FDA label bb63e5aa-0046-facd-e053-2995a90a8a21

5 WARNINGS AND PRECAUTIONS Pancreatitis: There have been reports of acute pancreatitis, including fatal pancreatitis. If pancreatitis is suspected, promptly discontinue GLYXAMBI. ( 5.1 ) 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. ( 5.2 ) Hypotension: Before initiating GLYXAMBI assess and correct volume status in patients with renal impairment, the elderly, in patients with low systolic blood pressure, and in patients on diuretics. Monitor for signs and symptoms during therapy. ( 5.3 ) 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. ( 5.4 ) Acute Kidney Injury and Impairment in Renal Function: Consider temporarily discontinuing in settings of reduced oral intake or fluid losses. If acute kidney injury occurs, discontinue and promptly treat. Monitor renal function during therapy. ( 5.5 ) Urosepsis and Pyelonephritis: Evaluate patients for signs and symptoms of urinary tract infections and treat promptly, if indicated ( 5.6 ) Hypoglycemia: Consider lowering the dose of insulin secretagogue or insulin to reduce the risk of hypoglycemia when initiating GLYXAMBI. ( 5.7 ) Necrotizing Fasciitis of the Perineum (Fournier's 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. ( 5.8 ) Genital Mycotic Infections: Monitor and treat as appropriate ( 5.9 ) Hypersensitivity Reactions: Discontinue GLYXAMBI, treat promptly, and monitor until signs and symptoms resolve. ( 5.10 ) Increased LDL-C: Monitor and treat as appropriate ( 5.11 ) Arthralgia: Severe and disabling arthralgia has been reported in patients taking DPP-4 inhibitors. Consider as a possible cause for severe joint pain and discontinue drug if appropriate. ( 5.12 ) 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. ( 5.13 ) 5.1 Pancreatitis Acute pancreatitis, including fatal pancreatitis, has been reported in patients treated with linagliptin. In the CARMELINA trial [see Clinical Studies (14.3) ] , acute pancreatitis was reported in 9 (0.3%) patients treated with linagliptin and in 5 (0.1%) patients treated with placebo. Two patients treated with linagliptin in the CARMELINA trial had acute pancreatitis with a 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 a history of pancreatitis are at increased risk for the development of pancreatitis while using GLYXAMBI.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 a history of pancreatitis are at increased risk for the development of pancreatitis while using GLYXAMBI. 5.2 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 2 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 a prior history of heart failure and a 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. 5.3 Hypotension Empagliflozin causes intravascular volume contraction. Symptomatic hypotension may occur after initiating empagliflozin [see Adverse Reactions (6.1) ] particularly in patients with renal impairment, the elderly, in patients with low systolic blood pressure, and in patients on diuretics. Before initiating GLYXAMBI, assess for volume contraction and correct volume status if indicated. Monitor for signs and symptoms of hypotension after initiating therapy and increase monitoring in clinical situations where volume contraction is expected [see Use in Specific Populations (8.5) ] . 5.4 Ketoacidosis Reports of ketoacidosis, a serious life-threatening condition requiring urgent hospitalization have been identified in postmarketing surveillance in patients with type 1 and type 2 diabetes mellitus receiving sodium glucose co-transporter-2 (SGLT2) inhibitors, including empagliflozin. Fatal cases of ketoacidosis have been reported in patients taking empagliflozin. GLYXAMBI is not indicated for the treatment of patients with type 1 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 1 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 due to illness or surgery, pancreatic disorders suggesting insulin deficiency (e.g., type 1 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. In patients treated with GLYXAMBI consider monitoring for ketoacidosis and temporarily discontinuing GLYXAMBI in clinical situations known to predispose to ketoacidosis (e.g., prolonged fasting due to acute illness or surgery). 