ketoacidosis: Assess patients who present with signs and symptoms of metabolic acidosis for ketoacidosis, regardless of blood glucose level. If suspected, discontinue GLYXAMBI, evaluate and treat promptly. Before initiating GLYXAMBI, consider risk factors for ketoacidosis. Patients on GLYXAMBI may require monitoring and temporary discontinuation of therapy in clinical situations known to predispose to ketoacidosis. (5.2). Volume Depletion: Before initiating GLYXAMBI, assess volume status and renal function in patients with impaired renal function, elderly patients, or patients on loop diuretics. Monitor for signs and symptoms during therapy. (5.3, 6.1). Urosepsis and Pyelonephritis: Evaluate patients for signs and symptoms of urinary tract infections and treat promptly, if indicated (5.4). Hypoglycemia: Consider lowering the dose of insulin secretagogue or insulin to reduce the risk of hypoglycemia when initiating GLYXAMBI (5.5). Necrotizing Fasciitis of the Perineum (Fourniers Gangrene): Serious, life-threatening cases have occurred in both females and males. Assess patients presenting with pain or tenderness, erythema, or swelling in the genital or perineal area, along with fever or malaise. If suspected, institute prompt treatment. (5.6). Genital Mycotic Infections: Monitor and treat as appropriate (5.7). Hypersensitivity Reactions: Serious hypersensitivity reactions (e.g., anaphylaxis, angioedema, and exfoliative skin conditions) have occurred with empagliflozin and linagliptin. If hypersensitivity reactions occur, discontinue GLYXAMBI, treat promptly, and monitor until signs and symptoms resolve. (5.8). Arthralgia: Severe and disabling arthralgia has been reported in patients taking DPP-4 inhibitors. Consider as possible cause for severe joint pain and discontinue drug if appropriate. (5.9). Bullous Pemphigoid: There have been reports of bullous pemphigoid requiring hospitalization. Tell patients to report development of blisters or erosions. If bullous pemphigoid is suspected, discontinue GLYXAMBI. (5.10). Heart Failure: Heart failure has been observed with two other members of the DPP-4 inhibitor class. Consider risks and benefits of GLYXAMBI in patients who have known risk factors for heart failure. Monitor for signs and symptoms. (5.11). 5.1 Pancreatitis. Acute pancreatitis, including fatal pancreatitis, has been reported in patients treated with linagliptin. In the CARMELINA trial [see Clinical Studies (14)], acute pancreatitis was reported in (0.3%) patients treated with linagliptin and in (0.1%) patients treated with placebo. Two patients treated with linagliptin in the CARMELINA trial had acute pancreatitis with fatal outcome. There have been postmarketing reports of acute pancreatitis, including fatal pancreatitis, in patients treated with linagliptin.Take careful notice of potential signs and symptoms of pancreatitis. If pancreatitis is suspected, promptly discontinue GLYXAMBI and initiate appropriate management. It is unknown whether patients with history of pancreatitis are at increased risk for the development of pancreatitis while using GLYXAMBI.. 5.2 Ketoacidosis. Reports of ketoacidosis, serious life-threatening condition requiring urgent hospitalization have been identified in clinical trials and postmarketing surveillance in patients with type and type diabetes mellitus receiving sodium glucose co-transporter-2 (SGLT2) inhibitors, including empagliflozin. Fatal cases of ketoacidosis have been reported in patients taking empagliflozin. In placebo-controlled trials of patients with type diabetes, the risk of ketoacidosis was increased in patients who received SGLT2 inhibitors compared to patients who received placebo. GLYXAMBI is not indicated for the treatment of patients with type diabetes mellitus [see Indications and Usage (1)].Patients treated with GLYXAMBI who present with signs and symptoms consistent with severe metabolic acidosis should be assessed for ketoacidosis regardless of presenting blood glucose levels, as ketoacidosis associated with GLYXAMBI may be present even if blood glucose levels are less than 250 mg/dL. If ketoacidosis is suspected, GLYXAMBI should be discontinued, patient should be evaluated, and prompt treatment should be instituted. Treatment of ketoacidosis may require insulin, fluid and carbohydrate replacement.In many of the postmarketing reports, and particularly in patients with type diabetes, the presence of ketoacidosis was not immediately recognized and institution of treatment was delayed because presenting blood glucose levels were below those typically expected for diabetic ketoacidosis (often less than 250 mg/dL). Signs and symptoms at presentation were consistent with dehydration and severe metabolic acidosis and included nausea, vomiting, abdominal pain, generalized malaise, and shortness of breath. In some but not all cases, factors predisposing to ketoacidosis such as insulin dose reduction, acute febrile illness, reduced caloric intake, surgery, pancreatic disorders suggesting insulin deficiency (e.g., type diabetes, history of pancreatitis or pancreatic surgery), and alcohol abuse were identified.Before initiating GLYXAMBI, consider factors in the patient history that may predispose to ketoacidosis including pancreatic insulin deficiency from any cause, caloric restriction, and alcohol abuse.For patients who undergo scheduled surgery, consider temporarily discontinuing GLYXAMBI for at least days prior to surgery [see Clinical Pharmacology (12.2, 12.3)].Consider monitoring for ketoacidosis and temporarily discontinuing GLYXAMBI in other clinical situations known to predispose to ketoacidosis (e.g., prolonged fasting due to acute illness or post-surgery). Ensure risk factors for ketoacidosis are resolved prior to restarting GLYXAMBI.Educate patients on the signs and symptoms of ketoacidosis and instruct patients to discontinue GLYXAMBI and seek medical attention immediately if signs and symptoms occur.. 