5.5 Acute Kidney Injury and Impairment in Renal Function Empagliflozin causes intravascular volume contraction [see Warnings and Precautions (5.3) ] and can cause renal impairment [see Adverse Reactions (6.1) ] . There have been postmarketing reports of acute kidney injury, some requiring hospitalization and dialysis, in patients receiving SGLT2 inhibitors, including empagliflozin; some reports involved patients younger than 65 years of age. Before initiating GLYXAMBI, consider factors that may predispose patients to acute kidney injury including hypovolemia, chronic renal insufficiency, congestive heart failure and concomitant medications (diuretics, ACE inhibitors, ARBs, NSAIDs). Consider temporarily discontinuing GLYXAMBI in any setting of reduced oral intake (such as acute illness or fasting) or fluid losses (such as gastrointestinal illness or excessive heat exposure); monitor patients for signs and symptoms of acute kidney injury. If acute kidney injury occurs, discontinue GLYXAMBI promptly and institute treatment. Empagliflozin increases serum creatinine and decreases eGFR. Patients with hypovolemia may be more susceptible to these changes. Renal function abnormalities can occur after initiating GLYXAMBI [see Adverse Reactions (6.1) ] . Renal function should be evaluated prior to initiation of GLYXAMBI and monitored periodically thereafter. More frequent renal function monitoring is recommended in patients with an eGFR below 60 mL/min/1.73 m 2 . Use of GLYXAMBI is not recommended when eGFR is persistently less than 45 mL/min/1.73 m 2 and is contraindicated in patients with an eGFR less than 30 mL/min/1.73 m 2 [see Dosage and Administration (2.2) , Contraindications (4) and Use in Specific Populations (8.6) ] . 5.6 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) ] . 5.7 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 a higher rate of hypoglycemia compared with placebo in a clinical trial. Therefore, a lower dose of the insulin secretagogue or insulin may be required to reduce the risk of hypoglycemia when used in combination with GLYXAMBI. 5.8 Necrotizing Fasciitis of the Perineum (Fournier's Gangrene) Reports of necrotizing fasciitis of the perineum (Fournier's gangrene), a 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. 5.9 Genital Mycotic Infections Empagliflozin increases the risk for genital mycotic infections [see Adverse Reactions (6.1) ] . Patients with a history of chronic or recurrent genital mycotic infections were more likely to develop genital mycotic infections. Monitor and treat as appropriate. 5.10 Hypersensitivity Reactions There have been postmarketing reports of serious hypersensitivity reactions in patients treated with linagliptin (one of the components of GLYXAMBI). These reactions include anaphylaxis, angioedema, and exfoliative skin conditions. Onset of these reactions occurred within the first 3 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 a patient with a 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 (one of the components of GLYXAMBI). If a hypersensitivity reaction occurs, discontinue GLYXAMBI, treat promptly per standard of care, and monitor until signs and symptoms resolve. GLYXAMBI is contraindicated in patients with a previous serious hypersensitivity reaction to linagliptin or empagliflozin [see Contraindications (4) ] . 5.11 Increased Low-Density Lipoprotein Cholesterol (LDL-C) Increases in LDL-C can occur with empagliflozin [see Adverse Reactions (6.1) ] . Monitor and treat as appropriate. 5.12 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. A subset of patients experienced a recurrence of symptoms when restarting the same drug or a different DPP-4 inhibitor. Consider as a possible cause for severe joint pain and discontinue drug if appropriate. 5.13 Bullous Pemphigoid Bullous pemphigoid was reported in 7 (0.2%) patients treated with linagliptin compared to none in patients treated with placebo in the CARMELINA trial [see Clinical Studies (14.3) ] , and 3 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 a dermatologist should be considered for diagnosis and appropriate treatment.

6 ADVERSE REACTIONS The following important adverse reactions are described below and elsewhere in the labeling: Pancreatitis [see Warnings and Precautions (5.1) ] Heart Failure [see Warnings and Precautions (5.2) ] Hypotension [see Warnings and Precautions (5.3) ] Ketoacidosis [see Warnings and Precautions (5.4) ] Acute Kidney Injury and Impairment in Renal Function [see Warnings and Precautions (5.5) ] Urosepsis and Pyelonephritis [see Warnings and Precautions (5.6) ] Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues [see Warnings and Precautions (5.7) ] Necrotizing Fasciitis of the Perineum (Fournier's Gangrene) [see Warnings and Precautions (5.8) ] Genital Mycotic Infections [see Warnings and Precautions (5.9) ] Hypersensitivity Reactions [see Warnings and Precautions (5.10) ] Increased Low-Density Lipoprotein Cholesterol (LDL-C) [see Warnings and Precautions (5.11) ] Severe and Disabling Arthralgia [see Warnings and Precautions (5.12) ] Bullous Pemphigoid [see Warnings and Precautions (5.13) ] 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 1-800-459-9906 TTY, or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a 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 Linagliptin The safety of concomitantly administered empagliflozin (daily dose 10 mg or 25 mg) and linagliptin (daily dose 5 mg) has been evaluated in a total of 1363 patients with type 2 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 a pooled analyses of these studies are shown in Table 1. Table 1 