5.3 Volume Depletion Empagliflozin can cause intravascular volume depletion which may sometimes manifest as symptomatic hypotension or acute transient changes in creatinine [see Adverse Reactions (6.1)]. There have been post-marketing reports of acute kidney injury, some requiring hospitalization and dialysis, in patients with type diabetes mellitus receiving SGLT2 inhibitors, including empagliflozin. Patients with impaired renal function (eGFR less than 60 mL/min/1.73 m2), elderly patients, or patients on loop diuretics may be at increased risk for volume depletion or hypotension. Before initiating GLYXAMBI in patients with one or more of these characteristics, assess volume status and renal function. In patients with volume depletion, correct this condition before initiating GLYXAMBI. Monitor for signs and symptoms of volume depletion, and renal function after initiating therapy.. 5.4 Urosepsis and Pyelonephritis. There have been postmarketing reports of serious urinary tract infections including urosepsis and pyelonephritis requiring hospitalization in patients receiving SGLT2 inhibitors, including empagliflozin. Treatment with SGLT2 inhibitors increases the risk for urinary tract infections. Evaluate patients for signs and symptoms of urinary tract infections and treat promptly, if indicated [see Adverse Reactions (6)].. 5.5 Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues. Insulin and insulin secretagogues are known to cause hypoglycemia. The use of empagliflozin or linagliptin in combination with an insulin secretagogue (e.g., sulfonylurea) or insulin was associated with higher rate of hypoglycemia compared with placebo in clinical trial. Therefore, lower dose of the insulin secretagogue or insulin may be required to reduce the risk of hypoglycemia when used in combination with GLYXAMBI.. 5.6 Necrotizing Fasciitis of the Perineum (Fourniers Gangrene). Reports of necrotizing fasciitis of the perineum (Fourniers gangrene), rare but serious and life-threatening necrotizing infection requiring urgent surgical intervention, have been identified in postmarketing surveillance in patients with diabetes mellitus receiving SGLT2 inhibitors, including empagliflozin. Cases have been reported in both females and males. Serious outcomes have included hospitalization, multiple surgeries, and death.Patients treated with GLYXAMBI presenting with pain or tenderness, erythema, or swelling in the genital or perineal area, along with fever or malaise, should be assessed for necrotizing fasciitis. If suspected, start treatment immediately with broad-spectrum antibiotics and, if necessary, surgical debridement. Discontinue GLYXAMBI, closely monitor blood glucose levels, and provide appropriate alternative therapy for glycemic control.. 5.7 Genital Mycotic Infections. Empagliflozin increases the risk for genital mycotic infections [see Adverse Reactions (6.1)]. Patients with history of chronic or recurrent genital mycotic infections were more likely to develop genital mycotic infections. Monitor and treat as appropriate.. 5.8 Hypersensitivity Reactions. There have been postmarketing reports of serious hypersensitivity reactions in patients treated with linagliptin. These reactions include anaphylaxis, angioedema, and exfoliative skin conditions. Onset of these reactions occurred predominantly within the first months after initiation of treatment with linagliptin, with some reports occurring after the first dose.Angioedema has also been reported with other dipeptidyl peptidase-4 (DPP-4) inhibitors. Use caution in patient with history of angioedema to another DPP-4 inhibitor because it is unknown whether such patients will be predisposed to angioedema with GLYXAMBI.There have been postmarketing reports of serious hypersensitivity reactions, (e.g., angioedema) in patients treated with empaglifozin. If hypersensitivity reaction occurs, discontinue GLYXAMBI, treat promptly per standard of care, and monitor until signs and symptoms resolve. GLYXAMBI is contraindicated in patients with hypersensitivity to linagliptin, empagliflozin or any of the excipients in GLYXAMBI [see Contraindications (4)].. 5.9 Severe and Disabling Arthralgia. There have been postmarketing reports of severe and disabling arthralgia in patients taking DPP-4 inhibitors. The time to onset of symptoms following initiation of drug therapy varied from one day to years. Patients experienced relief of symptoms upon discontinuation of the medication. subset of patients experienced recurrence of symptoms when restarting the same drug or different DPP-4 inhibitor. Consider as possible cause for severe joint pain and discontinue drug if appropriate.. 5.10 Bullous Pemphigoid. Bullous pemphigoid was reported in (0.2%) patients treated with linagliptin compared to none in patients treated with placebo in the CARMELINA trial [see Clinical Studies (14)], and of these patients were hospitalized due to bullous pemphigoid. Postmarketing cases of bullous pemphigoid requiring hospitalization have been reported with DPP-4 inhibitor use. In reported cases, patients typically recovered with topical or systemic immunosuppressive treatment and discontinuation of the DPP-4 inhibitor. Tell patients to report development of blisters or erosions while receiving GLYXAMBI. If bullous pemphigoid is suspected, GLYXAMBI should be discontinued and referral to dermatologist should be considered for diagnosis and appropriate treatment.. 5.11 Heart Failure. An association between DPP-4 inhibitor treatment and heart failure has been observed in cardiovascular outcomes trials for two other members of the DPP-4 inhibitor class. These trials evaluated patients with type diabetes mellitus and atherosclerotic cardiovascular disease.Consider the risks and benefits of GLYXAMBI prior to initiating treatment in patients at risk for heart failure, such as those with prior history of heart failure and history of renal impairment, and observe these patients for signs and symptoms of heart failure during therapy. Advise patients of the characteristic symptoms of heart failure and to immediately report such symptoms. If heart failure develops, evaluate and manage according to current standards of care and consider discontinuation of GLYXAMBI.