Adverse Reactions Reported in ≥5% of Patients Treated with Empagliflozin and Linagliptin a Predefined adverse event grouping, including, but not limited to, urinary tract infection, asymptomatic bacteriuria, cystitis GLYXAMBI 10 mg/5 mg n=272 GLYXAMBI 25 mg/5 mg n=273 n (%) n (%) Urinary tract infection a 34 (12.5) 31 (11.4) Nasopharyngitis 16 (5.9) 18 (6.6) Upper respiratory tract infection 19 (7.0) 19 (7.0) Empagliflozin Adverse 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. Linagliptin Adverse reactions reported in ≥2% of patients treated with linagliptin 5 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. Hypoglycemia Table 2 summarizes the reports of hypoglycemia with empagliflozin and linagliptin over a treatment period of 52 weeks. Table 2 Incidence of Overall a and Severe b Hypoglycemic Adverse Reactions Add-on to Metformin (52 weeks) GLYXAMBI 10 mg/5 mg (n=136) GLYXAMBI 25 mg/5 mg (n=137) a Overall hypoglycemic events: plasma or capillary glucose of less than or equal to 70 mg/dL or requiring assistance b Severe hypoglycemic events: requiring assistance regardless of blood glucose Overall (%) 2.2% 3.6% Severe (%) 0% 0% Laboratory Tests Empagliflozin and Linagliptin Changes in laboratory findings in patients treated with the combination of empagliflozin and linagliptin included increases in cholesterol and hematocrit compared to baseline. 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 [see Warnings and Precautions (5.11) ] . 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 a placebo-controlled clinical trial with linagliptin in type 2 diabetes mellitus patients with micro- or macroalbuminuria, a mean increase of 30% in lipase concentrations from baseline to 24 weeks was observed in the linagliptin arm compared to a mean decrease of 2% in the placebo arm. Lipase levels above 3 times upper limit of normal were seen in 8.2% compared to 1.7% patients in the linagliptin and placebo arms, respectively. 6.2 Postmarketing Experience Additional adverse reactions have been identified during postapproval use of linagliptin and empagliflozin. Because these reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Acute Pancreatitis, including Fatal Pancreatitis [see Indications and Usage (1) ] Ketoacidosis Urosepsis and Pyelonephritis Necrotizing Fasciitis of the Perineum (Fournier's gangrene) Hypersensitivity Reactions including Anaphylaxis, Angioedema, and Exfoliative Skin Conditions Severe and Disabling Arthralgia Bullous Pemphigoid Skin Reactions (e.g., rash, urticaria) Mouth Ulceration, Stomatitis Rhabdomyolysis

<table ID="t46571301563286981" width="75%"><caption>Table 1 Adverse Reactions Reported in &#x2265;5% of Patients Treated with Empagliflozin and Linagliptin</caption><col align="left" valign="middle" width="44%"/><col align="center" valign="middle" width="28%"/><col align="center" valign="middle" width="28%"/><tfoot><tr styleCode="Botrule"><td colspan="3">^aPredefined adverse event grouping, including, but not limited to, urinary tract infection, asymptomatic bacteriuria, cystitis </td></tr></tfoot><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> </td><td styleCode="Rrule"><content styleCode="bold">GLYXAMBI 10 mg/5 mg n=272 </content></td><td styleCode="Rrule"><content styleCode="bold">GLYXAMBI 25 mg/5 mg n=273 </content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> </td><td styleCode="Rrule"><content styleCode="bold">n (%)</content></td><td styleCode="Rrule"><content styleCode="bold">n (%)</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Urinary tract infection ^a</td><td styleCode="Rrule">34 (12.5)</td><td styleCode="Rrule">31 (11.4)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Nasopharyngitis</td><td styleCode="Rrule">16 (5.9)</td><td styleCode="Rrule">18 (6.6)</td></tr><tr><td styleCode="Lrule Rrule">Upper respiratory tract infection</td><td styleCode="Rrule">19 (7.0)</td><td styleCode="Rrule">19 (7.0)</td></tr></tbody></table>

<table ID="t53931301563286981" width="75%"><caption>Table 2 Incidence of Overall ^a and Severe ^b Hypoglycemic Adverse Reactions </caption><col align="left" valign="middle" width="44%"/><col align="center" valign="middle" width="28%"/><col align="center" valign="middle" width="28%"/><thead><tr><th styleCode="Lrule Rrule">Add-on to Metformin (52 weeks) </th><th styleCode="Rrule">GLYXAMBI 10 mg/5 mg (n=136) </th><th styleCode="Rrule">GLYXAMBI 25 mg/5 mg (n=137) </th></tr></thead><tfoot><tr><td colspan="3">^aOverall hypoglycemic events: plasma or capillary glucose of less than or equal to 70 mg/dL or requiring assistance ^bSevere hypoglycemic events: requiring assistance regardless of blood glucose </td></tr></tfoot><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Overall (%)</td><td styleCode="Rrule">2.2%</td><td styleCode="Rrule">3.6%</td></tr><tr><td styleCode="Lrule Rrule">Severe (%)</td><td styleCode="Rrule">0%</td><td styleCode="Rrule">0%</td></tr></tbody></table>